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Biomedical subjects

O H Drummer

Publications and source records attributed to O H Drummer.

At least 55 records · Page 3Linked to original sources
PubMed1994

Postmortem clomipramine: therapeutic or toxic concentrations?

Postmortem blood and liver concentrations of clomipramine were determined in ten cases by high performance liquid chromatography (HPLC). Blood concentrations ranged from 0.21 to 4.9 mg/L, and liver concentrations from 7.0 to 320 mg/kg. Two cases associated with clomipramine toxicity were clearly differentiated from other cases by the analysis of liver. The concentrations of clomipramine in these two cases were 3.3 and 1.8 mg/L in blood, and 280 and 320 mg/kg in liver. The liver concentrations were 10 to 30 fold greater in the deaths associated with drug toxicity compared with the other cases. One case, where cardiac blood was collected in place of femoral blood, showed a high blood concentration (4.9 mg/L), but an arguably therapeutic liver concentration (13 mg/kg). The analysis of femoral blood together with liver provides the best guide as to the significance of post-mortem clomipramine concentrations.

Adult↗
PubMed1993

Dual ultraviolet wavelength high-performance liquid chromatographic method for the forensic or clinical analysis of seventeen antidepressants and some selected metabolites.

A sensitive method suitable for the determination of tricyclic and other antidepressants in postmortem and clinical specimens is presented. The procedure, which utilizes reversed-phase HPLC combined with dual ultraviolet wavelength detection, enables the separation of 17 commonly prescribed antidepressants and some selected metabolites in a single extraction. Peak purity was confirmed using absorbance ratios at 220 nm and 254 nm wavelengths and revealed little interference from other eluting analytes. The blood detection limit for most antidepressants was 50 ng/ml. The most commonly observed antidepressants in 281 forensic cases analysed over a two-year period with the described method were dothiepin, amitriptyline, nortriptyline and doxepin.

Amitriptyline↗
PubMed1993

Simultaneous determination of 6-monoacetylmorphine, morphine and codeine in urine using high-performance liquid chromatography with combined ultraviolet and electrochemical detection.

A method is described for the simultaneous determination of 6-monoacetylmorphine (6-MAM), morphine and codeine in post-mortem urine specimens using reversed-phase high-performance liquid chromatography with dual ultraviolet spectrophotometric and electrochemical detection. The limits of detection for a 1-ml urine sample were 0.04 mg/l for 6-MAM and 0.05 mg/l for both morphine and codeine. The presence of 6-MAM in urine indicates prior use of heroin and enables differentiation between morphine- and heroin-related deaths.

Chromatography, High Pressure Liquid↗
PubMed1993

Deaths involving the benzodiazepine flunitrazepam.

A study of eight deaths involving the benzodiazepine flunitrazepam was performed to assess the contribution of this drug to the fatalities. Coronial deaths in Victoria in the 2-year period to mid-1991 were selected in which either flunitrazepam or flunitrazepam and ethanol were the principal toxicological findings. All bodies were subject to a full autopsy by forensic pathologists, and a full toxicological examination. No significant pathology was found at autopsy in any case. Very high concentrations of 7-aminoflunitrazepam, a metabolite of flunitrazepam, were present in all cases. In four cases no other significant drug was detected, whereas in the other four cases there were significant concentrations of ethanol (mean 1.6 g/L). In these two groups of cases the concentrations of 7-aminoflunitrazepam were 0.45 mg/L and 0.16 mg/L, respectively. Only moderate levels of flunitrazepam were detected, suggesting that 7-aminoflunitrazepam is produced postmortem and may be an important marker of flunitrazepam usage. The causes of death in these eight cases were probably either flunitrazepam toxicity or a combination of flunitrazepam and ethanol toxicity. Only one case appeared likely to have been a suicide. Our observations in these cases suggest that flunitrazepam may cause death in the absence of other drugs or significant disease. The presence of ethanol reduces the amount of flunitrazepam needed to cause death.

Adult↗
PubMed1993

Incidence of psychoactive cannabinoids in drivers killed in motor vehicle accidents.

