John Ruedy

Corticosteroids Prevent Early Deterioration in Patients with Moderately Severe Pneumocystis carinii Pneumonia and the Acquired Immunodeficiency Syndrome (AIDS)

OBJECTIVE To determine whether oral corticosteroids can prevent early deterioration in patients with acquired immunodeficiency syndrome (AIDS)-related Pneumocystis carinii pneumonia. DESIGN Prospective, double-blind, placebo-controlled, randomized trial. METHODS Included patients were having their first P. carinii pneumonia episode, had no other known active pulmonary pathology, had no contraindications for corticosteroids, received no anti-P. carinii pneumonia medications for more than 48 hours, and had oxygen saturation by pulse oximetry of 85% or more and less than 90% at rest or a 5-percentage-point decrease in oxygen saturation with exercise while breathing room air. Consenting subjects were randomly assigned to prednisone, 60 mg/d for 7 days, followed by a progressive tapering over 14 days or to an identical placebo. Early deterioration, the endpoint of the trial, was defined as a 10% decrease in baseline oxygen saturation on day 3 or thereafter. The cases of patients developing early deterioration were considered to be failures of treatment; the code was then broken, and the patients treatment was left to the judgment of the treating physician. Sequential analysis was done with the primary variable being development of early deterioration. RESULTS The trial was terminated 5 April 1989 on the basis of the sequential analysis when a total of nine episodes of early deterioration had occurred in the first 37 patients at an overall significance level of P = 0.0136. A total of 8 of 19 placebo-treated patients (42.1%) developed early deterioration compared with only 1 of 18 patients (5.6%) treated with corticosteroids. Baseline characteristics were not statistically different between the two treatment groups. The adjusted odds ratio for the treatment effect was 5.87 (95% CI, 1.27 to 27.4). The adjusted point estimates for the probability of early deterioration in the placebo and corticosteroid groups were 43% and 12%, respectively. All 8 patients in the placebo group developing early deterioration recovered rapidly with addition of corticosteroid treatment. The single patient with early deterioration in the corticosteroid group died on day 6 from overwhelming P. carinii pneumonia, as documented at autopsy. The corticosteroid group had an increased exercise tolerance on day 7 that persisted at day 30. CONCLUSION Oral corticosteroids prevent early deterioration and increase exercise tolerance in patients with moderately severe AIDS-related P. carinii pneumonia.

Development of HIV-1 resistance to (-)2'-deoxy-3'-thiacytidine in patients with AIDS or advanced AIDS-related complex

Objective: To determine the rate of development of in vitro HIV resistance to (‐)2′‐deoxy‐3′‐thiacytidine (3TC) and relate the effect of dose to emergence of resistance. Methods: HIV‐infected men and non‐pregnant women, aged ≥ 18 years, with a CD4 count ≤ 300 × 106/l cells were fòllowed in a Phase I/II study, in which they were evaluated for tolerance to 3TC and effect of this agent with regard to viral susceptibility. Peripheral blood and plasma samples were collected at regular intervals for analysis. HIV was isolated using umbilical cord blood mononuclear cells as targets. These cells were also used in determinations of median inhibitory drug concentration. Specific amplification of the 184 mutation site, associated with HIV resistance to 3TC, was performed by polymerase chain reaction, using specific primer pairs, on DNA harvested from infected peripheral blood mononuclear cells (PBMC) of donors or, alternatively, on DNA that had been reverse transcribed from plasma‐associated HIV RNA. Results: Phenotypic resistance was detected in approximately one‐third of individuals studied, who were followed between 8 and 56 weeks. Development of 3TC resistance occurred independently of dose, although time of first appearance of resistant HIV‐1 variants appeared reduced at high 3TC doses. Amino‐acid changes at codon 184 in HIV‐1 reverse transcriptase were associated with, and preceded, the development of phenotypic 3TC resistance. Most commonly, a Met to Ile substitution appeared transiently before being superceded by a Val substitution at codon 184. Conclusions: In vitro resistance to 3TC developed in a high proportion of subjects who received prolonged monotherapy with this drug. The development of resistance to 3TC was associated with appearance of mutated viral forms and the disappearance of wild‐type virus, with regard to codon 184, in both patient plasma and PBMC. AIDS 1995, 9:351‐357

