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By: Bertram G. Katzung MD, PhD
- Professor Emeritus, Department of Cellular & Molecular Pharmacology, University of California, San Francisco
The authors suggested that the inhibition is mediated by the early molecular events of the induction process (Clark et al buy cycrin 10 mg cheap menstruation age 9. Testosterone-16β hydroxylation activity was induced up to 15-fold buy cycrin 5mg low cost womens health 2 colon, and benzyloxyresorufin O-dealkylation was induced 10- fold by phenobarbital in both species of monkey discount 10mg cycrin mastercard menstrual cup 7 fold. The same exclusion criteria were applied to the two groups: age > 50 years order 10mg cycrin otc menopause goddess, recent illness, use of medication other than phenobarbital, use of illicit drugs, alcoholism, surgery, anaesthesia, blood or blood product transfusions, chemotherapy, exposure to ionizing radiation and unusual exposure to ultraviolet radiation within 1 year of exa- mination. The daily coffee consumption was 0–20 cups among the patients and 0–12 cups among the controls. The patients serum phenobarbital concentrations were consistently in the range 10–40 μg/mL, except for two patients on maintenance doses resulting in concentrations of 5 and 6 μg/mL. Phenobarbital induced aneuploidy, but not mutation or recombinational events in fungi; it did not induce sex-linked recessive lethal mutations, somatic cell mutations or mitotic recombination in Drosophila melanogaster. Although mutations were induced in some studies, the inconsistent positive results were weak and not clearly associated with a particular locus; both positive and negative results were obtained in experiments at the Tk and Hprt loci and tests for ouabain resistance. Similarly, results for the induction of both sister chromatid exchange and chromosomal aberrations were equally divided between positive and negative in different laboratories. Single studies in cultured mammalian cells for the induction of micronuclei and aneuploidy did not show any effect of phenobarbital treatment. Variable results were also obtained in assays for cell transformation conducted in different laboratories, but the differences may have been due partly to the different transformation assays used. Assays for gap-junctional inter- cellular communication, however, also gave variable results in different laboratories even when the same Chinese hamster lung V79 cell system was used in five of six studies. In a single study with Djungarian hamster fibroblasts, cell-to-cell communi- cation was actually enhanced. In cultured human lymphoblastoid cells, no significant increase in the frequency of mutations was observed in one study, while, in cultured human lymphocytes, chromosomal aberrations were induced in two studies; sister chromatid exchange was not induced in another study. A study of mutation induction in mice carrying the Escherichia coli lacI transgene as the target did not show any effect of phenobarbital. Studies of the bone-marrow cells of mice treated in vivo also did not show induction of sister chromatid exchange, micronuclei or chromosomal aberrations after treatment with phenobarbital alone. A significant response was observed in the single-cell gel electrophoresis assay with cells from the liver of mice given phenobarbital (140 mg/kg bw) by intraperitoneal injection 24 h before sacrifice, but not effect was seen with treatment 3 h before being killed; no effect was observed in a number of other organs. The frequency of morpho- logically abnormal sperm was not increased in mice treated with phenobarbital. Phenobarbital was reported to induce chromosomal abnormalities, including trans- locations, in male mouse primary spermatocytes after oral administration for 5 or 60 days. The authors noted that no statistical analysis was performed, because of the small group sizes, which also limited interpretation of the data (Okada et al. Karyotypic analysis indicated that the most frequent aberrations in these foci were a trisomy of chromosome 1 or of its long arm and a monosomy of chromosome 3 or its short arm (Sargent et al. This finding was confirmed in part, and extended, in another study that showed that phenobarbital inhibited gap-junctional intercellular communication in primary hepatocytes from male Fischer 344 rats and B6C3F1 mice, but