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Biomedical subjects

S F Gordon

Publications and source records attributed to S F Gordon.

17 recordsLinked to original sources
PubMed2001

Metabolic activation in drug allergies.

Drug allergies are a major problem in the clinic and during drug development. At the present time, it is not possible to predict the potential of a new chemical entity to produce an allergic reaction (hypersensitivity) in patients in preclinical development. Such adverse reactions, because of their idiosyncratic nature, only become apparent once the drug has been licensed. Our present chemical understanding of drug hypersensitivity is based on the hapten hypothesis, in which covalent binding of the drug (metabolite) plays a central role in drug immunogenicity and antigenicity. If this theory is correct, then it should be possible to develop in vitro systems to assess the potential of drugs to bind to critical proteins, either directly or indirectly after metabolic activation to protein-reactive metabolites (bioactivation) and initiate hypersensitivity. The purpose of this review is to assess critically the evidence to support the hapten mechanism, and also to consider alternative mechanisms by which drugs cause idiosyncratic toxicity.

Animals↗
PubMed2001

Antigenicity and immunogenicity of sulphamethoxazole: demonstration of metabolism-dependent haptenation and T-cell proliferation in vivo.

Sulphamethoxazole has been associated with the occurrence of hypersensitivity reactions. There is controversy as to whether the immune response is metabolism-dependent or -independent. We have therefore investigated the site of antigen formation and the nature of the drug signal presented to the immune system in vivo. Male Wistar rats were dosed with sulphamethoxazole, sulphamethoxazole hydroxylamine or nitroso sulphamethoxazole. Antigen formation on cell surfaces was determined by flow cytometry using a specific anti-sulphamethoxazole antibody. Immunogenicity was determined by assessment of ex vivo T-cell proliferation. Administration of nitroso sulphamethoxazole, but not sulphamethoxazole or sulphamethoxazole hydroxylamine, resulted in antigen formation on the surface of lymphocytes, splenocytes and epidermal keratinocytes, and a strong proliferative response of splenocytes on re-stimulation with nitroso sulphamethoxazole. Rats dosed with sulphamethoxazole or sulphamethoxazole hydroxylamine did not respond to any of the test compounds. CD4+ or CD8+ depleted cells responded equally to nitroso sulphamethoxazole. The proliferative response to nitroso sulphamethoxazole was seen even after pulsing for only 5 min, and was not inhibited by glutathione. Responding cells produced IFN-gamma, but not IL-4. Haptenation of cells by sulphamethoxazole hydroxylamine was seen after depletion of glutathione by pre-treating the rats with diethyl maleate. Splenocytes from the glutathione-depleted sulphamethoxazole hydroxylamine-treated rats responded weakly to nitroso sulphamethoxazole, but not to sulphamethoxazole or sulphamethoxazole hydroxylamine. Dosing of rats with sulphamethoxazole produced a cellular response to nitroso sulphamethoxazole (but not to sulphamethoxazole or its hydroxylamine) when the animals were primed with complete Freund's adjuvant. These studies demonstrate the antigenicity of nitroso sulphamethoxazole in vivo and provide evidence for the role of drug metabolism and cell surface haptenation in the induction of a cellular immune response in the rat.

Adjuvants, Immunologic↗
PubMed2000

Immunological principles of adverse drug reactions: the initiation and propagation of immune responses elicited by drug treatment.

