Disposition of 5-fluorouracil after intravenous bolus doses of a commercial formulation to cancer patients.

A high-pressure liquid chromatographic method that is used to determine the pharmacokinetic disposition of 5-fluorouracil from the plasma compartment is presented. The method requires only 0.5 ml of plasma for each determination and is sensitive to 0.1 mg of drug per liter. Novel methodology with the use of an ion-specific electrode technique for the determination of urinary excretion kinetics of 5-fluorouracil and its metabolites is also presented. This study demonstrated a much greater variability for the disposition of 5-fluorouracil by cancer patients than has been reported previously. The apparent volume of distribution for this drug varied more than 37-fold. Its plasma half-life varied more than 19-fold, and its urinary excretion half-life varied almost 400-fold. These data are compatible with the hypothesis that this variation could account, at least in part, for the variable therapeutic and toxic response to 5-fluorouracil. The methodology presented in this study is sufficiently simple and sensitive to allow assessment of this hypothesis by investigating cancer patients who receive therapeutic doses of 5-fluorouracil.

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

OBJECTIVE: To describe the rate of development of in vitro HIV resistance to zidovudine (ZDV) and its prognostic implications within the Multicentre Canadian AZT Trial (MCAT). METHODS: HIV-infected subjects in Centers for Disease Control (CDC) stages IIB, III and IVC-2 with CD4 cell counts > 270 x 10(6)/l 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. RESULTS: The 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. CONCLUSIONS: In 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.

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 > or = 18 years, with a CD4 count < or = 300 x 10(6)/l cells were followed 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.

Antihypertensive responses to spironolactone in normal renin hypertension.

The antihypertensive effect of spironolactone was studied in 20 patients with essential hypertension and normal stimulated peripheral renin activity (PRA). Single-blind 8-wk treatment periods of placebo, 100, 200, and 400 mg spironolactone were used in consecutive order. Average supine and erect blood pressures were lower than placebo values at the end of each treatment. A prominent orthostatic effect was observed. Changes in blood pressure were not related to changes in body weight, PRA, or blood urea nitrogen. A larger proportion (50%) of patients had a more normal erect diastolic pressure at the end of 400 mg/day than at the end of 100 mg/day (20%), but the response to 400 mg/day could not be predicted from the responses to lower doses. Larger doses of spironolactone were predictably associated with rises in serum potassium, PRA, and aldosterone excretion. Adverse effects were absent during therapy with 100 mg/day but were frequent during 200--400 mg/day. Although there are no apparent advantages in increasing spironolactone from 100 to 200 mg/day in this group of patients with normal renin hypertension, increasing the dose to 400 mg/day resulted in better blood pressure control with more frequent adverse effects.

Acebutolol and hydrochlorothiazide in essential hypertension.

Acebutolol (ABL) and hydrochlorothiazide (HCT) were compared in patients with mild to moderate essential hypertension and low or normal peripheral renin activity. ABL reduced mean supine blood pressure from 151/97 to 140/87 mm Hg and HCT reduced the mean supine blood pressure from 153/98 to 143/92 mm Hg. ABL reduced heart rate from 73 to 67 beats/min; during HCT therapy it rose from 74 to 77 beats/min. Although the same proportion of patients achieved normal diastolic pressures with ABL (11/19) and with HCT (10/19), tension-time indices were lower during ABL than during HCT therapy. The average daily dose was 621 mg of ABL and 168 mg of HCT. Stimulated peripheral renin activity increased with HCT and was the same or lower with ABL. ABL did not induce adverse effects on serum potassium or uric acid. ABL was as effective in lowering blood pressure HCT but induced larger reductions in tension-time index as a result of the lowerered heart rate.

Nutritional status of Quebec Indians.

The nutritional status of more than 80% of adult Indians in three bands in a remote area of Quebec was studied during the summer of 1978 and the findings were compared with the results of the 1970 and 1972 Nutrition Canada national and Indian surveys in which the Indian participation rate was 30%. In the present study, hematocrit, serum iron, transferrin saturation, serum vitamin E, serum folic acid, and urine thiamin excretion patterns showed only minor differences from Nutrition Canada's national and Indian survey. Serum total protein values were slightly higher in Indians than in the national sample, consistent with previous findings. A higher percentage of subjects had low serum concentrations of vitamin A and ascorbic acid than in the previous Indian survey, but not to such a marked degree.