did not do so in primary hepatocytes from male and female rhesus monkeys or from a human [sex unspecified] donor (Baker et al. In studies of the mechanism of inhibition of gap-junctional intercellular communi- cation, it was shown that phenobarbital (20–500 μg/mL) reduced gap-junctional inter- cellular communication between B6C3F1 mouse hepatocytes in culture. It was later shown that phenobarbital-induced inhibition of gap-junctional intercellular communication is a complex phenomenon. A similar transient decrease in gap-junctional intercellular communication after a 1-h exposure to phenobarbital was observed by Mesnil et al. Later studies from this group indicated that the inhibitory action of phenobarbital on gap-junctional intercellular communication is cell-specific rather than connexin-specific. Phenobarbital treatment led to an approximate fivefold increase in the volume fraction occupied by glucose-6-phosphatase-deficient liver lesions in Cx32Y/+ mice, whereas there was no such increase in Cx32Y/– mice. Even more pronounced differences were observed with respect to tumour response, phenobarbital clearly promoting the occurrence of large hepatomas in Cx32-proficient but not in Cx32-deficient mice. These results demonstrate that functional Cx32 protein is required for tumour pro- motion with phenobarbital (Moennikes et al. After oral administration of phenobarbital (50 mg/kg bw per day for up to 6 weeks) to Sprague-Dawley rats, a direct microinjection dye-transfer assay was carried out on fresh liver slices (0. The average area of dye spread decreased after 1 week and stayed at the same level up to week 6. The area and number of Cx32 spots per hepatocyte in the centrilobular zones of the liver also decreased between week 1 and week 6, whereas there was no change in the spots in the perilobular areas. When 50 liver tumours found in the control group were analysed, an activated H-ras gene was found in 15/18 hepato- cellular adenomas and 10/14 hepatocellular carcinomas. In C3H/He mice, Ha-ras codon 61 mutations occurred in 6/21 (29%) liver tumours from untreated mice, but in 0/15 (0%) tumours from mice given a diet containing phenobarbital at a concentration of 0. The absence of mutations in codon 61 (or in codon 12) in the phenobarbital-treated mice suggests a tumorigenic mechanism different from that of spontaneous tumours. One of eight tumours from control mice also carried a codon-61 mutation (Bauer-Hofmann et al. The same group analysed the pattern of codon 61 mutations in the Ha-ras gene of glucose-6-phosphatase-deficient hepatic lesions of male C3H/He mice given a diet containing 500 mg/kg sodium phenobarbital for 52 weeks. Ha-ras mutations were found in 12/21 lesions (57%) from untreated mice and in 4/16 (25%) in the pheno- barbital-treated group (p < 0. This result suggested that both normal and mutant alleles were present in each cell of the lesions (Bauer-Hofmann et al. Tumours from C3H/He mice were also screened for p53 mutations in exons 5, 7 and 8, which contain nearly all the mutations so far described. No p53 mutations were found in any of eight tumours recovered from mice treated with phenobarbital (Rumsby et al.
Protein C and other Antiprothrom bin and antiannexin V antibodies im ply risk of cofactors involved in the binding of antiphospholipid antibodies: throm bosis in patients with system ic autoim m une diseases order cycrin 5 mg without prescription womens health run 10 feed 10. Association between the prevalence of antibodies the role of phosphatidylethanolamine in the inhibition of activated to beta(2)-glycoprotein I discount cycrin 5 mg mastercard womens health care associates jacksonville nc, prothrom bin discount cycrin 5 mg on-line womens health toning station, protein C cheap cycrin 10 mg with visa womens health tacoma, protein S, and protein C activity by antiphospholipid antibodies. J Clin Invest annexin V in patients with system ic lupus erythem atosus and 1995; 95: 309-16. Atsum i T, Kham ashta M A, Am engual O, Donohoe S, M ackie I, venous throm boem bolism. Elevated anti-annexin V antibody levels in antiphospholipid effect of antiphospholipid antibodies on the protein C system. Pregnancy loss in the antiphospholipid-antibody syndrom e: antibodies and its cofactor, beta-2-glycoprotein I, show negligible a possible throm bogenic m echanism. N Engl J M ed 1997; 337: 