Indacrinone: modification of diuretic, uricosuric, and kaliuretic actions by amiloride.

The response to indacrinone, a new indanone diuretic, was studied in 12 healthy subjects. Ten milligrams alone and in combination with either 2.5 mg or 5 mg amiloride was given in a randomized double-blind study with placebo control to study its action and to assess the optimum combination. Indacrinone alone induced an increase in urine flow rate and in sodium, potassium, and hydrogen ion excretion for at least 8 hr. Indacrinone also induced an initial uricosuria in the first 4 hr, followed by urate retention in the subsequent 12 to 24 hr, with no resultant change in the mean 24-hr urate excretion and minimal changes in the serum urate concentrations. The addition of 2.5 mg amiloride to the 10 mg indacrinone lowered potassium excretion to control levels, whereas addition of 5 mg amiloride resulted in net retention of potassium. With both doses of amiloride, the increased free hydrogen ion excretion after indacrinone returned to placebo levels. There were minor increases in serum creatinine, consistent with volume depletion due to the diuresis. There was a reduction in urinary calcium excretion. Our study shows that the combination of 10 mg indacrinone and 2.5 mg amiloride induces useful diuresis with minimal overall effect on urate, potassium, and hydrogen ion excretion.

Inhibition of soluble glutathione S-transferase by diuretic drugs.

Glutathione transferases are believed to play an important protective role in the various tissues of animals and man by catalysing the glutathione conjugation of electrophilic drugs and electrophilic drug metabolites. Many of these compounds have the potential to react with vital cellular macromolecules in the absence of this enzyme system. We have investigated the interaction of a number of high ceiling diuretics with the glutathione transferases contained in the cytosolic fraction of the rat liver. Of bumetanide, ethacrynic acid, furosemide, indacrynic acid and tienilic acid, only ethacrynic acid was conjugated with glutathione. Further experiments revealed that ethacrynic, indacrynic and tienilic acids are all potent inhibitors of glutathione S- aryltransferase . Glutathione S- alkyltransferase and glutathione S-epoxide transferase were also inhibited by the diuretics, but to a lesser extent than glutathione S- aryltransferase . The diuretics giving the greatest inhibition of these reactions were chemically related to ethacrynic acid. The concept where inhibition of glutathione-S-transferase by a drug may enhance its own toxicity is considered. This mechanism has also the potential of enhancing the toxicity of other concurrently administered drugs which normally require glutathione S-transferase for detoxication.

Inhibition of purified rat liver glutathione S-transferase isozymes by diuretic drugs.

Seven soluble rat liver glutathione S-transferase isozymes were isolated and the inhibition of these isozymes by selected diuretics was investigated using 1-chloro-2,4-dinitrobenzene as substrate. All isozymes were inhibited to some extent under the experimental conditions used, but there was significant isozyme dependent selectivity of inhibition. The greatest inhibitory effect (over 80%) was found when the phenoxyacetic acid diuretics and indacrynic acid were incubated with glutathione S-transferase 3-3, 3-4 and 4-4. The sulphamoylbenzoic acid diuretics, furosemide and bumetanide, were found to have a lesser effect on the isozymes studies. As glutathione S-transferase are thought to play an important protective role in the various tissues of animals and man, by catalysing the glutathione conjugation of electrophilic drugs and drug metabolites, their inhibition may be toxicologically important.

Survival after unexpected high serum methotrexate concentrations in a patient with osteogenic sarcoma.

An 18-year-old female patient receiving adjuvant chemotherapy for osteogenic sarcoma developed a pruritic erythematous rash during infusion of the eighth dose of methotrexate (8 g/m2) in the series. In other respects, the infusion proceeded normally but the 24-hour serum concentration of methotrexate was unexpectedly and extremely high, 574 mumols/L. Dosing error was excluded, as was the hypothesis that the high concentrations were due to the presence of methotrexate-specific antibodies. Acute oliguria and renal failure were the primary manifestations of the drug-induced toxicity and the high concentrations can be attributed to decreased renal elimination of the drug over the first 24 hours. Treatment consisted of folinic acid rescue, forced diuresis, sequential charcoal haemoperfusion and haemodialysis, and repeated oral doses of activated charcoal. After examination of the contribution of the extracorporeal procedures and the charcoal to the elimination of the drug, the relative lack of morbidity was attributed primarily to the folinic acid rescue and the intensive supportive care.

