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Biomedical subjects

A D White

Publications and source records attributed to A D White.

At least 19 recordsLinked to original sources
PubMed2001

Nephrotoxicity in the elderly due to co-prescription of angiotensin converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs.

Both angiotensin converting enzyme inhibitors and nonsteroidal anti-inflammatory drugs can lead to functional renal insufficiency. In an observational study we assessed the frequency of this adverse effect in patients aged over 75 years receiving these drugs in combination. In one year, out of 1500 patients whose records were screened, 12 were prescribed this combination. 2 developed acute renal failure, of whom one died and the other recovered after discontinuation of both drugs. 4 patients showed deterioration in renal function, which returned to normal after one of the drugs was stopped. Renal function remained stable in 6 patients: patients with deterioration in renal function were older and more likely to be on diuretics. This drug combination is commonly nephrotoxic in the elderly and should be avoided, especially in those taking diuretics.

Acute Kidney Injury↗
PubMed2000

A rationalization of the acidic pH dependence for stromelysin-1 (Matrix metalloproteinase-3) catalysis and inhibition.

The pH dependence of matrix metalloproteinase (MMP) catalysis is described by a broad bell-shaped curve, indicating the involvement of two unspecified ionizable groups in proteolysis. Stromelysin-1 has a third pK(a) near 6, resulting in a uniquely sharp acidic catalytic optimum, which has recently been attributed to His(224). This suggests the presence of a critical, but unidentified, S1' substructure. Integrating biochemical characterizations of inhibitor-enzyme interactions with active site topography from corresponding crystal structures, we isolated contributions to the pH dependence of catalysis and inhibition of active site residues Glu(202) and His(224). The acidic pK(a) 5.6 is attributed to the Glu(202).zinc.H(2)O complex, consistent with a role for the invariant active site Glu as a general base in MMP catalysis. The His(224)-dependent substructure is identified as a tripeptide (Pro(221)-Leu(222)-Tyr(223)) that forms the substrate cleft lower wall. Substrate binding induces a beta-conformation in this sequence, which extends and anchors the larger beta-sheet of the enzyme. substrate complex and appears to be essential for productive substrate binding. Because the PXY tripeptide is strictly conserved among MMPs, this "beta-anchor" may represent a common motif required for macromolecular substrate hydrolysis. The striking acidic profile of stromelysin-1 defined by the combined ionization of Glu(202) and His(224) allows the design of highly selective inhibitors.

Binding Sites↗
PubMed2000

Cytogenetic abnormalities in the myelodysplastic syndromes and occupational or environmental exposure.

Patients with myelodysplastic syndromes (MDS) have high frequencies of cytogenetic abnormalities and evidence is accumulating of associations between exposure history and primary MDS. The objective of this article is to examine the relationship between histories of occupational or environmental exposure and presence of cytogenetic abnormalities. A case control study of MDS patients estimated lifetime exposure to more than 90 potential hazards in 400 age, sex, and area of residence matched patient and control pairs. A parallel cytogenetics study undertaken at time of diagnosis, independently of any knowledge of exposure history, identified 75 cytogenetically abnormal and 139 normal (186 not studied). Odds ratios of MDS patients and their matched controls were compared for 3 groups: cytogenetically abnormal, normal, and not known. The odds ratios for all exposures combined were possibly higher among cytogenetically abnormal 2.0 (95% confidence interval 0.8-5.9) than among normal 1.0 (0.6-1.8). This pattern was observed for exposure to semimetals, abnormal 4.0 (0.4-195.1) and normal 0.5 (0.1-1.0) and inorganic dusts, 1.6 (0. 6-3.8) and 0.4 (0.1-1.4) respectively. The pattern was principally in abnormalities in chromosomes 5 and 7. For organic chemicals and radiation, the odds ratios for both cytogenetically abnormal and normal were marginally raised: organic 1.8 (0.6-6.0) and 1.3 (0.6-2.9), respectively, and radiation 1.7 (0.5-5.6) and 1.3 (0.4-4.7) respectively. For radiation, abnormalities were mostly in chromosome 8. This study of association between exposures and cytogenetics in primary MDS complements those previously reported in secondary MDS and may provide some insight into pathogenetic mechanisms that lead to development of MDS. (Blood. 2000;95:2093-2097)

Bone Marrow↗
PubMed2000

Monitoring pregnancy outcomes after prenatal drug exposure through prospective pregnancy registries: a pharmaceutical company commitment.

