Changes in the concentrations of Δ9-tetrahydrocannabinol (THC) in the postmortem period were inve... more Changes in the concentrations of Δ9-tetrahydrocannabinol (THC) in the postmortem period were investigated in a series of cases by comparing concentrations in blood taken on receipt of the body in the mortuary (admission specimen, AD) with the concentrations obtained in blood taken at autopsy some time later and also from blood specimens taken antemortem. Overall, the median THC concentration in AD blood was 13.7 ng/mL (n = 239, range LOQ–220), while the median concentration at autopsy was 13.8 ng/mL (n = 106, range LOQ–810) and 1.9 ng/mL (n = 147, range LOQ–48) antemortem. Fourteen cases had all three specimens taken from the same decedent. The corresponding AM, AD and PM median concentrations were 4.0 (range LOQ–48), 15.5 (range 4.0–176) and 4.4 ng/mL (LOQ–56), respectively. The median elapsed times from AM to AD and AD to PM were 33 and 97.5 h, respectively. In contrast, acetaminophen showed no change in blood concentration from AM to AD (6.8 and 6.0 mg/L, respectively). These dat...
Drugs related to morphine represent not only large range of important therapeutic applications fo... more Drugs related to morphine represent not only large range of important therapeutic applications for the relief of moderate to severe pain but also give rise to a relatively large series of novel opioids that mimic the action of this naturally occurring analgesic. Most of these are based on fentanyl structures that are much more potent, and dangerous, than fentanyl itself. This publication reviews reports of fatalities attributed to 15 novel opioids with the view to assessing mortality associated with their misuse as well as reviewing published analytical procedures that would be able to detect these and other novel opioids. These drugs include reports of deaths to acetylfentanyl, acrylfentanyl, butr(yl)fentanyl, carfentanil, 2-and 4-fluorofentanyls, 4-fluorobutyrfentanyl, 4-fluoroisobutyrfentanyl, furanylfentanyl, aand 3-methylfentanyls, 4-methoxyfentanyl, ocfentanil, as well as AH-7921, U-47700 and MT-45. Most of these cases reporting a drug-caused death involved other drugs in addition to the opioid. No obvious minimum fatal concentration was discerned for any of the opioids for which details were provided, however, the more potent members required detection limits well under 1 ng/mL and often even well below 0.1 ng/mL requiring use of the most sensitive mass spectral detection procedures, particularly when screening specimens using a non-targeted mode. Four other novel opioids have been reported in admissions to hospitals include 4-chloroisobutryfentanyl, cyclopentylfentanyl and tetrahydrofuranfentanyl, all of which are likely to have the potential to cause death. It is also likely that other analogues will appear with time.
Clinical toxicology (Philadelphia, Pa.), Jan 17, 2018
Take-home naloxone (THN) programs have been implemented in order to reduce the number of heroin-o... more Take-home naloxone (THN) programs have been implemented in order to reduce the number of heroin-overdose deaths. Because of recent legislative changes in Australia, there is a provision for a greater distribution of naloxone in the community, however, the potential impact of these changes for reduced heroin mortality remains unclear. The aim of this study was to examine the characteristics of the entire cohort of fatal heroin overdose cases and assess whether there was an opportunity for bystander intervention had naloxone been available at the location and time of each of the fatal overdose events to potentially avert the fatal outcome in these cases. The circumstances related to the fatal overdose event for the cohort of heroin-overdose deaths in the state of Victoria, Australia between 1 January 2012 and 31 December 2013 were investigated. Coronial data were investigated for all cases and data linkage was performed to additionally investigate the Emergency Medical Services inform...
