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N H Shear

Publications and source records attributed to N H Shear.

At least 19 recordsLinked to original sources
PubMed1992

Advances in the diagnosis of adverse drug reactions.

The clinician plays a key role in the detection and diagnosis of adverse drug reactions (ADRs). The diagnosis of ADRs, however, is a complex task. In the past, there were no systematically applied diagnostic criteria for ADRs, no formal methods of case analysis, no standardized epidemiologic approaches, and a limited knowledge of mechanisms. This resulted in the overdiagnosis of ADRs, which has negative consequences such as limiting treatment options. Recently, there have been various improvements in the diagnosis of ADRs, such as the development of standardized decision aids and of in vitro diagnostic tests. This article briefly reviews some of this knowledge, discusses the role of in vivo and in vitro rechallenge, and summarizes a probabilistic approach for collecting relevant information and diagnosing ADRs. The intention is to increase awareness of the different approaches for diagnosing ADRs as well as to stimulate researchers to continue to collect pharmacoepidemiologic information, study the pharmacologic, immunologic, and genetic factors involved in the pathogenesis of drug reactions, and develop and test new diagnostic instruments under various clinical conditions.

Adverse Drug Reaction Reporting Systems↗
PubMed1992

Drug-induced hypothyroidism: the thyroid as a target organ in hypersensitivity reactions to anticonvulsants and sulfonamides.

Inherited defects in detoxification of reactive metabolites of drugs predispose patients to "hypersensitivity" reactions. Covalent interaction of metabolites with cell macromolecules leads to cytotoxic and immunologic outcomes, manifested clinically by multisystem syndromes with variable organ involvement. Hypothyroidism developed in 5 of 202 patients (age range, 1 to 81 years) we investigated for hypersensitivity reactions to anticonvulsants or sulfonamides shortly after their reaction. None had previous personal or family histories of autoimmune disease. All had low thyroxine levels, elevated levels of thyroid stimulating hormone, and autoantibodies including antimicrosomal antibodies. Patients were 2 to 18 years of age at presentation, and two were male. All returned to a euthyroid state within a year of presentation, and all remain well. The demographics, clinical presentation, and course of the patients is atypical of idiopathic lymphocytic thyroiditis. We investigated the pathogenesis of thyroid toxicity using the hydroxylamine metabolite of sulfamethoxazole as a model. The hydroxyalmine was toxic to thyroid cells in vitro, which did or did not express thyroid peroxidase activity, whereas the parent sulfonamide was toxic only to cells with active thyroid peroxidase. The purified enzyme converted sulfamethoxazole to the hydroxylamine. Formation of reactive drug metabolites by thyroid peroxidase in a host who is genetically unable to detoxify the metabolites may lead directly to cytotoxicity. Covalent binding to macromolecules, including thyroid peroxidase, also may lead to expression of neoantigens and formation of autoantibodies. Patients who have sustained hypersensitivity reactions to drugs should be investigated for possible involvement of the thyroid.

Adolescent↗
PubMed1991

In-vitro assessment of a hypersensitivity syndrome associated with sorbinil.

Sorbinil is a hydantoin aldose reductase inhibitor that has shown promise as therapy for patients with diabetic complications such as neuropathy and retinopathy. However, as many as 10% of patients receiving sorbinil have had adverse reactions characterized by fever, skin rash, and myalgia. Our previous studies of phenytoin suggested that susceptibility to reactions might result from an inherited detoxification defect. We did the current study to determine if sorbinil is metabolized to reactive intermediates and if cells from patients with a history of a reaction to sorbinil are appropriate for the in-vitro investigation of susceptibility. Microsome-generated metabolites of sorbinil (50 microM) were toxic to normal peripheral blood lymphocytes (7.9% +/- 0.3% dead cells [mean +/- SE]). Toxicity was increased in the presence of an epoxide hydrolase inhibitor (17.5% +/- 0.3% dead cells) and abolished by an inhibitor of cytochrome P-450. In contrast to cells from healthy controls and diabetics who tolerated sorbinil (7.9% +/- 0.7% and 7.8% +/- 0.4% dead cells, respectively), cells from the six patients who had sorbinil reactions showed significantly increased toxicity from metabolites of sorbinil and phenytoin (19.7% +/- 2.3% dead cells, P less than 0.001). Cells from three patients who had reactions to phenytoin were similarly sensitive to sorbinil metabolites (23.4% +/- 0.3% dead cells). We conclude that sorbinil is oxidatively metabolized to a potentially toxic intermediate. Certain patients may be at increased risk for developing hypersensitivity reactions. Development of this important new drug has been hampered by uncommon but potentially severe reactions. An increased understanding of the steps involved in the development of adverse reactions could lead to screening tests or to the development of safer compounds.

Adult↗
PubMed1991

Prominence of slow acetylator phenotype among patients with sulfonamide hypersensitivity reactions.