A high performance liquid chromatography (HPLC) assay was developed for the psychoactive cannabinoids Delta-9-Tetrahydrocannabinol (THC) and 11-Hydroxy-THC (11-OH-THC) using electrochemical detection (ECD). A C8 bonded column was used and the mobile phase consisted of acetonitrile, methanol and 0.01 M sulphuric acid at a flow rate of 1.5 mL/min. The detection limits for both THC and 11-OH-THC were 1.0 ng/mL. Preliminary screening of 193 drivers using an enzyme-multiplied immunoassay technique (EMIT) showed 21 tested positive on either blood, urine or both. Of these subjects 13 were confirmed as positive by the HPLC/ECD method in blood. Blood concentration for THC ranged from 1.4 ng/mL up to 20 ng/mL and for 11-OH-THC 2.5 ng/mL up to 85 ng/mL.

Accidents, Traffic↗
PubMed1992

Survey of drug-related deaths in Victoria.

OBJECTIVE: To audit drug-related deaths to determine the types of agents causing death in Victoria and to identify possible strategies for prevention of deaths in future. DESIGN: Retrospective audit of Coroner's case records. SUBJECTS: All deaths reported to the Coroner during 14 months from 1 July 1989 to 31 August 1990 in Victoria in which toxicological investigation was undertaken and drugs or poisons were detected and were believed to be a major cause of death. RESULTS: Of the 231 people who had drug-related deaths, 156 were males, 75 were females and the average age was 35.5 +/- 14 years. Heroin and morphine were judged to be the primary cause of death in 35% of subjects and methadone in a further 4.8%. Tricyclic antidepressants were responsible for 14% of deaths, with no deaths due solely to mianserin. Benzodiazepines were the prime cause of death in 6.5% of subjects, but were identified in 40%. Poisons and chemicals were involved in only 3% of deaths. Prescription drugs were primarily responsible for 47% of deaths. Forty-eight per cent of deaths occurred in known injecting drug users and 42% of all subjects had a clear history of antecedent depression. Only one drug-related death was clearly accidental, that of a two-year-old child taking his parents' medications, but the mode of most deaths was not clear, and may not have been suicide. Most deaths occurred outside hospital, only 25 subjects reaching hospital alive. CONCLUSIONS: Barbiturates and chloral hydrate are no longer major causes of drug-related deaths, probably because of decreased availability. Some drug-related deaths, especially those related to tricyclic antidepressants, may be prevented if deaths and hospitalisations due to toxic substances are monitored and the availability and scheduling of toxic substances are regularly reviewed.

Adolescent↗
PubMed1992

Methadone toxicity causing death in ten subjects starting on a methadone maintenance program.

Methadone maintenance therapy is designed to reduce the need for addicts to use heroin or other illegal opiates. Death in patients starting on such a program has not previously been documented. We report the death of 10 persons who died within days of starting a methadone maintenance program administered by general practitioners. Their bodies were subject to a full autopsy by forensic pathologists, with a full toxicological examination. The mean starting dose had been 53 mg, which had been increased to a mean of 57 mg by the final dose. Death occurred after a mean of 3 days. The mean blood methadone concentration at death was 2.1 mumol/L. Complete toxicological analysis showed that six subjects had additional drugs present including two with alcohol, two with benzodiazepines and morphine, and one with benzodiazepines alone. Pathological examination revealed the presence of chronic persistent hepatitis in all subjects and bronchopneumonia in five. The causes of death were given as methadone toxicity or methadone toxicity in combination with bronchopneumonia. Our observations highlight the dangers of methadone in the first days of starting on a maintenance program, particularly when the starting doses are relatively high and subjects have no demonstrated tolerance to opiates.

Adult↗
PubMed1992

Comparison of the pharmacokinetics and pharmacodynamics of perindopril, cilazapril and enalapril.