To investigate the extent of variability in the reporting of heroin-related deaths in Victoria, A... more To investigate the extent of variability in the reporting of heroin-related deaths in Victoria, Australia. Additionally, to identify opportunities to improve the accuracy and consistency of heroin-related death reporting by examining variability in the attribution, death certification, classification and coding of heroin-related death cases. Heroin-related deaths in Victoria, Australia over a two-year period (2012 - 2013) were identified using the National Coronial Information System (NCIS) and used as the 'gold standard' measure in this study. Heroin-related death data from the Australian Institute of Health and Welfare (AIHW) and Australian Bureau of Statistics (ABS) were then compared. Differences in the number of deaths reported as well as the classification and coding assigned to the identified heroin-related death cases were investigated by cross-referencing these datasets and by examining the assigned ICD-10 codes. A total of 243 heroin-related deaths were identified through the NCIS compared with 165 heroin-related deaths reported by the AIHW and assigned the heroin-specific ICD-10 code of T40.1. Forty percent of all the missed heroin-related death cases resulted from either the attribution of the death to morphine toxicity or with non-specific drug toxicity certification. A further 30% occurred where the cases had been attributed to heroin but there were irregularities in death certification. A further 24% occurred as a result of late initial registration of these deaths to the Registry of Births, Deaths and Marriages, and where these cases were then not assessed by the ABS for classification and coding purposes. In Victoria, Australia, in 2012 and 2013, the overall number of heroin-related deaths was underreported by 32% compared with the number of deaths currently identified by the Australian Bureau of Statistics and reported by the Australian Institute of Health and Welfare.
Heroin use is associated with a disproportionately high level of morbidity and mortality with mos... more Heroin use is associated with a disproportionately high level of morbidity and mortality with most deaths attributable to drug overdose. Aggregate heroin purity data has been used to examine the relationship between overdose and variability in street-level heroin, however heroin purity data alone may not be the most appropriate nor a sensitive enough measurement tool for this assessment. The aim of this study was to measure the variability in effective dose of street-level heroin seizures, accounting for variation in both purity and mass, and determine the proportion of samples with higher than expected effective dose that would not be detected using a purity-only measure. Data on Victorian heroin seizures ≤150mg in mass made between 01/01/2012 and 31/12/2013 were obtained from the Victoria Police Forensic Services Department. The effective dose of heroin in each sample was determined by multiplying the mass and purity variables. Effective dose outlier samples were considered as tho...
Clinical toxicology (Philadelphia, Pa.), Jan 6, 2018
The aim of this study was to investigate the safety of the management of non-fatal heroin overdos... more The aim of this study was to investigate the safety of the management of non-fatal heroin overdose in the out-of-hospital environment; irrespective of whether or not naloxone had been administered. Heroin toxicity-related deaths as well as heroin intoxication-related traumatic deaths following patient-initiated refusal of transport were investigated. Heroin-related deaths in the state of Victoria, Australia between 1 January 2012 and 31 December 2013 were investigated and data linkage to pre-hospital Emergency Medical Services performed, in order to identify whether the death was related to the last episode of care by paramedics. The number of non-fatal heroin overdose events over the study period were also examined. There were a total of 3921 heroin-related attendances by paramedics during the study period, including 2455 cases that involved treatment but where the patient was not transported to hospital. There were also 243 heroin-related deaths identified over the study period an...
This is a critical review to discuss the best practice approaches to mortuary operations in prepa... more This is a critical review to discuss the best practice approaches to mortuary operations in preparation for and the response to natural, mass fatality, disaster events, as identified by a review of published articles. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) Statement guided the identification of potential articles to use in this critical review. Subsequent searches were also conducted to identify articles relating to heat wave, and flood mortality. All identified peer-reviewed studies published in English which discussed the preparation and response of mortuaries to mass fatality natural disasters occurring in developed countries were included. Using the PRISMA-P method of identifying articles, 18 articles were selected for inclusion in this review. Although there are numerous articles which describe the mortuary response to mass fatality incidents, few articles analyzed the response, or discussed the roles which supported and enabled the organization to undertake the task of identifying disaster victims. It is thus difficult to determine objectively if the actions and activities outlined in the articles represent best-practice.
