Valerie A. Holmes RGN, BSc, PGCHET, PhD

A Guillain-Barré-like syndrome of rapidly progressive neuromuscular weakness and lactic acidosis has also been associated with stavudine use (Simpson et al diabetes test 2 year old effective dapagliflozin 5 mg. Many of the patients in this series had persistent neurological deficits even after cessation of antiretroviral drugs diabetic diet jenny craig discount dapagliflozin 5 mg line, and in 16% the syndrome was fatal blood sugar drops after eating purchase dapagliflozin 5 mg without a prescription. Risk factors for the development of hyperlactemia include combined stavudine and didanosine use diabetes type 2 review article dapagliflozin 10 mg order with visa, female gender diabetes melitus jenis 2 purchase generic dapagliflozin online, advanced immune suppression, and possibly ethnicity (Lactic Acidosis International Study Group, 2007). Stavudine has been associated with an increased rate of diabetes mellitus, even over a median followup of less than 1 year (Brambilla et al. This finding is confirmed in a report from the D:A:D study, in which diabetes was significantly associated with both stavudine and, to a lesser extent, zidovudine use after adjusting for risk factors underlying diabetes as well as lipid levels (De Wit et al. Hepatotoxicity and pancreatitis Although elevation of liver function tests has been reported in 11% of patients participating in a phase I trial of stavudine (Browne et al. Subsequently, hepatic steatosis has been described as a relatively common side effect with the use of stavudine, with overlap with other manifestations of mitochondria toxicity (McComsey and Lonergan, 2004; Ongolo-Zogo et al. Rat models suggest complex mechanisms for this steatosis and point to mitochondrial dysfunction and decreased hepatic cellular transport of lipids (Igoudjil et al. Using stavudine as monotherapy, pancreatitis was reported in 1% of patients in clinical trials and was associated with 14 deaths, 5 of which were considered drug-related (Bristol-Myers Squibb, 2012). In postmarking trials, pancreatitis was described as occurring at a rate of more than 1 case per 100 patient-years; however, as with all the mitochondrial toxicities, pancreatitis occurs more frequently when used in combination with didanosine (Moore et al. Other studies have questioned whether stavudine is associated with pancreatitis or pancreatic dysfunction (Manfredi et al. A recent literature review suggested an association with antiretroviral therapy through different mechanisms, including mitochondrial toxicity and hyperlipidemia (Oliveira et al. A large prospective cohort study has concluded that stavudine use in pregnancy is not associated with an increased frequency of birth defects (Gallant et al. Recent publications from pregnancy registries suggest the drug is safe regarding teratogenicity during the prepartum period (Liu et al. Other adverse effects Stavudine does not appear to impair renal function (Petersen et al. Adult patients treated with up to 24 times the recommended daily dose did not develop any acute toxicity (Bristol-Myers Squibb, 2012). An increased rate of subclinical hypothyroidism has been reported with prolonged use of stavudine (Madeddu et al. It has occasionally been used for postexposure prophylaxis, as it is better tolerated than previously used zidovudine. Stavudine, until recently, was widely used in developing countries because of its low cost, wide availability, and excellent short-term side effect profile. Stavudine has been extensively studied, initially as a monotherapeutic agent and subsequently as part of combination antiretroviral therapy. Bone marrow toxicity Stavudine is generally regarded to be less myelotoxic to human bone marrow precursor cells in vitro than zidovudine (Mansuri et al. In resource-limited settings, while tenofovir would be the first choice, stavudine would be preferable to zidovudine in individuals with baseline hemoglobin levels of < 80 g/dl. Zidovudine and stavudine have similar effects on human progenitor erythrocytes (Mansuri et al. In several other studies, there was no evidence of dose-related hematologic toxicity (Skowron, 1995). Macrocytosis is a feature of stavudine therapy, although less common than with zidovudine, and appears to have no clinical consequence (Eyer-Silva et al. The maximum tolerated dose was 2 mg/kg daily, with the major dose-limiting toxicities being peripheral neuro- 6e. Teratogenicity Embryotoxicity has been demonstrated with inhibition of blastocyst formation from two-cell embryos in vitro at concentrations of 100 µM or higher (Toltzis et al. A total of 41 subjects were enrolled in study 002 and 43 enrolled in 003, but a large number of patients prematurely withdrew from both studies (Browne et al. As the incidence of peripheral neuropathy was higher in patients receiving 40 mg twice daily, which was highly statistically significant, with no evidence of extra efficacy, the dose was decreased for all patients to 20 mg twice daily (Simpson and Tagliati, 1995; Hill et al. Stavudine combination therapy A Cochrane Database systematic review was performed to consider the efficacy and safety of the initial antiretroviral combination of stavudine, lamivudine, and nevirapine, as one of the most commonly prescribed regimens worldwide (Siegfried et al. This review found only two studies that provided data from randomized controlled trials of this combination, one being a small Australian study of 70 patients and the other being a large multicenter trial enrolling 1216 participants and being conducted in 14 countries. Their analysis, largely based on the latter study, found this combination provided virological control and that exchanging efavirenz for nevirapine was an equally efficacious option. The safety of stavudine could not be well assessed because all patients received regimens containing stavudine in the studies reviewed. However, it is noteworthy that severe peripheral neuropathy was observed in all treatment groups, with an overall rate of around 3%. A subsequent Cochrane review comparing stavudine to zidovudine showed minimal differences in efficacy or toxicity (Spaulding et al. For several years till 2010, due to cost and the availability of co-formulated tablets, stavudine in combination with lamivudine and nevirapine was the most prescribed regimen in developing countries in Africa and Asia. This combination with lamivudine and nevirapine has been evaluated in many Asian and African observational cohorts (Zhou et al. The combination of stavudine, lamivudine, and nevirapine has also been evaluated in a Western context (Tam et al. The main clinical trials of stavudine as part of combination therapy are discussed in the following paragraphs. The stavudine-containing regimen had superior results in terms of virologic suppression at 48 weeks compared to the zidovudine-containing regimen, without evidence of more serious toxicity emerging in this study caused by the stavudine plus didanosine combination (Eron et al. A total of 911 antiretroviral-naive participants were randomized to receive stavudine and didanosine plus nelfinavir or efavirenz or nelfinavir and efavirenz. Roughly one third of subjects had switched from stavudine by the end of the 3-year followup period. The addition of a protease inhibitor to this regimen was