Canadian multicenter azidothymidine trial: AZT pharmacokinetics.

The study objective was to describe the pharmacokinetics of azidothymidine (AZT) in a large population of early, asymptomatic human immunodeficiency virus (HIV)-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 microM.h, maximum concentration (Cmax) +/- SD, 7.3 +/- 4.7 microM; 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 microM.h, Cmax +/- SD 21.3 +/- 7.3 microM, 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 asymptomatic HIV disease when compared with previous reports in patients with later disease.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of zidovudine on platelet count in HIV-infected individuals.

Seventy-four HIV-infected homosexual males belonging to CDC groups IIB, III, and IVC2 were treated with increasing doses of zidovudine within the Multicentre Canadian AZT Trial. Following a 3 week observation period, consenting volunteers received 600 mg/day for 18 weeks, 900 mg/day for 9 weeks, and 1,200 mg/day for 9 weeks. This was followed by a 6 week washout period after which zidovudine was restarted at 1,200 mg/day for 18 weeks. Patients were followed for a total of 63 weeks. Every 3 weeks they underwent a full clinical and laboratory assessment. For the purpose of this analysis, subjects were divided according to the mean initial platelet value (greater than or equal to 150,000 or less than 150,000/L) into normals (n = 57) and thrombocytopenics (n = 12), respectively. Analysis of variance was used to compare the mean platelet values at each zidovudine dose. All comparisons were made against baseline values. Zidovudine increased platelet counts in normal and thrombocytopenic subjects. The magnitude of this effect varied depending on the baseline platelet count. Among normals, the platelet count increased from 241,000 +/- 45,000/L at baseline to 261,000 +/- 51,000/L (p less than 0.01). while receiving 600 mg/day of zidovudine. This effect was self-limited, reaching a peak by week 3. The platelet count decreased to baseline values despite increasing the dose of zidovudine to 900 or 1,200 mg/day. The platelet count further decreased to 218,000 +/- 43,000/L during the washout phase (washout vs. 1,200 mg, p less than 0.01).2+ not found to be dose related. The platelet count decreased to 101,000 +/- 34,000/L during the washout phase (washout vs. 1,200 mg/day, p less than 0.07).(ABSTRACT TRUNCATED AT 250 WORDS)

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.

Validity and reproducibility of a screening examination for neurological abnormality in persons exposed to methylmercury.

The validity and reliability of methods of screening for neurologic abnormality were assessed as part of an investigation of an outbreak of methylmercury exposure in two northern Canadian communities. Four hundred and forty-five Cree Indians were examined by one of five neurologists in a complete neurologic examination and by a trained paramedical observer in a short screening examination which included a selection of tests from the complete examination. The screening examinations were recorded on videotape and those for 176 men were reviewed by the five neurologists and the paramedical observer 1 year after the field studies. The prevalence of abnormality assessed in the field screening examination was greater than that assessed during the complete neurologic examination, for neurologic features included in both examinations. However, agreement between examinations in identifying individuals with abnormality was poor with the sensitivity of the screening examination falling under 50% for half of the neurologic features examined. In contrast, specificity was over 80% for 14 of 18 features. Review of the videotapes revealed marked interobserver variation in the assessment of the prevalence of neurologic abnormality and poor agreement with the neurologic examinations in the identification of abnormality in individuals, with kappa less than 0.2 for most neurologic features. The levels of agreement between the neurologic examinations and the screening examinations conducted in the field and by videotape review suggest that neither screening examination provides equivalent information in the identification of the presence of abnormality to that obtained in the neurologic examination.

Acute respiratory failure secondary to Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. A potential role for systemic corticosteroids.