OBJECTIVE: Glaxo Wellcome becomes aware of prenatal exposures to its medications as early as the clinical trial phase of development. An international process for monitoring prenatal exposure to all Glaxo Wellcome medicines has been developed. For specific products there are prospective pregnancy registries. STUDY DESIGN: The registries are observational, case-registration, and follow-up studies designed to detect evidence of teratogenicity associated with specific medications. After prenatal exposure to the registry medication, pregnancies are registered prospectively, through voluntary reports by health care providers. An advisory committee of independent scientists for each registry reviews data and advises in dissemination of information. Risk of birth defects, as defined by the Centers for Disease Control and Prevention, is compared with published risks both in women in the general population and in women with the underlying condition being treated, if available. RESULTS: The following data show results from the prospective first-trimester exposures registered since establishment of each registry. The published risk of birth defects in the general population range is 3% to 5%, and the risk in women with epilepsy is 6% to 9%. The proportions of outcomes with birth defects are as follows: in the Acyclovir (antiviral medication) Pregnancy Registry (1984-1998) (19/581), 3.3% (95% confidence interval, 2.0%-5.2%); in the Lamotrigine (monotherapy and polytherapy antiepileptic medication) Pregnancy Registry (1992-September 1998) (8/123), 6.5% (95% confidence interval, 3.1%-12.8%); in the Sumatriptan (migraine medication) Pregnancy Registry (1996-October 1998) (7/183), 3.8% (95% confidence interval, 1.7%-8.0%). The Valacyclovir, Bupropion, and Naratriptan registries have insufficient data for analysis. CONCLUSION: None of the registries has provided a risk estimate exceeding that expected in the disorder treated, and no pattern of defects has been observed. Whereas information from the larger registries is reassuring regarding risk, these studies cannot rule out possible small excess risks from use of these drugs in pregnancy. Data obtained through these registries are shared with the medical community as a supplement to animal toxicology studies to assist in weighing potential risks and benefits of treatment for individual patients. The success of the registries depends on the continued willingness of the obstetrics and gynecology community to notify the registries of prenatal exposures.

Abnormalities, Drug-Induced↗
PubMed2000

Experience of healthcare workers taking postexposure prophylaxis after occupational HIV exposures: findings of the HIV Postexposure Prophylaxis Registry.

OBJECTIVE: To collect information about the safety of taking antiretroviral drugs for human immunodeficiency virus (HIV) postexposure prophylaxis (PEP). DESIGN: A voluntary, confidential registry. SETTING: Hospital occupational health clinics, emergency departments, private physician offices, and health departments in the United States. RESULTS: 492 healthcare workers (HCWs) who had occupational exposures to HIV, were prescribed HIV PEP, and agreed to be enrolled in the registry by their healthcare providers were prospectively enrolled in the registry. Three hundred eight (63%) of 492 of the PEP regimens prescribed for these HCWs consisted of at least three antiretroviral agents. Of the 449 HCWs for whom 6-week follow-up was available, 195 (43%) completed the PEP regimen as initially prescribed. Forty-four percent (n=197) of HCWs discontinued all PEP drugs and did not complete a PEP regimen. Thirteen percent (n=57) discontinued > or =1 drug or modified drug dosage or added a drug but did complete a course of PEP Among the 254 HCWs who modified or discontinued the PEP regimen, the two most common reasons for doing so were because of adverse effects attributed to PEP (54%) and because the source-patient turned out to be HIV-negative (38%). Overall, 340 (76%) HCWs with 6-week follow-up reported some symptoms while on PEP: nausea (57%), fatigue or malaise (38%), headache (18%), vomiting (16%), diarrhea (14%), and myalgias or arthralgias (6%). The median time from start of PEP to onset of each of the five most frequently reported symptoms was 3 to 4 days. Only 37 (8%) HCWs with 6-week follow-up were reported to have laboratory abnormalities; review of the reported abnormalities revealed that most were unremarkable. Serious adverse events were reported to the registry for 6 HCWs; all but one event resolved by the 6-month follow-up visit. Fewer side effects were reported by HCWs taking two-drug PEP regimens than by HCWs taking three-drug PEP regimens. CONCLUSIONS: Side effects from HIV PEP were very common but were rarely severe or serious. The nature and frequency of HIV PEP toxicity were consistent with information already available on the use of these antiretroviral agents. Clinicians prescribing HIV PEP need to counsel HCWs about PEP side effects and should know how to manage PEP toxicity when it arises.

Adolescent↗
PubMed2000

Underutilization of antithrombotic therapy in atrial fibrillation.

