Larry A. Weinrauch

A Population-Based Study of Appetite-Suppressant Drugs and the Risk of Cardiac-Valve Regurgitation

BACKGROUND Recent case reports suggest that a combination of the appetite suppressants fenfluramine and phentermine is associated with an increased risk of cardiac-valve regurgitation. There are also reports of valvular disorders in persons taking fenfluramine or dexfenfluramine alone, particularly for more than three months. METHODS We conducted a population-based follow-up study and a nested case-control analysis of 6532 subjects who received dexfenfluramine, 2371 who received fenfluramine, and 862 who received phentermine to assess the risk of a subsequent clinical diagnosis of a valvular disorder of uncertain origin. For comparison, we identified a group of 9281 obese subjects who had not taken appetite suppressants who were matched to the treated subjects for age, sex, and weight. All subjects were free of diagnosed cardiovascular disease at the start of follow-up. The average duration of follow-up for all subjects was about four years. RESULTS There were 11 cases of newly diagnosed idiopathic valvular disorders, 5 after the use of dexfenfluramine and 6 after the use of fenfluramine. There were six cases of aortic regurgitation, two cases of mitral regurgitation, and three cases of combined aortic and mitral regurgitation. There were no cases of idiopathic cardiac-valve abnormalities among the subjects who had not taken appetite suppressants or among those who took only phentermine. The five-year cumulative incidence of idiopathic cardiac-valve disorders was 0 per 10,000 subjects among those who had not taken appetite suppressants (95 percent confidence interval, 0 to 15.4) and among those who took phentermine alone (95 percent confidence interval, 0 to 76.6), 7.1 per 10,000 subjects among those who took either fenfluramine or dexfenfluramine for less than four months (95 percent confidence interval, 3.6 to 17.8; P=0.02 for the comparison with subjects who had not taken appetite suppressants), and 35.0 per 10,000 subjects among those who received either of these medications for four or more months (95 percent confidence interval, 16.4 to 76.2; P<0.001). CONCLUSIONS The use of fenfluramine or dexfenfluramine, particularly for four months or longer, is associated with an increased risk of newly diagnosed cardiac-valve disorders, particularly aortic regurgitation.

Nephrotoxicity from angiographic contrast material: A prospective study

Three hundred and seventy-eight hospitalized patients undergoing nonrenal angiography were evaluated for subsequent changes in renal function. Acute renal failure was defined as a rise in the serum creatinine level of 1.0 mg/dl or more. Several factors that appeared to play no significant role in causing acute renal failure included: the volume of contrast material injected, the anatomic site of injection and the presence of a prior history of cardiovascular disease or diabetes mellitus. The single risk factor identified was the presence of preexistent azotemia (blood urea nitrogen of 30 mg/dl and serum creatinine of 1.5 mg/dl). Whereas nonazotemic patients had a 2 percent incidence of definite acute renal failure, patients with chronic azotemia (mean blood urea nitrogen/creatinine = 47/2.3 mg/dl) had a 33 percent incidence. Three patients required short-term dialysis, and two required potassium-exchange resin therapy. No patient required permanent dialysis, and no patient died of acute renal failure. The persistence of a positive nephrogram 24 hours after angiography was a sensitive detector of a rise in the serum creatinine level although more expensive than the creatinine determination. While urine sediment analysis confirmed the diagnosis in many cases, it was relatively insensitive. Monitoring of urine volume proved to be of little value. We recommend a screening serum creatinine determination 24 to 48 hours after infusion of angiographic contrast material in azotemic patients.

Coronary Angiography and Acute Renal Failure in Diabetic Azotemic Nephropathy

Thirteen juvenile-onset diabetics with azotemic diabetic nephropathy (mean serum creatinine level, 6.8 mg/dl) being evaluated fro renal transplantation underwent cardiac catheterization with angiography. All were followed for development of acute renal failure. Twelve (92%) developed some evidence of acute renal failure. Two required potassium exchange resin therapy. Six required dialysis acutely. There were no deaths. All patients who received greater than 65 ml/m2 of iodinated contrast developed acute renal failure. No patient with a hemoglobin value greater than 9.9 g/dl required dialysis or potassium exchange resin. The single patients without acute renal failure received less than 50 ml/m2 of iodinated contrast and had the highest hemoglobin value (12.0 g/dl). No cardiac or angiographic variables were predictive of acute renal failure. In this group at high risk for acute renal failure, radiographic contrast procedures should only be done if the information to be obtained is weighed against the potential for injury.

