Click to increase image sizeClick to decrease image sizeThis article refers to:Do Clinicians Have a Duty to Participate in Pragmatic Clinical Trials? Additional informationFundingThe author(s) reported there is no funding associated with the work featured in this article.

De Minimis Risk: A Proposal for a New Category of Research Risk Rosamond Rhodes a , Jody Azzouni b , Stefan Bernard Baumrin c , Keith Benkov a , Martin J. Blaser d , Barbara Brenner a , Joseph W. Dauben c , William J. Earle c , Lily Frank c , Nada Gligorov a , Joseph Goldfarb a , Kurt Hirschhorn a , Rochelle Hirschhorn d , Ian Holzman a , Debbie Indyk a , Ethylin Wang Jabs a , Douglas P. Lackey c , Daniel A. Moros a , Sean Philpott e , Matthew E. Rhodes f , Lynne D. Richardson a , Henry S. Sacks a , Abraham Schwab g , Rhoda Sperling a , Brett Trusko a & Arnulf Zweig h a Mount Sinai School of Medicine b Tufts University c The Graduate Center, CUNY d New York University Medical School, CUNY e Union Graduate College f Pennsylvania State University g Indiana University, Purdue h University of Oregon (Emeritus)

Mark Rothstein’s (2010) article seems to focus on the technological adequacy of deidentification procedures and the possibility of harm associated with their failure to guarantee anonymity. The paper, however, is actually an attack on the current practice of minimizing regulatory oversight of deidentified health information and biological specimens. Rothstein concludes that “utilitarian concerns about burdens on research are insufficient to justify dispensing with any consideration of the possible effects of the research on the individuals from whom the information and specimens are obtained” (3). Although Rothstein presents neither evidence nor argument for his sweeping conclusion, presumably it follows from the case of the Havasupai Indian tribe as well as several hypothetical conjectures of how deidentified data might expose subjects’ private information, along with opinion polls that ask whether people would like the opportunity to consent before their medical data or tissue samples are utilized in research. Rothstein maintains that the only gain from current policy is convenience and reduced burden on researchers, which he dismisses as an unacceptable “price to pay for safeguarding the privacy and autonomy of individuals” (3).

The effect of the barbiturate T2000 (1,3‐dimethoxymethyl‐5,5‐diphenyl‐barbituric acid; DMMDPB) on essential tremor, given in twice daily doses of 400 and 300 mg, was assessed in two brief, randomized, placebo‐controlled, parallel‐group, double‐blinded, single‐center trials in 12 and 22 patients, respectively. These trials represent the first clinical use of T2000 for a specific indication. The primary endpoint was the change in the mean scores of the treated and control groups based on the Fahn‐Tolosa‐Marin tremor scale. In the first study of 12 patients treated with 400 mg or placebo twice daily for 14 days, the mean change from baseline at day 14 was 19.3 (P < 0.0001) in the treated group and 9.0 (P = 0.0121) in the control group. Using a two‐factor mixed ANOVA model to evaluate within group and between group changes, the effect of T2000 was significantly different from that of the placebo group (P = 0.03). In the second study of 22 patients treated with 300 mg of T2000 or placebo twice daily for 20 days, statistically significant changes were seen in treated patients compared to baseline, but the ANOVA model did not demonstrate a significant treatment effect of T2000 compared to placebo. When the treated groups from each study are compared, the 800‐mg daily group is significantly different from the 600‐mg daily group (P = 0.02). Some treated patients in each study, but no placebo patients, experienced marked improvement. These results support further evaluation of T2000 in the treatment of essential tremor. © 2006 Movement Disorder Society

I is presently under evaluation for potential utility in essential tremor and seizure disorders. The compound lacks prominent sedative-hypnotic activity usually associated with this chemical class of drugs. I is biotransformed to monomethoxymethyl-5,5-diphenylbarbituric acid (II) and to 5,5-diphenylbarbituric acid (III) in the rat, dog and man. II and III appear to be active metabolites. I has limited aqueous solubility; in an effort to enhance absorption from the gastrointestinal tract, we evaluated the influence of a high fat breakfast on gastrointestinal absorption of I in 23 healthy non-smoking male volunteers between 19 and 54 years of age. The rate and extent of absorption was assessed by measuring the plasma levels of I, II and III over the course of 5 days after an oral dose of 400 mg of I. Results: The mean ratios for Cmax (fed/fasting) for I, II and III were 6.88, 3.14 and 1.59, respectively. Mean tmax ratios (fed/fasting) for the 3 compounds were 0.65, 0.44 and 0.88 for I, II and III. Mean ratios for AUC0-t (fed/fasting) for I, II and III were 2.81, 2.74 and 1.53, respectively. Mean terminal half-lives for I, II and III ranged between 18-26, 16-27 and 39-43 hours, respectively. Conclusion: A high fat meal enhances the oral absorption of T2000 in man as indicated by higher Cmax, earlier tmax and greater AUC after a high fat breakfast than in the fasting state. As expected, terminal half-lives of all 3 compounds did not change.

