Acute myocardial uptake of digoxin in humans: correlation with hemodynamic and electrocardiographic effects.

Acute myocardial uptake of digoxin was measured at a constant paced heart rate (75 beats/min) for 30 min after an intravenous bolus injection of 500 micrograms of digoxin in 14 patients with ischemic heart disease. Myocardial digoxin content, determined by serial measurement of aortocoronary sinus digoxin concentration gradients and coronary sinus blood flow, was expressed relative to coronary sinus blood flow at rest and correlated with simultaneous hemodynamic and electrocardiographic changes. Myocardial digoxin uptake was extensive (4.1 +/- 0.7% of total injected dose at 30 min) and prolonged, with rapid initial uptake (75.3 +/- 6.6% of maximum at 3 min), followed by a variable phase of slower accumulation. Peak left ventricular positive first derivative of left ventricular pressure (dP/dt) increased progressively (p less than 0.01), with a similar time course to that of myocardial digoxin accumulation; maximal change was 18.5 +/- 4.7% at 27 min. The ratio of inotropic effect to myocardial digoxin content did not vary significantly over the period of the experiment. However, peak inotropic effects in individual patients were not significantly related to peak myocardial digoxin content. The spontaneous PR interval increased transiently, with a peak increase of 5.9 +/- 1.8% (p less than 0.05) 12 min after digoxin administration. It is concluded that after intravenous bolus administration, 1) peak effects of digoxin on atrioventricular (AV) conduction occur early, whereas positive inotropic effects increase progressively for greater than or equal to 27 min; and 2) digoxin accumulation in the human myocardium is prolonged and is a determinant of inotropic effects, but not of prolongation of AV node conduction.

Simultaneous HPLC gradient analysis of 15 benzodiazepines and selected metabolites in postmortem blood.

The simultaneous identification and quantitation of 15 benzodiazepines and selected metabolites in postmortem blood, serum, or liver homogenate is described. The assay involves extraction with diethylether, followed by an acid clean-up step of the ether. Chromatographic separation was achieved on a Nova-Pak phenyl 18 column using ultraviolet detection at 240 nm. A gradient HPLC system was developed to improve separation of nitro-reduction metabolites from the solvent front and endogenous peaks. The mobile phases consisted of a gradient from 15 to 28% acetonitrile in 40 mM potassium phosphate buffer. Within-run and day-to-day precision were generally 10-15%. The method described is sensitive and reproducible for the analysis of benzodiazepine concentrations in postmortem tissues.

Capillary gas chromatographic drug screen for use in forensic toxicology.

A screening method is presented involving the use of capillary gas chromatography using a BP-5 column and nitrogen-phosphorous detection. This method is a quick yet reliable procedure for a large range of neutral and basic drugs and uses 1 mL or less of blood. Running standards that contain a number of commonly observed drugs with each batch of cases allows for more accurate tentative identifications of likely drugs in unknown cases and also provides a measure of quality assurance. This method is suitable for postmortem and clinical blood samples as well as plasma and serum.

A study of deaths involving oxycodone.

Nine deaths involving oxycodone were investigated to assess the contribution of this opiate to these fatalities. All except one of the bodies were subjected to a full autopsy by specialist pathologists with a subsequent thorough toxicological examination. No significant anatomical pathology was found at autopsy. All deaths gave concentrations of oxycodone in femoral blood higher than expected following normal therapeutic use. In three cases no other drug in toxic concentrations was detected. Two cases involved the presence of a high concentration of a benzodiazepine and in a further two cases a high concentration of alcohol in addition to other drugs in therapeutic concentrations were present. One case involved methamphetamine in significant concentrations and another involved high concentrations of oxazepam in combination with pethidine. In all cases the presence of oxycodone was given as a factor contributing to the death. In only one case were there circumstances clearly indicating suicide. Our observations suggest that oxycodone is at least as toxic as other opiates and will cause deaths if misused.

A fatality due to flurazepam.

A fatality attributed to suicidal ingestion of up to 2.2 grams of flurazepam is described. The deceased was a 52-year old female with a history of depression and suicidal attempts. No significant pathology was found at autopsy. Full toxicological analyses detected only flurazepam and metabolites in her tissues. The concentrations of flurazepam in femoral blood, liver, bile, vitreous humor and urine were 5.5 mg/L, 130 mg/kg, 33 mg/L, 1.3 mg/L and 3.3 mg/L, respectively. Analysis of gastric contents showed 600 mg of flurazepam. Desalkylflurazepam was also detected in blood, liver, bile and vitreous, but at much lower concentrations than the parent compound.

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.

Combined use of nitroglycerin and N-acetylcysteine in the management of unstable angina pectoris.