Sequelae of bacterial endocarditis

Abstract All cases of bacterial endocarditis confirmed or diagnosed at autopsy in the Philadelphia General Hospital during two periods were studied. Each period included approximately 10,000 consecutive autopsies. They were designated period I, the pre-antibiotic era, and period II, the antibiotic era. In period I there has been a significant decrease (p Infection in period II has been replaced by congestive heart failure in period II as the most common cause of death. Perforations of heart valves have increased from 15.6 per cent in period I to 44.5 per cent in period II, and are associated with most cases (64.5 per cent) of congestive heart failure in period II. The relationship of perforations of the valves to duration of illness, age of patient, valve involved, pre-existing valvular disease, adequacy of treatment and causative organism was studied. It is concluded that changes in the group of organisms associated with fatal cases account for the increase in perforations observed in period II, and that perforations of the valves secondary to the bacterial infection are responsible for the increased incidence of congestive heart failure.

Clinical correlates of in vitro HIV-1 resistance to zidovudine. Results of the Multicentre Canadian AZT Trial

ObjectiveTo describe the rate of development of in vitro HIV resistance to zidovudine (ZDV) and its prognostic implications within the Multicentre Canadian AZT Trial (MCAT). MethodsHIV-infected subjects in Centers for Disease Control (CDC) stages IIB, III and IVC-2 with CD4 cell counts > 270 x 106/I were treated with ZDV as part of a dose-range study. Participating volunteers underwent prospective clinical and laboratory evaluations at regular intervals. Viral cultures and sensitivity testing were performed every 12 weeks in a predefined subset of 50 volunteers. An isolate was designated ZDV-resistant if it had a median inhibitory concentration (IC50) for ZDV at least 50-fold higher than that of virus isolated from the same subject before initiation of antiviral chemotherapy. The relationship between resistance and subsequent disease progression was studied using the Mantel and Byar method, for which, at each instance of disease progression, 2 x 2 tables classifying progression versus resistance status were constructed. The observed number of progressions was compared with that expected under the null hypothesis using Mantel-Haenszel methods adjusted for baseline CD4: CD8 ratio. ResultsThe Kaplan-Meier estimate for the cumulative development of in vitro resistance was 64% [95% confidence interval (CI), 41–78] at 180 weeks. Baseline CD4: CD8 ratio was negatively associated (P = 0.10) with the subsequent development of resistance (proportional hazard, 0.44; 95% CI, 0.17–1.10). After adjusting for baseline CD4:CD8 ratio, the numbers of observed and expected progressions following the development of resistance were 15 and 7.6, respectively (P = 0.008). A similar relative risk of progression between resistant and non-resistant states was found in the two CD4:CD8 strata; observed and expected progressions were 4 and 2.3 and 11 and 5.2 in the high and low CD4: CD8 strata, respectively. ConclusionsIn vitro resistance to ZDV developed in 64% of subjects after 180 weeks of ZDV therapy. Lower CD4: CD8 ratio at baseline was associated with faster development of resistance. In addition, the development of resistance was found to be a marker of subsequent disease progression. This association persisted after adjustment for baseline CD4: CD8 ratio. Whether in vitro resistance to ZDV is merely a surrogate marker or a determinant of disease progression remains to be established.

Characterization of reverse transcriptase activity and susceptibility to other nucleosides of AZT-resistant variants of HIV-1. Results from the Canadian AZT Multicentre Study.

