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R J Flanagan

Publications and source records attributed to R J Flanagan.

At least 19 recordsLinked to original sources
PubMed2006

Characterization of a microparticulate strong anion-exchanger in the HPLC of acidic drugs.

The use of Waters Spherisorb S5SAX for the HPLC of acidic compounds, including a number of non-steroidal anti-inflammatory drugs (NSAIDs), has been investigated. Adequate retention, separation, and peak efficiency and symmetry were obtained for most analytes on a 250 x 4.6 mm i.d. column using methanol containing ammonium perchlorate (10 mmol L(-1), pH 6.7 or pH 8.3) as eluent. The results of changes in (i) eluent pH (constant ionic strength); (ii) eluent ionic strength (constant pH); and (iii) adding water to the eluent (constant pH) were consistent with a retention mechanism dominated by ion-exchange with the bonded strong anion-exchange (SAX) moieties. However, there were some unexpected observations, including (i) a general decrease in retention at eluent pH values above 7.7; (ii) a marked increase in retention on adding 1% (v/v) water to the eluent; (iii) a subsequent marked decrease in retention on adding 5% (v/v) or more water; and (iv) decreased column activity with time. These observations may be due to (i) interaction between the charged SAX moieties and ionised surface silanols (with ionization increasing at higher eluent pH values) and (ii) influence of the solvation of silanols, analytes, SAX moiety, and counter-ion varying with both pH and water content. Nevertheless, the factors influencing separation of individual NSAIDs remain unclear especially as no relation between log k and pKa exists for these compounds. Hydrophobic interactions are unlikely to be important since basic and neutral compounds were hardly retained. Ease of accessibility of the counter-ion to the SAX moiety for analyte displacement may be a factor.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Fatal poisoning in childhood, England & Wales 1968-2000.

We analysed deaths certified as due to poisoning in England & Wales, 1968-2000, in children aged <10 years by age, sex, circumstances of death, intent, and agents involved. The number of deaths fell from 165 (20.6 per million children) in 1968 to 30 (4.6 per million) in 2000, a decrease of approximately 80%. The age-specific death rates were similar in boys and girls. The rate was initially much higher, and fell more, in those aged <5 years. Most deaths (n=1923) occurred in fires, and had been attributed to inhaling combustion products. A small number (n=104) occurred in fires resulting from motor vehicle and other transport accidents. From 1979 (use of ICD-9) the coding of some of these deaths changed from poisoning with carbon monoxide to poisoning with 'other gases, fumes or vapours'. These 'fire deaths' do not appear as poisonings in mortality statistics based on a single underlying cause of death, and cannot be tabulated as poisoning in many countries. Fire deaths and deaths coded to accidental, deliberate, or undetermined poisoning (n=702) decreased substantially with time, and by 2000 numbered 14 and 10, respectively. Accidental deaths declined from 151 in 1968 to 23 in 2000, but homicides and open verdicts varied from 5 to 20 per year, with no clear trend. Deaths attributed to carbon monoxide and to 'other gases, fumes or vapours' (mostly fire-related) totalled 2431 (84% of all poisoning deaths). Overall, 10% of these deaths were either certified as homicides or open verdicts. However, homicide or open verdict was recorded in half of the 47 fatal opiate poisonings. Opioids have now superseded antidepressants as the commonest agents encountered in fatal poisoning with drugs in children.

Accidents↗
PubMed2005

Fatal poisoning with antipsychotic drugs, England and Wales 1993-2002.

