Serious adverse reactions to anorectic agents.
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Appetite Depressants↗
Biomedical subjects
S H Thomas
Publications and source records attributed to S H Thomas.
Prehospital fentanyl analgesia in air-transported pediatric trauma patients.
OBJECTIVE: To review the 5.5-year safety record of a protocol guiding fentanyl administration to pediatric trauma patients undergoing aeromedical transport. METHODS: Retrospective review of an urban aeromedical program's trauma scene responses from October 1991 to March 1997 identified the study population as all pediatric patients (age <15 years) receiving fentanyl for analgesia during air transport. Patients receiving fentanyl concurrently with other agents, eg, paralytics, were not studied. The air transport team consisted of a flight nurse and flight paramedic who provided protocol-driven patient care with off-line medical control. Study patients' flight records were reviewed to determine vital signs (systolic blood pressure [SBP], heart rate [HR], and oxygen saturation [SAT]) before and after fentanyl administration. Postfentanyl vital signs were reviewed for evidence of hemodynamic or ventilatory compromise. Pre- and postfentanyl vital signs were compared with the paired t test (P < 0.05). Flight records were also analyzed for narrative information, eg, naloxone administration and assisted ventilation, indicative of fentanyl side effects. RESULTS: Fentanyl (0.33-5.0 microg/kg) was administered 211 times to 131 patients who had a median age of 6.2 years (0.1-14 years), median Glasgow coma score (GCS) of 9 (3-15), and a mean pediatric trauma score of 8.3+/-2.4. Seventy-nine (60.3%) patients were intubated; these patients received 139 (65.9 %) of the 211 total fentanyl doses. No adverse effects from fentanyl were noted in flight record narratives. The median interval between fentanyl administration and postfentanyl vital sign assessment was 9.5 minutes (1-35 minutes). Median postfentanyl changes in SBP and HR were -4.7 and -2.9%, respectively. No patient became hypotensive after fentanyl administration. In nonintubated patients, mean postfentanyl SAT (99.2+/-1.3%) was not significantly different (P = 0.70) from prefentanyl SAT (99.1+/-1.3%), and no patient was noted to have clinically significant SAT decrement after fentanyl. CONCLUSION: Retrospective review of more than five years of prehospital fentanyl administration revealed no untoward events. Although prospective definitive demonstration of fentanyl's field use is pending, it is reasonable to continue discretionary fentanyl administration to injured pediatric children in pain.
Adolescent↗
Interhospital aeromedical transports: air medical activation intervals in adult and pediatric trauma patients.
The purpose of this study was to determine whether pediatric trauma patients were transferred from community hospitals to trauma centers more expeditiously than adults of similar injury acuity. The study analyzed the air medical activation time, defined as the time delay between patient arrival at community hospitals and subsequent request for air medical transport to a Level I trauma center. Retrospective analysis of all interfacility air medical trauma transports by one service from October 1994 to June 1995 identified 40 pediatric and 156 adult patients. The mean air medical activation times for pediatric and adult trauma Interfacility transports were 36.5 and 70.1 minutes, respectively (P = .016). The study shows that community hospitals are able to expedite transfer of pediatric trauma patients and suggests that transfer delays for adult trauma patients may be reducible.
Adolescent↗
In-flight oral endotracheal intubation.
This study's goal was to analyze aeromedical emergency medical services (EMS) endotracheal intubation (ETI) success rates for in-flight intubations, and to retrospectively compare in-flight ETI success rates with those achieved in hospital and trauma scene settings. Patients undergoing flight crew ETI during a 3-year study period were reviewed, and flight team-performed intubations were classified as in-flight, hospital (at referring hospital), or ground (at trauma scene). Flight crews attempted ETI in 302 patients, with success in 291 patients (96.4%). ETI success rates for in-flight, hospital, and ground groups were 94.2%, 96.8%, and 98.3%, respectively (P = .22). There were no differences among the groups in proportions of pediatric patients (P = .55) or multiple intubation attempts (P = .83). Use of paralytic agents was more frequent in ground and in-flight groups as compared with hospital group patients (P = .03). We conclude that with the aircraft and aeromedical crew studied, ETI was as likely to be successful in-flight as in other settings.
Adolescent↗
Disposition of intravenous 123iodopentamidine in man.
