The pharmacology of N-carbamoyl-2-(2,6-dichlorophenyl)acetamidine hydrochloride (LON-954) a new tremorogenic agent. The tremorogenic properties of a series of benzylimidoylurea derivatives are described. The most potent member, N-carbamoyl-2-(2,6-dichlorophenyl) acetamidine hydrochloride (LON-954), produces a reproducible, dose-dependent rest tremor in the mouse with oral doses of 5-100 mg/kg which is also seen in other species (rat, cat, dog, rabbit). The tremor is of constant frequency, rapid onset and short duration. It is not accompanied by akinesia, muscle ridigity, antinociceptive activity, parasympathomimetic effects or marked hypothermia and in these respects differs from tremor produced by oxotremorine. Pretreatment with a microsomal enzyme inhibitor had no effect on the tremor. An LD50 of 165 mg/kg p.o. was calculated in the mouse. After repeated administration both acute and chronic tolerance developed to the tremorogenic effects of LON-954. Evidence for a central site of action is presented, since the tremor could be reproduced following injection of small quantities (50-100 microgram) into the cerebral ventricles of the mouse. Furthermore, the use of spinal, decorticate and and decerebrate rats indicated that although tremor is not of cortical origin, it arises in an area rostral to the inferior colliculi. The mechanism underlying the tremor appears to involve dopaminergic pathways, since the action of LON-954 was antagonised by L-dopa and apomorphine and potentiated by pimozide. Atropine and carbachol were without effect. It is suggested that LON-954 could be used as an alternative to oxotremorine for the detection of anti-Parkinson drugs, particularly those exerting their effects through dopaminergic mechanisms.


[Drug influence on the acute thrombophlebitic edema (author's transl)]. The effect of benzopyrones on edema formation in acute thrombophlebitis was investigated in dogs. Thrombophlebitis was produced by the ligation of the femoral vein and the injection of turpentine oil. The benzopyrones delayed edema formation and sped its regression. Protein concentration in lymph and tissue fluid of the edematous extremity was not significantly higher than in the same fluids of the intact limb, and no significant differences were observed in lymphatic and tissue fluid protein concentrations between the treated and untreated animals. It is concluded that the benzopyrones have their main effect on edema in acute thrombophlebitis by causing proteolysis and enhancing the removal of protein from the tissue fluid.


[Development of new antiepileptic agents. III. Anticonvulsant activity of some derivatives of 1-(p-sulfamoylphenyl)-imidazolidinone-5 (author's transl)]. A series of derivatives of 1-(p-sulfamoylphenyl)imidazolidinone-5 were tested for anticonvulsant properties against electroshock and pentylenetetrazole seizures. They were also screened for analgesic, sedative and toxic effects. The substances that had the best anticonvulsant activities were those with halogen substitution in the ortho position of the 1-phenylring of 1-(p-sulfamoylphenyl)-3-phenylimidazolidinone-5. Additional substitutions on the basic structure (imidazolidinone-5) or on the 3-phenylring diminished the anticonvulsant activity. The anticonvulsants are less toxic than diphenylhydantoin. Some of the substances exhibited feeble analgesic and sedative properties.


Biological properties and clinical application of propolis. VII. Investigation of immunogenic properties of ethanol extract of propolis (EEP). Under experimental conditions parenteral administration of ethanol extract of propolis (EEP) solutions to rabbits induced no synthesis of antibodies as investigated by means of ring precipitation, double diffusion gel precipitation and complement fixation test.


Absorption and excretion of 3H-raubasine in human subjects and dogs. The pharmacokinetic behavior of (3,5,6-3H)-raubasine (RAU) was investigated in human subjects after oral administration and in dogs after both intravenous and oral administration. By the oral route RAU peak plasma levels appeared in human subjects after 1 h and in dogs after 2 h. Three-day cumulative urinary excretion was 22% by i.v. route and 13% by oral route in dogs, being 29% in human subjects after oral administration. Three-day cumulative faecal excretion in dogs was 51% by i.v. route and 57% by oral route whilst it was 24% in humans. From a comparison between the urinary excretion values observed after i.v. and oral administration, a RAU intestinal absorption of 59% may be obtained.


[Isolation and structure determination of the metabolites of 2-(1,3-dimethyl-xanthinyl-(7)-methyl)-4-methyl-morpholine--a xantinol derivative--from rat urine (author's transl)]. In the urine of rats the following metabolites of the xantinol derivative 2-(1,3-dimethyl-xanthinyl-(7)-methyl)-4-methyl-morpholine were found: 2-[1,3-dimethyl-xanthinyl-(7)-methyl]-morpholine and 2-[1,3-dimethyl-xanthinyl-(7)-methyl]-4-methyl-morpholin-5-one. These compounds represent about 13.7% of the p.o. applied 2-[1,3-dimethyl-xanthinyl-(7)-methyl]-4-methyl-morpholine. Their structure has been elucidated by IR-, PMR- and mass spectrometry.


Properties of the one-compartmental model with nonlinear elimination. The nonlinear pharmacokinetics applicable to renal excretion is investigated. General solutions are found and simulated concentration-time curves show the effect of various parameters. Equilibrium may or may not exist. An example shows that the additive property of linear pharmacokinetics is no longer valid in the nonlinear case.


[Iteration program for determining pharmacokinetic constants with a digital computer (author's transl)]. An iteration program is reported by which it will be possible to determine the constants k1 and y0 by the graphical constants tmax and k2. The program is designed for the desk-calculator HP 97. It makes a relatively exact determination of k1 and of y0 possible. By using these constants in the function of Bateman, the latter may be better defined than it would be possible by k1 determined from graphs. Furthermore application of this program saves drawing blood samples within the period of t0--tmax.


[Comparative study on the saluretic activity of etacrynic acid and BAY g 2821 in patients with cardiac decompensation (author's transl)]. In a randomised double-blind comparative study 40 mg 3-amino-1-(3,4-dichloro-alpha-methyl-benzyl)-2-pyrazolin-5-one (BAY g 2821), a novel diuretic agent, were tested against 50 mg etacrynic acid in patients with cardiac decompensation. BAY g 2821 has a rapid onset of action which slowly decreases until 12 h after administration. Within a period between the second and the fourth hour after administration, the efficacy of BAY g 2821 is superior to that of etacrynic acid. The difference is statistically significant. The total elimination of BAY g 2821 is markedly more pronounced than that of etacrynic acid throughout the 5-day treatment course. Neither subjective nor objective side effects were observed.


[Azapropazone plasma levels under simultaneous treatment with an antacid or laxative]. Azapropazone is a non-steroid antirheumatic drug, commonly used in long-term treatment of inflammatory and non-inflammatory rheumatic diseases. Since antacids and laxatives are often taken simultaneously the present study was concerned with the influence of a concomitant treatment with medium doses of dihydroxy-aluminium sodium carbonate, magnesium aluminum silicate, bisacodyl and anthraquinone cathartics on steady-state plasma levels of azapropazone when azapropazone was given as an oral dose 3 times daily to 15 patients. Azapropazone plasma levels were determined 5 h after azapropazone administration by a direct quantitative thin-layer chromatographic method. Azapropazone plasma levels during simultaneous treatment with antacids were 70.3 +/- 14.1 microgram/ml in comparison to 75.4 +/- 16.5 microgram/ml after azapropazone alone (p = 0.10). After the administration of the laxatives a mean plasma concentration of 68.2 +/- 10.1 microgram/ml was obtained, without laxative the average plasma level of azapropazone accounted for 65.1 +/- 8.1 microgram/ml (p greater than 0.05). There were virtually no effects of simultaneous treatment on azapropazone plasma levels. The results suggest that azapropazone can be given together with antacids and laxatives since there is no significant interaction.


[The influence of thiaminedisulfide monoorotate on the human memory (author's transl)]. Thiaminedisulfide monoorotate, which is easily soluble in water under neutral to weakly acidic reaction was studied for its possible positive influence on the human memory. The results indicate a significant improvement.


Calorimetric, 13C NMR, and 31P NMR studies on the interaction of some phenothiazine derivatives with dipalmitoyl phosphatidylcholine model membranes. 1. The dipalmitoyl phosphatidylcholine/water system was employed to study the interaction of phenothiazines with model membranes. In particular the effects of the drugs upon the lipid phase transition were examined using differential scanning calorimetry and NMR spectroscopy. The studied phenothiazines have peripheral (diethazine) or central (chlorpromazine) properties. 2. Both drugs were observed to lower the phase transition temperature of dipalmitoyl phosphatidylcholine. The molar activity of chlorpromazine is somewhat higher than of diethazine. At low concentrations the drugs affect the dipalmitoyl phosphatidylcholine pretransition endotherm. 3. In the 13C NMR spectra of the drug-containing samples the signal of the trimethylammonium group of dipalmitoyl phosphatidylcholine is broadened, whereas a narrowing of the signal of the fatty-acid chain methylene groups is observed. Further, addition of the phenothiazines causes higher values of the effective chemical shift anisotropy of the 31P in the phosphate group, in comparison to the pure dipalmitoyl phosphatidylcholine sample. 4. The results obtained by three different techniques indicate a higher fluidity in the fatty-acid chain region and a mobility reduction of the polar headgroup of the dipalmitoyl phosphatidylcholine molecules in the presence of the phenothiazines. These phenomena can be well accounted for by a model for the incorporation of the phenothiazines in the dipalmitoyl phosphatidyl-choline bilayer, in which the dialkylaminoalkyl chains are located near the polar headgroups and the ring system does not penetrate far beyond the glycerol backbone into the hydrocarbon phase.


Effect of irradiation on the erythrocyte membranes of homozygous Gunn rat sucklings. Erythrocyte membranes were isolated from irradiated Gunn's strain of jaundiced rat sucklings, and photodynamic action of bilirubin in vivo was investigated using sodium dodecyl sulfate-polyacrylamide-gel electrophoresis. The effectiveness of irradiation was verified in terms of decrease of plasma bilirubin concentrations and cerebellar bilirubin contents, and also by recovery from the cellbellar hypoplasia, a characteristic feature of the homozygotes (j/j). The cross-linking of erythrocyte membrane proteins by photodynamic action of bilirubin was demonstrated in vitro in rat erythrocytes as reported for human erythrocytes by Girotti (Biochemistry 14: 3377, 1975). The phenomenon, however, was not observed in vivo. Instead, a protein band with a mol. wt. of 32,000 was increased by the irradiation both in the homozygous (j/j) and heterozygous (j/+) Gunn rats.


