Steven F. Francom

Physiology and pharmacokinetics of a novel hemoglobin-based oxygen carrier in humans

OBJECTIVE To evaluate the physiology and pharmacokinetics of a novel hemoglobin-based oxygen carrier of bovine origin. DESIGN Randomized, single-blind, placebo-controlled, dose-escalation study. SETTING The Upjohn Research Clinics (Kalamazoo, MI). SUBJECTS Normal healthy adult men between the ages of 18 and 45 yrs. There were 18 subjects who received active treatment and 23 controls. INTERVENTIONS All subjects had phlebotomy of 15% of blood volume (performed in <15 mins) followed by isovolemic hemodilution (3:1, Ringers lactate to the volume of whole blood removed) over a 90-min period, and either active drug (polymerized bovine hemoglobin) or a control infusion of lactated Ringers solution (each infusion given over a total of 4.3 hrs). The subjects randomized to active treatment received a loading dose and a continuous infusion of polymerized bovine hemoglobin for a total dose of 16.5, 24.1, 30.2, 38.0, or 45.0 g. All subjects had an indwelling radial artery catheter (for blood pressure and arterial blood gas measurements), determination of cardiac function (by impedance plethysmography), serial pulmonary function tests (spirometry and diffusion capacity), and metabolic cart measurements. MEASUREMENTS AND MAIN RESULTS Pharmacokinetics of the plasma bovine hemoglobin demonstrated that the elimination of the hemoglobin-based oxygen carrier was a linear, first-order process and that there was no renal excretion. Peak plasma concentrations were between 1 to 2 g/dL and plasma half-life approached 20 hrs at the highest doses given. Diffusion capacity of oxygen was increased up to 20% above baseline in the 38.0 and 45.0 g groups in comparison with controls (approximately 14% below baseline) between 2 and 24 hrs after the infusion (p < .01). Other pulmonary function tests and arterial blood gas measurements were unremarkable. Arterial oxygen content and oxygen delivery tended to be greater in active groups than in controls. CONCLUSIONS The plasma concentrations of bovine hemoglobin were directly proportional to the doses administered. An increase in diffusion capacity paralleled the plasma bovine hemoglobin concentrations. Dosing of the hemoglobin-based oxygen carrier of bovine origin to a target plasma hemoglobin concentration can be achieved using pharmacokinetic principles with measurable effects on oxygen physiology.

Fish oil produces an atherogenic lipid profile in hypertensive men

The effects of fish oil supplements on plasma and platelet membrane lipids, lipoproteins, sex steroid hormones, glucose, insulin, platelet aggregation, and blood pressure in normal subjects (n = 13) and patients with essential hypertension (n = 13) were studied in this randomized, double-blind, placebo-controlled, two-way crossover study. Treatments consisted of 30 days of 5 g of n-3 fatty acids (ten 1-g capsules of fish oil daily) or placebo capsules (ten wheat germ oil capsules daily) with a one-month washout in between each crossover. Serum lipids and lipoproteins were measured before dosing and every two weeks during the study. Sex steroid hormones, glucose, insulin, and fatty acid composition in platelet membrane phospholipids were measured before dosing and at the end of each crossover. During treatment with fish oil, only the hypertensive had increases in total cholesterol (8%, p less than 0.026), LDL cholesterol (19%, p less than 0.006) and apolipoprotein B (18%, p less than 0.026). Serum androgens (total and free testosterone) were 30% lower in hypertensives than normotensives before any dosing, but were unchanged with placebo or fish oil capsules in either group. Plasma glucose, insulin, platelet aggregation, and the incorporation of n-3 fatty acids into platelet membrane phospholipid subfractions were similar in both normotensive and hypertensive men. Blood pressure was not affected by fish oil treatment in either group of men. These results provide evidence that fish oil may adversely affect serum lipids to yield an atherogenic lipid profile in hypertensive men.

Lifibrol: A novel lipid‐lowering drug for the therapy of hypercholesterolemia

To determine the effects of lifibrol on serum lipids in adult patients with primary hypercholesterolemia.

Effects of fish oil and endorphins on the cold pressor test in hypertension

The effects of fish oil and naloxone on blood pressure, catecholamines, and endorphins during the cold pressor test were evaluated in a randomized, double‐blind, placebo‐controlled, two‐way crossover trial of normotensive and medication‐free hypertensive men (n = 13 each). Subjects were given 5 gm ω‐3 fatty acids per day or placebo for 30 days with a 1‐month washout between interventions. The cold pressor test (hand in ice water for 5 minutes) was done at the end of the treatment periods. Intravenous naloxone (10 mg) or placebo was given before the cold pressor test. Fish oil‐treated, normotensive, or hypertensive groups had similar changes in blood pressure, plasma catecholamine levels, and β‐endorphins during the cold pressor test, but naloxone treatment was associated with fivefold and tenfold increases in plasma epinephrine and Cortisol levels, respectively. Naloxone may modulate sympathomedullary discharge through blockade of endorphin activity. It is unlikely that endorphins are involved in the blood pressure increase during the cold pressor test or that fish oil alters this response.

Inflammatory response to sodium lauryl sulfate in aqueous solutions applied to the skin of normal human volunteers.

