Preparative merits of the mixed anhydride (MA) method in the excess use of DDZ-amino acids in the peptide synthesis of biologically active new antamanide analogues. The mixed anhydride (MA) method of peptide synthesis is further simplified by the repetitive excess use of Ddz-amino acids. In six comparative preparations of decapeptides this is demonstrated by the ease and speed of the synthetic manipulations, the efficiency of the monitoring of the reactions and purifications, and by the complete recycling of excess amino acid derivatives. In using of Ddz-amino acyl isobutylformate mixed anhydrides, side reactions are effectively suppressed, as proved by good coupling of Ddz-proline on to prolyl-peptides. Hydrophilic, crystalline and biological active antamanide analogues are obtained containg various functional side groups. The known cis-conformation of the antamanide prolyl-prolyl bonds is also established in the analogues by 13C-n.m.r. measurements. All new compounds are characterized by molecular peaks in the mass spectra.


Isolated lateral meniscectomy. A study of twenty-six patients with isolated tears. To better define the role that the lateral meniscus plays in stabilizing the knee, a study was made of twenty-six patients who had an uncomplicated lateral meniscectomy between 1972 and 1977. Patients with any degree of ligament instability, cruciate or collateral, prior to lateral meniscectomy were eliminated from the study. Also eliminated were any patients with roentgenographic evidence of degenerative arthrits, osteochondritis dissecans, or loose bodies. Only patients whose operative reports stated that the articular cartilage of the lateral compartment was either grossly normal or showed Grade-1 chondromalacia (less than one centimeter in diameter and only softening of the cartilage) at the time of surgery were included in the review. The meniscal lesions included bucket-handle tears, horizontal cleavage tears, and multiple linear defects. No grossly cystic menisci were included in the study. Two menisci demonstrated cystic degenerative changes on histological section. In sixteen patients some degree of ligament instability developed. The longer the interval between injury to the meniscus and its excision, the less satisfactory the result. Only fifteen (54 per cent) of the patients reported satisfactory results, and twenty lost some motion of the knee. We concluded that stability of the knee joint is a multifactorial problem, in which the lateral meniscus certainly plays an important part.


Precision in the diagnosis of meniscal lesions: a comparison of clinical evaluation, arthrography, and arthroscopy. We assessed the accuracy of clinical evaluation, arthrography, and arthroscopy in the diagnosis of meniscal lesions in fifty knees in which arthrotomy was performed for disabling symptoms after evaluation by these three methods. At surgery, forty-seven menisci were removed, of which forty-four were abnormal and three were normal. In three patients with normal menisci, loose bodies were found in two and the exploration was negative in one. In the forty-four knees with a meniscal lesion, a correct diagnosis was made clinically forty time, arthrographically thirty-nine times, and arthroscopically thirty-two times. Most errors occurred in the knees with posterior horn lesions of the medial meniscus. Clinical diagnosis was least accurate for lesions of the lateral meniscus (four missed) and arthroscopy was least accurate for lesions of the posterior horn of the medial meniscus (ten missed). Arthrography appeared to provide collateral evidence of lesions not seen directly. Based on this study it was concluded that even with negative findings by arthroscopy and arthrography it still may be necessary occasionally to remove a meniscus on the basis of the clinical evaluation.


Symposium on chemical information utilization by FDA bureau of drugs chemists. Introductory remarks. This symposium was organized to acquaint the scientific community with the manner in which Bureau of Drugs chemists utilize available chemical information as it pertains to the various areas in which they are involved.


Changes in thyroid-stimulating immunoglobulins during antithyroid therapy. Thyroid-stimulating immunoglobulin (TSI) activity was measured by radioreceptor assay in sera from patients with Graves' disease, Hashimoto's thyroiditis, and thyroid cancer. In untreated Graves' disease (47 cases), TSI index was significantly lower [76.7 +/- 1.4 (SE)] than the average of a normal control group (30 cases; 94.4 +/- 1.9). In untreated Hashimoto's thyroiditis (25 cases), it was also significantly lower (83.0 +/- 2.4). In patients with thyroid cancer (19 cases), there was no significant difference from normal controls. After 131I treatment, the TSI index in Graves' disease decreased during 2--4 months, then increased and reached normal levels in 1 yr. During propylthiouracil treatment, the TSI index increased and reached a normal level in 5--6 months without the decreasing phase seen after 131I treatment. Free T4 index values were gradually decreased by both treatments. There was no significant relationship between TSI index and thyroid antibodies (microsomal antibodies and thyroglobulin antibodies) in untreated Graves' disease or Hashimoto's thyroiditis. It is concluded that 1) in the sera of patients with Graves' disease and Hashimoto's thyroiditis, there are immunoglobulin Gs that can displace TSH binding to thyroid membranes; 2) these immunoglobulins Gs are different from the classic antithyroid antibodies; and 3) 131T treatment of Graves' disease may enhance TSI production during the first 1--2 months after therapy.


Restoration of visual cortical plasticity by local microperfusion of norepinephrine. Using a newly developed technique of continuous microperfusion, we obtained further evidence in support of our hypothesis that the neocortical catecholamines (CAs), particularly norepinephrine (NE), are responsible for a high level of cortical plasticity. We used the visual cortical changes in ocular dominance which follow a brief monocular deprivation as a simple and reliable index of cortical plasticity. Local perfusion of kitten visual cortex with 1 mg/ml (4.0 mM) 6-hydroxydopamine (6-OHDA) prevented the effects of monocular deprivation in kittens, thus replicating the results we had obtained using intraventricular injections (Kasamatsu and Pettigrew, '76b, '79). Locally perfused NE at a concentration of of 10(-2) mg/ml (48.6 micron) restored visual cortical plasticity in animals which were no longer susceptible to brief monocular lid-suture. These numbers refer to the concentration of solutions in the cannula/minipump system. The effective concentrations at the site of recording (about 2 mm away) are probably much lower than these. This effect of NE perfusion was seen both in kittens which had received prior 6-OHDA treatment as well as in older animals which had outgrown the susceptible period. In the kittens we obtained as a nearly complete shift in ocular dominance toward the open eye and in the older animals a decrease in binocularity was obtained. The changes were found only in the local region of visual cortex perfused with either NE or 6-OHDA, while nearby cortical regions in the same animals were unaffected. There were no obvious changes in receptive field properties of individual neurons other than ocularity, and externally perfused NE did not itself reduce binocularity in normal animals: the effects of NE described about only occurred when the animal's visual experience was simultaneously altered. These results support the view that NE plays an important role in cortical plasticity.


Relative efficacy of carbenicillin indanyl sodium and of trimethoprim/sulfamethoxazole in urinary-tract infections. In a 10-day study, carbenicillin indanyl sodium cured urinary-tract infections in 22 of 30 patients (ages, 24-91). In 3 of the remaining patients the treatment was a failure; in 3 others the drug had to be discontinued because of diarrhea and vomiting; and in 2 instances it induced overgrowth of Candida albicans in the urine. Carbenicillin was lethal to Pseudomonas aeruginosa in all 9 cases, to Proteus mirabilis in all 6 cases, and to enterococcus in all 3 cases. A trimethoprim/sulfamethoxazole combination cured urinary-tract infections in 18 of 30 other patients (ages, 28-91), but failed in 3. In 3 patients it gave rise to a skin rash; in 2 to elevation of blood urea nitrogen and creatinine levels; in 1 to neutropenia; and in 1 to overgrowth of Candida albicans in the urine. Reinfection occurred in 2 patients. Carbenicillin indanyl sodium was more effective than the sulfonamide/trimethoprim combination.


Minimum nitrogen requirement from glandless cottonseed protein for nitrogen balance in college women. Seven women, 18 to 23 years of age, were fed cooked cottonseed products for 42 days in order to determine the minimum nitrogen requirements for glandless cottonseen flour after baking. The women consumed from 81 to 213 mg N/kg body weight from cottonseed protein. Nitrogen intake from each experimental period was calculated from the average nitrogen content of the cottonseed products consumed each day of the experiment period. Nitrogen excretion was determined from the measurement of nitrogen in a total collection of urine and feces for each experimental period plus an obligatory loss of 5 mg/kg body weight. Fasting blood samples were taken prior to the study and at the end of each 7-day experimental period thereafter. The minimum requirement for cottonseed protein to maintain a positive nitrogen balance was 106 mg N/kg body weight. For the "reference woman," weighing 58 kg, at least 6.1 g of cottonseed flour nitrogen would be required to maintain nitrogen equilibrium. Plasma amino acid values of threonine, proline, valine, isoleucine, leucine, tyrosine, and lysine decreased significantly from day 0 to day 7 of the study. There were no significant differences in these plasma amino acids thereafter. Cottonseed flour incorporated into baked products maintained nitrogen balance in college women with no change in their nutritional status.


[Mycotic aneurysm of the femoral artery after bacterial endocarditis. Surgical treatment (author's transl)]. The reported case consists in a 45-year-old patient with a mitral disease, who presented a bacterial endocarditis after a dental extraction, in the course of which he developed a mycotic aneurysm of the right superficial femoral artery; surgical treatment of this lesion was successful. One year later he was reoperated in relation with the progression of his previous mitral disease, and a Bjork-Shilley prosthesis was implanted. At the present time, 2 years and a half after the last operation the patient is free of symptoms. The clinical data, exploratory studies, the results which were obtained, and the surgical procedure applied are discussed. The rarity of this complication, the localization of the mycotic aneurysm, the surgical valve heart replacement, the pathologic findings of the resected valve and the satisfactory evolution of the patient are also pointed out.


[Non bacterial thyreoiditis, diagnosis and differential diagnosis (author's transl)]. Retrospective analysis of signs, symptoms, and laboratory data (BSR, thyroid scan, thyroxine, triiodothyronine, TRH-test and antibodies against thyroglobulin) was performed on 68 individuals. Diagnosis of subacute and of chronic thyreoiditis was proven in 26 patients and 21 patients respectively by cytological examination. It was excluded by the same procedure in 21 patients, in whom there were some indications of these two kinds of thyroiditis. The following mosaic of clinical and laboratory parameters showed a sensitivity of 0.73 at specificity of 0.95 for diagnosis and exclusion of the two diseases: spontaneous pain, pain by palpation, fever, elevated BSR, thyroid scan, free thyroxine index, and TRH-test.


Unsuppressed prolactin secretion in the male rat is pulsatile. The pattern of prolactin (Prl) secretion was studied in several different situations. In normal and castrated male rats, the plasma Prl level gently fluctuated along the course of time. When the presumed hypothalamic Prl inhibitory factor was suppressed by treatment with a pharmacological agent, pimozide (Pim), the plasma Prl concentration was elevated and the elevated plasma level fluctuated in an irregular and pulsatile manner. Another situation was examined. First, baseline Prl concentration was elevated by implantation of estradiol, which also caused a moderate fluctuation of the circulating Prl level. The Prl level was then lowered from the elevated plateau level by administration of a dopaminergic receptor agonist, ergocristine. During this partial blockade, the plasma Prl level fluctuated in episodic bursts. It is suggested that the inherent, unsuppressed secretion of Prl is pulsatile in nature, but that this pulsatile pattern is normally suppressed under the inhibiting influence of the hypothalamus.


