Richard L. Yost

Disposition of cefotaxime and its desacetyl metabolite in morbidly obese male and female subjects

Cefotaxime sodium (1 g) was injected intravenously in 12 normal (90-110% ideal body weight) and 11 obese (190-210% ideal body weight) male and female subjects. Plasma and urine levels were measured for cefotaxime and its active metabolite desacetylcefotaxime. Kinetic parameters were calculated. Results indicate that a dose adjustment for body weight in obese subjects is not needed, whereas a dose adjustment on the basis of body surface area is reasonable. Metabolite plasma levels in female subjects were significantly higher than in male subjects in both the normal and the obese populations.

Rapid chromatographic determination of cefotaxime and its metabolite in biological fluids

A reversed-phase high-performance liquid chromatographic assay for the simultaneous determination of cefotaxime and its metabolite desacetylcefotaxime in plasma and urine was developed. Plasma was deproteinized with small amounts of acetonitrile. After separation of the proteins the supernatant was extracted with a mixture of chloroform and 1-butanol. A phase separation was obtained leaving the cephalosporin and its metabolite in the aqueous part and extracting most of the interfering endogenous material. The aqueous phase was injected directly into the chromatograph. As part of the plasma water was dissolved in the acetonitrile--1-butanol--chloroform layer, the concentration of the cephalosporin in the aqueous phase was significantly higher than in the original plasma sample. Therefore, the usual diluting effect of the deproteinization could be avoided. In a similar way the assay was applicable to measure cefotaxime and its metabolite in urine. Calibration curves were set up and were linear up to 25 micrograms/ml for desacetylcefotaxime and 250 micrograms/ml for cefotaxime. The assay was applied to study the pharmacokinetics of cefotaxime and its metabolite in a healthy volunteer. In a similar way this deproteinization and extraction method was also applied to assay for ceftazidime, cephalexin, cephazolin and cefoxitin.

Obesity and post-operative pain

Patients underwent elective abdominal surgery for morbid obesity (mean = 154 kgs, n = 55) or cholecystectomy (mean = 71 kgs, n = 54). Post-operative narcotics were transformed into morphine equivalent units (ME). Morbidly obese patients received significantly fewer total doses than cholecystectomy patients and less total mg ME/kg over a five-day period. Sedative use for both groups was comparable. In the morbidly obese patients, preoperative psychiatric and drug usage data predicted 67% of the variance in number of doses and 69% of the variance in total mg ME/kg.

Epidemiology of Hyperuricemia in an Ambulatory Elderly Population

The relationship of serum uric acid concentration to age and sex was assessed in 1,701 participants in a geriatric multiphasic screening clinic. Included were 1,067 women and 634 men. The mean uric acid level for men was 6.35 mg/100 ml compared to 5.44 mg/100 ml for women. No statistically significant increases in serum uric acid between age groups were apparent, except for women over 84 years of age. The mean serum urate concentrations found in this geriatric study are higher than those reported for other population groups, suggesting a higher normal value for the elderly.

Effect of Dose and Ointment Application Technique on Nitroglycerin Plasma Concentrations

Each of ten non‐smoking, healthy male volunteers between the ages of 20 and 30 and within 10% of their ideal body weight received four nitroglycerin ointment (NTG‐O) treatments: ½″ NTG‐O over 3.94 in2 and 7.88 in2, and 1″ NTG‐0 over 3.94 in2 and 7.88 in2 in a randomized order. Eleven blood samples and 22 determinations of heart rate and blood pressure were obtained over each 6‐hour study period. Nitroglycerin plasma concentrations were determined by gas‐liquid chromatography with electron capture detection. Area under the nitroglycerin plasma concentration‐time curve (AUC), peak plasma concentration (Cmax), and time to peak concentration (Tmax) were determined for each study. Cmax and AUC values were corrected for the actual dose applied. Differences between AUC, Cmax and Tmax were tested using repeated measures analysis of variance. Change in surface area had no statistically significant effect on AUC, Cmax and Tmax. Mean AUC for the ½″ and 1″ doses differed (648 vs 2003 ng.ml−1 min, p = 0.016), as did Cmax (4.6 vs 12.4 ng.ml−1, p = 0.022); however, there was no correlation between individual doses and AUCs. Generally, NTG plasma concentrations within the proposed therapeutic range of 1.2–11.1 ng.ml−1 were detectable throughout each study interval. These data suggest that continuous absorption occurred throughout the 6‐hour dosing interval, that a trend toward increased AUC and Cmax occurred with the larger surface area, and that, in general, doubling the dose of NTG‐O doubles the AUC.