Prescription of atypical antipsychotics has increased in recent years. There have also been changes in the guidance on using older drugs, particularly the restriction in the use of thioridazine. We analysed deaths due to poisoning involving antipsychotics in England and Wales, 1993-2002, by age, sex, intent, and agents involved. We also studied antipsychotic prescribing in the community and poisoning deaths in England. Deaths attributed to adverse reactions in the course of normal treatment were not studied because these deaths are not classified as 'poisonings'. The number of deaths involving antipsychotics increased from around 55 per year 1993-1998 to 74 in 2000, and then fell to 53 in 2002. Around 25% of deaths had a verdict of accidental death and in about 60% of deaths a verdict of suicide or an open verdict was recorded. There were no deaths involving thioridazine in 2002, following its removal from use in 2001. However, the number of deaths associated with atypicals, most notably olanzapine and clozapine, has increased. Age-specific death rates were highest in those aged 30-39 and 40-49 years, and were very low in those aged under 20 and 70 or over. Death rates in males were greater than in females. For many drugs the proportion mentions either alone or with ethanol, was 25-45%, but for clozapine and olanzapine such mentions totalled 65-69%. Deaths per million prescriptions (clozapine excluded) were highest for quetiapine (31.3 per million), chlorpromazine (29.4 per million) and thioridazine (15.5 per million).

Accidents↗
PubMed2004

Suspected clozapine poisoning in the UK/Eire, 1992-2003.

OBJECTIVE: Toxicological analyses are often performed to investigate suspected poisoning, but the interpretation of results may not be straightforward. We studied suspected poisoning cases 1992-2003 where blood clozapine and N-desmethylclozapine (norclozapine) were measured in order to assess the relationship of these parameters to outcome. METHODS: Samples were referred from clinicians, pathologists/coroners, or via the Clozaril Patient Monitoring Service (CPMS, Novartis). Information was gathered from clinical, post-mortem, or coroners' reports. RESULTS: There were seven fatal [five male, two female; median (range) age 28 (24-41) year] and five non-fatal [four male, one female; median age 35 (26-41) year] clozapine overdoses. The median post-mortem blood clozapine and norclozapine concentrations were 8.2 (3.7-12) and 1.9 (1.4-2.4)mg/L, respectively [median clozapine:norclozapine ratio 4.4 (2.9-5.1)]. The median plasma clozapine and norclozapine concentrations (first or only sample) were 3.9 (1.7-7.0) and 0.40 (0.30-0.70)mg/L, respectively [median clozapine:norclozapine ratio 7.6 (5.3-18)] in the remainder. These overdoses were in patients who were poorly or non-adherent to clozapine, or who had taken tablets prescribed for someone else. In 54 further people who died whilst receiving clozapine [38 male, 16 female; median age 41 (22-70) year], the median post-mortem blood clozapine and norclozapine concentrations were 1.9 (0-7.7, n = 43) and 1.4 (0-6.0, n = 39)mg/L, respectively [median clozapine:norclozapine ratio 1.5 (0.4-7.6, n = 38)]. The median post-mortem increase in blood clozapine and norclozapine as compared to the most recent ante-mortem measurement was 489 (98-5,350)% and 371 (139-831)%, respectively [median sample time before death 14 (0-30, n = 21) days]. CONCLUSION: Clozapine poisoning cannot be diagnosed on the basis of blood clozapine and norclozapine concentrations alone. The analysis of ante-mortem blood specimens collected originally for white cell count monitoring and the blood clozapine:norclozapine ratio may provide additional interpretative information.

Adult↗
PubMed2003

Effect of post-mortem changes on peripheral and central whole blood and tissue clozapine and norclozapine concentrations in the domestic pig (Sus scrofa).