Integration of modern data in W.H.O. categorisation of lymphosarcomas. Its value for prognosis prediction and therapeutic adaptation to prognosis. The categorisation of lymphosarcomas with immune markers has enriched the prognostic value of W.H.O. classification. The prolymphocytic (centrofollicular B type and the null lymphoblastic subtype have a good prognosis while the (T or B) immunoblastic type and the T-lymphoblastic subtype have a poor prognosis.


[State of pulmonary surfactant in different species of animals]. The authors have shown that pulmonary surfactand activity in mice, rats, guinea pigs, hamsters, rabbits and dogs was within the normal limits with the fluctation of the air vesicle stability coefficient of from 0.84 to 0.93. Differences revealed in the surface active substance in different animal species depend on the frequency, expression and the nature of spontaneous pulmonary pathology. The data obtained can be used as the initial ones to study the surface pulmonary activity system under various experimentally-induced conditions of the pulmonary tissue.


How suitable are available pharmaceuticals for the treatment of sexually transmitted diseases? (2) Conditions presenting as sores or tumours. The pharmaceutical industry is not supplying the penicillin preparations that are required for the treatment of syphilis. For those in whom penicillin hypersensitivity is suspected there is a need for a safe injectable alternative that is effective if given once daily or, preferably, at two- or three-day intervals. Existing treatments for chancroid, lymphogranuloma venereum, and granuloma inguinale are described, but even collectively there are few cases and treatments for other sexually transmitted diseases merit priority. Treatments for scabies and pediculosis pubis, although not perfect, are reasonable. There is a need for better local treatment for condylomata acuminata and systemic immunological methods, including those that increase cell-mediated immunity, deserve attention. The same is true for molluscum contagiosum. There is an urgent need for an effective, safe treatment of herpes genitalis that is able to eradicate the virus from the host. If it is proved that the herpes virus is responsible for carcinoma of the cervix this could then be the most serious sexually transmitted disease as in many countries such carcinomas are responsible for approximate seven times more deaths in women than is syphilis in men and women together. The limitations of prophylactic methods in preventing all possibility of infection with one or more of the sexually transmitted diseases are discussed.


Hepatitis-B surface antigen and antibody in Black and White patients with venereal diseases. The prevalence of both the hepatitis-B surface antigen (HBsAg) and its specific antibody (anti-HBs) was significantly greater in the sera of White patients suffering from sexually transmitted diseases than that in White blood donors. However, Black patients with venereal diseases did not show an increased prevalence of either HBsAg or anti-HBs. These findings support the view that heterosexual transmission of the hepatitis-B virus is less likely to occur in populations in whom this infection is largely acquired before the age of sexual maturity.


Combination versus successive single agent chemotherapy in lymphocytic lymphoma. Fifty-three patients with advanced lymphocytic lymphoma were randomly assigned to treatment with the combination cyclophosphamide, vincristine, and prednisone (CVP) or the same agents used successively in maximal doses (C-V-P). Complete remissions occurred in 68% with CVP and 48% with C-V-P. For patients with nodular lymphoma, the complete remission rate was 81% with CVP and 46% with C-V-P. In patients with diffuse lymphoma a complete remission rate of 50% was obtained with both regimens. The median duration of response was longer for patients who obtained complete remission with CVP (37+ months) than for those entering remission with C-V-P (25+ months). More patients treated with CVP still survive. Current results suggest that CVP is a better induction regime than C-V-P in patients with nodular lymphoma. However, in patients with diffuse lympoocytic lymphoma, neither regimen results in more than 50% complete remissions or significant numbers of prolonged responses. More effective therapy is needed.


The lymph node in chronic lymphocytic leukemia. Lymph nodes were examined from 41 cases of typical chronic lymphocytic leukemia (CLL). Degree of immaturity was graded as absent to minimal (Grade I), moderate (Grade II) and marked (Grade III). A moderate degree of immaturity was found in the lymph node in 14 of 41 cases even though the cells seen on the initial bone marrow and peripheral blood smears obtained from these patients were essentially all mature. The morphology of these nodes could be confused with poorly differentiated lymphocytic or mixed lymphocytic-histiocytic lymphoma in terms of the degree of immaturity present. A marked degree of immaturity present. A marked degree of immaturity was found in 5 cases; the morphology of these cases resembled histiocytic lymphoma. In the remaining 22 cases immaturity was essentially absent. The morphology of these cases was similar to that of diffuse well differentiated lymphocytic lymphoma. Our studies suggest that a moderate degree of immaturity in the lymph node of patients with CLL does not indicate that these patients will have a marked shortening of their survival.


The diagnosis of hypersensitivity to ingested foods. Reliability of skin prick testing and the radioallergosorbent test with different materials. The diagnostic reliability in food allergy of skin prick tests (SPT) and the radio-allergosorbent test (RAST) was investigated in paediatric patients with respiratory and skin allergies. SPT and RAST were found to be reliable for the diagnosis of allergy to codfish, peas, nuts, peanuts and egg white. Positive SPT and RAST to cereals were common, but were most often without clinical significance or were correlated with respiratory allergy to the inhalation of flour dust. SPT and RAST were only partly reliable with regard to allergy to cow's milk, and were mostly reliable when used together and showing corresponding results. Experimental allergosorbents for RAST with soy beans and white beans were not reliable. The study shows the need to improve the diagnostic materials and to establish the diagnostic reliability of the material and tests used for each food item in question.


Lymphocytotoxic antibodies in patients with inflammatory bowel disease and their spouses--evidence for a transmissible agent. Serum lymphocytotoxic antibodies (LCA) were detected in twenty-seven out of fifty-three (51%) patients with inflammatory bowel disease (IBD) and in twenty-three out of their fifty-three (43%) unaffected spouses. The prevalence of LCA in both groups was significantly increased (P less than 0.001) compared to that in age- and sex-matched controls (11%) or in control spouses (6%). Concordant expression of LCA occurred in sixteen out of the fifty-three (30%) patient-spouse pairs compared to only one out of the fifty-three (2%) control-spouse pairs (P less than 0.001). In contrast to the LCA results, heterophile antibody titres were similarly distributed in all four study groups. It is suggested that LCA may represent markers of infectious agents in IBD and that their occurrence in unaffected close contacts of patients may indicate transmission of such agents to these subjects.


Contact dermatitis in the West of Scotland. Since 1970, more than 4,500 patients have been patch tested at the Contact Dermatitis Investigation Unit in Glasgow. The results of 1,312 patients patch tested to the 20 test substances as described by the ICDRG (Fregert et al. 1969) are presented. The data on frequency of the most common allergens observed are presented. The most common allergens observed are nickel, chromium, cobalt, neomycin, colophony, wool alcohols, balsam of Peru and rubber. The less common allergens are benzocaine, parabens, formaldehyde and turpentine.


[Cytological studies of sputum and bronchial secretions (author's transl)]. Cytological diagnosis was achieved in 89 of 206 (43.2%) malignant lung tumours verified histologically. The quality of cytological material, number of examinations, tumour size and differentiation, as well as careful handling of the material and experience of the cytologist, all influenced the rate of false-negative results. Cytological examination of sputum and bronchial secretions gave a higher rate of detecting malignant lung tumours than histological examination of material obtained by bronchoscopy.


A fluorescence approach of the determination of translational diffusion coefficients of lipids in phospholipid monolayer at the air-water interface. In the present work, it is shown that the photobleaching technique as well as experimentation based on fluorescence recovery after bleaching can be extended to monolayers spread at the air-water interface. A mathematical model is derived which allows the determination of translational diffusion coefficients of species diffusing in such a system. Using 12-(9-anthroyl)stearic acid (anthroylstearate) as a fluorescent probe, dispersed either in dipalmitoylphosphatidylcholine or in dipalmitoylphosphatidylglycerol in various conditions of subphase ionic composition and surface pressure of the monolayer, including phase transition domains, we are led to the following conclusions: 1. Anthroylstearate molecules seem to aggregate in 'microdomains' where their fluorescence properties remain unchanged regardless of the compression states of the host monolayer. 2. In any case, a break in the diffusion constants appears on compressing films of both dipalmitoylphosphatidylcholine and dipalmitoylphosphatidylglycerol. In particular, this break coincides with the liquid expanded to gel phase transition of these lipids when it occurs. 3. Diffusion of anthroylstearate in dipalmitoylphosphatidylglycerol depends strongly on the subphase ionic strength and on the nature of cations: Na+, Mg2+, Ca2+.


Contraceptive efficacy determination by postcoital testing. A new vaginal contraceptive method that offers the ease of use with none of the potentially harmful physiologic effects of hormonal contraception was subjected to direct in vivo tests of its efficacy in immobilizing spermatozoa and preventing their entry into the cervical canal. The new contraceptive, a small avoid only 2.8 cm long and 1.4 cm wide, is easily inserted into the vagina without the need for special applicators. It offers protection through the delivery of a highly effective spermicide by the effervescent formation of foam that disperses over the uterine opening. In the trials, no motile spermatozoa could be found in any samples obtained from the vagina, the os externum, or the cervical canal immediately after intercouse protected with the new agent. In no case were any sperm, even immotile sperm, observed in the cervical canal. By contrast, examination of 30 samples obtained immediately after coitus protected with another contraceptive agent (used as a control) revealed motile spermatozao in the cervical canal in nine cases, and propulsive motility was seen on five occasions. The new contraceptive proved highly effective in preventing conception.


[Long term follow-up after thyroidectomy]. Surgically treated Graves' patients should be submitted to long-term follow-up in order to detect early hypothyroidism, as well as relapses of hyperthyroidism which are not exceptional. The aim of the prolonged care after thyroidectomy for non toxic goiter is to detect a recurrence of the goiter and to control the prophylactic administration of thyroid hormones which should be prescribed in most cases. The follow-up after surgery for thyroid carcinoma depends on the histology of the tumor and on the type of postsurgical treatment.


Role of autonomic nervous system controlling surface tension in fetal rabbit lungs. After the maternal abdomen was opened under methoxyflurane anesthesia, fetal rabbits of 27.5 days gestation were given injections through the intact uterine wall of saline, pilocarpine, isoxsuprine, muscarine, phenylephrine, atropine, phenoxybenzamine, or propranolo, alone or in appropriate combinations. Fetal rabbits were delivered by hysterotomy and killed without breathing 2.5 h later. Static pressure-volume curves with air showed improved retention on deflation in fetal rabbits that had injections of pilocarpine, or isoxsuprine, but not of muscarine or phenylephrine. The effect of pilocarpine on the pressure-volume curve was blocked by atropine, phenoxybenzamine, and propranolol, and the effect of isoxsuprine was blocked by propranolol but not phenoxybenzamine. The data suggest that pilocarpine produces secretion of surfactant into lung air spaces by exciting the sympathetic nervous system, a known function of pilocarpine, rather than the parasympathetic nervous system. This may result in stimulation of the same beta-adrenergic receptors affected by isoxsuprine which is also thought to stimulate surfactant secretion.