Petit mal status in early childhood and dementia. The course of 117 children with so-called centrencephalic myoclonic-astatic petit mal (Doose et al. 1970) was evaluated with the question, whether petit mal status can be the cause of dementia frequently seen in these patients. A dementia is found definitely more frequently in patients with petit mal status. With regard to the animal experimental studies of Wasterlain (1978, Lit.) and Meldrum (1978, Lit.) it seems possible that the prlonged generalized hypersynchronous discharges of the petit mal status lead to a serious disturbance of the neuronal energy metabolism and thus to cerebral organic damages or disturbances of the brain development.


The drawing test -- a tool for assessment of arm-hand function in children of 1--3 years of age. The construction and evaluation of a simple drawing test for assessment of arm-hand function in children of 1--3 years of age are described. A thick crayon (1.2 x 10 cm) and a piece of white paper (20 x 30 cm) are the only equipment needed. The need, when assessing fine motor development, of a test for evaluation of arm-hand function and the advantages of the test described are discussed. It is concluded that the method is of diagnostic value in children with CNS and neuromuscular disorders and is a useful tool for clinical studies and for routine developmental examination.


Gross and fine motor performance in healthy Swedish children aged fifteen and eighteen months. Gross and fine motor performance have been assessed in thirtynine 15-month-old and thirtynine 18-month-old children selected through systematic sampling from a population of healthy newborns. The performance was estimated with corresponding subscales of Denver Developmental Screening Test and Motor age test. In addition fine motor performance was assessed by the "Drawing test" for which the expected performance at 15 and 18 months is given. Of the 78 children, 83% had crawled on hand and knees, 9% crept on their tummy and 8% shuffled on their bottom before walking. Median age for walking was 11.8 months, the 97th percentile 16.0 months. Of the 15-month-old children, 90% walked with ability to stop and start, and 90% of the 18-month-old were in addition able to walk backwards, run stiffly, climb up and down a standard staircase and seat themselves in an armchair of suitable size. Of the 15-month-old, 90% were able to build a tower of two cubes or more, and 90% of the 18-month-old were able to build a tower of three cubes or more (size 1 1/2 inch). Almost 90% of the 15-month-old and all of the 18-month-old had the cognitive ability to coordinate a crayon and paper. In drawing attempts of the 15 month-old, the weak unstable combination with a top-tong/tong grasp and 1/2 pronated forearm was the dominating hand-grasp fore-arm position. In the 18 month-old a more mature grasp and forearm combination, mainly palmar grasp with or without stablizing index finger + overpronated forearm, was found.


Generalized giant axonal neuropathy-a case with features of Fazio-Londe disease. We present the 8th case so far published of generalized giant axonal neuropathy. Many features of the neurological picture of this 8 year 8 month old boy were suggestive of progressive bulbar paralysis of childhood. Muscle and sural nerve biopsies disclosed typical nodular axonal swellings measuring between 10--29 nm. Ultrastructure of the inflated portions of the axon consisted almost exclusively of 10 nm filaments. Normally appearing constituents were found in the non-dilated portions of the axons with this particularity that glycogen and mitochondria were aggregated. Previous clinical and pathological evidence indicates that this rare disorder not only affects the peripheral nerves but also the whole CNS. Our case differs from the others reported in literature by its rapidly deteriorating course and by the prominent involvement of some brain-stem motor functions; we offer the theory that a link might be implicated between this entity and Fazio-Londe disease.


[Radiotherapy with 131J and 125J of Basedow's disease. Indications and results relative to the incidence of post-actinic hypothyroidism]. The indications for radioisotope management in Basedow's disease and the complications involved are explained. Particular reference is made to the possibility of early or late hypothyroidism when 131I and 125I are employed for this purpose. The physiopathogenetic bases for this are examined in relation to dosage and early diagnosis. Results obtained with small doses (fractionated in some cases) of these isotopes in 126 patients with thyrotoxicosis. One-year and later follow-up was directed to the clinical and functional responses to treatment in the light of age, sex, T4, maximum uptake, eff. T/2, thyroid size, and doses administered. Recurrences were rather frequent and further doses were given. However, early hypothyroidism was very rare. This appeared to be related to the dose administered and inversely to gland size. The results are compared with those in the literature.


Pulmonary responses to atmospheric pollutants. II. Effect of petrol vapour inhalation on secretion of pulmonary surfactant. Inhalation of air contaminated with petrol vapour has been shown to produce reduced surfactant levels in the lungs of rats. Pulmonary surfactant was obtained by endobronchial lavage followed by salt extraction and freeze drying to obtain the dry, hydrophobic product. During 45 days of continuous exposure, the lowest yield of surfactant was obtained after 15 days of treatment. During the following 30 days of treatment, the surfactant yield reached a relatively constant level, approximately half the mean value for control animals. Chromatographic analysis indicated no qualitative alteration in the phospholipid components of surfactant with increasing times of exposure to the irritant. It has been possible to correlate biochemical evidence of toxic lung injury with signs of cellular damage obtained from ultrastructural studies.


The effects of dexamethasone and prostaglandin F2alpha on production and release of surfactant in type II alveolar cells. Incubation of adult rat Type II alveolar pneumocytes with dexamethasone microM induced an increase of intracellular 3Hphosphatidyl choline (PC), a component of lung surfactant, from precursor 3Hcholine. Release of 3HPC into the media did not differ from control unless prostaglandin F2alpha-THAM microM was added to the dexamethasone-treated cells. This observation corresponds to the ontogenetically observed endogenous increases in cortisol during pregnancy followed by increases in prostaglandins associated with contractions. The model system will serve well to test whether various substances effect synthesis and/or release of pulmonary surfactants.


Plasma amino acid response to single test meals in humans. VI. Determination of available lysine. The plasma amino acid response to single test meals in young adults was used to determine the amount of physiologically available lysine in heat-treated milk samples. The plasma amino acid responses were evaluated as PAA ratios according to a modified calculation procedure based on the method proposed by Longenecker and Hause. The amount of available lysine was determined by two separate series of single-meal tests. In the first, a relationship was established between the plasma amino acid response (PAA ratio) and the dietary level of lysine (given as synthetic amino acid mixtures). This relationship could be described by linear regression (r = 0.90). This regression line was then used to quantitatively evaluate the lysine PAA ratios obtained from single test meals with heat-treated milk samples. The heat-treatment of the milk samples caused a marked reduction of the amount of physiologically available lysine. The quantitative estimates obtained by the present plasma amino acid technique were in good agreement with determinations of available lysine in the same milk samples based on rat bioassay and chemical analysis.


Levels of benzimidazole resistance in Haemonchus contortus and Trichostrongylus colubriformis recorded from an egg hatch test procedure. A method of using commercially available benzimidazole anthelmintics in an egg hatch test, to record levels of resistance is described. The test shows that a side-resistance is present to all the benzimidazole anthelmintics tested against both Haemonchus contortus and Trichostrongylus colubriformis after selection with thiabendazole. Additional selection on the field resistant strain of H contortus with thiabendazole showed increased levels of resistance to all the compounds tested while similar selection of T colubriformis failed to change the level of resistance after 20 generations. The level of resistance recorded by the egg hatch test in vitro is greater than that recorded for adults in vivo for the CF strain of H contortus and T colubriformis. Problems associated with reading the test are mentioned as are the different levels for the threshold of activity.


The dose response of several benzimidazole anthelmintics against resistant strains of Haemonchus contortus and Trichostrongylus colubriformis selected with thiabendazole. Dose response lines for eight benzimidazole anthelmintics and thiophanate were determined, using standardised strains of thiabendazole selected and resistant Haemonchus contortus and Trichostrongylus colubriformis. Against H contortus, thiophanate, thiabendazole, parbendazole and oxibendazole were inactive. Mebendazole was inactive at dose rates of 6.26 and 12.5 mg/kg, although significant activity occurred at 25 mg/kg. Fenbendazole, cambendazole, oxfendazole and albendazole demonstrated significant activity at dose rates equal to or greater than the recommended therapeutic level. Thiophanate was inactive against resistant T colubriformis. The remaining compounds only showed significant activity when used at dose rates in excess of the recommended therapeutic level. These results show that a side resistance exists among the benzimidazole anthelmintics and suggests that changes in dose response lines could be expected to occur if resistant strains are selected with benzimidazoles other than thiabendazole.


[Vascular rickettsiosis].

[Vascular rickettsiosis]. The authors discuss the problem of rickettsial and para-rickettsial etiopathogeny of some types of angiopathies earlier characterized by a febrile state. They are especially interested in vasculopathies occurring in endemia areas. The disease may involve the entire vascular system and the pathogenic agent remains in the mid membranes and in the adventitia, as can be seen by seriologic and anatomo-pathologic tests. There are diffuse or nodular lymphoblastic infiltrations (pan-vascular condition). The authors also demonstrate that treatment with higher tetracyclines (Reverin) is absolutely advised, and draw attention to the need to do systematic seriologic research on all patients hospitalized for cardio-vascular diseases.


Selective phospholipid adsorption and atherosclerosis. Disaturated (fully saturated) lecithins adsorb onto solid surfaces more readily than lecithins in which one or both fatty acids are unsaturated. If saturated lecithins adsorb to arterial walls as they do to glass and polystyrene surfaces, there may be increased probability of atherosclerosis when the disaturated lecithin content of plasma is elevated. Analyses of lecithins in plasma samples from patients with myocardial infarction, and from patients with premature atherosclerosis but with low concentrations of plasma cholesterol and triglycerides, are consistent with the hypothesis that a high concentration of disaturated lecithin in plasma may be a significant risk factor for atherosclerosis, independent of triglyceride and cholesterol concentrations.


Extra-anatomic bypass with expanded polytetrafluoroethylene. Expanded polytetrafluoroethylene has been used successfully for femoropopliteal bypass, aortopulmonary bypass and as a venous substitute. Thirteen patients with impending limb loss had extra-anatomic bypasses with expanded polytetrafluoroethylene. Five patients with unilateral iliac disease had femorofemoral bypass for impending limb loss, and five debilitated patients underwent axillofemoral and bifemoral bypass for limb salvage. Nine of ten patients had salvage of the extremities. Three patients had extended profundoplasty, two combined with polytetrafluoroethylene femoropopliteal bypass to isolated popliteal artery segments. Two of these patients had limb salvage. The patency rate is 92 per cent, and the limb salvage rate is 85 per cent in this difficult group of patients. The follow-up period extends to 28 months, and 12 patients are beyond one year. In six patients, polytetrafluoroethylene carotid subclavian bypass was performed for the subclavian steal syndrome; all patients had relief of the symptoms. One patient underwent axillary-axillary bypass with excellent results. Expanded microporous polytetrafluoroethylene with its high patency, shortened operating time, biocompatibility and excellent tissue incorporation is an excellent arterial substitute. The pliability and no requirement for preclotting make polytetrafluoroethylene ideally suited for patch angioplasty and suturing in areas difficult to expose.