Interpretation of the results of psychoactive or other drug measurements in post-mortem blood specimens may not be straightforward, in part because analyte concentrations in blood may change after death. There is also the issue of comparability of plasma (or serum) results to those obtained in whole blood. To investigate these problems with respect to clozapine, this drug (10mg/kg daily) was given orally to two pigs. Blood was collected 3h post-dose on day 7, the animals were sacrificed, and blood taken from central and peripheral veins for up to 48 h after death. Tissue samples were also collected immediately after death and at 48 h. Ante-mortem whole blood clozapine/N-desmethylclozapine (norclozapine) concentrations were 0.86/1.07 and 1.11/1.15 mg/l in pigs 1 and 2, respectively. Blood clozapine and norclozapine concentrations generally increased after death (central vein: clozapine up to 300%, norclozapine up to 460%; peripheral vein: clozapine up to 155%, norclozapine up to 185%). Initial blood and kidney clozapine and norclozapine concentrations were comparable in both animals, but were some two-fold higher in heart, liver and striated muscle in pig 2. In both animals, the heart and striated muscle clozapine and norclozapine concentrations had increased some two- to three-fold at 48 h, whilst the liver and kidney concentrations were essentially unchanged. The reason for the increase in heart and striated muscle concentrations at 48 h is unclear, but could be simple variation in sample site. The plasma:whole blood distribution of clozapine and norclozapine was studied in vitro. In human blood (one volunteer donor, haematocrit 0.50) the plots of plasma versus whole blood concentration were linear for both analytes across the range 0.1-1.5mg/l, although clozapine favoured plasma (plasma:whole blood ratio=1.12), whereas norclozapine favoured whole blood (ratio 0.68). In pig blood, the plots of plasma versus whole blood were non-linear in both cases, although clozapine favoured plasma to a greater extent than norclozapine. This may be due to lower plasma clozapine and norclozapine protein binding capacity in the pig as compared to man.

Adipose Tissue↗
PubMed2003

Adult respiratory distress syndrome and renal failure associated with citalopram overdose.

A 45-year-old man ingested 3000 mg of citalopram hydrobromide (2400 mg citalopram). He presented to the Emergency Department 2 hours post-ingestion with a pulse of 100 beats/min and blood pressure of 120/80 mmHg. His electrocardiogram (ECG) was normal. Chest X-ray showed bilateral shadowing, with no evidence of aspiration of gastric contents. Shortly after, he had three tonic-clonic seizures, requiring intravenous diazepam. Eight hours post-ingestion he became oliguric with deteriorating renal function, despite normal arterial and central venous pressures. He became increasingly hypoxic, with chest X-ray changes compatible with adult respiratory distress syndrome (ARDS). Despite treatment with 100% oxygen and continuous positive airway pressure, his gas exchange continued to deteriorate, requiring intubation and ventilation. His renal function also deteriorated with a peak creatinine of 492 micromol/L on day 4 in the absence of rhabdomyolysis. There was complete spontaneous recovery of renal function after 2 weeks. A peak plasma total citalopram (R+S enantiomers) concentration of 1.92 mg/L was recorded 2 hours post-ingestion. Total norcitalopram concentrations continued to rise up to 24 hours post-ingestion. Citalopram has been associated with seizures, ECG abnormalities, rhabdomyolysis and coma after overdose. The renal and respiratory complications seen in this patient have not been reported previously.

Citalopram↗
PubMed2002

Recording acute poisoning deaths.

Recording deaths from acute poisoning/substance abuse is not straightforward. The International Classification of Diseases (ICD), used to code mortality statistics, is aimed towards recording the underlying cause of death such as suicide or drug dependence rather than gathering data on poisoning per se. Despite the inherent difficulties clear trends can be observed from the data available for England and Wales. There have been marked changes in the compounds featuring in suicidal poisoning in the last 35 years reflecting changes in the availability of poisons, notably carbon monoxide and prescription barbiturates. However, although the number of poisoning suicides has decreased in the recent years, suicides from other means have increased in males (suicides in 1999, 75% male), hence there has been little change in the annual total of suicides. There are also striking differences in drug abuse- and volatile substance abuse (VSA)-related deaths between males and females. Drug abuse-related fatal poisoning (83% male, 1979-1999, European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) definition which does not include suicide), largely attributable to heroin and methadone, increased markedly during the 1990s, with a sharp rise in deaths attributed to accidental poisoning, although deaths involving methadone are now declining. VSA-related deaths (90% male, 1971-1999, almost entirely accidental deaths), nowadays predominantly from abuse of fuel gases (liquefied petroleum gas, LPG) from, for example, cigarette lighter refills, have declined from a peak in the early 1990s and are now becoming manifest in an older age group. These two latter instances especially provide examples where ICD-derived fatal poisoning data are inadequate and a 'poisons oriented' approach to data collection and analysis is necessary.