Warfarin is, among drugs, considered to have a narrow therapeutic index for which individual bioequivalence has been suggested. To establish the propriety of "switching," an individual bioequivalence study involving a replicate-design study and three "switchings" in healthy subjects was undertaken using the U.S.-brand warfarin sodium tablet and a generic product. A randomized, single-center, open-label, single-dose, four-way crossover replicate bioequivalence study was performed in 24 healthy male volunteers in which each subject received the same 5 mg warfarin test and reference tablets twice on different occasions under fasting conditions. Concentrations of warfarin in plasma were measured by a validated specific HPLC method. The individual pharmacokinetic parameters obtained with test and reference products were compared using pooled data and Liu's method. Bioequivalence was shown with both average and individual bioequivalence methods. The individual bioequivalence assessment did not show a subject-by-formulation interaction, nor did it add value to the bioequivalence assessment of warfarin.

Background and objectives: Carbamazepine is among those drugs that have been considered to have a narrow therapeutic plasma concentration range, that is, a narrow therapeutic index. Although the US Food and Drug Administration has approved new generic products based on standard single-dose bioequivalence studies, several state formularies, including the New Jersey Drug Utilization Review Council, have recently established additional criteria for acceptance of bioequivalence of narrow therapeutic index drugs, limiting the use of some approved generic drugs in specific states. To further validate the adequacy of single-dose studies for the determination of bioequivalence of narrow therapeutic index drugs, a multiple-dose study was conducted that more closely reflected therapeutic use.Methods: A single-center, multiple-dose, randomized, open-label, 2-way crossover bioequivalence study was conducted in 32 fasting volunteers at steady state, Subjects received the test and reference products as a 200 mg carbamazepine tablet 3 times a day in a crossover fashion. Concentrations of carbamazepine and carbamazepine-10,11-epoxide in plasma were measured by a validated specific HPLC method.Results: A total of 28 subjects completed the study, Pharmacokinetic parameters and measures of fluctuation for both products at steady state were similar, with 90% and 95% confidence intervals falling within 90% and 110%,Conclusion: The multiple-dose study provided reliable safety and bioequivalence data under rigorous statistical conditions and confirmed bioequivalence of test and reference products determined by a single-dose study.

While the three classical pharmacokinetic (PK) parameters, AUC, Cmax and tmax are adequate to assess bioequivalence of immediate release (IR) formulations, they are not designed to fully characterize the pharmacokinetic (PK) performance of controlled release (CR) formulations and provide only limited insight into the function of carbamazepine (CBZ) CR products. Thus, for reliable assessment of bioequivalence in CR formulations, there is a role for the use of additional criteria (parameters). The following are the proposed new parameters: MRT (mean residence time), Cmax/AUC, plateau time or POT (the time span associated with the concentrations within 25% of Cmax), tapical (the arithmetic mean of the times associated with POT) and Capical (the arithmetic mean of the concentrations within 25% of Cmax). The above proposed parameters, were utilized in a recent PK study of new CR products of CBZ (600 mg) designed for once daily dosing. The comparative PK analysis was conducted in a three-way crossover single dose studies of three CBZ CR formulations (Teril 600 CR tablet, CBZ 600 granulate and Timonil 600 Retard tablet). Teril 600 CR was found to be bioequivalent to Timonil 600 Retard while CBZ 600 granulate was not. This conclusion was reached utilizing both the classical and the proposed new parameters. The new parameters showed that CBZ 600 granulate has similar rate of absorption as the two 600 mg CR tablets, but its extent of absorption was lower. The new parameters examined in this paper are more attractive than the single point parameters, Cmax and tmax, for assessment of rate of absorption and the flatness of the plasma concentration versus time curve. Their potential benefit and practical utility was confirmed in this study, which demonstrated bioequivalence between a new CR and an innovator CBZ (600 mg) tablet. Absorption rate assessment is important in light of concentration-related side effects associated with CBZ therapy and the impact of fluctuations and the flatness of the CBZ plasma concentration curve on the drug efficacy and tolerability.

