Shunt metastases in posterior fossa tumors. Permanent (CSF-drainages for treatment of hydrocephalus in posterior fossa tumors have been used in the last few years, increasingly. The rare incidence of extracranial metastases and it's higher frequency in the same period of time has been remarkable. An additional case of metastasis via ventriculoperitoneal shunt is presented. Such deleterious complications of malignant CNS-tumors should be avoided, as progressively improving results with combined radio-chemotherapy have established a more encouraging prognosis.


The clinical features and HLA associations of reactive arthritis associated with non-gonococcal urethritis. Fifty-seven patients with arthritis associated with non-gonococcal genital infection have been studied. Synovitis characteristically affected one or a few joints, expecially the knee, ankle or metatarsophalangeal joints and was accompanied by tenosynovitis and enthesopathies--each in about one third of the patients. A quarter of the patients had ocular, cutaneous, or mucous membrane lesions (Reiter's syndrome). Although six patients developed a chronic or relapsing course, average duration of the acute episode in the majority was three to five months. Available evidence strongly suggests that infection following sexual intercourse, usually but not always with a new partner, was instrumental in the initiation of the disease. We have suggested the term 'sexually acquired reactive arthritis (SARA)' to emphasize the mode of acquisition of the disease, and note that similar syndromes are seen associated with gut infection. We consider that usage of the term Reiter's syndrome is correctly applied to only those cases which exhibited the characteristic triad of urethritis, arthritis and conjunctivitis with or without other cutaneous and mucous membrane lesions. Thirty-six of the 54 patients who were HLA typed (67 per cent) possessed the antigen HLA-B27. Of 30 who presented directly to a rheumatology unit 25 (82 per cent) were HLA-B27 positive. The other 24 patients initially attended a venereology clinic and only 11 (46 per cent) of these bore the antigen. This appears to reflect disease severity, HLA-B27 positive patients having a significantly longer duration of disease symptoms and a higher frequency of extra-articular manifestations, than those lacking this antigen.


Mycotic carotid artery aneurysm.

Mycotic carotid artery aneurysm. A painful, pulsatile neck mass with associated fever should suggest the presence of a mycotic carotid artery aneurysm. Diagnosis can be confirmed from angiograms. Broad spectrum antibiotics are indicated, and an operation should be performed promptly. The lack of tissue planes uninvolved by infection will almost always prevent vascular reconstruction. Carotid artery ligation with excision of the aneurysms is recommended.


The cuatico aspiration cannula as a depth guide during myelography. A technique for positioning the Cuatico needle in such a way as to avoid extra-arachnoid injection of contrast material is described, wherein the aspiration cannula serves as a depth guide. This technique also facilitates removal of contrast medium.


The contact angle induced by DPL at pulmonary epithelial surfaces. A contact angle has been measured at the surface of dog tracheal epithelium by means of two surface balances simultaneously monitoring the apparent surface tension of the same film in a Langmuir trough - one method dependent upon contact angle and the other independent of contact angle. This was confirmed by direct observation. The contact angle was absent for Ringer's solution alone but was induced by DPL deposited on the fluid surface in physiological concentrations. The contact angle varied from 9 degrees to 67 degrees for compression of the DPL film from 100% to 27.5% of its original area and displayed hysteresis with respect to area. These findings show that DPL has unusual surface properties in reducing surface tension yet decreasing wettability, i.e. acting as an anti-wetting agent. The physiological advantages of this unusual combination of properties are discussed in relation to maintaining pulmonary homeostasis and the forward propulsion of mucus which could be facilitated by the differential wettability of cilia induced by DPL. One possible disadvantage of DPL is indicated where fluid plugs might seal an airway - such as in the newborn.


Candida meningitis in the newborn.

Candida meningitis in the newborn. The incidence of Candida meningitis in the neonatal period is increasing, and 63% of reported patients have either died or are mentally retarded. We report a newborn with Candida meningitis and arthritis who did well after treatment with intravenous and intrathecal amphotericin B, along with oral flucytosine.


[Some indices of homeostasis in patients operated under nitrous oxide narcosis with neuroleptanalgesia for thyrotoxic goiter]. The authors believe that an operation under endotracheal anesthesia with phentanyl, droperidol and nitrous oxide does not substantially influence the indices of the water-electrolyte metabolism. Change of the intercellular liquid level in patients with severe thyrotoxicosis might be associated with the changed functions of the cardiovascular system.


Studies on the action of pesticides upon the endocrines using in vitro human thyroid cells culture and in vivo animal models. I. Herbicides--aminotriasole (amitrol) and atrazine. The action of aminotriasole (amitrol) and atrazine in doses of 0.001--1 mg and 0.0001--.01 mg/1.5 ml medium, respectively, upon cell cultures of human thyroid was studied in order to find out their influence on cell multiplication, proteic synthesis, enzymatic activity of thyroid cells, and hormonal synthesis. The results varied according to the dose utilized and the type of thyroid cell studied. The acute experiment carried out on rats treated 15 days with 500 ppm amitol and 50 ppm atrazine revealed variations in the T3, T4 and LH synthesis. Amitrol showed a strong inhibitory action on T3 and T4 secretion, whereas atrazine stimulated it.


Effects of socioeconomic status on incidences of three sexually transmitted diseases. A new socioeconomic index scored for census tract characteristics (income, education, and household crowding) was used for study of the socioeconomic patterns of incidences of syphilis, gonorrhea, and squamous cell carcinoma of the uterine cervix in Oregon's three metropolitan statistical areas. Cases of syphilis and gonorrhea were reported, but cases of uterine cancer were found by intensive searches of records from hospitals and pathology laboratories. For all three diseases there was a striking inverse relationship between incidence and urban socioeconomic status, a fact that indicated that this distribution pattern is probably real and not a function of reporting bias. This strong socioeconomic effect on the incidence of sexually transmitted diseases probably reflects corresponding differences in frequencies of nonmarital sexual contacts among the different socioeconomic strata; these differences should be recognized in our efforts to develop more rational control measure for application in the community. From the information available about contacts of persons with syphilis, it appeared that this socioeconomic incidence pattern was a function of heterosexual behavior.


Rat lymphocytic thyroiditis associated with ingestion of an immunosuppressive compound. Lymphocytic thyroiditis was induced in young Wistar rats by feeding them the immunosuppressive compound frentizole [1-(6-methoxy-2-benzothiazolyl)-3-phenyl urea] for 1 year. About half of the rats given 0.060 and 0.150% frentizole in the diet had lymphocytic thyroiditis. The incidence of thyroiditis was low in the group given the high dose because of severe anemia and hepatic disease which resulted in increased mortality. Reversibility of the thyroid lesion was indicated by reduced incidence rates at 15 and 18 months after treatment was stopped at 1 year. The thyroiditis was characterized by interstitial infiltrates of many lymphocytes and plasma cells and fewer macrophages with mild degenerative changes in the follicular epithelium. This inflammatory cell infiltrate was generally diffuse but occasionally was multifocal, particularly in thyroid glands of rats late in the reversibility phase of the study. The inflammatory cell infiltrate caused the thyroid glands to be several times normal size. Sera from rats with lymphocytic thyroiditis contained hemagglutinating antibody against rat perfect correlation between the presence of anti-thyroglobulin antibody and enlarged thyroid glands. Fine granular deposits of IgG and complement were identified in some areas of the follicular basement membrane. We concluded that the lymphocytic thyroiditis was immunologically mediated, at least in part, by anti-thyroglobulin antibody.


Heterophile antibodies. Part II. An evaluation of the effect of autologous blood group substances on the natural formation of agglutinating antibodies to sheep red blood cells. This study shows that some substances in human secretions can inhibit the agglutination of sheep red blood cells by human antibodies. When present in adequate concentrations, they can also inhibit the reaction of the donor's own sheep red blood cell antibody activity in vito. The subjects in whom this phenomenon was found almost always had low agglutinating antibody titers to sheep red blood cells. The inhibiting activity of saliva for sheep red blood cell antibodies was influenced by the ABH secretor status. Substances reacting against sheep red blood cell antibodies occur in the secretions in considerably smaller quantities than ABH substances.


Heterophile antibodies. Part III. Evidence for linkage of high responder activity to sheep red blood cells and the formation of specific antibodies to HBsAg. Group A, B and O subjects who produce immune antibodies to group A1 or B red blood cells also produce high titer antibodies to sheep red blood cells. Sheep red blood cells appear to possess AB-like as well as non-AB determinants on their surface membranes, each capable of producing and reacting with antibodies of their respective specificities. The antibodies against AB-like determinants preferentially agglutinate A or B cells whereas non-AB-like determinants preferentially stimulate hemolytic antibodies. Human antibodies reacting with these two kinds of determinants on sheep red blood cells may be produced in response to microorganisms possessing very similar factors on their membranes. Individuals who possess AB-like determinants in their secretions, similar to the determinants present on sheep red blood cells (or microorganisms), often make weaker antibodies to these red blood cells. Subjects lacking corresponding anti-sheep inhibitors in their secretions generally produce stronger sheep red blood cell antibodies. There is a positive correlation between the formation of antibodies to HBsAg and strong agglutinating antibodies to sheep red blood cells, indicating that similar determinants may be found on HBsAg virus and on sheep red blood cells. No such correlation was found for anti-tetanus antibodies.


Pulmonary blastomycosis in children. Amphotericin B therapy and a review. Two children, aged 3 months and 4 years, respectively, were treated with ten weeks of amphotericin B for culture proved pulmonary blastomycosis. Organisms were easily demonstrated in nasopharyngeal or sputum specimens on admission. Although organisms were present until the 12th and 19th days of therapy, respectively, they were viable through only the seventh and 12th days of therapy. Both patients had thrombophlebitis, anemia, neutropenia, hypokalemia, fever, and vomiting develop during therapy. The less toxic drug hydroxystilbamidine isethionate, given for only 17 to 30 days, has been used successfully in at least six previously reported cases. Long courses of amphotericin B therapy may not be necessary for the treatment of pulmonary blastomycosis in selected children.


Thyroid antigen associated immune complex glomerulonephritis in Graves' disease. A 60 year old hyperthyroid black woman with long-standing Graves' disease treated with methimazole presented with anasarca and congestive heart failure. She was found to have the nephrotic syndrome with a urinary protein excretion of 32 g/day. Light and electron microscopy revealed a stage II membranous glomerulopathy. Direct and indirect immunofluorescence demonstrated immunoglobulin G (IgG), immunoglobulin M (IgM), third component of complement and thyroglobulin in a granular diffuse pattern consistent with an immune complex glomerulonephritis. Total thyroidectomy led to a decrease in proteinuria with little change in glomerular filtration rate during an 11 month follow-up period. We believe this to be the first report of immune complex glomerulonephritis associated with thyroid antigen in Graves' disease.