Fatal poisonings in children comprise a small proportion of cases investigated by an Australian c... more Fatal poisonings in children comprise a small proportion of cases investigated by an Australian coroner; however, they present a major opportunity for death prevention. This study aimed to examine fatal child poisonings in Australia to (1) estimate the rate of acute poisoning deaths in children; (2) describe the key characteristics of the cohort; and (3) describe the outcomes of coronial recommendations made as a death prevention measure. Retrospective case series. The National Coronial Information System (NCIS), a database of cases reported to an Australian coroner. Ninety poisoning deaths reported to an Australian coroner between January 2003 and December 2013 involving children (≤ 16 years of age). Logistic regression, Pearson's correlation coefficient and descriptive statistics were used to examine the significance of associations. The primary outcome measures were poisoning type and cause of death. Covariates included age and mental illness. There were marginally more males (52.2%) [confidence interval (CI) = 44.4-45.6] in the cohort and most occurred in the 13-16-year age group (58.9%) (CI = 7.5-12.5). Deaths were typically unintentional (61.1%) (CI = 17.9-27.1) and occurred in the home (68.9%) (CI = 6.8-15.7). The most common form of poisoning was due to opioids (24.4%), followed by carbon monoxide (20%) and volatile substances (18.9%) (CI = 18.5-19.6). Males had slightly higher odds of dying from prescription opioids compared with females [odds ratio (OR) = 1.9, CI = 0.7-5.1], but this was not statistically significant. A recommendation was made by a coroner in 12 cases, 10 of which related to poisons (including drugs). Of these, eight recommendations were implemented. In Australia between 2003 and 2013 there were on average eight acute poisoning deaths in children each year, most commonly involving prescription opioids and adolescents. There has been a downward trend in mortality since 2003. These cases generated more than twice as many recommendations for public safety compared with other Australian coroners' cases.
The prevalence of overdose deaths from opioids is still generally increasing throughout the world... more The prevalence of overdose deaths from opioids is still generally increasing throughout the world. Heroin is still the predominant illicit opioid of interest to toxicology laboratories because of its continuing widespread availability and its ability to elicit respiratory depression and coma. In many countries methadone continues to play a major role in cases of drug toxicity because of its large-scale use to treat opioid dependency and its high potency and long duration of action. Increasingly, buprenorphine is being used as an alternative pharmacotherapy, and although apparently safer than methadone, it still has an inherent risk of toxicity when used with CNS depressants such as benzodiazepines or when injected. Morphine continues to be the dominant analgesic; however, oxycodone, hydromorphone, hydrocodone, and fentanyl are increasingly being used and will require increasing efforts by toxicology laboratories to ensure that these substances are adequately covered by testing programs.
The objectives of this paper were to determine the number of heroin-related deaths in Victoria fo... more The objectives of this paper were to determine the number of heroin-related deaths in Victoria for the years 1997-1998 and to detail the demography and toxicology findings, and also compare heroin death rates for this decade. The number of deaths attributed to the intravenous use of heroin has increased dramatically in Victoria since 1990. The increases were 5-fold. There were 166 deaths in 1997 and 268 in 1998. The heroin death is typified by a median age of 30 for males and 29 for females, although the age range is from children as young as 15 to adults in their sixth decade of life. Over 85% of cases were using other central nervous system depressants, with benzodiazepines (45%) and alcohol (36%) being the most common. Approximately 60% occurred indoors at a private residence, the remainder occurred in public places and other locations. A similar number (60%) died alone. A wide distribution of deaths occurred throughout the metropolitan and regional areas showing a growing spread in the heroin problem in the community.