Most patients with atrial fibrillation should be considered for antithrombotic therapy. In a retrospective survey we investigated practice in two hospitals. For patients at high risk, established guidelines recommend warfarin, or aspirin if anticoagulants are contraindicated; for those at medium risk, either may be used. Of 156 with atrial fibrillation (acute, chronic or paroxysmal), 119 were at high risk, mean age 79 years. According to the guidelines, 89 of these were suitable for anticoagulation but only 49 (55%) received warfarin; 27 received aspirin and 13 neither. Of 27 patients at medium risk (mean age 70 years), 6 were not prescribed any antithrombotic therapy. This survey indicates that guidelines on antithrombotic therapy are commonly disregarded and that, in particular, warfarin is underutilized in the group for whom it is most indicated.

Acute Disease↗
PubMed2000

Colonic perforation associated with slow-release diclofenac sodium.

Upper gastrointestinal tract complications due to non-steroidal anti-inflammatory drugs are well recognised. However, adverse effects on large intestinal mucosa are less common and less well recognised, even though they carry a significant morbidity and mortality. Here we report a case of colonic perforation in a healthy woman without any underlying colonic pathology associated with ingestion of slow release diclofenac sodium.

Aged↗
PubMed2000

Diagnoses in discharge communications: how far are they reliable?

To discover whether general practitioners are correctly notified of a patient's final diagnosis following hospital discharge, an observational study was undertaken in a district general hospital. The final diagnosis was compared with the diagnosis documented in the discharge summary and the take-home prescription. Two hundred discharges were studied. Only 163 (81%) discharge summaries and 138 (69%) take-home prescriptions had the correct diagnosis; 24 (12%) take-home prescriptions did not have any diagnosis at all. In some cases the diagnosis differed between the discharge summaries and the take-home prescriptions. Only in 122 (61%) cases was the final diagnosis correctly documented in both instances. Communication regarding diagnosis in discharge letters is less than adequate. Every effort should be made to improve this.

Diagnosis↗
PubMed2000

Progressive heart block in active rheumatoid arthritis.

A 68-year-old woman presented with active rheumatoid arthritis (RA) and severe extra-articular manifestations. During the course of her treatment, her electrocardiogram (ECG) transformed from normal sinus rhythm to left bundle branch block and finally to complete heart block (CHB). Investigations ruled out an ischaemic event. A permanent pacemaker was inserted due to the symptoms of heart failure and she made an uneventful recovery. CHB in RA is probably a marker of severity of the disease.

Acute Disease↗
PubMed1999

Sex and race differences in short-term prognosis after acute coronary heart disease events: the Atherosclerosis Risk In Communities (ARIC) study.

BACKGROUND: Case fatality after myocardial infarction (MI) among patients admitted to the hospital may differ between men and women and blacks and whites. Furthermore, a different pattern of sex and race differences in case fatality may occur when coronary deaths outside the hospital are included in the analysis. The ARIC study provides community-based data to examine 28-day case fatality rates after coronary heart disease (CHD) events. METHOD AND RESULTS: Surveillance of out-of-hospital CHD deaths and hospitalized MI was conducted in 4 U.S. communities from 1987 to 1993. Hospital discharges and death certificates were sampled, medical records abstracted, and interviews conducted with witnesses of out-of-hospital deaths. MI and out-of-hospital death classifications followed a standard algorithm. Linkage of hospitalized MIs to fatality within 28 days ensured complete ascertainment of case fatality rate. Comorbidities and complications during hospital stay were compared to assess possible explanatory factors for differences in case fatality. Overall, age-adjusted 28-day case fatality (MI plus CHD) was higher in black men compared with white men (odds ratio 1.78, 95% confidence interval 1.4-2.2) and in black women compared with white women (odds ratio 1.5, 95% confidence interval 1. 2-2.0). Although men had higher overall case fatality rates than did women, this difference was not statistically significant. After a hospitalized MI, 28-day case fatality rate was not statistically significantly different between men compared with women or blacks compared with whites. CONCLUSION: Race and sex differences in case fatality after hospitalized MI were not evident in these data, although when out-of-hospital deaths were included, men and blacks were more likely than women and whites to die within 28 days of an acute cardiac event. A majority of deaths occurred before hospital admission, and additional study of possible reasons for these differences should be a priority.

Adult↗
PubMed1999

The Pregnancy Registry program at Glaxo Wellcome Company.

Registries can be used to provide an early warning system for potential teratogenic effects associated with the use of specific medications during pregnancy. Glaxo Wellcome has developed 5 international registries: (1) the Acyclovir Pregnancy Registry, (2) the Antiretroviral Pregnancy Registry, (3) the Lamotrigine Pregnancy Registry, (4) the Sumatriptan Pregnancy Registry, and (5) the Bupropion Pregnancy Registry. The purpose of these registries is to gain more information about the potential teratogenicity of these drugs during pregnancy. Two potential limitations of such registry data are recognized: (1) the utility of the data collected depends on the size of the sample; and (2) the registered patients may not be representative of all patients using the medication. However, these types of registry reports can be a valuable and cost-effective way to collect data regarding the use of medications during pregnancy when conventional methods (eg, cohort studies) are not appropriate or feasible.