found to result in worse virological control and increased adverse events. In this study, 291 antiretroviral drug­naive subjects were randomized to one of the three treatment strategies and were followed for 96 weeks. In the D:A:D study to assess the relative risk of nucleoside reverse transcriptase inhibitors to increase myocardial risk, stavudine did not emerge as a drug with significant risk (Worm et al. Stavudine use in pregnancy and the perinatal period Stavudine is well tolerated in pregnancy (Weinberg et al. No transmission was noted in women who had received therapy for more than 7 weeks before delivery. The co-prescription of stavudine and didanosine is contraindicated in pregnancy, due to concerns regarding high rates of lactic acidosis. Epidemiologic studies have suggested an increased rate of persistent mitochondrial dysfunction in children exposed to nucleoside reverse transcriptase inhibitor in utero (Blanche et al. This finding is controversial and has not been reproduced in all studies (Perinatal Safety Review Working Group, 2000). At 48 weeks, 85%, 80%, and 81% of children receiving stavudine, zidovudine, and abacavir, respectively, had a viral load < 400 copies/ml, with no significant differences in grade 2­4 clinical or grade 3­4 laboratory adverse events (Mulenga et al. Denholm and Steven Wesselingh, of the Infectious Diseases Unit, Alfred Hospital, in Melbourne, Australia. The nucleoside reverse transcriptase inhibitors didanosine, lamivudine, stavudine and zidovudine show little effect on the virulence of Candida albicans in vitro. Viral efficacy maintained and safety parameters improved with a reduced dose of stavudine: a pilot study. Initial studies on the cellular pharmacology of 3-deoxythymidin-2-ene (d4T): a potent and selective inhibitor of human immunodeficiency virus. Both 2,3-dideoxythymidine and its 2,3-unsaturated derivative (2,3-dideoxythymidinene) are 7d. Stavudine use in pediatric populations There have been very few randomized controlled studies of stavudine in children. In this study, the drugs were well tolerated over 48 weeks but with incomplete virologic suppression (Kline et al. After 6 months of therapy, there was a significantly greater virologic suppression in the children who received a stavudine-containing regimen (70% with virologic suppression on stavudine-based ritonavirboosted lopinavir regimen; 86% on stavudine-based efavirenz regimen) compared to those receiving an abacavir-containing regimen (54% with virologic suppression on abacavir-based 7. Clinical uses of the drug 3767 potent and selective inhibitors of human immunodeficiency virus replication in vitro. Metabolism and mechanism of antiretroviral action of purine and pyrimidine derivatives. Marked inhibitory activity of masked aryloxy aminoacyl phosphoramidate derivatives of dideoxynucleoside analogues against visna virus infection. Differential patterns of intracellular metabolism of 2,3-didehydro-2,3-dideoxythymidine and 3-azido-2,3-dideoxythymidine, two potent anti-human immunodeficiency virus compounds. Long-term results of initial therapy with abacavir and lamivudine combined with rfavirenz, amprenavir/ritonavir, or stavudine. Increased prevalence of hypothyroidism among human immunodeficiency virus-infected patients: a need for screening. Low-dose zalcitabine-related toxin neuropathy: frequency, natural history, and risk factors. A high incidence of lactic acidosis and symptomatic hyperlactataemia in women receiving highly active antiretroviral therapy in Soweto, South Africa. Randomization to once-daily stavudine extended release/lamivudine/efavirenz versus a more frequent regimen improves adherence while maintaining viral suppression. Poster presented at the 43rd Interscience Conference on Antimicrobial Agents, American Society for Microbiology, Chicago. Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway. Determination of stavudine, a new antiretroviral agent, in human plasma by reversed-phase high performance liquid chromatography with ultraviolet detection. Meeting report of the second conference on antiretroviral drug optimization, Cape Town. Maternal-fetal transfer and amniotic fluid accumulation of nucleoside analogue reverse transcriptase inhibitors in human immunodeficiency virus-infected pregnant women. Comparative activity of 2,3-saturated and unsaturated pyrimidine and purine nucleosides against human immunodeficiency virus type 1 in peripheral blood mononuclear cells. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. In vitro and in vivo disposition and metabolism of 3-deoxy-2,3-didehydrothymidine. In vitro toxicity of 3-azido3-deoxythymidine, carbovir and 2,3-didehydro-2,3-dideoxythymidine to human and murine haematopoietic progenitor cells. Symptomatic hyperlactataemia in adults on antiretroviral therapy: a single-centre experience. Scaling up of highly active antiretroviral therapy in a rural district of Malawi: an effectiveness assessment. Stavudine concentrations in women receiving postpartum antiretroviral treatment and their breastfeeding infants. Generation of multiple drug resistance by sequential in vitro passage of the human immunodeficiency virus type 1. Divergent anti-human immunodeficiency virus activity and anabolic phosphorylation of 2,3-dideoxynucleoside analogs in resting and activated human cells. Susceptibility of human T cell leukemia virus type 1 to reverse-transcriptase inhibitors: Evidence for resistance to lamivudine. Potentiation of stavudine anti-human immunodeficiency virus activity by 5-fluorouracil. Acute pancreatitis associated with different combination therapies in patients infected with human immunodeficiency virus. Inhibitory effect of 2, 3-didehydro-2,3-dideoxynucleosides on infectivity, cytopathic effects, and replication of human immunodeficiency virus. A single-dose study to assess the penetration of stavudine into human cerebrospinal fluid in adults. Systematic review of clinical trials evaluating low doses of stavudine as part of antiretroviral treatment. Susceptibility of human T cell leukemia virus type I to nucleoside reverse transcriptase inhibitors. Cellular pharmacology of 2,3-dideoxy-2, 3-didehydrothymidine, a nucleoside analog active against human immunodeficiency virus. The formation of 2,3unsaturated pyrimidine nucleosides via a novel beta-elimination reaction. High doses of stavudine induce fat wasting and mild liver damage without impairing mitochondrial respiration in mice. High prevalence of lipoatrophy in pre-pubertal South African children on antiretroviral therapy: a cross sectional study. In vitro bone marrow toxicity of nucleoside analogs against human immunodeficiency virus. High-performance liquid chromatographic determination of 2,3-didehydro-3-deoxythymidine, a new anti-human immunodeficiency virus agent, in human plasma and urine. Pharmacology of nucleoside and nucleotide reverse transcriptase inhibitor-induced mitochondrial toxicity. Nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity as an etiology for lipodystrophy. Predictors of longterm viral failure among Ugandan children and adults treated with antiretroviral therapy. Pharmacokinetics of the anti-human immunodeficiency virus nucleoside analog stavudine in cynomolgus monkeys. Development and application of an in vitro model for screening anti-hepatitis B virus therapeutics.