Selective mass treatment in a venereal disease control program. To control syphilis among prostitutes and seasonal farm workers in Fresno County, California, we developed a program of selective mass treatment of prostitutes. From August 1976 to July 1977, 512 women entered the program. Overall, 4.6 per cent of women treated prophylactically for syphilis were actually infected. Compared to cases in the previous year, infectious syphilis cases among prostitutes and seasonal farm workers decreased 51.3 per cent and 26.8 per cent, respectively.


Immunosuppression by surface-active material: lack of species specificity. Surface-active material isolated from the lungs of both dogs and rats was tested for its ability to suppress the in vitro proliferative responses of dog, mouse, or human lymphocytes to a variety of immunologic stimuli. Both dog and rat surface-active material exerted a dose-dependent suppressive effect on the proliferative responses of each species of lymphocyte, regardless of the nature of the immune stimulus (mitogen, antigen, or alloantigen). The data indicated that surface-active material acts by directly inhibiting the responding lymphocyte and not by activating suppessor cells. The immunosuppression could not be attributed to lymphocyte cytotoxicity. Although the mechanism of this immunosuppressive action of surface-active material remains undefined, the present data clearly indicate that such activity is not species specific.


Biochemical characterization of clonally isolated and continuously cultured type II cells from adult rat lung. Clonally isolated and continuously cultured type II alveolar epithelial cells from adult rat lung (L-2) were compared to clonally cultured rat lung fibroblasts with respect to composition and biochemical function. There was no difference in phospholipid composition betweem those 2 cell types. After incubation with tritiated choline, the specific activity (cpm/nmol of lipid phosphorus) of disaturated phosphatidylcholine (PC) was lower than that of total PC in both cell types. Our findings suggest that, in our cell cultures, disaturated PC is not synthesized as a specific component of pulmonary surfactant, but more likely as a component of cell membranes. The increased DNA content of the L-2 cells indicates transformation and may be associated with the inability to synthesize surfactant. Under the described conditions, we are hesitant to use the clonally derived L-2 cell line as a model system for the study of pulmonary surfactant synthesis and secretion.


Operative arthroscopy.

Operative arthroscopy. In a period of 20 months, over 200 patients (age ranged from high school students to middle-aged persons) with knee injuries were treated by operative arthroscopy. The majority of the injuries were incurred while the patients had been participating in athletic events, either competitive or recreational. Operative arthroscopy offers the advantage of shortened hospital stay, rapid rehabilitation, lack of disfiguring scar, and reduced costs. Patients are followed yearly after the first postoperative year. Improved long-term results from diagnostic and operative arthroscopy, as compared to conventional surgical procedures, are expected. The proof of those expectations will be determined in the next several years as this group of patients requiring partial meniscectomies or procedures for pathologic and degenerative conditions is reevaluated.


Graves' disease following acute (subacute) thyroiditis. The development of Graves' disease with positive thyroid-stimulating antibody titers is described in a woman, five months after onset of the putatively viral disorder, acute (subacute) thyroiditis. There was no evidence of transient hyperthyroidism during the acute episode. The arguments for and against a causal relationship between the two diseases have been reviewed. The present experience adds to the earlier suggestion that the association may represent cause and effect.


Chief cell intracytoplasmic fat used to evaluate parathyroid disease by frozen section. The chief cells of parathyroid adenomas were found to contain less intracytoplasmic fat than normal parathyroid glands and/or the adjacent rims of nonadenomatous parathyroid tissue. The amount of sudanophilic material in the chief cells was relatively uniform for each individual adenoma, but varied between patients. In half of the patients with parathyroid adenomas, Sudan-positive granules were generally absent from the adenomatous cells, whereas in the other half the granules were easily identifiable. The chief cells of secondary hyperplasia showed a less uniform pattern in each gland. In some areas, the stain for intracellular fat was negative, while adjacent cells contained prominent Sudan-positive granules. These findings suggest that staining frozen sections for intracellular fat is a useful but limited aid in the differentiation of parathyroid adenomas from normal parathyroid gland tissue.


Ultrastructural observations on gynecomastia. Ten cases of gynecomastia were studied by electron microscopy. The ducts showed proliferation of both epithelial and myoepithelial cells. Intracytoplasmic lumina, previously thought to be a feature of malignant breast lesions, were seen. Squamous metaplasia was observed in some cases. The stroma showed fibroblasts, myofibroblasts, and, occasionally, pericytes. The general morphology of gynecomastia is similar to that of benign lesions of the female breast at the ultrastructural level. The features of the stromal cells reflect the effects of estrogenic stimulation.


Age-related changes resembling fibrocystic disease in iodine-blocked rat breasts. It has been reported that dietary restriction and chemical blockade of iodine causes histopathologic changes in peripubertal female rat breasts. This study extended the age range to include midreproductive life and perimenopausal rats; there is a wider spectrum of structural alterations that are associated with the older breast, with sodium perchlorate as the blocking agent. In 16-week-old rats, breasts showed general increased parenchymal activity and growth, regressing after removal of the block. In 42-week-old rats, breasts showed noticeable calcospherite deposition, intralobular fibrosis, and cystic changes resembling human fibrocystic disease. In 52-week-old rats, breasts exhibited atypical lobules cytologically, papillomatosis, sclerosing adenosis, calcifications, and a lobular transformation of a histologically dysplastic type. It is the older rat that experiments will more closely parallel the human condition.


Myxoid adrenal cortical carcinoma: a light and electron microscopic study. An adrenal cortical carcinoma demonstrating a peculiar myxoid background similar to that of a myxoma was found in a 41-year-old woman who also had parathyroid hyperplasia and clinical evidence of a pituitary tumor. The electron microscopic study demonstrated its value in establishing the diagnosis that was not possible to make with absolute certainty at the light microscopic level alone. The combination of endocrine disorders strongly suggests the possibility of an unusual multiple endocrine syndrome.


Intrahepatic biliary papillomatosis.

Intrahepatic biliary papillomatosis. A 66-year-old man had intrahepatic biliary papillomatosis. This benign tumor has great growth potential that can present a difficult management problem.


Caroli's disease: a rarely recognized entity. Caroli's disease, well known in the European literature, has been recognized infrequently in this country. The disease is characterized by cystic dilation of intrahepatic bile ducts and is complicated by formation of gallstones, cholangitis, and hepatic abscesses. Surgical intervention and therapy with antibiotics is often unsuccessful and Gram-negative septicemia is a common cause of death. Cysts may be present in other organs, such as kidney, pancreas, and spleen, and may be helpful in the early diagnosis of this rare disease.


Extracerebral leptomeningeal astrocytoma mimicking a meningioma. A 49-year-old woman with a two-year history of headaches that became progressively more frequent was found on computerized tomographic scan to have a dense, enhancing right frontoparietal mass. The tumor mimicked a meningioma in that it indented the inner table of the skull, was well demarcated from the underlying brain, and microscopically lacked the fibrillated cell processes and background that characterize astrocytomas. The 80- to 100-A cytofilaments were sparse and seen in few cells. It was only by the immunoperoxidase stain for glial acidic protein that the diagnosis of an extra-axial leptomeningeal astrocytoma was established.


Leptomeningeal myeloma.

Leptomeningeal myeloma. Multiple myeloma commonly produces neurologic symptoms when it involves the cranium or vertebrae, but rarely invades the CNS or meninges. Intracranial or intraspinal myeloma without lesions in the adjacent bone is extremely rare. To our knowledge, there are only ten reported cases of isolated myeloma in dura and/or brain, and only two limited to the leptomeninges. We wish to report the third case of isolated leptomeningeal myeloma. Both myeloma cells and abnormal globulins were present in the CSF, but absent from serum and bone marrow. Analysis of these 13 cases in dura, brain, or leptomeninges strongly supports the concept that abnormal proteins do not reach the CSF from the serum but are produced by myeloma cells in situ.


Light and electron microscopic observations of blood vessels in neurilemoma. A study of 105 cases of neurilemoma disclosed frequent alterations of blood vessels, including hyalinized walls. Many vascular walls were formed by tumor cells. Two cases were analyzed by electron microscopy, and showed fenestrae, patent interendothelial gap junctions, and leakage of RBCs. The presence of erythrocytes in the gap junction and outside vessels is a factor acounting for xanthochromia of the CSF, and serum leakage for the frequent increase in CSF protein in cases of neurilemoma. Attenuation of endothelial cells increases the liability of vessels to bleed within the tumor. Massive bleeding may cause subarachnoid hemorrhage on rare occasions. Hyalinized vessels and dense collagen are features contributing to the relative infrequence of major hemorrhage. Evidence is presented that Schwann and perineural cells are similar.


Two forms of encephalitis in opportunistic toxoplasmosis. Two adult patients receiving immunosuppressive therapy experienced toxoplasma cerebritis. In one, the brain findings were typical of this form of the disease in adults, but the clinical features and brain lesions of the other were atypical, and had some resemblance to those seen in congenital toxoplasmosis. It is suggested that two patterns of encephalitis can occur in opportunistic toxoplasma infections, a common form with random foci of gland necrosis associated with numerous intracerebral organisms, and another with vascular lesions and periventricular necrosis. The latter has morphologic features in common with congenital encephalitis, and may also have a similar pathogenesis.


Deuterium NMR studies of cerebroside-phospholipid bilayers. 2H-NMR was used to probe the interaction of non-hydroxy fatty acid cerebroside and 2-hydroxy fatty acid cerebroside with the polar head group and with the acyl chains of dipalmitoylphosphatidylcholine in unsonicated bilayers. It is shown that the interior of the bilayer exhibits uniformly increasing orientational order as the concentration of both types of cerebroside increases, whereas the surface of the bilayer, as reflected by the head group motion, becomes disordered. The extent of the disorder at the surface is dependent upon the type and concentration of the cerebroside. These results are discussed in terms of hydrogen-bonding interactions.


Study of STDs in patients attending venereal disease clinics in Khartoum, Sudan. During the period October 1976 to January 1978, 290 patients were examined for sexually transmitted diseases in three venereal clinics in Khartoum Providence. Clinical and laboratory findings showed that nongonococcal urethritis was the commonest STD in men (35.1%), with gonorrhoea the second commonest (25.9%). Most of the patients with STDs were aged between 20 and 30 years. Of the infected men, 49.3% had acquired their infections from prostitutes.