Adverse Drug Reaction Reporting Systems↗
PubMed1999

X-ray structure of human stromelysin catalytic domain complexed with nonpeptide inhibitors: implications for inhibitor selectivity.

Effective inhibitors of matrix metalloproteinases (MMPs), a family of connective tissue-degrading enzymes, could be useful for the treatment of diseases such as cancer, multiple sclerosis, and arthritis. Many of the known MMP inhibitors are derived from peptide substrates, with high potency in vitro but little selectivity among MMPs and poor bioavailability. We have discovered nonpeptidic MMP inhibitors with improved properties, and report here the crystal structures of human stromelysin-1 catalytic domain (SCD) complexed with four of these inhibitors. The structures were determined and refined at resolutions ranging from 1.64 to 2.0 A. Each inhibitor binds in the active site of SCD such that a bulky diphenyl piperidine moiety penetrates a deep, predominantly hydrophobic S'1 pocket. The active site structure of the SCD is similar in all four inhibitor complexes, but differs substantially from the peptide hydroxamate complex, which has a smaller side chain bound in the S'1 pocket. The largest differences occur in the loop forming the "top" of this pocket. The occupation of these nonpeptidic inhibitors in the S'1 pocket provides a structural basis to explain their selectivity among MMPs. An analysis of the unique binding mode predicts structural modifications to design improved MMP inhibitors.

Binding Sites↗
PubMed1998

A novel compound that elevates high density lipoprotein and activates the peroxisome proliferator activated receptor.

In the current studies we describe the effects of PD 72953 and related compounds on lipoprotein levels in chow-fed male rats. After 2 weeks, 10 mg/kg of PD 72953 daily was as effective as 100 mg/kg gemfibrozil for elevating HDL-cholesterol. At 100 mg/kg, PD 72953 further elevated HDL-cholesterol to 232% of control levels, and was associated with increased HDL size and plasma apoE (169% of control), despite no change in hepatic apoE mRNA. ApoA-I rose transiently (at 1 week), but by 2 weeks only apoE remained elevated. PD 72953 dose-dependently reduced plasma apoB, VLDL-cholesterol, LDL-cholesterol, and triglyceride. Hepatic apoC-III mRNA reduction parallelled triglyceride lowering. After 1 week, 30 and 100 mg/kg per day PD 72953 reduced plasma apo-CIII levels by 30 and 34%, and triglycerides by 60 and 83%, respectively. PD 72953 treatment had no effect on triglyceride production rates; however, 125I-labeled VLDL apoB disappearance was enhanced. We compared PD 72953 to a structurally similar diacid, PD 69405, that also reduced VLDL and LDL, but had no effect on HDL elevation. Compared to PD 72953, PD 69405 further accelerated 125I-labeled VLDL apoB disappearance, decreased triglyceride production, and elevated the ratio of post-heparin hepatic to lipoprotein lipase activity. Whole animal studies, transient transfection studies in HepG2 cells, and chimeric receptor studies in kidney 293 cells suggest that PD 72953 is a ligand for the peroxisomal proliferation activated receptor alpha (PPARalpha), and PPARgamma. Overall, PD 72953 may act through a peroxisomal proliferation activated receptor and result in plasma triglycerides and apoB-containing lipoprotein reduction, while also raising HDL cholesterol. Reduced apoC-III may allow triglyceride-rich remnants to more efficiently bind and present substrate to peripheral tissue lipoprotein lipase, and therefore allow enhanced shedding of remnant phospholipid surface for HDL production.

Animals↗
PubMed1996

Heterocyclic ureas: inhibitors of acyl-CoA:cholesterol O-acyltransferase as hypocholesterolemic agents.

A series of diaryl-substituted heterocyclic ureas was prepared, and their ability to inhibit acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and to lower plasma total cholesterol in cholesterol-fed animal models in vivo was examined. N-(2,6-Diisopropylphenyl)-N'-tetrazole or isoxazole-substituted heterocyclic ureas proved optimal. A carbon chain of 11-14 carbons substituted 1,3 with respect to the amine provided the optimal side chain. Substitution of the alkyl chain generally lowered activity. Tetrazole urea 2i dosed at 3 mg/kg lowered plasma total cholesterol (TC) 67% in an acute, cholesterol-fed (C-fed) rat model of hypercholesterolemia and 47% in C-fed dogs. Tetrazole 2i, dosed at 10 mg/kg, also lowered TC 52% and raised HDL cholesterol 113% in rats with pre-established hypercholesterolemia.