[The effect of some non-narcotic analgetics on respiration (author's transl)]. Report on a Hungarian analgetic "Probon" belonging in its effects to the minor analgetics. It does not show any depressing action on the respiratory centre and has a bronchodilatory effect. It does not cause sideeffects nor dependence and does not lose in efficacy even in long lasting application and in old people.


[Method of determining and the makeup of the aliphatic hydrocarbon fractions of sunflower, cottonseed and soya oils and of oil cakes]. To determine the content and composition of aliphatic carbohydrates in vegetable oils and oil cakes a method including alkaline hydrolysis, partition and thin-lower chromatography, gas-liquid chromatography and chromate-mass-spectrometry was devised. The content of n-isoalkans, isoprenoids, monocycloparaffins, bi-and tricyclic naphthenes, steranes and terpenes, olifines, squalene and other polyenes in sunflower, cotton, soya oils and oilcakes was measured.


Lactose malabsorption among Masai children of East Africa. There is much disagreement about milk and its use in feeding programs both in the United States and internationally. A few authors suggest that milk consumption should not be encouraged in lactose intolerant populations due to adverse symptoms. Others suggest, however, that small or modest quantities of milk can be tolerated and can be nutritionally useful to such groups. Data are presented in this paper that show that 1) the Masai regularly drink considerable quantities of milk without apparent symptoms, 2) milk is an important constituent of the Masai diet, and 3) 62% of 21 Masai examined were malabsorbers of lactose as measured by the lactose tolerance test. This finding of lactose malabsorption in a nomadic cattle raising and milk drinking people is interesting and is contrary to the views often expressed by anthropologists and others. An ability to drink nutritionally useful quantities of milk does not, however, necessarily mean that milk production or imports should be encouraged in the Lesser Developed Countries.


[In search of a surgical treatment of endocrinologic exophthalmia (author's transl)]. Surgical "decompression" of the orbit does not ensure correction of endocrinologic exophthalmia. This is due to profound changes in the deep orbital tissues. The authors have tried to solve the problem through a different approach: adapting the orbit to its pathological content. They developed an osteotomy that yields promising results: eight patients amounting to 15 orbits have been operated and exophthalmia was reduced in 12 (mean 3 mm).


Glucocorticoid therapy for the induction of pulmonary maturity in severely hypertensive gravid women. Twenty hypertensive gravid women who had their pregnancies terminated for maternal indications because of the severity of pre-eclampsia or chronic hypertension were studied. They were treated at 27 to 33 weeks of gestation with 48 hours of betamethasone therapy prior to delivery. There was one antepartum fetal death, and it is believed that this death was preventable. There was an incidence of respiratory distress syndrome (RDS) of 23% with two neonatal deaths secondary to RDS, for a treated neonatal survival of 85.7%. All losses were from mothers with pre-eclampsia. Pregnancy-related hypertension is not thought to be an absolute contraindication to glucocorticoid therapy for the induction of pulmonary maturity.


Changes in human amniotic fluid lecithin/sphingomyelin ratio and dipalmitoyl lecithin associated with maternal betamethasone therapy. In an effort to understand the biochemical changes responsible for the decreased incidence of neonatal RDS observed in premature infants delivered after maternal glucocorticoid therapy we have compared quantitative changes in L/S ratio and qualitative changes in dipalmitoyl lecithin in serial amniotic fluid samples from 20 pregnant women treated with betamethasone and 11 patients who had repeated amniocentesis at similar gestational age but did not receive glucocorticoids. Initial L/S ratio values were not significantly different between treated (1.24 +/- 0.24 [S.D.]) and control (1.09 +/- 0.29 [S.D.]) groups but the values obtained within 1 week after therapy (1.49 +/- 0.21 [S.D.]) were significantly higher (t=3.8; p less than 0.01) than those obtained after a similar period in the untreated group (1.24+/- 0.29 [S.D.]). However, only one of the treated patients reached a mature L/S ratio (2.0 or more). Simultaneously, 10 of 17 treated patients exhibited increases in the amount of dipalmitoyl lecithin within the first week after treatment, wheras no change was detected in serial samples from six control patients (p = 0.016). These results indicate that qualitative changes in amniotic fluid lecithin composition are a part of the fetal response to glucocorticoids which may be responsible for the decreased incidence of RDS observed after treatment.


[Fluorimetric determination of tranylcypromine in plasma as its 1-dimethylamino-naphthaline-5-sulfonic acid chloride by direct measurement of TLC-plates (author's transl)]. A fluorimetric method for analysis of tranylcypromine from plasma is described. After extraction from plasma tranylcypromine reacts with 1-dimethylamino-naphthaline-5-sulfonic acid chloride (DANS-Cl) in order to form the highly fluorescent DANS-tranylcypromine. After chromatographic separation on silicagel plates quantitation is achieved by in situ fluorescence determination. The recovery of tranylcypromine from plasma is 64% with a coefficient of variance of about +/- 6%.


[Antimalarial 6-aminoquinolines. VIII. 2- and 4-amino derivatives (author's transl)]. Ten 2- or 4-amino derivatives 10b-I of 6-(4-diethylamino-1-methylbutylamino)-5,8-dimethoxyquinoline were synthesised with the aim of studying the influence of these substituents on antimalarial activity and toxicity of the 6-aminoquinolines. The 4-dialkylamino derivatives 10c-h were less active against P. vinckei (mouse) than 4-alkoxy derivatives. The 4-amino derivative 10b was inactive.


[Semi-quantitative determination of resistance in agar (author's transl)]. The sensitivity of microorganisms to antimicrobial preparations is determined--using agar as the test medium--by means of a semi-quantitative method involving two concentrations, i.e. a low concentration relating to serum levels easily attained at the commonly used dosage level of the various antibacterially acting preparations, and a high concentration corresponding to serum levels attainable at increased dosage via the appropriate route of administration. The inoculum is distributed with a multi-inoculator making a simultaneous inoculation of 25 strains possible. For 25 antibiograms with 20 antibiotics 40 Petri dishes are required, inoculation take 15 min. The method described is suited above all for laboratories with large workload where a great number of resistance determinations must be carried out rapidly, precisely at a low cost.


Synthesis and anthelminthic activity of alkyl-(5-acyl-1-H-benzimidazol-2-yl) carbamates. A series of alkyl-(5-acyl-1-H-benzimidazol-2-yl)-carbamates were prepared and screened for anthelminthic activity. Some of them were found to be fully active at low, atoxic oral dose levels against gastro-intestinal nematodes. The activity against Symphacia muria and Strongyloides ratta is indicated. From these studies methyl (5-benzoyl-1-H-benzimidazol-2-yl) carbamate (mebendazole) and methyl [5-(4-flourobenzoyl)-1-H-benzimiazol-2 yl]carbamate flubendazole) were selected for detailed investigation.


Synthesis of 2-aryl-4,4-spiro-morpholinium compounds of possible biologic interest. The preparation of some 2-hydroxy-2-aryl-4,4-polymethylenemorpholinium bromides (II) by ring closure of the corresponding N-phenacyl-N-hydroxy-ethylpiperidinium (pyrrolidinium) bromide (III) and the synthesis of 2-ethoxy (IV) and of 2,3-dehydro derivatives (VI) are described. The synteshis of 2-phenyl-4,4-pentamethylene-morpholinium bromide (VII) from the hydrogenation of either the 2-phenyl or 2-p-bromophenyl-2,3-dehydromorpholinium derivativies (VI) is also reported. Proof of the chemical structures is provided by IR, UV, and NMR spectroscopy. The synthesized compounds did not present any significant pharmacologic activity.


Quantitative structure-activity relationships. VI. Non-linear dependence of biological activity on hydrophobic character: calculation procedures for bilinear model. The bilinear model, log 1/C = a log P--b log (betaP + 1) + c, is a new model for the qunatitative description of non-linear relationships between hydrophobic character and biological activity. In contrast to the parabolic Hansch model the bilinear model considers the particular effect that a linear relationship exists between lipophilicity and biological activity up to a point where this linear relationship breaks down to a non-linear relationship. Two different calculation procedures for the bilinear mode, a stepwise iteration method and the Taylor series iteration method, are explained and demonstrated with examples. The bilinear model and the parabolic Hansch model are compared by means of the statistical parameters r, s and F, by a partial F test and by an analysis of the residuals obtained with both models.


Drug evaluation on haemopoietic cells in vitro. I. A micro agar colony assay with semi-automatic optical monitoring. A micro method was developed to culture myelomonocytic colonies from mouse bone marrow cells in semi-solid agar contained in glass capillary tubes. Parameters affecting colony formation in capillaries were studied. An optical, semi-automatic scanning system using the light scattering properties of the colonies was developed; the system was mostly composed of commercially available equipment. The daily growth of single colonies within the tubes was followed. Combined with the capillary technique the scanning system provides an easy, accurate and sensitive method to quantitate the formation of haemopoietic colonies. This is the basis of a micro assay for the evaluation (screening) of drug effects on mammalian cell colonies in vitro offering several advantageous features.


Further absorption studies with the anti-diarrhoeal agent ethacridine lactate in the dog. 2-Ethoxy-6,9-diaminoacridine lactate (ethacridine lactate, Rivanol, Metifex) has been administered orally to the dog once daily for 14 days, tritium labelled matterial having been given on days 1 and 14. The extent and rates of urinary excretion of radioactivity and the peak plasma levels and total radioactivity half-lives following the radiolabelled doses on days 1 and 14 were essentially the same. There was no significant change following multiple dosing in the level of urinary acridine-like material as determined fluorimetrically, which compared to approximately 0.01% of the dose found in the 0--24 h urine. It was concluded that, following oral administration of 3H-ethacridine lactate (5 mg/kg), less than 0.1% of the dose is absorbed as acridine-like material. Multiple dosing for 14 days does not alter this very low degree of oral absorption. In a separate study tritiated ethacridine lactate (30 microgram/kg) was administered i.v. to the dog. Approximately 84% of the radioactivity was eliminated in the 0--72 h post dose period, the majority of it being excreted via the faeces. There was a rapid loss of radioactivity from the plasma, followed by a long terminal phase in which acridine-like material was estimated to have a half-life of about 15 h.


The effects of silybin on experimental phalloidine poisoning. Histochemical and histoenzymological studies carried out on liver slices of the mouse show that silybin both as prophylactic and curative treatment, inhibits the disorders of metabolic activity brought about by phallodine and maintains enzymatic activities at levels comparable with those of the control animals. Silybin, when administered alone, produces only minor changes in activities. As with silymarin, the only notable effect is an increased activity of alkaline phosphatase. The mode of action of these two substances appears to be the same.