Incorporation of 3H-thymidine in the nephron of Gasterosteus aculeatus L. and its stimulation by methyltestosterone. A high-speed scintillation autoradiographic study. The rate of 3H-thymidine incorporation into different parts of the renal proximal tubule of female sticklebacks treated with methyltestosterone was investigated using high-speed scintillation autoradiography. The results are compared with those from normal males before or after mucous transformation of the kidney. Labelled cells are observed in all parts of the proximal tubule, with marked variations from one segment to another. They are numerous in part 2 of the proximal tubule, particularly in the distal region. Male sex hormones affect the labelling rate in all parts of the nephron, especially in the distal region of part 2 of the proximal tubule. In that particular area, new tubule formation by budding is observed in some individuals, but this process does not appear to be a general one. Correlation between the frequency of these figures and the time of treatment could not be established. Comparing the action of sex hormones in females with that in males reveals a difference in reactivity in the proximal zone of part 2 of the proximal tubule, where methyltestosterone has a strong action in females; in contrast, in "mature" and "immature" males, only a few labelled cells are present in this region. It is concluded that kidney enlargement during the breeding season does not result only from a swelling of cells belonging to part 2 of the proximal tubule, as was generally believed, but also from a lengthening or even a proliferation of the proximal tubules, induced by an increase in mitotic activity controlled by male sex hormones.


Acquired C1 inhibitor deficiency in a case of lymphosarcoma of the spleen. Reversal of complement abnormalities after splenectomy. A patient with an extensive lymphosarcoma of the spleen without involvement of other lymphoid organs and hypogammaglobulinaemia showed the characteristic complement profile of an acquired C1-inhibitor deficiency. Both functional and immunochemical studies revealed extremely low levels of the inhibitor of C1-esterase. Correction of the low levels of early acting complement components and of the low C1-inhibitor level followed the splenectomy. In vitro tests showed that lymphosarcoma tissue pieces or cells were able to interact with complement, resulting in a depletion of the haemolytic activity. These findings provide evidence that tumour cells were responsible for the abnormalities of the complement system.


[Cyst of the medial meniscus of the knee]. We had the opportunity to observe a case of cyst of the medial meniscus of the knee. We observed unusual findings; association with a meniscal tear and communication through the tear with the articular cavity.


Antibody response to monovalent A/New Jersey/8/76 influenza vaccine in pregnant women. The decision to implement a mass immunization program with A/New Jersey/8/76 (Hsw1N1) influenza vaccine provided a unique opportunity to evaluate immunological responses during pregnancy. Fifty-nine pregnant and 27 nonpregnant women participated in this study. Influenza virus hemagglutination-inhhibition antibody titers were determined to A/New Jersey/8/76 (Hsw1N1), A/Japan/305/57 (H2N2), and A/Hong Kong/8/68 (H3N2) before and after a single dose of monovalent (200 chick cell agglutination units) influenza A/New Jersey/8/76 (Hsw1N1) vaccine. The difference in titers between pregnant and nonpregnant women was insignificant. Treatment of the sera with 2-mercaptoethanol disclosed a similar immunoglobulin M response to the vaccine in both groups. The mean fold rise in heterologous antibody titer was similar in pregnant and nonpregnant women. This study demonstrated that pregnant women were able to respond to an original myxovirus antigen, influenza A/New Jersey/8/76, in a manner equivalent to nonpregnant, age-matched controls.


Appearance of Graves' disease on orbital computed tomography. Extraocular muscle enlargement was symmetrical in 70% and asymmetrical in 30% of patients with Graves' ophthalmopathy. True unilateral muscle involvement occurred in 6%. Computed tomography (CT) showed bilateral orbital involvement in 50% of patients presenting clinically with unilateral eye signs. In patients without a clinically apparent ophthalmopathy, CT demonstrated muscle enlargement in 40%. The medial and inferior rectus muscles were the most frequently and most severely involved. Orbital radiation therapy can result in a decrease in size of involved muscles.


Direct sagittal computed tomography in Graves' ophthalmopathy. Standard axial transverse orbital computed tomography scans show the medial and lateral rectus muscles very well but section the superior and inferior rectus muscles obliquely. Determining enlargement of the superior and inferior recti in Graves' disease can therefore be difficult on axial transverse scans. We have obtained sagittal, coronal, and axial transverse orbital scans in a series of patients with Graves' ophthalmopathy and have compared the images in each plane. Direct sagittal and coronal scans were obtained without image regeneration from axial transverse sections by using a wide-aperture Varian body scanner and a special accessory table. Sagittal and coronal scans can demonstrate enlargement of the superior or inferior muscles even in cases in which the medial and lateral recti are normal. Since scans performed at approximately 20 degrees to the sagittal plane are parallel to the long axis of the orbit, they demonstrate orbital anatomy better than scans in the true sagittal plane.


State of unesterified fatty acids in skim milk. By a multiple extraction procedure the unesterified fatty acids of skim milk have been shown in at least three entities: a) free dissociated and undissociated fatty acids, b) fatty acids associated with the membrane material in skim milk, and c) fatty acids of unknown origin requiring acidification to pH 1.5 for extraction.


The influence of prenatal or neonatal administration of 2-bromo-alpha-ergocryptine on pituitary prolactin secretion and normal and neoplastic mammary growth in adult mice. In view of the clinical use of 2-bromo-alpha-ergocryptine (CB-154) during pregnancy, longterm effects of perinatal exposure to this drug on pituitary prolactin secretion and mammary tumorigenesis were studied experimentally using a high mammary tumor strain of SHN female mice. Pregnant mice were given daily subcutaneous injections of 0.3 mg CB-154 for 4 days from day 12 to day 15 of pregnancy (prenatal treatment). Another group of mice received daily dose of 0.06 mg CB-154 for the first 5 days of postnatal life (neonatal treatment). Either prenatal or neonatal treatment with CB-154 resulted in little alteration of the pattern of estrous cycle, ovarian structure and pituitary and plasma levels of prolactin. There was no difference between the control and mice treated neonatally with CB-154 in mammary tumorigenesis. On the other hand, somewhat delayed mammary tumor appearance was observed in mice treated prenatally with CB-154. These findings postulate that there is little deleterious influence of perinatal exposure to CB-154 on pituitary-ovary-mammary gland systems at advanced ages.


Biopotencies in rats of several forms of alpha-tocopherol. The bipotencies of several forms of vitamin E were determined by the rat fetal-resorption bioassay. RRR-alpha-tocopheryl acetate compared with 2-ambo-alpha-tocopheryl acetate had a mean relative potency (RP) of 1.66, significantly higher than the currently accepted value of 1.36. RRR-alpha-tocopheryl hydrogen succinate compared with 2-ambo-alpha-tocopheryl acetate had a mean RP of 1.125, significantly lower than the currently accepted value of 1.21. RRR-alpha-tocopherol compared with 2-ambo-alpha-tocopherol had a mean RP of 1.31, not significantly different from the currently accepted value of 1.36. Some preparations of all-rac-alpha-tocopheryl acetate compared with 2-ambo-alpha-tocopheryl acetate had a mean RP of 0.81, and compared with RRR-alpha-tocopheryl acetate had a mean RP of 0.52. Both RP values are significantly lower than the currently accepted values of 1.00 and 0.725 (the reciprocal of 1.36) respectively. Similar biological activities were obtained for oily and dry preparations of the same forms of alpha-tocopheryl acetate. A basic assumption of stoichiometric equivalence for the acetate and hydrogen succinate of RRR-alpha-tocopherol, inherent in the currently accepted values, was shown to be incorrect. The results show that the unit/weight relationships for the various forms of vitamin E currently assigned by the National Formulary have not been validated using a bioassay based on biological function.


The kinetics of macrophage and surfactant replacement in hamster lung following bronchopulmonary lavage. The effects of bronchopulmonary lavage with isotonic NaCl have been investigated in the hamster, and methods are described for separating pulmonary surfactant from cells in lavage fluid and for the quantitative isolation of surfactant from lung. It has been shown that hamsters almost invariably survived a lavage which consisted of ten successive washes each of 2 ml saline. This procedure removed about 80 per cent. of the total surfactant originally present and the surfactant content of the lung was restored to normal within 24 hr. The same procedure however removed at most only about 25 per cent. of the total number of macrophages in the lung and although a second lavage performed immediately after the first removed large numbers of macrophages, if a delay of several hours elapsed between the two lavages, the yield of macrophages was greatly reduced. The reasons for this behaviour are not understood, and it is likely to be one of the factors which limits the frequency with which pulmonary lavage can be repeated.


Carbenicillin prodrugs: stability kinetics of alpha-phenyl and alpha-indanyl esters in aqueous solution. Both ester and beta-lactam degradations of alpha-esters of carbenicillin disodium, carbenicillin indanyl sodium, and carbenicillin phenyl sodium in aqueous solution at 35 degrees and at 0.5 ionic strength were investigated. The reactions were followed by spectrophotometric assay, reversed-phase high-pressure liquid chromatography, and colorimetric assay. The degradation pathways were established, and the rate-pH profiles for ester and beta-lactam cleavage reactions are given for pH 1-11. Below pH 3, the beta-lactam degradation of the prodrugs proceeded exclusively. Above pH 7, the degradation was superseded by the ester hydrolysis to carbenicillin, beta-Lactams of both prodrugs are around three times more stable than carbenicillin disodium at pH 1, six times at PH 2, and 17 times at pH 3. The half-lives for carbenicillin production were predicted to be 17 hr for carbenicillin indanyl sodium and 8.5 hr for carbenicillin phenyl sodium at pH 7.0 and 37 degrees.


Pharmacokinetics and relative bioavailability of oral theophylline capsules. The oral bioavailability of liquid-filled theophylline capsules relative to a nonalcoholic aminophylline solution was determined in normal volunteers. In addition, theophylline absorption and elimination kinetics were reexamined. There were no statistically significant differences between the bioavailability of capsules and liquid as measured by the area under the curve (AUC) from time 0 leads to infinity (p greater than 0.05). The bioavailability parameters of Cmax, tmax, and AUC were determined from actual serum theophylline concentration-time data and from a nonlinear least-squares fit of the serum concentration-time data. Theophylline absorption from the capsules was noticeably faster than from the liquid in most subjects, although the differences in absorption rates were not significantly different (p greater than 0.05). The determined apparent volume of distribution, elimination half-life, and plasma clearance of theophylline were similar to values reported by other investigators. Marked inter- and intraindividual variations in the elimination half-life were noted.


Urinary iodine excretion rates following intrathecal injections of iodinated organic carbonates. Oily iodinated organic carbonates were investigated for use as myelographic media. The urinary excretion of total iodine was used to monitor the apparent elimination rate of these compounds from the subarachnoid space. Within the chain length series of C2-C6, the decrease of elimination rates and disposition rate constants with increasing chain length was demonstrated. This observation is consistent with a dissolution rate-limited elimination model. Such a model was derived and successfully NONLIN computer fitted to the observed elimination data. The model-derived parameter of clearance from the cerebrospinal fluid through the lipid "blood-brain barrier" correlated well with the compound's water solubilities and projected octanol-water partition coefficients. Additional compounds need to be tested to evaluate the postulated model system.