Adolescent↗
PubMed2001

HPLC of basic drugs on microparticulate strong cation-exchange materials - a review.

Propylsulphonic acid (SCX)-modified silica HPLC columns used with methanol or aqueous methanol eluents of appropriate pH and ionic strength can give good retention and peak shape for basic drugs. In the system studied, eluent pH influenced retention via protonation of basic analytes, the pK(a) of the analyte indicating the pH where retention begins to decrease at constant ionic strength. At constant pH, retention is inversely proportional to ionic strength for protonated bases and quaternary ammonium compounds. The underlying retention mechanism appears to be ion-exchange with the SCX moieties, although ionized surface silanols may also contribute to retention at higher eluent pH values. In capillary electrochromatography (CEC) unprecedented efficiencies, but similar selectivity, to that observed in conventional HPLC have been obtained for a standard range of basic drugs using Waters Spherisorb S3SCX.SCX-modified silica columns can be used in the HPLC of many basic drugs, including some compounds that are poorly retained on unmodified silica using methanol-rich eluents. N-Desalkyl and sulphoxide metabolites are often resolved at an appropriate eluent pH. Even analogues differing by a methylene unit in a side-chain remote from a basic centre are often resolved. Applications of Waters Spherisorb S5SCX columns include HPLC of antimalarials such as chloroquine and quinine, cardioactive drugs, for example amiodarone and flecainide, antipsychotics (clozapine, olanzapine), and antidepressants (amitriptyline, clomipramine, dothiepin, fluoxetine) and their N-desalkyl metabolites. Major practical features of these systems are that (i) acidic and neutral compounds are not retained, (ii) solvent extracts can be injected directly, and (iii) eluent recycling can be performed routinely.

Cation Exchange Resins↗
PubMed2000

Monitoring of clozapine and norclozapine plasma concentration-time curves in acute overdose.

CASE REPORT: A 40-year-old schizophrenic man was found unconscious, with constricted pupils, sinus tachycardia, and twitching of the limbs. There were signs of lung infection, which was treated with antibiotics, and mild rhabdomyolysis. He regained consciousness over 8 hours, and reported taking 3-4 g clozapine. Recovery was uneventful. Measured peak clozapine and norclozapine concentrations were 3.53 mg/L and 0.70 mg/L, respectively. The concentration-time curves were biphasic, with secondary peaks at approximately 36 hours postadmission. Terminal elimination half-lives were 16.9 hours and 22.5 hours for clozapine and norclozapine, respectively. CONCLUSION: Clozapine and its metabolite norclozapine can show biphasic plasma concentration-time curves after overdosage.

Acute Disease↗
PubMed1998

Guidelines for the interpretation of analytical toxicology results and unit of measurement conversion factors.

A data compilation has been published on the World Wide Web [http:// www.leeds.ac.uk/acb/annals] which aims to assist in the interpretation of analytical toxicology results in individual patients. 'Therapeutic' or 'normal' plasma/whole blood/urine concentrations, as well as the concentrations associated with serious toxicity (if known), for some 700 analytes of toxicological interest are given together with (when possible) relative atomic or formula masses, and mass/amount and amount/mass concentration conversion factors. This paper gives background and supplementary information which should be borne in mind when providing interpretation or using the Web table. Supplementary tables listing (i) common therapeutic drug monitoring assays and guidelines for interpretation of results, (ii) emergency toxicology analyses which may influence active treatment, (iii) blood carboxyhaemoglobin saturation and clinical features of toxicity, (iv) information important when interpreting the results of toxicology investigations, (v) factors which may affect interpretation of analytical toxicology results, and (vi) conversion factors for volatile compounds are included.

Computer Communication Networks↗
PubMed1995

Continuous-infusion verapamil with etoposide in relapsed or resistant paediatric cancers.