Asymptomatic Coronary Artery Disease: Angiography in Diabetic Patients Before Renal Transplantation: Relation of Findings to Postoperative Survival

Twenty-one juvenile-onset diabetic patients with azotemic nephropathy underwent coronary angiography and left ventriculography before renal transplantation or chronic hemodialysis. Two-year survival of 12 patients with no coronary artery disease (group A) was 88% compared to 22% for nine patients with coronary artery disease (group B) (P less than 0.025). Each group A patient underwent renal transplantation (nine live-related, three cadaveric). Four group B patients received cadaveric allografts. Among group A patients two cadaveric allografts functioned while in group B patients no allografts were successful. In the absence of coronary artery disease, results were similar to those reported for nondiabetic persons. In the presence of coronary artery disease, 62% of the deaths were due to myocardial infarction or sudden death. These results indicate that atherosclerotic coronary artery disease is a major determinant of survival in diabetic patients undergoing chronic hemodialysis or renal transplantation.

Effect of Glycemic Control on Heart Rate Variability in Type I Diabetic Patients With Cardiac Autonomic Neuropathy

Diabetic cardiac autonomic neuropathy (CAN) is associated with a high risk of cardiovascular events. Previous studies have shown that strict glycemic control slows the deterioration of CAN as assessed by standard autonomic function tests but fails to show reversibility. The aim of this study was to evaluate the effect of glycemic control on early and advanced CAN in type I diabetic patients using power spectral analysis of heart rate variability (HRV). Ten patients with early and 13 patients with advanced CAN were enrolled in a program of intensified insulin treatment. Standard autonomic function tests and 24-hour time and frequency domain HRV parameters were obtained at baseline, 3, 6, and 12 months. Hemoglobin A1C decreased from 9.5 +/- 0.4% to 8.4 +/- 0.5% (p = 0.02) in the early CAN group, and from 9.3 +/- 0.4% to 8.2 +/- 0.5% (p = 0.006) in the advanced CAN group. In general, both time and frequency domain HRV indexes tended to improve in patients with early CAN but continued to deteriorate in patients with advanced CAN. The low- and high-frequency power increased in patients with early CAN (229 +/- 95 to 626 +/- 563 ms2 and 62 +/- 30 to 183 +/- 168 ms2, respectively). The high-frequency power significantly improved at 12 months over baseline (p = 0.04), indicating increased parasympathetic tone. By contrast, these parameters continued to deteriorate in patients with advanced CAN (65 +/- 32 to 46 +/- 8 ms2 and 193 +/- 75 to 144 +/- 33 ms2, respectively). Autonomic function tests showed no significant change in both groups. These data show that a reversible metabolic component of CAN exists in patients with early CAN. Power spectral analysis of HRV allows early identification of potential reversibility as early as 1 year after the institution of strict glycemic control.

Myocardial dysfunction without coronary artery disease in diabetic renal failure

Fifteen patients with diabetes of juvenile onset and azotemic nephropathy were found to have no evidence of significant coronary artery disease after cardiac catheterization, coronary angiography and ventriculography. Three groups were delineated in terms of myocardial function. There were no differences among the groups in age, sex distribution, duration of diabetes, hypertension or azotemia, presence of surgical arteriovenous fistula or blood concentrations of hemoglobin, cholesterol, urea nitrogen, creatinine or uric acid. Some evidence of myocardial dysfunction was found in eight patients (59 percent)—four with diffuse myocardial dysfunction and four with elevation of left ventricular end-diastolic pressure alone. The hypothesis of a diabetic cardiomyopathy is discussed in terms of a spectrum that may include patients with pressure-volume abnormalities alone; patients with increased left ventricular end-diastolic pressure and an abnormal pressure-volume curve; and patients with a diffusely abnormal ventriculogram, decreased ejection fraction, increased left ventricular end-diastolic pressure and an abnormal pressure-volume curve.

Asymptomatic coronary artery disease: angiographic assessment of diabetics evaluated for renal transplantation.

SUMMARY Twenty-one insulin-dependent diabetics with azotemic nephropathy were evaluated for renal transplantation by selective coronary angiography and cine left ventriculography. All had hypertension, retinopathy, neuropathy, and required salt restriction plus diuretics for volume overload. There was no clinical or electrocardiographic evidence of ischemic coronary artery disease in twenty.Ten patients (five males, five females, mean age 29.3 years; mean duration of diabetes 18.9 years; mean serum cholesterol 264 mg%) had no significant coronary artery disease and no ventricular wall motion abnormalities.Nine patients (seven males, two females; mean age 38.7 years; mean duration of diabetes 21.9 years; mean serum cholesterol 239 mg%) had significant coronary artery disease, seven demonstrating focal abnormalities in left ventricular wall motion.Two patients (one male, one female; mean age 36.5 years; mean duration of diabetes 28.5 years; mean serum cholesterol 250 mg%) had no significant coronary artery disease, but demonstrated diffusely abnormal left ventricular wall motion with diminished ejection fraction.Thirty-eight percent had significant coronary artery disease unpredictable by electrocardiographic clinical data. The finding of no significant coronary artery disease in 52% of a group with severe renalhypertensive complications of diabetes is surprising. Two patients may have a demonstrated cardiomyopathy.