Pharmacokinetics of amixetrine in the dog. Relation of dose-to-plasma concentration. N-[(2-Phenyl-2-isoamyloxy)-ethyl-pyrrolidine]-hydrochloride (amixetrine) was administered  to dogs at increasing doses, by i.v. and oral routes. Plasma determinations of active principle were carried out by gas liquid chromatography. The sensitivity limits of the method was 0.1 micrograms/ml of plasma. The evolution of the absorption coefficient and variations in half-life as a function of dose, were studied. The results indicate a non-linear, two-compartment open model. A first-pass effect and enzymatic saturation are envisaged.


[Studies on the mechanism of action of clonidine after pretreatment with reserpine (author's transl)]. The effects of 3.7--30 micrograms 2-(2,6-dichlorophenolamino)-2-imidazoline hydrochloride (clonidine)/kg i.v. on the arterial blood pressure and the central nervous activities of the sympathetic and the phrenic nerves were studied in 33 anaesthetized, relaxed and artificially respirated cats. In part of the experiments the animals were pretreated with reserpine at a dosage of 2X0.3 mg/kg. In normal animals clonidine caused a fall in blood pressure, a reduction of nicotinic pressure effect and an inhibition of sympathetic activity. In pretreated animals the antinicotinic as well as the sympathetic inhibitory actions of clonidine were significantly increased at a dosage of 30 micrograms/kg. The single application of reserpine caused no changes of these two parameters. As a result clonidine probably caused a stimulation of central nervous postsynaptic alpha-adrenoceptors and after the pretreatment with reserpine in addition to this an inhibition of the release of epinephrine.


[The influence of a combination of clonidine and acetylandromedol on blood pressure and central sympathetic tone of the cat (author's transl)]. The effects of acetylandromedol alone and in combination with 2-(2,6-dichlorophenolamino)-2-imidazoline hydrochloride (clonidine) on the arterial blood pressure and the preganglionic discharges of the cervical sympathetic and phrenic nerves were studied in 36 anaesthetized cats. At a dosage of 10--40 micrograms/kg i.v. acetylandromedol produced a fall of blood pressure and an increase of the central nervous sympathetic activity. Both effects lasted longer than 1 h. The combination of 40 micrograms acetylandromedol/kg with 15 micrograms clonidine/kg i.v. caused a decrease of the sympathetic activity. A depression of the respiratory centres was not observed. 10 micrograms acetylandromedol/kg in combination with 15 micrograms clonidine/kg produced a significantly more pronounced hypotensive action than the single application of 20 micrograms acetylandromedol/kg or 30--120 micrograms clonidine/kg.


Effects of 3-trifluoromethyl-alpha-ethylbenzhydrol (RGH-3332), a new enzyme inducer, on the microsomal drug metabolism. Part I. Intensity and duration of action of several compounds which are metabolized in the liver, are reduced in rats following pretreatment with 3-trifluoromethyl-alpha-ethylbenzhydrol (RGH-3332, Zixoryn), e.g., hexobarbital, methohexitone, glutethimide, hydroxymephenesine, chlorzoxazone, zoxazolamine, ketamine, chlordiazepoxide, diphenylhydantoin, ethylmorphine and pentylenetetrazol, hydroquinone, acenocumarol, respectively. Hypnotic effect of barbital is not altered by RGH-3332. Hexobarbital, meprobamate, mephenesine, nikethamide, canrenone, metyrapone, antipyrine, bromsulphophthalein, inocyanin green, bilirubin disappearance are enhanced, excretion of ascorbic acid is increased after RGH-3332 treatment. The effect of RGH=3332 is inhibited by D,L-ethionine. Hepatic cytochrome P450 concentration is increased following treatment with RGH-3332. Results of in vivo studies proved that 3-trifluoromethyl-alpha-ethylbenzhydrol has enzyme inducing activity.


Effects of 3-trifluoromethyl-alpha-ethylbenzhydrol (RGH-3332), a new enzyme inducer on the central nervous system of rats. Part II. 3-Trifluoromethyl-alpha-ethylbenzhydrol (RGH-3332, Zixoryn) had been reported to induce the hepatic mixed function oxydase system similarly to phenobarbital [5]. CNS effects of both compounds were tested on immature rats, age 14 days, in the developmental phase of quick morphological and functional growth. A marked difference in total locomotor activity, exploratory behaviour and reaction to both compounds between immature and adult rats is reported. Toxicity of RGH-3332 is favourable in itself and in comparison to that of phenobarbital in both age groups. CNS effects are neglibile compared to the main effect, they can be observed only in 6--8fold doses eliciting maximum inductive response in case of RGH-3332, while CNS effects are caused by phenobarbital at lower doses than that required for maximum inductive response.


Metabolism of 14C-3-trifluoromethyl-alpha-ethylbenzhydrol in rats. Metabolism of 3-trifluoromethyl-alpha-ethyl-benzhydrol (I), hepatic enzyme inducer has been studied in rats. Five metabolites in bile and four in urine, as well as minute amounts of the original drug (I) were identified. The only major metabolite in bile and one of the two major metabolites in urine were found to be aromatic hydroxylated products of I, i.e., 3-trifluoro-methyl-4'-hydroxy-alpha-ethylbenzhydrol (II). The results of enzymatic hydrolysis with beta-glucuronidase/arylsulfatase suggest that hydroxyl groups of metabolites are conjugated. Considering the structure of metabolites isolated a probable order of metabolite formation is outlined.


3-Trifluoromethyl-alpha-ethylbenzhydrol (RGH-3332). Liver enzyme induction and D-glucaric acid excretion. The enzyme inducing effect of 3-trifluoromethyl-alpha-ethylbenzhydrol (RGH-3332, Zixoryn) has been studied in man by means of determining urinary D-glucaric acid output. RGH-3332 was given for ten days, 300 mg/day to 13, 600 mg/day to 11 and 900 mg/day to 11 patients orally. A significant increase of glucaric acid excretion was found in all three groups confirming the enzyme inducing effect of RGH-3332. A tendency to dose-effect relationship was observed. No signs of adverse drug effects were found by laboratory tests. Minor gastrointestinal side effects were observed in two cases of 35 subjects.


[A contribution to the pharmacodynamics of guanidine hydrochloride (author's transl)]. The concentration of guanidine was determined in blood serum and urine of healthy humans following oral administration of guanidine hydrochloride. The biological half life is 12 h, the renal clearance is 40--50 ml. An improved method for the determination of guanidine in body fluids is described.


Domperidone (R 33812) in the prophylactic treatment of chemotherapy-induced emesis. A multicentre evaluation. Domperidone (R 33812) was injected i.v. for the prevention of nausea and vomiting in a total of 395 cytostatic treatment courses in 172 patients. The total dose ranged from 1 to 40 mg and was given in one or several doses. Even after the administration of severely emetic substances, vomiting and nausea were largely prevented in hospitalized patients, but the results were rather poor in ambulatory patients. In all of the cytostatic treatment schedules very favourable results were obtained.


Absolute bioavailability of digoxin tablets. Ten healthy male volunteers each received 0.5 mg digoxin orally and i.v. in a randomised, cross-over sequence with at least two weeks between doses. Plasma concentration and cumulative urinary excretion of digoxin were measured up to 6 and 144 h, respectively, after administration using a radioimmunoassay method. Absolute bioavailability (i.e. the percentage absorption from tablets compared to i.v. injection) was calculated by four methods: by comparing areas under plasma concentration/time curves (AUC) up to 6 h and to infinity, also by comparing cumulative urinary excretion up to 144 h (t max.) and to infinity. The mean of the two extrapolated values for the absolute bioavailability of digoxin (Sandoz) tablets is 78%.


[Antimalarial 6-aminoquinolines. XI. 2-, 3-, and 4-alkyl-, aryl-, and arylalkyl derivatives (author's transl)]. 23 derivatives 17a--z of 6-(4-diethylamino-1-methylbutylamino)-5,8-dimethoxyquinoline (1a) were synthesized with the aim of studying the influence of an increased lipophilicity on the biological activity. 17a--z are active against P. vinckei (mouse), but none of these derivatives is superior to the 2,4-dimethyl derivative 1d. Flat molecules (e.g. 17k and 17e) and their bulky hydrogenated derivatives (17I and 17f) show a comparable activity. This indicates that a flat structure is not essential for the activity of the 6-aminoquinolines.


[Synthesis and virostatic activity of adamantan-1-carbonic acid amidines (author's transl)]. 33 different adamntyl amidines containing four different structural types were synthesized and checked for virostatic activity. The activity of compounds of type II seems to originate in their ability to form H-bonds. The strength of antiviral activity is at least partly determined by the electronic effects of substituents at the benzene ring.


[In vitro investigations of rifampicin. Correlation between minimal inhibitory concentration and minimal inhibitory zone]. Regression analyses demonstrated a good correlation between the minimum inhibitory concentrations of rifampicin determined by the agar dilution method in Mueller-Hinton or Iso-Sensitest agar and the diameters of the inhibition zones produced by the antibiotic in the agar diffusion test on the same two media. The inhibition zone diameters produced in cultures of gram-positive bacteria most of which are highly sensitive to rifampicin (MIC less than 0.125 microgram/ml), are greater than 32 mm. Clearly discernible zones of inhibition ranging from 9 to 24 mm in diameter are, however, also found with gram-negative bacteria, which are less sensitive to the drug (MIC 4--32 microgram/ml. The simple agar diffusion method consequently provides a reliable indication of the sensitivity of bacteria to rifampicin.


Quantitative studies on acid hydrolysis of digitoxin. Hydrolysis of 3H(G)-digitoxin by hydrochloric acid and human gastric juice is described. Incubation temperatures of 37 degrees C and 22 degrees C were chosen for electrolyte solutions, and 37 degrees C for the experiments with gastric juice. After dichloromethane extraction, the radioactive metabolites were separated by thin-layer chromatography, localized and quantified by a radiochromatogram scanner. The degradation products separated by TLC were digitoxigeninbis-digitoxoside, digitoxigenin-mono-digitoxoside, and digitoxigenin. After 10 min of incubation at pH 1, digitoxin amounted to 38.6% of the total radioactivity in electrolyte solution and 37.6% in gastric juice. After 60 min, the percentage of digitoxin decreased to 5.9% and 0%, respectively. After 120 min at 22 degrees C, amounts of unhydrolyzed digitoxin were: at pH 1 55%; and at pH 2 84%. After 10 min at pH 1, and 60 min at pH 2, digitoxin was hydrolyzed to such an extent that bioavailability should have been significantly reduced. Absorption of digitoxin (liquid) from the stomach was studied during gastroscopy in five patients. Among them, significant differences in absorption kinetics and bioavailability existed, as revealed by radioimmunological measurements of the digitoxin blood levels.


