Presence Of Other Drugs Research Articles

Heroin Overdose as Cause of Death: Truth or Myth

Heroin-related deaths have many causes and occur in a heterogenous group of patients. The current paper examines critically the literature on deaths attributed to heroin overdose, and examines the characteristics and complexity of such deaths. In particular, the dominance of the widely held belief that heroin-related fatalities are a consequence of overdose is challenged. The presence of other drugs (primarily central nervous system depressants such as alcohol and benzodiazepines) being commonly detected at autopsy and study of pationts with acute opioid overdose who arrive in Emergency departments do not prove this coherency. Furthermore, deaths attributed to overdose are likely to have morphine levels no higher than those who survive, or heroin users who die from other causes. It is concluded that the term overdose may in many cases be a misleading term, since it implies the same mechanism of death in all cases. In order to determine the impact of co-intoxicants on mortality and morbidity after opioid overdose, future studies should measure serum levels of opioids and suspected co-intoxicants in both survivors and fatalities and conduct similar prospective follow-ups for defined adverse events including death.

Methadone-Related Deaths in Palm Beach County

The authors reviewed cases investigated by the Palm Beach Medical Examiner's Office in which postmortem toxicologic studies indicated the presence of methadone over the period from 1998 to 2002, to examine the role of the drug in these deaths. There were 139 methadone-positive cases, including 75 in which the death was attributed to combined drug toxicity and 23 to methadone toxicity alone. Methadone was most frequently used in conjunction with other prescription or illicit drugs, most commonly benzodiazepines and/or cocaine. There was considerable overlap in the postmortem blood methadone concentrations among the groups. Concentrations ranged from 0.114 mg/L-1.939 mg/L (mean .0559 mg/L) in cases where death was attributed to methadone toxicity; 0.050 mg/L-1.903 mg/L (mean 0.411 mg/L) in cases of combined drug toxicity; 0.069 mg/L-0.644 mg/L (mean 0.224 mg/L) in deaths attributed to other drugs; 0.062 mg/L-1.090 mg/L (mean 0.344 mg/L) among deaths attributed to natural causes and 0.072 mg/L-2.7 mg/L (mean 0.605 mg/L) among deaths due to trauma. The concentrations of methadone detected indicate that it may not be possible to establish a lethal methadone range because some deaths occurred at methadone concentrations below previously reported lethal ranges, and because of the presence of other drugs. Determining the cause of death in methadone-positive cases necessitates correlation with autopsy results and investigative findings.

Predicting Solubility in Multiple Nonpolar Drugs–Cyclodextrin System

This study presents a model to predict the solubility of a nonpolar drug DA in the presence of other nonpolar drugs D1…Dn in a complexing ligand L system such as hydroxypropyl‐β‐cyclodextrin (HPβCD). Using an equilibrium approach, the model describes the molecular interactions among these drug species and the ligand. The model indicates that the solubility of DA invariably decreases as a result of the presence of D1…Dn. Furthermore, the decrease in DA solubility is related to the sum of the products of the intrinsic solubilities of the other drugs and drug–ligand complexation constants. To test the model, three steroids (prednisolone, 17α‐hydroxyprogesterone, and progesterone) were used as model compounds in HPβCD solutions. The experimental data showed that the solubility of any particular drug decreased in the presence of other drugs. At all tested HPβCD concentrations, these experimental solubility data were in good agreement with the predicted solubility data. This result lends strong support to the reliability and effectiveness of the proposed model. © 2002 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:2301–2306, 2002

Therapeutic Drug Monitoring: Chemical-Clinical Correlations of Atypical Antipsychotic Drugs

