ascorbic-acid and Drug-Hypersensitivity

Topics: Adult; Aged; Ascorbic Acid; Drug Eruptions; Drug Hypersensitivity; Eczema; Erythema Nodosum; Exanthema; Female; Humans; Lymphocyte Activation; Male; Medical History Taking; Middle Aged; Occupational Diseases; Penicillins; Photosensitivity Disorders; Pyridoxine; Radioallergosorbent Test; Skin Diseases; Stevens-Johnson Syndrome; Sulfonamides; Surveys and Questionnaires

Topics: Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Agranulocytosis; Anemia, Hemolytic; Anemia, Hemolytic, Autoimmune; Ascorbic Acid; Autoantibodies; Autoimmune Diseases; Blood Transfusion; Chloroquine; Colitis; Colitis, Ulcerative; Drug Hypersensitivity; Drug Therapy; Hemoglobinuria; Hemoglobinuria, Paroxysmal; Humans; Internal Medicine; Leukopenia; Lupus Erythematosus, Systemic; Neutrophils; Purpura; Purpura, Thrombocytopenic; Purpura, Thrombotic Thrombocytopenic; Splenectomy; Thrombocytopenia; Thyroiditis; Toxicology; Vitamins

Sulfamethoxazole (SMX) is an effective drug for the management of opportunistic infections, but its use is limited by hypersensitivity reactions, particularly in HIV-infected patients. The oxidative metabolite SMX-nitroso (SMX-NO), is thought to be a proximate mediator of SMX hypersensitivity, and can be reduced in vitro by ascorbate or glutathione. Leukocytes from patients with SMX hypersensitivity show enhanced cytotoxicity from SMX metabolites in vitro; this finding has been attributed to a possible "detoxification defect" in some individuals. The purpose of this study was to determine whether variability in endogenous ascorbate or glutathione could be associated with individual differences in SMX-NO cytotoxicity. Thirty HIV-positive patients and 23 healthy control subjects were studied. Both antioxidants were significantly correlated with the reduction of SMX-NO to its hydroxylamine, SMX-HA, by mononuclear leukocytes, and both were linearly depleted during reduction. Controlled ascorbate supplementation in three healthy subjects increased leukocyte ascorbate with no change in glutathione, and significantly enhanced SMX-NO reduction. Ascorbate supplementation also decreased SMX-NO cytotoxicity compared to pre-supplementation values. Rapid reduction of SMX-NO to SMX-HA was associated with enhanced direct cytotoxicity from SMX-NO. When forward oxidation of SMX-HA back to SMX-NO was driven by the superoxide dismutase mimetic, Tempol, SMX-NO cytotoxicity was increased, without enhancement of adduct formation. This suggests that SMX-NO cytotoxicity may be mediated, at least in part, by redox cycling between SMX-HA and SMX-NO. Overall, these data indicate that endogenous ascorbate and glutathione are important for the intracellular reduction of SMX-NO, a proposed mediator of SMX hypersensitivity, and that redox cycling of SMX-HA to SMX-NO may contribute to the cytotoxicity of these metabolites in vitro.

Topics: Adult; Aged; Antioxidants; Ascorbic Acid; Cell Separation; Cyclic N-Oxides; Drug Hypersensitivity; Female; Glutathione; HIV Infections; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Oxidation-Reduction; Spin Labels; Sulfamethoxazole

Twelve children, aged six to 13 years, whose parents reported an improvement in behavioural problems with use of the Feingold (K-P) diet for an average period of 12 months, were challenge-tested with 40 mg of acetylsalicylic acid in a double-blind, cross-over trial with ascorbic acid as a placebo. The children were tested within three hours of ingestion of either the experimental or placebo tablet with a battery of psychological and neurological tests, and were rated by a parent on an enlarged Conners' Parent-Teacher Questionnaire for four days after the ingestion of the tablet. It was found that significance was reached in tests of general cognitive capacity, line walking and the "finger-to-nose" tests, as well as increased disturbance in sleep patterns in these children.