The formation of an S-nitrosothiol compound, S-nitroso-N-acetylcysteine (SNAC) has recently been ... more The formation of an S-nitrosothiol compound, S-nitroso-N-acetylcysteine (SNAC) has recently been proposed to mediate the augmentation of the anti-aggregatory and haemodynamic effects of glyceryl trinitrate observed in the presence of N-acetylcysteine. This study investigated the effects on an isolated coronary artery preparation of acute and prolonged exposure to S-nitrosothiol compounds and nitric oxide (NO). 2 Single doses of NO and of the S-nitrosothiol compounds, SNAC and S-nitroso-N-acetylpenicillamine (SNAP), induced rapid, but transient, relaxations in U46619-contracted bovine isolated coronary artery rings. Peak relaxation responses to SNAP and NO were attenuated in the presence of N-acetylcysteine, cysteine, ascorbic acid and methylene blue. The duration of the relaxation responses to SNAC was two to three times longer than those to SNAP and NO. In the presence of N-acetylcysteine (but not cysteine, ascorbic acid or methylene blue) the duration of the relaxation responses to SNAP and NO (but not to SNAC) was markedly increased. H.p.l.c. assay confirmed that, in the presence of N-acetylcysteine, SNAP and, to a lesser degree, NO were converted to the relatively more stable and longer acting vasodilator, SNAC. 3 When compared to control rings, coronary artery rings superfused with glyceryl trinitrate were subsequently markedly less responsive to the vasodilator actions of glyceryl trinitrate, whereas responsiveness to SNAC or NO was only marginally reduced. On the other hand, coronary artery rings superfused with SNAC or NO were subsequently less responsive to glyceryl trinitrate, SNAC and NO. Thus prolonged vascular exposure to SNAC or NO induced a form of tolerance different from that induced with glyceryl trinitrate and which is possibly associated with impaired guanylate cyclase activity. 4 Coronary artery rings superfused with NO were markedly less responsive to glyceryl trinitrate and NO, whereas responses to the endothelium-dependent vasodilator A23187 and to theophylline were not significantly attenuated. 5 It is concluded that formation of the more stable vasodilator SNAC occurs on incubation of N-acetylcysteine with SNAP or NO. While coronary artery responsiveness to SNAC and NO is virtually unchanged in the presence of glyceryl trinitrate-induced tolerance, after prolonged exposure to SNAC or NO tolerance may develop to these vasodilators with cross-tolerance to glyceryl trinitrate but not A23187. Thus, formation or therapeutic utilization of SNAC may acutely circumvent the problem of glyceryl trinitrate-induced tolerance but, during prolonged vascular exposure to SNAC, attenuation of vascular responsiveness may occur to a wide range of vasodilators.
Changes in the concentrations of Δ9-tetrahydrocannabinol (THC) in the postmortem period were inve... more Changes in the concentrations of Δ9-tetrahydrocannabinol (THC) in the postmortem period were investigated in a series of cases by comparing concentrations in blood taken on receipt of the body in the mortuary (admission specimen, AD) with the concentrations obtained in blood taken at autopsy some time later and also from blood specimens taken antemortem. Overall, the median THC concentration in AD blood was 13.7 ng/mL (n = 239, range LOQ–220), while the median concentration at autopsy was 13.8 ng/mL (n = 106, range LOQ–810) and 1.9 ng/mL (n = 147, range LOQ–48) antemortem. Fourteen cases had all three specimens taken from the same decedent. The corresponding AM, AD and PM median concentrations were 4.0 (range LOQ–48), 15.5 (range 4.0–176) and 4.4 ng/mL (LOQ–56), respectively. The median elapsed times from AM to AD and AD to PM were 33 and 97.5 h, respectively. In contrast, acetaminophen showed no change in blood concentration from AM to AD (6.8 and 6.0 mg/L, respectively). These dat...
Drugs related to morphine represent not only large range of important therapeutic applications fo... more Drugs related to morphine represent not only large range of important therapeutic applications for the relief of moderate to severe pain but also give rise to a relatively large series of novel opioids that mimic the action of this naturally occurring analgesic. Most of these are based on fentanyl structures that are much more potent, and dangerous, than fentanyl itself. This publication reviews reports of fatalities attributed to 15 novel opioids with the view to assessing mortality associated with their misuse as well as reviewing published analytical procedures that would be able to detect these and other novel opioids. These drugs include reports of deaths to acetylfentanyl, acrylfentanyl, butr(yl)fentanyl, carfentanil, 2-and 4-fluorofentanyls, 4-fluorobutyrfentanyl, 4-fluoroisobutyrfentanyl, furanylfentanyl, aand 3-methylfentanyls, 4-methoxyfentanyl, ocfentanil, as well as AH-7921, U-47700 and MT-45. Most of these cases reporting a drug-caused death involved other drugs in addition to the opioid. No obvious minimum fatal concentration was discerned for any of the opioids for which details were provided, however, the more potent members required detection limits well under 1 ng/mL and often even well below 0.1 ng/mL requiring use of the most sensitive mass spectral detection procedures, particularly when screening specimens using a non-targeted mode. Four other novel opioids have been reported in admissions to hospitals include 4-chloroisobutryfentanyl, cyclopentylfentanyl and tetrahydrofuranfentanyl, all of which are likely to have the potential to cause death. It is also likely that other analogues will appear with time.