154- effects on endothelial cell m ediated protein C activation. Antiphospholipid antibodies accelerate plasma coagulation Autoantibodies directed against the epiderm al growth factor-like by inhibiting annexin-V binding to phospholipids: a «lupus dom ains of throm bom odulin inhibit protein C activation in vitro. Clin Exp to phospholipid-binding plasma proteins in patients with thrombosis Im m unol 2000; 120: 537-43. Throm b Haem ost 1992; 67: heparan sulfate proteoglycan in system ic lupus erythem atosus. Ferro D, Pittoni V, Quintarelli C, Basili S, Saliola M, Caroselli C, factor-like activity in m onocytes by anticardiolipin antibodies. Coexistence of antiphospholipid antibodies and endothelial Im m unol 1994; 153: 1328-32. Lupus anticoagulant and history of throm bosis are not associated Arthritis Rheum 1997; 40: 834-41. Predisposing factors to in mononuclear blood cells of patients with primary antiphospholipid throm bosis in system ic lupus erythem atosus. Fibrinolysis abnorm alities in system ic lupus syndrom e is related to high induced tissue factor expression on erythem atosus and their relation to vasculitis. Effects of hum an m onoclonal anticardiolipin antibodies system ic lupus erythem atosus and throm bosis. Br M ed J 1990; on platelet function and on tissue factor expression on m onocytes. Anti-tissue factor potential and antiphospholipid antibodies in system ic lupus pathway inhibitor activity in patients with primary antiphospholipid erythem atosus and other connective tissue disorders. Antibodies to b2-glycoprotein-I associated with antiphospholipid cells in throm bosis and vasculitis. Scand J Rheum atol 1997; 26: syndrome suppress the inhibitory activity of tissue factor pathway 145-50. Coagulation activation and fibrinolytic im balance pathway inhibitor in the antiphospholipid syndrom. Arthritis in subjects with idiopathic antiphospholipid antibodies - a crucial Rheum 1999; 42: S281. Sem in Throm b Hem ost 2000; factor activity by sera from patients with antiphospholipid syndrome: 26: 85-90. Anti-beta 2-glycoprotein-I antibodies and anti-endothelial cell Possible role of inhibition of prostacyclin form ation. Throm b for anticardiolipin antibodies binding to activated platelets: Res 1988; 50: 847-55. Effects of beta-2-glycoprotein I and monoclonal anticardiolipin in patients with system ic lupus erythem atosus. Arthritis Rheum antibodies in platelet interaction with subendothelium under flow 1999; 42: 2689-97. Antiphospholipid antibodies and complement glycoprotein-I antibodies and platelet activation in patients activation in patients with cerebral ischem ia. Clin Exp Rheum atol with antiphospholipid antibodies: association with increased 1992; 10: 455-60. Shibata S, Sasaki T, Hirabayashi Y, Seino J, Okamura K, Yoshinaga Throm b Haem ost 1998; 79: 42-5. Effect of lupus erythem atosus: association of hypocom plem entem ia with anticardiolipin/β2-glycoprotein-I com plexes on production of poor prognosis. Im m une m ediated m echanism for throm bosis: activation by anticardiolipin antibodies. Ann Rheum Dis 1991; 50: antiphospholipid antibody binding to platelet m em branes. Effect of plasma from patients with primary antiphospholipid transm em brane m igration of phosphatidylserine. Keywords: antiphospholipid syndrome; antiphospholipid antibody; beta-2 glycoprotein I; isotypes; domain speciﬁc antibodies 1. It has a wide range of potential clinical manifestations: most commonly presenting with arterial or venous thrombosis, which may occur in the absence of other risk factors. Rather, the diagnosis is made by the combination of clinical features together with supportive laboratory ﬁndings. The 5th domain contains a C-terminal extension and an additional disulphide bond that confers a positive charge resulting in an afﬁnity for anionic phospholipids. How these multiple hits align to result in thrombosis is likely to be complex and multifactorial. Indeed, peptides derived from domain 5 have been shown to display potent antibacterial activity against a variety of bacteria . Therefore, further discussion regarding how to balance these conﬂicting ideas from the standpoint of the diagnostic laboratory is required to achieve a pragmatic testing strategy that is helpful to clinicians. Methodological differences between studies such as differences in patient demographics and clinical phenotypes (e.