Pes anserinus transposition for chronic anteromedial rotational instability of the knee. Forty-eight men and three women were reviewed an average of thirty-one months after pes anserinus transposition for chronic anteromedial rotational instability of the knee. Their ages ranged from eighteen to forty-two years (average twenty-five years). All but four of the injuries occurred during sport. The interval between injury and operation averaged thirty months. During this time twenty-three patients had had other operations of which eighteen were for excision of menisci. A further sixteen patients required excision of one or both menisci at the time of pes anserinus transposition. After operation large haematomata had to be expressed from four wounds. One patient had a pulmonary embolism All made a complete recovery. Worthwhile improvement of stability during activity was found in forty-two of the fifty-one knees. Pre-existing degeneration of articular cartilage associated with severe instability of long duration was the main cause of failure. Good motivation was important for success. Four grades of disability are described according to the severity of symptoms. It was found that a successful operation gave approximately one grade of improvement on this scale. Arthroscopy is recommended to identify torn menisci and degenerative changes before pes anserinus transposition is undertaken. An important advantage of this operation is its simplicity. When more elaborate ligamentous reconstructions are necessary for severe instability, pes anserinus transposition can be usefully added to complete the repair.


Infant feeding practices in East Harlem. Infant feeding practices among low-income infants in East Harlem were surveyed prior to undertaking a nutrition education program. Data were obtained from 24-hr. recalls on 153 infants seen in a well-baby clinic. Intakes of energy, protein, fat, ascorbic acid, iron, and sodium showed wide variations among infants of similar ages. Nutrient intakes were similar for black and Puerto Rican infants, although some ethnic differences were observed in the types of milk and solid foods consumed. Black infants received formula for a longer period, while Puerto Rican infants were transferred to whole cow's milk at a younger age. In contrast black infants were introduced to table foods earlier.


Early physiologic and biochemical effects of thoracic X-irradiation on the pulmonary surfactant system. A study of surfactant physiology and biochemistry was undertaken in mice who received varying doses of X-irradiation to the thorax. During the first 12 weeks after X-irradiation, the period which precedes radiation pneumonitis, there is an increase in the amount of DPC in both the lung and the alveolar surface lining layer. This increase begins about 7 days after irradiation, returns to control levels by 12 weeks, and coincides with a fall in the total number of AM's. Over-all synthesis of DPC in the lung and its transport to the alveolar surface, as determined by incorporation of 3H from glycerol and 14C from palmitate into PC in vivo, remained unchanged from control levels. These results may be explained in part by proliferation of type 2 pneumocytes following X-irradiation and by decreased removal of surfactant from the alveolar surface, possibly as a result of the depletion of the AM population. No changes in mechanical properties of the lung or in situ E tis or E surf occurred at this stage, nor were changes detected in the surface properties of the alveolar lavage fluid.


The minimum cottonseed protein required for nitrogen balance in women. This study was designed to assess minimum amount of nitrogen from deglanded (LCP) and glandless (GSF) cottonseed protein required to maintain nitrogen balance in young adult women. Fourteen women aged 19 to 25 were divided into two groups, one group was fed LCP and the other GSF in a purified formula diet for the entire study. The protein level constituted approximately 15% of the total energy intake initially. After reaching and maintaining equilibrium, the protein level for each subject was decreased until that lowest level was found that would maintain the individual in nitrogen balance. Nitrogen status was calculated using the formula: Nitrogen Status = N Intake--N Output (Urinary + Fecal + other Obligatory Loss). Regression data for each subject was used to define nitrogen intake required to maintain equilibrium. The nitrogen intakes showed similar results for the two forms of cottonseed with a mean value of 0.106 g N per kg body weight to maintain equilibrium. The quality of cottonseed protein was between reported values in men for soybean and wheat protein.


[The effect of intravenous prostaglandin F 2 alpha on the motility of the gastrointestinal tracts after major abdominal surgery (author's transl)]. TThe effect of prostaglandin F 2 alpha was studied clinically and electromyographically on the motility of the gastric antrum, duodenum, jejunum, ileum and transverse colon in 20 patients by giving 2 hours intravenous drip infusion at 0.3 approximately 0.5 microgram/kg/min for 2 hours after major abdominal surgery. Folling results were obtained. 1. The motility of stomach and colon was least active than any other site of alimentary tract during 48 hours after surgery. This seems to be one of the most important causes of so called postoperative ileus. 2. Recovery from reflex inhibition of motility of the alimentary tract after surgery was seen in duodenum at first, and then in jejunum and ileum in order. It was proved that intravenous drip infusion of PGF 2 alpha at 0.3 approximately 0.5 microgram/kg/min for 2 hours had produced the increase of electrical activity in any site of gastrointestinal tract and subsequently brought about increasing of propulsive movement. The effect of PGF 2 alpha is proportional to its concentration. 4. tit was concluded that PGF 2 alpha could be administered most effectively by intravvenous drip infusion at 0.5 microgram/kg/min 3 times daily for 3 days after surgery for the satisfactory recovery from the postoperative ileus, and no appreciable side effect was observed.


Rationalisation and modification of a germ-free isolator design. A modified design of polyvinyl chloride isolator, suitable for small laboratory animals utilises room space more effectively than previous models and is particularly useful where accommodation is restricted. The standard attachments and ancillary equipment used with other flexible isolators are compatible with the modified isolator.


[Identification of thyroglobulin-binding cells in the blood of Hashimoto patients (author's transl)]. We developed a new method for demonstration and enumeration of antigen-binding cells, the principle and application of this method is demonstrated using peripheral blood lymphoid cells from Hashimoto patients, non-Hashimoto, non Graves' disease goiter patients and in patients without thyroid disease. A significantly higher number of thyroglobulin-binding cells was observed in the peripheral blood of Hashimoto patients as compared to members of the two other groups. The results of the FICA-tests were compared to conventional serological data of the individual patients.


[Hydrocortisone for the treatment of cerebral vasopasm--(1) experiments in dogs (author's transl)]. The usefulness of hydrocortisone for the treatment of cerebral vasospasm was investigated using dogs by measuring changes in cerebral arterial diameter in angiograms as well as in other parameters such as blood pressure, intracranial pressure and CBF. The intrathecal (50-300 mg) or intravenous (100 mg/kg) injection of hydrocortisone resulted in a marked dilatation of cerebral arteries both in control animals and vasospastic animals after subarachnoid hemorrhage. The intrathecal injection caused a temporary rise in blood pressure immediately following the injection. Cerebrospinal fluid pressure was increased progressively. On the other hand, the intravenous injection resulted in a fall in blood pressure and a transient rise in cerebrospinal fluid pressure. CBF showed a tendency to increase both with intrathecal and intravenous injection. With intravenous injection a high CSF level of cortisol was found 1 and 2 hours after the injection and it was correlated to the degree of cerebral arterial dilatation, indicating that a significant amount of hydrocortisone could penetrate into the CSF and dilate the intracranial vessels by its direct pharmacological action.


[A case of malignant lymphoma (lymphosarcomatous type) of the brain (author's transl)]. A relatively rare case of malignant lymphoma of the brain was reported. A 64-year-old male was admitted to our hospital, October 2, 1976, complaining of right hemiparesis and expressive aphasia. Neurological and radiological examinations revealed a huge space-occupying lesion in the left frontoparietal region. An external decompressive surgery and biopsy were performed. The excised specimens was diagnosed as malignant lymphoma (lymphosarcoma type) histologically. Radiation (5000 rad of 60Co) and chemotherapy with anticancer drugs were carried out after the operation. The patient, however, died at seven months after the onset. On necropsy the tumor was infiltrated extensively in the left frontal, parietal, temporal and occipital lobes, but extended not to the thalamus, basal ganglia and ventricular system. This case was suggested primary malignant lymphoma of the brain, according to the physical and radiological examinations of the whole body, although the autopsy was performed only about the brain. The nomenclature, clinicopathological and immunological problems of malignant lymphomas of the nervous system were also discussed, reviewing the previously reported cases.


Isolation and characterization of proteins associated with the lung surfactant system. Rabbit lung washings and purified lung surfactant were delipidated without precipitation or loss of protein. This enabled effective study of the proteins by electrophoretic and immunoelectrophoretic techniques. The lung washings contained secretory immunoglobulin A and several serum proteins. The protein composition of purified lung surfactant was the same as the unfractionated lung washings confirming our previous study which indicated that there is no specific protein associated with surfactant phospholipids obtained by alveolar lavage with isotonic saline.


The role of alveolar recruitment and de-recruitment in pressure-volume hysteresis in lungs. Gil and Weibel (1972) have demonstrated the importance of alveolar recruitment at relatively low inflating pressures, which has also been noted by Klingele and Staub (1970). These findings are incorporated into a model of alveolar mechanics which presents a possible solution to the questions concerning the classical theory of PV hysteresis which are raised by the mercury filled lung and the Tween 20 rinsed lung experiments. A mathematical model was used to test the hypotheses and curves consistent with the experimental data are generated by a small computer. It is concluded that according to the model, the classical theory of PV hysteresis is valid under normal physiologic conditions but alveolar recruitment and de-recruitment become important factors in alveolar mechanics under conditions of alveolar instability.


Studies in chronic lymphocytic leukaemia. The kinetics of 51Cr-labelled lymphocytes. 1. 9 Studies of lymphocyte transport are reported in which the 51Cr labelling technique of Hersey (1971) was employed on 8 patients with chronic lymphocytic leukaemia (CLL) and 1 with lymphosarcoma. 2. A new approach to the analysis of the data was formulated employing the principles of impulse analysis. This allowed the quantitation of cell transport between various locations making the minimum number of assumptions. It was also possible to take account of the principal defect of this label, its tendency to elute from live cells. 3. In spite of marked lymphocytosis, numbers of cells moving between those tissues whose lymphocytes exchange relatively slowly and the bloodstream was found to be normal. The blood and lymph nodes may therefore accumulate lymphocytes in response to a transport defect which hinders the progress of these cells from one pool to another. 4. The finding that CLL lymphocytes fluxes are normal in certain locations casts doubt on the hypothesis that lymphocyte proliferation is uncontrolled in this disease. An alternative possibility is that cell proliferation is regulated so as to maintain these fluxes within the normal range.


Filter columns for preparation of leukocyte-poor blood for transfusion. Filter columns (Imugard filters) packed with cotton wool prepared from Gossypium barbadense cotton removed 95--100% of leukocytes from packed red cell suspensions. Recovery of red cells was about 95%. The efficacy was similar for ACD and heparinized blood. Blood was filtered below 10 degrees C within 30 min under pressures of less than 0.2 kg/cm2. The shape and functions of the red cells were not altered by filtration. No pyrogenic or toxic substances, and little particulate matter were eluted from the filters.