Pharmacokinetics and efficacy of rectal versus oral sustained-release morphine in cancer patients.

Sustained-release morphine (MST) given by the rectal route was compared with oral MST in an open randomised cross-over trial in ten patients with cancer who received stable doses of MST. No significant difference was found in the areas under the curve of the concentration-time profiles (AUC) following oral or rectal administration for parent morphine. The AUCs determined for morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G) after oral administration were approximately twice those obtained following rectal administration. The maximal concentration achieved was lower and the time to maximal concentration was longer following rectal administration for morphine, M6G and M3G. The relative mean arrival times following rectal administration were significantly longer for morphine and M3G but not for M6G. These findings suggest slower absorption but less first-pass metabolism of MST after rectal administration. No significant difference was noted between the oral and the rectal route in measurements on visual-analogue scales for pain or side effects. We recommend the rectal route as being suitable for MST administration when the oral route is no longer available. In changing from oral to rectal administration, the same dose and dose interval may be used, but dose adjustment may be needed.

The influence of vancomycin concentration and the pH of plasma on vancomycin protein binding.

A review of numerous studies of the protein binding of vancomycin suggests major discrepancies among their results. The reported percent protein binding of vancomycin varies from 0% to 98%. The influence of pH and concentration on the protein binding of vancomycin was investigated in this study. There was a significant difference (p < 0.001) in percent protein binding in vancomycin-spiked plasma samples across the pH range of 7.0-8.0. There was no significant difference (p > 0.05) in percent protein binding in vancomycin-spiked plasma samples across the concentration range of 2-80 mg/L. It is likely that some of the variation reported to date may be due to a lack of control of pH during the measurement of protein binding of vancomycin.

Stability of midazolam and fentanyl in infusion solutions.

The administration of drugs by subcutaneous infusion is routinely practiced in palliative medicine for the management of patients who are no longer able to take oral medication. It is not uncommon for two or more drugs to be combined in subcutaneous infusion solutions. The combination of an opioid and a short-acting benzodiazepine is frequently required. Unfortunately, the stability of benzodiazepines and newer opioids, such as fentanyl, has not been determined. This study examined the stability of solutions containing either fentanyl alone or fentanyl and midazolam in combination. Eight different solutions were assessed for up to 7 days following preparation. The solutions were prepared in polypropylene syringes using 0.9% saline as a diluent. Duplicate syringes were stored at approximately 5 degrees C, 22 degrees C, and 38 degrees C. High performance liquid chromatography was the analytical technique used to measure fentanyl and midazolam. Initial concentrations ranges were 13.2-38.9 micrograms/mL for fentanyl and 282-959 micrograms/mL for midazolam. It was found that fentanyl (+/- midazolam) was very stable (> 95%) when stored at temperatures ranging from 5 degrees C to 38 degrees C for at least 1 week. Midazolam (+ fentanyl) was not as stable as fentanyl under the same storage conditions and underwent time-dependent decomposition of up to 12.1% (observed at 7 days when stored at 38 degrees C). When stored at 22 degrees C and 38 degrees C, more than 90% of initial midazolam concentrations were retained for 4 days following preparation and for 7 days when stored at 5 degrees C. The clinical implications of these results are that, on the basis of physicochemical stability, subcutaneous infusion solutions containing fentanyl and midazolam may be prepared at intervals of 4 days (or 7 days if stored under refrigerated conditions).

Binding of disopyramide to alpha 1-acid glycoprotein in plasma measured by competitive equilibrium dialysis.