Summary: Purpose: Concern persists that the criteria used to establish bioequivalence of generic drugs may not adequately guarantee the interchangeability of antiepileptic medications (AEDs), particularly controlled‐release (CR) formulations. We examined the utilization of several new parameters, in addition to AUC, peak plasma concentration (Cmax), and time to reach Cmax (tmax), for the assessment of bioequivalence and in vivo performance of CBZ and other CR products. These new parameters may offer additional information for evaluation of CR products that yield a prominent plateau in the plasma time‐concentration curve. They include mean residence time (MRT), Cmax/AUC, plateau time or POT (the time span associated with the concentrations within 25% of Cmax), tapical, and Capical, (the arithmetic mean of the POT times and concentrations within 25% of Cmax respectively). Additional parameters for multiple‐dose studies include the percentage fluctuation and the flatness of the steady state‐concentration curve. Methods: These proposed parameters were used in two recent (single and multiple dose) two‐way crossover studies of a new CR product of CBZ (Teril 400 CR) in comparison with Tegretol CR Divitab. Results: Teril 400 CR was found to be bioequivalent to Tegretol CR Divitab, by using both the classic and the additional proposed parameters. Both CBZ CR products have similar rates of absorption and similar flatness of their plasma time‐concentration curves as assessed by visual inspection and the proposed parameters. Conclusions: The additional parameters examined may supplement the traditional single‐point parameters, Cmax and tmax for assessment of rate of absorption and the flatness of the concentration curve. Their potential benefit and practical utility was confirmed in these two studies. Absorption‐rate assessment is important in light of concentration‐related side effects associated with CBZ therapy and the impact of fluctuations and the flatness of the CBZ plasma concentration curve on the drug efficacy and tolerability.

A paucity of information is available concerning the use of levodopa and carbidopa during pregnancy. Particularly lacking is whether these agents cross the placenta and whether levodopa undergoes metabolism in the fetus. The present study carried out in aborted fetal tissues demonstrates that levodopa crosses the placental barrier and suggests that it may be metabolized in fetal tissues, including the brain and spinal cord. The possibility exists that early exposure to levodopa or dopamine may alter the normal neuronal development in the fetus, and caution in the use of levodopa during pregnancy should be observed.

L-deprenyl (selegiline) has been reported as a safe effective adjunctive agent to levodopa in the control of Parkinson's symptoms, as well as a means of preventing the progressive nature of the disease process. In an ongoing study, now in its 12th year, L-deprenyl has been administered 1. as monotherapy or 2. in combination with levodopa, to previously untreated patients in the early phases of the disease; 3. added to an existing regimen of levodopa when optimal therapeutic results are not being obtained. This report reviews our experience in each of these three treatment categories. Results obtained to date, indicate that L-deprenyl administered alone does not prevent the occurrence of signs of Parkinson's disease. Its administration with levodopa, as initial therapy, allows for use of lower dosage and less side-effects of the latter agent. When L-deprenyl is added to sub-optimal responders to levodopa, it attenuates fluctuating responses, particularly those of the 'end-of-dose' variety.

ABSTRACT While interest in philosophy and medicine has burgeoned in the past two decades, there remains a need for an analysis of the intellectual activity embodied in good medical practice. In this setting, ethical and scientific decision‐making are complexly interrelated. The following paper, collaboratively written by physicians and philosophers, presents a view of applied (clinical) science and applied ethics. Making extensive use of illustrations drawn from routine case material, we seek to indicate a variety of philosophic issues to be found in daily practice, elucidate various levels of critical reasoning within the medical setting, and demonstrate a remarkable similarity between medical and ethical decision‐making.

ABSTRACT — There are at present numerous pharmacological agents available for the control of parkinson symptoms. None are ideal; all have their limitations. The most potent is levodopa administered with a peripheral decarboxylase inhibitor. However, because its effectiveness declines after long-term use and side effects increase in severity, it should be reserved for individuals with established symptoms which are functionally impairing. In patients with minimal symptoms, anticholinergic agents, or agents which facilitate dopaminergic mechanisms normally operative in the nervous system, should be used. In a limited trial, deprenyl has produced promising results during this phase of parkinsonism. Deprenyl's major usefulness however, has been demonstrated in patients under treatment with levodopa which has become complicated by fluctuating responses – particularly those of the end-start-dose variety. In such patients, it is possible to achieve an increase in "on" time and a decrease in the severity of parkinsonism. In most patients, such a response can maintained for a period of two years or longer.

In previous reports we demonstrated a correlation between the capacity of drugs to depress the terminals of cat soleus nerves and their capacity to block ouabain-induced ventricular rhythm disorders. To test this correlation we examined the neurodepressant activity of INPEA, an agent which has been reported to be ineffective in antagonizing digitalis-induced arrhythmias. We found INPEA to have neurodepressant actions but that expression of these actions required more drug than had been used in previous studies of the drug's antiarrhythmic activity. When the neurodepressant doses were tested, they were found to be effective in antagonizing ouabain-induced ventricular tachycardia and death. The results are discussed with regard to the role of neural and myocardial depression in the control of digitalis-induced arrhythmias.