Clinical toxicology (Philadelphia, Pa.), Jan 17, 2018
Take-home naloxone (THN) programs have been implemented in order to reduce the number of heroin-o... more Take-home naloxone (THN) programs have been implemented in order to reduce the number of heroin-overdose deaths. Because of recent legislative changes in Australia, there is a provision for a greater distribution of naloxone in the community, however, the potential impact of these changes for reduced heroin mortality remains unclear. The aim of this study was to examine the characteristics of the entire cohort of fatal heroin overdose cases and assess whether there was an opportunity for bystander intervention had naloxone been available at the location and time of each of the fatal overdose events to potentially avert the fatal outcome in these cases. The circumstances related to the fatal overdose event for the cohort of heroin-overdose deaths in the state of Victoria, Australia between 1 January 2012 and 31 December 2013 were investigated. Coronial data were investigated for all cases and data linkage was performed to additionally investigate the Emergency Medical Services inform...
To investigate the extent of variability in the reporting of heroin-related deaths in Victoria, A... more To investigate the extent of variability in the reporting of heroin-related deaths in Victoria, Australia. Additionally, to identify opportunities to improve the accuracy and consistency of heroin-related death reporting by examining variability in the attribution, death certification, classification and coding of heroin-related death cases. Heroin-related deaths in Victoria, Australia over a two-year period (2012 - 2013) were identified using the National Coronial Information System (NCIS) and used as the 'gold standard' measure in this study. Heroin-related death data from the Australian Institute of Health and Welfare (AIHW) and Australian Bureau of Statistics (ABS) were then compared. Differences in the number of deaths reported as well as the classification and coding assigned to the identified heroin-related death cases were investigated by cross-referencing these datasets and by examining the assigned ICD-10 codes. A total of 243 heroin-related deaths were identified through the NCIS compared with 165 heroin-related deaths reported by the AIHW and assigned the heroin-specific ICD-10 code of T40.1. Forty percent of all the missed heroin-related death cases resulted from either the attribution of the death to morphine toxicity or with non-specific drug toxicity certification. A further 30% occurred where the cases had been attributed to heroin but there were irregularities in death certification. A further 24% occurred as a result of late initial registration of these deaths to the Registry of Births, Deaths and Marriages, and where these cases were then not assessed by the ABS for classification and coding purposes. In Victoria, Australia, in 2012 and 2013, the overall number of heroin-related deaths was underreported by 32% compared with the number of deaths currently identified by the Australian Bureau of Statistics and reported by the Australian Institute of Health and Welfare.
Heroin use is associated with a disproportionately high level of morbidity and mortality with mos... more Heroin use is associated with a disproportionately high level of morbidity and mortality with most deaths attributable to drug overdose. Aggregate heroin purity data has been used to examine the relationship between overdose and variability in street-level heroin, however heroin purity data alone may not be the most appropriate nor a sensitive enough measurement tool for this assessment. The aim of this study was to measure the variability in effective dose of street-level heroin seizures, accounting for variation in both purity and mass, and determine the proportion of samples with higher than expected effective dose that would not be detected using a purity-only measure. Data on Victorian heroin seizures ≤150mg in mass made between 01/01/2012 and 31/12/2013 were obtained from the Victoria Police Forensic Services Department. The effective dose of heroin in each sample was determined by multiplying the mass and purity variables. Effective dose outlier samples were considered as tho...
