George S. Hughes

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.

The effects of gastric pH and food on the pharmacokinetics of a new oral cephalosporin, cefpodoxime proxetil.

The effects of alteration of gastric pH and food on the pharmacokinetics of 200 mg doses of cefpodoxime proxetil tablets were studied in two separate randomized, open label, crossover studies in healthy subjects. In the pH study (n = 17 subjects), there was a lead‐in period done under fasting conditions, followed by randomization to a four‐way crossover of pentagastrin (6 µg/kg, subcutaneously), ranitidine (150 mg orally, 10 and 2 hours before dosing with the antibiotic), sodium bicarbonate (12.6 gm), or aluminum hydroxide (120 cc). Gastric pH was determined by nasogastric aspirates before and 10 minutes after the intervention, just before the antibiotic was given. Peak plasma concentrations (Cmax) and area under plasma concentration–time curve (AUC) were highest in fasting and pentagastrin periods and were 35% to 50% lower for all of the other periods (p < 0.0001). Gastric pH and Cmax and AUC were inversely related (r = 0.66 and r = 0.62; p < 0.0001 for both). In the food study (n = 16 subjects), there were two lead‐in periods, one done while subjects were fasting and one while they were normal diet, followed by randomization to a four‐way crossover of either high or low protein diets, or high or low fat diets. There were six meals in each diet. Dosing with the antibiotic was done at the midpoint of the fourth meal. Cmax and AUC were 22% to 34% higher for all diets than for the fasting period (p < 0.0001), whereas the time to Cmax was unchanged. These studies demonstrated that absorption of cefpodoxime proxetil is best at low gastric pH or in the presence of food, which suggests that the role of gastrointestinal function on the pharmacokinetic profile is complex.

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.

Effects of a Novel Hemoglobin-Based Oxygen Carrier on Percent Oxygen Saturation as Determined With Arterial Blood Gas Analysis and Pulse Oximetry

STUDY OBJECTIVE Hemoglobin-based oxygen carrier 201 (HBOC-201) is a polymerized hemoglobin of bovine origin being developed for use in hemorrhage during surgery or trauma. Pulse oximetry is commonly used in clinical practice to assess percent saturation of hemoglobin (Spo2). The ability to measure Spo2 in the presence of HBOC-201 will be important for the use of this compound in patient care. METHODS We carried out a randomized, single-blind, placebo-controlled study at the Upjohn Research Clinics in Kalamazoo, Michigan, with normal, healthy adult men and women as subjects. The members of four groups of adult subjects (N=24) each received 45 g of HBOC-201 (nine each, men and women) or a control solution (Ringers lactate) (three each, men and women). Each subject underwent phlebotomy (about 15% of estimated blood volume) followed by 3:1 hemodilution with Ringers lactate and then either HBOC-201 or control solution. An indwelling arterial catheter in the radial artery was used for serial arterial blood gas sampling. Arterial blood gas measurements were made with a cooximeter (Instrumentation Laboratories). Fingertip pulse oximetry was used (Criticare 504-US; Criticare, Incorporated). Paired pulse oximetry and arterial blood gas sampling were made serially (at approximately hourly intervals) over 24 hours. RESULTS The mean +/- SEM difference for Spo2 for arterial blood gas analysis compared with the pulse oximetry reading in the presence of HBOC-201 was 1.1% +/- 0.75%; in controls it was .1% +/- 0.64% (P<.001) for each) over the 24 hours after dosing. This relationship was constant despite increased concentrations of plasma hemoglobin (between 1 and 2g/dl [10 to 20 g/L]) in the HBOC-201 groups. CONCLUSION Accurate determinations of Spo2 can be made with pulse oximetry in subjects given HBOC-201 over the normal range of Spo2.

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.

Pharmacokinetic and Tolerance Studies of Cefpodoxime after Single‐ and Multiple‐Dose Oral Administration of Cefpodoxime Proxetil

Cefpodoxime proxetil, a third generation, broad‐spectrum, oral cephalosporin, was administered in single doses of 100, 200, 400, 600, and 800 mg (dose expressed as Cefpodoxime equivalents) and multiple doses of 100, 200, and 400 mg twice daily to healthy volunteers. The pharmacokinetics of the active metabolite, cefpodoxime, and tolerance of Cefpodoxime proxetil were determined. Results from the single‐dose study indicate that Cefpodoxime exhibits nonlinear pharmacokinetics over the dose range of 100 to 800 mg. This nonlinearity is primarily due to differences in dose‐normalized AUC and Cmax, urinary recovery, and half‐life between one or more of the higher‐dose treatment groups and the 100‐mg dosing group. After multiple‐dose (twice daily) administration for 15 days, steady state is achieved on the second day of dosing, and there is no drug accumulation. Cefpodoxime pharmacokinetics are linear with dose over the clinically relevant dosing range of 100 to 400 mg. Microbiologic and HPLC plasma assay results are highly correlated, with close agreement between HPLC‐ and microbioiogic‐determined pharmacokinetic parameter estimates. Cefpodoxime proxetil was well tolerated in both studies. The most frequent medical events were related to gastrointestinal problems and consisted of transient loose stools in three subjects in the single‐dose study and antibiotic‐associated diarrhea in one subject in the multiple‐dose study.