In the last few years, new drugs for the treatment of schizophrenia have been introduced in therapy which have noticeably improved the quality of life of many schizophrenic patients. These new "atypical" drugs have chemical, pharmacological and clinical properties which are different from those of the classical neuroleptics. The most used drugs among the "atypical" antipsychotics are clozapine, olanzapine, quetiapine and risperidone. Despite several differences in their pharmacokinetic and pharmacodynamic profiles, they show some common properties: e.g. they don't cause extrapyramidal side effects, and they are active against the negative as well as positive symptoms of schizophrenia. The need for clinical monitoring of patients undergoing therapy is still evident because the onset of side effects is often related to high plasma concentrations of the drug. The clinical monitoring of patients can significantly improve the knowledge of pharmacological interactions among different CNS drugs, as well as enhance the compliance of the patients, thus leading to higher treatment efficacy. In order to carry out efficient clinical monitoring, reliable analytical methods are needed to determine the analytes even at very low concentrations and in the presence of other drugs. For this purpose, analytical techniques such as gas or liquid chromatography are often used coupled with sensitive and selective means of detection, such as fluorimetric, electrochemical or mass spectrometry detectors. The most recent studies on the determination of atypical antipsychotics will be reviewed in addition to the issue of sample pretreatment which is a critical step when the analysis of biological fluids is concerned.

Postmortem Forensic Toxicology of Trazodone

Trazodone is a popular antidepressant medication that has been available for approximately 30 years. It has a reputation as a safe drug with relatively few reported fatalities attributed solely to it. We review the pharmacology and forensic toxicology of trazodone and report toxicology and cause and manner of death in a series of 37 deaths in which trazodone was detected. Although the normal upper therapeutic blood concentration for trazodone is about 2 mg/L, fatalities are rarely attributed solely to it at blood concentrations below 9 mg/L. Considering the pharmacology of the drug, potential interactions between other drugs with serotonin reuptake properties need to be considered, as does the increased susceptibility to the toxic effects in patients with pre-existing heart disease. In the cases reviewed, none were attributed solely to trazodone, although trazodone was frequently present together with other serotonergic drugs, such as the selective serotonin reuptake inhibitors like fluoxetine and sertraline. Ten cases had blood trazodone concentrations above 2 mg/L. Of these cases, trazodone played a primary role in the death of three subjects, with blood concentrations all greater than 9 mg/L. We confirm the conclusions of others that trazodone is a relatively safe drug except in massive overdose, although its toxicity may be influenced by the presence of other drugs and underlying pathophysiology.

Postmortem Forensic Toxicology of Selective Serotonin Reuptake Inhibitors: A Review of Pharmacology and Report of 168 Cases

This paper reviews the complex pharmacology of the new class of antidepressant medications exhibiting selective inhibition of serotonin reuptake. The four selective serotonin reuptake inhibitors (SSRIs) considered--fluoxetine, fluvoxamine, sertraline and paroxetine--can result in toxicity and death through contributing to serotonergic excess resulting in serotonin syndrome, inhibiting the metabolism of other centrally acting drugs, leading to accumulation of toxic concentrations, and exerting complex vasoactive effects on the vascular smooth muscle. This latter feature is of particular concern in patients with preexisting heart disease. An analytical method involving isolation of the drugs by liquid/liquid extraction at alkaline pH into n-butyl chloride, and analysis by gas chromatography/mass spectrometry (GC/MS) is described, together with some of its limitations. Toxicologic and cause and manner of death data were examined in 60 deaths involving fluoxetine, 5 involving fluvoxamine, 75 involving sertraline, and 28 involving paroxetine. Deaths involving drug toxicity were generally a result of ingestion of multiple drugs, and in only a small number of the cases was death attributed principally to the SSRI involved. The potential for drug interactions between members of this class of drugs is discussed as well as their metabolites and a variety of other therapeutic and abused drugs which can contribute to their toxicity. In the absence of other risk factors, the lowest concentrations determined to have resulted in death were 0.63 mg/L for fluoxetine, 0.4 mg/L for paroxetine, and 1.5 mg/L for sertraline. We had insufficient data to make even this crude assessment for fluvoxamine. Drug-induced elevation of serotonin concentrations may be a significant risk factor for patients with atherosclerotic cardiovascular disease (ASCVD). Other factors including preexisting disease and the presence of other drugs and their pharmacology need to be carefully considered before determining the appropriate cause and manner of death in these cases.