Zidovudine treatment results in the selection of human immunodeficiency virus type 1 variants whose genotypes confer increasing levels of drug resistance diabetes type 1 kidney failure dapagliflozin 5 mg purchase with visa. A controlled trial of zidovudine in primary human immunodeficiency virus infection diabetes insipidus osteoporosis cheap dapagliflozin generic. Synergistic inhibition of human immunodeficiency virus type 1 replication in vitro by two-drug and three-drug combinations of 3-azido-3-deoxythymidine diabetes warning signs and symptoms order cheap dapagliflozin online, phosphonoformate diabetic diet vs renal diet purchase dapagliflozin 5 mg overnight delivery, and 2 diabetes type 2 glucagon buy dapagliflozin once a day,3-dideoxythymidine. Comparisons of anti-human immunodeficiency virus activities, cellular transport, and plasma and intracellular pharmacokinetics of 3-fluoro-3-deoxythymidine and 3-azido3-deoxythymidine. Treatment of chronic woodchuck hepatitis virus infection in the eastern woodchuck (Marmota monax) with nucleoside analogues is predictive of therapy for chronic hepatitis B virus infection in humans. Inhibition of human immunodeficiency virus in vitro by combinations of 3-azido-3-deoxythymidine and foscarnet. Mutagenic study of codons 74 and 215 of the human immunodeficiency virus type 1 reverse transcriptase, which are significant in nucleoside analog resistance. Interactions between drug resistance mutations in human immunodeficiency virus type 1 reverse transcriptase. Zidovudine-resistant human immunodeficiency virus selected by passage in cell culture. Evaluation of the quality of life associated with zidovudine treatment in asymptomatic human immunodeficiency virus infection. Mitochondrial ultrastructural and molecular changes induced by zidovudine in rat hearts. Anti-human immunodeficiency virus agent 3-azido-3-deoxythymidine inhibits replication of Epstein-Barr virus. Penetration of zidovudine and 3-fluoro-3-deoxythymidine into the brain, muscle tissue, and veins in cynomolgus monkeys: relation to antiviral action. Safety and efficacy of switching to alternative nucleoside analogues following symptomatic hyperlactatemia and lactic acidosis. Intravascular distribution of zidovudine: role of plasma proteins and whole blood components. Interaction between zidovudine prophylaxis and mode of delivery in the French Perinatal Cohort. Randomized double-blind, placebo-controlled trial of twice-daily zidovudine in asymptomatic haemophiliacs infected with the human immunodeficiency virus type 1. Pharmacokinetics and pharmacodynamics of high-dose zidovudine administered as a continuous infusion in patients with cancer. Pharmacokinetics of lamivudine, zidovudine, and nevirapine administered as a fixed-dose combination formulation versus coadministration of the individual products. Phylogenetic and genetic analysis of feline immunodeficiency virus gag, pol, and env genes from domestic cats undergoing nucleoside reverse transcriptase inhibitor treatment or treatment-naïve cats in Rio de Janeiro, Brazil. Efficacy of antenatal zidovudine in reducing perinatal transmission of human immunodeficiency virus type 1. Virological suppression at 6 months is related to choice of initial regimen in antiretroviral-naive patients: a cohort study. Cisplatin combined with zidovudine enhances cytotoxicity and oxidative stress in human head and neck cancer cells via a thiol-dependent mechanism. Alternating versus continuous drug regimens in combination chemotherapy of human immunodeficiency virus type 1 infection in vitro. A multicenter trial of oral zidovudine in children with advanced human immunodeficiency virus disease. Safety and tolerance of intermittent intravenous and oral zidovudine therapy in human immunodeficiency virus-infected pediatric patients. Ganciclovir antagonizes the antihuman immunodeficiency virus type 1 activity of zidovudine and didanosine in vitro. Placebo-controlled trial to evaluate zidovudine in treatment of human immunodeficiency virus infection in asymptomatic patients with hemophilia. Zidovudine myopathy: a distinctive disorder associated with mitochondrial dysfunction. Potential use of human stem cell factor as adjunctive therapy for human immunodeficiency virus-related cytopenias. Combined therapy with recombinant granulocyte colony-stimulating factor and erythropoietin decreases hematologic toxicity from zidovudine. Quantitation of zidovudineresistant human immunodeficiency virus type 1 in the blood of treated and untreated patients. Pharmacokinetics of zidovudine and lamivudine in neonates following coadministration of oral doses every 12 hours. Long-term safety and efficacy of zidovudine in patients with advanced human immunodeficiency virus disease. Intravenous and oral zidovudine pharmacokinetics and coagulation effects in asymptomatic human immunodeficiency virus-infected hemophilia patients. Frequency of multinucleoside analogueresistant genotypes observed during antiretroviral therapy. Combination treatment with azidothymidine and granulocyte colony-stimulating factor in children with human immunodeficiency virus infection. Correlation of clinical progression in human immunodeficiency virus-infected children with in vitro zidovudine resistance measured by a direct quantitative peripheral blood lymphocyte assay. Contribution of nucleosideanalogue reverse transcriptase inhibitor therapy to lipoatrophy from the population to the cellular level. The pharmacokinetics and safety of zidovudine in the third trimester of pregnancy for women infected with human immunodeficiency virus and their infants: phase I acquired immunodeficiency syndrome clinical trials group study (protocol 082). Development and significance of zidovudine resistance in children infected with human immunodeficiency virus. Pharmacokinetics of zidovudine in end-stage renal disease: influence of haemodialysis. Effects of 3-azidothymidine on platelet counts, indium-111-labelled platelet kinetics, and antiplatelet antibodies. Mechanism and site dependency of intestinal mucosal transport and metabolism of thymidine analogues. Azidothymidine is effective against human multiple myeloma: a new use for an old drug Effects of bone marrow stimulatory cytokines on human immunodeficiency virus replication and the antiviral activity of dideoxynucleosides in cultures of monocyte/ macrophages. Different pattern of activity of inhibitors of the human immunodeficiency virus in lymphocytes and monocyte/macrophages. Dideoxycytidine alone and in an alternating schedule with zidovudine in children with symptomatic human immunodeficiency virus infection. The