Mark Moran

Prevention of Acute Graft Rejection by the Prostaglandin E1 Analogue Misoprostol in Renal-Transplant Recipients Treated with Cyclosporine and Prednisone

Prostaglandins of the E series have been shown to have immunosuppressive properties. To study the effects of the prostaglandin E1 analogue misoprostol on renal function and graft rejection after transplantation, we conducted a randomized, double-blind, placebo-controlled trial in 77 renal-allograft recipients. The subjects received misoprostol (200 micrograms four times daily by mouth; n = 38) or placebo (n = 39) for the first 12 weeks after transplantation, in addition to standard immunosuppression with cyclosporine and prednisone. They were then observed for an additional four weeks after the drug or placebo was discontinued. Treatment with misoprostol was associated with a significant improvement in renal function as judged by the mean (+/- SEM) serum creatinine concentration (128 +/- 7 vs. 158 +/- 11 mumol per liter after 12 weeks; P = 0.03) and creatinine clearance (84 +/- 6 vs. 69 +/- 5 ml per minute per 1.73 m2 of body-surface area; P = 0.05). There was a significant reduction in the incidence of acute rejection in the group treated with misoprostol as compared with the placebo group (10 of 38 vs. 20 of 39; P = 0.02), and there was less need for rehospitalization after transplantation (4 +/- 1 days with misoprostol vs. 10 +/- 2 days for placebo; P = 0.03). Although blood levels of cyclosporine did not differ significantly between the groups, they tended to be higher in the misoprostol group, as did the incidence of acute nephrotoxicity due to cyclosporine (13 of 38 vs. 8 of 39). Infectious complications tended to be fewer in the misoprostol-treated group (14 of 38 vs. 21 of 39). We conclude that misoprostol improves renal function and safely reduces the incidence of acute rejection in renal-transplant recipients treated concurrently with cyclosporine and prednisone.

The immunosuppressive properties of new oral prostaglandin E1 analogs

Prostaglandins play an important role in cell-mediated immune responses. Their clinical use has been limited by poor oral bioavailability, short half-lives, and significant toxicity profiles. We studied the immunosuppressive properties of new, synthetic, prostaglandin E1 (PGE1) methyl ester analogs (misoprostol, enisoprost) with oral bioavailability using an allogeneic in vitro immunoassay. Our results show that the PGE1 analogs suppress alloproliferative responses and supplement the immunosuppressive activity of cyclosporine and methylprednisolone. Moreover, we demonstrate that addition of recombinant interleukin-2 to the PGE1 analogs restores alloimmune responsiveness and the expression of surface class II antigen and IL-2 receptors on responder lymphocytes. These studies, together with preliminary in vivo data in rodents and man, suggest that the new synthetic oral PGE1 analogs may provide therapeutic efficacy in clinical transplantation and a variety of immunologically mediated diseases.

Coronary hemodynamic effects of atrial natriuretic peptide in humans

Studies of the effects of atrial natriuretic peptide on the coronary circulation have yielded conflicting results in animals and have not been fully investigated in human subjects. To further characterize the direct coronary hemodynamic actions of atrial natriuretic peptide in humans and to assess the safety of its administration in patients with coronary artery disease, incremental doses of synthetic atrial natriuretic peptide and nitroglycerin were infused into the left coronary artery in 14 patients, 11 of whom had coronary artery disease. Both agents caused dose-related increases in total coronary sinus blood flow. The largest dose of atrial natriuretic peptide given to all patients (100 micrograms) increased mean coronary sinus blood flow from 127 +/- 7 to 149 +/- 9 ml/min (p less than 0.05) and decreased coronary vascular resistance from 0.93 +/- 0.07 to 0.81 +/- 0.05 mm Hg/ml per min (p less than 0.05); mean arterial blood pressure and heart rate were not affected by this dose of atrial natriuretic peptide. The greatest changes in coronary sinus blood flow (+25%) and coronary vascular resistance (-18%) after atrial natriuretic peptide administration occurred in the patients with coronary artery disease and no other associated cardiovascular disease. The maximal effects of atrial natriuretic peptide were similar to those of nitroglycerin, and no untoward effects were observed. Thus, atrial natriuretic peptide is a direct coronary vasodilator in humans. Its maximal dose effects are similar to those of nitroglycerin and were well tolerated in this small group of patients. The physiologic importance and therapeutic potential of atrial natriuretic peptide in patients with coronary artery disease merit further investigation.