[The palmitic/stearic acid ratio (P/S) in amniotic fluid for the determination of fetal lung maturity. The advantages of a simplified analysis by gas-liquid chromatography (author's transl)]. The assessment of fetal lung maturity in amniotic fluid is of undisputed usefulness but still not available to all centers caring for high risk pregnancies. This is mainly due to laboratory problems. In search of a rapid and reliable method which can also be used for analysis of mailed specimens, we found the determination of the P/S ratio by gas-liquid chromatography very useful. The detailed procedure of a simplified P/S determination is presented. This method can be introduced with reasonable effort by any larger hospital. Smaller departments can send amniotic fluid specimens to an external laboratory. P/S ratios proved stable during an incubation of amniotic fluid at room temperature for two days.


[Clinical experience with the chemotherapy of gynecologic cancer]. The report is given about the experiences with chemotherapy of gynecological cancer. The best results were achieved with the long time prolonged therapy of the ovarian cancer. Very good results were registered by the stages III. and IV. of cervix uteri cancer and by all recurrencies of the stages I. and II. of cervical carcinoma. By all cases of advanced corpus uteri cancer and its recurrencies was used systematically chemotherapy.


Cord serum prolactin in relation to the time of the day, the sex of the neonate and the birth weight. Serum prolactin was measured in 581 blood samples collected immediately after birth from 563 single new-born and from 9 pairs of twins. Cord serum prolactin is high at birth: the mean level is some 5 times higher than in adults. There is no sex difference in cord serum prolactin concentration in the neonate. Mean serum prolactin is significantly higher at 1.00 and 2.00 a.m. Thus a circadian periodicity in serum prolactin concentration seems to appear already during foetal life well before the organization of sleep rhythm. Cord serum prolactin increases with birth weight ranging from 1500 g to 3500 g. Thus, the control of levels of circulating prolactin changes during foetal life resulting in a progressive increase starting from mid-pregnancy. Mean cord serum prolactin at birth is lower in twins than in single new-borns. There is no significant difference in serum prolactin between the first and the second twin.


Determination of luteinizing hormone in bovine blood by radioligand receptor assay and comparison with radioimmunological evaluation. A sensitive and specific radioligand receptor assay (RRA) using rat testis homogenate as the receptor source is described for measurement of luteinizing hormone (LH) in bovine blood. Interfering and non-specific substances in blood were removed by means of ion-exchange chromatography on CM-Sephadex C-50. Criteria of validation such as recovery of added LH to plasma or serum, reproducibility, and specificity gave good results. Inhibition curves obtained with bovine plasma and serum were parallel to those obtained with the bovine standard preparation. The range of the dose-response curve was between 0.5-20 ng of bovine LH. The pattern of LH concentrations in purified serum samples under different physiological conditions such as during the oestrus cycle and after administration of GnRH showed a very close correlation whether measured by means of radioimmunoassay (RIA) or receptor assay. Values of RRA-LH were consistently higher than those of RIA-LH. Thus the lower the RIA-LH levels, the more pronounced were the discrepancies between results of both assay systems. The mean ratio of RRA-LH/RIA-LH for basal levels (less than 1 ng RIA-LH/ml plasma) was 17.8 as compared to a mean ratio for higher peak values (more than 20 ng RIA-LH/ml plasma) of only 1.2.


Radioimmunoassay of 3,3',5'-triiodothyronine (reverse T3) on small reusable sephadex columns. A simple radioimmunoassay for serum reverse triiodothyronine on small reusable Sephadex G 25 fine columns has been developed. The assay was unaffected by serum volumes of up to 100 microliter. The recovery of reverse T3 added to serum was in the mean 98.3 +/- SEM 3.2% and the coefficient of variation within and between assay determinations 5.4% and 7.5%, respectively. The detection limit was 2.2 pg reverse T3/column. Serum reverse T3 in 58 euthyroid controls was in mean 48 +/- SD 9 ng/100 ml, and was positively correlated to age (P less than 0.001). No overlap was found between the control group, and the hypo- and hyperthyroid group respectively. Three patients with T3-toxicosis had a normal serum rT3.


Iodoamino acid composition of poorly iodinated human thyroglobulin fractionated by isopycnic centrifugation. The distribution of iodotyrosines and iodothyroinines has been studied in poorly iodinated 19 S thyroglobulins isolated by sucrose gradient centrifugation from five human thyroid tissue. The 19 S thyroglobulins have been fractionated by isopycnic centrifugation and 34.5% rubidium chloride gradient. The distribution of iodoamino acids depends on the total iodine content of each fraction. The variations in MIT) and DIT residues with increasing levels of iodination are not identical, the elevation of DIT residues being higher than that of MIT. The number of T4 residues increases quite rapidly after 5 atoms of iodine while T3 increases slightly and slowly. It is shown here that, even after fractionation of poorly iodinated thyroglobulin, the synthesis of thyroid hormones is observed at a level of iodine content as low as 1.4 and 1.8 atoms per molecule of thyroglobulin. This shows that the thyroglobulin fractions obtained by isopycnic centrifugation are still heterogeneous, although less than the initial non-fractionated thyroglobulin. In order to explain our data, it must be admitted that a large proportion of thyroglobulin molecules are not iodinated.


The relationship between circulating free and bound insulin, insulin antibodies, insulin dosage and diabetic control in insulin treated diabetics. Free and bound insulin concentrations, blood glucose and anti-insulin antibody binding characteristics have been determined in 100 insulin treated diabetics; medium serum free insulin was 11 mU/l when fasting and rose to 30 mU/l after the mid-day meal. Significant correlation between blood glucose and serum free (but not bound) insulin was found. No relationship between insulin antibodies and daily insulin dose or diabetic control were found, nor a relationship between free insulin and antibody characteristics.


Inhibition of angiotensin III action by DES-ASP1-,ILEU8-angiotensin II in man. In 5 normal men intravenous infusion of 600 ng/kg/min of des-asp1-ileu8-angiotensin II (AIIIA) inhibited a rise in blood pressure as well as increase in plasma aldosterone caused by an intravenous infusion of 20 or 100 ng/kg/min of des-asp1-angiotensin II (angiotensin III, AIII). This result and our previous study on simultaneous infusions of 600 ng/kg/min of AIIIA and 20 ng/kg/min of angiotensin II (AII) in the same 5 normal men demonstrate that this dose of AIIIA antagonizes AIII and AII on the adrenal cortex as well as peripheral arterioles and that AIIIA has the same degree of inhibitory effect on the aldosterone-stimulating action of AIII and on that of AII in man.


The effects of arginine vasotocin on pregnant Mare's serum-induced ovulation in the immature female rat. Arginine vasotocin (AVT) treatment (1 microgram/injection) every two hours beginning at 06.00 h on the morning preceding expected ovulation significantly inhibited ovulation in 29-day-old immature female rats treated 2 days earlier with 30 IU of PMS. Pre-ovulatory plasma surges and pituitary decreases in LH, FSH and prolactin as measured by radioimmunoassay were not eliminated by AVT treatment. However, there appeared to be an early rise in plasma FSH in these rats and the maximum plasma LH value attained during the surge period in PMS-treated rats was elevated by AVT treatment. Arginine vasotocin significantly inhibited the increase in ovarian weight which occurs in PMS-treated rats on the day preceding ovulation and uterine weights were consistently depressed in AVT-treated rats. The results of this study indicate that AVT likely inhibits PMS-induced ovulation at the level of the ovary, although the possibility cannot be ruled out that inhibition resulted from the advancement of the plasma FSH rise. These data and other studies investigating the effects of AVT on reproduction indicate that AVT is possibly capable of acting at more than one level of the hypothalamo-hypophyseal-gonadal axis.


Suggestion of abnormal testicular steroidogenesis in some oligospermic men. Androgen biosynthesis in the testis may be analyzed in some detail by means of techniques of in vitro incubation of small testicular biopsy specimens with suitable radiolabelled precursors. Sixty-six tissue specimens from 33 patients who underwent bilateral testicular biopsies because of infertility were incubated in vitro with [3H]pregnenolone in order to investigate the possibility of abnormalities in their steroid biosynthetic activity. As a normal control, testicular tissue obtained by testicular biopsy from a young normal volunteer was used. The distribution of metabolites in the incubates of testes from 8 infertile men differed greatly from the remaining 25 patients and the normal control. The major steroids formed from pregnenolone by the testes of those 8 men were 17-hydroxypregnenolone, dehydroepiandrosterone, 20alpha-dihydropregnenolone and and 20alpha-dihydro-17-hydroxypregnenolone. Very small amounts of delta4-3 oxo products (progesterone, 17-hydroxyprogesterone, androstenedione and testosterone) were formed suggesting a deficiency of 3beta-hydroxy-steroid-dehydrogenase activity in the testes of these 8 men, possibly related to the derangement of their spermatogenic function.


The effect of local testicular irradiation on testicular histology and plasma hormone levels in the male rat. Adult male rats were subjected to local testicular irradiation, plasma hormone levels and testicular histology being quantified at intervals up to 52 days thereafter. LH and FSH increased coincidently with spermatid but not with spermatocyte or spermatogonia depletion. Testosterone levels seemed to decrease but this effect was not significant. Oestradiol levels showed no significant changes. From the correlations between the various parameters it was concluded that the lack of inhibin was the main cause of the increase in both LH and FSH and that spermatids provide the signal for production of this non-steroidal inhibitor. The site of inhibin production was not definitively established but the results would be consistent with production of inhibin by the Sertoli cells in association with spermatids.


Kininase inhibition by glucagon.

Kininase inhibition by glucagon. In vitro glucagon (1-100 microgram/ml) has been shown to inhibit the degradation of bradykinin by kininases present in kidney microsomes and erythrocytes. Glucagon was less active on kininases present in plasma and was inactive on purified pancreatic carboxypeptidase B. In conscious dogs the intravenous infusion of glucagon (10 microgram/min) increased urine flow (160%) and urine kinin excretion (130%) and decreased urine kallikrein excretion (14%). It is suggested that in vivo inhibition of kininases might contribute to the biological effects of glucagon.