Accelerated mouse sperm penetration in vitro in the presence of caffeine. Evidence for accelerated mouse sperm penetration into eggs in vitro, and hence for accelerated capacitation, was obtained when the fertilizing ability of sperm suspensions was tested after preincubation, for a period of time insufficient to permit full capacitation under standard conditions, in the presence or absence of caffeine. When eggs were fixed after 1 h, the majority (76.7%) in the caffeine-containing medium were fertilized compared with only 32.1% in the caffeine-free medium. When fixation was later, after 1 h 15 min, fertilization levels were high (approximately 90%) in both groups, but significant differences in the stages of egg activation and sperm head decondensation reached were observed. In the absence of caffeine, early stages of nuclear development were predominant, while in the presence of caffeine, a significant proportion of eggs had reached terminal stages of activation. There was also some evidence for precocious sperm, but not egg, nuclear development when fertilization occurred in caffeine-containing medium.


Environmental lead and children: the Omaha study. Blood lead (Pb B) was determined in 1232 samples from 831 children in Omaha and correlated with air lead (Pb A) concentrations of 0.02-1.69 microgram/m3 from 1971 to 1977. A bivariate equation for ages 6-18 yr based on these data predicts an increase in Pb B of 1.4 microgram/dl as Pb A increases from 1 to 2 microgram/m3. Pb B increases 7 microgram/dl as the mean values for soil and house dust Pb increase from 100 to 750 microgram/g. Multiple regression analysis shows that the combined effects of air, soil, and house dust Pb account for 21% of the variance of Pb B, with a high intercorrelation of all 3 variables. Since the variance of repeat sampling in individuals accounted for 38% of the total variance of Pb B, approximately 40% is unexplained and requires measurement of Pb from dietary and other sources.


Subtle obstructive uropathy resulting from encasement of the ureters by tumor. The diagnosis of obstructive uropathy may be difficult in the occasional case in which there is little or no dilatation of the collecting system. A case is presented in which anuric renal failure resulted from encasement of the ureters by tumor. The excretory urogram revealed a delayed pyelogram and a dense nephrogram with minimal dilatation of the collecting systems. The combination of a dense nephrogram and delayed pyelogram should raise the possibility of obstruction, regardless of the appearance of the collecting systems.


Professional and spatial mobility of osteopathic physicians. The study examines changes in location of osteopathic and medical doctors in a 20-county area of rural Missouri over a 14-year period. Losses of osteopathic physicians were greater than medical doctors. However, there was a convergence over the 14-year period in background characteristics of the two types of physicians. The finding of greater spatial mobility of DOs is placed in the context of professional mobility of osteopathy. It is also argued that as practice opportunities for DOs increase, background factors associated with early socialization become more influential in choice of practice sites. The relationship of practice opportunities to choice of practice sites can be extended to foreign medical school graduates and "new health practitioners."


Absorption of a non-ionic contrast agent from cerebrospinal fluid to blood. Intrathecal injection of a non-ionic contrast agent in the lumbar area of rabbits resulted in: (1) a rapid rise in blood iodine level with a maximum after 23-46 min; (2) low concentrations in cisterna magna during the observation period (24 h); and (3) complete or almost complete disappearance of visible contrast medium on the radiographs within 30 min. This indicates that after injection in the lumbar area of the rabbit most of the contrast medium absorption takes place from the lumbar area. Similar injections in cisterna magna showed the following: (1) a slow rise in blood level with a maximum after 150-275 min; (2) little or no disappeared of visible contrast medium on the radiographs within the first hour. This indicates that in the rabbit the absorption from the subarachnoid space of the spine takes place at different rates dependent on the level at which the injection has been made and the area of deposition of contrast medium.


[Unusual autoimmune and neoplastic associated diseases in Sjogren's syndrome]. In an unselected series of 12 patients with Sjögren's syndrome the following autoimmune diseases were observed: severe myxedema due to Hashimotos thyroiditis in four, subclinical thyroid hypofunction in one, diffuse hyperthyroidism in one, glomerulonephritis in two, chronic active hepatitis in one, lupus erythematodes disseminatus in three (one with idiopathic thrombocytopenic purpura), classical rheumatoid arthritis in two. A rare familial occurrence was seen in two sisters. The only male in this group exhibited coexistence of a benign adenolymphoma of the parotid gland (Warthin's tumor) with a malignant non-Hodgkin lymphoma.


Bovine leucosis (lymphosarcoma): a clinical study of 60 pathologically confirmed cases. The clinical features of 60 pathologically confirmed cases of bovine leucosis (lymphosarcoma) are described. The majority of cases could be classified into one of four distinct clinical forms, ie, juvenile multicentric, thymic, skin and adult multicentric. Diagnosis of leucosis in animals with these forms was possible on clinical grounds alone. Five animals, four of which were adult, could not be thus classified and diagnosis required haematological and, or, pathological examinations. The clinical, epidemiological and serological findings would suggest that the cases were examples of sporadic bovine leucosis.


[Biosynthesis of enniatin by washed cells of Fusarium sambucinum]. Biosynthesis of the depsipeptide membrane ionophore--enniatin B by the washed mycelium Fusarium sambucinum Fuck 52 377 was studied. Metabolic precursors of enniatin B, alpha-ketovaleric acid, 14C-L-valine, and 14CH3-methionine, were added to the system after starvation. The amino acid content in the metabolic pool increased 1.5 times after addition of alpha-ketovaleric acid, 2.2 times after that of valine, and 2.5 times after addition of methionine. 14C-L-valine and 14CH3-methionine were incorporated into the molecule of enniatin B. Valine methylation in the molecule occurred at the level of synthesized depsipeptide. Amino acids of the metabolic pool performed the regulatory function in the synthesis.


Bovine venereal campylobacteriosis (vibriosis) in north east Scotland. Since January 1978 four outbreaks of bovine venereal campylobacteriosis, associated with Campylobacter fetus subspp fetus, have been investigated. The herds demonstrated a variety of presenting signs, and the outbreaks were confirmed by vaginal mucus agglutination tests and isolation of C fetus subspp fetus. A greater recovery of C fetus was achieved by reducing the oxygen tension in the atmosphere used for incubation to a greater extent than usual. Bradford's brucella agar was found to be a suitable selective media for C fetus.


[Mechanism of enhancement of the radiotherapeutic effect on rat transplantable neoplasms by dihydro-monocalcium-phosphate]. A combined effect of dihydro-monocalcium phosphate and radiotherapy on transplanted tumors in rats resulted in 80--90% inhibition of the neoplasms growth and a greater sorption capacity of cells than in x-ray irradiation. Whereas, the character of changes in the mitotic activity under x-irradiation and the combination therapy was identical.


[Modern differential-therapeutic aspects of the drug therapy of chronic gout]. The present paper adopts a definite attitude to the differentiated therapy of the disturbances of the uric acid metabolism. This demands an exacter subdivision of the kind of the metabolic disturbance (types Ia, Ib, IIa, IIb, and III). On the basis of this classification in types an individually adapted therapy is possible. It might form the prerequisite of a still more effective meeting of the nephrogenic complications of the gout and of the reduction of the side effects of the necessary permanent therapy.


[Effects of different types of newborn infant feeding on intestinal microbiocenosis]. From 70 to 90% of premature infants on breast and additional feeding with a mixture of the "Similak" type showed normal bifidoflora, the main component of biocenosis of infant intestines. No positive shifts in the intestinal microflora composition or recovery of the bifidoflora physiological for children were recorded during feeding premature infants with pasteurized donor milk and additional feeding with kefir, a mixture of "Malyutka" and dry acidophilus mixture "Malyutka". Positive results of using the above food in conjunction with bifidumbacterin point to the perspectiveness of using bifidobacteria in the development of therapeutic additives to the infant diet.


[Use of propiono-acidophilus milk in the complex treatment of intestinal dysbacteriosis in infants with staphylococcal infections and sepsis]. Antistaphylococcal properties of the new lactic acid mixture propionic acidophilic milk (PAM) against the microbe isolated from feces of children suffering from staphylococcal sepsis were comparatively studied by the dilution and diffusion methods. PAM was found to have more pronounced antimicrobial properties against pathogenic staphylococcus than acidophilic milk and kefir. It is recommended to include PAM into the diet of children with intestinal dysbacteriosis.


[Changes in opposite directions of tryptophanpyrrolase and 3-OH-anthranilic oxidase after a loading dose of tryptophan]. A loading dose of tryptophan induces a marked increase of tryptophan-pyrrolase (substrate induction) and a decrease of 3-OH-anthranilic-oxidase values in rat liver; in the kidneys of the same experimental animals the 3-OH-anthranilic-oxydase is instead unchanged. In other experimental conditions (surrenectomized or pyridoxine depleted rats, with or without tryptophan loading; with prednisolone loading) a more or less important substrate induction is always reported, whereas no variation occurs in the values of 3-OH-anthranilic-oxydase. These data are not sufficient to state whether there is a connection between the opposite responses of the two enzymatic activities obtained after tryptophan loading in rat liver homogenate. On the other hand, it should be kept in mind that they do not represent the overall effect induced by the aminoacid loading, but refer only to one moment of the action exerted by the loading itself. In order to acquire a thorough knowledge of the observations made so far and to formulate some assumptions which may be helpful for the interpretation of the relevant mechanisms, it is necessary to investigate the kinetics of both enzymes, and to study their regulatory mechanisms in particular after tryptophan loading.


The spontaneous urinary excretion of tryptophan metabolites "via kynurenine" in women with regards to the prepuberty, sexual maturity and menopause. High values of anthranilic acid, 3-OH-kynurenine, xanthurenic acid and 3-OH-anthranilic acid are observed in the spontaneous urinary excretion of tryptophan metabolites in girls in the prepubertal age. The highest differences are between the 3-hydroxy metabolites especially the 3-hydroxykynurenine. On the other hand, this metabolic excretion in postmenopausal women is statistically identical to that of women in sexual maturity.


The effect of allopurinol on the kynurenine formation in humans following a tryptophan load. The effect of allopurinol on the kynurenine formation in three manic depressive patients, two in remission and on in depression, has been studied during long-term treatment with L-tryptophan. The patients were loaded with 100 mg L-tryptophan per Kg body weight prior to and after one week on allopurinol, 300 to 500 mg per day. The area under curve (AUC) of plasma total and free tryptophan increased slightly in the patients in remission but not in the depressive. The former showed no change in the AUC of plasma kynurenine whereas an increase was seen in the depressive. The results suggest that allopurinol does not inhibit the human tryptophan pyrrolase definitely during loadings with L-tryptophan.


