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Biomedical subjects

Neil H Shear

Publications and source records attributed to Neil H Shear.

At least 37 records · Page 2Linked to original sources
PubMed2003

Cytotoxic T lymphocyte reactivity to gp100, MelanA/MART-1, and tyrosinase, in HLA-A2-positive vitiligo patients.

Vitiligo is a common depigmentation disorder thought to result from autoimmune destruction of melanocytes. Recent studies suggest a role for cell-mediated immune responses to melanocyte differentiation antigens, including gp100, MelanA/MART-1, and tyrosinase, in vitiligo pathogenesis. This study investigated T cell reactivity to MelanA/MART-1, tyrosinase, and gp100, in HLA-A2-positive patients with vitiligo. Melanocyte-specific T cell responses were measured ex vivo via enzyme-linked immunospot assay following stimulation with MelanA/MART-1, tyrosinase, and modified gp100 epitopes. Antigen-specific T lymphocyte reactivity to gp100 peptides was seen in 15 of 17 (88%) patients, with many demonstrating very high reactivity at levels comparable with those observed with common recall antigens. Reactivity to gp100 was noted to be associated with disease activity. Antigen-specific T lymphocyte reactivity to MelanA/MART-1 and tyrosinase peptides was not observed ex vivo in our patients, and only one patient demonstrated responses to MelanA/MART-1 and tyrosinase peptides following in vitro re-stimulation. Our findings implicate T cell reactivity to gp100 in patients with active disease and support the concept of an immunopathologic mechanism in vitiligo, in which cell-mediated responses to normal melanocyte antigens play a crucial part.

Antigens, Neoplasm↗
PubMed2003

Lupus-associated toxic epidermal necrolysis: a novel manifestation of lupus?

BACKGROUND: Toxic epidermal necrolysis is an acute mucocutaneous reaction characterized by extensive cutaneous and mucosal sloughing and systemic involvement. It is generally associated with drug ingestion. OBJECTIVE AND METHODS: We describe 2 patients who developed typical clinical and histopathologic features of toxic epidermal necrolysis with unusual subacute progression, absence of systemic involvement or high-risk drug ingestion, and features of lupus erythematosus. CONCLUSION: We propose that this constellation of features represents a new entity not previously described. This entity may represent a more severe variant of Rowell's syndrome or, alternatively, a novel manifestation of lupus erythematosus

Adult↗
PubMed2003

Reactive metabolites and adverse drug reactions: clinical considerations.

Idiosyncratic reactions can affect many different organ systems, either as -an isolated event (e.g., hepatitis) or as part of a syndrome (e.g., drug hypersensitivity syndrome). Formation of reactive metabolites of drugs in conjunction with a decreased ability for detoxification is believed to be the initiating step in many idiosyncratic reactions. The drug hypersensitivity syndrome, defined by the presence of fever, rash and internal organ involvement, is estimated to occur in approx 1 in 1000 to 1 in 10,000 exposures with drugs such as anticonvulsants sulfonamide antibiotics, allopurinol, and dapsone. Symptoms usually start within 2-8 wk of drug initiation. Serum sicknesslike reaction, most frequently found after 7-14 d of drug exposure, is distinguished by a fever, cutaneous eruption and arthralgias. Medications such as cefaclor, minocycline and bupropion are most frequently implicated in this reaction. In contrast, drug-induced lupus can occur l-2 yr after initiation of medication. Drug-induced lupus is characterized by musculoskeletal complaints and fever and weight loss. Drugs most commonly associated with drug-induced lupus include procainamide, hydralazine, chlorpromazine, isoniazid, and minocycline. Management of patients who develop idiosyncratic reactions includes discontinuation of the implicated drug, initiation of corticosteroids (when appropriate), and symptomatic relief as required. Internal organ involvement, which may initially be asymptomatic, should be monitored. Confirmatory or diagnostic tests are not readily available in most areas, except for research purposes.

Drug Hypersensitivity↗
PubMed2003

Safety of celecoxib in individuals allergic to sulfonamide: a pilot study.

OBJECTIVE: To evaluate cross reactivity between sulfonamide antimicrobials and celecoxib in patients with histories of allergies to sulfonamide antimicrobials. METHODS: Immunocompetent patients with a history of sulfonamide antimicrobial allergy who were being considered for therapy with celecoxib were prospectively enrolled. Sulfamethoxazole and trimethoprim skin prick and intradermal testing and/or an in vitro lymphocyte toxicity assay were performed. If skin testing was negative, an oral challenge with sulfamethoxazole and trimethoprim was performed. Oral challenges with celecoxib were administered to all patients. RESULTS: Twenty-eight immunocompetent patients (26 female; mean age 60 years) were evaluated. History of sulfonamide antimicrobial allergy included urticaria (n = 7), cutaneous eruptions (n = 9), and other (n = 12). Four of the 28 patients who were skin prick tested were positive to sulfamethoxazole and two of the ten patients who underwent in vitro testing were positive to sulfamethoxazole. All 28 patients were administered celecoxib and tolerated the medication. Phone call follow up in 25 patients disclosed that 15 patients continued to take celecoxib, while five patients did not take celecoxib following the oral challenge, and five discontinued celecoxib due to adverse effects, lack of drug efficacy or physician preference. CONCLUSIONS: Confusion exists regarding the potential for cross reactivity between sulfonamide antimicrobials and other sulfonamide-containing compounds. The six sulfonamide-allergic patients tolerated celecoxib uneventfully. This pilot study supports the hypothesis that the potential for cross-reactivity between celecoxib and sulfonamide antimicrobials appears to be low. However, further investigations are required to confirm this.