Pneumocystis carinii pneumonia (PCP) remains the most frequent life-threatening complication of HIV infection. A retrospective study was undertaken in an attempt to establish the incidence of acute respiratory failure (ARF) in AIDS-related PCP, its mortality, and the impact of adjuvant systemic corticosteroids on its outcome. Of 127 AIDS-related PCP episodes diagnosed at St. Paul's Hospital between Jan 1, 1981, and March 31, 1987, 27 developed ARF (21 percent), and the 24 who consented to ICU admission for ventilatory support were reviewed. All were given IV pentamidine or trimethoprim-sulfamethoxazole or both sequentially. Overall mortality of ARF secondary to AIDS-related PCP was 50 percent. The use of adjuvant systemic corticosteroids was associated with a decreased mortality. Of the 18 patients treated with IV hydrocortisone (400 to 1,000 mg/day in divided doses for the duration of ARF followed by a tapering regimen over 10 to 15 days), seven (39 percent) died, while five of six (84 percent) treated without corticosteroids died (p = 0.05). Survivors received ventilation for 5 +/- 2 (mean +/- SD) days and all were discharged from hospital after 20 +/- 4 days. Survivors were also younger (34 +/- 8 vs 43 +/- 10 years, p = 0.034) and presented earlier (14 +/- 3 vs 34 +/- 7 days after onset of symptoms p = 0.017). Known AIDS, previous PCP episodes, and arterial blood gas values at the onset of ARF did not correlate with outcome. We conclude that ARF secondary to AIDS-related PCP merits aggressive management. In particular, younger patients presenting early after the onset of respiratory symptoms appear to have a better prognosis. The decreased mortality associated with the use of adjunctive corticosteroids supports the need for prospective controlled evaluation of this therapeutic modality.

Aerosol pentamidine-induced bronchoconstriction. Predictive factors and preventive therapy.

OBJECTIVE: To describe the frequency of aerosol pentamidine-induced bronchoconstriction, its relationship to non-specific airway responsiveness, and its response to preventive therapy using salbutamol, ipratropium bromide, or sodium cromoglycate. METHODS: Consecutive HIV-infected individuals starting prophylactic AP were eligible if they had not been previously treated with this agent. Simple spirometry was performed before and 10 min after a single 60-mg dose given through an ultrasonic nebulizer. Methacholine challenge was performed in all subjects 24 h to four days after the initial AP dose. Subjects with a change in FEV1 (delta FEV1) greater than or equal to 10 percent decrease after the initial AP dose were restudied on three separate occasions (greater than 24 hours apart) after premedication with two puffs of salbutamol (200 micrograms), ipratropium bromide (40 micrograms), or sodium cromoglycate (2 mg), in random order. RESULTS: Fifty-three subjects were studied. The median delta FEV1 after a single dose of AP was -7.0 percent (range: -47 percent, 1.8 percent). The delta FEV1 following AP was only partially predicted by the degree of nonspecific bronchial responsiveness as measured by a standard methacholine challenge. Age, current smoking, history of asthma, baseline FEV1, or a prior episode of PCP failed to predict the delta FEV1 following AP. Eighteen subjects (34 percent) had a delta FEV1 greater than or equal to 10 percent decrease (median: -17.0 percent). In these subjects, after premedication with salbutamol, ipratropium bromide, and sodium cromoglycate, the median delta FEV1 was 1.0, 0.8, and -9.6 percent, respectively. CONCLUSION: Aerosol pentamidine produced a decrease in FEV1 greater than or equal to 10 percent in 34 percent of subjects. This was not accurately predicted by the methacholine response. The bronchoconstriction induced by AP was effectively prevented by either salbutamol or ipratropium, whereas cromoglycate was only partially effective.

Pathologic dependence of oxygen consumption on oxygen delivery in acute respiratory failure secondary to AIDS-related Pneumocystis carinii pneumonia.

Oxygen consumption is pathologically dependent on oxygen delivery in ARDS and sepsis. We asked whether oxygen consumption is dependent on oxygen delivery in severe acute respiratory failure secondary to AIDS-related PCP. In five patients who had AIDS-related PCP, diffuse bilateral pulmonary infiltrates, no evidence of bacterial infection, and acute respiratory failure requiring mechanical ventilation with arterial oxygen tensions less than 75 mm Hg while breathing at least 50 percent oxygen, and PEEP greater than 10 cm H2O, we determined oxygen delivery and consumption by calculation from thermodilution cardiac output and arterial and mixed venous oxygen contents. Oxygen delivery was increased using transfusion of two units of packed red blood cells over one hour. Oxygen delivery increased 22 percent (638 +/- 204 to 778 +/- 201 ml/min.m2, p less than or equal to 0.006). Oxygen consumption increased 11 percent (134 +/- 34 to 149 +/- 29 ml/min.m2, p less than or equal to 0.02). The oxygen extraction ratio did not change. We conclude that similar to ARDS and sepsis, oxygen consumption may be pathologically dependent on oxygen delivery in patients who have severe acute respiratory failure secondary to AIDS-related PCP.