A further contribution to the choice of the dose for L-tryptophan load test. The analysis of the results of a study on the urinary excretion of metabolites "via kynurenine" after the ingestion in man of different amounts of tryptophan is reported. Of the three doses of L-tryptophan administered to the subjects, that is 2 g pro capite, 50 mg/Kg and 75 mg/Kg body weight, it is preferable to choose that of 50 mg/Kg b.w. as a load test. Such a dose assures an excretion of the more important metabolites without significant variations between men and women and without producing overloading effects.


The effect of environment on tryptophan metabolism "via kynurenine" in oral contraceptives users. We have studied tryptophan metabolism "via kynurenine" in women who were oral contraceptives users, living in two different egyptian environments: in the city of Alexandria or in a rural area near Tanta and, in comparison, in control groups of women living in the same environments but who were not contraceptives users. In the non contraceptives users of Tanta we have registered a higher elimination of some metabolites (anthranilic acid, kynurenic acid, xanthurenic acid and 3-OH-anthranilic acid) which might be related to the way of life and environment. The pattern of the kynurenine pathway metabolites of the contraceptives users (studied 1, 3 and 12 months after contraceptives administration) shows some differences with respect to the controls, both in the spontaneous elimination and in that after tryptophan load. These differences are especially evident for anthranilic acid glucuronide, kynurenine and kynurenic, anthranilic and xanthurenic acids. Some differences may be observed after 1 month of contraceptives administration. The effect of tryptophan oral load is superimposed on those of environment and contraceptives use; in the spontaneous elimination of tryptophan metabolites an accomodation to the contraceptives administration is evident. The discrepancies between some of our results and those of the literature might be related to the influence of environmental factors and of the way of life.


[Toxicity and tolerance of tryptophan and its metabolites]. For the therapeutic use of tryptophan it is necessary to know its toxicity and pharmacological effects; but very few data are reported in literature on these aspects. On the other hand there are many researches on tryptophan metabolism after a load test and related side effects. From these data it appears that a tryptophan dose of 100 mg/Kg body weight per os is usually well tolerated with exception of some short and slight gastric troubles (vomit, etc.). The lack of references to repeated and long lasting administrations (chronic toxicity) and of a therapeutic index must be filled. Side effects due to a single dose of 5.OH-tryptophan, e.g. head twitches, resemble those due to serotonine. With regard to the most important metabolites of the kynurenine pathway, the available data have been obtained with kynurenine and especially with xanthurenic acid. These compounds have a low toxicity and do not appear to have important pharmacological properties. However, systematic researches are necessary before using these compounds either in load tests or for therapy in man.


The vulvar clinic: an eight-year appraisal. One thousand forty-three patients made 2,750 visits to the Vulvar Clinic at the Milwaukee County Medical Complex from July, 1970, to July, 1978. This experience is analyzed and the various diseases are grouped in order of frequency. The results shed light on those vulvar problems most likely to be encountered in general office practice and point the way toward future areas of research.


Acceleration of pulmonary surfactant maturation in stresses pregnancies: a study of neonatal lung effluent. To determine the maturation of pulmonary surfactant at birth, phospholipid patterns in tracheal or pharyngeal aspirates of 54 newborn infants were analyzed by two-dimensional thin-layer chromatography. The compositions of phospholipids and their surface tension-lowering abilities were assessed after gestations with various complications. Preterm infants with respiratory distress syndrome (RDS) lacked phosphatidylglycerol and had lower lecithin/sphingomyelin ratios than infants without RDS. An acceleration of both phosphatidylcholine (lecithin) and phosphatidylglycerol concentrations was observed in 21 preterm infants born after prolonged rupture of the membranes and treatment with isoxuprine. In these infants, the phospholipid pattern of lung effluent was similar to that of term infants even at gestational ages less than or equal to 30 weeks. Biochemical lung maturation was delayed in aneccephalic infants, infants of diabetic mothers, and one infant of a mother with hypothyroidism.


Studies on receptor for mouse erythrocytes in lymphocytes of patients with malignant lymphoma. In a group of 30 healthy subjects and 27 patients with the diagnosis of non-Hodgkins, lymphoma, the rosette test was performed with erythrocytes of mice of the C57 BL strain according to the method of Stathopoulos and Elliott. Lymphocytes were isolated from peripheral blood, and in four cases also from lymph nodes, on an Uropolinum-Polfa gradient. In healthy subjects, 12.6 +/- 6.9% of lymphocytes possessed receptors for mouse erythrocytes. The values in the group of patients were significantly higher (31.8 +/- 26.8%). Moreover, in the group of chronic lymphocytic leukemia, the values (68.0 +/- 20%) were significantly higher than in the group with lymphosarcoma (9.7 +/- 7.7%). Results of the rosette test with lymphocytes isolated from lymph nodes were the same as with blood lymphocytes of these patients: a high level of 68% was observed in a patient with chronic lymphocytic leukemia, and low levels (between 2% and 9%) in three patients with lymphosarcoma. It was concluded that the rosette test with erythrocytes from mice of the C57 BL strain detects low differentiated forms of B lymphocytes and could be useful in the diagnosis of chronic lymphocytic leukemia and differentiation from lymphosarcoma.


[Morphology of pulmonary atelectasis in patients operated on and not operated on taking into account pulmonary surfactant state]. The results of clinico-anatomical analysis and of histological examinations of 210 cases of atelectasis with simultaneous study of lung surfactant (126 cases) are described. Electron microscopic examinations of lung tissues were conducted in 8 cases of early autopsy. The postoperative atelectases were compared with those in nonoperated patients. The postoperative atelectases were characterized by substantially larger lesions and prevalence of reflectory, aspiratory, and polyetiological types of lesions. A certain dynamics of changes in the lung surfactant activity was established: a substantial increase of the activity during in the acutest phase of atelectasis and its significant decline towards the end of the first week of the disease. The changes of the surfactant indices directly depend on the synthesizing activity of type II pneumocytes. The decrease of the surfactant occurs secondarily as atelectasis advances.


[Determination of drug-albumin binding in buffered bovine serum albumin solutions applying a modified ultrafiltration process (author's transl)]. The construction of two ultrafiltration devices which, under application of high-pressure liquid chromatographic (HPLC) technique, allow the determination of unbound portions of drugs in albumin solutions is described. The usefulness of this method and its advantages compared with prevailing methods are demonstrated by means of determination of the unbound portion of carbamazepine, chlorpromazine, phenobarbital and phenprocoumon in buffered bovine serum albumin solutions (4%). The binding of each drug to albumin was characterised by determining the overall binding constant (K1), the apparent binding constant (k+), the free reaction energy (delta F0), the number of binding sites per albumin molecule (n), the rate of taking up of drug by albumin (V) and the unbound portions of the drug (alpha).


[Human thyroglobulin radioimmunoassay--Preliminary results in serum and thyroid tissue (author's transl)]. A specific double antibody radioimmunoassay for the measurement of Thyroglobulin (HTg) in human serum was developed according to the method of Van Herle. The sensitivity of the assay is 2.5 ng/ml. The mean concentration of HTg in 47 normal subjects was 15,1 ng/ml. Elevated HTg levels were found in patients with Graves' disease (12 cases) and in patients with metastases of differentiated thyroid carcinomas (14 cases). In patients with metastases of differentiated thyroid carcinoma the Tg level increases under stimulation by endogenous TSH. Sera obtained after total thyroid ablation for thyroid carcinoma did not contain demonstrable amounts of HTg. This technique was also applied to the assay of HTg in thyroid tissue.


[A contribution to the stereospecific synthesis of antifungal imidazolyloxime-ethers/Oxiconazole nitrate (Sgd 301-76), a new broadspectrum antifungal agent (author's transl)]. A stereospecific synthesis of antifungal imidazolyloxime-ether derivatives is reported. The compound Sgd 301-76 (oxiconazole nitrate) = (Z)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)-O-(2,4-dichlorobenzyl)-ethanoneoxime-nitrate was selected for clinical trials. The (E)- and (Z)-assignments, respectively, were made on the basis of 1-H-NMR-spectral data.


[Structure-activity relationship of isocamphane derivatives/Two examples (author's transl)]. In a short review the dependence of the activity of isocamphane derivatives on their chemical structure is shown by means of two examples. In the first example--that of drug research--the choleretic activity of Felogen analogues is discussed. In the second example the dependence of the camphoraceous odour on the molecular shape in accordance with Amoore's stereochemical theory of odour and the influence of a certain osmophoric group on the nuance of a fragrance is shown.


[Statistical and epidemiological studies on cases of infectious mononucleosis treated in the Infectious Diseases Division of the Livorno Hospitals between 1964 and 1977]. Reference is made to a series of 133 patients with infectious mononucleosis admitted to a hospital department over a period of 14 yr. The incidence of the disease is assessed in terms of sex, age, season, and occupation. Its duration and the average length of hospital stay are also computed. Particular attention is directed to 25 cases with a negative serum finding.


[Blood count, leukocyte alkaline phosphatase activity, and blood sugar levels in Wistar rats as a function of the reaction type (level of higher nervous activity) of the animal]. The corpuscular blood composition, ALP activity and glucose level of 20 E+ and 20 E- adult male Wistar rats were measured without stress. We wanted to find differences due to the specific reaction type--emotive/non-emotive--of the animals. E+ animals had higher counts of small erythrocytes and a higher total number of leucocytes than E- rats. When the compositions of the blood of several inbred strains were compared, the composition of the red blood, total number of leucocytes and lymphocytes of E- -Wistar rats and E- -Sprague-Dawley rats were most similar. Differences in the activity of the ALP and in the glucose levels we found are similar to those in literature on this topic. When measured in a condition of inactivity the lower glucose values of E+ Wistar rats correspond to the excretion of smaller amounts of urinary catecholamines. Our findings, as well as those mentioned in the literature, confirm the assumption that the reaction type--which corresponds to the type of higher nervous activity--influences all functions of the organism including the composition of the blood.


Effects of S-methylmethionine (vitamin U) on experimental nephrotic hyperlipidemia. The effects of S-methylmethionine sulfonium chloride (MMSC, vitamin U) on aminonucleoside-induced nephrotic hyperlipidemia in rats were investigated. We found that repeated oral administration of MMSC (dose: daily 1000 mg/kg) exhibited significant amelioration of plasma chloresterol and phospholipids levels. Also, the treatment improved nephrotic syndrome itself by producing an increase of urinary volume and a decrease of urinary protein excretion. The results suggest that MMSC may be useful as single or combined therapy for human nephrotic syndrome and its related hyperlipidemia as a safety drug.