Investigation of the Crystallization of Phenytoin in Normal Saline

A study was designed to determine if the admixture of phenytoin in normal saline would remain physically stable for a suitable period of time to allow for intravenous infusion. Five phenytoin concentrations (1.0 mg/ml, 2.5 mg/ml, 5.0 mg/ml, 7.5 mg/ml, and 10.0 mg/ml) were prepared in triplicate by adding a sufficient volume of normal saline to the appropriate volume of phenytoin sodium injection to produce a total volume of 100 ml. Aliquots of all solutions were withdrawn at zero, 1, 8, 16, and 24 hours. Solutions were filtered through a 0.22 micron millipore filter and the concentration of phenytoin and pH of each solution was determined. A significant concentration difference was not seen between zero time and 24 hours. The pH of the samples ranged from 9.75 to 11.00. While phenytoin sodium appears to be stable in the concentrations tested when sodium chloride 0.9% is the vehicle, several important factors must be considered and caution must be used if the admixture is administered intravenously.

Evaluation of Hypertensive Therapy in a Skilled Nursing Facility

Treatment of hypertension in the elderly has recently received increased attention. Both systolic and systolic plus diastolic hypertension are risk factors for cardiovascular and cerebrovascular diseases in patients older than age 65, but the value of antihypertensive therapy in reducing morbidity and mortality has not been adequately studied. The authors evaluated the appropriateness of antihypertensive therapy prescribed for elderly patients in a skilled nursing home and determined the effect reductions in antihypertensive therapy had upon the function and mental status of these patients. Of the 120 patients surveyed, 26.7 percent were found to have a diagnosis of hypertension, and 1/3 of these patients were not receiving any medications at the time of the study. Assessment of the remaining treated patients resulted in a recommendation to alter therapy in 43 percent of the cases. Results from this study suggest that periodic assessment of antihypertensive therapy in long-term care facilities should be considered.

Effect of Antacid on Bioavailability of a Sustained-Release Theophylline Preparation

The effect of coadministration of an antacid on bioavailability of a sustained-release theophylline tablet preparation (Theo-Dur) was studied by crossover comparison in five young, healthy, nonsmoking volunteers. Water 90 ml, or “high potency” aluminum-magnesium hydroxide antacid (Mylanta II) 10 ml and water 80 ml were administered concurrently with sustained-release theophylline 600 mg. Eleven blood samples were collected over the next 24 hours. Serum was analyzed with high pressure liquid chromatography technique to determine theophylline concentration. Peak serum concentration (Cmax) and time to peak concentration (tmax) were determined, and area under the 24-hour serum concentration-time curve (AUC) was calculated by the trapezoidal rule for each subject at each study interval. The Students paired t-test was used to compare Cmax, tmax, and AUC for both treatments. A uniform difference was found between groups in Cmax. Cmax was higher in subjects when treated with the antacid (10.45 ± 3.03 vs. 8.30 ± 2.90 μg/ml, p < 0.05) than when given theophylline alone. The mean tmax for the two treatments did not differ (10.4 ± 1.67 h—combination vs. 10.8 ± 1.1 h—theophylline, p > 0.05). Likewise, mean AUC was unchanged by the coadministration of antacid (140.65 ± 41.6 μg/ml·h—combination vs. 155.13 ± 46.6 μg/ml·h—theophylline, p > 0.05). The use of a high-potency antacid product did not decrease the extent of theophylline absorption from this sustained-release product, but did increase Cmax and, presumably, rate of absorption. High-potency aluminum-magnesium antacids can probably be used in combination with this sustained-release theophylline tablet without detriment to therapy.

Investigation of a Dosage Regimen for Intravenous Theophylline

A study was designed to evaluate the validity of the dosage guidelines for theophylline recommended by Hendeles and Weinberger. A total of seven asthmatic smokers and non-smokers were entered and studied. Theophylline serum concentrations were determined prior to the start of therapy and at intervals following initiation of an infusion. The mean theophylline concentration attained for all subjects was 10 μg/ml, however, five of the six patients completing the study did not achieve the predicted serum theophylline concentration. Further study of higher dosage designed to achieve a concentration of 12 μg/ml is suggested.

Interaction of Chloral Hydrate and Furosemide A Controlled Retrospective Study

Untoward reactions were recently reported in six patients following the concomitant administration of chloral hydrate orally and furosemide intravenously. A retrospective epidemiologic study was initiated to evaluate this report. Medication records of adult medical and pediatric patients who received care at Shands Teaching Hospital from July, 1969 to May, 1975 were scanned by computer to identify patients exposed to either chloral hydrate or flurazepam and furosemide. Five thousand two hundred and sixty-two patients were found to have received furosemide alone or in combination with either chloral hydrate or flurazepam. Computer records of these patients were reviewed to identify patients who received either chloral hydrate or flurazepam and then, in the twenty-four hours following the administration of the sedative-hypnotic, received furosemide. This procedure resulted in a final study population consisting of 43 patients who received both chloral hydrate and furosemide. Medical records of the study group and three control groups were then reviewed to determine if untoward symptoms similar to those reported previously were evident. One patient in the study group exhibited symptoms of the reaction and two patients were identified as having possible reactions. No patient in any of the control groups exhibited manifestations of the reaction.