‘McGill AIDS Centre, McGill University, Montreal, Canada. dToronto General Hospital, University of Toronto, Toronto, Canada. eSt. Paul’s Hospital, University of British Columbia, Vancouver, Canada. fFederal Centre for AIDS, Ottawa, Canada. gMontreal General Hospital, Montreal, Canada. h IAF Biochem, Montreal, Canada. ‘Address correspondence to Dr. Mark A. Wainberg, Jewish General Hospital, 3755 Cote Ste-Catherine Road, Montreal, Canada H3T 1E2. /This paper is dedicated to the memory of Dr. Bernard Belleau, Emeritus Professor of Chemistry, McGill University, who synthesized certain of the novel nucleoside structures described in this paper. Dr. Belleau died suddenly on July 2, 1989 and will be remembered by all who worked with him as a colleague and friend. Jewish General Hospital.

Should Calcium Be Used in Cardiac Arrest

Calcium salts have been recommended for and used in the treatment of various forms of cardiac arrest for many years. Although calcium plays a major role in excitation-contraction coupling, it can have a deleterious effect in some processes of cellular injury. Clinical trials suggest that calcium salts are not effective in ventricular fibrillation and asystole, but that some patients with electromechanical dissociation may have a favorable hemodynamic response. Because of the potential risks of calcium salts, their use should be limited to specific subsets of patients with cardiac arrest.

Canadian multicenter azidothymidine trial : AZT pharmacokinetics

Summary:The study objective was to describe the pharmacokinetics of azidothymidine (AZT) in a large population of early, asymptomatic human immunodeficiency virus (HlV)-infected individuals. The study design was a multicenter, prospective, descriptive single-dose pharmacokinetic study. Each of 66 fasting, male, HIV-infected homosexuals older than 18 years of age and in CDC classifications II, III, and IVC2 received a single 400-mg oral dose of AZT with subsequent pharmacokinetic measurements performed during an 8-h period for AZT and its major metabolite, glucuronylazidothymidine (GAZT). Results were obtained in 65 patients (36 smokers, 29 nonsmokers), of whom 3 were noted to have hepatic dysfunction. In those with normal hepatic function, the following parameters were described: AZT, area under the curve (AUC) ± SD, 9.9 ± 5.7 μ.M.h, maximum concentration (Cmax) ± SD, 7.3 ± 4.7 μ.M; time to maximum concentration (Tmax) ± SD, 0.93 ± 0.42 h, and half-life (t1/2) ± SD, 1.0 ± 0.8 h. Corresponding values for GAZT were: AUC ± SD 35.7 ± 10.3 μM.h, Cmax ± SD 21.3 ± 7.3 μ.M, Tmax ± SD 1.2 ± 0.50 h, t1/2 ± SD 0.98 ± 0.62 h, No significant differences were found in comparisons of study site, CDC classification of disease, smokers versus nonsmokers, and in patients with hepatic dysfunction, although a higher AUC and earlier Cmax for AZT was noted in the latter group. It is concluded that AZT pharmacokinetics are similar in patients with early asymptomtic HIV disease when compared with previous reports in patients with later disease. This study finds no difference in pharmacokinetics of AZT in smokers versus nonsmokers and suggests a trend to a decreased presystemic elimination in patients with hepatic dysfunction.

Oral corticosteroids in patients with mild Pneumocystis carinii pneumonia and the acquired immune deficiency syndrome (AIDS)