Direct and indirect effects of ethanol on isometric tension in rabbit isolated strip auricle. Besides the negative inotropic action of ethanol on cardiac muscle, this paper describes also an "indirect effect" which appears when the ethanol treated isolated strip auricle preparation is washed with low Ca Tyrode solution. This effect depends on the previous concentration of ethanol in the isolated organ bath. A kinetic analysis of the washout effect of ethanol shows that just the first tension diminution phase is altered by the action of ethanol. The results suggest that alcohol may act also on inner membranes of myofibrils.


[The effects of oxprenolol on cardiac function during hypovolemic shock in dogs (author's transl)]. Effects of beta-receptor blockade by oxprenolol, which significantly prevented subendocardial necroses during hemorrhagic shock in dogs, on shock tolerance and myocardial function were analyzed. Overall mortality was not altered by beta-receptor blockade. Cardiac output and contractility (dp/dtmax) before, during and after a hypovolemic period of 120 to 210 min with mean arterial pressure = 40 +/- 5 mmHg showed no significant difference with or without oxprenolol treatment. Increase of heart rate during hemorrhage was abolished completely by oxprenolol and as a consequence of this duration of the diastolic filling period was about three times longer (p less than 0.001) and stroke volumes were greater. Stress metabolism was improved. Hyperglycemia and metabolic acidosis were diminished and arterial oxygen tension was higher in the treated group. Incidence of lethal ventricular fibrillation was higher and pulsus alternans found only in the control group. The beneficial effects of beta-receptor blockage on the course of hemorrhagic shock are explained by the prevention of the catecholamine induced tachycardia and thereby increased coronary perfusion and decreased myocardial oxygen consumption and by the intrinsic sympathicomimetic activity of oxprenolol.


Effect of verapamil and nifedipine on ischemic myocardial metabolism in dogs. The effect of pretreatment with verapamil (100 micrograms/kg i.v.) or nifedipine (10 micrograms/kg i.v.) on ischemic myocardial metabolism was studied in dogs anesthetized with pentobarbital. The results are summarized as follows: 1. Verapamil or nifedipine lowered both systolic and diastolic blood pressures markedly, and increased heart rate slightly. 2. Verapamil or nifedipine increased both endo- and epicardial phosphorylase activities significantly. 3. Coronary artery ligation increased the phosphorylase activity, and also increased the levels of glucose-6-phosphate, fructose-6-phosphate, and lactate, and decreased the levels of glycogen, fructose-1,6-diphosphate, and phosphocreatine in both endo- and epicardial layers, without affecting the level of the endo- and epicardial adenosine triphosphate. 4. In the presence of verapamil or nifedipine, coronary artery ligation did not increase but decreased the phosphorylase activity that had been increased by verapamil or nifedipine alone. 5. Changes in the levels of intermediates induced by coronary artery ligation were not markedly influenced by pretreatment of the dog with verapamil or nifedipine.


[The influence of cephaloridine on several methods for the determination of creatinine (author's transl)]. Cephalosporins, especially cephaloridine (Kefspor), are examined in vitro for their influence on several methods for the determination of creatinine. Two chemical methods frequently used in clinical laboratories (Jaffé test reaction) and one enzymatic creatinine analysis are used for this purpose. Depending on the quality of cephalosporin added, excessively high creatinine contents are determined with the two chemical methods, whereas there seems to be no effect on the enzymatic creatinine determination method. The significance of these findings for clinical diagnostics is discussed.


Penetration of antibiotic into interstitial tissue fluid following parenteral administration of lysine cephalexin. Serum and interstitial fluid levels of antibiotic have been measured at various times following i.m. administration of equivalent doses of lysine cephalexin and sodium ampicillin, in a cross-over design, to dogs fitted with s.c. implanted silastic "tissue cages" and the results subjected to pharmacokinetic analysis. Serum concentrations of cephalexin were consistently higher than those of ampicillin and elimination half-lives were calculated as 1.73 h and 0.87 h, respectively. The rate of appearance of cephalexin in the interstitial fluid (Ka 1.741 h-1 was faster than that for ampicillin (Ka 0.946 h-1) and the maximum concentration obtained also proved to be higher. The half-life of cephalexin in the interstitial fluid (6.79 h) was almost four times longer than that in serum whereas that of ampicillin (2.03 h) was only a little more than twice as long. As a consequence a greater concentration and retention in interstitial fluid was obtained with cephalexin at all times tested. Since the interstitial fluid levels of cephalexin were still relatively high 8-12 h after the administration of a single dose repeated administration of lysine cephalexin 2 or 3 times daily is expected to result in a beneficial accumulation of cephalexin in the interstitial fluid.


Metabolism and pharmacokinetics of 4-(p-chlorophenylthio)butanol (W-2719) in the rat and dog. 4-(p-Chlorophenylthio)butanol (W-2719) administered orally to rats and dogs is rapidly absorbed, metabolized and excreted. The only major biotransformation product found in blood was p-chlorophenylthioacetic acid (W-2683). No W-2719 or the intermediary p-chlorophenylthiobutyric acid (W-2718) could be found in plasma after oral administration of the drug. When W-2719 was given i.v. to dogs, both W-2719 and W-2718 appeared in plasma but each had a very short half-life of about 10 min. After an oral dose of W-2719 to dogs the plasma content of W-2683 peaked at 4-6 h, amounting to approximately 20% of the dose. More than 91% of the dose was excreted with 48 h, 83% in urine and 9% in feces. The predominant excretion product in urine was p-chlorothiophenol, most of which was excreted in a conjugated form. The other major urinary metabolite was W-2683, while smaller amounts of W-2718 and unchanged drug were also found. No significant effect of prolonged dosing of 14C-W-2719 to dogs was observed on plasma 14C levels, peak time, 14C half-life or excretion and composition patterns.


3,3-Bis-(4-hydroxyphenyl)-7-methyl-2-indolinone (BHMI), the active metabolite of the laxative sulisatin. The disodium salt of the sulphuric diester of 3,3-bis-(4-hydroxyphenyl)-7-methyl-2-indolinone (sodium sulisatin, Laxitex), a synthetic laxative with two phenolic groups esterified with sulfate, has been studied in order to find out if its laxative properties may be attributed to the unaltered compound or to its diphenolic derivative BHMI. We first studied the effect of homogenates of the gastrointestinal tract of rats and of rat cecal content of the hydrolysis of sulfate ester bonds of sulisatin. Results show that sulisatin can be hydrolyzed by cecal content while homogenates of stomach, small intestine and large intestine have no hydrolytic effect. Sulisatin is also a substrate of arylsulfate sulphohydrolase obtained from the snail Helix pomatia. The unaltered drug has no effect on the intestinal motility since it does not change the intestinal transit speed in rats pretreated with neomycin sulfate. Sulisatin (1.5, 3 and 6 mg) is unable to inhibit water absorption in rat colon while small amounts of BHMI (15 and 30 micrograms) may inhibit it significantly. It is concluded that sulisatin passes unaltered through the small intestine and is hydrolyzed in the large intestine by the intestinal microflora to its diphenolic derivative BHMI, which is responsible for the laxative activity of the drug.


The gastrointestinal and autonomic effects of 3-methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide hydrochloride (tiquinamide). 3-Methyl-5,6,7,8-tetrahydroquinoline-8-thiocarboxamide hydrochloride (tiquinamide), a potent gastric anti-secretory compound, affords good protection against stress- and chemically-induced gastric and duodenal erosions. It causes a dose-related delay in gastric emptying and intestinal transit, and does not have a primary effect on gastric mucosal blood flow. The only actions of tiquinamide on the peripheral autonomic nervous system are weak, but apparently specific, histamine H2-receptor blocking activity, and non-competitive inhibition of acetylcholine and histamine responses at 10(-3) mol/l. Since no other effect on isolated tissues can be detected, it seems unlikely that the antisecretory action of tiquinamide involves a direct action on the peripheral autonomic nervous system.


[The effects of flavonoids on rat liver during chronic palloidin intoxication/Morphological and biochemical studies (author's transl)]. Continuous intraperitoneal administration of phalloidin (0.5 mg/kg body weight/day) leads to an alteration of intracellular contractile acto-myosinfilaments in rat liver. The hepatocytes show an accumulation of fibrillar material with some loss of contractile function of the pericanalicular web. Biochemically an increase of serum transaminases and alkaline phosphatase occurs. Histochemically the liver exhibitis changes in the distribution of some hepatocellular enzymes. The influence of the flavonoid (+)-cyanidanol-3 on these phalloidin-induced lesions was studied by histochemical, immunofluorescence and biochemical methods. The results imply, that (+)-cyanidanol-3 is probably protecting the plasma membrane of hepatocytes and therefore reduces the entrance of phalloidin into the cytoplasm. In addition an increased activity of the reticuloendothelial system was observed, perhaps resulting from the flavonoid administration. Both effects could be discussed as mechanisms of flavonoid action in the liver.


ATP contents and condensed configuration of rat liver mitochondria induced by rising ionic strength. Experiments using shifts in ionic strength between 0.15 and 0.8 mol/l revealed that from 0.3 mol/l KCl onward toward higher concentration condensed mitochondria are observed. Parallel with increasing condensation, the ATP contents were found to rise up to 0.6 mol/l KCl. At 0.8 mol/l KCl already destroyed mitochondria were found. Also, at this concentration of KCl, ATP contents did not rise any longer. The SH reagent 2-mercaptopropionylglycine was effective at about physiological ionic strength only. Up to concentrations of 0.6 mol/l KCl H+/O ratios were not different from the controls at physiological ionic strength, but the effect of valinomycin was effectively reduced by high concentrations of KCl. It is suggested that condensation of mitochondrial structure is correlated with increases in ATP content.


The effect of 2-ethyl-3-(4-hydroxybenzoyl)-benzofuran (benzarone) on the metabolism of arterial tissue and cultured arterial smooth muscle cells. Studies on the action of 2-ethyl-3-(4-hydroxybenzoyl)-benzofuran (benzarone) on the metabolism of cultured arterial smooth muscle cells and arterial tissue had the following results: 1. On incubation of calf arterial tissue in the presence of 0.03--0.1 mmol/l benzarone (8--26 micrograms/ml medium) the metabolic transformation of [14C]-glucose to [14C]-lactate and 14CO2 and the incorporation of 14C radioactivity into the total lipids is not significantly altered as compared with control values. In cultured human arterial smooth muscle cells 0.03 mmol/l benzarone stimulates the incorporation of [14C]-acetate and [3H]-palmitate into the cellular lipids while the receptor mediated uptake of homologous low-density lipoproteins (LDL) by the cells and their release are not influenced. 2. In concentrations greater than 0.2 mmol/l benzarone the glucose utilisation of arterial tissue is enhanced, while the labelling of lipids, in particular the labelling of the triglyceride fraction, is depressed. Under the same conditions the protein biosynthesis and the incorporation of [14C]-acetate and [3H]-palmitate into the total lipids of cultured arterial smooth muscle cells are decreased.