This study evaluates the use of a multidrug resistance (MDR) modulator (verapamil) in combination with a standard dose of single-agent etoposide in relapsed or refractory paediatric malignancy. A total of 20 patients (median age 6.5 years) were treated with an infusion of verapamil (loading dose 0.1 mg kg-1, followed by continuous infusion 0.15 mg kg-1 h-1) for 72 h. Etoposide was given daily (150 mg m-2 day-1) for three doses (each over 1 h); the first dose was given 12 h into the verapamil infusion. Cardiovascular toxicity was monitored by ECG and 2 hourly blood pressure and pulse recordings. Verapamil and norverapamil plasma concentrations were measured daily. Disease response was assessed after two courses. A total of 29/35 treatment courses were given at the desired verapamil dose; five courses required a dose reduction owing to cardiovascular toxicity. No patient required intensive monitoring. All patients who developed cardiovascular toxicity were over 14 years old. There was no correlation between plasma verapamil or norverapamil concentrations and toxicity. There were six partial responses (three rhabdomyosarcoma, three neuroblastoma) after two courses, but because of variation in the dose and schedule of etoposide these cannot be unequivocally contributed to MDR reversal. In conclusion, a regimen using a continuous infusion of verapamil combined with divided-dose etoposide is tolerable in children, and this strategy may be effective in refractory neuroblastoma and rhabdomyosarcoma.

Adolescent↗
PubMed1995

Effect of urinary alkalinisation and acidification on the tissue distribution of hexachlorophene in rats.

1. Urinary alkalinisation may be helpful in treating acute poisoning with uncouplers of oxidative phosphorylation containing a phenolic hydroxyl (pKa 4-6) or other acidic moiety. 2. We studied the effects of urine alkalinisation and acidification on the tissue distribution of hexachlorophene (HCP, pKa 5.7) in male Sprague Dawley rats (10 rats/group). 3. Ammonium chloride (10 mL kg-1, 2% m/v) or sodium bicarbonate (10 mL kg-1, 2% m/v) were administered by gavage on three occasions over 24 h, prior to a single gavage dose of HCP (180 mg kg-1). Controls received aqueous sodium chloride (10 mL kg-1, 0.9% m/v) followed by either HCP (180 mg kg-1) or vehicle alone. 4. Urine pH, body mass and body temperature were monitored during the study and, at the conclusion of the experiment (12 h post-HCP dose), organ mass (liver, kidney, brain), and plasma, urine and tissue HCP concentrations were measured. 5. No clinical features of toxicity were observed in any group. However, sodium bicarbonate significantly reduced median HCP in liver--median plasma and kidney HCP concentrations were also reduced but not significantly. Conversely, ammonium chloride significantly increased median HCP concentrations in liver and kidney--median plasma HCP was also increased but not significantly. 6. The results provide some support for the hypothesis that blood pH influences the tissue distribution of uncouplers of oxidative phosphorylation containing an acidic moiety. Urinary alkalinisation may be useful in treating acute poisoning with these compounds.

Ammonium Chloride↗
PubMed1995

The poisoned patient: the role of the laboratory.

The past 20 years have seen many advances in methods for the assay of drugs and other poisons in biological fluids, with consequent improvement in the reliability of results. Therapeutic drug monitoring, drugs of abuse and laxative/diuretic screening, and occupational health monitoring have developed considerably. The value of assays with overt medico-legal implications and which require a high degree of analytical expertise (such as brain death and child abuse screening, and cases of suspected iatrogenic poisoning) has become more clearly defined. Emergency toxicological analyses are now sometimes requested to monitor treatment with (e.g.) chelating agents. However, paracetamol apart, the growth in requests for other emergency toxicology analyses has been small, at least in the UK. What are the challenges for the future? With the increasing role of analytical toxicology, training and quality assurance should have a higher profile. Standardisation of the units used in reporting results should also be pursued. The need for simple, reliable, low-cost methods for the assay of drugs, pesticides and industrial chemicals in biological specimens remains, especially in developing countries. Interpretation of results remains difficult and can only be improved by construction of an improved data base. Biological monitoring to assess occupational/environmental exposure to metals, industrial chemicals and pesticides is likely to increase in importance. Interpretation of results in individual cases can here be simplified by regulation.

Humans↗