Clinical toxicology (Philadelphia, Pa.), Jan 6, 2018
The aim of this study was to investigate the safety of the management of non-fatal heroin overdos... more The aim of this study was to investigate the safety of the management of non-fatal heroin overdose in the out-of-hospital environment; irrespective of whether or not naloxone had been administered. Heroin toxicity-related deaths as well as heroin intoxication-related traumatic deaths following patient-initiated refusal of transport were investigated. Heroin-related deaths in the state of Victoria, Australia between 1 January 2012 and 31 December 2013 were investigated and data linkage to pre-hospital Emergency Medical Services performed, in order to identify whether the death was related to the last episode of care by paramedics. The number of non-fatal heroin overdose events over the study period were also examined. There were a total of 3921 heroin-related attendances by paramedics during the study period, including 2455 cases that involved treatment but where the patient was not transported to hospital. There were also 243 heroin-related deaths identified over the study period an...
This is a critical review to discuss the best practice approaches to mortuary operations in prepa... more This is a critical review to discuss the best practice approaches to mortuary operations in preparation for and the response to natural, mass fatality, disaster events, as identified by a review of published articles. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P) Statement guided the identification of potential articles to use in this critical review. Subsequent searches were also conducted to identify articles relating to heat wave, and flood mortality. All identified peer-reviewed studies published in English which discussed the preparation and response of mortuaries to mass fatality natural disasters occurring in developed countries were included. Using the PRISMA-P method of identifying articles, 18 articles were selected for inclusion in this review. Although there are numerous articles which describe the mortuary response to mass fatality incidents, few articles analyzed the response, or discussed the roles which supported and enabled the organization to undertake the task of identifying disaster victims. It is thus difficult to determine objectively if the actions and activities outlined in the articles represent best-practice.
Fatal poisonings in children comprise a small proportion of cases investigated by an Australian c... more Fatal poisonings in children comprise a small proportion of cases investigated by an Australian coroner; however, they present a major opportunity for death prevention. This study aimed to examine fatal child poisonings in Australia to (1) estimate the rate of acute poisoning deaths in children; (2) describe the key characteristics of the cohort; and (3) describe the outcomes of coronial recommendations made as a death prevention measure. Retrospective case series. The National Coronial Information System (NCIS), a database of cases reported to an Australian coroner. Ninety poisoning deaths reported to an Australian coroner between January 2003 and December 2013 involving children (≤ 16 years of age). Logistic regression, Pearson's correlation coefficient and descriptive statistics were used to examine the significance of associations. The primary outcome measures were poisoning type and cause of death. Covariates included age and mental illness. There were marginally more males (52.2%) [confidence interval (CI) = 44.4-45.6] in the cohort and most occurred in the 13-16-year age group (58.9%) (CI = 7.5-12.5). Deaths were typically unintentional (61.1%) (CI = 17.9-27.1) and occurred in the home (68.9%) (CI = 6.8-15.7). The most common form of poisoning was due to opioids (24.4%), followed by carbon monoxide (20%) and volatile substances (18.9%) (CI = 18.5-19.6). Males had slightly higher odds of dying from prescription opioids compared with females [odds ratio (OR) = 1.9, CI = 0.7-5.1], but this was not statistically significant. A recommendation was made by a coroner in 12 cases, 10 of which related to poisons (including drugs). Of these, eight recommendations were implemented. In Australia between 2003 and 2013 there were on average eight acute poisoning deaths in children each year, most commonly involving prescription opioids and adolescents. There has been a downward trend in mortality since 2003. These cases generated more than twice as many recommendations for public safety compared with other Australian coroners' cases.
The prevalence of overdose deaths from opioids is still generally increasing throughout the world... more The prevalence of overdose deaths from opioids is still generally increasing throughout the world. Heroin is still the predominant illicit opioid of interest to toxicology laboratories because of its continuing widespread availability and its ability to elicit respiratory depression and coma. In many countries methadone continues to play a major role in cases of drug toxicity because of its large-scale use to treat opioid dependency and its high potency and long duration of action. Increasingly, buprenorphine is being used as an alternative pharmacotherapy, and although apparently safer than methadone, it still has an inherent risk of toxicity when used with CNS depressants such as benzodiazepines or when injected. Morphine continues to be the dominant analgesic; however, oxycodone, hydromorphone, hydrocodone, and fentanyl are increasingly being used and will require increasing efforts by toxicology laboratories to ensure that these substances are adequately covered by testing programs.