Clinical Studies and the Price of Information

With the performance of clinical studies, pharmaceutical sponsors purchase data on the open market. The price of an individual study is usually known. Whether the price represents a good value, however, often is not. Moreover, whether two trials of different drugs have similar values is also frequently uncertain. The purpose of the current work was to ask and to devise a means of answering these questions. The multiple regression technique was applied to a sample of 56 clinical trials. Although therapeutic class and study location significantly influenced trial costs, the most important factor was the amount, but not the kind, of data collected. The number of case report forms alone accounted for approximately 65% of the variability in the price of clinical trials. Using the model, individual trials could be compared for value and the price range of new trials predicted.

The Measurement of Efficiency in Clinical Research and Development

To improve efficiency in clinical research and development (CR&D), sponsors alter procedures or technologies, sometimes without measuring the impact of such changes. To evaluate the effects of procedural and technological changes, we proposed to objectively measure efficiency within Searles department of CR&D. Efficiency was defined as output/input per fiscal year. Considering financial investment and people as fundamental inputs, we identified a small number of key outputs. Using data from the preceding three fiscal years, we determined the most important indices of efficiency to be (a) the sum of (protocols initiated + reports written) per person; (b) average total expenses per (protocol + report); (c) average clinical grant costs per center receiving drug for the first time; (d) average clinical grant costs per new protocol initiated; (e) the numbers of case report forms processed per person in CR&D worldwide; (f) the numbers of case report forms processed per person in the data handling group alone; and (g) average total expenses per case report form. Values for these seven indices have established a useful baseline. Using them, we plan to measure the effects of subsequent changes in technology, policies, and procedures on the efficiency of clinical research.

Prostaglandins and the release of insulin: A review and a proposal

The effect of prostaglandins or the inhibition of their synthesis on the release of insulin is controversial. Dispute exists because there are apparently disparate experimental results. When the following factors are considered, however, much of the disparity is eliminated: 1) the experimental setting--in vitro or in vivo; 2) the experimental model--animal or human; 3) the experimental additive--the type of nonsteroidal antiinflammatory drug or specific prostaglandin; 4) the relationship of insulin levels to insulin secretion, degradation, and the observed hypoglycemic response. On the basis of such considerations the following conclusions are advanced. 1) From animal studies in vitro it appears that prostaglandins can directly augment insulin release. 2) Results from animal experiments in vivo, however, suggest that systemic prostaglandin administration diminishes insulin release. 3) No human studies have been performed in vitro which examine the insulin secretory response of pancreatic tissue to prostaglandins. 4) Prostaglandins reduce stimulated insulin levels in normal human subjects and in those with diabetes mellitus. Whether insulin secretion is reduced, or clearance is increased, is unknown. 5) Finally, the critical experiment remains to be done, that is the simultaneous examination of insulin, C-peptide, and glucose kinetics during an infusion of a prostaglandin.

The Abecedarian Risk Manager—ALPHA, BETA, AND CASH

There is much believed, but nothing sacred, about a p-value of 0.05. This number, 0.05, is potentially the most dangerous in all of drug development. For example, the finding of a p-value <0.05 in Phase II may directly result in a costly Phase III effort for a given drug. This p-value, however, is also a measure of the probability that the decision to proceed is wrong. Moreover, when a portfolio is considered, p-values measure the relative risk of misallocating resources among projects. If the costs of Phase III differ significantly between projects, it may be irrational to rely upon the typical threshold p-value of 0.05. As a result, required p-values should vary inversely with projected future costs. The principles that underlie this assertion lend themselves to a general model for rational decision making in drug development, particularly where costs dominate and risk is adjustable.