Roberta Tankanow

Interaction study between digoxin and a preparation of hawthorn (Crataegus oxyacantha).

Hawthorn, an herbal supplement, is currently being evaluated for the treatment of heart failure. The flavonoid components of hawthorn may be responsible for hawthorns beneficial effects in the treatment of heart failure. However, these components may also affect P‐glycoprotein function and cause interactions with drugs that are P‐glycoprotein substrates, such as digoxin, which is also used to treat heart failure. Therefore, the purpose of this study was to determine the effect of hawthorn on digoxin pharmacokinetic parameters. A randomized, crossover trial with 8 healthy volunteers was performed evaluating digoxin 0.25 mg alone (D) for 10 days and digoxin 0.25 mg with Crataegus special extract WS 1442 (hawthorn leaves with flowers; Dr. Willmar Schwabe Pharmaceuticals) 450 mg twice daily (D + H) for 21 days. Pharmacokinetic studies were performed for 72 hours. There were no statistically significant differences in any measured pharmacokinetic parameters. The AUC0‐∞, Cmax‐Cmin, Cmin, and renal clearance for the D group were 79 ± 26 mcg•h/L, 1.4 ± 0.7mcg/L, 0.84 ± 0.2 mcg/L, and 74 ± 10 mL/min versus 73 ± 20 mcg•h/L, 1.1 ± 0.1 mcg/L, 0.65 ± 0.2 mcg/L, and 81 ± 22 mL/min for the D + H group, respectively (p > 0.05). Following 3 weeks of concomitant therapy, hawthorn did not significantly alter the pharmacokinetic parameters for digoxin. This suggests that both hawthorn and digoxin, in the doses and dosage form studied, maybe coadministered safely.

Kinetics, dynamics, and bioavailability of bumetanide in healthy subjects and patients with congestive heart failure

Four healthy subjects and six patients with congestive heart failure (CHF) were given 3 mg oral and intravenous doses of bumetanide in a random crossover fashion. Bumetanide was analyzed by HPLC, and sodium and potassium was analyzed by flame photometry. Aside from a modest reduction in renal clearance, the kinetics of bumetanide in CHF were similar to those in healthy subjects. The extent of bioavailability was 81%, with a variability of 20% to 25% about the mean for both groups. The cumulative dynamic responses to bumetanide, whether administered orally or intravenously, were essentially the same in each group. Pharmacodynamic modeling showed that there were no significant differences between healthy subjects and patients with CHF in either ER50 (bumetanide urinary excretion rate producing 50% of maximum drug effect) or S (slope), although the baseline effect was 15 times lower in CHF. The maximum effect attributable to bumetanide was twofold higher in healthy subjects and there was a significant correlation between this parameter and creatinine clearance (r = 0.964; p < 0.001). Overall, these results indicate that a predictable transition from 3 mg intravenous to oral doses of bumetanide is possible in CHF.

Radiosensitization with carotid intra‐arterial bromodeoxyuridine ± 5‐fluorouracil biomodulation for malignant gliomas

Bromodeoxyuridine (BUdR), a nonhypoxic radiosensitizing drug, is a halogenated pyrimidine analog that is incorporated into the DNA of dividing cells in a competitive process with thymidine. BUdR sensitizes cells to radiation therapy. 5-Fluorouracil (5-FU) inhibits the endogenous synthesis of thymidine, resulting in increased incorporation of the BUdR. Neurons and glial cells have a very low mitotic rate; they will not incorporate BUdR and will not be sensitized. BUdR and 5-FU are best delivered intra-arterially (IA) because of their regional advantage. We infused BUdR ±5-FU over 8½ weeks, before and during 59.4-Gy focal conformal external beam radiation therapy, through a permanently implanted pump with a catheter placed retrograde through the external carotid artery to the carotid bifurcation. Sixty-two patients with grades III or IV glioma were entered into one of two trials, with 23 patients receiving BUdR alone and 39 patients receiving BUdR + 5-FU. The maximum tolerated dose (MTD) of BUdR alone was 400 mg/m2/d for 834 weeks. The Kaplan-Meier median survival (KMS) was 20 months. In the BUdR + 5-FU trial, the MTD of BUdR was also 400 mg/m2/d and 5-FU was 5 mg/m2/d with a KMS of 17 months. The KMS of all 62 patients in both trials 1 and 2 was 18 months. Pathologic grading used both the original World Health Organization (WHO) and 1993 modified WHO systems. The KMS of grade IV patients was 13.8 months (48 patients) with the original system and 17 months (58 patients) with the modified system. The 2-year survival rate was 21% with the original and 28% with the modified grading system. The dose-limiting toxicity was a reversible unilateral focal forehead dermatitis, blepharitis, and conjunctivitis. Continuous IA halopyrimidine infusion may enhance the effectiveness of radiation in the treatment of malignant glioma.

