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Biomedical subjects

N H Shear

Publications and source records attributed to N H Shear.

At least 145 records · Page 8Linked to original sources
PubMed1989

Perception of teratogenic risk by pregnant women exposed to drugs and chemicals during the first trimester.

We assessed the perception of teratogenic risk by 80 women attending an antenatal consultation service for drug, chemical, and radiation exposure. Women exposed to agents not known to be teratogenic assigned themselves a risk of 24% +/- 2.8% for major malformation before the relevant medical literature was delivered to them and 14.5% +/- 3% thereafter. These women accurately estimated the risk for major malformation in the general population (5.6% +/- 1.3%). The tendency to terminate pregnancy when exposed to a nonteratogen significantly decreased after the consultation. Eleven patients exposed to drugs known to be teratogenic assigned a risk of 36.2% +/- 11.7% before the interview and did not change their perception thereafter (36.7% +/- 15.8%). Similarly, their tendency to continue or terminate pregnancy did not change; three of them eventually chose to terminate the pregnancy. Advising women about their teratogenic risk early in pregnancy may prevent unjustified termination of many pregnancies and may help to inform women exposed to proven teratogens about the known risk.

Abortion Applicants↗
PubMed1989

Pharmacogenetics and cutaneous drug reactions.

Variations in therapeutic efficacy and ADRs in the population are known for many drugs. When individuals are adversely affected by their therapy, it suggests the possibility of a pharmacogenic predisposition. Genetic variants and polymorphism affect the metabolism and sites of action of many agents, and the expression of genetic variations is modified by both host and external factors. Many of these metabolic defects are well-described and are important to the clinician who is evaluating an adverse reaction to either old or new drugs. The systematic evaluation of drug effects demands attention to subgroup and individual variation in metabolism of the drug and susceptibility to its effects. Practically every class of drug shows individual variation in responses and once the variation has been recognized and categorized, there are implications for other drugs (some seemingly unrelated) and for family members.

Drug Eruptions↗
PubMed1988

Temperature-dependent skin disorders.

The skin is important in preserving homeostasis between man and his environment. One main role of the skin is in thermoregulation, where cutaneous blood flow, and hence skin temperature, vary widely in order to help preserve core body temperature. Under extreme conditions, frostbite or burns may occur. Prolonged exposure to moderate degrees of heat or cold can result in erythema ab igne and chilblains. Temperature plays a direct role in some of the physical urticarias and is one of several important pathogenic factors in conditions such as Raynaud's syndrome, cold panniculitis, and cryoglobulinemia. These and other temperature-dependent skin disorders are reviewed.

Animals↗
PubMed1988

Anticonvulsant hypersensitivity syndrome. In vitro assessment of risk.

Arene oxide metabolites of aromatic anticonvulsants (phenytoin, phenobarbital, and carbamazepine) may be involved in the pathogenesis of hypersensitivity reactions. We investigated 53 patients with clinical sensitivity to anticonvulsants by exposing their lymphocytes in vitro to drug metabolites generated by a murine hepatic microsomal system. The diagnosis of a hypersensitivity reaction was corroborated by in vitro rechallenge for each drug (phenytoin, n = 34; phenobarbital, n = 22; carbamazepine, n = 25) when cytotoxicity (% dead cells) exceeded 3 SD above the mean result for controls. Cross-reactivity among the drugs was noted. 7 out of 10 patients who had received all three anticonvulsants had adverse reactions to each. 40 out of 50 patients tested to all three drugs in vitro were positive to each. Adverse reactions were indistinguishable among anti-convulsants. Skin rash (87%), fever (94%), hepatitis (51%), and hematologic abnormalities (51%) were common clinical features of each drug. 62% of reactions involved more than two organs. Cells from patients' parents exhibited in vitro toxicity that was intermediate between values for controls and patients. In vitro testing can help diagnose hypersensitivity to anticonvulsants. Cells from patients may also be used for prospective individualization of therapy to decrease risk of adverse reaction. Cross-reactivity among the major anticonvulsants is common and should be considered before deciding on alternative therapy.

Adolescent↗
PubMed1988

Metabolism of dapsone to a hydroxylamine by human neutrophils and mononuclear cells.

Dapsone is an effective anti-inflammatory agent in conditions in which inflammation is mediated by neutrophils. Dapsone also has been associated with agranulocytosis. We found that neutrophils, which had been activated by a phorbol ester or opsonized zymosan, oxidized dapsone to its nitroderivative. It appears as if this is due to oxidation of dapsone by myeloperoxidase to the hydroxylamine, followed by nonenzymatic oxidation of the hydroxylamine to the nitroderivative. The hydroxylamine can be isolated if ascorbic acid is added to the incubations. Monocytes also contain myeloperoxidase and activated mononuclear leukocytes also metabolize dapsone to the hydroxylamine. Dapsone also causes a mononucleosis-like syndrome. The reactive hydroxylamine could be responsible for both the pharmacologic and toxic properties of dapsone.