Linking budgets to desired academic outputs at Dalhousie University.

In 1993, faced with continuing university budget reductions and dissatisfaction with the budget-allocation process, the Faculty of Medicine at Dalhousie University undertook a financial planning process. The goal was to develop a new resource-allocation model to better link academic budget support to desired academic outputs over a three-year period. Department heads categorized academic outputs (e.g., teaching, research, administration, and subcategories of these), determined their relative values (expressed as percentages of the total department budget to be projected), and identified acceptable units of measuring the outputs (e.g., for teaching in the first and second years of medical school, the unit was the number of teaching hours). When dollar values were assigned to the units of measure, the new model was used to calculate budget allocations for all departments. However, many departments showed large negative shifts in their budgets; these shifts were too large to be achieved within three years because of departments' contractual obligations. Therefore, a practical limit in budget shift was determined. This adjustment permitted a three-year projection of academic budgets to be made for each department. The use of the resource-allocation model has achieved the Faculty's goal by creating a better rationalization of budgets to academic outputs, but carries the risk that departments might abandon essential but "undervalued" academic activities.

A profile of academic physicians in British Columbia.

To determine the extent of involvement of British Columbia's physician community in the operation of the province's only medical school, the authors sent questionnaires to all physicians who had any affiliation with the University of British Columbia (UBC). About 20 percent of the province's physicians were involved in some capacity with the UBC Faculty of Medicine, which accepts about 120 students into the first year annually. Most faculty held "clinical" appointments, meaning that they pursued largely non-academic careers. Full-time academic appointees worked more than 20 percent more hours annually than did their "clinical" counterparts, and average hours for men exceeded those for women. As many as two-thirds of the full-time faculty were also engaged in sufficient clinical practice activity to be classified as full-time practicing physicians by a definition adopted by a provincial Joint Medical Manpower Committee.

The effect of metronidazole on the incidence of postoperative wound infection in elective colon surgery.

A prospective randomized clinical trial assessing the relative effectiveness of erythromycin-neomycin and metronidazole-neomycin as a preoperative bowel preparation was carried out. Bacteriologic studies of feces and colon content revealed no significant difference in the reduction of aerobic bacteria between the two groups. There was, however, a significantly greater reduction in anaerobic bacteria in the feces and colon contents of patients receiving metronidazole. Wound infection rate was 25% in the erythromycin group, and organisms recovered from the wound in all cases were fecal in nature. Two wound infections occurred in the metronidazole group (5%) and in both cases the organisms recovered were staphylococci of presumed skin origin. These studies suggest that anaerobic bacteria are the major contributors to wound infection after colon surgery and that their specific reduction is associated with a lower incidence of wound infection.

Characterization of zidovudine resistant variants of HIV-1 isolated from patients on prolonged therapy.

As part of a clinical trial to assess zidovudine related toxic effects, the authors followed 48 initially asymptomatic individuals who received prolonged therapy with this drug at several tertiary care institutions. Blood samples had been obtained for viral isolation every three months and had yielded infectious HIV-1 progeny in over 94 percent of cases. After one year of therapy, over 30 percent of individuals had developed variants of HIV-1 that displayed in vitro resistance to zidovudine. Six of these zidovudine resistant variants of HIV-1 were compared with drug sensitive isolates obtained from the same subjects prior to initiation of treatment. The drug resistant variants were generally as infectious per mg viral protein for both susceptible T cell lines and peripheral blood mononuclear cells as the corresponding parental isolates from which they were derived. The drug resistance phenotype remained stable, in that zidovudine-insensitive species could still be identified, following many replication cycles in the absence of drug pressure. However, the percentage of zidovudine resistant viruses appeared to diminish in culture over time under such conditions. This was demonstrated by the fact that lower percentages of cells became infected in the presence of the drug, if the viruses used for infection had been propagated in the absence of the drug. In addition, higher concentrations of such viruses were required to initiate infection in the presence of the drug, and these viruses possessed lower IC50's for zidovudine. This suggests that zidovudine resistant variants of HIV-1 may be unlikely to possess any growth advantage in the absence of the drug.

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.