Topics: Adolescent; Allergens; Ascorbic Acid; Aspirin; Child; Clinical Trials as Topic; Double-Blind Method; Drug Hypersensitivity; Female; Follow-Up Studies; Humans; Hyperkinesis; Male; Placebos; Surveys and Questionnaires

Sulfonamide hypersensitivity has a high incidence in HIV infection and correlates with low CD4+ counts, but the mechanisms are not understood. The aims of this study were to determine whether trimethoprim/sulfamethoxazole (TMP/SMX) led to SMX adduct formation, immunogenicity, or signs of drug hypersensitivity in SIV-infected rhesus macaques, and whether differences in antioxidants, pro-inflammatory mediators, or SMX disposition were predictive of drug immunogenicity.. Four of 9 of SIV-positive (44%), and 3 of 7 SIV negative (43%) macaques had drug-responsive T cells or antibodies to SMX. Two macaques developed facial or truncal rash; these animals had the highest levels of lymph node drug adducts. Antioxidants, pro-inflammatory mediators, and SMX metabolites were not predictive of drug immunogenicity; however, the Mamu DRB1*0401/0406/0411 genotype was significantly over-represented in immune responders.. Unlike other animal models, macaques develop an immune response, and possible rash, in response to therapeutic dosages of TMP/SMX. Studying more animals with CD4+ counts <200cells/μl, along with moderately restricted ascorbate intake to match deficiencies seen in humans, may better model the risk of SMX hypersensitivity in HIV-infection. In addition, the role of Mamu-DRB1 genotype in modeling drug hypersensitivity in retroviral infection deserves further study.

Topics: Animals; Anti-Infective Agents; Antioxidants; Ascorbic Acid; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cytochrome-B(5) Reductase; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Hypersensitivity; Female; Glutathione; HIV Infections; Interferon-gamma; Lipopolysaccharides; Lymph Nodes; Macaca mulatta; Male; Trimethoprim, Sulfamethoxazole Drug Combination

Patients with haematologic malignancies have a reportedly high incidence of sulfamethoxazole (SMX) hypersensitivity. The objective of this study was to determine whether deficiencies in sulfonamide detoxification pathways, to include glutathione (GSH) and ascorbate (AA), and cytochrome b(5) (b5) and cytochrome b(5) reductase (b5R), were prevalent in these patients. A secondary pilot objective was to determine whether the incidence of drug hypersensitivity following intermittent trimethoprim-SMX (TMP-SMX) prophylaxis approached that reported for high dose daily regimens.. Forty adult patients with haematologic malignancies (HM) and 35 healthy adults were studied; an additional 13 HM patients taking ascorbate supplements (HM-AA) were also evaluated. Twenty-two of 40 HM patients were prescribed and were compliant with TMP-SMX 960 mg three to four times weekly.. There were no significant differences between HM and healthy groups in plasma AA (median 37.2 µm vs. 33.9 µm) or red blood cell GSH (1.9 mmvs. 1.8 mm). However, plasma AA was correlated significantly with leucocyte b5/b5R reduction (r= 0.39, P= 0.002). Deficient b5/b5R activities were not found in HM patients. In fact, patients with chronic lymphocytic leukaemia or myeloma had significantly higher median activities (80.7 µmol mg(-1) min(-1)) than controls (18.9 µmol mg(-1) min(-1), P= 0.008). After 3-4 weeks of treatment, no patients developed SMX-specific T cells and only one patient developed rash.. Deficiencies of blood antioxidants and b5/b5R reduction were not found in this population with haematologic malignancies, and the development of skin rash and drug-specific T cells appeared to be uncommon with intermittent TMP-SMX prophylaxis.