Topical chemotherapy of cutaneous Leishmaniasis

Cutaneous leishmaniasis (CL) is one of the most important causes of chronic ulcerative skin lesions. The disease is endemic in many parts of the world, presenting a range of clinical forms - acute, chronic, recurrent and diffuse(1). Several species of Leishmania are involved, including L. major, L. tropica and L. aethiopica in the Old World, and several members of the L. braziliensis and L. mexicana complexes in the New World. Some forms of the disease produce only mild, self-limited lesions, while at the other extreme are the destructive mucocutaneous forms caused by L. braziliensis and L. panamensis(1-7). In all cases, chemotherapy tends to be difficult - often requiring prolonged parenteral administration of toxic drugs such as pentavalent antimonials or amphotericin B. Such drugs are also expensive and relatively inefficient in the sense that much of the active ingredient is excreted by the patient before reaching its target. Consequently, there is renewed interest in the development of active formulations suitable for topical application directly onto the lesions.

Short- and long-term reproducibility of heart rate variability in patients with long-standing type I diabetes mellitus

Heart rate variability (HRV) has been used to assess cardiac autonomic function noninvasively, understand the pathophysiologic mechanisms of heart disease, evaluate therapy, and assess long-term prognosis. We examined both the short- and long-term reproducibility of the time and frequency domain HRV parameters in 23 type I diabetics over a 12-month interval. Entry criteria included juvenile onset diabetes before age 35 years, >24-year duration of diabetes, diabetes difficult to control, and albuminuria. Standardized noninvasive autonomic testing and 24-hour ambulatory electrocardiographic recordings were obtained. Fifteen men and 8 women (mean age 36.7 years) were enrolled. Fifty-three percent of the men and 75% of the women were smokers, and women had higher cholesterol than men. All HRV parameters were markedly decreased when compared with normal persons. Using Pearson correlation, the time domain indicators of parasympathetic activity demonstrated very strong correlations at 3 and 6 months compared with baseline, with good correlations at 1 year. The average SD of all 5-minute RR intervals maintained a very strong correlation for the entire year (r >0.94). In the frequency domain, the measures of parasympathetic and sympathetic activity maintained a solid correlation for the entire study period. Reproducibility of HRV was also examined using repeated-measures analysis of variance. The time and frequency domain parameters demonstrated very little variation over the study period of 12 months. Thus, our investigation demonstrated that HRV in long-term diabetics using 24-hour ambulatory recordings is abnormal and reproducible over a 12-month interval; very little variation in all HRV parameters, especially in parameters of parasympathetic activity, occurred during the study period.

Efficacy of ketoconazole in cutaneous leishmaniasis

Ketoconazole is a new antimycotic agent of special value in the management of systemic fungal infection (Heel 1982). In experimental studies in vitro, using human monocytes (Berman 1981), ketoconazole, especially hydrolized ketoconazole, was found to be highly effective against Leishmania major intracellular amastigotes. The oral administration of ketoconazole has recently been reported to give good results in cutaneous and mucocutaneous leishmaniasis caused by L. braziliensis, in an uncontrolled study (Urcuyo and Zaias 1982). In the present work, the efficacy of ketoconazole in the treatment of cutaneous leishmaniasis caused by L. major was examined. Eight patients, (seven males and one female, aged 16-41 years) with cutaneous leishmaniasis were treated. Diagnosis was made by protozoological examination of smears and cultures from several lesions as previously described (Even-Paz et al. 1982). All the patients were in good general health and had not received any previous topical or systemic treatment against leishmaniasis. Routine laboratory investigations, including ESR, CBC, SMAC-20 and urinalysis, were performed prior to starting ketoconazole therapy. All patients received 400 mg ketoconazole (Nizoral, Janssen, Beerse, Belgium) in one single dose daily with their breakfast for 28 days. No topical treatment was used. The patients were checked every 2 weeks by protozoological examination. Laboratory routine investigations were made again after the end of