The vasodilator effects of nitroglycerin (NTG) are mediated via activation of guanylate cyclase; this process is believed to require the availability of free sulfhydryl groups. Previous studies in man have shown that the sulfhydryl donor N-acetylcysteine (NAC) potentiates the systemic and coronary vasodilator effects of NTG. Furthermore, interaction of NTG and NAC may lead to the formation of S-nitroso-NAC, which strongly inhibits platelet aggregation. The effects of intravenous NTG combined with intravenous NAC (5 g 6 hourly) were compared with those of intravenous NTG alone in a double-blind trial in 46 patients with severe unstable angina pectoris unresponsive to conventional treatment, which included calcium antagonists and cutaneous nitrates in all but one patient. Treatment with NTG/NAC (24 patients) and that with NTG alone (22 patients) was associated with a similar frequency of episodes of chest pain and of increments in NTG infusion rate for pain control (10 vs 17; p = NS). The NTG/NAC group had a significantly lower incidence of acute myocardial infarction than the NTG/placebo group (three vs 10 patients; p = .013). Symptomatic hypotension occurred frequently in the NTG/NAC group (seven vs 0 patients; p = .006). Lactate-pyruvate ratios and venous NTG concentrations were not significantly affected by NAC. Subsequently, another 20 consecutive patients were treated with intravenous NTG and continuously infused NAC (10 g/day). Seven remained pain free during the first 24 hr of NTG infusion; 11 required increments in NTG infusion rate for pain control. Acute myocardial infarction occurred in one patient, while none developed symptomatic hypotension.(ABSTRACT TRUNCATED AT 250 WORDS)

Nitroglycerine/N-acetylcysteine in the management of unstable angina pectoris.

N-acetylcysteine (NAC) has been shown to potentiate the haemodynamic and antiplatelet effects of nitroglycerine (NTG) in man, and to limit the development of haemodynamic tolerance to NTG. These effects may be mediated. by the formation of S-nitroso-NAC, which induces vasodilation and strongly inhibits platelet aggregation. In a randomized double-blind study in 46 patients with severe unstable angina pectoris unresponsive to standard treatment (including cutaneous nitrates and calcium antagonists in 45 patients) we compared the effects of intravenous (IV) NTG with those of IV NTG combined with IV NAC (5 g 6 hourly). Treatment with NTG/NAC (24 patients) was associated with a similar frequency of episodes of chest pain as treatment with NTG alone (22 patients), but somewhat fewer increments in infusion rate for pain control (10 vs 17; P NS). The NTG/NAC group had a significantly lower incidence of acute myocardial infarction than the NTG/placebo group (3 vs 10 patients; P = 0.013). Symptomatic hypotension occurred frequently in the NTG/NAC group (7 vs 0 patients; P = 0.006). It is concluded that combined administration of NTG and NAC in patients with unstable angina pectoris may augment the clinical efficacy of NTG, largely by reducing the incidence of acute myocardial infarction. However, the high incidence of severe hypotension with NTG/NAC suggests that this regimen should be used with some caution.

Determinants of acute hemodynamic and electrophysiologic effects of verapamil in humans: role of myocardial drug uptake.

To examine the relationship between myocardial verapamil content (MVC) and acute effects in humans, coronary sinus catheterization was used in 22 patients to determine myocardial uptake of verapamil after bolus intravenous (i.v.) verapamil (4 mg) injection. Verapamil-induced effects on hemodynamic and electrophysiologic parameters were measured simultaneously and correlated with MVC per unit baseline coronary sinus blood flow (MVC:F). Myocardial uptake of verapamil was rapid: peak MVC (1.2 +/- 0.2% of injected dose) occurred at 5.4 +/- 0.4 min; at 30 min, residual MVC was 71.1 +/- 3.4% of maximum. Peak MVC:F in individual patients was inversely related to the extent of coronary artery disease (p less than 0.005) but not to left ventricular (LV) systolic function. Verapamil produced significant (p less than 0.001) early reductions in arterial pressure and systemic vascular resistance (SVR); cardiac index (CI) increased, left ventricular (LV) positive dP/dt was unchanged. Verapamil prolonged (p less than 0.01) PR and AH intervals (maximum at 12-18 min) and atrioventricular (AV) nodal effective and functional refractory periods (ERP, FRP) (maximum at 30 min). In individual patients, the extent of changes in AH intervals (r = 0.69; p less than 0.05) and LV dP/dt (r = 0.62; p less than 0.05) correlated with peak MVC:F. We conclude that after i.v. injection, verapamil uptake by the human myocardium is rapid and more extensive in patients with minor coronary artery disease. Despite the hysteresis between MVC and drug effects, MCV is a determinant of inotropic and electrophysiologic effects of verapamil.