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Drugs against herpes virus infections are only active during the acute and not the latent phases of the viruss life cycle discount cycrin 10mg without prescription pregnancy calendar week by week. Valganciclovir (Valcyte) order 5 mg cycrin with amex womens health jackson mi, a prodrug version of ganciclovir generic 5 mg cycrin mastercard women's health center evergreen, is orally bioavailable buy cycrin 10 mg online pregnancy xanax effects. The antisense oligonucleotide fomivirsen (Vitravene) is used for the same purpose. Vidarabine (Vira-A) is an adenosine analog used for herpetic and vaccinial eye infec- tions in immunocompromised patients. Stavudine (Zerit) is another thymidine analog that can cause peripheral neuropathy. Both drugs cause peripheral neuropathy and should not be coadministered with one another. Didanosine (Videx) is an adenosine analog and can also cause peripheral neu- ropathy. Protease inhibitors can cause a characteristic “buffalo hump deposit of fat on the upper back. Atazanavir (Reyataz) can be given once daily instead of requiring multiple doses like the other protease inhibitors do. Others common protease inhibitors include saquinavir (Invirase), indi- navir (Crixivan), and nelfinavir (Viracept). It is a peptide that binds to gp41 and prevents fusion of viral and host cell membranes. Chemotherapy is useful for disseminated cancers that cannot be removed by surgery or as supplemental treatment after surgery or radiation. Using surgery or radiation to shrink the tumor before chemotherapy increases the number of dividing cells, which increases the effectiveness of chemotherapy. Adjuvant chemotherapy is used with surgery or radiation to treat unde- tectable metastases when they are small and highly sensitive to anticancer drugs. A greater proportion of nondividing cells will survive chemotherapy compared to dividing cells. They are only effective against replicating cells, particularly malignancies with a high growth fraction. Cell cycle phase specific drug classes include antimetabolites, bleomycin pep- tide antibiotics, vinca alkaloids (microtubule inhibitors), and etoposide. Cell cycle phase nonspecific drug classes include alkylating agents, most anticancer antibiotics, cisplatin, and nitrosoureas. Because of this log kill, additional rounds of chemotherapy are necessary in order to completely eradicate the tumor. Myelosuppression is common because the bone marrow is a rapidly proliferat- ing tissue. The leukopenia is greater than the thrombocytopenia, which is greater than the anemia. The drugs for which bone marrow depression is not the dose-limiting toxicity include: i. Nausea and vomiting are common side effects that can be managed with antiemet- ics, including: a. Anthracyclines (doxorubicin, daunorubicin, idarubicin, epirubicin and mitox- antrone) are cardiotoxic. Vinca alkaloids (vincristine, vinblastine and vinorelbine); platinum compounds (cisplatin, carboplatin and oxaliplatin); and taxanes (paclitaxel and docetaxel) are neurotoxic. Administering allopurinol (Zyloprim) or rasburicase (Elitek) to treat hyper- uricemia associated with tumor lysis syndrome, especially in leukemia and lymphoma patients. Some chemotherapeutic agents, particularly alkylating agents, can cause new, treatment-induced cancers up to several years after treatment. Teratogenicity and carcinogenicity can also occur, again especially with the alkylating agents. Some cancers are inherently resistant to certain agents; other cancers can develop resistance by mutation, especially after long-term administration of low doses of the drug. Resistance is minimized by short-term, intensive, intermittent therapy with combinations of drugs. Multidrug resistance occurs due to stepwise selection for the permeability glycoprotein (P glycoprotein). Because P glycoprotein is a multidrug efflux pump, its activity provides cross-resistance for several structurally unrelated drug classes. Some organs naturally express high levels of P glycoprotein, including the kidneys, intestines, liver, and pancreas. Each drug in the combination should be active against the tumor to provide max- imum cell killing within the range of tolerance. The drugs should have different mechanisms of action to kill the maximum num- ber of cells in heterogeneous tumors. The drugs should have different toxicities so that they can all be given at full strength and emergence of resistance can be delayed. The drugs are usually administered in treatment cycles and time must be allowed for host tissue recovery between cycles. They react with nucleophilic groups on nucleic acids and may cause secondary cancers like leukemias several years after treatment. Mechlorethamine (Mustargen), which is a potent vesicant with a very short half-life (a few minutes).