Administration, Oral↗
PubMed2003

The kidney--the body's playground for drugs: an overview of renal drug handling with selected clinical correlates.

A greater understanding of transport mechanisms contributing to renal drug handling may be useful in predicting drug clearance and drug interactions. Renal clearance is a dynamic process expressed as the sum of the rates of glomerular filtration and tubular secretion minus the rate of tubular reabsorption. Because the transport of drugs is often against a concentration gradient, renal secretion is mostly an active process involving a variety of transporter mechanisms. Discoveries from molecular biology techniques and gene 'knock-out' experiments have identified a variety of renal tubular proteins responsible for the transport of organic cations, organic anions, neutral and cationic hydrophobic compounds, anionic conjugates and specific agents such as prostaglandins. The discovery of a P-glycoprotein (P-gp) transporter at the apical membrane of renal tubular cells is particularly important. By elucidating compounds that act as substrates, inhibitors or inducers of transport proteins, pharmacologists and clinicians may better understand renal drug clearance. This paper provides a brief overview of several identified renal transport proteins including organic anion transporters, organic cation transporters, ATP-dependent transporters (multidrug resistance [P-gp] and multi-drug resistance associated protein), nucleoside transporters (sodium-dependent purine nucleoside transporter and concentrative nucleoside transporter 1) and peptide transporters. A special focus on known P-gp-mediated drug interactions is included to demonstrate the clinical relevance of transporter protein science. At the patient level, this may lead to novel approaches to alter in vivo pharmacokinetics and improve drug safety through a greater understanding of toxic substrate clearance and drug interactions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Drug eruptions: approaching the diagnosis of drug-induced skin diseases.

Adverse drug reactions are a major problem in drug therapy, and cutaneous drug reactions account for a large proportion of all adverse drug reactions. Cutaneous drug reactions are also a challenging diagnostic problem since they can mimic a large variety of skin diseases, including viral exanthema, collagen vascular disease, neoplasia, bacterial infection, psoriasis, and autoimmune blistering disease, among others. Furthermore, determining that a particular medication caused an eruption is often difficult when the patient is taking multiple drugs. In this review, we will describe and illustrate a thoughtful, comprehensive, and clinical approach to the diagnosis and management of adverse cutaneous drug reactions. A morphologic approach to drug eruption includes those that are classified as maculopapular, urticarial, blistering or pustular with or without systemic manifestations. Exanthematous drug eruptions, drug hypersensitivity syndrome, urticaria and angioedema, serum sickness-like reactions, fixed drug eruptions, drug-induced autoimmune blistering diseases, Stevens-Johnson syndrome, toxic epidermal necrolysis, drug-induced acne, acute generalized exanthematous pustulosis, lichenoid drug eruptions and photosensitivity eruptions will be discussed.

Adverse Drug Reaction Reporting Systems↗
PubMed2003

Clinical pharmacology consultations: consultation requests may be misleading -- an organized approach to drug-induced hepatitis.

The present case report describes a consultation with the Clinical Pharmacology Consultation Service at the Sunnybrook & Women's College Health Sciences Centre, Toronto, Ontario, for drug-induced hepatitis in a patient with multiple drug exposures. The original question to be addressed was whether dalteparin was responsible for an acute rise in liver transaminases. The approach involved establishing a best possible diagnosis of the adverse event, obtaining a comprehensive history of drug exposure and evaluating the possible contributory role of alternate etiologies supported by a literature search. On balance, based on temporal relationships and previous case reports, ranitidine was considered to be the most likely causal agent. The initial consultation request was to investigate the likelihood that daltaperin caused hepatitis; however, a systematic and comprehensive approach led to the conclusion that it was more likely to be ranitidine-induced hepatitis.

Adverse Drug Reaction Reporting Systems↗
PubMed2002

Serum tumour necrosis factor-alpha and transforming growth factor-beta levels in chronic hepatitis C patients are immunomodulated by therapy.

Our aims were: (i) to characterize serum levels of tumour necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta) in non-cirrhotics with hepatitis C; (ii) to correlate levels of theses cytokines with degree of disease at baseline; (iii) to characterize the immunomodulatory effects of therapy with response and (iv) to compare profiles of cytokines in patients treated with pegylated-interferon alpha-2b monotherapy (PMT) vs its combination with ribavirin (PCT1-low dose ribavirin and PCT2-high dose ribavirin). We studied 56 patients that were part of two randomized, controlled, clinical trials. At baseline, high TNF-alpha levels paralleled the degree of inflammation as determined by histology. In PCT2, a significant reduction was seen in levels of TNF-alpha, TGF-beta and fibrosis scores when comparing baseline with follow-up. In sustained responders, regardless of therapy, the histological activity scores were lower at follow-up as compared to baseline. In conclusion, PCT2 is able to constantly reduce and sustain TNF-alpha levels, which is responsible for the sustained decline in liver inflammation as shown by the histological activity index and it is also able to reduce fibrosis as judged both by TGF-beta levels and fibrosis scores.

