Ronald S. Shapiro

Unidirectional absorption of gentamicin from the peritoneum during continuous ambulatory peritoneal dialysis

Gentamicin kinetics were determined after intravenous or intraperitoneal injection in five patients undergoing continuous ambulatory peritoneal dialysis (CAPD). Our objective was to determine rate of absorption of gentamicin from the peritoneum into the systemic circulation and vice versa. After intraperitoneal instillation of 1 mg/kg in the CAPD fluid during a 6‐hr dwell time, the antibiotic appeared in the serum within 15 min in four of five patients. Peak serum concentrations ranged between 1.6 and 7.2 mg/l (x̄ ± SD = 3.52 ± 2.22) in all five patients and the time to reach peak concentration was 3.8 ± 1.5 hr. Peritoneal gentamicin clearance was 13 ml/min. Percent extraction of gentamicin from the PD fluid within the 6 hr of intraperitoneal exposure ranged from 65% to 100% (x̄ ± SD = 86.8 ± 13.2). The fraction of the intraperitoneal dose absorbed into systemic circulation was found to be 0.84 independently by calculating the ratio of AUCip and AUCiu. When the same dose of gentamicin was injected intravenously (1 mg/kg), no gentamicin could be detected in the peritoneal fluid in three of five patients and only a very small amount of the drug was present for a brief period of time in the remaining two. The kinetic parameters of intravenous gentamicin were: volume of distribution, 0.3 l/kg; elimination rate constant, 0.028 hr−1; plasma clearance 0.009 l/kg · min−1; and half‐life 27.4 hr. In two patients with acute peritonitis treated with intraperitoneal gentamicin, peak serum concentrations were found to range between 3.5 and 4.5 mg/l. These data suggest that gentamicin is rapidly absorbed from the peritoneal fluid into the blood compartment, but that occurrence of the reverse exchange is negligible. Thus, CAPD would not be expected to alter the elimination characteristics of intravenous gentamicin. Instillation of gentamicin in CAPD fluid may allow rapid absorption to reach therapeutic serum concentrations.

Smoking and warfarin disposition.

Nine cigarette smokers ingested an average daily 0.032 mglkg dose of sodium warfarin for 2 wk while continuing to smoke and for an additional 2 wk after having abstained from cigarette smoking for a month washout phase. Steady‐state plasma levels of warfarin, clearances, t½, apparent volumes of distribution, steady‐state prothrombin times, and plasma thiocyanate levels were measured during both the smoking and nonsmoking phases. During the nonsmoking phase there was a 13% increase in average steady‐state warfarin level and a 13% decrease in warfarin clearance rate. There also was a 23% increase in warfarin t½ and an 11% increase in the apparent volume of distribution. Prothrombin time did not change. Thiocyanate levels were 3 to 4 times as high during the smoking than the nonsmoking phase. It appears that cigarette smoking does affect warfarin clearance, t½, and apparent volume of distribution, though the net effect on warfarins pharmacodynamic activity is negligible, at least at doses which are ineffective therapeutically.

Warfarin Elimination and Responsiveness in Patients with Renal Dysfunction

Plasma warfarin half-life was estimated in four patients with renal dysfunction and five normal control subjects. Hypoprothrombinemic responsiveness to a single oral dose of warfarin (0.75 mg/kg) was also evaluated for both groups. The mean warfarin half-life of 29.9+/-5.0 (S.E.M.) hours for renal patients was significantly shorter than the 44.8+/-6.0 hours half-life for normal controls (P less than 0.05). Additionally, a positive correlation was found between warfarin half-life and creatinine clearance. Pharmacologic responsiveness to warfarin was comparable for both groups. It therefore appears that patients with renal dysfunction do not possess an increased susceptibility, either pharmacokinetic or pharmacologic, to the hypoprothrombinemic effect of warfarin.

