Allen E. Cato

Hemodialysis Using Prostacyclin Instead of Heparin as the Sole Antithrombotic Agent

Anticoagulation during hemodialysis is necessary to prevent clotting of the blood on contact with the dialysis membrane. Heparin is the usual anticoagulant used, but systemic anticoagulation may persist for hours, and hemorrhage is common. We successfully used an infusion of prostacyclin, which has an in vitro half-life of three to five minutes, as the sole anticoagulant in 10 patients on long-term hemodialysis and in one patient undergoing dialysis for acute renal failure (this patient bled severely on three occasions when heparin was used). Prostacyclin was infused intravenously for 10 minutes before dialysis and into the arterial line of the dialyzer during dialysis. We adjusted the rate of infusion into the dialyzer to prevent prostacyclin-induced hypotension. Each patient completed 240 minutes of dialysis and received a total of 423 +/- 91 ng of prostacyclin per kilogram of body weight (mean +/- S.E.M.; range, 56 to 780). Prostacyclin caused no clinically important changes in the intrinsic clotting system, and there were no hemorrhages or clotting of the coil. We conclude that prostacyclin can safely replace heparin as the sole antithrombotic agent during hemodialysis and may be more advantageous if anticoagulation is contraindicated.

The effect of multiple doses of ritonavir on the pharmacokinetics of rifabutin

To investigate the effects of ritonavir on the pharmacokinetics of rifabutin.

A Critical Review of the Safety and Antiemetic Efficacy of Delta-9-Tetrahydrocannabinol

Over the past six years, both governmental institutions and private enterprise have expressed great interest and activity in the isolation of chemical constituents from the Cannabis sativa plant and synthesis of novel cannabinoid compounds with potential medicinal uses. Evaluation of the safety and antiemetic efficacy of delta-9-tetrahydrocannabinol, the primary psychoactive cannabinoid component of marijuana, comprises one of several very active areas of cannabinoid clinical research. The results of clinical studies of the safety and antiemetic efficacy of delta-9-tetrahydrocannabinol in patients receiving cancer chemotherapy are critically evaluated. Deficiencies in current knowledge of the clinical pharmacology of delta-9-tetrahydrocannabinol are discussed in the context of antiemetic drug evaluation.

Pharmacokinetic interaction between ritonavir and didanosine when administered concurrently to HIV-infected patients

The effect of coadministration of ritonavir and didanosine (ddI) on the pharmacokinetics of these drugs was investigated in a single-center, three-period, crossover study. Eighteen asymptomatic, HIV-positive men were assigned randomly to 6 different sequences of 3 regimens: ddI (200 mg every 12 hours) alone for 4 days, ritonavir (600 mg every 12 hours) alone for 4 days, and 4 days of ddI with ritonavir under dose-staggering conditions. Although not statistically significant, ritonavir concentrations were slightly higher on average (<10%) with concurrent administration of ddI compared with those of ritonavir alone. In contrast, ddI concentrations were lower with concurrent administration compared with those of ddI alone; maximum concentration and area under the concentration-time curve were reduced by about 15% (p < .05). The ddI elimination rate constant was unaffected by ritonavir, suggesting no change in ddIs systemic metabolism. Adverse events were similar between regimens. The relatively minor changes in ritonavir and ddI pharmacokinetics are probably not clinically relevant; therefore, dosage adjustment of either compound appears unnecessary when administered concurrently. However, the combination regimen of ddI and ritonavir continue to be evaluated clinically.

Effects of prostacyclin infusion in uremic patients: Hematologic and hemodynamic responses

The effects of sequential prostacyclin infusions at 2, 4, and 8 ng/kg/min for 1 hr were determined in six patients with chronic renal failure. Diastolic blood pressure decreased in a dose‐dependent fashion from 74 ± 4 mm Hg (x̄ ± SEM) to 70 ± 4, 66 ± 5, and 55 ± 5 during the 2, 4, and 8 ng/kg/min infusions, respectively; systolic blood pressure was not affected by prostacyclin. The fall in diastolic blood pressure was associated with a progressive rise in heart rate from 77 ± 3 to 91 ± 4 bpm and lowering of body temperature from 36.7 ± 0.1 to 36 ± 0.2°. The threshold concentration of adenosine diphosphate that evoked reversible and irreversible platelet aggregation increased progressively from 1.2 to 2.8 and from 2.8 to 6 μM, respectively, during the prostacyclin infusions. Prostacyclin infusions had no effect on prothrombin time, activated partial thromboplastin time, or platelet count, but template bleeding time increased (not statistically significantly) from 5.8 to 12.3 min. In three of six patients, the 8 ng/kg/min infusion was terminated prematurely due to nausea, vomitting, and/or hypotension. We conclude that platelet aggregability can be inhibited in patients with chronic uremia by infusing 4 ng/kg/min prostacyclin without causing untoward side effects. When infused at hemodynamically tolerable doses, prostacyclin might serve as an in vivo inhibitor of platelet aggregation during hemodialysis or cardiopulmonary bypass.

Academic-Drug Industry Fellowships

The UNC/BW fellowship, like other industry/academia collaborative fellowships, provides a unique training experience in clinical research. Both academia and the pharmaceutical industry have opened their doors and allowed clinical pharmacists to spend a year or more developing clinical research skills and an understanding of the drug development process. Is it worth it? Is this program a benefit to the individuals, to the sponsors, or to the profession of pharmacy? The survey of these fellows provides us with the individuals perspective on the benefit and quality of the fellowship. Most believed the fellowship provided them with training to meet their needs and interests. However, given this small number of individual opinions and comments, how do we determine whether the fellowship is meeting the original goal to train clinical pharmacists to be clinical researchers? By looking at the career paths of those who have completed the program, we may gain insight into whether the fellows are involved with research. Since the fellowship has been in existence for only six years, we really can look only at the initial placement of these clinical pharmacists. A majority have gained employment with clinical research responsibilities within the pharmaceutical industry. One measure of the research capabilities of these fellows is their contributions to the scientific literature; 10 papers and 3 abstracts have been generated by fellows since they completed their fellowships (Appendix I). As expected, the research contributions of the two-year fellows are greater than that of the one-year fellows. Seven one-year fellows did not have a publication.(ABSTRACT TRUNCATED AT 250 WORDS)

Preparing Clinical Pharmacists for the Drug Development Task

be recognized as essential; a quality faculty without research fellows is shortchanging itself and its products. In the Department of Clinical Pharmacy at the University of Tennessee College of Pharmacy, we invested well over

Multidose Pharmacokinetics of Ritonavir and Zidovudine in Human Immunodeficiency Virus-Infected Patients

250 000 in our research fellowship program this year. To be sure, we could have added a few new faculty with these dollars, but such a decision would have left EDUCATION & TRAINING PROGRAMS