On-line solid-phase extraction of cephalosporins

Using a single, on-line solid-phase sample clean-up procedure, serum concentrations of ten cephalosporins (cefaloridine, cefalotin, cefamandole, cefazolin, cefodizime, cefoperazone, cefoxitin, ceftizoxime, ceftriaxone and cefuroxime) were assayed on a C 18 column, using UV detection. Serum samples diluted with water were directly injected, without any sample preparation, into the extraction column (alkylamino packing) where the drugs were separated from the serum components. Using an on-line column-switching system, cephalosporins were transferred and separated on the analytical column by ion-pair high-performance liquid chromatography. The proposed method was rapid and efficient: it requires a small serum volume (10 μl) and it can be automated. Recovery was nearly complete. Detection limits varied from 0.5 to 2 μg/ml from extraction of 10 μl of serum. The method was highly specific even in the presence of other drugs commonly found in clinical samples and provides a rapid, simple technique suitable for use in routine microbiological practice.

Heroin in the United Kingdom: different forms, different origins, and the relationship to different routes of administration

Heroin exists in the United Kingdom in several different forms, which vary not only in their country of origin and purity, but also in their suitability for use by either injecting or by 'chasing the dragon'. The availability of these different forms of heroin has varied considerably over time. A review of the characteristics and availability of these various forms of heroin in recent years is presented, accompanied by consideration of their probable intended use by injection or by 'chasing the dragon'. Samples of black market heroin in the salt form are usually used by injection, whereas the base form is usually taken by 'chasing the dragon'. The heroin yield to the drug user from samples of heroin taken by 'chasing the dragon' varies according to its base or salt format and according to the presence of other drugs in the sample. Heroin samples from different countries of production mostly conform to either base or salt form. Novel approaches at the macro level to prevention and control of heroin-related problems through influence upon this complex heroin market-place should now be considered.

An automated preparation device for the determination of drugs in biological fluids coupled on‐line to a gas chromatograph/mass spectrometer

An on-line, solid-phase extraction gas chromatography/mass spectrometry method for the automated pretreatment of biological fluids is proposed. Several drugs of abuse were used as model compounds. The analytes are trapped on a home-made RP-C18 column and subsequently eluted with chloroform. The fraction of the organic solvent containing the largest drug concentration is injected into the CG/MS via a single interface. Detection limits of 0.5-10 ng/mL are achieved by using 1 mL of urine or serum; the relative standard deviation is ca. 3-4%. The selectivity of the method allows the analytes to be determined in the presence of other drugs of abuse. To demonstrate the potential of the proposed approach, the method was applied to the determination of cocaine, codeine and methadone in human urine obtained from patients in a hospital. © 1997 John Wiley & Sons, Ltd.

Dopamine D2-like sites in schizophrenia, but not in Alzheimer's, Huntington's, or control brains, for [3H]benzquinoline.

Although the basis of schizophrenia is not known, evidence indicates a possible overactivity of dopamine pathways. In order to detect any new dopamine receptor-like sites which may be altered in schizophrenia, the present study used a new radioligand, a [3H]benzo[g]quinoline. The receptors were labelled by this ligand in the presence of other drugs to block the known dopamine D1, D2, D3, or D5 receptors (no D4-selective ligands are available to block D4). Using this method, we found that schizophrenia brain striata had elevated levels of a D2-like site not detected in control human postmortem brains or in Alzheimer's, Huntington's, or Parkinson's disease brains. The ligand acted as an agonist at this D2-like site, because binding was abolished by guanine nucleotide. The binding of the ligand to the D4 receptor, however, was not sensitive to guanine nucleotide. The site differed from D2 itself, because S- and R-sulpiride were equally potent at the D2-like site. The D2-like sites were present in rat and mouse brain but were absent in brain slices from transgenic mice where D2 had been knocked out. The abundance of the receptor was not related to premortem use of antipsychotic drugs. Future research should examine the biochemical differences between the D2 dopamine receptor and these D2-like sites in schizophrenia.