Protein Binding of Coumarin Anticoagulants in Disease States

Excessive hypoprothrombinaemia accompanying the use of coumarin oral anticoagulants may be associated with changes in coumarin disposition which, in turn, can arise from changes in coumarin plasma protein binding. Coumarins bind extensively to human serum albumin with primary binding affinity constants of approximately 105 L/mole. The nature of coumarin-albumin binding is chiefly hydrophobic although hydrogen bonding and electrostatic interactions are also involved. Differences in analytical techniques and conditions have given rise to varied values for numbers of binding sites, binding affinity constants, and extent of albumin, serum, or plasma binding. However, the extent of coumarin binding appears to hold relatively constant over expected therapeutic concentration ranges. The plasma binding of warfarin is characterised by marked interindividual differences.Apparent volumes of distribution of coumarins approximate the size of the albumin space and are apparently dose independent with the exception perhaps of dicoumarol (bishydroxycoumarin) which has been reported to exhibit a decreasing apparent volume of distribution with increasing dose. Volumes of distribution increase as the free coumarin fraction increases. Plasma albumin serves as a storage depot for coumarins, and their hepatic elimination is restrictive; that is, limited to the free fraction perfusing the liver. Increases in the free fraction of coumarins will be accompanied by increased clearance rates, and changes in hepatic blood flow rates will have negligible effects on coumarin half lives.Conditions which may be associated with diminished coumarin binding to albumin and enhanced elimination include: thyrotoxicosis, hyperbilirubinaemia, fasting, stress, diabetes mellitus, acute myocardial infarction, cirrhosis, hepatic tumours, and renal dysfunction. However, the only pathological condition in man which is clearly accompanied by decreases in coumarin plasma binding, is renal dysfunction. The cause of diminished warfarin binding in patients with renal dysfunction has not been elucidated, although the presence of an endogenous warfarin-binding inhibitor seems likely.It is not clear whether conditions leading to increases in coumarin free fractions require adjustments in coumarin dosage schedules. Theoretical considerations suggest that neither increased disbribution volumes nor clearance rates associated with increasing the free coumarin fraction will lead to changes in the average steady slate plasma levels of free drug. A preliminary study in patients with renal dysfunction suggests that warfarin dosage regimens do not require adjustment in such patients. However, increases in the coumarin free fraction, apparent volume of distribution, and clearance rate may be attended by increases in peak unbound coumarin levels and decreased trough levels of unbound coumarin thereby making anticoagulant control more difficult. Ultimately, these possibilities must be confirmed or rejected on the basis of additional clinical investigations.

Contribution of cyanate to the albumin binding defect of uremia

Abstract The binding of [ 14 C]warfarin to normal human serum albumin (HSA), carbamoylated albumin, and plasma of patients with renal failure was investigated. Warfarin binding to extensively carbamoylated albumin (exhibiting a molar ratio of homocitrulline: albumin of ca . 7) was markedly diminished. The decrease in binding was apparently due to a decrease in the primary binding affinity constant. The K a for warfarin binding to HSA was 1.6 × 10 5 M −1 compared to 0.88 × 10 5 M −1 for carbamoylated HSA. Binding to normal plasma was significantly greater than to plasma from uremic patients. Mean fractions bound (±S.E.M.) were 98.0 ± 0.2 and 94.1 ± 1.6 respectively (P 14 C]warfarin to carbamoylated albumin with a homocitrulline: albumin molar ratio of 0.5 was marginally diminished, suggesting that the carbamoylation of albumin that occurs during renal failure contributes only slightly to the defective plasma binding of warfarin in uremia.

Massive post-transplant proteinuria with minimal histological changes.

Three patients developed massive proteinuria, hypoalbuminemia, and edema after transplantation. These findings occurred in the immediate post-transplant period in two patients, and renal failure developed. The third patient developed proteinuria 4 months post-transplantation. There was complete remission of proteinuria in two patients and recovery of renal function in one. Renal histology was similar in all. Light microscopy demonstrated that the glomeruli contained a mild increase in mesangial matrix, but were otherwise normal. No significant interstitial cellular infiltration or fibrosis was present. Immunofluorescence microscopy revealed no staining for immunoglobulins or complement. Electron microscopy demonstrated fusion of foot processes, but the glomerular basement membrane was normal. No electron-dense deposits were found. The usual causes of post-transplant nephrotic syndrome were ruled out. We believe these three patients represent a unique disorder of the transplanted kidney.