Adverse drug reactions account for between 2 to 5% of all hospital admissions and can prevent the administration of an otherwise effective therapeutic agent. Hypersensitivity or immune-mediated reactions, although less common, tend to be proportionately more serious. There is convincing evidence to implicate the immune system in the pathogenesis of hypersensitivity reactions. Our understanding of the way in which the immune system recognises drugs is based on the hapten hypothesis; the onset of hypersensitivity involves drug bioactivation, covalent binding to proteins, followed by uptake, antigen processing and T cell proliferation. Central to this hypothesis is the critical role of drug metabolism, with the balance between metabolic bioactivation and detoxification being one important component of individual susceptibility. The purpose of this review is to classify drug hypersensitivity reactions in terms of their clinical presentation, and also to consider recent advances in our understanding of the chemical, biochemical and, in particular, cellular immunological mechanisms of hypersensitivity. The following topics are reviewed: (i) drug disposition and cellular metabolism; (ii) mechanisms of antigen processing and presentation; (iii) the role of cytokines and co-stimulatory molecules in the induction and maintenance of a polarised immune response; and (iv) the application of the hapten hypothesis, danger hypothesis and serial triggering model to drug hypersensitivity. A greater understanding of the mechanism(s) of hypersensitivity may identify novel therapeutic strategies and help to combat one of the more severe forms of adverse reactions to drugs.

Animals↗
PubMed1995

Clinical experience with a seven-day estradiol transdermal system for estrogen replacement therapy.

OBJECTIVE: To describe the efficacy, safety, and wearability of estrogen replacement therapy of a 7-day estradiol transdermal system (Climara), developed using new drug-in-adhesive technology. STUDY DESIGN: The pharmacokinetics of the 7-day system were investigated in single- and multiple-dose studies, a relative bioavailability study of the two patch sizes, and comparative studies with the twice-weekly transdermal system (Estraderm). Safety and efficacy in the treatment of vasomotor symptoms compared with conjugated equine estrogens (Premarin) and placebo were evaluated in two 11-week, randomized, double-blind, multicenter trials in 603 women; the data are combined in this report. Irritation and adhesion were also evaluated in comparative studies with Estraderm, Micropore (an inert once-weekly tape), and placebo controls. RESULTS: Blood levels were sustained for the full 7 days of patch wear, there was no drug accumulation, and a physiologic estrone to estradiol ratio was maintained. Pharmacokinetics studies showed dose proportionality of the 0.05 and 0.1 mg/day patches. Both patch sizes significantly decreased the frequency of hot flushes compared with placebo and were comparable with conjugated equine estrogens. There was a statistically significant difference between the two patch sizes. The mean overall decline in the hot flush rate was 74.6% for the 0.1 mg patch versus 64.5% for the 0.05 mg patch (p < or = 0.05). The combined data also showed that the onset of efficacy is within 1 to 2 weeks after the start of therapy and that efficacy is fully sustained during the 7-day patch wear period with some diminution of effect during the treatment-free week of each cycle. Treatment was well tolerated. Adverse events led to withdrawal from the studies in 8.9% of subjects. In most of these (6.8% of subjects), the cause was adverse skin reactions. Skin irritation was similar to Estraderm in comparative studies, whereas adhesion was significantly better with Climara. CONCLUSION: The Climara patch delivers estradiol for a full 7 days. Clinical efficacy of both patch sizes is comparable with currently accepted therapy and is sustained for the entire week of patch wear. A significant difference in response between the two doses supports dose titration. The patch is well tolerated and has excellent adhesion.

Administration, Cutaneous↗
PubMed1992

Laparoscopic uterine suspension.

Laparoscopic uterine suspension is an effective method of correcting symptomatic uterine retroversion. Eighty patients with deep dyspareunia reproduced by palpation of their retroverted uterus underwent a modified Gilliam uterine suspension under laparoscopic visualization. There were no intraoperative or postoperative complications requiring laparotomy, and symptoms were relieved in 74 patients.

Adolescent↗
PubMed1989

A trial using early preoperative administration of cefonicid for antimicrobial prophylaxis with hysterectomies.