Dopamine D2‐like sites in schizophrenia, but not in Alzheimer's, Huntington's, or control brains, for [3H]benzquinoline

Although the basis of schizophrenia is not known, evidence indicates a possible overactivity of dopamine pathways. In order to detect any new dopamine receptor-like sites which may be altered in schizophrenia, the present study used a new radioligand, a [3H]benzo[g]quinoline. The receptors were labelled by this ligand in the presence of other drugs to block the known dopamine D1, D2, D3, or D5 receptors (no D4-selective ligands are available to block D4). Using this method, we found that schizophrenia brain striata had elevated levels of a D2-like site not detected in control human postmortem brains or in Alzheimer's, Huntington's, or Parkinson's disease brains. The ligand acted as an agonist at this D2-like site, because binding was abolished by guanine nucleotide. The binding of the ligand to the D4 receptor, however, was not sensitive to guanine nucleotide. The site differed from D2 itself, because S- and R-sulpiride were equally potent at the D2-like site. The D2-like sites were present in rat and mouse brain but were absent in brain slices from transgenic mice where D2 had been knocked out. The abundance of the receptor was not related to premortem use of antipsychotic drugs. Future research should examine the biochemical differences between the D2 dopamine receptor and these D2-like sites in schizophrenia. Synapse 25:137–146, 1997. © 1997 Wiley-Liss, Inc.

Fatal heroin 'overdose': a review.

The current paper examines critically the literature on deaths attributed to heroin overdose, and examines the characteristics and circumstances of such deaths. In particular, the dominance of the widely held belief that heroin-related fatalities are a consequence of overdose is challenged. Deaths attributed to overdose represented in the literature are typically older, heroin-dependent males not in drug treatment at the time of death. Fatalities involving only heroin appear to form a minority of overdose occasions, the presence of other drugs (primarily central nervous system depressants such as alcohol and benzodiazepines) being commonly detected at autopsy. Furthermore, deaths attributed to overdose are likely to have morphine levels no higher than those who survive, or heroin users who die from other causes. It is concluded that the term overdose is, in many cases, a misleading term, since it implies the same mechanism of death in all cases, an implication that is neither clinically useful nor consistent with published data. Implications for the prevention of heroin-related deaths are discussed.

Microbiological Method for Determining Macrolides in Animal Feeds in the Presence of Other Drugs by Thin-Layer Chromatography Detection

A method was developed to separate, detect, and quantitate erythromycin (ERY) and tylosin (TYL) in animal feeds in the presence of 11 other drugs: 3 nitrofurans, 2 tetracycline antibiotics, 3 sulfonamides, 2 coccidiostats, and 1 antibacterial growth promoter. ERY and TYL were separated from coexisting drugs, detected by thin-layer chromatography, and quantitated microbiologically by an agar diffusion method. Analysis of 125 experimental animal feed samples fortified at 5 levels (7.5-400 ppm) with ERY and TYL and at 1 level (50 ppm) with the rest of the drugs gave limits of quantitation of 2 and 5 ppm, recoveries of 90.3 and 92.4%, and relative standard deviations of 4.3-7.3% and 3.6-6.1%, respectively.

Determination of Tetracyclines in Animal Feeds in the Presence of Other Drugs by Thin-Layer Chromatography and Microbiological Method

This method was developed to separate, detect, and quantitate oxytetracycline (OTC) or chlortetracycline hydrochloride (CTC.HCl) in animal feeds in the presence of 11 other drugs: 3 nitrofurans, 2 macrolide antibiotics, 3 sulfonamides, 2 coccidiostatics, and 1 antibacterial growth promoter. OTC or CTC.HCl was separated from coexisting drugs and detected by thin-layer chromatography, then quantitated microbiologically by the agar diffusion method. Analysis of 125 experimental animal feed samples fortified at 5 levels (7.5-400 ppm) with OTC or CTC.HCl and at 1 level (50 ppm) with the rest of the drugs, respectively, gave a limit of quantitation of 1.25 or 0.625 ppm, a recovery of 90.6 or 92.9%, and a coefficient of variation of 2.9-6.1 or 2.3-4.4%.

Spectrophotometric Determination of Narcotine

Abstract Narcotine reacts with potassium iodate and antimony potassium tartarate to give a yellowish orange colour having maximum absorbance at 430–440 nm. The reaction is specific for narcotine, having 1 ug/10 ml as visual limit of identification and provides a basis for a new spectropho-tometric determination of pure narcotine and in the presence of other drugs. The maximum tolerable limits of these are reported.