This study compared the disposition of the radiopharmaceutical [123I]iodopentamidine with that of pentamidine after intravenous infusion by measuring plasma concentrations of each using scintilation counting and high-performance liquid chromatography (HPLC), respectively. There was rapid hepatic uptake and biliary excretion of the 123I label. Distribution kinetics of the 123I label were similar to those of pentamidine, but its elimination half-life (41 +/- 27 h) was longer than that of pentamidine measured by HPLC (11 +/- 8 h). [123I]iodopentamidine distribution reflects that of pentamidine, but elimination of the radiopharmaceutical appears slower.
Adult↗
A pharmacokinetic and pharmacodynamic interaction study between nebivolol and the H2-receptor antagonists cimetidine and ranitidine.
AIMS: The study was designed to investigate the effects of the H2-receptor antagonists, cimetidine and ranitidine on the pharmacokinetics and pharmacodynamics of nebivolol in healthy volunteers. METHODS: Twelve healthy volunteers took part in a randomized placebo-controlled cross-over study. Each subject received on three separate occasions placebo, cimetidine (400 mg twice daily) or ranitidine (150 mg twice daily) for 24 h before and 48 h after a single oral dose of nebivolol (5 mg). Nebivolol and its individual (+) and (-) enantiomers were determined tby h.p.l.c. RESULTS: Ranitidine had no significant effect on nebivolol pharmacokinetics. Cimetidine, however, resulted in a 21-23% increase in Cmax of unchanged nebivolol and of each enantiomer plus its hydroxylated metabolites. Cimetidine significantly (p < 0.05) increased the AUC [mean +/- s.d. (95% C.I. of differences in mean)] for unchanged (+/-)-nebivolol [7.76 +/- 3.07 ng ml-1 h with placebo; 11.50 +/- 5.40 (1.75, 8.76) ng ml-1 h with cimetidine], (+)-nebivolol plus its hydroxylated metabolites [73.0 +/- 18.0 ng ml-1 h with placebo; 91.5 +/- 25.7 (1.0, 23.1) ng ml-1 h with cimetidine] and (-)-nebivolol plus its hydroxylated metabolites [101 +/- 32 ng ml-1 h with placebo; 123 +/- 38 (3.3, 27.0) ng ml-1 h with cimetidine]. Statistical analysis of the resting blood pressure and heart rate and exercise data did not suggest any consistent effects of ranitidine or cimetidine upon the pharmacodynamic effects of nebivolol. CONCLUSIONS: There was no interaction between ranitidine and nebivolol. Although cimetidine inhibited nebivolol metabolism, it did not have a significant influence on the pharmacodynamics of the drug.
Adult↗
Methotrexate pneumonitis in a patient with rheumatoid arthritis.
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Antirheumatic Agents↗
Nebuliser therapy in the intensive care unit.
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Critical Care↗
Paracetamol poisoning in the north east of England: presentation, early management and outcome.
1. Paracetamol is increasingly involved in self-poisoning in the United Kingdom and remains a common cause of fatal poisoning. 2. To document the epidemiology and early management of paracetamol poisoning data were collected on consecutive patients with suspected paracetamol poisoning presenting to 6 hospitals in the North East of England over 12 weeks in 1994. 3. There were 400 presentations (attendance rate 1.14/10(3) population/yr) involving 343 persons (45% male). Paracetamol concentrations at 4 h correlated weakly with reported paracetamol dose (R = 0.49, P < 0.0001) and were similar comparing those treated and not treated by gastric decontamination. 4. In 38 (9%) cases paracetamol concentrations were above the appropriate nomogram treatment line, including 3% and 20% of patients who reported ingesting less than and more than 12 g respectively. In 21 patients acetylcysteine treatment was deferred until admission to the ward, the mean delay involved was 2.8 h. 5. One patient died, from arrhythmias caused by co-ingested dothiepin. 6. Paracetamol poisoning is common. Most cases do not have potentially toxic plasma paracetamol concentrations, but those who do often present late and antidotal treatment may be delayed inappropriately.
Acetaminophen↗
Comparison of jet and ultrasonic nebulizer pulmonary aerosol deposition during mechanical ventilation.