effect of antiviral therapy on the natural history of human immunodeficiency virus infection in a cohort of hemophiliacs. Effect of anticancer drugs on the glucuronidation of 3-azido-3-deoxythymidine in human liver microsomes. Rapid phenotypic reversion of zidovudine-resistant feline immunodeficiency virus without loss of drug-resistant reverse transcriptase. Effect of stage of disease and drug dose on zidovudine susceptibilities of isolates of human immunodeficiency virus. Enzymatic assay for measurement of zidovudine triphosphate in peripheral blood mononuclear cells. Biological comparison of wild-type and zidovudine-resistant isolates of human immunodeficiency virus type 1 from the same subjects: susceptibility and resistance to other drugs. Comparative effects of antifungal agents on zidovudine glucuronidation by human liver microsomes. Severe transient neonatal lactic acidosis during prophylactic zidovudine treatment. Combination therapy with zidovudine and didanosine selects for drug-resistant human immunodeficiency virus type 1 strains with unique patterns of pol gene mutations. Antiretroviral concentrations in breast-feeding infants of women in Botswana receiving antiretroviral treatment. Prolonged, but not diminished, zidovudine absorption induced by a high-fat breakfast. Zidovudine disposition in patients with severe renal impairment: influence of hemodialysis. Evaluation of synergy between carbovir and 3-azido-2,3-deoxythymidine for inhibition of human immunodeficiency virus type 1. Long-term persistence of zidovudine resistance mutations in plasma isolates of human immunodeficiency virus type 1 of dideoxyinosine-treated patients removed from zidovudine therapy. Zidovudine-resistant human immunodeficiency virus type 1 genomes detected in plasma distinct from viral genomes in peripheral blood mononuclear cells. Development and significance of nucleoside drug resistance in infection caused by the human immunodeficiency virus type 1. Clinical uses of the drug 3695 limited settings: clinical results from 4 African countries. Safety and efficacy of lamivudine-zidovudine combination therapy in zidovudineexperienced patients. Infection of human monocytederived macrophages by human immunodeficiency virus mediated by cell-to-cell transmission. Pharmacokinetics of zidovudine phosphorylation in peripheral blood mononuclear cells from patients infected with human immunodeficiency virus. Pharmacokinetics of zidovudine phosphorylation in patients infected with the human immunodeficiency virus. A trial with 3-azido-2,3dideoxythymidine and human interferon- in cats naturally infected with feline leukaemia virus. Zidovudine-induced fatal lactic acidosis and hepatic failure in patients with acquired immunodeficiency syndrome: Report of two patients and review of the literature. Oral mucosa pigmentation: a new side effect of azidothymidine therapy in patients with acquired immunodeficiency syndrome. Dilated cardiomyopathy in an adult human immunodeficiency virus type 1-positive patient treated with a zidovudine-containing antiretroviral regimen. Cerebrospinal fluid findings in patients before and during longterm oral zidovudine therapy. Pharmacokinetic evaluations of low- and high-dose zidovudine plus high-dose acyclovir in patients with symptomatic human immunodeficiency virus infection. Zidovudine disposition during hemodialysis in a patient with acquired immunodeficiency syndrome. Prolonged immunostimulatory effect of low-dose polyethylene glycol interleukin 2 in patients with human immunodeficiency virus type 1 infection. Restricted transport of 3-azido-3deoxythymidine and dideoxynucleosides through the blood-brain barrier. Inhibition of visna virus replication by 2,3 -dideoxynucleosides and acyclic nucleoside phosphonate analogs. Cross-resistance analysis of human immunodeficiency virus type 1 variants individually selected for resistance to five different protease inhibitors. Antiviral effects of 3-azido-3deoxythymidine, 2,3-dideoxycytidine, and 2,3-dideoxyadenosine against simian acquired immunodeficiency syndrome-associated type D retrovirus in vitro. Efficacy of combination therapy with interferon and azidothymidine in chronic type C hepatitis: a pilot study. High-dose zidovudine plus valganciclovir for Kaposi sarcoma herpesvirus-associated multicentric Castleman disease: a pilot study of virus-activated cytotoxic therapy. L-735,524: an orally bioavailable human immunodeficiency virus type 1 protease inhibitor. Effects of dideoxyinosine and dideoxycytidine on the intracellular phosphorylation of zidovudine in human mononuclear cells. Poly(ethylene oxide/propylene oxide) copolymer thermo-reversible gelling system for the enhancement of intranasal zidovudine delivery to the brain. Abbreviated regimens of zidovudine prophylaxis and perinatal transmission of the human immunodeficiency virus. A simplified weight-based method for pediatric drug dosing for zidovudine and didanosine in resource-limited settings. Durability of initial antiretroviral therapy in a resource-constrained setting and the potential need for zidovudine weight-based dosing. In vivo compartmentalization of human immunodeficiency virus: evidence from the examination of pol sequences from autopsy tissues. Kinetics and inhibition of reverse transcriptase from human and simian immunodeficiency viruses. Response of humanimmunodeficiency-virus-associated neurological disease to 3azido-3-deoxythymidine. A randomized pilot study of alternating or simultaneous zidovudine and didanosine therapy in patients with symptomatic human immunodeficiency virus infection. Although international guidelines no longer contain didanosine-containing regimens in preferred first- or second-line antiretroviral therapy, there is no guidance for management of patients who remain on didanosine. In 2012 at least 20 countries spent a total of $1 to $2 million on purchasing didanosine (Dziuban et al. The concentration can be expressed as in micromolars or micrograms per milliliter (1 µg/ml is approximately equivalent to 5 µM). A compound that is closely related to didanosine, 2,3dideox-yadenosine (ddA) was first synthesized in 1964 (Robins and Robins, 1964). At relatively high concentrations (10­100 µM) didanosine reportedly inhibits reverse transcription in resting T-lymphocytes (Watson and Wilburn, 1992). Didanosine has little or no in vitro activity against Pneumocystis jiroveci (Walzer et al. The L74V reverse transcriptase mutation by itself conferred only limited resistance to didanosine and was associated with limited cross-resistance to zalcitabine, abacavir, and lamivudine but not to zidovudine (St.