Topics: Adult; Aged; Anti-Infective Agents; Ascorbic Acid; Case-Control Studies; Cell Proliferation; Cytochrome-B(5) Reductase; Dose-Response Relationship, Drug; Drug Hypersensitivity; Female; Glutathione; Hematologic Neoplasms; Humans; Inactivation, Metabolic; Male; Middle Aged; Statistics as Topic; Sulfamethoxazole; Sulfonamides; T-Lymphocytes; Trimethoprim, Sulfamethoxazole Drug Combination; Young Adult

Sulfonamide antimicrobials such as sulfamethoxazole (SMX) have been associated with drug hypersensitivity reactions, particularly in patients with AIDS. A reactive oxidative metabolite, sulfamethoxazole-nitroso (SMX-NO), forms drug-tissue adducts that elicit a T-cell response. Antioxidants such as ascorbic acid (AA) and glutathione (GSH) reduce SMX-NO to the less reactive hydroxylamine metabolite (SMX-HA), which is further reduced to the non-immunogenic parent compound by cytochrome b (5) (b5) and its reductase (b5R). We hypothesized that deficiencies in AA and GSH would enhance drug-tissue adduct formation and immunogenicity toward SMX-NO and that these antioxidant deficiencies might also impair the activity of the b5/b5R pathway. We tested these hypotheses in guinea pigs fed either a normal or AA-restricted diet, followed by buthionine sulfoximine treatment (250 mg/kg SC daily, or vehicle); and SMX-NO (1 mg/kg IP 4 days per week, or vehicle), for 2 weeks. Guinea pigs did not show any biochemical or histopathologic evidence of SMX-NO-related toxicity. Combined AA and GSH deficiency in this model did not significantly increase tissue-drug adduct formation, or splenocyte proliferation in response to SMX-NO. However, combined antioxidant deficiency was associated with decreased mRNA and protein expression of cytochrome b (5), as well as significant decreases in SMX-HA reduction in SMX-NO-treated pigs. These results suggest that SMX-HA detoxification may be down-regulated in combined AA and GSH deficiency. This mechanism could contribute to the higher risk of SMX hypersensitivity in patients with AIDS with antioxidant depletion.

Topics: Animals; Anti-Infective Agents; Antioxidants; Ascorbic Acid; Ascorbic Acid Deficiency; Cell Proliferation; Cytochrome-B(5) Reductase; Cytochromes b5; Drug Hypersensitivity; Glutathione; Guinea Pigs; Inactivation, Metabolic; Liver; Male; Sulfamethoxazole; T-Lymphocytes

Sulfonamide antimicrobials such as sulfamethoxazole (SMX) have been associated in humans with hypersensitivity reactions, to include fever, skin eruptions, hepatotoxicity, and blood dyscrasias. These reactions also occur in dogs, the only non-human species known to develop a similar spectrum of sulfonamide hypersensitivity. Sulfonamide hypersensitivity is not well understood, but has been hypothesized to be due to the generation of the reactive oxidative metabolite, nitroso sulfamethoxazole (SMX-NO). SMX-NO, unlike the parent sulfonamide, is cytotoxic in vitro, haptenizes tissue proteins, and is immunogenic in rodents. The purpose of this pilot study was to determine whether SMX-NO, when administered to dogs, would lead to drug-tissue adducts, anti-drug antibodies, antioxidant depletion, or clinical evidence of drug hypersensitivity. Four dogs were randomized to one of four treatments: SMX-NO 1 mg/kg; SMX-NO 3 mg/kg; SMX-NO 10 mg/kg; or vehicle control. Dosing was by the intraperitoneal route, once daily for four consecutive days per week, for 2 weeks total, followed by a third week of observation. Following this, all dogs were challenged with trimethoprim-sulfamethoxazole, 25 mg/kg for 12 h for 2 weeks. No dog developed clinical or biochemical evidence of drug hypersensitivity. Plasma cysteine and leukocyte reduced glutathione were not depleted during dosing; however, ascorbate was significantly depleted by week 2 following SMX-NO at 10 mg/kg. Anti-SMX antibodies (IgG or IgM by ELISA) were not detected in any dogs at any time points. SMX-hemoglobin adducts were detected in the spleen in SMX-NO dosed dogs; however, these adducts were not accompanied by an immunologic or systemic response. The results of this pilot study indicate that SMX-NO dosing in dogs, using a dosing protocol shown to be immunogenic in other species, produces modest ascorbate depletion and hemoglobin adduct formation, but is insufficient to produce an immunologic response or a clinical syndrome of sulfonamide hypersensitivity in this susceptible species.