Unusual heterozygotes of congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Three otherwise healthy relatives of patients with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency and salt-wasting presented with clinical and/or biochemical findings, which exceeded those usually seen in heterozygotes: Two females (1 mother and 1 prepubertal sister of a patient with CAH) had marked hypertrichosis and hirsutism and excreted pregnanetriolone in their urine. The mother had increased basal plasma 17alpha-OH-progesterone (296 ng/100 ml), which increased to 7170 ng/100 ml after ACTH as in homozygotes of CAH. One adult male (brother of a patient with CAH) was clinically normal, but also excreted pregnanetriolone and had a high plasma 17alpha-OH-progesterone (1905 ng/100 ml), which increased further to 6352 ng/100 ml after ACTH. It is concluded that these subjects represent unusually marked heterozygotes of CAH rather than mild homozygotes. In females, this condition should be included in the differential diagnosis of idiopathic hirsutism, in males, it will pass unnoticed, unless relatives of patients with CAH are systematically tested.


Evidence for extratumoural storage of catecholamines in pheochromocytoma patients. Following the removal of a pheochromocytoma in three female patients the daily excretion of catecholamines and their metabolites was still considerably elevated for about one week. The excretion rates declined during this period with half-lives of 1.8 to 10.9 days for catecholamines and 2.1 to 4.7 days for metanephrines, vanilmandelic acid, and vanilglycol. The cumulative urinary excretion of catecholamines and their metabolites following surgical removal of the tumour was nearly as high as the catecholamine content of the pheochromocytomas. This large amount of catecholamines must have been located outside the tumour, most probably within the sympathetic nerve, where it is subject to release following physiological stimuli. Furthermore, this fact may provide an explanation for hypertensive crises in pheochromocytoma patients.


The metabolism of prostaglandin E2 by tissues from the human uterus and foeto-placental unit. The biosynthesis and metabolism of prostaglandin E2 was studied in cell-free homogenates of tissues from the uterus and foeto-placental unit using specific in vitro methods. The results show that the synthesis of prostaglandin E2 is greater in endometrial tissue from the secretory phase (53.07 +/- 39.05; ng/100 mg wet tissue/h) than from the proliferative phase of the uterine cycle. Furthermore, endometrial tissue forms more of this compound than myometrium (P less than 0.005). During early pregnancy, synthesis is decreased (25.10 +/- 16.62); at term, myometrium produces more prostaglandin E2 than decidua. During labour, however, decidual tissue accumulates more of this compound (52.73 +/- 18.04) than either myometrium (34.71 +/- 13.19) or cord (28.63 +/- 11.71). The catabolic enzymes are most active in the placenta and chorion, followed by the cord, myometrium, decidua and amnion, but the differences have only a slight effect on the amounts of prostaglandin E2 which remain at the end of the incubation. The results suggest a high turnover of prostaglandin E2 in the decidua, myometrium and cord.


Serum-testosterone during oral administration of testosterone in hypogonadal men and transsexual women. Testosterone tablets of crystal size 2-5 micrometer were administered orally for 10 dags to 3 human subjects with low endogenous serum testosterone (se-T) levels. Fifty mg testosterone increased se-T slightly, while one daily dose of 200 mg maintained the se-T level within normal range for men for more than 12h. No cumulative effect was seen. Seven further subjects with low androgen production ingested 100 or 200 mg testosterone of crystal size 125-400 micrometer. Blood samples were taken frequently during the 24 h period following administration of the testosterone and se-T levels determined. Testosterone levels in serum increased in 6 patients and was maintained within the normal male range for 5-7 h. In one subject a slight but significant increase in se-T was observed although the level did not reach the normal male range. Although it has been shown that it is possible to use orally administered testosterone to maintain se-T levels in the normal male range, the convenience to the patient must be balanced against the cost and possible side effects of the large doses required.


Inhibition of testosterone 5 alpha-reductase by and antiandrogenicity of allenic 3-keto-5,10-secosteroids. (4R)-5,10-seco-19-norpregna-4,5-diene-3,10,20-trione(II), A 3-keto-5,10-secosteroid which is an irreversible inhibitor of delta 5-3-ketosteroid isomerase was tested for its possible antiandrogenicity in the hamster flank organ test. The organs of female animals topically treated with 4 microgram of testosterone propionate (TP) for 4 weeks enlarged in size and showed pigmentation resembling adult males. When compound II was applied concomitantly with TP, androgenic stimulation was completely blocked and the flank organs remained small like those of female animals. These results suggest that compound II may be a useful anti-androgen when applied topically. It may well act mainly by inhibition of the formation of 5alphs-reduced metabolites was markedly inhibited.


Reversibility of the effects of cyclophosphamide on collagen: biochemical studies on skin and granulation tissue and determination of thermal stability of tail tendons of rats. Granulation tissue was produced in rats by subcutaneous implantation of viscose cellulose sponges. Treatment with cyclophosphamide in a dose of 10 mg/kg/day for 14 days caused an increase in acid soluble OH-proline and a decrease in alpha/beta ratio of acid soluble collagen of granulation tissue. Forty-two days of continuous cyclophosphamide treatment caused a decrease in dry weight, in free OH-proline, and in salt soluble OH-proline in granulation tissue. These findings are in accordance with previous observations of a decreased collagen synthesis and an inhibited collagen degradation in granulation tissue after cyclophosphamide treatment. In skin, the only change after cyclophosphamide was a decrease in total content of OH-proline and an increase in alpha/beta ratio of acid soluble collagen after 42 days of treatment. No effect of the subcutaneous sponge implantation was observed on the collagen variables in the skin. In comparison with unstarved controls, a reduction in dry weight and in free OH-proline in granulation tissue, as well as an increase in salt soluble OH-proline in the skin were observed 28 days after a 14-day treatment with cyclophosphamide. These observations indicate a sustained effect of cyclophosphamide on collagen 28 days after cessation of treatment. In addition the thermal stability of rat tail tendons was decreased 28 days after withdrawal of cyclophosphamide to the same extent as after starvation for 42 days and after 42 days of continuous cyclophosphamide treatment. It is concluded that the cyclophosphamide-induced collagen alterations, which may be of importance in the anti-inflammatory action of cyclophosphamide, are only in part reversible, 28 days after cessation of 14 days of cyclophosphamide treatment.


Glucose and cation transport in rat jejunum, ileum and colon in vivo: control experiments, and effect of cationic surfactant. Osmotically balanced solutions of glucose (0.5-300 mM) and sodium chloride, containing cetrimonium bromide (cetrimide, 0.8-4.1 mM), were instilled into the jejunum, ileum and colon of anaesthetized rats. Net transport of glucose, sodium and potassium was studied by their disappearance from, or accumulation into the intestinal lumen during 15 min incubation. Cetrimide caused the following shifts in normal jejunal and ileal glucose absorption: At low luminal glucose levels, absorption was strongly depressed and may be converted to net secretion. At intermediate levels, inhibition was less pronounced, and at high luminal glucose levels absorption was enhanced. Similar changes were seen in the colon. Furthermore, cetrimide caused a three-fold change in the regression lines relating net sodium fluxes to the initial sodium concentration: The lines became steeper, the correlation was improved and the sodium concentration value corresponding to zero net transport was elevated. Net potassium secretion was increased. These changes are all consistent with the view that surfactants cause an increase in passive permeability. Quantitatively, the effect of cetrimide increased with localization in the order colon greater than ileum greater than jejunum. Benzalkonium chloride (0.5-1.7 mM) was tested in the ileum only, and caused quite similar effects.


Lithium effect on temperature rhythm in psychiatric patients. The diurnal rhythm of oral temperature was studied in 55 lithium treated patients, 51 other psychiatric patients, and 58 healthy subjects. The lithium treated patients had a higher temperature than the normal controls during the 24-hour period and their temperature maximum was shifted towards an earlier time. When the lithium intake was postponed for 12 hours, temperature temporarily decreased to control values, but returned to the higher level after the lithium dose. The temperature results are discussed in relation to lithium induced changes in electrolyte metabolism.


Excretion of methyl mercury in rat bile: the effect of diethylmaleate, cyclohexene oxide and acrylamide. Diethylmaleate, cyclohexene oxide and acrylamide administered intraperitoneally to rats, have been shown markedly to inhibit biliary excretion of methyl mercury. Simultaneously the sulphhydryl and sulphide content of the bile decreases. These results probably reflect the conjugation of acrylamide, diethylmaleate and cyclohexene oxide to glutathione in the liver, thereby blocking the biliary excretion of methyl mercury. A high concentration of liver glutathione seems to be a prerequisite for the normal translocation of methyl mercury from liver to bile. These results indicate that methyl mercury is transported from liver to bile as a glutathione complex.


Whole blood chromium level and chromium excretion in the rat after zinc chromate inhalation. Studies on absorption and excretion of chromium in the rat exposed to known atmospheric concentrations of zinc chromate in an inhalation chamber and the influence of diurnal variations in physical activity have been carried out. Chromium analyses were performed on samples of blood, urine and faeces using a method for determining chromium in small samples of biological material based on flameless atomic absorption spectrometry. Zinc chromate is absorbed quickly during exposure and excreted mainly via urine. An accumulation of chromium in blood was observed, followed by a slow elimination. It is suggested that chromium from zinc chromate enters the blood in the hexavalent state.


Studies on the duration of local anaesthesia: a possible mechanism for the prolonging effect of dextran on the duration of infiltration anaesthesia. The mechanism of the prolonged effect of dextran on the duration of local anaesthesia has been studied. Using radio-active mepivacaine it was found that dextran prolonged the duration of infiltration anaesthesia in guinea-pigs by delaying the absorption of the local anaesthetic agent. Experiments in vitro indicate that molecular complexes between the local anaesthetic and dextran may be formed and it is assumed that the delayed absorption might be due to the formation of such molecular complexes. This hypothesis was strengthened by experiments in which dental infiltration anaesthesias were performed in healthy volunteers.


Dextran-induced lowering of prekallikrein proactivator and prekallikrein in rat plasma. The intravenous injection into rats of dextran (average MW 70,000) 10 mg/100 g caused marked hypotension after a delay of about 5 minutes. Blood samples collected by cardiac puncture at this time were tested for the amounts of prekallikrein activator (PKA) and kallikrein after acetone- and then kaolin activation of the plasminogen-free plasma. PKA was assayed by measuring the initial rate of release of benzoyl arginine esterase (BAEe) activity in a preparation of partially purified human prekallikrein, and kallikrein was assayed by measuring the BAEe esterase activity. Significant reductions of both parameters were registered, and the amount of high molecular weight kininogen (HMWK) present in the plasma was also reduced. Pretreatment of the rats with epsilon-aminocaproic acid intraperitoneally (200-300 mg/100 g) abolished the dextran-caused decreases in the plasma levels of the above mentioned factors, and reduced the fall in blood pressure. The addition of purified human HMWK to the plasma before the acetone activation procedure was started, increased the yield of PKA activity in the final enzyme preparation. When PKA was assayed after kaolin activation of plasma at 0 degrees using the method developed by Laake & Vennerød (1973a & b) for the determination of PKA (activated factor XII) in human plasma, no differences were registered between plasma from rats treated with dextran and plasma obtained from control rats. It is suggested that the low PKA activity of the acetone activated enzyme preparation from plasma of rats treated with dextran was due to the loss of HMWK or a fraction of HMWK.