Effects of unsaturated fatty acids in phospholipids on the in vitro activation of the lipoprotein lipase and the triglyceride lipase. The effects of different types of phospholipids on the lipoprotein lipase (LPL) and on the hepatic triglyceride lipase (TGLH) were studied by comparative in vitro incubation. Substrates were prepared by homogenization in glycerol of 3H-labelled triolein plus phosphatidylcholine (either dipalmitoyl PC, or ovolecithin or highly unsaturated PC, EPL Nattermann). Enzymes were obtained from rat adipose tissue, myocardium, lungs and liver and human adipose tissue and post-heparin plasma, respectively. The enzyme activities as determined in mmol/ml medium showed differences of highly statistical significance (p less than 0.001). In any tissue investigated the enzyme activities of LPL or TGLH followed the sequence: highly unsaturated PC (EPL) greater than ovo-lecithin greater than dipalmitoyl-lecithin. This was true for the enzymes of rat and human origin as well. It was concluded that the observed LPL and TGLH activation may account for the beneficial therapeutic effects of highly unsaturated phosphatidylcholine (EPL) in human hyperglyceridemias.


3-Chloro-4-(phenylsuccinimido)-benzenesulfonamide (GS 385), a new anticonvulsant: its quantitative determination, pharmacokinetics and metabolism using high performance liquid chromatography. A high-performance liquid chromatographic method (HPLC) involving dual wave length detection was developed for the determination of a new anticonvulsant, 3-chloro-4-(phenylsuccinimido)-benzenesulfonamide (suclofernide, GS 385, Sulfalepsin), and three of its metabolites: 3-chloro-4-(p-hydroxyphenylsuccinimido)-benzenesulfonamide (I), 3-chloro-4-(3'-phenylsuccinamyl)-benzenesulfonamide (II) and 3-chloro-4-(2'-phenylsuccinamyl)-benzenesulfonamide (III). The concentrations of GS 385 in blood samples from epileptic patients under chronic treatment with this drug was found in the range of 8--11 micrograms/ml. Pharmacokinetic curves of GS 385 blood levels in rats receiving single doses of the drug showed a maximum concentration of 22--23 micrograms/ml 1.5 h after oral application. The quantity of GS 385 in rat feces, bile and brain was also estimated. The p-hydroxy (I) and acid (II, III) metabolites of GS 385 were detected in both rat feces and bile, whereas only the acid metabolites were found in rat urine.


[Comparative pharmacokinetics of paracetamol in humans following single oral and rectal administration (author's transl)]. The pharmacokinetic behaviour of N-acetyl-p-aminophenol (paracetamol) after single dose applications of 500 mg and 1000 mg dosages in the form of liquids, tablets and suppositories was compared. The estimation of the pharmacokinetic constants by a simultaneous curve fitting with a direct search procedure, based on an open two-compartment model, showed for the liquid as well as for the tablet formulation a good conformable and dosage proportional behaviour of the relative bioavailability. In opposite to the oral application, the suppositories had a significantly reduced invasion kinetics with a comparable elimination kinetics characterized by a lowering of Cmax and an increase of Tmax-values with comparable AUCs. The calculation of collapse-coefficients showed, with the exception of one suppository formulation, for all administrations a pharmacokinetic behaviour deviating from an open one-compartment model. The clinical consequences resulting from the pharmacokinetic behaviour of the different galenic formulations and routes of administrations are discussed.


Single-dose pharmacokinetics of the trypanosomicide benznidazole in man. The single-dose pharmacokinetics of N-benzyl-2-nitro-1-imidazole acetamide (benznidazole, Radanil) following administration of 1 tablet Radanil (100 mg) was investigated in six healthy volunteers. The absorption of the drug was fairly rapid. Peak plasma levels of 2.2--2.8 microgram/ml were reached after 3--4 h. The log c versus time curves showed little interindividual variation. The shape of the curves indicates that the drug follows the kinetics of a one-compartment model. The elimination half-lives ranged from 10.5 to 13.6 h, with a mean value of 12 h. The relative bioavailability of the compound (oral tablet versus oral solution) was checked in three of the subjects and found to be 91.7% on an average.


[Treatment of various types of hyperlipoproteinaemia with a combination of Mg-chlorophenoxy-isobutyrate and mesoinositol-hexanicotinate (author's transl)]. 50 patients with different types of hyperlipoproteinaemia were treated with a combination of Mg-chlorophenoxyisobutyrate (700 mg) and mesoinositol-hexanicotinate (500 mg) (Atroplex) twice daily. 7 patients had type IIa, 39 patients type IIb or IV and 4 patients type V. After a period of one month without any treatment the patients were treated during two months. While the effects of this combination on cholesterol of type IIa patients was poor, the drug had an excellent lipid-lowering effect in the patients with type IIb, IV and V. After 14 days' treatment the plasma cholesterol and triglyceride levels in patients of type IIb or IV were significantly lowered. This effect became even more pronounced after one-month treatment. There was no significant difference between the effect of one-month treatment and that of two-month treatment. About two-thirds of the patients of type IIb or IV were responders. No serious side effects could be observed during our study.


[Circadian-induced change in the pharmacokinetic pattern exemplified on hexobarbital/Retrospective analysis of experimental data (author's transl)]. The present study dealt with data from a study to evaluate circadian influences on the pharmacokinetics of hexobarbital. It could be seen that the pharmacokinetic model changes from an open one-compartment model to an open two-compartment model in dependence of the time of application. The curve fitting to an open two-compartment model reached high correlations when the test substance was applied at 18 h. The pharmacokinetic parameters to be evaluated did not fit to literature data. After application of the substance at 10 h in the morning the curve fitting to an open one-compartment model correlated highly. The pharmacokinetic parameters at this time comparable with the known literature.


[New evaluation and presentation of dose effect studies]. One of the bases of drug research are the experimentally gained dose-effect curves. Projecting these correlations upon the plane of a co-ordinate system distortions ensue as will have to be demonstrated. Rules to avoid these projective distortions are discussed, gaining simple linear relations between dose and effect. Some examples are described.


[Chromatographic separation of racemic thalidomide and teratogenic activity of its enantiomers (author's transl)]. Racemic thalidomide is chromatographically separated on optically active polyamide giving both enantiomers. After i.p. administration only the S-(-)-enantiomer is teratogenic on SWS mice and Natal rats.


[The broncholytic effect of carboanhydrase inhibitors in subjects with healthy lungs (author's transl)]. Carboanhydrase inhibitors are said to have a positive effect on respiratory insufficiency. We examined this, especially regarding the bronchial system. Actions and reactions of the human bronchial system can be followed by measurement of the anatomical dead space breath by breath. We have developed a new method which was tested by classical broncho-effective substances. Our experiments show in case of two men with healthy lungs that the three carboanhydrase inhibitors acetazolamide, methazolamide, and dichlorphenamide have a pronounced broncholytic effect. The effect is greater than that of fenoterol. In addition the bronchial peristalsis and the bronchial compliance are increased. In contrast to fenoterol carboanhydrase inhibitors have no cardiac side effect.


[Analytical data and preparation of important 3-hydroxy-5-phenyl-1,4-benzodiazepin-2-one derivatives (author's transl)]. The article describes analytical data (TLC, IR, MS) of 7-chloro-1-methyl-1,3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one (3-hydroxydiazepam) and 7-cyclopropyl-methyl-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazpin-2-one (3-hydroxy-prazepam). Analytical properties of important derivatives (N-oxides, 3-acetoxy compounds, re-arrangement products) are also reported. Besides preparation methods are given for the synthesis of these substances, considering in particular preparation as solution-reactions as well as reaction on the TLC-plate.


[Synthesis of several benzyloxphenyl derivatives with local anesthetic activity (author's transl)]. Several 2- and 4-benzyloxy- and 4-(2'- and 4'-substituted) benzyloxy-beta-substituted amino-propiophenones, some of the corresponding alcohols, some 4-benzyloxy-alpha-substituted amino-acetophenones were synthetised and tested for their pharmacological activity.


New approach of the extrapolation procedure in the determination of acid-base constants of poorly soluble pharmaceuticals. A new approach to the graphic extrapolation procedure is proposed for the determination of pK-value of pharmaceuticals poorly soluble in water. It is based on a direct potentiometric method for the determination of acid-base constants in non-aqueous and mixed solvents in which no preliminary calibration of the galvanic cell is needed (glass and calomel electrodes). In this way the applicability of the graphic extrapolation procedure is enlarged for a great number of organic solvents miscible with water for which no buffer pH-standards are available.


Investigation of the common mechanism of action of antibacterial compounds containing gamma-pyridone-beta-carboxylic acid structure by principal component. On the basis of 576 in vitro antibacterial positive results of 99 compounds containing gamma-pyridone-beta-carboxylic acid structure conclusions have been drawn on the mechanism of action of the derivatives by principal component analysis. It has been found that the compounds exert their effect essentially by influencing two types of physiological processes or series of processes. The more important of the two "mechanisms", responsible for 50-95% of the activity of the compounds, is common for the compounds investigated, and is associated with the gamma-pyridone-beta-carboxylic acid structure.


Impedance rheoplethysmography. The role of estimation of vasodilatory activity. The activity of a number of vasodilatory drugs was studied, with the help of impedance rheoplethysmography, on the vascular bed of the hind limb of anaesthetized rabbits. The vasodilators under study induce changes in rheoplethysmogram to a more or less important degree. The results were compared with those obtained with electromagnetic flowmetry. This method seems to be useful in the study of vasodilators because it allows to measure their effects and the duration thereof in a non-aggressive way. This method using flowmetry, allows to study in an analytical way those substances' effects on artery, vein and also capillary.


Effects of niludipine (Bay a 7168) on the cardiovascular system with a note on its calcium-antagonistic effects. 1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid-bis-(2-propoxyethyl)-ester (niludipine, Bay a 7168), a newly synthesized vasodilator, was three to ten times more potent than nifedipine in dilating the coronary artery of the canine heart-lung and isolated fibrillating heart preparations, but had weaker direct cardiac depressant effects. This drug had a strong and highly selective calcium antagonistic effect on the smooth muscle and also had stronger vasodilating activity on renal and femoral vascular beds as compared to nifedipine. It inhibited myocardial oxidative metabolism in canine and guinea pig hearts.


