Jan Feyzi

A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease.

BACKGROUND Anemia is associated with an increased risk of cardiovascular and renal events among patients with type 2 diabetes and chronic kidney disease. Although darbepoetin alfa can effectively increase hemoglobin levels, its effect on clinical outcomes in these patients has not been adequately tested. METHODS In this study involving 4038 patients with diabetes, chronic kidney disease, and anemia, we randomly assigned 2012 patients to darbepoetin alfa to achieve a hemoglobin level of approximately 13 g per deciliter and 2026 patients to placebo, with rescue darbepoetin alfa when the hemoglobin level was less than 9.0 g per deciliter. The primary end points were the composite outcomes of death or a cardiovascular event (nonfatal myocardial infarction, congestive heart failure, stroke, or hospitalization for myocardial ischemia) and of death or end-stage renal disease. RESULTS Death or a cardiovascular event occurred in 632 patients assigned to darbepoetin alfa and 602 patients assigned to placebo (hazard ratio for darbepoetin alfa vs. placebo, 1.05; 95% confidence interval [CI], 0.94 to 1.17; P=0.41). Death or end-stage renal disease occurred in 652 patients assigned to darbepoetin alfa and 618 patients assigned to placebo (hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P=0.29). Fatal or nonfatal stroke occurred in 101 patients assigned to darbepoetin alfa and 53 patients assigned to placebo (hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001). Red-cell transfusions were administered to 297 patients assigned to darbepoetin alfa and 496 patients assigned to placebo (P<0.001). There was only a modest improvement in patient-reported fatigue in the darbepoetin alfa group as compared with the placebo group. CONCLUSIONS The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and moderate anemia who were not undergoing dialysis did not reduce the risk of either of the two primary composite outcomes (either death or a cardiovascular event or death or a renal event) and was associated with an increased risk of stroke. For many persons involved in clinical decision making, this risk will outweigh the potential benefits. (ClinicalTrials.gov number, NCT00093015.)

Intracavernous self-injection for impotence: a long-term therapeutic option? experience in 78 patients

A total of 78 patients 17 to 84 years old reported their experience via questionnaire with the papaverine-phentolamine injection technique for impotence. The mean number of injections used was 30.7. Penile induration occurred in 13 patients (16 per cent) and it was generally of limited extent. A higher incidence of induration was observed in those with vasculogenic impotence. Prolonged erection was reported by 23 per cent of the patients, 8 per cent of whom experienced erection for more than 12 hours. Priapism occurred exclusively in diabetic patients and patients with a neurological etiology of impotence. A total of 22 per cent of the patients reported moderate to severe pain with injection, 35 per cent indicated decreased quality of erection with time in response to the vasoactive agents and 28 per cent believed this therapy to be unsatisfactory. Among those who discontinued the injections 5 cited variability of erectile response (duration or quality) as the reason for discontinuation. A decrease in the effectiveness of the injections with time may be anticipated among some patients. For patients who face a penile implant without other options penile self-injection with vasoactive drugs is a reasonable alternative in that complications do not prevent successful prosthetic implantation.

Protein S and protein C level changes with adjuvant tamoxifen therapy in postmenopausal women

Tamoxifen citrate is a synthetic antiestrogen that provides survival benefit when given as adjuvant treatment in postmenopausal women with breast cancer. Venous thrombophlebitis may complicate tamoxifen treatment at a rate of approximately one per 800 treatment-years. To explore the possible procoagulant effects associated with tamoxifen therapy we evaluated changes in protein S and C activity levels in 58 postmenopausal women with surgically resected breast cancer who were disease-free and participating in a double-blind, placebo-controlled, randomized toxicity study of tamoxifen. The changes in protein C activities for the tamoxifen group (mean level = 113%) compared to those in the placebo group (mean level = 115%) were not significant (p = 0.45). Protein S activity levels increased while protein C activity levels decreased from baseline at 24 months in both tamoxifen and placebo groups. We conclude that the possible thrombophlebitis-promoting effect of tamoxifen in postmenopausal women is unlikely to be explained on the basis of protein S and protein C activity level changes.