Adult↗
PubMed2002

Mechanism of Impila (Callilepis laureola)-induced cytotoxicity in Hep G2 cells.

OBJECTIVES: To determine the mechanism(s) of Impila (Callilepis laureola)-induced toxicity in human hepatoblastoma Hep G2 cells in vitro and the possible prevention of this toxicity by N-acetylcysteine (NAC). DESIGN AND METHODS: Cells were treated with an aqueous extract of Impila (10 mg/mL) for up to 24 h. NAC (5 mM) was administered either concomitantly with Impila or one hour post Impila treatment. Cytotoxicity was quantitated spectrophotometrically by the metabolism of the tetrazolium dye MTT. Total glutathione (GSH) was measured using the Tietze assay. RESULTS: Impila produced cytotoxicity and depleted GSH in a concentration- and time-dependent manner. A significant depletion in GSH was observed after 15 min (p < 0.0001 vs. control), whereas significant cytotoxicity was only observed after at least 3 h (p < 0.0001 vs. control). Both concomitant and posttreatment with NAC prevented Impila-induced GSH depletion and resulted in a significant decrease in Impila-induced cytotoxicity (p < 0.001 vs. NAC-untreated cells). CONCLUSION: Our results suggest the mechanism of Impila-induced cytotoxicity in Hep G2 cells in vitro involves depletion of cellular GSH. Preventing GSH depletion by supplementing cells with NAC reduces cytotoxicity.

Acetylcysteine↗
PubMed2002

Ethanol signals for apoptosis in cultured skin cells.

Ethanol is commonly used in cosmetic and pharmaceutical preparations. To test whether ethanol may cause apoptosis in skin cells, we treated A431 epidermoid skin cells and neonatal human primary skin cells with different concentrations of ethanol, for different time periods. Ethanol was toxic to cells in both a dose- and time-dependent manner and increased the percentage of cells undergoing apoptosis. Treatment of cells with 40 and 100 mM ethanol increased release of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) into culture medium and increased its expression in cells. The TNF-alpha was toxic to A431 epidermoid skin cells at concentrations similar to those released by cells on exposure to ethanol. Ethanol-treated cells examined by electron microscopy showed organelle damage, condensed chromatin, and apoptotic bodies. Therefore, even at low concentrations, ethanol may induce apoptosis in skin cells by enhancing the effects of TNF-alpha.

Analysis of Variance↗
PubMed2002

Drug eruptions and other adverse drug effects in aged skin.

The elderly are at higher risk for suffering the annoying and hazardous skin reactions that are associated with drug therapy. If a serious reaction occurs, the aged are also at higher risk for major morbidity and mortality compared with younger individuals. Early consideration of a drug cause and prompt cessation of all potentially associated drugs may improve a patient's outcome. Thus, a prompt, careful, and accurate characterization of a drug-related reaction is important in optimizing patient care, along with close monitoring for associated internal toxicities and other medical complications of severe cutaneous reactions.

Aged↗
PubMed2002

Task force report: future research needs for the prevention and management of immune-mediated drug hypersensitivity reactions.

Immune-mediated drug hypersensitivity reactions (IDHR) have a significant impact on clinical practice, drug development, and public health. However, research to understand IDHR mechanisms and to develop diagnostic and predictive tests has been limited. To stimulate more research, a task force with representatives from the key stakeholders (research clinicians, regulatory scientists, and immunotoxicologists from the pharmaceutical industry) was assembled to identify critical data gaps and opportunities and to make recommendations on how to overcome some of the barriers to IDHR research and address research needs. It is hoped that this report will act as a springboard for future discussions and progress toward increased funding and development of organizational structures for IDHR research.

Drug Design↗
PubMed2002

Drug interactions: Proteins, pumps, and P-450s.

UNLABELLED: The two major concerns in drug safety are adverse drug reactions and drug interactions. When multiple drug therapies are prescribed, drug interactions become an important consideration for patients and physicians. The life of a drug is reviewed with emphasis on absorption, distribution, metabolism, and excretion. Pharmacokinetic and pharmacodynamic mechanisms for drug interactions are reviewed. The contributions of P-glycoprotein, pharmacogenetic variation, and genetic polymorphisms to drug interactions are highlighted. Prediction of drug interactions is possible with knowledge of which agents are likely to cause alterations in drug metabolism. (J Am Acad Dermatol 2002;47:467-84.) LEARNING OBJECTIVE: At the conclusion of this learning activity, participants should have an understanding of the life of a drug. This knowledge should help predict important potential drug interactions.

ATP Binding Cassette Transporter, Subfamily B, Mem↗