In this double‐blind study, the intensity and duration of the inflammatory response induced by various concentrations of sodium lauryl sulfate (SLS) solution on the forearms of 36 normal male volunteers was dependent, upon the concentration and number of applications of SLS. One 24‐h application of the 4% or 5% aqueous SLS solution or two successive 24‐h applications of the 2% or 3% SLS solutions were sufficient to cause an inflammatory response in the epidermis. Such response makes the skin more permeable for the testing of topical formulations of compounds to document their propensity to irritate.

Lack of Effects of Beta-Carotene on Lipids and Sex Steroid Hormones in Hyperlipidemics

Beta-carotene in doses of up to 300 mg daily raises high-density lipoprotein cholesterol levels within 2 to 4 weeks in healthy subjects. The authors, in this study, investigate the short-term effects of high-dose beta-carotene upon serum lipids, lipoproteins, and selected sex steroid hormones in 59 adult patients with Type IIa or IIb hyperlipidemia and 36 healthy subjects. Volunteers took beta-carotene (300 mg) or wheat germ oil capsules daily for 30 days. Lipids were measured on days 1, 14, 21, and 30. Betacarotene, retinol, free and total testosterone, and estradiol levels were measured on days 1 and 30. Total high-density lipoprotein cholesterol levels increased 10% (p < 0.01) over baseline in all groups by day 14 but returned to baseline by day 30. Total cholesterol, low-density lipoprotein cholesterol, and triglyceride levels transiently increased between days 14 and 21 by up to 9%, 8%, and 20%, respectively, only in the patients with hyperlipidemia treated with beta-carotene, but returned to baseline on day 30. Apolipoproteins A and B were unchanged. Despite 20-fold increases of plasma beta-carotene levels there, were no reports of carotenodermia and no alteration in sex steroid hormones, retinol levels, hepatic transaminases, or persistent changes in serum lipids that were attributable to beta-carotene.

A structural model for the Markov chain of change in vote intention

Assuming a first-order Markov chain, we propose a structural model for the transition probabilities in vote intention. The proposed model utilizes the ordering among the categories representing vote intentions and carries the flavor of distance models. It also allows a stochastic ordering among distributions reflecting the extent of change. The model is easy to fit and provides a nice interpretation of the data. The model is applied to a panel study of vote intention acquired through six successive interviews before the 1940 Presidential election in Erie County, Ohio.

The effect of ketoconazole and transdermal estradiol on serum sex steroid hormones levels

SummaryIn this randomized, open-label trial, 24 subjects were studied. There were 12 subjects with essential hypertension and 12 normotensive controls who received, after an initial control period, 48 h of treatment with a transdermal estradiol patch or ketoconazole tablets every 8 h for six doses, or in combination. LHRH (100 μg) and ACTH (250 μg) were given at 48 h of each treatment. Each treatment was one week apart.In both normotensive and hypertensive men ketoconazole reduced adrenal and gonadal androgens, raised 11-deoxycortisol and 17 α-hydroxyprogesterone levels; blunted the rise of cortisol to ACTH and had no effect on the response of LH to LHRH. Transdermal estradiol raised serum estradiol levels, blunted the time to peak plasma concentration of LH to LHRH and produced a normal response to ACTH. Although baseline level of total and free testosterone and DHEA-S were lower in hypertensive men, the response of the pituitary (LH) to LHRH and adrenal axis with ACTH were similar in both normotensive and hypertensive men. Blood pressure was unaffacted by any of the treatment interventions in either normotensive or hypertensive men.Although ketoconazole or transdermal estradiol reduce androgens, there was no evidence that this reduction in androgens was involved with the short term regulation of blood pressure in hypertensive men.

Cardiovascular and hormonal effects of pramipexole, a novel dopamine agonist

Clinical Pharmacology & Therapeutics (1996) 59, 178–178; doi: 10.1038/sj.clpt.1996.210

Recruitment of Volunteers for Phase I and Phase II Drug Development Studies

Subject participation is crucial to drug development studies. Numbers of subjects are greatly reduced between the initial recruitment and study completion. The purpose of this study was to determine where major losses of subjects occurred and characterize the reasons why the subjects did or did not participate. All studies were conducted at The Upjohn Research Clinics, Kalamazoo, Michigan, which comprise a 76- bed facility that specializes in Phase I and II trials. A 1987–1988 retrospective survey of 157 studies showed that of 9,028 subjects who met protocol entry criteria 5,906 (65%) attended the informed consent. Of the areas where subjects were lost, 3,122 (35%) subjects failed to attend the informed consent and 2,073 (35%) subjects withdrew between the informed consent and the start of the study or during the medical screen. After entry into the study, 247 (6%) subjects failed to complete the studies due to side effects or withdrawal on their own volition. The subjects population was mainly white (92%), male (72%), and between 18 and 55 years of age, with black subjects (5%) and females (28%) represented the least. The greatest losses occurred due to failure to attend the informed consent or pass the medical screen. According to our data, we must recruit twice the number of volunteers needed to fulfill study requirements. Future investigation should be directed to identify those characteristics of potential volunteers who initially express an interest to participate in a study, but who decline to show up for the informed consent session.