A single dose of cefonicid given 3.5-5.0 hours or 0.5-1.0 hour preoperatively was compared with cefoxitin given as five doses beginning 0.5-1.0 hour preoperatively for prophylaxis of infection in 202 patients undergoing vaginal or abdominal hysterectomy. The administration of cefonicid 3.5-5.0 hours preoperatively was intended to simulate situations where surgery may be delayed or prolonged. The trial was double-blind, and patients were randomized to one of the three regimens. Operative site infections were noted in 6.2 percent of patients (7/113) who received cefonicid 3.5-5.0 hours preoperatively, in 7.0 percent of patients (3/43) who received cefonicid 0.5-1.0 hour preoperatively, and in 4.3 percent of patients (2/46) who received cefoxitin (p greater than 0.05). Enterococci were isolated most frequently from operative-site infections. When administered 3.5-5.0 hours preoperatively, cefonicid was as effective as more traditional regimens.

Adolescent↗
PubMed1988

Results of a randomized, multicenter, comparative trial of a single dose of cefotetan versus multiple doses of cefoxitin as prophylaxis in cesarean section.

In a multicenter, open, randomized, comparative trial, 308 women undergoing cesarean section were given a single 1 gm dose of cefotetan or three 2 gm doses of cefoxitin after cord clamping to reduce the incidence of postoperative infectious morbidity. Of the 286 evaluable patients, 195 received cefotetan and 91 received cefoxitin. Most patients were in active labor and one third had ruptured membranes. Microorganisms cultured from the endocervix or intraoperatively from the endometrium or abdominal wall operative sites were comparable for the two groups. In this multicenter study, the difference between the percentage of patients receiving cefotetan who did not develop clinical signs and symptoms of infection (93%) and the percentage of patients receiving cefoxitin (85%) considered clinical successes was statistically significant (p = 0.02, chi 2). The bacteriologic response rate for patients taking cefotetan was also significantly higher than that for patients taking cefoxitin (93% versus 85%, p = 0.03). Isolates recovered from the endocervix, endometrium, or operative site were comparable for the two groups. Both drugs were well tolerated. In this evaluation, cefotetan administered in a single dose of 1 gm was more effective as a prophylactic agent than multiple 2 gm doses of cefoxitin in the reduction of infectious morbidity in this large series of patients undergoing cesarean section.

Adolescent↗
PubMed1988

Comparison of cefotetan and cefoxitin prophylaxis for abdominal and vaginal hysterectomy.

The safety and efficacy of parenteral prophylaxis with either cefotetan or cefoxitin were evaluated in a prospective, randomized study of 355 subjects undergoing abdominal or vaginal hysterectomy. Each subject received either a single 1 gm dose of cefotetan intravenously 30 to 60 minutes before operation or three 2 gm doses of cefoxitin, the first 30 to 60 minutes before operation and subsequent doses 6 and 12 hours later. Prophylaxis was successful in 69 of 70 (98.6%) receiving cefotetan and 32 of 33 (97.0%) receiving cefoxitin who underwent vaginal hysterectomy. Prophylaxis was successful in 160 of 169 (94.7%) receiving cefotetan and in 79 of 83 (95.2%) receiving cefoxitin who underwent abdominal hysterectomy. Both drugs were well tolerated and without serious side effects or complications. On the basis of these findings, we conclude that a single 1 gm dose of cefotetan given before operation is as safe and effective as a multiple-dosing regimen of cefoxitin in subjects undergoing vaginal hysterectomy and in those undergoing abdominal hysterectomy at institutions where prophylaxis is indicated.

Abdomen↗
PubMed1988

Results of a single-center study of cefotetan prophylaxis in abdominal or vaginal hysterectomy.

In a single-center clinical trial, a single 1 gm dose of cefotetan was as effective as a prophylactic agent as multiple 2 gm doses of cefoxitin in the prevention of postoperative infectious morbidity in women undergoing abdominal or vaginal hysterectomy. Among the 39 clinically evaluable women in the cefotetan group and 19 clinically evaluable women in the cefoxitin group, the successful clinical response rates were 97% and 95%, respectively. None of the women in either group who had vaginal hysterectomies developed postoperative complications. One woman in each group developed a major wound infection at the abdominal hysterectomy site. Although the satisfactory bacteriologic response rate was higher among the 36 bacteriologically evaluable women in the cefotetan group than among the 12 bacteriologically evaluable women in the cefoxitin group (83% versus 80%), the difference was not statistically significant. No drug-related adverse reactions were reported for any patient.

