Serum aminoglycoside clearance is predicted as poorly by renal aminoglycoside clearance as by creatinine clearance in critically ill patients.

OBJECTIVE: To determine the relationships among serum aminoglycoside clearance, renal aminoglycoside clearance, measured creatinine clearance, and estimated creatinine clearance derived from a standard formula in critically ill patients. SETTING: A ten-bed general ICU in a university hospital. PATIENTS: Eighteen critically ill patients who were being treated with gentamicin or tobramycin for severe infections, and were hemodynamically stable. INTERVENTIONS: The various clearances were measured simultaneously after the administration of a dose of aminoglycoside by assaying serial blood samples for aminoglycoside and creatinine concentration, and by measuring the content of these substances in urine collected over the same time period. OUTCOME MEASURES: The slopes, intercepts and coefficients of determination (r2) of the various regressions were determined, along with the 95% confidence intervals for the prediction of serum aminoglycoside clearance from each other variable. RESULTS: Renal aminoglycoside clearance, creatinine clearance, and estimated creatinine clearance accounted for only 58%, 59%, and 62%, respectively, of the variance in serum aminoglycoside clearance. Only 64% of the variance in renal aminoglycoside clearance was explained by creatinine clearance. Substantial and variable nonrenal aminoglycoside clearance was evident. CONCLUSIONS: The 95% confidence intervals for the prediction of serum aminoglycoside clearance from each index of renal function indicated that none of these indices provided acceptable accuracy for the prediction of serum aminoglycoside clearance and dosage requirements in critically ill patients. Renal aminoglycoside clearance was not better than creatinine clearance in this respect, and thus no other index of renal function is likely to be more accurate. This finding implies that the only accurate method of determining the dose requirements to achieve target serum concentrations in such patients will be individualized pharmacokinetic dosing.

Variability in the elimination of mianserin in elderly patients.

1. Two studies of the elimination of mianserin are reported. 2. In the first study, the oral clearance of mianserin was measured in 15 elderly patients at steady state. In a sub-group of eight patients who completed studies at two different doses there was evidence of enhanced oral clearance at the higher dose. 3. In the second study, the elimination half-life was estimated in 12 patients who were observed to have disproportionately high mianserin concentrations with respect to dose. All had half-lives greater than or equal to 2.5 days with a mean of 6 +/- 2.8 (s.d.) days. In six of the patients the profile of elimination was suggestive of saturable elimination. 4. The sparteine oxidation status was measured in seven of the patients showing slow mianserin elimination. Only one was a 'poor oxidiser' of sparteine, suggesting no concordance with this phenotype. 5. It is concluded that there is marked variability in the elimination of mianserin in elderly patients.

Circadian pharmacokinetics of methotrexate.

Six patients with intermediate- and high-grade non-Hodgkin's lymphoma were treated with 400 mg/m2 i.v. methotrexate (MTX) at 0600 and 1800 hours. Despite evidence of circadian rhythms in renal function, the pharmacokinetics of total and free serum MTX showed no significant difference between these two times. The marked two-fold circadian variation in MTX pharmacokinetics previously reported in rats was not observed in these patients.

Co-administered oral metoclopramide does not enhance the rate of absorption of oral diazepam.

Intravenous metoclopramide is known to increase the rate of absorption of oral diazepam if administered at the same time. It has been suggested that oral metoclopramide has the same effect. In this study, six healthy volunteers received oral diazepam (0.2 mg/kg) on two separate occasions, either alone or with oral metoclopramide (10 mg), given simultaneously. In contrast to the effects of intravenous metoclopramide, oral metoclopramide did not increase the rate of absorption of oral diazepam.

Pharmacokinetics and effect on blood pressure of doxazosin in normal subjects and patients with renal failure.

The antihypertensive efficacy and pharmacokinetics of a single 1 mg oral dose of doxazosin were investigated in five healthy male volunteers, six patients with renal failure not on hemodialysis, and four patients with end-stage renal failure studied between two hemodialyses. The dialyzability of doxazosin was studied in five patients. The maximum fall in blood pressure of both volunteers and patients occurred between 4 and 8 hours. In four of five volunteers the blood pressure had returned to baseline within 10 to 12 hours, whereas in the patients with renal failure it took as long as 72 hours. Maximum plasma concentrations were reached in 2.6 to 3.6 hours. The mean AUC did not differ significantly between the groups. The mean (SE) elimination t1/2 was 12.6 hours (3.3) in the volunteers and 13.3 hours (1.8) in the patients with renal insufficiency (not significant). Doxazosin was not appreciably dialyzable.

Possible mechanism for mianserin induced neutropenia associated with saturable elimination kinetics.

Two cases of mianserin induced neutropenia associated with prolonged elimination of the drug were studied. In each case the pharmacokinetic profile suggested saturable elimination kinetics, and the temporal relation of mianserin concentrations and the neutrophil count suggested a direct toxic effect of mianserin on the bone marrow. Until further studies are carried out the plasma mianserin concentration and neutrophil count should be measured in any patient who develops an infection while taking this drug.

Doxepin plasma concentrations in clinical practice. Could there be a pharmacokinetic explanation for low concentrations?