OBJECTIVE To assess the effect of oral corticosteroids in patients with mild Pneumocystis carinii pneumonia and the acquired immune deficiency syndrome (AIDS). DESIGN Prospective, double blind, placebo controlled, randomized trial. METHODS Included were AIDS patients having their first episode of P. carinii pneumonia, who had no other known active pulmonary pathology, who had no contraindications for corticosteroids and who had received no other anti-P. carinii medications for more than 48 h. Subjects received either prednisone, 60 mg/day for 7 days, followed by a progressive tapering over 14 days, or identical placebo. The present analysis pertains to patients with mild P. carinii pneumonia as defined by a baseline resting oxygen saturation greater than 90% and a decrease in oxygen saturation during exercise while breathing room air of not less than 5 percentage points. Early deterioration, the end-point of the trial, was defined as a 10% decrease from baseline oxygen saturation on day 3 or thereafter. RESULTS At study termination, there were 12 subjects in the placebo group and 11 in the corticosteroid group. Baseline characteristics were not statistically different between the treatment groups. Early deterioration developed in 7 and 1 patients in the placebo and corticosteroid groups respectively (P = 0.027). In addition, by day 3, a number of parameters were less favorable in the placebo group relative to the corticosteroid group including median oxygen saturation (85% vs 97%; P = 0.003), lactic dehydrogenase (1514 vs 763; P = 0.013), median respiratory rate (30 vs 22; P = 0.003), median heart rate (100 vs 81; P = 0.002), and median temperature (39 vs 37; P = 0.024). Even though patients suffering early deterioration in the placebo group were switched to corticosteroids, significant differences between the groups remained at day 30 with regard to exercise tolerance. More than half of patients assigned to the corticosteroid group exercised for a median of 6.5 min on day 30 (P = 0.017). CONCLUSION Oral corticosteroids prevent early deterioration and increase exercise tolerance in patients with mild AIDS-related P. carinii pneumonia as defined on the basis of pulse oximetry.

Intraoperative cyanosis: a case of dapsone-induced methaemoglobinaemia.

Intraoperative cyanosis is most commonly caused by hypoxaemia. The anaesthetist is required to perform a rapid series of diagnostic manoeuvres and take remedial action. Occasionally methaemoglobin, sulfhaemoglobin, or haemoglobin M, undetected preoperatively, is the cause of the cyanosis. We report a case of methaemoglobinaemia secondary to dapsone ingestion that was diagnosed intraoperatively. Dapsone, a sulfone, is used therapeutically to treat leprosy and dermatitis herpetiformis. The differential diagnosis of cyanosis, and the origin and fate of methaemoglobin are discussed. in addition the diagnostic steps and the laboratory investigations required to make the diagnosis are listed.RésuméLa cyanose intraopératoire est le plus souvent provoquée par V hypoxémie. Ľ anesthésiste est demandé ďaccomplir rapidement une série de manoeuvres diagnostiques afin ďy remédier, Occasionnellement la méthémoglobine, la sulfhémoglobine ou ľhémoglobine M, non détecté en période préopératoire est la cause de cyanose. On rapporte le cas ďune méthémoglobinémie secondaire à ľingestion de dapsone ayant été diagnostiquée en période opératoire. Le dapsone, un sulfone, est utilisé afin de traiter la lèpre et la dermatite herpétiforme. Le diagnostic différentiel de la cyanose ainsi que ľorigine et le sort de la méthémoglobine sont discutés. En plus les manoeuvres diagnostiques et ľinvestigation du laboratoire requis pour confirmer le diagnostic sont énumérées.

Clinical significance and characterization of AZT-resistant strains of HIV-1.

A number of laboratories have now independently confirmed that zidovudine (AZT)-resistant strains of human immunodeficiency virus type 1 (HIV-1) may be isolated from patients undergoing prolonged therapy with this drug. In certain instances, such drug-resistant viral isolates have been obtained from patients with clinical acquired immune deficiency syndrome (aids), while in others, isolation of drug-resistant strains has been achieved in the case of HIV seropositive, asymptomatic subjects. Most of the evidence points to a series of mutations within the polymerase gene of HIV-1, which encodes viral reverse transcriptase, as being responsible for development of the drug-resistant phenotype. It further appears that over 50% of patients treated with AZT for periods longer than six months are likely to yield drug-resistant strains of HIV-1 in their circulation. Furthermore, the development of drug resistance soon after initiation of AZT therapy may potentially be correlated with the likelihood of AZT treatment failure. In several instances, cross resistance has been observed between AZT and other nucleosides being considered for potential therapy of HIV-1-associated disease.