Abdomen↗
PubMed1982

Noninvasive carotid evaluation using pulsed Doppler imaging for patients with ophthalmic disorders.

Pulsed Doppler imaging provides an accurate, noninvasive technique for evaluation of the carotid bifurcation. We have found it useful in evaluating patients with amaurosis fugax and ocular emboli. It can also be used to evaluate blood flow within ocular and orbital tumors. The continuous wave Doppler is useful for detection of abnormal orbital blood flow in patients with dural-cavernous fistulae.

Adolescent↗
PubMedDate not supplied

Ofloxacin versus trimethoprim/sulfamethoxazole in the treatment of uncomplicated urinary tract infection.

A multicenter randomized study was conducted to compare the efficacy and safety of ofloxacin with that of trimethoprim/sulfamethoxazole (TMP/SMX) in the treatment of uncomplicated urinary tract infection in adults. Patients were randomized to receive either oral ofloxacin 200 mg daily for three days (102 patients), or oral TMP/SMX 160 mg/800 mg twice daily for seven days (100 patients). The pathogen was eradicated in 73 (97.3%) of the 75 evaluable patients receiving ofloxacin and in 66 (97.1%) of the 68 evaluable patients receiving TMP/SMX. The most frequently isolated pathogens were Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis. More urinary pathogens were susceptible to ofloxacin than to TMP/SMX, although this difference was not statistically significant. The clinical cure rate for patients receiving ofloxacin was 93.3%, with 4% improved and 2.7% failed. For patients receiving TMP/SMX, the clinical cure rate was 86.4%, with 12.1% improved and 1.5% failed. Side effects were reported by 29.7% of the patients receiving ofloxacin and by 40.4% of the patients receiving TMP/SMX. Drug-related adverse experiences, as determined by the investigators, occurred in 5% of the ofloxacin patients and in 15.2% of the TMP/SMX patients, a statistically significant difference. No patients receiving ofloxacin, compared with three patients receiving TMP/SMX, discontinued therapy because of an adverse reaction. These results indicate that short-course ofloxacin is as effective as TMP/SMX in the treatment of uncomplicated urinary tract infection. Ofloxacin therapy is also better tolerated than TMP/SMX.

Adolescent↗
PubMedDate not supplied

Efficacy and safety of a seven-day, transdermal estradiol drug-delivery system: comparison with conjugated estrogens and placebo. The Transdermal Estradiol Patch Study Group.

OBJECTIVE: To evaluate the efficacy and safety of a new, seven-day, transdermal estradiol system in healthy postmenopausal women with hot flushes. METHODS: Two studies are described. In the first study, subjects were randomized to treatment with a 0.05 mg/day estradiol patch, a 0.1 mg/day estradiol patch, or a placebo patch; and in the second study, to treatment with either of the two estradiol patches or oral conjugated estrogens (as Premarin) 0.625 mg/day. Efficacy was evaluated on the basis of diary entries recording hot-flush frequency and severity. Subjects' and investigators' global assessments of treatment efficacy were recorded at follow-up visits. RESULTS: In Study 1, both the 0.05-mg and 0.1-mg estradiol patches were significantly more effective than placebo in reducing hot flushes and were associated with higher global assessments. In Study 2, all three active treatments produced a significant reduction in the number of hot flushes compared with base-line. There were no statistically significant between-group differences, although the response to the 0.1-mg estradiol patch was greater, and to the 0.05-mg estradiol patch less, than the response to conjugated estrogens. The patches were generally well tolerated. Skin irritation from the patch was the most common adverse experience in both studies. CONCLUSIONS: The new, seven-day, transdermal system effectively and safely treats post-menopausal vasomotor symptoms.

Administration, Cutaneous↗