Anti-Inflammatory Agents↗
PubMed1988

Synthesis and in vitro toxicity of hydroxylamine metabolites of sulfonamides.

Among the most serious side effects of sulfonamides are hypersensitivity reactions, the pathogenesis of which has been suggested to be mediated by reactive metabolites. We have previously demonstrated dose-related covalent binding and toxicity of reactive intermediates of sulfonamides generated by a murine hepatic microsomal activating system. We hypothesized that hydroxylamine (H/A) metabolites might be likely candidates for mediating such toxicity; accordingly, we synthesized chemically the H/As of sulfadiazine and sulfamethoxazole. Synthesis was performed using 4-nitrobenzenesulfonyl chloride and either 2-aminopyrimidine or 3-amino-5-methylisoxazole, respectively, as starting materials. The resulting nitro derivatives were reduced to the corresponding H/A with hydrogen in the presence of a poisoned platinum catalyst. After synthesis and purification, toxicity of the H/As to lymphocytes of normal volunteers was evaluated using three cytotoxicity assays: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide dye conversion, trypan blue dye exclusion and propidium iodide dye exclusion. The H/As of sulfadiazine and sulfamethoxazole displayed dose-related toxicity. 1.6 mM sulfadiazine H/A produced 82% cell death, whereas 400 microM sulfamethoxazole H/A produced 62% cell death; the parent sulfonamides were not toxic to cells. The toxicity of sulfamethoxazole H/A was decreased by coincubation with glutathione or N-acetylcysteine; there was a 47% decrease in toxicity when coincubated with 100 microM glutathione, whereas there was a 55% decrease displayed when coincubation was done with 500 microM N-acetylcysteine. H/A metabolites of the sulfonamides or their nitroso derivatives, normally detoxified by conjugation to glutathione, may be the proximate toxins mediating sulfonamide hypersensitivity.

Cell Survival↗
PubMed1986

Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity.

Individual differences in metabolism of the sulfonamides may predispose patients to idiosyncratic reactions. Sulfonamides are metabolized by N-acetylation (mediated by a genetically polymorphic enzyme) and oxidation to potentially toxic metabolites. We examined 6 patients who had severe reactions to sulfonamides and compared them with 20 controls. Acetylator phenotype was determined with caffeine, a safe in-vivo probe of enzyme activity. All 6 patients were slow acetylators (expected, 55%; p less than 0.05). Detoxification of oxidative metabolites was studied in vitro with a lymphocyte assay evaluating cell death from metabolites generated by a murine hepatic microsomal system. Cells from each patient showed increased toxicity from sulfonamide metabolites but not from the drugs themselves. Cells from parents of 3 patients had intermediate toxicity from sulfonamide metabolites, whereas cells from a sibling of 1 patient had a normal response. Susceptibility to sulfonamide reactions may be due to interaction of metabolic pathways, possibly under genetic control, regulating N-acetylation and specific detoxification of toxic metabolites of the drugs.

Acetylation↗
PubMed1985

In vitro evaluation of a toxic metabolite of sulfadiazine.

We have demonstrated the in vitro production of a potentially toxic metabolite of sulfadiazine Human lymphocytes were incubated with sulfadiazine and a murine hepatic microsomal drug metabolizing system. Toxicity to cells was assessed by trypan blue dye exclusion. Covalent binding of labelled sulfadiazine to microsomes also was studied. Sulfadiazine toxicity to cells was dependent on microsomes and NADPH. Binding and toxicity were decreased when microsomes were boiled or cytochrome P-450 inhibited, and by the addition of N-acetylcysteine or glutathione. The data suggest the production of a toxic intermediate of oxidative metabolism of sulfadiazine which is detoxified by conjugation with glutathione. Covalent binding of such metabolites to cell macromolecules could lead to cell death and, by acting as haptens, to secondary hypersensitivity reactions.

Cell Survival↗
PubMed1983

Pharmacogenetics and adverse drug reactions in the skin.

Hereditary variations in the handling of a drug (pharmacogenetics) may result in adverse reactions in the skin. Such reactions could result from: (1) an inherited defect in enzymes responsible for drug metabolism (formation or detoxification of potentially toxic metabolites); (2) altered susceptibility of an endogenous metabolic pathway to inhibition by a drug. Increased alcohol-dehydrogenase activity or decreased aldehyde-dehydrogenase activity will predispose an individual to ethanol-induced flushing. Decreased uroporphyrinogen decarboxylase may result in porphyria cutanea tarda. Slow acetylators are more susceptible to developing drug-induced lupus erythematosus. A hypersensitivity syndrome may result if a patient is unable to detoxify the toxic metabolites of a drug such as phenytoin. A pharmacogenetic defect should alert the clinician to the possibility of cross-reactivity with other drugs or potential drug reactions in relatives of the patient.

Chemical and Drug Induced Liver Injury↗
PubMedDate not supplied

Antihistamines.

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Dermatitis↗
PubMedDate not supplied

Antimalarials.

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Antimalarials↗