Topics: Animals; Anti-Infective Agents; Antibody Formation; Ascorbic Acid; Biotransformation; Cysteine; Dogs; Drug Hypersensitivity; Female; Glutathione; In Vitro Techniques; Pilot Projects; Random Allocation; Spleen; Sulfamethoxazole

Previously we reported that a mega-dose of Vitamin C enhanced the initial stage of delayed-type hypersensitivity reaction in Balb/c mice. In this study its effects were further evaluated as follows. Mice were administered Vitamin C intraperitoneally at 0.625 mg/day or at 5mg/day for variable days before, during, or after being sensitized with DNFB. T cells were isolated in each group and examined. When stimulated antigen-specifically or non-specifically in vitro, mice showed elevated thymidine uptake and a shift of cytokine secretion profiles toward Th1, i.e., elevated levels IL-2, TNF-alpha, and IFN-gamma, and lowered level of the Th2 cytokine IL-4, only when Vitamin C was administered during sensitization. T cells from those mice administered Vitamin C before sensitization or after challenge showed the same T cell properties as those from PBS-treated mice. Mice were also given 0.625 mg/day of Vitamin C during primary and/or secondary immunizations with KLH and secondary specific antibody titers in sera were measured. The total specific antibody titer was lowered in Vitamin C-treated animals whenever treatments were administered, and this was entirely attributed to decreased levels of IgG1 and IgE antibodies. Based on these results, we suggest that an exogenously administered mega-dose of Vitamin C shifts immunity in Balb/c mouse toward Th1 and that these affects occur only when Vitamin C is administered during T cell activation.

Topics: Animals; Antioxidants; Ascorbic Acid; Cell Proliferation; Cytokines; Dinitrofluorobenzene; Drug Hypersensitivity; Hemocyanins; Hypersensitivity, Delayed; Immunoglobulin E; Immunoglobulin G; Inflammation; Lymphocyte Activation; Mice; Mice, Inbred BALB C; T-Lymphocytes; Time Factors

Topics: Ascorbic Acid; Child, Preschool; Drug Hypersensitivity; Family; Female; Humans; Male

Topics: Anemia, Iron-Deficiency; Ascorbic Acid; Bacteremia; Chronic Disease; Drug Hypersensitivity; Erythropoietin; Ferritins; Humans; Injections, Intravenous; Iron; Kidney Diseases; Predictive Value of Tests; Recombinant Proteins; Renal Dialysis

I previously described that bowel tolerance (the amount that almost causes diarrhea) to oral ascorbic acid, increases in a person somewhat proportionally to the "toxicity" of his disease. Ascorbic acid ameliorates symptoms and sometimes cures certain diseases at high threshold levels near bowel tolerance. High concentrations of ascorbate cause the redox potential of the redox couple (ascorbate/dehydroascorbate, AA/DHA) to become reducing in diseased tissues. Allergic and sensitivity reactions are frequently ameliorated and sometimes completely blocked by massive doses of ascorbate. I now hypothesize that one mechanism in blocking of allergic symptoms is the reducing of the disulfide bonds between the chains in antibody molecules making their bonding antigen impossible. I further hypothesize that antibodies seek to match antigens only in areas where stray free radicals or a relatively oxidizing redox potential exists. The redox state of normal, healthy tissue does not allow for the bonding of antibodies to antigen. When antioxidant, free radical scavenging systems are overwhelmed, inflammatory, hypersensitivity, and "autoimmune" conditions may result.