While some similarities in embryonic responses were noted cheap 5 mg cycrin visa pregnancy 5 weeks 2 days, the failure of closure of the cranial region in many embryos exposed to methimazole was not seen in embryos exposed to ethylenethiourea generic cycrin 10 mg line pregnancy exercise classes, and other effects seen in ethylenethiourea-exposed embryos were not seen in those exposed to methimazole (Stanisstreet et al buy discount cycrin 5mg online breast cancer jerseys. The effect of methimazole-induced hypothyroidism during the neonatal period on testicular development was studied in Sprague-Dawley rats purchase 10 mg cycrin with amex pregnancy toxemia. Only male offspring were maintained in the litters [number of litters per group not specified]. Serum thyroid hormone concentrations were depressed at 25 days of age, but were normal by day 45. Body-weight gain was reduced early in life and remained 11% lower than that of controls at 90 days of age. At 90 days of age, the testis weights were increased by 18%, and daily sperm production was slightly increased. Postnatal development of Swiss Webster mice was examined after administration of 0 (10 dams) or 0. Body weights were reduced through young adulthood, after which the effect was no longer significant. Developmental milestones (incisor eruption, eye opening, vaginal opening, testis descent) were unaffected. Surface–righting time (tested on days 7–11), negative geotaxis (tested on days 6, 8 and 10) and swimming ontogeny (tested on days 4–20) were affected by exposure. There were no effects on rotarod performance on day 52 or on brain weights on day 120 (Rice et al. Neurological effects were studied in Fischer 344 rats exposed to methimazole in the drinking-water from gestational day 17 through lactational day 10 at a dose of 0, 0. A number of indicators of neurological maturation, behaviour, thermoregulation, neurophysiology and morphology were measured at various ages. Thermoregulation (day 12) was reduced and kidney weights increased (day 11) at concentrations ≥ 0. Body weight (day 12) and auditory brainstem responses (day 90) were affected at the highest concentration. Methimazole induced chromosomal aberrations in a cell line derived from mouse mammary carcinoma and inhibited cell-to-cell communication in a primary culture of rat thyrocytes. No chromosomal aberrations were induced in bone-marrow cells, spermatogonia or primary spermatocytes of mice treated subcutaneously with methimazole for up to 5 days. The frequency of sister chromatid exchange was increased in T lymphocytes of mice given 0. Subcutaneous injection of methimazole did not induce dominant lethal mutations in male mice. This is the probable basis of the tumorigenic activity of methimazole for the thyroid in experimental animals. It inhibited gap-junctional intercellular communication in primary rat hepatocytes in vitro. The earlier analysis showed more malignant thyroid neoplasms in patients receiving these drugs than in those treated with surgery or 131I, but the excess may have been due to closer surveillance of the patients given drugs owing to more frequent use of thyroidectomy. In the later analysis, patients with hyperthyroidism treated only with anti-thyroid drugs had a modest increase in the risk for death from cancer, due chiefly to oral cancer and cancer of the brain. Neither report provided information on the type, quantity or dates of anti-thyroid drug use. Two case–control studies of cancer of the thyroid showed no significant asso- ciation with treatment with anti-thyroid medications. In one study in mice, it increased the incidence of thyroid follicular-cell adenomas but only in conjunction with a low-iodine diet. In rats, glucuronidation is the major metabolic pathway; less is known about its meta- bolism in humans. This is the probable basis for the tumorigenic activity of methimazole for the thyroid in experimental animals. While the overall incidence of malformations in the infants of women given methimazole during pregnancy does not appear to be elevated, there is equivocal evidence for an association with the occurrence of aplasia cutis, a skin defect. Most of the studies in experimental animals focused on the consequences of hypothyroidism subsequent to perinatal or early postnatal exposure of rats to methimazole; effects on adult neurobehavioural and testicular function were found. Neurobehavioural effects have also been reported in mice exposed perinatally to methimazole. Methimazole has not been adequately tested for its ability to induce gene mutations. It induced chromosomal aberrations in mammalian cells in vitro, but the results of studies of its ability to induce chromosomal damage in vivo were mainly negative. There is limited evidence in experimental animals for the carcinogenicity of methimazole. Overall evaluation Methimazole is not classifiable as to its carcinogenicity to humans (Group 3). Thyroid, 9, 647–652 Medical Products Agency (2000) Uppsala Medicines Evaluation Board Agency (2000) the Hague Meyer-Gessner, M. A comparison of the mutagenic action of several nitroimidazoles and some imidazoles. Since that time, new data have become available, and these have been incorporated into the monograph and taken into consideration in the present evaluation. Methylthiouracil is no longer in clinical use in most countries, although it may be used to a limited degree in some eastern European countries. It has not been registered for human use since 1958 in Sweden, 1986 in the United Kingdom and 1988 in the Netherlands (Medical Products Agency, 2000; Medicines Control Agency, 2000; Medicines Evaluation Board Agency, 2000).