Immunoneutralization of corticotropin-releasing hormone prevents the diurnal surge of acth

To determine whether CRH is required for the evening rise in plasma ACTH, rats were injected at 0800 hr with CRH antiserum (anti-CRH) or normal rabbit serum (NRS). Blood samples were taken through venous catheters at 0800 hr before treatment and at 1300, 1700, and 2100 hr. Plasma was assayed for immunoreactive ACTH and corticosterone. There was no significant difference in pretreatment values between the two groups. Immunoneutralization of CRH abolished the rise in plasma ACTH seen at 1700 hr in the NRS group but had little effect on earlier levels. The diurnal elevation in plasma corticosterone continued after anti-CRH treatment, but peak levels occurred earlier. Plasma ACTH and corticosterone were significantly correlated at the time of the diurnal surge, but not at 0800 hr or 1300 hr in the NRS controls or at any time point in the anti-CRH group. These results suggest that CRH is required for the diurnal surge of plasma ACTH. They also confirm previous observations by others that the adrenal cortex does not require active CRH or a diurnal surge of ACTH in order to exhibit a significant diurnal increase in secretion of corticosterone, and that factors other than CRH may be relatively more active than CRH in regulation of ACTH secretion during the time of circadian inactivity.

Relating Cerebral Ischemia and Hypoxia to Insult Intensity

Abstract: The contributions of five variables believed to influence the brains metabolism of O2 during hypoxia [duration, PaO2, ΔCMRO2 (the difference between normal and experimental oxygen uptake), O2 availability (blood O2 content · CBF), and O2 deficit (ΔCMRO2· duration)] were assessed by stepwise and multiple linear regression. Levels of brain tissue carbohydrates (lactate, glucose, and glycogen) and energy metabolites [ATP, AMP, and creatine phosphate (CrP)] were significantly influenced by O2 deficit during hypoxia, as was final CMRO2. After 60 min of reoxygenation, levels of tissue lactate, glucose, ATP, and AMP were related statistically to the O2 deficit during hypoxia; however, CMRO2 changes were always associated more significantly with O2 availability during hypoxia. Creatine (Cr) and CrP levels in the brain following reoxygenation were correlated more to ΔCMRO2 during hypoxia. Changes in some brain carbohydrate (lactate and glucose), energy metabolite (ATP and AMP) levels, and [H+]i induced by complete ischemia were also influenced by O2 deficit. After 60 min of postischemic reoxygenation, brain carbohydrate (lactate, glucose, and glycogen) and energy metabolite (ATP, AMP, CrP, and Cr) correlated with O2 deficit during ischemia. We conclude that “O2 deficit” is an excellent gauge of insult intensity which is related to observed changes in nearly two‐thirds of the brain metabolites we studied during and following hypoxia and ischemia.

Changes in mean plasma ACTH reflect changes in amplitude and frequency of secretory pulses.

ACTH is secreted in an episodic manner from the anterior pituitary. Unanesthetized rats with indwelling jugular and femoral venous cannulae were continuously bled and simultaneously infused with isotonic fluid by peristaltic pump. Two-minute blood samples were collected for up to five hours in 8 male rats. ACTH was measured by radioimmunoassay. The resulting time series were analyzed for significant secretory pulses with the PULSAR program. Elevations or declines in mean plasma ACTH levels were associated with significant changes in amplitude and frequency of secretory pulses.