Radiosensitization with Carotid Arterial Infusion of Bromodeoxyuridine (BUdR) ± 5 Fluorouracil (5FU) Biomodulation with Focal External Beam Radiation (FEBT) for Malignant Gliomas

A permanently implantable pump system has been developed for safe continuous intraarterial (IA) carotid BUdR ± 5FU infusion.[l] BUdR ± 5 FU is delivered IA because of its regional advantage (Rd). Fifty-four patients (41 Grade IV, 13 Grade III) were entered on one of two studies for the treatment of malignant gliomas with IA BUdR ± 5FU infused continuously for 8 1/2 weeks with FEBT to 5940 cGy the last 6 1/2 weeks. Twenty-three patients (18 Grade IV, 5 Grade III) were treated with BUdR alone with the maximum tolerated dose of 400 mg/m2/day for 8 1/2 weeks. The median survival was 20 months (2.4 S.E.). In the second trial, 31 patients were entered on IA BUdR + 5FU with a Kaplan Meier estimated median survival of 20.5 (4.5 SE.) months. The maximum tolerated dose of IA BUdR/5FU was 400 mg/m2/day of BUdR and 5 mg/m2/day of 5FU. The Kaplan Meier estimated median survival of all patients in trials 1 and 2 (total 54) is 20.5 (1.9 S.E.) months. The Kaplan Meier estimated median survival of the 41 Grade IV and 13 Grade III was 14 (2.9 S.E.) and 50 months (14 S.E.), respectively. The only vascular complication has been one transient episode of amaurosis fugax. The dose limiting toxicity in both trials has been a reversible self limited unilateral focal forehead dermatitis, iritis, conjunctivitis and blepharitis. Continuous IA infusion of BUdR ± 5 FU is feasible, safe, and represents a potential means of enhancing the effectiveness of FEBT in the treatment of malignant gliomas.

Tetrathiomolybdate versus Trientine in the Initial Treatment of Neurologic Wilson's Disease

ABSTRACT Background : The initial treatment of the neurologic presentation of Wilsons disease is problematic. Penicillamine, used for years on most patients, causes neurologic worsening in up to half of such patients, and half of those who worsen never recover. Zinc, ideal for maintenance therapy, is too slow for these acutely ill patients. We have developed tetrathiomolybdate (TM) for this type of patient, and it has worked well in open label studies. Trientine, another anticopper drug on the market approved for penicillamine intolerant patients, had not been tried in this type of patient. Here, we report on a double blind trial of TM versus trientine in the neurologically presenting Wilsons disease patient. Design and Methods : The study was a double blind design in which patients received either TM plus zinc, or trientine plus zinc, for 8 weeks This study was originally published in reference 1. Patients were accepted if they presented with neurologic symptoms from Wilsons disease, if they had not been treated longer than 4 weeks with penicillamine or trientine. Patients were followed in the hospital for the 8 weeks of treatment with weekly semiquantitative neurologic and speech examinations, to evaluate possible neurologic worsening. They also had blood and urine studies done weekly. At discharge from hospital they were continued on zinc maintenance therapy, and returned at yearly intervals for 3 years for further evaluation. Results : Twenty-three patients were entered into the trientine arm and 6 reached criteria for neurologic deterioration, while 25 patients were entered into the TM arm and only 1 deteriorated ( p Interpretation : TM is a superior choice to trientine for the initial therapy of neurologic Wilsons disease.