Hypertrichosis of the eyelashes has been reported within 2 weeks of commencing zidovudine without an increase in other body hair length (Klutman and Hinthorn metabolic disorder kidneys discount dapagliflozin 5 mg buy on line, 1991) diabetic compression socks purchase dapagliflozin us. Zidovudine administration in high doses to pregnant mice was associated with pregnancy failure in one study (Toltzis et al diabet-x callus 10 mg dapagliflozin purchase mastercard. There is in vitro evidence of embryonic toxicity diabetes mellitus type zwei proven 10 mg dapagliflozin, resulting from failure to develop to the blastocyst stage when embryos are exposed to very high 3674 Zidovudine concentrations of zidovudine diabetes mellitus merck 5 mg dapagliflozin free shipping, but not with other nucleoside analogs, such as didanosine (Toltzis et al. No reduction in spermatogenesis or follicular development was seen in mice and rats receiving oral zidovudine (Sikka et al. However, in pigtailed macaques who received zidovudine during pregnancy, fetal growth was normal, and there was no evidence of behavioral delay in infants (Ha et al. Rates of treatment discontinuation due to toxicity, anemia of at least moderate severity, neutropenia, thrombocytopenia, and disturbances of serum electrolytes or liver function tests of at least moderate severity were not different in women who received zidovudine compared with those in the placebo group. There was no evidence of excess fetal or neonatal deaths, premature labor, delayed fetal development, or excess congenital abnormalities attributable to zidovudine exposure. The hemoglobin concentration was lower at birth in infants exposed to zidovudine (mean difference between groups < 1 g/dl), but this difference had resolved by 12 weeks of age (Connor et al. Other available data generally support the safety of zidovudine use in pregnancy, although transient lactic acidosis is reported in neonates administered zidovudine chemoprophylaxis (Scalfaro et al. In a retrospective study of 43 pregnant women who were prescribed oral zidovudine in doses ranging from 300 to 1200 mg per day, the drug was well tolerated and not associated with teratogenic effects, even with exposure to zidovudine during the first trimester (Sperling et al. In a followup study of the offspring of 7 pregnant women who were prescribed 18 mg/kg zidovudine after the 16th week of gestation, all infants developed macrocytosis and two developed anemia, which in both cases resolved within the second month of life (Ferrazin et al. Some of the available human data also point to mitochondrial dysfunction after perinatal use of this class of drugs. No serious long-term toxicity from zidovudine was observed by age 18 months, including no infant with symptoms suggestive of mitochondrial dysfunction and no malignancy in the zidovudine exposed group (Chotpitayasunondh et al. Generally, zidovudine has been found to be safe in this context, despite a report of two cases of hepatotoxicity and rash occurring with combined prophylactic use of zidovudine 7. Observation of 224 healthcare workers administered 1000 mg of zidovudine daily for 4­6 weeks in Italy found that > 50% experienced mild side effects, such as nausea, malaise, fatigue, and headache, which led to drug cessation in 29 cases (13%). Subsequent observations of American healthcare workers confirmed that minor, reversible adverse effects, such as nausea, malaise, fatigue, and headache, are experienced by up to 75% of individuals using zidovudine monotherapy as postexposure prophylaxis, with associated zidovudine discontinuation rates > 30% (Tokars et al. More recent observation of adverse events among individuals prescribed 28 days of combination antiretroviral therapy for nonoccupational postexposure prophylaxis also found that zidovudine-based regimens were associated with high rates of discontinuation of therapy (around 30%) due to side effects such as nausea, malaise, and headache (Winston et al. The serum level of zidovudine approximately 8 hours postingestion was 24 µg/ml (Spear et al. No clinical toxicity was observed in a 27-month-old boy who ingested 130 mg zidovudine (10. A f4-day-old infant inadvertently given 10 times the recommended dose of zidovudine for 2 days developed a metabolic acidosis that resolved within 24 hours and neutropenia that persisted for 5 weeks (Livshits et al. A brief review of the major clinical trials leading to current clinical use of zidovudine is provided in the following sections (see Table 225. Most studies demonstrated a delay in disease progression without long-term survival advantages in this context. This is consistent with current understanding of the rapid development of resistant viral strains (and therefore lack of durable treatment benefits) in patients using antiretroviral monotherapy. Despite this, 42% reduction in mortality with didanosine and 32% with zalcitabine (vs. Viral load < 400 copies/ml at 48 weeks in 70% (atazanavir) and 64% (efavirenz) Viral load < 400 copies/ml at 48 weeks in 51% in both arms, but in the subset with viral load > 100,000 copies/ml at baseline, those in the abacavir arm did poorly (viral load < 400 copies/ml at 48 weeks in just 31% vs. However, extended followup of the study cohort found no survival benefit associated with zidovudine therapy (Volberding et al. Of note, zidovudine use was associated with a reduction in quality of life that approximated the improvement in life quality derived from the delay in disease progression (Lenderking et al. This is also supported by observational data from a cohort of 936 asymptomatic patients in Italy (Vella et al. However, a lack of sustained benefit, including a lack of improved survival, has also been confirmed in randomized, placebo-controlled trials (Anonymous, 1994; Mannucci et al. However, in 119 patients who had received 1­8 weeks of prior zidovudine exposure, there was no difference between zidovudine and didanosine. In the 118 patients who had received 8­16 weeks of prior zidovudine therapy, the 500-mg dose of didanosine was associated with less disease progression than zidovudine and the 750-mg dose of didanosine was associated with greater survival, although 2 patients in this arm died of pancreatitis. Overall there was no significant difference between the two didanosine doses (Dolin et al. Studies involving patients with more prolonged prior zidovudine exposure showed clinical (but not survival) benefits from switching to didanosine (Kahn et al. Zidovudine in combination with other nucleoside analogs Some of the studies examining zidovudine in combination with another nucleoside analog versus zidovudine monotherapy 3678 Zidovudine included participants who had extensive prior zidovudine experience (Fischl et al. However, where trials were conducted using zidovudine-naive subjects (or those with only minimal prior zidovudine exposure) therapy with more than one nucleoside analog has generally been found to be superior to monotherapy. However, the low dose of zidovudine used in the monotherapy arm limited the ability to compare monotherapy with combination therapy (Meng et al. Despite premature discontinuation of study medication in 71% of participants, the study provided strong evidence for the superiority of combination therapy in terms of survival. After a median followup time of 30 months, there was a reduction in mortality of 42% in those treated with zidovudine and didanosine and 32% in those treated with zidovudine and zalcitabine compared with the zidovudine monotherapy group (Anonymous, 1996). A randomized trial compared combination therapy with zidovudine and didanosine with alternating regimens of each drug alone in 41 patients with advanced disease. However, a survival benefit has been observed in both randomized placebo-controlled trials and observational studies of patients receiving aciclovir with zidovudine compared with zidovudine alone (Cooper et al. This strategy is not employed today because alternative antiretroviral agents with different side effect profiles are available for patients affected by significant bone marrow suppression from zidovudine. The first evidence