Lactose malabsorption among adult Indians of the Great Basin and American Southwest. The prevalence of primary adult lactose malabsorption and the pattern of milk use were studied among 109 Indians from various tribes of the American Great Basin and Southwest. Included were 100 persons who reported being full-blooded Indians as well as three with Mexican admixture and 6 with some European ancestry. Lactose malabsorption was found in 92% of the full-blooded Indians but in only 50% Indians who acknowledged European admixture. These results agree with those of studies of native Americans done elsewhere which show very high prevalences of such lactose malabsorption among adults reported as fullblooded and lower prevalences among individuals with admitted European ancestors. The suggestion made is that in pre-Colombian times, before interbreeding with Europeans began on any scale, such lactose malabsorption may have been nearly universal among native American adults. Most of the Indians studied consumed abundant milk since childhood but were nevertheless predominantly malabsorbers as adults. This argues against the induction hypothesis advanced by some to explain the striking ethnic differences that occur around the world in primary adult lactose malabsorption.


The incidence of urolithiasis in peptic ulcer patients. Two hundred patients suffering from peptic ulcer have been examined for urinary stones. Two hundred healthy controls have been similary studied. In 14 patients from the first group (7%) urinary calculi were found, whereas the percentage in the second group was only 1%. This difference is statistically significant (P less than 0.01) (x2 distribution test). The increased incidence of peptic ulcer was attributed to the consumption of calcium in combination with easily absorbable alkalis (sodium bicarbonate). These findings must be considered in therapy for peptic ulcer diathesis.


Gastric carcinoma 16 years after gastric lymphoma irradiation. A case of gastric carcinoma, occurring 16 years after irradiation for gastric lymphoma, is presented. Factors which may have contributed to gastric carcinogenesis in this patient are discussed.


Ultrasonic evidence of inflammatory thickening and fluid collection within the retrobulbar fascia: the T sign. A case of nonfebrile and nonpyogenic but inflammatory exophthalmos in a 60-year-old woman is presented in illustration of a diagnostic enigma which has previously eluded physical and roentgen examination. With painful limitation of rotation, a less than satisfactory diagnosis of tenonitis or, less commonly, orbital pseudotumor usually has been made. The convenient assistance of contact (nonimmersion) B-scan ultrasound gives objective evidence of fluid within Tenon's space and communicating into the vaginal spaces beneath the optic nerve sheath appearing as homogeneous and echolucent areas. Concurrently there is thickening of the posterior bulbar complex and muscle sheaths evidenced by increased echo density. A definitive finding as the echolucent "T sign" lends substantial and specific basis for clinical management. Rapid improvement in exophthalmos, rotations, and discomfort following oral steroids (without antibiotics) further supports the etiologic concept of both noninfectious and nonendocrine ophthalmopathy. The T sign is suggested as a specific finding, rather than an artifact, differentiating this exophthalmos from neoplastic invasion or thyroidopathy.


The practice of infant feeding among Asian immigrants. Nutritional problems are very common in infants and young children of Asian immigrants; most arise as a result of inadequate weaning. An Asian infant should be weaned onto a diet which takes into consideration his parents' religious and cultural customs which affect diets.


Concurrence of Grave's disease and Hashimoto's thyroiditis. Early histological changes in the thyroid gland were examined in 30 patients with juvenile thyrotoxicosis, by means of needle biopsy. Based on the degree of lymphocytic infiltration and degenerative changes in follicular epithelium, results were classified into four groups. A: hyperplastic changes without cellular infiltration (6 patients, 20%); B: hyperplastic changes with areas of focal thyroiditis less than 30% of specimen (10 patients, 33%); C: those with 30 to 60% areas ot thyroiditis (10 patients, 33%); D: almost diffuse thyroiditis (4 patients, 13%). Moderate to severe lymphocytic thyroiditis was frequently present in the early stage of hyperplastic thyroid glands. The clinical significance of the 4 histological groups was evaluated. Neither clinical signs nor routine laboratory tests could differentiate these groups except group D, in which thyrotoxic signs were mild and transient. However, serum antithyroid antibodies tended to increase in accordance with severity of thyroiditis. The rate of remission was high in groups C and D, whereas relapse was frequent in group A. These results suggest that Grave's disease and chronic lymphocytic thyroiditis are closely related in the early stage of thyrotoxicosis in children, and that the clinical course may be considerably altered by the degree of associated thyroiditis.


Relationship between tubal function, craniofacial morphology and disorder of deglutition. 26 children without hearing impairment have been examined by otolaryngologists and orthodontists. According to the tubal function test in a pressure chamber they were classifed into a group with good and poor tubal function. The E.N.T. examination was unconclusive for a possible relationship between rhinological findings, mode of breathing, sinusitis, size of tonsils, nasal airway resistance and tubal function. Adenoids proved to be a mechanical impairment for active tubal function as stated by many authors. The cephalometric analysis of lateral head films combined with a static and dynamic-functional evaluation of tongue posture revealed significant differences between children with good and poor tubal function. Subjects with a vertical craniofacial growth pattern seem to be predisposed for poor tubal function. Analysing static tongue posture in children with poor tubal function the tongue lies more retracted in a backward position. The back of the tongue is flattened in relation to the palatal arch. In children with good tubal function there is a much closer contact between the back of tongue and the hard palate. Subjects with poor tubal function have an increased incidence of abnormal deglutition combined with tongue-thrust, teeth-apart swallowing, lack of sealing off the anterior oral cavity and contraction of the circumoral musculature. In children with good tubal function one can find the somatic type of swallowing that means no contractions of the circumoral muscles, no tongue-thrust during deglutition but contact of the molars and contraction of the masseter muscle.


[Functional morphology of stria vascularis after treatment with ethacrynic acid or atoxyl (author's transl)]. Surface alterations of the stria vascularis and Reissner's membrane were studied in guinea pigs following intravenous or intraperitoneal administration of ethacrynic acid or atoxyl. DC-potential was measured in the same animals during intoxication. In addition we studied changements in potassium concentration (perilymph, endolymph) of the atoxyl-treated animals.


Basic study of nasal provocative test. Second report: assessment method on provocative reaction. Because no simple and precise method is available to test intensity of the reaction resulted from a nasal provocative test in diagnosis of nasal allergy, comparisons were made among the conventional test methods of rhinoscopy (RS), rhinomanometry (RM) and the carbon powder elimination test (CET) devised by the authors. The rhinoscopy shows high positive rates and has advantages being free from any special equipment, prolonged time or the patients' cooperation, but also had disadvantages such as requirement of skill of examiner and problems in objectivity. The carbon powder elimination test is a preferable method in that it is not only equipped with the advantages of the rhinoscopy but also makes up for its disadvantages, but a disadvantage of CET is requirement of longer time than RS. Rhinomanometry had lower positive rates and requires a special equipment, prolonged time and the skillful patients' cooperation. The disadvantage is that its impracticableness in many patients--26% impracticableness even in adult patients, but the method is fully objective. From these findings the value of Carbon Powder Elimination Test in judging provoked reactions is recognized.


[The objectivation of auditory and optical imaginations in the electroencephalogramm (author's transl)]. This study describes two new DC-potentials, which are related to auditory or optical imagination. The "auditory imagination potential" (AIP) is a negative DC-shift on the vertex lasting during the whole period of an auditory imagination. During an optical imagination there is a similar negative DC-shift in the ocipital region only. These "imagination potentials" can be already recognized in the "raw-EEG" by means of a special experimental technique. The magnitude of amplitudes correlates with the degree of concentration of the subject. In the case of intense imaginations potentials with amplitudes up to 20 muV and a duration of some seconds are recorded. The comparison between the vertex and the occipital lead permits the examination of the alternate occurence of auditory and optical conscious processes. The "imagination potentials" (AIP and OIP) are not related to any external stimulation or motor reaction and represent modality-specific EEG-correlates of cognitive, conscious processes (memory and imagination). Their significance for the "objective audiometry" is discussed.


[Earstructures in one case of anencephalie (author's transl)]. According to the majority of cases under observation the following anomalies could be found: extended, separated or manifold developed crura of the stapes, reduction in the circular windings of the cochlea down to 1 1/2 with a normal development of Corti's organum, reduction of the nerve structures of the nervus cochlearis to a munimum and an open facial canal.


Preliminary report on the effects of hyperoxia on cochlear potential in chinchilla. Anesthestized chinchilla with round window electrodes were placed in a Plexiglas chamber. When they inhaled 100% oxygen at 1 atm, two types of neural effects were observed: 1. fast and reversible AP depression in response to brief exposure to 100% O2; and 2. a slowly developed chronic depression of AP and latency shift due to multiple hyperoxic exposures. The severity of the latter is a function of the dosage of the O2 inhaled, i.e., the concentration of oxygen and the length of time of exposure. For the type-1 effect, carbon dioxide deprivation is felt to be the immediate cause while the type-2 effect is mainly due to O2 toxicity developed at the intracellular level by high O2 concentration. The possible role of superoxide in the auditory O2 toxicity was discussed.


[Activity of parotid isoamylases in the ethionine-treated rat (author's transl)]. In order to investigate the effects of ethionine (an antagonist of the essential amino acid, methionine) on the enzyme synthesis in the rat-parotid gland, rats were fed methionine-deficient diet and treated with DL-ethionine for 4 and 10 days. Compared with the controls, not only the synthesis but also the secretion of parotid isoamylases was impaired by ethionine. Acinar isoamylase activities dropped initially but increased distinctly after 10 days of ethionine treatment, possibly due to intra- as well as extracellular impairment of acinar protein secretion. After another 10 days during which no ethionine was given, the described changes were no longer observed.


[Pendular test and ENG in rabbits (author's transl)]. 25 rabbits are investigated by the pendular test. By an angular acceleration of 90 degrees/s2 the averaged values of the nystagmic parameters are: the amplitude 12 mm, the frequency 8 beats in a half periode, the angle velocity of the slow component 50--60 mm/s and the threshold for the pendular test 2--5 degrees/s2 and the rotationstest 1 degree/s2. There is no vestibular habituation and no fatigue. Always the nystagmic reaction is clear and reproducible.


Salivary gland scintigraphy. Diagnostic verification of parotid saliva flow through the maxillary sinus and nose. The diagnostic value of salivary gland scintigraphy in patients without access to the salivary gland duct orfice is exemplified and discussed. The necessity for careful dental examination and treatment in patients with an oroantral fistula is emphasised.