Cortical pO2 distribution during oligemic hypotension and its pharmacological modifications. pO2 measurements in the cerebral cortex of cats have shown that the distribution of oxygen within the tissue becomes considerably affected by hypovolemic hypotension, in particular in the late period of oligemia. Pharmacological studies on this model show that the treatment of shock with a vasodilating drug such as papaverine leads to shunt-perfusion, thus impairing the oxygenation of brain tissue. In contrast, administration of the metabolically active drug dihydroergotoxine (DET, Hydergine) results in an improvement of the tissue pO2 distribution in the direction of a pre-shock state.


Hypoglycemic activity of amine derivatives. Preliminary observations. Dicyclohexylamine and related amino compounds as well as some simple secondary amines with branched aliphatic substituents were found to decrease blood glucose levels of fasted, glucose-loaded, or streptozotocin-diabetic rats, and of fasted mice. Structure-activity relationships are discussed.


Effects of dobutamine on coronary circulation and cardiac metabolism of the dog. Effects of (+/-)-4-[2-(3-p-hydroxyphenyl-1-methyl-amino)ethyl]pyrocatechol (dobutamine) on coronary circulation and cardiac metabolism were investigated using the heart in vivo and the isolated perfused heart of dogs. In the heart in vivo dobutamine 1--30 microgram/kg i.v. and 1--100 microgram i.c. produced dose-dependent increases in coronary perfusion pressure, coronary blood flow, heart rate and left intraventricular pressure. In the perfused heart dobutamine 10 microgram i.c. increased coronary flow, heart rate, cardiac contractility and myocardial oxygen consumption. Delta redox potentials decreased but did not show negative values. Propranolol 0.1 mg/kg i.v. and 0.1 mg i.c. inhibited these effects of dobutamine. Dobutamine shows basically the same actions as isoproterenol, but does not reduce the coronary perfusion pressure by the relatively high dose applied. The results suggest that dobutamine may have a selective adrenergic beta 1 receptor stimulating action on the heart and have a merit in maintaining the coronary perfusion pressure.


Influence of somatostatin on blood pressure and plasma renin activity in the rat. In the anaesthetized rat synthetic somatostatin can interfere with the renin-angiotensin system by increasing plasma renin activity and decreasing normal blood pressure or counteracting several types of experimental hypertension.


Experimental studies on the intestinal uptake of organic and inorganic magnesium and potassium compounds given alone or simultaneously. The peroral administration of magnesium and potassium compounds in effective doses (ED50) to rats yielded the following results: 1. Magnesium or potassium given as chlorides are significantly better absorbed than the corresponding aspartates. 2. In the presence of aspartate in higher concentrations the absorption of both magnesium and potassium is inhibited to a certain degree. 3. Increasing amounts of chloride cannot abolish the inhibitory effect of aspartate on potassium absorption, in contrast magnesium, which, in the presence of aspartate is better taken up when chloride is provided. 4. High concentrations of magnesium may perhaps impede the uptake of potassium to a small degree but not vice versa. 5. Magnesium losses from the body--induced by treatment with 9-alpha-fluorocortisol-acetate--can be effectively substituted by peroral administration of chloride-containing magnesium compounds over a reasonable time. The simultaneously occurring loss of potassium cannot be corrected correspondingly by potassium supplements.


ATP contents and structure of rat liver mitochondria in the presence of 2-mercaptopropionylglycine. 2-Mercaptopropionylglycine was found to be efficient in the treatment of chronic hepatitis. Interest was focussed on the possible mode of action of that reagent at the subcellular level. ATP contents in mitochondria were increased after anaerobic preincubation and after addition of ADP and 2-mercaptopropionylglycine. Concomitantly, we found an increase in condensed configuration of mitochondria. If the reagent was added before ATP-Mg2+ (ADP) the mitochondrial structure was well preserved, though, throughout of orthodox configuration. In comparison the control specimens were grossly swollen. It is proposed that the reagent may act at the level of mitochondrial energy coupling.


A study on cerium-induced liver injury in rats after pretreatment with spironolactone, phenobarbital, pregnenolone-16 alpha-carbonitrile and nafenopin. A number of drugs known to induce liver microsomal enzymes were studied with respect to their effect on the elevated liver triglyceride (TG) concentration and serum glutamic oxaloacetic acid transaminase (GOT) and glutamic pyruvic acid transaminase (GPT) activities induced by an i.v. injection of cerium in rats. Pretreatment with pregnenolone - 16 alpha - carbonitrile (PCN) and 2-methyl-2-[p-(1,2,3,4-tetrahydronaphth-1-yl)phenoxy]-propionic acid (nafenopin) decreased the liver TG concentration significantly. Spironolactone and phenobarbital pretreatment also decreased the TG level in comparison to controls, but the difference was not statistically significant. Both GOT- and GPT-activities in serum increased on the first day after cerium injection and reached a maximum after 3 days. All the drugs significantly reduced the elevated levels. After 7 days the activity was almost normal in all the surviving animals.


The metabolites of 14C-sulpiride in the rat. The elimination of total radioactivity after i.p. application of carbonyl-14C-labelled sulpiride (SP) was estimated in urine and feces. An average of 30% of administered radioactivity was found in feces, 50% in urine. By preparative thin-layer chromatography of urine SP and five metabolites were isolated. On the basis of chromatographic-spectrophotometric comparisons to synthesized standards four metabolites were identified: O-desmethyl-SP, 5-oxo-pyrrolidine-SP, N-desethyl-SP and O-desmethyl-5-oxo-pyrrolidine-SP. The chemical structure of one metabolite could not be established.


On the mechanism of amphetamine-induced behavioural changes in the mouse. I. An observational analysis of dexamphetamine. The effects of dexamphetamine have been studied on 18 separate items of observed behaviour in the mouse. The intensity of dexamphetamine action was assessed by scoring differences in behaviour from control (vehicle injected) mice and by measuring ED50 values for dexamphetamine to cause detectable differences from controls for each individual item. The experiments were performed blind in that the observer had no knowledge of the dose of dexamphetamine given to the test group or even whether these had received dexamphetamine at all. The results show a clear division of behavioural items into two groups according to ED50 values; group 1 with ED50 values greater than 15 mg/kg was associated with falls in whole-brain norepinephrine. Group 1 contained elements of increased motor activity, the stereotypies (except compulsive gnawing) and certain aspects of increased alertness. Group 2 consisted of compulsive gnawing and the remaining aspects of increased alertness. Compulsive gnawing was negatively correlated in intensity with the majority of other behavioural items but no other evidence was found for a smooth replacement of one type of activity by another with increasing dose.


[Enteral absorption of sulfasomidine depending on age (author's transl)]. After intravenous and oral application of 25 mg 6-(sulfanilamido)-2,4-dimethyl-pyrimidine (sulfasomidin)/kg body-weight to 29 newborns, 8 infants and 9 older children the completeness and rate of absorption were determined. Sulfasomidine was completely absorbed in newborns (mean value 95.7%) as well as in older children (mean value 94.4%). Concerning the rate of absorption there were age-dependent differences. Using the Bateman function for the kinetic model of intestinal absorption the rate constant of invasion k1 was significantly lower in the first week of life compared to that in older children. In agreement with these data the time tmax of the maximum serum concentration was significantly prolonged in newborns compared to that of older children.


Loperamide in patients with radiotherapy-induced diarrhoea. 63 patients (23--78 years) with irradiation-induced diarrhoea, the majority of them resistant to treatment with diphenoxylate, were started on 4-(p-chlorophenyl)-4-hydroxy-N,N'-dimethyl-alpha,alpha-diphenyl-1-piperidine butyramide (loperidine, Imodium) 4 mg daily. Doses were further adapted individually and the trial lasted for 3--72 days. Daily frequency and consistency of stools improved significantly, and abdominal cramps were clearly reduced. Stools became normal in 41 patients after a median time of 16.5 days (median daily dose: 4 mg), they improved in six other patients, but remained unchanged in eight and deteriorated in one patient. The remaining seven cases were not evaluated. No side-effects could be attributed to the drug.


[Ambroxol, comparative studies of pharmacokinetics and biotransformation in rat, rabbit, dog and man (author's transl)]. Pharmacokinetics and biotransformation of trans-4-(2-amino-3,5-dibromo-benzylamino)cyclohexanol hydrochloride (ambroxol, NA 872 Cl) was studied using the 14C-labelled compound. Absorption after oral administration was found to be fast and complete. Elimination half-life of radioactivity in the blood was estimated as 20--25 h in rat, dog and man and as 2 h only in rabbit. This apparent elimination half-life is governed by the disposition of acidic metabolites of NA 872. In man and rabbit radioactivity is excreted almost completely into the urine, whereas in rat and dog biliary excretion is also observed. Routes of biotransformation are similar in all 4 species. NA 872 is metabolized by phase I reactions to NA 873 and finally to dibromoanthranilic acid. Phase II reactions with the parent compound and metabolites are observed mainly in man and rabbit.


[Ambroxol, studies of biotransformation in man and determination in biological samples (author's transl)]. 15 mg trans-4-[2-amino-3,5-dibromo-benzyl)-amino]-cyclohexanol-hydrochloride (ambroxol, NA 872) was administered i.v. and orally to healthy volunteers. The metabolic pattern in urine and plasma was similar for both routes of administration. Biotransformation reactions are straightforward, yielding two major products of phage I reactions identified as 6,8-dibromo-3-(trans-4-hydroxycyclohexyl)-1,2,3,4-tetrahydro-quinazoline and 3,5-dibromo-anthranilic acid. These metabolites as well as the parent compound are also converted to conjugates, predominantly glucuronides. Quantification of unlabelled ambroxol in biological fluids is achieved by radiochemical derivatisation with 14C-labelled formaldehyde in imitation of the biotransformation.


[Transmission and scanning electron microscopic investigation of the structure of so-called Clara cells of the bronchial system]. The epithelium of the bronchi and bronchioles were systematically examined in the lungs of rabbits. Particular attention was paid to the morphology of the Clara cells in the secretory phases. The apocrine secretion of these cells could be reconstructed from the results obtained. On the basis of morphological observations, the Clara cells produced a serous secretion which was mixed with the mucous secretion of the goblet cells in the bronchi. From these morphological results, the effect of substances which break down the secretion and also the morphological relationship of the Clara cells gain special interest.


[Therapeutic study on ambroxol in chronic bronchopulmonary diseases (author's transl)]. The clinical activity of trans-4-[(2-amino-3,5-dibromo-benzyl)-amino]-cyclohexanol-hydrochloride (ambroxol, NA 872) as well as its influence on lung function was examined in a total of 63 patients (34 suffering from silicosis, 28 from chronic obstructive bronchitis and 1 from cryptococcosis). Additionally, the content of phospholipids was controlled in the sputum of the patient group. It was shown that the activity of ambroxol was better in the silicosis group than in the bronchitis group. The cause was discussed. Presumably the twofold site of action in the silicosis group (secretolysis and surfactant stimulation) might be the reason for this.