Antihypertensive effect of Niludipine (Bay a 7168) on conscious renal-hypertensive dogs. In conscious renal-hypertensive dogs (one kidney Grollman type) oral administration of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid-bis-(2-propoxyethyl)-ester (niludipine, Bay a 7168) (1 and 3 mg/kg) produced a rather prompt fall of blood pressure and an increase in heart rate. With 3 mg/kg p.o. of niludipine a fall of blood pressure was marked at its peak effect attained about 45 min after dosing and lasted about 3 h. Prior administration of propranolol (30 mg/kg p.o.) greatly prevented an increase in heart rate accompanying the fall of blood pressure produced by 3 mg/kg p.o. of niludipine but was of no effect on the antihypertensive action. These results, taken together with previous results indicating niludipine to have a potent coronary vasodilator action, suggest that niludipine will be useful as an antihypertensive drug, especially when hypertension is associated with ischemic heart disease or when the reduction of blood pressure is urgent. Combined use of niludipine with a beta-adrenergic blocking agent is recommended.


The effects of a deproteinized blood extract on the myocardial changes developing during experimentally induced intermittent hypoxia. Myocardial hypoxia induced by intermittent cross-clamping of the aorto-coronary bypass during closed-heart surgery provokes progressive derangement of the myocardial metabolism. The principal changes observed after 18 min of hypoxia (without protection) were a marked swelling of mitochondria, distortion of cristae, reduction in glycogen content, interstitial oedema, focal destruction of I-band material and coagulation necrosis of myofilaments. Another characteristic change is the decoupling of oxidative phosphorylation. These morphological and biochemical changes were successfully prevented by the administration of Solcoseryl (Actihaemyl), a dialysis concentrate from deproteinised calf blood. The less pronounced structural and functional mitochondrial changes in protected hearts suggest that the myocardium is able to tolerate a more severe hypoxia under Solcoseryl protection.


Effect of perhexiline maleate on lipid metabolism in the rat. The effect of long-term (7-11 weeks) administration of perhexiline maleate (Pexid) on liver, lung, plasma and bile lipids was studied in adult male Sprague-Dawley rats. Maximum non-toxic doses of the drug (80 mg/kg/day) produced a fall of total cholesterol concentration in liver, lung and plasma, a fall of total lung phospholipid concentration, and an elevation of bile flow and biliary bile acid excretion. Minimum lethal doses (160 mg/kg/day) produced an increased liver concentration of total phospholipids and gangliosides and decreased lung concentration of gangliosides. Plasma transaminase activity was not significantly affected in either of the treated groups.


Comparative study of the inductive effect of two psychomoderators--tetrabamate and complexe 1656--and of phenobarbital on liver microsomal enzymes in rats. Tetrabamate (Atrium) and Complexe 1656, two psychosedative drugs, are complexes formed by phenobarbital with its N-substituted derivatives. We have studied the induction effect of all these compounds on the microsomal liver enzymes in male rats. Tetrabamate and Complexe 1656 were found to be equally effective in increasing the amount of microsomal proteins, cytochrome P-450 and the in vitro aniline p-hydroxylation and amino-pyrine N-demethylation activity. These effects were similar to those obtained after a treatment with an equivalent dose of phenobarbital. Febarbamate and difebarbamate had no significanteffect on microsomal enzymes. The inductive effect of tetrabamate and of its analogue seems essentially due to the phenobarbital content of these complexes.


Studies of absorption, distribution and excretion of 2,6-xylidide of 2-pyridone-3-carboxylic acid (isonixine). The absorption, tissue distribution and excretion of 14C-labelled 2,6-xylidide of 2-pyridone-3-carboxylic acid (isonixine) have been investigated in the rat after intragastric and intraduodenal administration. Isonixine was rapidly absorbed from the gastro-intestinal tract. The half-life of absorption was 3.15 h. The product was soon distributed in the whole organism. The radioactive metabolites were excreted rapidly, the major route being the urinary tract (85% in 72 h). There was no evidence of long-term storage of isonixine in the body. These results were confirmed by autoradiographic studies in the mouse after oral administration.


The effect of some pyrimido-pyrimidine derivatives on blood coagulation and platelet aggregation. Two pyrimido-pyrimidine derivatives, Chinoin 105 and Chinoin 123, respectively, were investigated with respect to the inhibition potency on platelet aggregation. It was shown that Chinoin 105 is a powerful inhibitor of aggregation of thrombocytes without effect on routine coagulation parameters in vitro. Chinoin 123 has a moderately inhibitory effect on the investigated reactions. An additive effect of Chinoin 105 to the inhibitory potential of PGE1 on platelet aggregation was proven.


Radioisotopic and synthetic studies related to caroxazone metabolism in man. Labelled 2-oxo-2H-1,3-benzoxazine-3(4H)-acetamide (caroxazone), has been synthesized by condensing N-(2-hydroxylbenzyl/glycinamide with 14C phosgene. Metabolic studies were performed administering the labelled drug to man and recovering metabolites from the urines. Beside the unchanged drug, five metabolites were identified and confirmed by synthesis, namely (3,4-dihydro-3-carboxamidomethyl-2-oxo-2H-1,3-benzoxazin-4-yl)urea (IX), N-carboxamidomethyl o-hydroxymethylphenyl carbamate (V), 4-methoxy-2-oxo-2H-1,3-benzoxazine-3(4H)acetamide (VIIIa), 2-oxo-2H-1,3-benzoxazine-3(4H)acetic acid (III) and 4-hydroxy-2-oxo-2H-1,3-benzoxazine-3(4H)acetamide (IV).


[Circadian fluctuations of pharmacokinetic parameters after oral administration of hexobarbital (author's transl)]. To 4 male and 2 female subjects hexobarbital was applied orally at different times of the day: 2, 10, 18 h. Serum concentrations of hexobarbital were determined by HPLC procedure and the resulting pharmacokinetic parameters in a rotating iterative program. Application at 18 h resulted in a shorter invasion time, a higher maximum concentration and a delayed elimination; in addition, the AUC was elevated in relation to application at 2 or 10 h. In the 2 female subjects a different pattern was observed. The results lead to the assumption that application of hexobarbital is more effective in the evening than in the morning.


[Comparative study of relative biovailability of several spironolactone formulations in a steady-state test (author's transl)]. By the US Food and Drug Administration spironolactone is regarded as a drug with problems related to bioavailability. A steady-state study was performed comparing the 50- and 100-mg formulations of two manufacturers with each other. Applying a fluorimetric method to both canrenone and canrenoate--the major biologically active metabolites of spironolactone--the two brands were compared in 11 volunteers for the 50 mg, and in 10 volunteers for the 100 mg dosage form.


The effect of essential fatty acid deprivation on the metabolic transformations of [1(-14)C]linolenate in developing rat brain. Linolenic acid undergoes rapid metabolism in the brain of 21-day-old rats. Radioactivity is rapidly transferred from linolenic acid to the C20 (n--3) fatty acids while that in docosapentaenoic acid (22 : 5 n--3) and docosahexaenoic acid (22 : 6 n--3) gradually increases. A greater proportion of the radioactivity is associated with the polyunsaturated and less with saturated and monounsaturated fatty acids in essential fatty acid-deprived rats relative to controls.


[Effect of the main components of blood on pulmonary surfactant]. The effect of the main blood constituents on surface activity of substrates containing pulmonary surfactant has been investigated. Mixing of hemolysate, serum, albumin, and fibrinogen with lung extracts and washings, their application in the form of a monolayer or administration into the hypophase of the washing monolayer raised the surface tension (ST) of these substrates. Hemoglobin, serum lipids and cholesterol exerted an opposite action. The contact of all above blood constituents, that elicited varied effects on the ST of the medium containing the surfactant with pulmonary vesicles led to an increase in their stability coefficient determined according to the method of Pattle.


Thyroid adenylate cyclase stimulating immunoglobulins in thyroid diseases. The occurrence of serum immunoglobulins with capacity to stimulate thyroid adenylate cyclase (TSAb) was studied in seventy-two healthy volunteers and 120 unselected patients with various thyroid diseases. A high frequency of TSAb (82.5%, P less than 0.00006) was found in Graves' disease, while TSAb was present only in 13--20% of serum from patients with nontoxic nodular goitre, nontoxic diffuse goitre, toxic adenoma, toxic nodular goitre and myxoedema. These patients had low level of TSAb compared to patients with Graves' disease. In patients with Graves' disease there was no correlation between the level of TSAb and hormonal status except serum triiodothyronine (rs = 0.29, P less than 0.05), and no relation with eye involvement or presence of microsomal thyroid antibodies was found. The results indicate that the human thyroid adenylate cyclase assay system with 1 hour incubation periods is a sensitive method for detection of immunoglobulins with TSH-like capacity to stimulate the thyroid gland.


Effects of radioiodine on thyrotrophin binding inhibiting immunoglobulins in Graves' disease. We have studied the effects of 131I therapy on thyrotrophin binding inhibiting immunoglobulins (TBII) in fifty-five patients with Graves' disease and five patients with toxic multinodular goitre (MNG). A group of forty patients with Graves' disease and four patients with toxic MNG were treated with drugs and acted as controls. In 78% of patients treated with 131I there was a marked increase in the serum TBII activity during the 3 months following therapy, whereas drug-treated patient showed a decrease (77%) or no change in TBII activity over the same period. TBII activity was not detectable in patients with toxic MNG before or after drug or 131I therapy. Consideration of the mechanisms involved in the changes in serum TBII activity after 131I treatment or during drug treatment provide insight into the basic defects responsible for the development of hyperthyroid Graves' disease and suggest that both the thyroid and immune system are involved.


Hepatitis B surface antigen in pregnant women. Screening of HBsAg in 289 randomly selected normal pregnant women was done with counterelectrophoresis. Ten percent were found to be HBsAg positive. All of the 289 cord blood samples were HBsAg negative. Babies born to the HBsAg positive mothers were followed 2-8 months (average 3.5 months) after delivery and 37.5% were positive for HBsAg. Accordingly, the vertical transmission of HBsAg was postulated to occur during labor or after birth.


Characterization of a cellulase producing mold, Trichoderma sp. W-10 isolated from infected mushroom spawn. A potent cellulase producing mold, Tichoderma sp. W-10 suitable for enzyme production with solid state culture was isolated from infected mushroom spawn, its characteristics and taxonomic studies were carried out. As a result, this mold was identified as Trichoderma koningii (Oudemans) according to the keys of Gilman and Rifai's classification system and the morphological features described by Komatsu. Meanwhile, a detail survey of physiological, cultural and biochemical characteristics were also described.