Disposition of Cefpodoxime Proxetil in Hemodialysis Patients

The disposition of cefpodoxime after single, oral 200‐mg doses of cefpodoxime proxetil (cefpodoxime equivalents) was investigated in an open‐Jabel study of six patients with end‐stage renal disease currently maintained on hemodialysis. Subjects were randomly assigned to one of two treatment groups, which differed in the sequence of the interdialytic and intradialytic periods. Doses were separated by at least 2 weeks. Blood samples were serially collected for 48 hours after each treatment; if obtainable, urine was also collected over this same period. During the intradialytic period, hemodialysis was scheduled to begin approximately 3 hours after dosing, and dialysate was collected before and until the end of dialysis. Average cefpodoxime elimination half‐life for the interdialytic period was 18.0 ± 6.5 hours; apparent total body clearance was 28.6 ± 13 mL/minute. The half‐life during hemodialysis, 2.66 ± 0.74 hours, was considerably shorter than that after hemodialysis, 19.2 ± 3.5 hours, in the intradialytic period of the study. Hemodialysis clearance of cefpodoxime was 120 ± 31 mL/minute, which was 57.1 ± 13% and 71.7 ± 25% of the hemodialysis clearance for urea nitrogen and creatinine, respectively. The 2.86 ± 0.25 hour hemodialysis session removed 22.4 ± 2.9% of the administered dose, as assessed by cefpodoxime recovery in dialysate. A maximum rebound in cefpodoxime plasma concentration of 0.41 ± 0.33 mcg/mL was observed, at about one‐half hour after the end of hemodialysis. Based on these results, dosage adjustment is not required, but extension of the dosing interval is warranted. The recommended dosing interval for cefpodoxime proxetil in patients with end‐stage renal disease is three times a week, after hemodialysis.

Verapamil‐induced natriuretic and diuretic effects: Dependency on sodium intake

The influence of dietary sodium on the antihypertensive effects of verapamil and on components of sodium, water, and calcium metabolism was studied in nine white patients 50 to 65 years old with normal renin hypertension. Diets consisting of 109 and 259 mEq Na were given for 5 days each before the study drug was given. On days 4 and 9, intravenous verapamil (0.075 mg/kg) and oral verapamil (80 mg) were given, followed by 80 mg at 8‐hour intervals for three doses. On days 1,4, 5, 9, and 10, serum and urine electrolytes, osmolality (urine [Uosm], serum [Sosm], and osmolar clearance [Cosm]), calcium plasma renin activity (PRA), and levels of serum aldosterone, 1,25‐hydroxyvitamin D, serum ionized calcium, parathyroid hormone, atrial natriuretic hormone (atriopeptin), and erythrocyte calcium and electrolytes were measured. On days 5 and 10, serial plasma samples for measurement of verapamil and norverapamil levels were drawn immediately after the last oral dose of verapamil. After verapamil, Uosm and Cosm decreased during both 109 and 259 mEq sodium diets (Uosm, p < 0.025; Cosm, p < 0.01 and p < 0.025, respectively), but free water clearance increased during each diet (p < 0.01). Urine volume and sodium excretion increased with the 259 mEq sodium diet (p < 0.025 and p < 0.01, respectively). There were no significant changes in measured values of components of calcium metabolism with either diet or after verapamil. The pharmacokinetics of verapamil were similar during each diet. Twenty‐four hours after the last oral dose of verapamil, supine mean arterial pressure (MAP) decreased ~5 mm Hg (109 mEq sodium diet; p < 0.025), whereas supine MAP declined ~10 mm Hg compared with baseline values during the 259 mEq sodium diet (p < 0.01). Standing MAP declined by 8 mm Hg with either diet after verapamil (p < 0.025 to p < 0.01). Thus the antihypertensive effects of verapamil are present regardless of sodium intake and are accompanied by natriuresis and diuresis during a high‐sodium diet.

Single Dose Pharmacokinetics of Cefpodoxime Proxetil in Infants and Children

SummaryThe pharmacokinetics of cefpodoxime were evaluated in 30 paediatric patients (12 females and 18 males, 1.0 to 17.2 years of age) with normal renal and hepatic function following a single oral dose (4.5 ± 0.8 mg/kg, range 2.7 to 5.0 mg/kg) of cefpodoxime proxetil. Cefpodoxime was quantitated from repeated blood and urine samples obtained over a 12-hour postdose period by HPLC. Apparent peak plasma cefpodoxime concentrations ranged between 0.8 and 3.4 mg/L (2.2 ± 0.6 mg/L), and were observed between 2 and 4 hours following drug administration. A lag-time (0.46 ± 0.26 hours, range 0 to 1.1 hours) was evident in 27 of 29 subjects. Mean (± SD) values for the absorption rate constant (Ka), absorption half-life (t½Ka), and time for 90% absorption were 0.84 ± 0.44h−1, 0.82h and 3.6 ± 0.6h, respectively. Values for the elimination rate constant (Kel), apparent total plasma clearance (CL/F) and apparent steady-state volume of distribution (Vdss/F) were 0.41 ± 0.06h−1, 0.42 ± 0.15 L/h/kg (range 0.16 to 0.93 L/h/kg) and 1.08 ± 0.49 L/kg (range 0.47 to 2.9 L/kg), respectively. The mean renal clearance (CLR) for cefpodoxime in 18 subjects was 0.11 L/h/kg and represented 26% of the mean CL/F. Inverse linear correlations were found between patient age and both CL/F (r = 0.67, p < 0.001) and Vdss/F (r = 0.55, p < 0.01), thus demonstrating developmental dependence for these 2 parameters. Accordingly, when CL/F, Vdss/F and Ka were compared between patients less than 5 years of age and those aged 5 years or more, significant differences were found (i.e. 0.57 ± 0.16 vs 0.36 ± 0.1 L/h/kg for CL/F, 1.52 ± 0.56 vs 0.89 ± 0.3 L/kg for Vdss/F and 1.12 ± 0.77 vs 0.73 ± 0.18h−1 for Ka); the larger values for each parameter being seen in the youngest age group. These data support a developmental dependence in the disposition of cefpodoxime in paediatric patients following the administration of the prodrug ester, cefpodoxime proxetil.