of the superior and more durable efficacy of triple antiretroviral drug combinations emerged in the mid-1990s. Even in zidovudine-experienced patients, triple therapy (including zidovudine) trials conducted when protease inhibitors became available demonstrated substantial clinical, immunologic, and virologic benefits from antiretroviral therapy, including three agents (Collier et al. Complete suppression was achieved in more patients treated with the combination of zidovudine, lamivudine, and efavirenz (70%) than in patients treated with zidovudine, lamivudine, and indinavir (48%). In addition, significantly more patients ceased study medications due to adverse events in indinavir-based regimens (Staszewski et al. Initial therapy consisted of either zidovudine­lamivudine or didanosine­stavudine together with either efavirenz or nelfinavir. The combination of zidovudine, lamivudine, and efavirenz was associated with delayed virologic failure of both the first and second antiretroviral regimen (Robbins et al. Zidovudine use in the context of triple nucleoside analog therapy has also been investigated. Randomized data are lacking to support the use of zidovudine with more recently introduced antiretroviral agents. However, observational data support the efficacy of the triple combination of zidovudine with lamivudine and raltegravir (an integrase inhibitor) in both treatment-naive and experienced patients (Kang et al. Zidovudine has fallen out of favor both because of high rates of less-serious short-term toxicities (such as nausea malaise and headache) and because of the risk of long-term side effects such as mitochondrial toxicity and related lipoatrophy. The mechanism of this effect may be through prolongation of platelet survival, with zidovudine therapy associated with decreased plasma levels of glycocalicin, a platelet protein that correlates inversely with platelet survival (Panzer et al. The response time may be highly variable (median, 9­12 weeks), but bleeding episodes resolve with therapy and the positive effects of zidovudine on platelet count may persist for more than 18 months even with 7. Some reports suggest that high doses (1000 mg per day) of zidovudine may be more effective at increasing platelet count than standard doses (500­600 mg per day) (Boyar and Beall, 1991; Landonio et al. More recent work provides strong evidence for the efficacy of combination antiretroviral therapy in this setting (Atta et al. Subsequent reports also supported a possible role for zidovudine in the management of this condition (Dalakas et al. There is no direct evidence available for this strategy in the setting of postexposure prophylaxis and no randomized trial is ever likely to be undertaken. In particular, both animal and human data support the safety and efficacy of zidovudine for use in this context. The women 3682 Zidovudine were treated with zidovudine (100 mg orally five times daily before delivery, 2 mg/kg i. Subsequent work has also demonstrated the importance of commencing infant zidovudine therapy as soon as possible (and within the first 48 hours) after birth for maximum efficacy (Wade et al. A recent study has shown clearly that combining extended zidovudine therapy (up to 6 weeks of age) with extended nevirapine treatment of newborns substantially reduced the incidence of nevirapine resistance (Lidström et al. Thymidine and zidovudine metabolism in chronically zidovudine-exposed cells in vitro. Zidovudine did not enhance the antiviral effect of interferon-alpha (Janssen et al. A pilot study examined the efficacy of adding zidovudine to interferon-alpha in the treatment of hepatitis C virus. A total of 30 patients with chronic hepatitis C infection were enrolled for interferon-alpha (3­6 million units per day for 3 weeks and then three times weekly for 21 weeks) with oral zidovudine (500 mg per day, commencing at the beginning of week 8 of interferon-alpha therapy). Lactic acidemia in human immunodeficiency virus-uninfected infants exposed to perinatal antiretroviral therapy. A case of acute encephalopathy caused by the human immunodeficiency virus apparently responsive to zidovudine. Kinetic and inhibitor studies of acetaminophen and zidovudine glucuronidation in rat liver microsomes. In vitro inhibition of hepatitis B virus replication by 2,3 -dideoxyguanosine, 2,3 -dideoxyinosine, and 3-azido-2,3-dideoxythymidine in 2. Thymidine and 3-azido-3-deoxythymidine metabolism in human peripheral blood lymphocytes and monocyte-derived macrophages. Ribavirin antagonizes inhibitory effects of pyrimidine 2,3-dideoxynucleosides but enhances inhibitory effects of purine 2,3-dideoxynucleosides on replication of human immunodeficiency virus in vitro. Pharmacokinetics of zidovudine administered intravenously and orally in children with human immunodeficiency virus infection. The pharmacokinetics of zidovudine administered by continuous infusion in children. The in vitro and in vivo antiretrovirus activity, and intracellular metabolism of 3-azido-2,3dideoxythymidine and 2,3-dideoxycytidine are highly dependent on the cell species. Acquired immune deficiency syndrome-related pulmonary non-Hodgkin lymphoma regressing after zidovudine therapy. Zidovudine-based lyticinducing chemotherapy for Epstein-Barr virus-related lymphomas. Treatment of adult T-cell leukaemia/ lymphoma: current strategy and future perspectives. Meta-analysis on the use of zidovudine and interferon-alfa in adult T-cell leukemia/lymphoma showing improved survival in the leukemic subtypes. Synergistic cytotoxic effect of azidothymidine and recombinant interferon alpha on normal human bone marrow progenitor cells. Persistent mitochondrial dysfunction and perinatal exposure to antiretroviral nucleoside analogues. A high incidence of lactic acidosis and symptomatic hyperlactatemia in women receiving highly active antiretroviral therapy in Soweto, South Africa. Ordered appearance of zidovudine resistance mutations during treatment of 18 human immunodeficiency virus-positive subjects. Zidovudine sensitivity of human immunodeficiency viruses from high-risk, symptom-free individuals during therapy. Effects of discontinuation of zidovudine treatment on zidovudine sensitivity of human immunodeficiency virus type 1 isolates. Phase I evaluation of zidovudine administered to infants exposed at birth to the human immunodeficiency virus. Effect of continuous-infusion zidovudine therapy on neuropsychologic functioning in children with symptomatic human immunodeficiency virus infection. Short-term, combined use of paracetamol and zidovudine does not alter the pharmacokinetics of either drug. Susceptibilities of human immunodeficiency virus type 1 enzyme and viral variants expressing multiple resistance-engendering amino acid substitutions to reserve transcriptase inhibitors. Inhibition of human immunodeficiency virus type 1 replication in vitro by the bisheteroarylpiperazine atevirdine (U-87201E) in combination with zidovudine or didanosine. Lactic acidosis complicating the acquired immunodeficiency syndrome (Brief report). Bisheteroarylpiperazine reverse transcriptase inhibitor in combination with 3-azido-3-deoxythymidine or 2,3-dideoxycytidine synergistically inhibits human immunodeficiency virus type 1 replication in vitro. Safety of late in utero exposure to zidovudine in infants born to human immunodeficiency virus-infected mothers: Bangkok. Sustained elevation of platelet counts by long-term azidothymidine treatment of immunosuppressed mice. Treatment of human immunodeficiency virus infection with saquinavir, zidovudine, and zalcitabine. Heterosexual transmission of human immunodeficiency virus type 1 variants associated with zidovudine resistance. Reduction of maternal­ infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Comparative assessment of antiretrovirals in human monocyte-macrophages and lymphoid cell lines acutely and chronically infected with the human immunodeficiency virus. Zidovudine-induced mitochondrial myopathy is associated with muscle carnitine deficiency and lipid storage. Treatment of human immunodeficiency virus-related polyneuropathy with 3-azido-2,3- dideoxythymidine.