[Clinical experience with ambroxol syrup (author's transl)]. In an open trial trans-4-[(2-amino-3,5-dibromo-benzyl)-amino]-cyclohexanol hydrochloride (ambroxol, NA 872) in the form of ambroxol syrup was given to non-hospitalised patients suffering from acute and chronic bronchitis. A marked reduction in coughing and dyspnoea as well as an improvement in expectoration was apparent. The maximum effect was reached on the third day of treatment. The effect can be maintained by consistent prolongation of the therapy. There were no side effects.


[Results of a clinical trial with ambroxol as to postoperative therapy of bronchitis (author's transl)]. The clinical testing of trans-4-[(2-amino-3,5-dibromo-benzyl)amino]cyclohexanol-hydrochloride (ambroxol, NA 872) in surgical patients was carried out over a period of 7 days. Regular application of 60 mg/day showed a clear improvement in subjective symptoms, particularly in cases of bronchitic syndrome. In some patients improvement could be demonstrated objectively by means of sputum viscosimetry. The clinical effect is principally one of facilitation of expectoration and fluidification of mucus, which often prior to therapy is rather viscous. This leads to a favourable influence of the post-operative treatment period. As a rule the substance is well-tolerated. The recommended dose of the drug for the average treatment is 2 ampoules/day i.v. (30 mg) and a single to twice daily inhalation of 2 ml (15 mg) for 5--7 days post-operatively.


[Effect of furosemide on the hemodynamics of the kidney medulla during salt depletion]. In sodium depleted rats cortical and medullary blood flow was studied before and after 4-chloro-N-(2-furylmethyl)-5-sulfamoyl-anthranilic acid (furosemide). 86Rb was used as an indicator of renal hemodynamics. Its activity was assessed in systemic blood and in tissue slices of the kidney. At the beginning of the experiments the animals were loaded p.o. with 1.3 ml/100 g b.w. of isotonic saline. 3 h later a rapid i.v. injection of 50 muCi (=5.6 MBq) 86Rb was given to 12 control and 9 furosemide treated animals. After 0.7 mg/100 g b.w. of furosemide the sodium and water excretion rises to 820% and 860% resp. (p less than 0.0005). Systemic body hematocrit increases from 47 to 49%. The renal cortical blood flow is not influenced by furosemide. Compared with controls there is a decrease in blood flow through the outer medulla from 1.57 +/- 0.65 to 1.00 +/- 0.37 ml/g.min, through the inner medulla from 0.75 +/- 0.30 to 0.59 +/- 0.23 ml/g.min, and through the papillary tips from 0.85 +/- 0.40 to 0.46 +/- 0.18 ml/g.min. However, these hemodynamics changes are not significant. It is concluded that the decrease in renal medullary hemodynamics of furosemide-treated rats is due to a stimulation of the renin-angiotensin system.


[Bacteriological and clinical evaluation of a dicloxacillin-ampicillin combination (author's transl)]. This paper presents the results of the bacteriological and clinical assessment of the dicloxacillin-ampicillin combination Totocillin. The bacteriological examinations show that a synergistic and hyperadditive effect particularly on Staphylococcus, but also on E. coli, Klebsiella-Enterobacter and in a few cases on Proteus spp. is achieved with the combination. Clinical experience in urinary tract infections evidences the good efficacy of the combined preparation, which on statistical evaluation proved to be significantly more active than ampicillin alone. Satisfactory therapeutic results with the combination were yielded also in infections not involving the urinary tract.


[Changes in erythrocyte shape and volume caused by silymarin]. In vitro treatment of fresh human red cells with silymarin as well as its individual components silybin and silydianin (10(-4) and 10(-3) g/ml of water-soluble sodium or hemisuccinate sodium salt) resulted in disc-crenated sphere transformation of the erythrocyte shape, silydianin being least effective. 10(-4) g/ml of each compound tested, causing only slight changes of the shape of the erythrocytes, significantly increased their maximum diameter, whereas 10(-3) g/ml silymarin or silybin, resulting in a marked sphering of the cells, significantly decreased their maximum diameter. Mean cell volume in isotonic medium determined by Coulter counter method was significantly increased by 10(-3) g/ml silymarin, silybin, silydianin and, above all, chlorpromazin. 2 x 10(-5) g/ml chlorpromazine significantly increased the critical haemolytic volume in hypotonic medium, determined by microhaematocrit method, whereas an insignificant increase of the critical haemolytic volume was induced by 2.7 x 10(-4) g/ml silymarin.


[Penetration of a non-steroidal anti-inflammatory drug into human skin in vitro and in vivo. Tissue concentrations and flow rates of p-butoxyphenylacetohydroxamic acid (author's transl)]. The penetration of p-butoxyphenylacetohydroxamic acid (BPHS; Parfenac) from a crean and an ointment into human skin in vivo and in vitro was investigated. From both preparation forms high tissue concentrations were achieved. Flow rates through the horny layer could be calculated, that from the ointment being considerably higher (3.8 . 10(-8) mol/cm2 . h) than that from the cream (7 . 10(-9) mol/cm2 . h). A control experiment in vivo proved that the in vitro data are relevant. The difference between dermal concentrations in vitro (with abolished capillary function) and that in vitro (with capillary system functioning) reflected the fast absorption of the drug by the vessels.


[Rectal absorption of phenobarbital in children as affected by different vehicles]. 68 infants received 7--15 mg phenobarbital and sodium-phenobarbital/kg body weight by suppositories of different melting-points and hydroxyl-values (Witepsol H 12, W 35, E 76). The kinetic analysis of the serum concentration curve shows that the rate of rectal absorption is significantly increased if sodium-phenobarbital instead of phenobarbital is applied. The absorption rate is faster using suppositories with a lower melting-point (32.5 degrees C) compared to suppositories with a higher one (37.5 degrees C). Increasing the amount of hydroxyl values in the vehicle the absorption rate of phenobarbital becomes faster. Comparing the area under the serum concentration curve after intravenous and rectal application in 8 infants the absorption ratio was 74%.


Thermography as a tool for evaluating the local tolerance of i.m. administration of drugs. Until today the local tolerance of i.m. administration of various drugs has been possible to register only by asking the patients about their subjective feelings. In this study using a new galenic form of trimethoprim/sulfamethoxazol (Bactrim) developed for i. m. administration and ampicillin we could find that thermography can be used as a very exact method to measure the local tolerance of i.m. administered drugs. In fact, the thermography gave reaction before the patient reported any pain and in cases where pain existed the thermography findings correlated well with the reports of the test persons.


[Transformation of tetrahydro-1,3-oxazine into 1,3,5-tris(3-hydroxypropyl)-hexahydro-1,3,5-triazine--a question of stability (author's transl)]. At room temperature tetrahydro-1,3-oxazine (THO) is converted into the very viscous 1,3,5-tris(3-hydroxypropyl)-hexahydro-1,3,5-triazine (THT) over several weeks. On heating to ca. 125 degrees C THO will be reformed from THT. The structure of THT was proven by mass-, 1H- and 13C-NMR spectra.


The liquid chromatographic analysis and pharmacokinetics of the semi-synthetic cephalosporin 3-methyl-7-[4-(1,4,5,6-tetrahydro-2-pyrimidyl)-phenylacetamido]-delta 3-cephalosporanic acid (I). A high-pressure liquid chromatographic method is described for the analysis of the cephalosporin 3-methyl-7-[4-(1,4,5,6-tetrahydro-2-pyrimidyl)-phenylacetamido]-delta 3-cephalosporanic acid (I) in human plasma and urine. The analysis was carried out on a reverse-phase column and the column effluent was monitored by UV absorption at 236 nm. The lower limits of detection are 0.5 micrograms ml-1 and 0.2 micrograms ml-1 for plasma and urine, respectively. The correlation coefficient for the analysis of this cephalosporin in serum was 0.966 in comparison with a microbiological assay. Plasma and urine levels of (I) in three volunteers given an i.v. dose (500 mg) of the compound have been measured by this method and pharmacokinetic evaluation of the results performed assuming a two-compartment open model. The plasma half-life of the cephalosporin was 0.55 +/- 0.18 h up to 1--2 h after dosing and 2.2 +/- 0.7 h thereafter. At steady-state, the volume of the central compartment was 8--20 l and the volume of distribution was 12--31 l. A  comparison of total clearance with renal clearance suggested that 97 +/- 2.6% of the compound would be excreted unchanged via the kidney and this was consistent with that observed experimentally.


The effects of pemoline on nuclear fusion, karyokinesis, and cytokinesis in caffeine treated cells. The effect of 0.2% caffeine combined with 5-phenyl-2-imino-4 oxazolidone (pemoline, Tradon), in different ways, on mitosis in lateral roots of Vicia faba L. has been studied by means of aerated hydrocultivation. The results show that prolonged treatment with 10(-6) g/ml or 3 x 10(-4) g/ml (=saturated solution) pemoline to a certain degree compensates the negative influences of caffeine on mitotic index during and after the caffeine treatment. Depending on the duration of treatment 10(-6) g/ml pemoline are able to increase rates of nuclear fusions, bimitoses and 4n-mitoses, while 3 x 10(-4) g/ml have the opposite effects. The number of irregular cytokineses is increased by 10(-6) g/ml, whereas no abnormal cell walls are formed during treatment with 3 x 10(-4) g/ml pemoline. The conclusion is that pemoline has the same sites of action as caffeine, partly antagonistically, partly synergistically.


[Development of new antiepileptics. IV. Anticonvulsant activity of some derivatives of 1-(p-sulfamoyl-phenyl)-pyrrolidin-2-one (author's transl)]. A series of derivatives of 1-(p-sulfamoyl-phenyl)-pyrrolidin-2-one were tested for anticonvulsant properties in rats and mice. The substance 1-(o-chloro-p-sulfamoyl-phenyl)-4-phenyl-pyrrolidin-2-one (1725) was found to have potent anticonvulsant activities in rats and mice against seizures induced by electroshock or pentylenetetrazol. The unsubstituted phenyl ring has to be in position 4, otherwise the activity of the product is weakened. The ortho position of the halogen atom on the N-phenyl is also important for the anticonvulsant effect; chlorine acts better than fluorine. The anticonvulsants tested also potentiate the sleeping time induced by pentobarbitone and attenuate the motor activity of mice. 1-(o-Chloro-p-sulfamoyl-phenyl)-4-phenyl-pyrrolidin-2-one (1725) has a LD50 of 1000 mg/kg p.o.; the lesser active substances generally have a LD50 greater than 5000 mg/kg p.o. Toxic effects of large doses were manifested by sedation and diarrhoea.


[On drug metabolisation by mitochondria of rat liver (author's transl)]. Highly purified rat liver mitochondria, in spite of the permeability barrier of the mitochondrial membrane, are able to oxidise tertiary amines to amine oxides, to reduce N-oxides of tertiary amines and to oxidise substituted primary alcohols to the corresponding acids via instable aldehydes. This new information on the role of mitochondria in the metabolism of drugs was obtained with the aid of previous results on the biotransformation of the local anaesthetic fomocaine.