Massive Post-transplant Proteinuria

A case of massive proteinuria following an A-match living donor transplantation is described. All attempts to define the cause of the proteinuria failed. The proteinuria resolved while the patient was on triple-drug therapy. Presently, the patient remains well with minimal proteinuria and excellent renal function.

The Influence of Dirithromycin on the Pharmacokinetics of Cyclosporine in Healthy Subjects and in Renal Transplant Patients.

The effect of a standard regimen of the investigational macrolide antibiotic, dirithromycin, on the single-dose kinetics of orally administered cyclosporine (CSA) was investigated in healthy young males and on the steady-state disposition kinetics of cyclosporine in a panel of renal transplant patients. Eight male volunteers participated after giving informed consent. CSA was administered in three single doses (15 mg kg(minus sign1) p.o. each) in each of three phases: (1) prior to a 14-day regimen of dirithromycin; (2) at the end of a 14-day regimen of dirithromycin (500 mg p.o. qAM); and (3) 2 weeks after the last dose of a 14-day regimen of dirithromycin. Pharmacokinetic parameters of CSA were estimated, and the differences among treatments were assessed by analysis of variation. No significant differences among treatment (phase) means were detected (p < 0.05). We conclude that a typical 14-day regimen of dirithromycin failed to alter the disposition kinetics of CSA when taken orally healthy young adult males. The effect of a standard regimen of dirithromycin on the steady-state disposition kinetics of orally administered CSA was investigated in a panel of 15 stable renal transplant patients. Pharmacokinetic parameters for CSA were evaluated prior to, during, and 2 weeks after discontinuing a 14-day (500 mg day(minus sign1)) oral regimen of dirithromycin. Dirithromycin elicited small but significant changes in the following parameters: C(av) was increased by 16% during dirithromycin treatment, and the changes in normalized C(av) were comparable. Likewise, C(SS,min) and normalized C(SS,min) were increased by 19% and 20%, respectively, during dirithromycin treatment. CSA oral clearance, CL/F(SS), decreased by 17% during dirithromycin treatment. C(SS,max) and normalized C(SS,max) were increased by 13% and 17%, respectively, during dirithromycin treatment but were not significantly different from those either before or after dirithromycin. The magnitude of the pharmacokinetic changes for CSA during dirithromycin treatment (<15% in normal subjects and 15--20% in renal transplant patients) when considered in the context of the therapeutic range of cyclosporine concentrations was relatively small, and not likely to warrant special attention to the dosing of CSA in such patients beyond routine whole-blood CSA and serum creatinine monitoring.

Clinical evaluation of a noninvasive technology for the treatment of chronic joint symptoms

A device that emits thermal kinetic energy and photonic energy has been developed for the treatment of chronic knee pain. We conducted a clinical trial pilot study in which 69 patients with chronic knee pain were randomly allocated to one of four treatment groups with approximately 17 patients per group. One group was treated with the operational device; a second group was treated with the device emitting only thermal kinetic energy; a third group was treated with the device config ured to emit only photonic energy; and the fourth group was treated with a complete sham device. Several parameters, eg, number of steps climbed, knee circumferences, pain rank during flexion, and flexion angle achieved prior to pain perception, were assessed immediately prior to treatment and immediately after the application of a 25-minute treatment under fully blinded conditions. Analysis of variance with the Tukey multiple compari- sons procedure was used for comparing treatment results. The fully or partially activated device was superior to the sham device in patients with chronic knee pain. The results suggest that this device may have benefit for patients with chronic knee pain, and that larger, more robust studies of the device are warranted.

Diminution of Electroencephalographic Muscle Tremor Artifact

While caring for a patient in an intensive care unit, we were able to help clear muscle tremor artifact from the electroencephalographic (EEG) recording. A 62-year-old woman had been admitted 14 days previously with profound dehydration and renal failure subsequent to a viral syndrome. She had been unattended at home and had deteriorated. Intravenous fluids with central pressure monitoring, parenteral nutritional supplementation, and hemodialysis treatments were administered. An EEG was