Jordan L. Cohen

Prevalence and significance of acquired immunodeficiency syndrome-related retinal microvasculopathy.

We performed ophthalmologic examinations on 127 subjects with or at risk for human immunodeficiency virus (HIV) infection over a one-year period to determine the prevalence and significance of retinal cotton-wool spots and hemorrhages (AIDS-related retinal microvasculopathy). Of 26 asymptomatic homosexual men, of whom 13 were HIV seronegative and 13 were HIV seropositive, none manifested this retinopathy. Three of 34 patients (9%) with AIDS-related complex and 29 of 67 patients (43%) with AIDS manifested retinopathy on the initial examination. This difference in the prevalence of retinopathy between groups was statistically significant (P less than .05). Patients with AIDS demonstrated 7.2 times greater odds of manifesting retinopathy than patients with AIDS-related complex (P less than .05). Within the group of patients with AIDS, the T helper (CD4) to suppressor (CD8) cell ratio was significantly associated with retinopathy at the initial ocular examination. The CD4:CD8 ratio of the total group of AIDS and AIDS-related complex patients with retinopathy was significantly lower than that of patients without retinopathy (P less than .05). There was no significant association between retinopathy and any specific past or concurrent opportunistic infection or neoplasm. The presence of retinopathy was not associated with symptoms in any patient. The lesions of AIDS-related retinal microvasculopathy may be an important finding in the evaluation of patients suspected to have HIV-related disease.

Distribution of adriamycin in cancer patients. Tissue uptakes, plasma concentration after IV and hepatic IA administration

Twenty patients with solid tumors received 30 mg/M2 of adriamycin. Various tissue samples were intra‐operatively obtained from 18 patients, about 1.5–5 hours after an intravenous (IV) bolus dose. Normal liver showed the highest levels of adriamycin uptake (2.3–19.8 μg/g); lymph nodes were second; muscle and bone marrow, next; fat and skin had the lowest adriamycin uptake (0.04–0.40 μg/g). Tumor tissue, excluding that with much necrosis and hemorrhaging, had adriamycin concentrations which approximated those of the liver (1.1–9.2 μg/g). Six patients, all with hepatic malignancies, had prolonged plasma concentration studies after IV administration; 5 also had adriamycin administered directly into the hepatic artery catheter. Adriamycin‐plasma‐time courses were similar, whether the drug was administered by bolus directly into the hepatic artery or peripheral vein. The concentration of metabolites after hepatic intraarterial administration was definitely higher than that after IV administration. Patients with hepatic dysfunction had delayed plasma clearance and secondarily elevated levels approximately 160 and 300 minutes after administration.

Pharmacokinetic changes in aging

A multitude of factors influence the prescribing, dosing, and clinical monitoring of long-term drug therapy in elderly patients. These include life-style and environment, possible multiple disease states and concomitant medications, compliance, and continuous changes in physiology, all of which can--with advancing age--gradually alter the pharmacodynamics and pharmacokinetics of drugs. The physiologic changes associated with aging that can affect the absorption, distribution, excretion, and metabolism of drugs are reviewed and related to the clinical use of several drugs that are widely used in elderly patients. Important clinical factors may also magnify or counteract the physiologic changes that occur with respect to altered drug response. Finally, the pharmacokinetic properties of the available oral hypoglycemic agents are described as they relate to selection of an optimal drug in elderly diabetic patients.

Effect of diltiazem on renal clearance and serum concentration of digoxin in patients with cardiac disease

The effect of diltiazem on digoxin serum concentration was evaluated in 9 patients who had been treated chronically for heart disease with digoxin, 0.25 mg/day. The indications for digoxin therapy were arrhythmias in 5 patients and mild heart failure in the other 4. Renal digoxin clearance was also evaluated in 8 of these patients. Serum digoxin concentration was measured at control, 7 +/- 2 days after initiation of 120 mg/day of diltiazem and 11 +/- 5 days after increasing the dose of diltiazem to 240 mg/day. Serum digoxin concentration was 0.9 +/- 0.4 ng/ml at control, 0.8 +/- 0.4 ng/ml with 120 mg/day of diltiazem, and 0.8 +/- 0.3 ng/ml during therapy with 240 mg/day. The differences between these values were not significant. Renal digoxin clearance also did not show a significant change after diltiazem therapy (44 +/- 15 ml/min before diltiazem and 46 +/- 13 ml/min with 240 mg/day of diltiazem). This study shows no effect of diltiazem in doses of 120 to 240 mg/day on serum digoxin concentration or renal digoxin clearance in patients who are treated chronically for heart disease with digoxin. In this dose range, diltiazem has advantages over verapamil, which markedly elevates digoxin levels.

Clinical pharmacokinetics of high-dose metoclopramide in cancer patients receiving cisplatin therapy.

Using a sensitive and specific high-pressure liquid chromatographic (HPLC) assay, we measured serum levels of metoclopramide in 18 cancer patients receiving high-dose intravenous (IV) therapy to prevent cisplatin-induced emesis. Ten patients were treated with one or more courses with metoclopramide alone (1.0 to 3.0 mg/kg) in an open-label study, and eight patients were treated with a fixed 2.0 mg/kg dose of metoclopramide with or without adjunct dexamethasone (20 mg) using a randomized, crossover design. The pharmacokinetics of metoclopramide were determined, and the relationship between serum levels and clinical response was evaluated. The pharmacokinetic parameters of high-dose metoclopramide were found to be similar to those reported for standard promotility doses, and no dose dependency was demonstrated over the range of doses studied. No clear correlation between serum metoclopramide levels and prevention of cisplatin-induced emesis was observed. The addition of dexamethasone resulted in clinical improvement in two of eight patients, but had no effect on serum metoclopramide levels or kinetic parameters. Results in this study population do not show metoclopramide levels to be related to antiemetic effect following IV cisplatin therapy.