SPECTROPHOTOMETRIC DETERMINATION OF ATROPINE

Abstract Atropine reacts with sodium nitrite and 1-naphthylamine to give an orange color having maximum absorbance at 460-470 nm. The reaction is specific for atropine, having 0.1 μg/10ml as visual limit of identification and provides a basis for a new spectrophotometric determination of pure atropine in urine, from pharmaceutical preparations in minute quantities, and in the presence of other drugs. The maximum tolerable limits of these are reported.

Blood alcohol levels in suicide cases.

The aim was to investigate the relationship between alcohol consumption prior to suicide and the act of suicide. This was a retrospective total ascertainment survey of a three year cohort of suicides in Western Australia. Coroner's records of suicide in Western Australia between 1986 and 1988 inclusive. The study involved 515 consecutive suicides: 414 males and 101 females. Information on blood alcohol levels at time of death, presence of other drugs at time of death, drug and alcohol abuse history, psychiatric history, life events prior to death and method of suicide were collected. It was found that 35.8% of cases had a positive blood alcohol reading. Those who had been drinking alcohol prior to suicide were younger, more likely to be male, more likely to have chosen carbon monoxide as the method of suicide, more likely to have experienced a break up of a relationship and less likely to have sought professional help than those who had not been drinking. Data from the present study do not provide evidence for a causal relationship between alcohol consumption and suicide. Differences between those who had consumed alcohol and those who had not are suggestive of a contributory role of alcohol to a decision to commit suicide in a subset of suicide cases.

Mazicon (flumazenil/Roche).

Flumazenil exerts its effect by competitive inhibition of the benzodiazepine agonist from the receptors in the CNS, thereby blocking the effect of the agonist. Flumazenil, in doses to 1.0 mg intravenously, has been shown in clinical trials to be effective for the complete reversal of benzodiazepine sedation after intravenous conscious sedation or general anesthesia. It is effective even in the presence of other drugs, including opioids. Most patients are aroused and completely alert within a few minutes after the administration of flumazenil and maintained their alertness throughout the 180-min observation period.

Enhancement of Athletic Performance with Drugs

Drug use among athletes has become a recognised problem in sports. Athletes may use drugs for therapeutic indications, for recreational or social reasons, as ergogenic aids or to mask the presence of other drugs during drug testing. Stimulants were some of the first drugs used and studied as ergogenic aids. Amphetamines may increase time to exhaustion by masking the physiological response to fatigue. Caffeine may improve utilisation of fatty acids as a fuel source thereby sparing muscle glycogen. Cocaine and other sympathomimetic drugs have little or no effect on athletic performance. Anabolic steroids appear to have the potential to increase lean muscle mass and strength under certain conditions. Human growth hormone may also be used for an anabolic effect, but data on this effect are lacking. Erythropoietin may represent a pharmacological alternative to blood doping by increasing red blood cell mass. The use of narcotic analgesics is not necessarily ergogenic but can be harmful if used to allow participation of an athlete with a severe injury. According to the American College of Sports Medicine alcohol does not possess an ergogenic effect. However, it may be used to reduce anxiety or tremor prior to competition. Marijuana does not increase strength. Tobacco products may produce psychomotor effects or control appetite which may be beneficial to some athletes. Other drugs used by athletes include beta-blocking agents, diuretics, and a variety of nutritional supplements. In addition, diuretics and probenecid may be taken to mask drug contents in the urine. Whether the ergogenic effects are real or perceived, the potential for adverse effects exists for all of these drugs. Potential health complications represent a serious risk to an otherwise healthy population. Further research on the long term health risks in athletes taking ergogenic drugs is needed.

Making a Choice of Inotropes and Vasodilators in Clinical Situations

There are five variables affecting cardiac output: heart rate and rhythm; contractility; ventricular preload; and ventricular afterload. The choice of specific drugs to augment myocardial performance is based on the spectra of their effects on these variables. In order to use inotropes and vasodilators efficiently in clinical situations, it is important to recognize the dose-response relationship, to consider route and rate of administration, and to take into account the presence of other drugs as well as the abnormal pathophysiology of the patient. The safe and effective use of inotropes and vasodilators in critically ill patients is most readily achieved when there is a systematic plan for introducing the drug, evaluating its effects, and adjusting those hemodynamic variables that can be controlled.