[Rat intestinal disaccharidases during cyclophosphamide treatment (author's transl)]. Rat intestinal disaccharidase activities were investigated during treatment with different doses of 2-[bis-(2-chlorethyl)-amino]-tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide (cyclophosphamide). In all experiments, disaccharidase activities decreased--although not too drastically--within 2--3 days after beginning treatment. Loss of activity was not reversed during the period of experimentation. Contrary to previous investigations, cyclophosphamide did not exert direct toxic effects on intestinal disaccharidases. Decrease of intestinal disaccharidase activities can be interpreted to be due to cyclophosphamide effects on the proliferation cycle of epithelial crypt cells resulting in a decreased number of full-function cells.


Microfluorometric investigations on the cell cycle progression of experimental ascites tumors treated with alkaloidic drugs. The effects of the antitumor agents vincristine (VCR) and vincaleucoblastine (VLB) on the cell cycle progression of three different ascites tumor cell lines in vivo (Ehrlich, Crocker S 180, and leukemia L 1210) were studied in detail by flow microfluorometric techniques over a 5-day period of drug treatment and during the post-treatment course. These investigations give evidence that the tumor lines employed show completely different sensitivity against VCR and VLB. During the treatment massive polyploidization was demonstrated to be, in general, the second response of treated cells overcoming an initial proliferative block in the G 2 phase of their life cycle.


The effect of digoxin on endothelaemia in rats and its modification by a combination of troxerutin and coumarin. The effect of digoxin on endothelium was tested with the method based on counting of circulating endothelial cells in rats. Digoxin in low doses had a protective and in high doses a damaging effect on endothelium. The latter effect was effectively suppressed by a concomitant administration of a combination of troxerutin and coumarin (Venalot).


Hypoglycemic activity of amine derivatives. A possible mode of action. Experiments were carried out to explain the hypoglycemic effect of dicyclohexylamine (DCH) and related compounds. The agents antagonized blood glucose increase in intact and hepatectomized rats infused with glucose, but not in intact rats receiving epinephrine, and induced liver glycogen rise in normal fasted but not in adrenalectomized rats. No effect on blood glucose of pancreatectomized dogs was found. DCH lowered blood triglycerides without influencing the concentration of plasma fatty acids. Intestinal absorption of glucose was not influenced by low concentrations of the amines. Hypoglycemia may result, at least in part, from stimulated glucose transformation in the muscle tissue without an enhancement of anaerobic glycolysis.


Effect of dobutamine, a new cardioselective sympathomimetic drug, on myocardial oxygen balance in conscious dogs. The effects of (+/-)-4-(2-[3-(p-hydroxyphenyl)-1-methylpropyl]-amino)-ethyl-pyrocatechol hydrochloride (dobutamine) on myocardial O2 balance were investigated in healthy conscious dogs with experimental AV-block. Dobutamine, injected as a bolus of 3, 6, 10 micrograms/kg, increased myocardial contractility, coronary flow, coronary venous O2 saturation and aortic pressure, while initially decreasing SA-node rate. Following ganglionic blockade the effects of dobutamine on myocardial contractility were unchanged while those on coronary flow and coronary venous O2 saturation were reduced by 30%. Aortic pressure and heart rate showed a dose dependent, long-lasting increase. The effects of dobutamine on heart rate and myocardial contractility could be abolished by beta 1-adrenoceptor blockade with practolol (2 mg/kg) while the effects on coronary flow and myocardial O2 extraction were reduced by 40% after practolol. Following beta 1 + 2 adrenoceptor blockade with propranolol, dobutamine increased aortic pressure and coronary flow while coronary resistance and myocardial oxygen extraction were unaffected.


On the mechanism of amphetamine-induced behavioural changes in the mouse. III. Effects of apomorphine and Fla 63. The effects on 18 items of dexamphetamine-induced behaviour of increasing the ratio of dopaminergic to noradrenergic activity have been investigated in mice. The dopamine-beta-oxidase inhibitor bis-(4-methyl-1-homopiperazinyl-thiocarbonyl)-disulfide (Fla 63) produced varying degrees of reduction in the intensity of all items except raised body position, which was enhanced. Apomorphine alone induced compulsive gnawing and increased locomotor activity but produced long-lasting suppression of these and certain other items induced by dexamphetamine. Vocalisation, touch and startle responses and stereotyped sniffing were, however, unaffected while compulsive grooming and elevated body position were enhanced. The results are discussed in the context of the relative contribution of noradrenergic and dopaminergic mechanisms to the behavioural effects of dexamphetamine.


Pulse NMR study of phase transitions in dipalmitoyl phosphatidylcholine multilayer systems. Pretransition and main transition of aqueous dipalmitoyl phosphatidylcholine (DPPC) dispersions were investigated by pulse NMR. The second moment M2 inter of the proton absorption line shows significant changes at 42 degrees C and about 35 degree C. Over the whole investigated temperature range between 25 and 50 degree C a superposition of at least two distinct second moments assigned to different molecular regions was observed.


An in vivo comparison of acetate and palmitate as precursors of surfactant phosphatidylcholine. 3-Day-old rabbits were injected simultaneously with [(3)H]acetate and [(14)C]-palmitic acid. The specific activities of lung, lamellar body and surfactant phosphatidylcholine and disaturated phosphatidylcholine were measured at time intervals from 10 min to 23 h following isotope administration. Palmitic acid contained 87% of the acetate radioactivity recovered from lung and surfactant phosphatidylcholine. The relative specific activities of surfactant phosphatidylcholine and disturated phosphatidylcholine labeled with acetate were 2.02 and 1.86 times those measured using the palmitic acid label. Apparently the palmitic acid synthesized from acetate is preferentially incorporated into lung phosphatidylcholines and disaturated phosphatidylcholines which are destined to become surfactant.


Lipid peroxidation and its inhibition by tinoridine, II. Ascorbic acid-induced lipid peroxidation of rat liver mitochondria. Incubation of rat liver mitochondrial suspension with ascorbic acid and Fe2+ resulted in the formation of malondialdehyde and a decrease in the turbidity of the suspension. The maximum amount of malondialdehyde formed during the peroxidation reaction was estimated to be 1 mol per approximately 6 mol of mitochondrial phospholipids. Tinoridine and alpha-tocopherol at the concentration of 5 micron and 1 mM, respectively, completely inhibited the peroxidative disintegration of mitochondria. From the relationship between the concentration of tinoridine and the amount of malondialdehyde formed, it was demonstrated that 1 mol of tinoridine prevents the formation of about 6 mol of malondialdehyde. These findings suggest that there is a limit in the chain reaction of the lipid peroxidation of mitochondria and that the limit is the membrane sphere which is capable of releasing 6 molecules of malondialdehyde and contains about 36 molecules of the constitutive phospholipids.


Age-dependent pattern of autonomic heart rate control during hypoxia in fetal and newborn lambs. Autonomic nervous control of heart rate (HR) during hypoxia was studied longitudinally using 9 chronically catheterized fetal lambs (109 day to term) and 10 newborn lambs (2--28 days old). Changes in heart rate (deltaHR) during hypoxia were age-dependent. Before 120 days of gestation deltaHR was insignificant, but between 120 days to term bradycardia occurred. The newborn response was marked tachycardia. Autonomic influences on HR were quantified using atropine and propranolol blockade. In fetal lambs, antagonistic increases in parasympathetic and sympathetic outflows were evident during hypoxia. In hypoxic lambs 120 days to term, net bradycardia reflected predominant parasympathetic cardio-deceleration; before 120 days of gestation both the parasympathetic and sympathetic outflows increased, but no net deltaHR occurred. In hypoxic newborn lambs, sympathetic and parasympathetic changes contributed synergistically to the net tachycardia. Thus the pattern of autonomic control of HR during hypoxia differs in fetal and newborn lambs. Changes in sympathetic and parasympathetic influences are antagonistic in the fetus, but synergistic in the newborn.


Synthesis of 1-sn-lysophosphatidylcholine and mixed acid 1-sn-phosphatidylcholine. An investigation of the biochemical effects of L-lysophosphatidylcholine (1-acyl-sn-glycerol-3-phosphorylcholine) requires as a control for its detergent action the metabolically inert, unnatural enantiomer, D-lysophosphatidylcholine (3-acyl-sn-glycerol-1-phosphorylcholine). The latter can be easily prepared in milligram quantities from the commercially available DL-phosphatidylcholine. For this purpose rac-1,2-dipalmitoyl-sn-glycerol-3-phosphorylcholine is solubilized with the aid of one-half its weight of taurocholate and hydrolyzed with phospholipase A2 to completion and the intact residual 2,3-dipalmitoyl-sn-glycerol-1-phosphorylcholine recovered by chromatography. The pure D-phosphatidylcholine is then subjected to methanolysis in the presence of octylamine and the product isomerized with glacial acetic acid. The 3-palmitoyl-sn-glycerol-1-phosphorylcholine thus obtained is chromatographically pure, possesses correct optical rotation and NMR spectrum, and is resistant to hydrolysis by phospholipase A2 following reacylation to the diacylphosphatide. Acylation of the 1-sn-lysophosphatide provides a convenient method for preparation of mixed acid 1-sn-phosphatidylcholines which are not otherwise available.


Propranolol in thyrotoxicosis: II. Serum thyroid hormone concentrations during subtotal thyroidectomy. Propranolol alone was used to prepare 20 thyrotoxic patients, 19 women and 1 man, for subtotal thyroidectomy. Serum thyroxine (T4) and triiodothyronine (T3) concentrations were measured immediately before, at several stages during and after the surgical procedure. As judged primarily by the cardiovascular response, an average of 80 mg (range 40 to 120 mg) of propranolol qid for 8 days (range 3 to 18 days) was required to prepare the patients. During the various stages of surgical removal there was no change from the initial mean (+/- SEM) T4 concentration of 25.0 +/- 2.5 microgram/dl (321.8 +/- 32.2 nmol/l) or T3 concentration of 4.2 +/- 0.6 microgram/l (6.45 +/- 0.92 nmol/l) (P greater than 0.2). At discharge on the fifth postoperative day values were significantly lower, 12.9 +/- 1.5 microgram/dl (166.0 +/- 19.3 nmol/l) and 1.9 +/- 0.2 microgram/l (2.9 +/- 0.31 nmol/l), respectively (P less than 0.001). There were no operative complications but four patients had transient hypoparathyroidism. After 1 year 2 of 18 patients had permanent hypoparathyroidism and 4 of the 18 followed up for 1 year had permanent hypothyroidism requiring thyroid hormone replacement. There was no instance of recurrent thyrotoxicosis. The authors conclude that during surgical manipulation of the gland no release of thyroid hormones into the circulation was detected and that, using propranolol as the sole agent, thyrotoxic patients can be rapidly and safely prepared for subtotal thyroidectomy.