A modification of equilibrium dialysis in which alpha 1-acid glycoprotein and plasma compete directly for disopyramide has been used in conjunction with binding curves to measure the extent of the alpha 1-acid glycoprotein-disopyramide interaction. At concentrations in the therapeutic range, 80-90% of disopyramide was bound to alpha 1-acid glycoprotein for plasma from each of six healthy adults. Also, equilibrium dialysis data are presented, indicating that pH does not influence the binding of disopyramide within the therapeutic range.

A new Australian kindred with the syndrome of hypertension and hyperkalaemia has dysregulation of atrial natriuretic factor.

A family with the syndrome of hypertension and hyperkalaemia affecting six members in two generations is reported from Australia, where the first two sporadic cases were described. All family members had hyperkalaemia, hyperchloraemia and normal creatinine clearance. Only one affected adult and no affected children were hypertensive, possibly because of habitual low-salt diets. Plasma potassium fell significantly during fludrocortisone acetate administration, and urine potassium increased during saline infusion, consistent with renal tubular responsiveness to mineralocorticoid. Low plasma renin activity and pressor hyper-responsiveness to angiotensin II suggested sodium volume overload, but atrial natriuretic factor (ANF) was normal or only slightly elevated when compared with clearly elevated levels in primary aldosteronism. Plasma ANF was unresponsive to the usually reliable stimulus of angiotensin infusion in the two brothers affected and to saline infusion in one of them. These findings are consistent with a renal tubular avidity for sodium, leading to volume expansion, suppression of renin, and, depending on dietary sodium intake, hypertension. A role for dysregulation of ANF in the pathophysiology is possible.

Effects of opioids and sedatives on survival in an Australian inpatient palliative care population.

AIMS: To assess whether opioid and sedative medication use affects survival (from hospice admission to death) of patients in an Australian inpatient palliative care unit. BACKGROUND: Retrospective audit. Newcastle Mercy Hospice--a tertiary referral palliative care unit. All patients who died in the hospice between 1 February and 31 December 2000. METHODS: Length of survival from hospice admission to death, and the median and mean doses of opioids and sedatives used in the last 24 h of life. Comparison of these with published studies outside of Australia. RESULTS: In this study, the use of opioids, benzodiazepines and haloperidol did not have an association with shortened survival and the only statistical significant finding was an increased survival in patients who were on 300 mg/day or more of oral morphine equivalent (OME). The proportion of patients requiring greater than or equal to 300 mg OME/day (at 28%) was higher than published studies, but the mean dose of 371 mg OME/day was within the range of other studies. The proportion of patients receiving sedatives (94%) was higher than other studies, but the median dose of parenteral midazolam equivalent of 12.5 mg per 24 h was lower than other studies from outside Australia. CONCLUSIONS: There was no association between the doses of opioids and sedatives on the last day of life and survival (from hospice admission to death) in this population of palliative care patients.

Simple mandatory minute volume.

An easily constructed system for mandatory minute volume is described, using a Brompton Manley ventilator, a thin polyvinylchloride bag in a glass jar, and an Ambu "E" valve.

Usefulness of estimating individual pharmacokinetic data for aminoglycoside therapy in seriously ill patients.

This study proposes the use of individual pharmacokinetic parameters to predict effective dosages of aminoglycosides for patients with serious infections. Parameters were calculated for 51 patients using a one-compartment model. This model required a trough and three postinfusion aminoglycoside concentrations from each patient, as well as least squares linear regression. A total of 56 dosing regimens (37 gentamicin, 19 tobramycin) were predicted from these parameters and the efficacy of this approach was examined by comparing the predicted peak (8 mg/l) and trough (1.5 mg/l) concentrations with the observed peak and trough concentrations measured 24 h later. Aminoglycoside concentrations in serum were measured using a fluorescence polarisation immunoassay. Parameters varied widely, as the following ranges demonstrate: Volume of distribution 0.16-0.52 l/kg; clearance 0.04-0.17 l/kg/h; half-life 1.1-5.3 h. The doses predicted ranged from 3.2-16.9 mg/kg/day, with an average of 8.6 (standard deviation [SD] 3.4) mg/kg/day. The measured peak (mean 7.5; SD 1.6) and trough (mean 1.95; SD 0.57) concentrations closely approximated the predicted levels. The equations used underestimated trough concentrations mainly because of aminoglycoside accumulation. The changing pharmacokinetic parameters for each patient meant that regular drug assays were still required to fine-tune the dosing regimen. Two patients (4%) developed significant nephrotoxicity. Ototoxicity was not assessed. We conclude that individual pharmacokinetic data for aminoglycoside therapy can be used effectively to predict dosages for desired concentrations in seriously ill patients. The dose required was on average 1.5-2 times the normal recommended dosage.