Furthermore diabetic smoothies 5 mg dapagliflozin, a recent comparative study to evaluate both pediculicidal and ovicidal activity of five head lice products used in the period between 1984 and 2000 indicated that all lice treated with Ovide lotion (0 diabetic ulcer stages buy dapagliflozin 5 mg low price. Jones and English (2003) recommended malathion as a second-line therapy because of the flammability of the formulation diabetes mellitus wound healing buy genuine dapagliflozin on line, reserving it for treatment of pyrethroid-refractory cases diabetes in dogs pain purchase 10 mg dapagliflozin mastercard. It is important to treat all hairy areas of the body with the malathion formulation diabetes test blood dapagliflozin 5 mg without a prescription. All products available for head and pubic lice are too irritating and/or dangerous to use for controlling P. If it is necessary to treat for infestation at this site, malathion 1% can be combined with mechanical treatment (Charfi et al. Adults Ideally, all close contacts of an infected individual with pediculosis or scabies should be treated (Burgess, 2001). Head lice infestation is best treated with a lotion or liquid formulation rather than a shampoo because a shampoo is too dilute to be effective. Treatment with topical malathion should be avoided in persons with allergies, asthma, epilepsy, open wounds, or preexisting medical conditions. Patients with eczema or otherwise damaged skin should be treated A single application of malathion 0. Treatment should be applied to the whole body surface, including the neck, scalp, and ears, but not the eyes, and left on for 8­12 hours, usually overnight (Bignell, 2005) and then washed off. It is also important to treat sexual partners and avoid sexual activity during the treatment period, and to treat close household contacts to prevent reinfection. Newborn infants and children Malathion should not be used in children under two years of age, and caution is needed when using in children under six years (Potts, 2001). Drug interactions Given the topical use of malathion, no drug interactions are expected unless there is concomitant use of other topical agents. When applied in accordance with the rate of application and safety precautions specified on the label, malathion can be used without posing unreasonable risks to human health or the environment. At high doses, it can overstimulate the nervous system, causing nausea, dizziness, or confusion; at very high doses poisoning can lead to convulsions, respiratory paralysis, and death (Casey and Vale, 1994; Yamashita et al. Many cases of malathion toxicity have been reported since its first use in children and adults (Goldman and Teitel, 1958; Namba et al. Following oral ingestion, the acute toxicity of malathion can result in death, as has been reported to have occurred in deliberate overdose (Ganguly and Bhattacharyya, 1973; Lewin et al. Important manifestations of acute toxicity include delayed onset respiratory paralysis and delayed polyneuropathy (Karalliedde and Senanayake, 1988). Accidental poisoning occurring after ingestion of malathion as syrup or a liquid oral medication leads to the rapid development of symptoms (15 minutes in children) after ingestion, consisting of coma, pulmonary edema, miosis, hypersalivation, muscle flaccidity, fasciculations, reduction in blood cholinesterase activity, and fecal and urinary incontinence (Goldman and Teitel, 1958; Namba et al. The accidental ingestion or inhalation of malathion can damage mucosal epithelial cells of the upper aerodigestive tract (Tisch et al. Furthermore, low dosages (25­50 mg/kg) of malathion disrupted rat behavior without significant reduction in cholinesterase activity (Kurtz, 1977). Malathion has been reported to cause allergic responses in some exposed people and in guinea pigs (Cushman and Street, 1983). Studies in animals suggest that the neurotoxicity of malathion is heightened in infancy, with toxicity occurring at dose levels that ranged from 1. Drug distribution the elimination half-life of malathion in humans is 6­7 hours after exposure (Tuomainen et al. Blood screening can be used to monitor malathion exposure and/or toxicity in humans (Liu and Pleil, 2002; Gergov et al. Any drug entering the bloodstream is rapidly degraded, even if ingested (Moeller and Rider, 1962; Baker et al. Clinically important pharmacokinetic and pharmacodynamic features There are no data to directly correlate the clinical activity of malathion with its pharmacokinetic and pharmacodynamic parameters. Excretion Urine is the major route of malathion elimination in humans (Drevenkar et al. Urinalysis represents another reliable method for detecting malathion toxicity and exposure (Vasilic et al. Malathion metabolites are also excreted in human feces, as reported in an exploratory study conducted among 2-dayold neonates (Ostrea et al. Clinical trials assessing the efficacy or effectiveness of malathion for the treatment of head lice and scabies. Results between studies are not directly comparable as study design, inclusion criteria, number of applications, formulations of products, outcome measures, and follow-up periods differed considerably. Adverse reactions and toxicity 3433 Number of study participants followed up In each of the five groups, 50 adult fully vital lice were tested Reference Oliveira et al. The lice were monitored at different points in time (5, 10, 20, 30, 60, 120, and 180 minutes and 6 and 24 hours) Cure rate at final assessment Nyda L and Prioderm killed all head lice after 5 min. Lice treated with Hedrin resurrected after several hours and did not show a significantly higher mortality compared with the control group after 24 h Scabies Burgess et al. Treatments were allocated semi-alternately, two patients given malathion to one given benzyl benzoate Hanna et al. Studies in experimental animals have also reported that malathion affects cholinergic functions during embryonic development (Aluigi et al. Studies in humans have shown that chromosomal aberrations, sister chromatid exchanges, and mitotic indices were observed in human peripheral leukocytes treated in vitro with different concentrations (0. Zeljezic and GarajVrhovac (2002) found that the mean value of sister chromatid exchange and number of cells with higher sister chromatid frequency in a population of workers occupationally exposed to a mixture of insecticides including malathion was significantly higher than in the control group. Consequently, the potential risk of chromosome damage for malathion exposure in vivo is therefore considered to be relatively low. In vitro studies of the genotoxicity of malathion and its analogs, malaoxon and isomalathion, indicated that malathion is a potential mutagen and carcinogen (Blasiak et al. The reported genotoxicity of malathion may be a consequence of its metabolic biotransformation to , or the presence of, malaoxon and/or isomalathion, as well as other unspecified impurities in commercial formulations of malathion. These findings suggest that technical grade malathion is a potent genotoxic agent and may be regarded as a potential germ cell mutagen also. Although direct toxic effect of malathion on human reproductive organs has not been