During therapeutic use of doxepin, we have often observed unexpectedly low doxepin plasma concentrations in patients on moderate dosages, e.g. 100 to 200mg daily. While non-compliance seemed the most likely explanation, we present the data for 6 patients in whom we considered non-compliance unlikely. The data can be explained by hypothesizing that in some patients, there is not a linear dosage-plasma concentration relationship and that on a steady dosage, plasma concentrations are not always maintained. If these phenomena can be more carefully documented they may assume clinical importance; indeed for 2 of the patients studied the falling plasma concentrations on a steady dosage were associated with a recurrence of depression.

Tinidazole pharmacokinetics in severe renal failure.

The single-dose pharmacokinetics of intravenously and orally administered tinidazole were studied in normal subjects and patients with severe chronic renal failure. The clearance of tinidazole was also measured in patients on regular haemodialysis. After intravenous administration the mean elimination half-life of tinidazole was 17.1 +/- 2.3 (SD) hours in the normal subjects and 16.9 +/- 4.9 hours in patients with renal failure; the mean apparent volumes of distribution were 0.80 +/- 0.09 L/kg and 0.69 +/- 0.09 L/kg, respectively. Following oral administration the mean elimination half-life was 15.6 +/- 1.6 hours in the normal subjects and 18.4 +/- 3.5 hours in patients with renal failure; there were no statistically significant differences in these pharmacokinetic parameters. There was no accumulation of the major metabolite (hydroxymethyl tinidazole) in normal subjects or in patients with renal failure. Tinidazole clearance during haemodialysis was 71 +/- 7.7 ml/min. In the presence of renal failure no modification of tinidazole dosage would appear to be necessary. Tinidazole should be administered in full dosage following haemodialysis.

A simple method for determining thiopental in plasma.

A simple rapid HPLC method for the measurement of thiopental is described. Plasma was deproteinised with 50% (v/v) acetonitrile in methanol containing flufenamic acid as an internal standard. Chromatography was carried out on a C-18 mu Bondapak reverse phase column using 220 mL of buffer (1.79 g of ammonium dihydrogen phosphate and 1.75 g of sodium sulfate adjusted to pH 7.9 with ammonium hydroxide) in 300 mL of methanol. Detection at 280 nm was near the absorption maxima of both thiopental and flufenamic acid. The method is linear up to 75 micrograms/mL and is therefore suitable for the measurement of thiopental in plasma from patients sedated by thiopental infusion. The sensitivity can be increased such that single dose studies can be investigated.

OV-225 as a stationary phase for the determination of anticonvulsants, mexiletine, barbiturates, and acetaminophen.

Rapid methods of analysis for anticonvulsants (phenobarbitone, carbamazepine, primidone and phenytoin simultaneously and ethosuximide), barbiturates, mexiletine, lidocaine and acetaminophen are described. All drugs are chromatographed on OV-225 at various temperatures and detected using a nitrogen specific detector. OV-225 has proved to be superior to the more common SE-30, OV-17 and OV-1 phases, particularly for the simultaneous determination of the four anticonvulsants. No problems relating to the bleed of cyanopropyl containing stationary phase into the nitrogen specific detector have been encountered.

Blood alcohol levels. How accurately can they be guessed?

Volunteers were asked to guess their blood alcohol level immediately before having their venous level measured by gas chromatography. Thirty-one percent were able to guess to within 20 mg per 100ml of the measured amount. There was a tendency for people to over-estimate if the level was low and to under-estimate the higher values. Blood alcohol concentrations ranged from nil to 295mg per 100ml with both high and low being recorded throughout the evening.

Phenobarbital in the acute management of febrile convulsions.

Blood levels of phenobarbital were determined after a single oral or intramuscular (IM) dose in children in the hospital after febrile convulsions. At a dose of 15 mg/kg, both the oral and IM routes gave therapeutic blood levels within 90 minutes. Absorption from the IM route before 90 minutes was inconsistent and would be unlikely to arrest an established convulsion within a critical time period. For use as a drug to prevent convulsions, oral phenobarbital at 15 mg/kg deserves further study.

Cyanide poisoning of cattle grazing "reed sweet-grass"

Abstract Extract Reed sweet-grass, Poa aquatica (Glyceria maxima, Glyceria acquatica), a member of the Gramineae family, is an introduced plant found in wet places in various localities in both the North and South Islands, but mainly in Otago and Southland (Allan, 1940 ). Garner ( 1961 , p. 318) quotes Quisumbine (1947) as listing 25 species belonging to the family Gramineae, including Poa aquatica, which contain hydrocyanic acid. Connor (1951) , however, does not list Poa aquatica as one of the poisonous plants of New Zealand, and no previous references to poisoning by this plant have been found.

Drug overdoses: Is one stomach washing enough?

Naso-gastric tube aspirates were taken from patients with drug overdoses who had been given a gastric lavage and admitted to the resuscitation ward. Although care was taken to conduct thorough washouts, it was found that these were not always efficient. In several cases an amount equivalent to a therapeutic dose of drug was recovered in later aspirates. There was no correlation between the amount of drug recovered in the initial stomach washings and that found in the aspirates. It was concluded that routine aspiration of gastric contents at hourly intervals after admission was of considerable value in removing any residual drugs.