Oral piritrexim : a phase II study in patients with advanced soft tissue sarcoma

Piritrexim is a lipid soluble dihydrofolate reductase (DHFR) inhibitor that rapidly and passively diffuses into cells [1,2]. It has been synthesized as an antifolate compound potentially capable of circumventing methotrexate resistance from arising via various mechanisms [3]. A phase II evaluation of this drug was organized at the Memorial Sloan Kettering Cancer Center (MSKCC) to evaluate the anti-tumor activity and toxicity in patients with advanced soft tissue sarcoma. Preliminary results have been previously presented [4]. Adult patients with soft tissue sarcoma with a clearly measurable indicator lesion(s) and a Karnofsky Performance Status of 70% or greater were eligible for entry regardless of prior treatment. Classic oncologic response criteria were used. Patients were scheduled to receive a dose of 160 mg/m 2, administered orally twice daily for five consecutive days every three weeks. Following unexpected severe toxicity in two patients (both with prior pelvic irradiation who initiated treatment at a dose of 120 mg/m2), the protocol was amended to initiate treatment at a dose of 120 mg/m 2 in all patients and 80 mg/m 2 in those patients with prior radiation to the pelvis. The dose was subsequently escalated or deescalated based on toxicity. Twenty-six patients with soft tissue sarcoma were entered on study. Table 1 summarizes the demographic data and the results. One-hundred and thirty-one courses of therapy were administered to the 26 patients for a mean of 5 courses and a median of 3.5 courses per patient. Fourteen of the patients initiated treatment at a dose of 120 mg/m 2 bid, eleven initiated treatment at a dose of 80 mg/m 2 bid and one initiated treatment at a dose of 160 mg/m z. Two patients obtained a partial response. Of twelve evaluable patients with leiomyosarcoma, one patient obtained a partial response (for response rate of leiomyosarcoma upper limit 95% confidence interval = 34%). The other patient who obtained a partial response was the only patient entered with endometrial stromal sarcoma. Grade 2 or greater toxicity was observed in 80% of patients. Severe (grade 3 -4 ) myelopoietic toxicity was associated with 17 courses of treatment in nine patients, severe oral mucositis with nine courses of treatment in seven patients, severe maculo-papular pruritic rash with four courses in four patients and severe emesis with three courses in three patients. Generally, these toxicities occurred concurrently. This complex of toxicities represents the dose limiting toxicity of piritrexim. Piritrexim was evaluated in this phase II study because of its activity in the sarcoma 180 preclinical model, because of the activity of methotrexate in patients with soft tissue sarcoma and because of the anti-tumor efficacy of metoprine in previous studies in patients with sarcoma. Two clinically beneficial objective responses were observed, an overall response rate of 11%. Piritrexim is a potentially active agent in the treatment of soft tissue sarcoma but with an upper limit of a 95~ confidence

Data Monitoring Experience in the Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure: Potentially High-Risk Treatment in High-Risk Patients

The Metoprolol CR/XL Randomized Intervention Trial in Chronic Heart Failure (MERIT-HF) was a double-blind, randomized, placebo-controlled trial in 3,991 patients with New York Heart Class II–IV heart failure and LVEF ≤0.40. The two primary objectives were to determine the effect of metoprolol CR/XL on all-cause mortality and on the combined endpoint of all-cause mortality or all-cause hospitalizations (time to first event). There was a two-week placebo run-in period. after which patients were randomized to either metoprolol CR/XL at a dose of 12.5 mg (NYHA III–IV) or 25mg (NYHA II) once daily or matching placebo. The randomized treatment was titrated up to 200 mg once daily or to the highest tolerated dose over an eight-week titration phase. The trial was designed to follow patients for a total mean follow-up of 2.4 years. The Data and Safety Monitoring Board (DSMB) had two tasks. The first was to review all reported Serious Adverse Events (SAEs) on a monthly basis and produce a short report to the sponsor aimed for regulatory agencies. This was done because the sponsor had received a waiver for expedited reporting of SAEs from regulatory agencies including the U.S. Food and Drug Administration (FDA). The second was to perform three pre-specified interim analyses of total mortality. After the second interim analysis, at the point of observing one-half of the targeted number of deaths, the trial was stopped early by the International Steering Committee on recommendation of the DSMB (mean follow-up time 1 year). Final results showed that all-cause mortality was lower in the metoprolol CR/XL group compared to the placebo group (145 deaths, corresponding to 7.2% per patient-year of follow-up for the metoprolol CR/XL group versus 217 deaths, 11.0% per patient-year of follow-up for the placebo group, p = 0.0062 adjusted for interim analyses, p = 0.00009 nominal). The second primary endpoint of all-cause mortality combined with all-cause hospitalizations was also lower for the metoprolol CR/XL group (641 events) compared to placebo (767 events), p = 0.00012 nominal. The procedures developed by the DSMB to implement the required intense safety follow-up will be described.