Measurement of gliclazide in plasma by radial compression reversed-phase liquid chromatography.

We describe a rapid, specific, and precise analysis for gliclazide in plasma by radial compression, reversed-phase, "high-performance" liquid chromatography. Gliclazide and the internal standard, 3-chlorogliclazide, are eluted after 4.4 and 6.8 min, respectively. Only 100 microL of plasma and minimal sample workup are required. The limit of detection for gliclazide in plasma is 0.5 mg/L (1.55 mumol/L) at 229 nm. Precision (CV) of the assay for 10 and 1 mg of gliclazide per litre is 2.1% and 6.4%, respectively.

Rapid HPLC analysis of cefoxitin in plasma and urine.

A rapid, specific and precise method is described for the analysis of cefoxitin in plasma and urine by reversed-phase, high performance liquid chromatography (HPLC). Cefoxitin and the internal standard, 3-isobutyl-l-methyl xanthine are eluted after 5.3 and 7.5 min, respectively. The assay sensitivity limit is 1 to 2 mg/l of cefoxitin sodium at 254 nm. Commonly prescribed antibiotics do not interfere. The assay is suitable for routine monitoring and pharmacokinetic studies of cefoxitin.

Comparison of Sawchuk-Zaske and Bayesian forecasting for aminoglycosides in seriously ill patients.

1. Individual pharmacokinetic parameters and predicted steady-state serum concentrations of aminoglycosides were calculated by Sawchuck-Zaske (SZ) and Bayesian methods. 2. Predicted concentrations were compared with observed steady-state concentrations for 36 seriously ill patients with systemic infections. Four aminoglycoside concentrations were used for the SZ method. Differing numbers of serum aminoglycoside samples were used in the Bayesian parameter estimation: one sample Bayesian used one post-infusion concentration, two sample Bayesian used a trough plus one post-infusion concentrations and four sample Bayesian used a trough plus three post-infusion concentrations. 3. 79% of the SZ predictions were with +/- 2 mg l-1 of the observed peak concentrations, and 72% of the two sample Bayesian predictions were within the same range. 82% of SZ and the two sample Bayesian predictions were within +/- 1 mg l-1 of the observed trough concentrations. 4. A confidence interval comparison of estimated pharmacokinetic parameters and precision for the predicted concentrations showed no important differences between the SZ and the two sample Bayesian. The four sample Bayesian was the most precise method. 5. We conclude that the Bayesian forecasting method utilizing a trough plus one post-infusion concentrations is as useful as the SZ method which requires three to four serum concentrations in individualizing aminoglycoside therapy for seriously ill patients.

Abnormal renal urate homeostasis in systemic disorders.

Abnormalities of renal handling of urate occur in a wide variety of physiological and pathological conditions and are mediated by factors including renal blood flow, glomerular filtration rate, urine flow rate, urinary constituents, metabolites, hormones and drugs. The determination of the aetiological factors in each abnormal situation is complex and the problem is discussed in relation to a variety of conditions including renal tubular disorders and mental intoxications, hypertension, toxaemia of pregnancy, glycogen storage disease, fructose administration, hereditary fructose intolerance, as well as obesity, regular alcohol consumption and hyperlipoproteinaemia. Apart from those diseases, usually genetically determined, which are associated with excessive production of urate, the most common causes of hyperuricaemia act at a renal level and result in a reduction in the net renal excretion of urate.