[The so-called chronic hyperplastic pharyngitis in childhood. A histological screening (author's transl)]. The clinical picture of chronic pharyngitis is well defined but insufficiently clarified as to its morphological nature. In our study of 12 children with chronic pharyngitis who underwent adeno-tonsillectomies small pieces of tissue of the posterior wall of the pharynx were microscopically examined. In most instances inflammatory infiltrations were absent. Present was a variably developed hyperplasia of the lymphatic tissues. In the more pronounced hyperplasias there was a lymphoepithelial disintegration that could account for the clinical manifestations and that perhaps could also be considered as a disposing factor for a bona fide pharyngitis. The micromorphological changes were divided into 4 stages.


[Effect of N'-methyl-N'-beta-chlorethylbenzaldehyde hydrazone on aerobic glycolysis in Ehrlich ascites cells]. N'-Methyl-N'-beta-chloroethylhydrazones are potent inducers of aerobic glycolysis of Ehrlich ascites carcinoma (E.A.) cells without influencing directly the respiration which is reduced only after glycolysis is at its maximum. This induction of glycolysis is not influenced by simultaneous blocking of respiration by potassium cyanide. A primary attack on the cell membrane leading to an increased glucose influx is discussed because of the in vitro inhibition of these beta-chloroethylhydrazones of glyceraldehyde-3-phosphate oxidoreductase.


Inhibition of cholinesterase by epinephrine and norepinephrine. Acetylcholinesterase and monoamine oxidase were found to be inhibited by each other's substrate. The inhibition of acetylcholinesterase by low concentration of epinephrine or norepinephrine was found to follow first-order reaction kinetics. The constants characterising this inhibition, the bimolecular rate ka (51.8 M-1 min-1 for epinephrine and 15.9 M-1 min-1 for norepinephrine) and the enzyme inhibitor dissociation constant (8.52 mM for epinephrine and 12.2 mM norepinephrine) were determined. The inhibition of acetylcholinesterase by epinephrine was found to be of the mixed type while its inhibition by norepinephrine was of the competitive type.


Biological properties and clinical application of propolis. VIII. Experimental observation on the influence of ethanol extract of propolis (EEP) on the regeneration of bone tissue. Artificially induced bone tissue losses after the application of ethanol extract of propolis (EEP) showed an accelerated rate of ossification. The osteogenetic process was just about half as long as in the control group.


[Xanthinol nicotinate and wound healing]. In an experimental study the local effect of i.v. applied xantinol-nicotinate (Complamin) on healing skin incisions in rats was studied. In conclusion, there was a higher ultimate tensile strength of wounds treated by the agent, based on the increased synthesis of collagen fibres. This statement was proved by the alteration of free hydroxyproline in serum. Histologically, there was an intensive vascularization of the wound healing area. Concerning the elastic behaviour we found a more rigid regenerative tissue in the early phases of healing on account of the enhanced thickness of the wound area.


Major pharmacological effects of 6-methoxytetrahydro-beta-carboline, a drug elevating the tissue 5-hydroxytryptamine level. Major pharmacological effects of 6-methoxy-1,2,3,4-tetrahydro-beta-carboline (6-methoxytryptoline, 6-MeOTHBC) are described. It seemed to have a weak effect of its own on 5-HT-receptors. It is concluded that most of the effects, like the increase of rectal temperature after peripheral administration and decrease and then increase after intrahypothalamic application as well as the antagonism of the group toxicity of amphetamine without effect on norepinephrine toxicity or barbiturate sleeping time, can result from the increase of tissue 5-HT-concentration and/or inhibition of 5-HT-uptake.


Inhibition of bile salt excretion and bile flow by spasmolytic drugs. An additional therapeutic effect in the treatment of biliary colics? The influence of the spasmolytic drugs hyoscin-N-butylbromide (HBB, Buscopan) and Extractum opii (E. opii) on bile flow, bile salt and bilirubin excretion is investigated in the cholecystectomized, unanaesthetized pig and compared with the results after acute, quantitative interruption of the enterohepatic circulation (EHC) by biliary drainage. The results demonstrate that HBB and E. opii induce a significant decrease in bile flow and bile salt excretion. A further analysis suggests that this effect is due to an inhibition of intestinal motility and transit time, followed by a delay of the EHC of bile salts with a decrease in biliary bile salt excretion and bile salt dependent bile flow. The results point out a second mechanism that might be responsible for the effectiveness of spasmolytic drugs in the treatment of biliary colics: the lowering of intraluminal pressure by inhibition of bile salt dependent bile flow.


Experiments on the influence of an aromatic retinoid on the chemical carcinogenesis in rats by butyl-butanol-nitrosamine and 1,2-dimethylhydrazine. In male Sprague-Dawley rats it was tested whether the induction of carcinomas of the bladder by butyl-butanol-nitrosamine (BBN) and the induction of carcinomas of the colon by 1,2-dimethylhydrazine (DMH) could be influenced by an aromatic retinoid ethyl-allyl-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate (RO 10-9359). Neither an inhibitory nor an enhancing effect of the retinoid on carcinogenesis was observed.


[Increase in rat liver synthesis of fatty acids and glycerol phospholipids following parenteral application of silybin-dihemisuccinate]. 1. 1 h after i.p. injection of 150.6 mg/kg silybin-dihemisuccinate the synthesis of fatty acids and glycerolipids was studied. 2. Measured as 3H incorporation after i.v. injection of 3H2O the synthesis of fatty acids was enhanced by silybin. Incorporation of [1-14C]-acetic acid in fatty acids of the postmitochondrial supernatant of liver homogenates was not influenced by silybin. The enhanced synthesis of fatty acids seems to be caused by an enhanced concentration of citrate, which was paralleled by a lowered pyruvate concentration and pyruvate-dehydrogenase activity. 3. In liver homogenates of silybin-treated animals the acylation of [U-14C]-glycerol-3-phosphate was increased as a measure of glycerolipid synthesis.


The role of the anterior pituitary gland in progestagen-induced proliferative mammary gland changes in the beagle. Widespread use of the Beagle dog for long-term toxicity studies of hormonal contraceptives including progestagens-only, have resulted in proliferative mammary gland changes. The "tumorigenic potency" of progestagens in the dog has been related to an interaction between progestagens and prolactin (PRL) or growth hormone (GH) secretion. We therefore investigated the effect of a hydroxy-progesterone type progestagen (cyproterone acetate, CPA) and a nortestosterone type progestagen (norethisterone oenanthate) on serum PRL and GH concentrations. Furthermore, the effect of CPA on the GH and PRL producing cells of the anterior pituitary was examined immunoenzyme-cytochemically. Regardless of the structural type of the progestagens tested and the presence of mammary gland enlargement, serum PRL and GH levels were not clearly enhanced. Similarly, the immunoenzyme-cytochemical investigations of the anterior pituitary gland after treatment with CPA showed the PRL cells to be unaffected. In contrast, the GH producing cells exhibited obvious morphological signs of increased secretory activity even before related changes in serum GH concentrations became detectable.


Zipeprol metabolism in man and in the animal. The urinary metabolism of 1-(2-methoxy-2-phenyl)-ethyl-4-(2-hydroxy-3-methoxy-3-phenyl)-propyl-piperazine dihydrochloride (zipeprol) was studied in man, the dog and the rat. Zipeprol metabolites seemed comparable in man and rat. The principal metabolites isolated from urine were identified by TLC, GLC, IR and mass spectrometry. Zipeprol is partially eliminated untransformed from the body, is mainly metabolised by N-dealkylation, oxidation, hydroxylation and methylation.


[Isolation and pharmacodynamic activity of the sesquiterpene valeranone from Nardostachys jatamansi DC]. The known sesquiterpene valeranone (= Yatamanson) was isolated from the subterranian parts of Nardostachys yatamansi (DC). It was pharmacologically investigated in animal experiments of sedative, tranquilizing and antihypertensive properties. In some experiments, typical for tranquilizers, certain activities could be demonstrated such as the prolongation of barbiturate hypnosis, the impairment of rotarod performance, an anticonvulsive activity on electric shock and potentiation of the body-temperature lowering activity of reserpine. In three other pharmacological models an anti-ulcer action was detected. In general the activity of valeranone was lower than those of the standard substances used. As regards the hypotensive property only a weak activity was demonstrated. In toxicological studies on rats and mice an oral LD50 of greater than 3160 mg/kg was found, which suggests the possibility of a therapeutically useful dose ratio.


[Antibiotic concentration in postoperative wound fluid during short-term prevention with cephalosporins]. Antibiotic concentrations were measured in wound fluid from Redon-drains and in serum during short-time prophylaxis in orthopaedic surgery. 1. Chephaloridine and cephazolin concentrations in wound fluid rose to therapeutic levels. 3 h after i.v. application of 1 g concentrations in wound fluid and in serum were nearly identical. 6 and 12 h after application the concentrations in wound fluid were significantly higher than those in the serum. 2. At the end of the 12-h interval of administration the mean concentrations of both antibiotics as well in wound fluid as in serum remained at therapeutic levels. 3. For reasons of their good diffusion into the wounds both cephaloridine and cefazolin should be appropriate for short-time prophylaxis in orthopaedic surgery.


Serum prolactin levels after a single and subchronic oral administration of chlorpromazine and sulpiride. A cross-over study in healthy volunteers. The effect of a single antianxiety dose of chlorpromazine (100 mg) and sulpiride (200 mg) on serum prolactin and gonadotrophins was studied in 6 healthy women in a cross-over study. Another 10 healthy students, 5 women and 5 men, ingested cross-over sulpiride 50 mg t.i.d. for 2 weeks and chlorpromazine 10 mg t.i.d. for 1 week followed by 20 mg t.i.d. for the second week, and serum prolactin levels were measured on the 7th and 14th day after the beginning of the treatment. In acute study sulpiride caused a fivefold increase in serum prolactin at 1 h. Chlorpromazine induced a slower and smaller increase. Prolactin concentrations remained raised for at least 6 h. The initial raised prolactin concentration induced by sulpiride was associated with antidiuresis. The only change in gonadotrophins was the decrease of serum LH caused by chlorpromazine at 3 h. Subchronic administration of sulpiride (50 mg t.i.d.) caused in both sexes a significantly (P less than 0.05 to 0.01) greater increase of prolactin than did chlorpromazine (10 or 20 mg t.i.d.). It is concluded that in doses useful in the treatment of neurotic patients sulpiride causes a greater increase in serum prolactin levels than does chlorpromazine.