1. The pharmacokinetic and pharmacodynamic responses to enalapril, perindopril and cilazapril have been studied in essential hypertensives (2, 4 and 8 mg perindopril and 2.5 mg cilazapril, single dose and steady state) and normotensive volunteers (10 mg enalapril, single dose). 2. Plasma levels of the active diacid compounds reached similar peaks after single dose administration of the drugs. However, perindoprilat levels persisted for 5 days whereas cilazaprilat levels were not detectable beyond 12 h. 3. The higher levels of perindoprilat were associated with a greater inhibition of plasma angiotensin-converting enzyme (ACE) activity in both acute and steady state studies. 4. The potency of the active diacids in inhibiting plasma ACE activity was perindoprilat greater than cilazaprilat greater than enalaprilat. 5. There was a close relationship between plasma concentration, ACE inhibition and blood pressure decrease. Although both cilazapril and perindopril administration reduced blood pressure in hypertensive subjects, only perindopril exerted 24 h blood pressure control at the doses used.

Adult↗
PubMed1992

A death involving probenecid.

A death following deliberate ingestion of approximately 75 g of probenecid in a 36-year-old man is described. Tissue concentrations of probenecid were highest in serum (710 mg/L) and liver (550 mg/kg). Probenecid was also detected in vitreous and bile. Ethanol was also detected in blood at 0.13 g/100 mL.

Adult↗
PubMed1992

A fatality due to propofol poisoning.

This report describes a suicide by self-administration of propofol in a 29-year-old female radiographer. This is the first published report of death by overdosage with propofol. Propofol was detected in tissues using high performance liquid chromatography. Post mortem femoral blood and liver concentrations of propofol were 0.22 mg/L and 1.4 mg/kg, respectively. The scene suggested that a dose of 400 mg was used.

Accidents↗
PubMed1991

Pharmacology of celiprolol.

The pharmacology of celiprolol and its relationship to some other beta-adrenoceptor antagonists is described. Celiprolol is a potent beta blocker on beta 1-adrenoceptors and exhibits cardioselectivity both in vitro and in vivo in the pithed rat, but shows no significant in vitro alpha 1-blocking action. Celiprolol differs from atenolol in that it has an intrinsic sympathomimetic activity (ISA) for beta 1-adrenoceptors, which is reflected in its relative lack of negative inotropic effects in humans. In the pithed rat, celiprolol's ISA was demonstrated at much lower doses than for pindolol, even though pindolol has a similar potency to celiprolol in antagonizing the heart rate effects of isoproterenol. It was completely blocked by propranolol, indicating that celiprolol behaves like a partial agonist for beta 1-adrenoceptors, whereas the ISA developed by pindolol was only partially blocked by propranolol. These data suggest a different mechanism for the development of ISA between celiprolol and pindolol.

Adrenergic beta-Agonists↗
PubMed1990

Effect of chronic enalapril treatment on enzymes responsible for the catabolism of angiotensin I and formation of angiotensin II.

We have investigated the effect of chronic administration of enalapril on the carboxypeptidases responsible for the formation of angiotensin II from angiotensin I and other peptidases known to recognize angiotensin I as a substrate in the rat. These studies have shown an increase in activity in rate of formation of des-Leu-angiotensin I in both kidney S2 and P2 centrifugal fractions as well as a decrease in the rate of degradation of angiotensin I substrate. Similar increases in the formation of A(1-8) have been observed in kidney using A(1-9) as substrate. These two enzyme activities have been named carboxypeptidase K1 and K2, respectively to reflect their presence in rat kidney. These changes were accompanied by significant decreases in the activity of an amastatin-sensitive aminopeptidase and endopeptidase 24.11 in the kidney P2 fraction. These data suggest that chronic treatment with ACE inhibitors may differentially affect the activity of other enzymes capable of degrading angiotensin causing a substantial re-direction of angiotensin metabolism.

Aminopeptidases↗
PubMed1990

Influence of food on the bioavailability of a sustained-release verapamil preparation.

