End Of Drug Infusion Research Articles

Ceftriaxone-bilirubin-albumin interactions in the neonate: An in vivo study

The in vivo bilirubin-albumin binding interaction of ceftriaxone (CRO) was investigated in 14 non-jaundiced newborns, aged 33-42 weeks of gestation, during the first few days of life after they had reached stable clinical condition. CRO (50 mg/kg) was infused intravenously over 30 min. The competitive binding effect of CRO on the bilirubin-albumin complex was estimated by determining the reserve albumin concentration (RAC) at baseline, at the end of CRO infusion, and at 15 and 60 min thereafter. Immediately after the end of drug administration, RAC decreased from 91.9 (+/- 25.1) mumol/l to 38.6 (+/- 10.1) mumol/l (P = 0.0001). At the same time the plasma bilirubin toxicity index (PBTI) increased from 0.64 (+/- 0.40) before drug infusion to 0.96 (+/- 0.44) thereafter (P = 0.0001). The highest displacement factor (DF) was calculated to be 2.8 (+/- 0.6) at the end of drug infusion. Average total serum bilirubin concentrations decreased from a baseline value of 59.6 (+/- 27.0) mumol/l to 55.2 (+/- 27.1) mumol/l (P = 0.026). Sixty minutes after the end of CRO infusion, RAC was 58.3 (+/- 21.7) mumol/l, PBTI regained baseline, but DF was still 1.9 (+/- 0.2). No adverse events were recorded. Our results demonstrate significant competitive interaction of CRO with bilirubin-albumin binding in vivo. Thus, ceftriaxone should not be given to the neonate at risk of developing bilirubin encephalopathy.

Effects of isradipine on plasma renin activity in sodium-loaded and -depleted conscious rabbits.

The antihypertensive effect of calcium antagonists is altered little by high salt intake or concomitant diuretic treatment. We therefore investigated whether modest changes in the salt balance might alter the acute response of the renin-angiotensin system to the calcium antagonist isradipine in conscious rabbits. Mongrel rabbits with indwelling arterial and venous catheters were pretreated with either a single subcutaneous injection of 20 mg/kg furosemide 24 h before the experiment [sodium depletion (SD)] or the addition of 0.45% NaCl to the drinking water, which was available ad libitum for 24 h [sodium loading (SL)]. Compared with SL, SD pretreatment modestly increased plasma renin activity and lowered body weight; mean arterial pressure and heart rate were unchanged. Isradipine (10, 30, and 100 micrograms/kg) infused into the femoral vein catheter decreased blood pressure and increased heart rate similarly in both groups. Increases in plasma renin activity plotted as a function of the decreases in blood pressure showed a significantly steeper slope in SD than in SL animals. When blood pressure started to recover 15 min after the end of drug infusion, plasma renin activity decreased in SL animals only. Therefore, SL or SD strongly influences the responsiveness of the renin-angiotensin system to calcium antagonists, and this may be one reason why high salt intake does not diminish the antihypertensive effect of calcium antagonists and a calcium antagonist/diuretic combination may not yield optimal therapeutic results.

Deliberate Hypotension With Nicardipine or Nitroprusside During Total Hip Arthroplasty

To induce deliberate hypotension during anesthesia, nicardipine was administered to patients undergoing total hip arthroplasty and was randomly compared with nitroprusside. Hemodynamic measurements were performed before and 10, 20, 30, and 60 min after starting to administer either nicardipine (n = 12) or nitroprusside (n = 12) (B, T1, T2, T3, and T4, respectively); at the end of drug infusion (T5); and 10, 20, and 60 min later (T6, T7, and T8, respectively). Plasma renin activity and catecholamine levels were measured at B, T1, T5, T6, and T7. In addition, plasma nicardipine concentration was measured in five patients at T1, T2, T5, T7, and T8. As with nitroprusside, nicardipine administration (1-3 micrograms.kg-1.min-1, after a titration dose of 4.7 +/- 1.5 mg) resulted in hypotension (up to -34% +/- 3%), a decrease in systemic vascular resistances (up to -49% +/- 4%), and increases in heart rate (up to +17% +/- 6%), cardiac index (up to +37% +/- 8%), plasma norepinephrine (up to +63% +/- 17%) and epinephrine (up to +232% +/- 68%) levels, and plasma renin activity (up to +336% +/- 207%). Ten and 20 minutes after discontinuation of the hypotensive drug, nicardipine led to persistent vasodilation and hypotension, which differed significantly from the hypertensive rebound observed after nitroprusside discontinuation, despite a similar increase in plasma renin activity and catecholamine levels. Our results indicate that after the infusion was terminated, the nicardipine-induced vasodilation was opposed to the vasoconstrictive effects of angiotensin II and catecholamines, thus avoiding hypertensive rebound.(ABSTRACT TRUNCATED AT 250 WORDS)

Extent of baroreceptor resetting in response to sodium nitroprusside and verapamil.