Animals↗
PubMed1996

Heterocyclic amides: inhibitors of acyl-CoA:cholesterol O-acyl transferase with hypocholesterolemic activity in several species and antiatherosclerotic activity in the rabbit.

A series of heterocyclic amides were synthesized and evaluated as inhibitors of acyl-CoA: cholesterol O-acyltransferase (ACAT) in vitro and for cholesterol lowering in cholesterol-fed rats. Compounds were evaluated for cell-based macrophage ACAT inhibition, bioactivity, and adrenal toxicity. Candidates were selected for evaluation in cholesterol-fed dogs and, ultimately, the injured cholesterol-fed rabbit model of atherosclerosis. The heterocyclic amides potently inhibited rabbit liver ACAT (IC50's = 0.014-0.11 microM), and the majority of compounds significantly lowered plasma cholesterol (42-68%) in an acute cholesterol-fed rat model at 3 mg/kg. The most efficacious compounds in the rat were evaluated for bioactivity in vivo and arterial ACAT inhibition in a cell-based macrophage ACAT assay. Two highly bioactive analogs, (+/-)-2-(3-dodecylisoxazol-5-yl)-2-phenyl-N-(2,4,6-trimethoxypheny l) acetamide (13a) and (+/-)-2-(5-dodecylisoxazol-3-yl)-2-phenyl-N-(2,4,6-trimethoxypheny l) acetamide (16a), were selected for further study and were found to be nontoxic in a guinea pig model of adrenal toxicity. Compounds 13a and 16a lowered total cholesterol in the cholesterol-fed rat, rabbit, and dog models of pre-established hypercholesterolemia. Compound 13a in the injured cholesterol-fed rabbit model of atherosclerosis was effective in slowing the development of cholesteryl ester-rich thoracic aortic lesions, reducing lesion coverage by 53% at a dose of 1 mg/kg.

Acetamides↗
PubMed1996

Economic impact of treatment of HIV-positive pregnant women and their newborns with zidovudine. Implications for HIV screening.

OBJECTIVES: To estimate the economic impact of (1) treating pregnant women who are human immunodeficiency virus (HIV)-positive with zidovudine and (2) voluntary screening programs for pregnant women for HIV infection and offering treatment with zidovudine to those found to be HIV-positive. MAIN OUTCOME MEASURES: Number of cases of pediatric HIV infection and costs of screening, zidovudine treatment, and pediatric HIV infection treatment. DESIGN: Health care costs associated with treatment of HIV-positive pregnant women and their newborns are estimated as the costs of zidovudine and its administration and the reduction in costs of treating pediatric HIV infection. The lifetime costs of pediatric HIV infection are derived from the published literature. Estimates of the reduction in maternal-to-fetal transmission rates are taken from the AIDS [acquired immunodeficiency syndrome] Clinical Trials Group (ACTG) Protocol 076. Costs of a voluntary screening program include costs of screening tests and counseling. Sensitivity and threshold analyses are performed to determine the impact of changes in input parameter values including zidovudine treatment costs, efficacy of treatment, costs of pediatric HIV infection, prevalence of HIV infection in pregnant women, screening test sensitivity and specificity, and pregnancy termination rates on the results. RESULTS: Assuming transmission rates are reduced from 25.5% to 8.3% as found in the ACTG 076 trial, treatment costs of $104,502 for 100 HIV-positive pregnant women and their newborns are offset by the reduction of $1,701,333 associated with fewer cases of pediatric HIV infection for a net savings of $1,596,831. The sensitivity and threshold analyses show that overall cost savings from treatment of HIV-positive pregnant women and their newborns are achieved for a wide range of possible maternal treatment costs, efficacy rates, and lifetime pediatric HIV treatment costs. In the base-case analysis for the voluntary screening program, overall cost savings are seen when HIV prevalence rate among pregnant women is greater than 4.6 per 1000. However, this threshold prevalence rate is sensitive to changes In parameter value-especially pediatric HIV treatment costs, counselling costs, efficacy of treatment, and years of additional HIV treatment for the pregnant women. CONCLUSIONS: Offering zidovudine treatment to pregnant women known to be HIV-positive will decrease the number of cases of pediatric HIV infection and reduce health care costs. Voluntary screening programs for pregnant women will further decrease the number of cases of pediatric HIV infection. The effect of a screening program on health care costs varies according to HIV prevalence and the costs associated with the screening program.

AIDS Serodiagnosis↗