[Anaplastic carcinoma of the thyroid gland with chondroid, osteoid, and marocellular metaplasia of the stroma, associated with Hashimoto's lymphocytic thyroiditis]. Anaplastic, mostly spindle-cellular, carcinoma of the thyroid gland was diagnosed bioptically in a 65-year-old woman. Necroptically it was found that the carcinoma was associated with Hashimoto's lymphocytic thyroiditis. In the hitherto-differentiated carcinomatous parts the papillary component prevailed and the original lymphocytic stromal infiltration was in evidence here. In the anaplastic parts isolated macrocellular elements occurred and, in some places, also chondroid and osteoid structures, especially the structures of macrocellular bone tumor character. These structures were entirely missing in the distant metastases and were, therefore, evaluated as a stromal nontumorous metaplastic process.


Thyroid binding antibodies and other immunological abnormalities in patients with Graves' ophthalmopathy: effect of treatment with cyclophosphamide. Patients with Graves' ophthalmopathy were studied for a possible role of thyroid binding antibodies (TBAb) as measured by a radioreceptor assay, and for in vitro evidence of immunoreactivity to orbital antigens. The effect of cyclophosphamide (CY) treatment on the immunological parameters and the clinical course of the eye disease was also studied. The mean TBAb index for all patients with eye disease was significantly less than that for the normal and for patients with Graves hyperthyroidism who lacked eye disease. The mean TBAb index for patients with ophthalmopathy and past or present hyperthyroidism was significantly less than for those patients with eye disease but no associated hyperthyroidism ('euthyroid Graves' disease'). TBAb levels did not correlate with the severity of duration of the eye disease and did not change during treatment with CY. Significant titres of serum antibodies against human eye muscle extract or subcellular fractions, or macrophage inhibitory factor (MIF) production in response to human orbital tissue extract were not detected in patients with eye disease. The congestive changes improved in all patients treated with CY, although the degree of proptosis and eye muscle involvement improved in only 3 of 24 and 11 of 20 patients respectively with these abnormalities. TBAb are unlikely to play a role in the pathogenesis of Graves' ophthalmopathy and the hyperthyroidism and eye disease should be considered separate autoimmune disorders. The apparently anomalous finding of a higher mean TBAb index in patients with eye disease and hyperthyroidism than in those with hyperthyroidiam alone may reflect a more severe defect of suppressor T cell function in the former group. Because evidence for specific immunoreactivity against orbital antigens was not found in this study other approaches to defining the underlying immunological mechanisms will have to be sought.


Comparison of radioassay and haemagglutination methods for anti-thyroid microsomal antibodies. Parallel measurements of circulating anti-thyroid microsomal (anti-M) antibodies by radioassay and haemagglutination were performed on subjects with or without thyroid disorders. Three-quarters (75.4%) of control subjects had undetectable antibody levels (less than 10 u/ml) by radioassay and only 3.1% had concentrations of greater than or equal to 75 u/ml. Abnormally elevated levels (greater than or equal to 75 u/ml) were found in most of the patients with Hashimoto's thyroiditis (94.1%) or idiopathic myxoedema (86.7%), in the majority (75.0%) of those with Graves' disease and only in a minority of those with other thyroid disorders. The percentage of positive sera by haemagglutination was very similar in all groups to that of abnormal values observed in the radioassay. Direct comparison of parallel tests on a total of 631 sera revealed a highly significant correlation (r = 0.91, P less than 0.001) between the two methods, but elevated antibody titres by haemagglutination were found in some sera with negative radioassays. All these sera were from a single patient with thyroid carcinoma associated with Hashimoto's thyroiditis and had elevated levels of anti-thyroglobulin (anti-Tg) antibodies. Evidence that such discrepancies were due to anti-Tg antibodies reacting with microsomal-bound Tg was provided by the demonstration that the haemagglutination produced by these sera could be completely inhibited by the addition of Tg. A similar inhibition was observed with two rabbit antisera to human Tg, but not with sera from patients with thyroid autoimmune disorders containing high levels of anti-microsomal anti-bodies.


Abnormalities in lung elastic properties and surfactant function in adult respiratory distress syndrome. We have examined the lungs from five patients who died with the adult respiratory distress syndrome (ARDS). Pressure volume curves were obtained and bronchoalveolar lavage fluid was studied on a surface balance. The pressure volume curves revealed reduced compliance compared to normal or near normal lungs. A significant loss of volume was also found. The data obtained from the surface balance studies show a normal range of minimum surface tension when compared to "normals," but  the ARDS lung lavage fluid revealed an increase in surface film compressibility relative to "normal." The increased compressibility may be an important factor contributing to the stiff lungs of patients with the adult respiratory distress syndrome.


Measurement of 111in DTPA clearance during radionuclide cisternography. A new preparation of 111In DTPA for intrathecal administration has been tested and found to be a safe and highly efficacious cisternographic agent. The rate of removal of 111In DTPA from the C.S.F. and from the whole body has been measured and has been found to be of no diagnostic value in the distinction between patients with cerebral atrophy and those with normotensive hydrocephalus. Long-term retention studies show no evidence of significant long-term retention of indium in the C.S.F. The absorbed radiation dose has been investigated and found to be in good agreement with previous estimates based upon extrapolated data.


A negative association of HLA-BW52 with Graves' disease and insulin-dependent diabetes mellitus with juvenile onset among Japanese population. The present study demonstrated that a decreased frequency of HLA-BW52 was a common characteristic shared by the patients with Graves' disease and insulin-dependent diabetes mellitus with juvenile onset among Japanese.


The pathogenesis and significance of menisceal cysts. From a total of 1571 surgically excised menisci, 112 (7.1 per cent) were found by gross and microscopic examination to contain one or more cysts. All of these cysts were associated with tears, either primarily horizontal or with a horizontal component. Tracks were often demonstrable leading from the tear to the cysts, and in some cases of osteoarthritis, detritus of bone could be found in their periphery. It is concluded that the cysts are fuelled by synovial fluid. The relationship of cysts to "myxoid" change of the meniscus is discussed.


[Caecal lymphosarcoma. Prognostic and therapeutic interest of endoscopic diagnosis (author's transl)]. Primary lymphoreticulosarcomas aremare, scarely 0.3% of all malignant lesions of the digestive tract. Previously, only, slight clinical differences permitted differentiation before operation of this lesion from a common adenocarcinoma. Now the increasing use of colonic endoscopy permits one to determine preoperatively the lymphosarcomatous nature of a colonic tumour. Thus it is possible to carry out an appropriate preoperative assessment with lymphography and sternal marrow examination and also peroperative exploration with liver biopsy and lateral aortic lymph node biopsy. Treatment includes surgery, radiotherapy and chemotherapy, a more and more important place being reserved for the latter. Finally the recent histological classification of K. Lennert permits a more accurate prognosis.


Autoclavable ultrahigh-efficiency filter for use with flexible film germfree animal isolators. An autoclavable ultrahigh-efficiency filter unit, which accommodated 99.98% efficient respirator filter cartridges, was built for use with flexible film germfree animal isolators.


[Survey on retrolental fibroplasia in France]. From 1964 to 1976, 20 cases of retrolental fibroplasia were recorded in the south of France while 38 cases were recorded in the north from 1970 to 1977. The more children are immature, the more they are liable to suffer from this disease. Etiological factors are apparently not limited to oxygen, which however plays the most important part in the process.


Total fluoride intake of infants.

Total fluoride intake of infants. The fluoride content of commercially prepared infant foods processed in fluoridated and nonfluoridated plants has been determined. The use of fluoridated water during processing has been shown to increase significantly the fluoride content of certain infant foods. The data obtained have been employed to calculate the minimum and maximum total daily fluoride intake for infants up to 6 months of age. The maximum total daily fluoride intake for infants up to 6 months of age is 0.127 mg of fluoride per kilogram of body weight. An infant consuming human milk or cow's milk and living in a community that does have fluoridated water has a substantially lower total daily fluoride intake.


Lactobezoar in the low-birth-weight infant. Lactobezoar is an unusual complication associated with infant feeding. Seven low-birth-weight infants developed lactobezoars, including one whose case was complicated by gastric perforation. Six of these infants were fed formulas specifically designed for the low-birth-weight infant. Abdominal distention or regurgitation were the most frequent symptoms. The diagnosis was confirmed or made prospectively on supine or cross table lateral chest roentgenograms that included the upper abdomen. Treatment consisted of withholding feeding for 24 hours. There was no recurrence of symptoms following resumption of feedings.


Acute pulmonary blastomycosis in children: clinical course and follow-up. The clinical courses of 14 children with acute pulmonary blastomycosis were studied. All the patients had a remarkably similar illness limited to the lungs with fever, malaise, and respiratory symptoms (cough, sputum production, chest pain, and vomiting). Despite eventual recovery with treatment in all instances, 13 of the 14 children persisted in having abnormal roentgenograms. Three children have demonstrated persistent mild obstructive airway disease for two to 12 months after completion of therapy. These data suggest that the initial illness following childhood infections with Blastomyces dematitidis is usually an acute pulmonary disease without systemic dissemination. Evidence of residual lung abnormalities conflicts with the recent concept of this being a benign, self-limited illness. Our findings suggest the importance of long-term follow-up as well as a need for more complete understanding of the full clinical spectrum and prognosis of acute pulmonary blastomycosis.


National Health Insurance. Physical therapists' attitudes. APTA members living in New England were surveyed by a mail questionnaire to assess their attitudes toward National Health Insurance. Respondents' strata included educators, private practitioners, and clinicians. Generally, respondents believed that National Health Insurance was inevitable, would not cause unnecessary use of physical therapy services, and would not affect the individual therapist's professional freedom. The majority of the respondents judged themselves not well informed about the health plan. Respondents' perceptions of their peers' views of National Health Insurance were inaccurate. Options favored by the respondents under a hypothetical health plan are reported. Results indicate that the physical therapists surveyed generally favored National Health Insurance and thought the APTA should represent them in planning such a program. No significant differences in attitude toward National Health Insurance could be attributed to respondent strata or any of the personal data collected.


An improved radionuclide method for the diagnosis of gastroesophageal reflux and aspiration in children (milk scan). A radionuclide study using technetium-99m-labelled milk feeding is described for the detection of gastroesophageal reflux and aspiration in children. A comparison of findings in 39 patients referred for both radiographic and radionuclide studies showed that barium studies were positive in 25.6% and radionuclide studies in 59% of cases, reflecting the sensitivity of the radionuclide technique. This technique is also physiological and allows prolonged patient monitoring. It is simple to perform and should prove useful in the evaluation of patients suspected of having gastroesophageal reflux and aspiration.


Prevention and treatment of neonatal respiratory distress syndrome. New approaches greatly enhance the physician's ability to assess fetal lung maturation prior to delivery, to understand the processes involved in that maturation, and to anticipate appropriate treatment protocol, all factors contributing to improved mortality and morbidity rates.


Comparison of bioavailability of two dipyridamole formulations. The experiment carried out on 6 volunteers shows a better bioavailability of a 75 mg single oral dose of Persantin (Boehringer) than of the same dose of Curantyl (Germed). The difference is due to the manner in which the dragées are manufactured: the bioavailability of both preparations was the same when the dragées were pulverized before oral administration.