Delayed hypersensitivity reactions are among the most severe adverse effects of the sulfonamides in current clinical use. These reactions appear to occur because of differences in the metabolism and detoxification of reactive metabolites of the sulfonamides. N-Acetylation is a major metabolic pathway for the sulfonamides. Slow acetylation phenotype might be a risk factor for the development of these reactions. We determined the acetylation phenotype of 21 patients who had suffered hypersensitivity reactions to the sulfonamides. There were 11 females and 10 males in the group, with a mean age of 15 years (age range, 1.8 to 50 years). Their acetylator phenotype was determined by determining the ratio of urinary caffeine metabolites (1-methylxanthine to 5-amino-6-formylmethyluracil after an oral dose of 50 mg caffeine). Nineteen (90%) of the patients were slow acetylators compared to a 55% incidence of slow acetylators in a race-matched control population (p less than 0.008). This suggests that a slow acetylator phenotype is a risk factor for the development of sulfonamide hypersensitivity reactions and provides further support for the role of imbalances in genetically determined pathways of metabolism and detoxification of the sulfonamides in the pathogenesis of these reactions.

Acetylation↗
PubMed1991

Mycoplasma pneumoniae infections and Stevens-Johnson syndrome. Report of eight cases and review of the literature.

On the basis of a literature review and eight cases of our own, we analyzed 37 cases of Mycoplasma pneumoniae (MP) infection and Stevens-Johnson syndrome (SJS). Our clinical and laboratory findings do not differ from those reported in the literature for MP infection with no exanthem or for SJS of various etiologies. Eighty percent of the children presented with symptoms of upper respiratory tract infection (URTI) (cough, fever, sore throat, malaise, headache), with a mean of 10 days (range 1 to 30) before skin rash broke out. Skin manifestations occurred in 94.2% of the patients after 3 to 21 days (mean 10.3 days) of fever. The exanthem, composed predominantly of maculopapular and vesicular, was distributed chiefly on the trunk and extremities and lasted less than 14 days in 87.8% of the patients. Stomatitis was observed in 91.6% of the patients and conjunctivitis in 50%. No consistent pattern seems to emerge by which one could predict the existence of MP infection causing SJS. The complications of SJS associated with MP seem less frequent (2.7%) and much less severe than in cases where SJS arises from other reported causes. Because coincidence cannot be excluded from the assessments of the degree and rate of improvement for the few patients treated with corticosteroid, from the low frequency of complications, and from the mortality rate of zero in this series of patients, the use of corticosteroids for SJS associated with MP infection is questionable.

Adolescent↗
PubMed1989

Diagnosis of sulfonamide hypersensitivity reactions by in-vitro "rechallenge" with hydroxylamine metabolites.

STUDY OBJECTIVE: To determine whether differences in in-vitro detoxification of sulfonamide-reactive metabolites can be detected among the lymphocytes from controls, patients with sulfonamide hypersensitivity reactions, and patients with nonhypersensitivity reactions to the sulfonamide agents. DESIGN: In-vitro toxicity assay on lymphocytes. SETTING: Clinics for adverse drug reactions in an adult and pediatric tertiary care center. PATIENTS: Peripheral blood lymphocytes were obtained from 46 normal volunteers and 76 patients referred to the clinic for assessment of adverse drug reactions to sulfonamide agents. Thirty-one patients had clinical histories consistent with a diagnosis of hypersensitivity reaction, whereas 45 patients had clinical histories felt to be inconsistent with a diagnosis of hypersensitivity reaction. INTERVENTIONS: Lymphocytes were assayed with tetrazolium to determine toxicity from the hydroxylamine of sulfamethoxazole. MEASUREMENTS AND MAIN RESULTS: The lymphocytes from patients with a history of hypersensitivity reactions showed markedly increased toxicity across a tenfold-concentration toxicity-concentration curve compared with those from controls and patients with a history of nonhypersensitivity reactions. These differences were highly significant (P less than 0.01). No difference was found between the toxicity shown by the lymphocytes from controls and that shown by the lymphocytes from patients with a history of nonhypersensitivity reactions. CONCLUSIONS: Metabolic differences in the production and detoxification of reactive metabolites of sulfonamide agents are important determinants of hypersensitivity reactions to these agents. These results suggest that the hydroxylamine derivative of sulfamethoxazole may be a reactive metabolite mediating these reactions. Sulfonamide hydroxylamines are useful in the diagnosis and study of the pathogenesis of hypersensitivity reactions to sulfonamide agents.

Adult↗
PubMed1989

Neuroblastoma after prenatal exposure to phenytoin: cause and effect?

We evaluated the causality of the association between intrauterine exposure to phenytoin and postnatal neuroblastoma using an in vitro lymphocyte toxicity assay for phenytoin-induced reactions in an unusual sibship. In addition, we investigated intrauterine phenytoin exposure in a case series of infants and children with neuroblastoma diagnosed over 17 years at our center. The response of lymphocytes from our index case with neuroblastoma exposed in utero to phenytoin was within the normal range, whereas the mother and a sibling with fetal hydantoin syndrome (FHS) exhibited an intermediate toxicity. None of the 188 cases of childhood neuroblastoma diagnosed between 1969 and 1988 had been exposed in utero to phenytoin, indicating that, statistically, the drug cannot be associated with neuroblastoma in more than two cases with this malignancy in our cohort, or in 1.5% of all cases of neuroblastoma. Although our data do not suggest an association between phenytoin in pregnancy and postnatal neuroblastoma, it is still possible that there is an increased risk for neuroblastoma in children with FHS.

Bone and Bones↗
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↗