Topics: Animals; Antigen-Antibody Reactions; Ascorbic Acid; Autoimmune Diseases; B-Lymphocytes; Biological Evolution; Disulfides; Drug Hypersensitivity; Food Hypersensitivity; Histamine H1 Antagonists; Humans; Hypersensitivity; Oxidation-Reduction; Pneumonia, Pneumocystis; Receptors, Antigen, T-Cell

Topics: Animals; Ascorbic Acid; Chromium; Dose-Response Relationship, Immunologic; Drug Hypersensitivity; Flavonoids; Guinea Pigs; Niacinamide; Potassium Dichromate; Pyridoxic Acid; Pyridoxine; Rabbits; Thiamine; Time; Vitamins

The clinical histories of 81 patients with hypersensitivity reactions to nitrofurantoin, 66 of whom had pulmonary reactions, were studied. Of all patients, 94% were women and of these, 43% were between 40 and 59 years of age. The nitrofurantoin preparation that contained vitamin c caused significantly fewer hypersensitivity reactions than the others. Acute pulmonary reactions appeared a mean of 8.7 days after the start of nitrofurantoin treatment. Typical for these were high fever, dyspnoea, cough, blood eosinophilia, bilateral pneumonic or pleuro-pneumonic infiltrations, a reduced transfer factor of the lung and, as revealed in pulmonary biopsy specimens, vasculitis, interstitial inflammation and alveolar exudation. Symptoms of subacute and chronic pulmonary reactions developed after at least 1 and 6 months of treatment, respectively. Findings of interest were anti-nuclear antibodies in serum, capillary sclerosis, interstitial fibrosis and inflammation in pulmonary tissue. Most patients with an acute pulmonary reaction recovered within 15 days, but in more than half of those with chronic reactions slight signs of pulmonary fibrosis persisted on follow-up. The findings suggest that the interstitial pulmonary changes caused by nitrofurantoin are largely the result of an Arthus-type immune complex-mediated reaction.

Topics: Acute Disease; Adult; Aged; Ascorbic Acid; Chronic Disease; Drug Combinations; Drug Hypersensitivity; Female; Humans; Male; Middle Aged; Nitrofurantoin; Pneumonia; Pulmonary Fibrosis

Topics: Adult; Anaphylaxis; Ascorbic Acid; Drug Hypersensitivity; Female; Humans; Periodontal Diseases

Topics: Adult; Anti-Bacterial Agents; Ascorbic Acid; Brucellosis; Chronic Disease; Drug Hypersensitivity; Female; Humans; Immunotherapy; Male; Middle Aged; Muramidase; Oleandomycin; Phagocytosis; Physical Therapy Modalities; Pigments, Biological; Prodigiosin; Pyrroles; Serratia marcescens; Stimulation, Chemical; Tetracycline; Vitamins

Topics: Anaphylaxis; Ascorbic Acid; Drug Hypersensitivity; Humans; Iatrogenic Disease; Male; Medication Errors; Middle Aged; Penicillin G; Skin Tests; Urticaria

Topics: Aminosalicylic Acids; Ascorbic Acid; Bone Conduction; Dihydrostreptomycin Sulfate; Drug Hypersensitivity; Hearing; Humans; Kanamycin; Pantothenic Acid; Streptomycin; Sulfates; Tuberculosis, Pulmonary; Viomycin

Topics: Adrenal Cortex Hormones; Agranulocytosis; Anti-Bacterial Agents; Ascorbic Acid; Blood Transfusion; Drug Hypersensitivity; gamma-Globulins; Humans; Morphinans

Topics: Adult; Aged; Anti-Bacterial Agents; Ascorbic Acid; Drug Hypersensitivity; Erythema Multiforme; Female; Humans; Hypersensitivity, Delayed; Hypersensitivity, Immediate; Infant; Male; Middle Aged; Oxyphenbutazone; Penicillins; Pigmentation Disorders; Prednisolone; Purpura; Rutin; Skin Tests; Stevens-Johnson Syndrome; Surgical Procedures, Operative; Urea

Topics: Ascorbic Acid; Cortisone; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Humans; Hypersensitivity; Vitamins