reported, 3434 Lindane and Malathion it has been reported that organophosphorous pesticides decrease sperm quality (Recio-Vega et al. Epidemiologic studies assessing maternal exposure to individual pesticides and abortion, fetal death, or congenital defects, while inconclusive, suggest an association between the pesticides and these adverse outcomes (Garcia, 2003). Another study reported that pesticide exposure poses a risk to pregnant women (Goldman et al. The most specific study on the influence of malathion on pregnant women and their offspring reported that malathion metabolites could be identified in the meconium of 2-day-old neonates (Ostrea et al. In rats, malathion is more toxic to newborn rats than to the pre-weaning rats and adults when it is orally administered (Lu et al. Although malathion produced teratogenic effects on zebrafish embryos (Cook and Paradise, 2005; Fraysse et al. Although in one histopathologic study on the carcinogenic capacity of malathion and its oxygen analog malaoxon in rats and mice, no carcinogenic potential was observed (Huff et al. Chemico-pathological changes in the liver of industrial workers chronically exposed to cotton dust. Childhood aplastic anaemia in Lucknow, India: incidence, organochlorines in the blood and review of case reports following exposure to pesticides. Intestinal absorption of hexachlorobenzene and hexachlorocyclohexane and isomers in rats. Interaction between organophosphate compounds and cholinergic functions during development. Oxidative stress and histopathological changes in the heart following oral lindane (gamma hexachlorohexane) administration in rats. Concentrations of selective metabolites of organophosphorus pesticides in the United States population. In vitro studies on the genotoxicity of the organophosphorus insecticide malathion and its two analogues. Comparative teratogenicity of chlorpyrifos and malathion on Xenopus laevis development. Although there are numerous clinical trials of treatment of head lice infestations with malathion, there have been no trials published on the use of malathion for the treatment of body and pubic lice. Malathion has also been licensed and prescribed for use in scabies (Connolly, 2008), but is considered as an alternate treatment option for this indication (Elgart, 1999), behind permethrin, which is recommended as the first-line agent for management of scabies (Roos et al. He obtained honors degrees in veterinary and human medicine- later working as a clinician in both fields-and was awarded a Ph. Decreasing malathion application time for lice treatment reduces transdermal absorption. Monitoring of malathion and its impurities and environmental transformation products on surfaces and in air following an aerial application. Randomised, controlled, assessor blind trial comparing 4% dimeticone lotion with 0. Relationship of treatment-resistant head lice to the safety and efficacy of pediculicides. The comparative toxicity of various contact insecticides to the louse Pediculus humanus (L. Percutaneous absorption, dermatopharmacokinetics and related bio-transformation studies of carbaryl, lindane, malathion and parathion in isolated perfused porcine skin. Controlled study of malathion and d-phenothrin lotions for Pediculus humanus var capitis­infested schoolchildren. Plasma polychlorobiphenyl and organochlorine pesticide level and risk of major lymphoma subtypes. Gas chromatographic­tandem mass spectrometric analytical method for the study of inhalation, potential dermal and actual exposure of agricultural workers to the pesticide malathion. Reproductive toxicity and toxicokinetics of lindane in the male offspring of rats exposed during lactation. Serious poisoning by hexachlorocyclohexane; clinical and laboratory observations on five cases. The rate of urinary excretion of phosalone residues in occupationally exposed persons. Prevalence and treatment of Pediculus capitis infestation among aboriginal school children in northern Taiwan. The chronic toxicities of technical benzene hexachloride and its alpha, beta and gamma isomers. American Academy of Pediatrics Guidelines for the Prevention and Treatment of Head Lice Infestation. Development of a zebrafish 4-day embryo­larval bioassay to assess toxicity of chemicals. Nationwide comparative trial of pyrethrins and lindane for pediculosis in children: experience in northeastern United States. Detection of small amounts of pesticides in human biological material by thin-layer chromatography. Esterase-mediated malathion resistance in the human head louse, Pediculus capitis (Anoplura: Pediculidae). Simultaneous screening for 238 drugs in blood by liquid chromatography­ionspray tandem mass spectrometry with multiple-reaction monitoring. Risk behaviors for pesticide exposure among pregnant women living in farmworker households in Salinas, California. Histoenzymatic studies on the liver cell after the administration of gamma-benzene hexachloride (lindane). Infestation status of head louse and treatment with lindane shampoo in children of primary school and kindergarten in Chinju-shi, Kyongsangnam-do, Korea. A contribution to the question of the possible hepatocarcinogenic effects of lindane. Development of hepatocellular carcinomas in rats treated with benzene hexachloride. Paramyeloblastic leukaemia appearing simultaneously in two blood cousins after simultaneous contact with gammexane (hexachlorocyclohexane). Review of common therapeutic options in the United States for the treatment of pediculosis capitis. Time course of changes in hepatic microsomal parameters, antioxidant enzymes, lipid peroxidative indices and morphological characteristics. Dose-dependent study of the effects of acute lindane administration on rat liver superoxide anion production, antioxidant enzyme activities and lipid peroxidation. Teratogenicity studies on pesticidal formulations of dimethoate, diuron and lindane in rats. Dependency of penetration kinetics in serum upon frequency of application, time and mode of washing. Distribution of lindane in brains of control and phenobarbital pretreated dogs at the onset of lindane-induced convulsions. Human blood and environmental media screening method for pesticides and polychlorinated biphenyl compounds using liquid extraction and gas chromatography­mass spectrometry analysis. Comparative trial of treatment with Prioderm lotion and Kwellada shampoo in children with head lice. Resistance to organochlorine insecticides in head lice and trials using alternative compounds. Comparative efficacy of treatments for pediculosis capitis infestations: Update 2000. Comparative in vitro pediculicidal efficacy of treatments in a resistant head lice population in the United States. A randomized, investigator-blinded, time-ranging study of the comparative efficacy of 0. Regression analysis of pesticide use and breast cancer incidence in California Latinas. Dermal absorption of the insecticide lindane (1 delta, 2 delta, 3 beta, 4 delta, 5 delta, 6 beta-hexachlorocyclohexane) in rats and rhesus monkeys: effect of anatomical site. Breast cancer incidence and its possible spatial association with pesticide application in two counties of England.

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