We investigated the effect of sodium nitroprusside, verapamil, and hemorrhage on the resetting of the aortic baroreceptors of normotensive control rats to hypotension, and the reversal of resetting of baroreceptors of one-kidney, one clip hypertensive rats to normotension. Using whole-nerve recording, the extent (%) of resetting (or reversal of resetting) observed 15 minutes after a maintained fall in mean arterial pressure (MAP) was evaluated by the ratio between changes of systolic threshold pressure for baroreceptor activation and changes of control diastolic pressure exhibited by the rats, multiplied by 100. Three groups of normotensive control rats showed a MAP decrease to hypotensive levels of 33%, 39%, and 41%, respectively, with sodium nitroprusside, verapamil, and hemorrhage. The corresponding extent of resetting was 96 +/- 3%, 39 +/- 2%, and 46 +/- 4%, respectively. Only in the group treated with verapamil did MAP and systolic threshold pressure not revert completely to normotensive levels 15 minutes after the end of drug infusion. Three groups of one-kidney, one clip hypertensive rats showed MAP normalization of 30%, 37%, and 31%, respectively, with sodium nitroprusside, verapamil, and hemorrhage. The corresponding extent of reversal of resetting to normotension was 107 +/- 3%, 40 +/- 2%, and 60 +/- 9%, respectively. Again, only in the group treated with verapamil did MAP and systolic threshold pressure not revert to hypertensive levels 15 minutes after infusion. Besides indicating that different vasodilators can differently modulate the rapid (15-minute) resetting (or reversal of the resetting) due to similarly maintained fall in MAP, these data suggest that verapamil has a nonspecific effect on the baroreceptors, whereas sodium nitroprusside appears to affect baroreceptor transduction.

Clearance calculations in hemodialysis: application to blood, plasma, and dialysate measurements for ethambutol.

With the increasing use of artificial kidneys, numerous reports have appeared describing the pharmacokinetics of administered drugs in dialysis patients. Unfortunately, different investigators use different measures of dialysis clearance in reporting their results. Few studies have appeared in which actual measurements have been made in blood and dialysate as well as in plasma to experimentally show the variability of individual measurements and to demonstrate the inaccuracy of certain clearance measurements. We do so here, using the drug ethambutol. The effect of the artificial kidney on the removal of ethambutol was investigated in four uremic patients undergoing chronic hemadialysis. Ethambutol was administered by i.v. infusion over 30 min. Hemodialysis started at the end of drug infusion. Blood, plasma, and dialysate samples were collected periodically over 3 hr and analyzed for ethambutol content. Dialysis clearance was calculated by arterial-venous difference and by simultaneous dialysate measurement. The extraction efficiency of the hollow fiber dialyzers ranged from 36.2% to 43.8% in terms of blood and from 38.0% to 45.4% in terms of plasma. The mean clearance values due to dialysis were 108.08 and 88.1 ml/min measured with plasma and blood as body fluids of reference, respectively. Dialysis clearance calculated by dialysate measurement had a mean of 85.9 ml/min expressed as plasma and 74.7 ml/min expressed as blood. This study demonstrates that dialysis clearance when calculated using A-V difference and plasma flow is generally underestimated, particularly for a drug which extensively partitions into red blood cells. Ethambutol had a partition coefficient (blood/plasma) of greater than 1 in all four patients. The beta phase exhibited a mean half-life of approximately 2 hr on dialysis in comparison to off dialysis half-lives of 7 hr or longer in renal failure. Although ethambutol exhibits a markedly reduced half-life of the drug during hemodialysis, its recovery in the dialysis fluid during a 3-hr dialysis period constitutes only a small fraction of the dose administered.

Intravenous administration of diazepam in patients with chronic liver disease.

The EEG response and drug kinetics after intravenous infusion of diazepam at 1-0 mg/min until nystagmus, dysarthria, and moderate sedation developed, has been investigated in five normal subjects and 17 patients with chronic liver disease. Diazepam induced adequate premedication with a similar clinical response in all subjects with no adverse reactions. Maximal response was during or within five minutes of infusion. The dose of diazepam required in liver chronic disease was 17-9 +/- 1-4 mg (M +/- SEM) compared with 27 +/- 5-4 mg in controls (p less than 0-01). Dose correlated significantly with serum albumin (p less than 0-05). Baseline mean dominant frequency (MDF) and slow wave index (SWI) significantly correlated with albumin (p less than 0-01). After diazepam, the MDF decreased and SWI increased. The change was greatest at the time of maximal clinical response. It was greater in liverdisease and was greatest in patients with previous hepaticencephalopathy. In spite of reduced dose requirements in liver disease, there was no significant difference in plasma concentration at the end of drug infusion...