The effects of food on the bioavailability of a sustained-release (SR) formulation of verapamil (SR-verapamil; Isoptin SR) were determined in an open, three-way single-dose study involving 12 volunteers receiving (in randomized order) the SR preparation (1 X 240 mg) either fasting or with food and a conventional formulation of verapamil (3 X 80 mg) fasting. Compared with the conventional formulation, SR-verapamil had a reduced Cmax, prolonged tmax, and unchanged t1/2, consistent with its SR formulation. The AUC was 80% of the conventional preparation. Concomitant food administration significantly prolonged the tmax of SR-verapamil from 7.3 +/- 3.4 to 11.7 +/- 6.3 h, but had little effect on Cmax, t1/2, or AUC. Similar results were obtained with the metabolite, norverapamil. Food administration also had little effect on the blood pressure and ECG effects of SR-verapamil. Cautions regarding taking this preparation with food therefore appear to be unnecessary.

Adult↗
PubMed1990

The effect of hepatic cirrhosis on the pharmacokinetics and blood pressure response to nicardipine.

The present study was designed to compare the pharmacokinetic handling of a single oral dose of nicardipine in normal subjects and in patients with hepatic cirrhosis and to compare the sensitivity of the two groups to its hypotensive effect. Nicardipine plasma concentrations were substantially higher in the subjects with hepatic cirrhosis with impaired antipyrine clearance, as shown by a significantly higher average Cmax and AUC. The terminal elimination half-life in this group varied from 0.8 to 60.2 hours (median, 11.7 hours), compared with 0.6 to 4.1 hours (median, 1.4 hours) in the group of eight subjects with normal liver function. In the cirrhotic patients with impaired antipyrine clearance, the AUC of the pyridine metabolite averaged 10% of that of the parent drug, whereas in normal subjects the ratio averaged 48%. This finding suggests less conversion of nicardipine to this metabolite in subjects with impaired hepatic function. Peak blood pressure decreases were greater in the cirrhotic group, which was in keeping with the higher plasma levels in these subjects.

Adult↗
PubMed1990

Biliary excretion and conjugation of diacid angiotensin-converting enzyme inhibitors.

The metabolism and biliary excretion of the diacid angiotensin-converting enzyme inhibitors enalapril, lisinopril, perindopril and ramipril have been studied in an isolated perfused rat liver model. Inhibitors were presented to the livers at a dose of 100 micrograms. The hepatic clearance of lisinopril was very low (0.072 ml/min) and was hardly excreted into the bile. The clearances of enalapril, perindopril and ramipril were higher at 0.63, 0.87 and 9.9 ml/min, respectively, and were excreted into bile. The amounts of ester prodrugs excreted in bile were 4.0, 6.1 and 14%, respectively, whereas the diacid forms were excreted to the extent of 46, 27 and 71% of the administered dose, respectively, over 4 hr. Glucuronide metabolites were only detected in bile in significant concentrations for perindopril and ramipril. Base hydrolysis of the perfusate samples showed that lisinopril was not significantly metabolized to conjugates and that little metabolism of enalapril occurred other than rapid conversion to the diacid form. However, both perindopril and ramipril were extensively metabolized beyond the diacid form. These differences in hepatic handling can in part be explained by their octanol-buffer partition coefficients but may also be related to the introduction of a bicyclic ring in perindopril and ramipril which increases their ability to be metabolized and excreted into bile. These differences in hepatic handling of angiotensin-converting enzyme are likely to influence their clinical usefulness, particularly in renal and hepatic disease.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Comparison of high-performance liquid chromatography and the Abbott fluorescent polarization radioimmunoassay in the measurement of methotrexate.

A modified high-performance liquid chromatographic (HPLC) technique for the assay of methotrexate is described and compared to the Abbott Fluorescence Polarization Radioimmunoassay. The reproducibility (coefficient of variation) at low concentrations was similar for the two assays: 8.1 and 8.5% for the Abbott and HPLC assay, respectively. The limit of detection of the two assays was also similar at 0.01 microM. The correlation coefficient for Abbott versus HPLC was 0.9833 with a gradient of 0.9545. Aspirin was the only drug that interfered with HPLC. Methotrexate's metabolite 7-hydroxymethotrexate did not interfere with the Abbott assay. Plasma half-lives were similar to oncology patients in the two rheumatological patients studied. The 7-hydroxymethotrexate half-life was 15 h.

Administration, Oral↗