[Pharmacokinetics of multilayer vincamine dragees. Study of normal subjects]. The study deals with the bioavailability of a newly developed vincamine multi-layer dragee (Pervincamin forte retard) which showed an extremely continuous release of the active principle in vitro. Furthermore the correlation between half-life and age of the volunteers was to be established. The investigations were performed on six volunteers. After GC analysis of the vincamine-serum concentration the following pharmacokinetic profile could be established: The substance appears in the streaming blood with an invasion half-life of 53 min. The maximum is reached after 3 h. After oral application of 16 mg the concentration will amount to 36 ng/ml. The apparent elimination half-life caused by the sustained release from of the multi-layer dragee was 9.13 h. 24 h after application there was still a mean serum concentration of 5.74 ng/ml to be detected. Between age of the subjects and serum half-life is a marked linear correlation.


[Tissue levels in human tonsils (tonsillae palatinae) following administration of different antibiotics (penicillin G, ampicillin, lincomycin)]. For determination of tissue levels of different antibiotics in human tonsils penicillin G, ampicillin or lincomycin is given i.v. to patients before tonsillectomy. The concentration of the individual substances is determined in tonsils and serum by agar diffusion method. The results are compared by diagrams of tissue and serum levels and statistically assessed. For therapeutic evaluation the absolute tissue levels at tonsillectomy are compared to the values of minimum inhibitory concentration (MIC) for most frequent germs in the stomato-maxillo-facial region. According to these results recommendations for antibiotic therapy of inflammatory processes of buccal cavity are given.


[Studies on chemical structure and analgetic activity of phenyl substituted aminomethylcyclohexanoles (author's transl)]. Phenyl substituted aminomethylcycloalkanole derivatives were synthetized and tested for analgetic activity. Substances with a high ratio between acute toxicity and analgetic efficacy were selected for further investigations. Structure-activity relationships of this group were evaluated and compared with those of morphine and morphine-like 4-phenylpiperidino derivatives. The basic structural requirement for the new compounds is a cycloalkane ring with a phenyl group and a dimethylaminomethyl residue in ortho-position. The analgetic activity is improved if the aromatic ring is substituted with an oxygen containing group in meta-position. In contrast to classical narcotic analgesics the analgetic efficacy is not lost in derivatives bearing a hydrogen substituent at the central carbon atom.


[On separation of isomeres, structural elucidation and pharmacological characterization of 1-(m-methoxyphenyl)-2-(dimethylaminomethyl)-cyclohexan-1-ol (author's transl)]. 1-(m-Methoxyphenyl)-2-(dimethylaminomethyl)-cyclohexan-1-ol (L 201) was split into the cis- and trans-isomers and the conformations of the two isomers were determined by 13C-NMR-spectroscopy. Molecule models showed that both conformeres were similar to the geometrical structure of morphine. The adaptation of the morphine structure was better with the more active trans-isomer than with the cis-isomer. Tramadol, the trans-isomer, was separated into its optical antipodes. When tested for analgesia in the electro-stimulation test with mice, all compounds showed analgetic activity. The trans-isomer was more active than the cis-isomer and the (+)-form of the trans-isomer was more active than the (--)-form. Given by s.c. route, the (+)-transisomer E 382 was 1/3 as active as morphine. However, the Straub-tail reaction and the withdrawal jumping tests yielded more favourable results with L 201 and tramadol than with E 382.


[Quantitative pupillometric determination of sensitivity to pain (author's transl)]. 1. Pain-induced pupillary dilatation was investigated by means of a method which compensates for the pupillary light reflex. Electric pain stimuli of varied intensity were applied to the forearm. Pure tone (T), pure pain (S) and combined tone-pain (TS) stimuli were used in stochastic or periodic succession. 2. The amplitude of pupillary dilatation increased in the order T, S, TS, In these experiments the sum of the T and S reactions is lower than the TS reaction, in contrast to summation patterns in other nervous structures. The amplitudes of pupillary dilatation and the intervals between stimuli and maximal dilatation increased linearly with increasing stimulus intensity. The latency period, however, is not systematically influenced by the intensity of the stimuli. Adaptation is delayed by stochastic application of the stimuli.


[Algo-pupillometric investigation of the analgesic effect of tramadol (author's transl)]. 1. The analgesic efficacy of 1-(m-methoxyphenyl)-2-(dimethylaminomethyl)-cyclohexan-1-ol (tramadol; Tramal) (75 and 100 mg) was investigated in 22 young, healthy volunteers by means of an algo-pupillometric method. 2. Tramadal itself causes a slight miosis which becomes statistically significant only 3 h after administration. 3. In the algo-pupillogram the effect of tramadol is shown to be biphasic during the first 80 min. Thereafter the pupillary reaction steadily decreases, reaching a minimum after about 3.5--4 h in both dosages. 4. At the time of maximum effect the pupillary reaction of subjects given 75 or 150 mg tramadol is calculated to be equal to that of untreated individuals to whom only 60% or 10%, respectively, of the stimulus intensity has been applied.


[The effect of tramadol on psychic and psychomotor performance in man (author's transl)]. 1. 1-(m-Methylphenyl)-2-(dimethylaminoethyl)-cyclohexan-1-ol (tramadol; Tramal) (75 mg) did not affect the physical working capacity as measured by means of bicycle ergometer in healthy volunteers. 2. Tramadol also had no effect on psychomotor performance in the eye-hand coordination test.


[The effect of tramadol and other analgesics on the pain threshold in human dental pulp (author's transl)]. In 60 young, healthy volunteers the analgesic efficacy of 1-(m-methoxyphenyl)-2-(dimethylaminomethyl)-cyclohexan-1-ol (tramadol; Tramal), dextropropoxyphene and a commercial drug mixture (acetylsalicylic acid 200 mg; phenacetin 200 mg; codeine phosphor. 10 mg; caffeine anhydr. 50 mg; phenobarbital 25 mg) was investigated by determining the pain threshold in dental pulp. All three drugs increased the pain threshold considerably but there was no difference in the analgesic effect of the three drugs.


[The effect of tramadol, a new analgesic, on respiration and cardiovascular function (author's transl)]. 1. The effect of 1-(m-methoxyphenyl)-2-(dimethylaminomethyl)-cyclohexan-1-ol (tramadol; Tramal), a new i.v. administered analgesic, on respiration and cardiovascular function was investigated in 15 patients in a clinic of general surgery. 2. Blood gas analysis revealed that tramadol, unlike morphine-like analgesics, does not depress respiration. 3. The drug did not affect blood pressure, and the observed slight increase in heart rate was transient and statistically not significant.


[The effect of tramadol on the EEG and the electronystagmogram (author's transl)]. 1-(m-Methoxyphenyl)-2-(dimethylaminomethyl)-cyclohexan-1-ol (tramadol; Tramal) in oral doses of 150 mg/kg caused no essential changes in the EEG pattern in man. Only the alpha-rhythm of the occipital leads was more synchronized and the amplitude somewhat higher. beta-Waves increased slightly, but the delta-waves were not significantly changed. Tramadol induced no measurable alterations in the electronystagmographic recordings of quick voluntary eye movements or follow-up to-and-fro eye movements. In the optokinetic and postrotatory nystagmus, however, there was a moderate decrease in the total amplitude and maximal angular velocity of the slow nystagmic stage. The results of EEG and electronystagmographic investigations indicate that tramadol has a moderate relaxant (central depressant) effect.


[Examination of psychic effects of a new analgesic agent of the cyclohexanols series. A contribution to a possible psychic dependence potential of tramadol (author's transl)]. A double-blind trial was performed with 30 male students of the University of Düsseldorf. The volunteers were divided at random into two groups containing 15 subjects each. One group received 1-(m-methoxyphenyl)-2-(dimethylaminomethyl)-cyclohexan-1-ol (tramadol; Tramal), and the other placebo. The latter served as the controls. On three occasions at regular intervals in the course of one week the volunteers were questioned on the basis of Janke and Debus's "Eigenschaftswörterliste" (EWL) (attribution word list). The interviews were carried out 1 h after the injection (1 ampoule 100 mg i.m.). The results in the sense of any euphoretic or dysphoretic effects are discussed.


[The "paired cards" system. A practical and generally applicable procedure for the clinical trial of drugs (author's transl)]. A system is described which is suitable for the simulataneous double-blind study of several drugs effective in the same field of indication (e.g. analgesics). The procedure uses sequential analysis and therefore requires only limited materials, costs and personnel. It produces significant results with a minimum of patients.


From etiology and pathogenesis to therapy of multiple sclerosis. The Author describes the histopathologic picture of the Multiple Sclerosis and Experimental Allergic Encephalitis and discusses some etiopathogenetic hypotheses elaborating on the immunogenetic and immunopathological aspects. The therapeutical problem is analyzed in all its various facets: cortisone derivatives, immunosuppressive products and reabilitation therapy aiming simultaneously at motion reeducation and at individual and group psycotherapy.


Vitamin D status of Asian infants.

Vitamin D status of Asian infants. Vitamin D intakes of infants aged 6 and 18 months from the Asian community in Southhall, Middlesex, were studied to assess the effectiveness of food fortification as a means of preventing vitamin D deficiency. Infants aged 6 months generally had similar diets to white children of the same age and had reasonable vitamin D intakes owing to consumption of fortified dried milks and cereals, reinforced by health visitors and baby clinics. Children aged 18 months, however, ate largely Asian diets and had much lower vitamin D intakes than the 6-month-old group with a corresponding increase in symptoms of vitamin D deficiency. Hence new measures for preventing vitamin D deficiency should probably be aimed at children aged over 1 year. The results of this survey suggest that fortifying chapati flour would be the most effective method of doing this.


[Furosemide in newborns infants with idiopathic respiratory insufficiency syndrome]. Due to the interstitial pulmonary edema present in neonates with idiopatic respiratory distress syndrome (IRDS), it was believed furosemide would be useful in its treatment. In newborns with this syndrome, the effect of said diuretic was studied in blood gases, oxygen alveoloarterial difference and right to left short circuit. Twenty-two infants with similar clinical and laboratory characteristics were included in the study. Out of them, 11 were given furosemide (1 mg/kg/single dosis) and the remaining cases were controls. No difference was shown between both groups in PaO2 and PaCO2 and therefore, the alveoloarterial difference of oxygen nor the right to left short circuit during 60 minutes that the study lasted were either affected even if the infants who were given furosemide showed a significantly greater urinary flow. Due to the above results, the use of furosemide is not recommended for children with IRDS to eliminate an interstitial edema.


Clinical and antimicrobial effects of haloprogin cream in diaper dermatitis. Haloprogin cream was applied four times a day for one week over the diaper area of eight infants affected by diaper dermatitis. All patients experienced complete clearing. Candida albicans was isolated from seven patients prior to treatment but failed to grow in cultures obtained after completion of the treatment.