The objectives of this paper were to determine the number of heroin-related deaths in Victoria fo... more The objectives of this paper were to determine the number of heroin-related deaths in Victoria for the years 1997-1998 and to detail the demography and toxicology findings, and also compare heroin death rates for this decade. The number of deaths attributed to the intravenous use of heroin has increased dramatically in Victoria since 1990. The increases were 5-fold. There were 166 deaths in 1997 and 268 in 1998. The heroin death is typified by a median age of 30 for males and 29 for females, although the age range is from children as young as 15 to adults in their sixth decade of life. Over 85% of cases were using other central nervous system depressants, with benzodiazepines (45%) and alcohol (36%) being the most common. Approximately 60% occurred indoors at a private residence, the remainder occurred in public places and other locations. A similar number (60%) died alone. A wide distribution of deaths occurred throughout the metropolitan and regional areas showing a growing spread in the heroin problem in the community.
The formation of an S-nitrosothiol compound, S-nitroso-N-acetylcysteine (SNAC) has recently been ... more The formation of an S-nitrosothiol compound, S-nitroso-N-acetylcysteine (SNAC) has recently been proposed to mediate the augmentation of the anti-aggregatory and haemodynamic effects of glyceryl trinitrate observed in the presence of N-acetylcysteine. This study investigated the effects on an isolated coronary artery preparation of acute and prolonged exposure to S-nitrosothiol compounds and nitric oxide (NO). 2 Single doses of NO and of the S-nitrosothiol compounds, SNAC and S-nitroso-N-acetylpenicillamine (SNAP), induced rapid, but transient, relaxations in U46619-contracted bovine isolated coronary artery rings. Peak relaxation responses to SNAP and NO were attenuated in the presence of N-acetylcysteine, cysteine, ascorbic acid and methylene blue. The duration of the relaxation responses to SNAC was two to three times longer than those to SNAP and NO. In the presence of N-acetylcysteine (but not cysteine, ascorbic acid or methylene blue) the duration of the relaxation responses to SNAP and NO (but not to SNAC) was markedly increased. H.p.l.c. assay confirmed that, in the presence of N-acetylcysteine, SNAP and, to a lesser degree, NO were converted to the relatively more stable and longer acting vasodilator, SNAC. 3 When compared to control rings, coronary artery rings superfused with glyceryl trinitrate were subsequently markedly less responsive to the vasodilator actions of glyceryl trinitrate, whereas responsiveness to SNAC or NO was only marginally reduced. On the other hand, coronary artery rings superfused with SNAC or NO were subsequently less responsive to glyceryl trinitrate, SNAC and NO. Thus prolonged vascular exposure to SNAC or NO induced a form of tolerance different from that induced with glyceryl trinitrate and which is possibly associated with impaired guanylate cyclase activity. 4 Coronary artery rings superfused with NO were markedly less responsive to glyceryl trinitrate and NO, whereas responses to the endothelium-dependent vasodilator A23187 and to theophylline were not significantly attenuated. 5 It is concluded that formation of the more stable vasodilator SNAC occurs on incubation of N-acetylcysteine with SNAP or NO. While coronary artery responsiveness to SNAC and NO is virtually unchanged in the presence of glyceryl trinitrate-induced tolerance, after prolonged exposure to SNAC or NO tolerance may develop to these vasodilators with cross-tolerance to glyceryl trinitrate but not A23187. Thus, formation or therapeutic utilization of SNAC may acutely circumvent the problem of glyceryl trinitrate-induced tolerance but, during prolonged vascular exposure to SNAC, attenuation of vascular responsiveness may occur to a wide range of vasodilators.
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Papers by Olaf Drummer