High Pressure Liquid Chromatographic Analysis of Metoclopramide in Serum

Metoclopramide has recently been approved at dose levels of 1 to 2 mg/kg for the treatment of nausea and vomiting resulting from cancer chemotherapeutic agents. A rapid, sensitive reverse phase HPLC quantitative procedure for metoclopramide in serum is described. The method involves a single-step extraction of metoclopramide and disopyramide (internal standard) from alkalinized serum into benzene and utilizes a reverse-phase C-8 system with a mobile phase of 11:22:66, methanol: acetonitrile: pH 3.7 acetate buffer, and UV detection at 268 nm. The method is highly reproducible and has a limit of sensitivity of 2.5 ng/ml from a 2.0 ml serum sample. The method has been successfully applied to clinical pharmacokinetic studies involving administration of IV oral metoclopramide to cancer patients receiving highly emetogenic cis-diamminedichloroplatinum.

N‐Acetylprocainamide kinetics and clinical response during repeated dosing

Kinetics of and clinical responses to N‐acetylprocainamide (NAPA) were evaluated in 10 patients with chronic ventricular arrhythmias who had not responded to usual doses of currently available antiarrhythmic drugs. Kinetic data analysis was by measured NAPA concentrations (n = 149) collected during repeated dosing. Response was evaluated with serial 24‐hr ambulatory ECGs. An a priori kinetic model based on earlier studies predicted NAPA concentrations well (r =0.94, SEE = 3.6 mg/l). The capability for defining patient‐specific estimates for drug disposition with six or seven serum concentrations measured at the outset of therapy was subsequently confirmed with larger data sets from the same patients. Mean values for elimination rate (0.082 hr−1 ± 0.017) and volume of distribution (1.25 l/kg ± 0.28) were of the same order as in earlier single‐dose studies. A substantial degree of interpatient and intrapatient variability in the absorption rate for NAPA was observed. NAPA was not found to be clinically effective in any of the 10 patients, although two patients demonstrated a >70% reduction in frequency of premature ventricular contractions. There were adverse effects in all patients, which frequently required dose reduction or cessation of therapy. In this group of patients with resistant arrhythmias, NAPA was no more effective than baseline therapy, and adverse effects often limited complete evaluation. The kinetic analysis demonstrated the feasibility of a strategy for developing patient‐specific kinetic models that may have applications to other antiarrhythmic drugs.

Examination of the correlation of serum metoclopramide levels with antiemetic efficacy in patients receiving cisplatin

SummaryThe existence of a threshold serum metoclopramide level above which total protection from cisplatin-induced vomiting is more likely to occur has been proposed. We monitored serum metoclopramide levels prior to the third metoclopramide dose in the first cisplatin treatment cycle in patients receiving metoclopramide 2 mg/kg×4 as part of a randomized double-blind cross-over study comparing single-agent metoclopramide with combination metoclopramide and dexamethasone. Serum samples from 35 patients (17 receiving single-agent metoclopramide and 18 receiving the combination) were analyzed using reverse-phase high-pressure liquid chromatography (HPLC). A wide variation in metoclopramide levels was observed (range 273–3380 ng/ml). Serum levels obtained from the same patient on multiple treatment cycles were well correlated, and the addition of dexamethasone did not alter serum metoclopramide levels. No threshold level could be identified for the two groups (single-agent or combination antiemetic therapy) considered individually or considered together. However, significantly more vomiting episodes and a lower incidence of total protection were noted in patients with metoclopramide levels above 1469 ng/ml receiving metoclopramide alone. This effect was nullified in the combination antiemetic group. Our data do not support a directly proportional relationship between serum metoclopramide level and antiemetic protection. However, a non-linear relationship with a possible agonist/antagonist effect is suggested.

Comparative radiopharmacokinetics of 18F-5-fluorouracil administered i.v. to rats bearing a mammary tumor

In an attempt to compare the efficacy of various 5-fluorouracil (5-FU) regimens, we studied the kinetics of 18F-labeled and unlabeled 5-FU in rats. 18F-5-FU was synthesized in our laboratory and was administered in tracer doses to Fischer rats bearing either the 13762 or the R3230 mammary adenocarcinoma, and to Sprague-Dawley rats bearing the Walker-256 carcinosarcoma, with or without pre-treatment with a therapeutic dose of unlabeled 5-FU. In addition, the non-radioactive 5-FU was administered to control rats of both strains. All animals were followed for 70 min either by measuring their 18F blood levels continuously using an extracorporeal blood-loop, or by determining their 5-FU blood levels at discrete time intervals. The biphasic kinetic profile was characterized by determining alpha and beta rate constants and their corresponding half-lives. Differences in 18F elimination, as measured by the area under the curve during the elimination phase, were observed between the pre-treated 13762-bearing rats and the untreated group bearing the same tumor, as well as the pre-treated non-tumored controls and both W-256-bearing groups. Such differences could reveal changes in the ability of those rats to metabolize 5-FU, and hence correlate to the level of active metabolite(s) available to their tumor sites.

Gentamicin penetration into diseased appendix tissue

Summary: Gentamicin concentrations in appendix tissue, serum, and peritoneal fluid were obtained in suspected cases of gangrenous or perforated appendicitis. Despite widely ranging gentamicin concentrations, no infectious complications developed. Correlations were made between the pathologic state of the tissue and the tissue gentamicin concentration. Correlations were also made with tissue gentamicin concentrations and the time after the antibiotic dose to the time of sampling.