Increased delivery of aerosol to a model lung (attached to a mechanical ventilator) has been demonstrated with an ultrasonic nebulizer as compared to a jet nebulizer. This study examined whether the increased aerosol deposition with an ultrasonic nebulizer could also be demonstrated in vivo. Seven patients (6 male and 1 female) were studied during mechanical ventilalion (Siemens Servo 900C, Middlesex, UK) after open heart surgery. Two studies were performed in each patient. In the first study, aerosol was delivered via a Siemens Servo 945 nebulizer system (high setting) driving a System 22 Acorn jet nebulizer (Medic-Aid, Sussex, UK) containing 3 mL (99m)technetium-labelled human serum albumin (99mTc-HSA) (50 microg; activity 74 MBq). In the second study, a DP100 ultrasonic nebulizer (DP Medical, Meylan, France) containing 12 mL 99mTc-HSA (50 microg; activity 185 MBq) was used. Pulmonary deposition was quantified using a gamma camera. The humidification of the circuit and the ventilator settings were kept constant according to the patient's clinical requirements. The total lung aerosol deposition (mean+/-SD), as a percentage of initial nebulizer activity, was greater using the ultrasonic nebulizer than using the jet nebulizer (53+/-1.4 vs 2.3+/-0.9%; p<0.002). The ultrasonic nebulizer was also associated with a reduction in the time required to complete nebulization (9 vs 21 min, respectively) (p<0.0001). Use of the DP100 ultrasonic nebulizer more than doubled lung deposition compared with the System 22 jet nebulizers in mechanically-ventilated patients. Their efficiency, speed of drug delivery, and compatibility with mechanical ventilator circuits make ultrasonic nebulizers potentially attractive for use during mechanical ventilation.
Administration, Inhalation↗
Mortality from venous thromboembolism and myocardial infarction in young adults in England and Wales.
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Adult↗
Utilization of appetite suppressants in England: a putative indicator of poor prescribing practice.
The use of appetite suppressants, a putative inverse marker of prescribing quality, was analysed in the former Northern Regional Health Authority (RHA) and in England using National Health Service prescribing data and sales and patient-linked prescribing data supplied by Intercontinental Medical Statistics (IMS). The number (in thousands) of National Health Service prescriptions for appetite suppressants dispensed fell from 393 in 1991 to 235 in 1994. Per capita prescribing frequency varied threefold between different RHA and between individual Family Health Service Authorities (FHSA) within the former Northern RHA (NRHA). Prescribing frequency was higher in the spring and summer quarters and reduced in the winter quarter. Of 532 general practices in the NRHA, 82 (15%) prescribed no appetite suppressants between April 1993 and March 1994, while 70 (13%) prescribed more than 500 defined daily doses (DDDs) per 1000 patients, accounting for 47% of all prescribing. Only 53% of pharmacy purchases of appetite suppressants were accounted for by NHS prescribing and as little as 21% for phentermine, indicating substantial prescribing outwith the NHS. In 1991, 73,759 DDDs were supplied to pharmacies each day, the majority being diethylpropion (31,226) and phentermine (24,349). The fall in NHS prescribing is welcome as these drugs are of dubious clinical value and may be associated with serious adverse effects. Because of substantial non-NHS prescribing, routinely available prescribing data does not accurately quantify total prescribing of these agents.
Journal Article↗
Concentration-related pharmacodynamic effects of thioridazine and its metabolites in humans.
OBJECTIVE: To measure cardiac and other effects of thioridazine and relate these to the plasma concentration of the parent drug and its principal metabolites. METHODS: A double-blind, randomized-order crossover study involving nine healthy male subjects compared the effects of single doses of thioridazine (10 mg and 50 mg) with placebo. Plasma concentrations of thioridazine and its ring sulfoxide, side-chain sulfoxide, and side-chain sulfone metabolites were measured, together with effects on the ECG, blood pressure, salivary flow, and a batch of psychomotor tests for 72 hours after administration. RESULTS: Thioridazine, 50 mg, reduced standing systolic blood pressure (mean peak changes from baseline [95% CI] -32 mm Hg [-55, 10 mm Hg]; p < 0.01 versus placebo) and diastolic blood pressure (-14 mm Hg [-26, -2 mm Hg]; p < 0.05), increased standing heart rate (7 beats/min [-1, 16 beats/min]; p < 0.05), impaired psychomotor function, and prolonged the JT (20 ms1/2 [7, 34 ms1/2]; p < 0.05), QTa (22 ms1/2 [8, 36 ms1/2]; p < 0.05), and QTc (22 ms1/2 [11, 33 ms1/2]; p < 0.01) intervals, but had no effect on QT dispersion (-12 ms1/2 [-31, 6 ms1/2]). Thioridazine, 1.0 mg, also significantly increased QTc, but the effect was less marked (9 ms1/2 [-1, 19 ms1/2]; p < 0.05). Plasma thioridazine and metabolite concentrations did not correlate significantly with these effects. Maximum effects on QTc occurred after peak concentrations of thioridazine but before peak concentrations of the ring sulfoxide and side-chain sulfone metabolites. CONCLUSIONS: These data suggest that thioridazine has dose-related effects on ventricular repolarization and that the parent drug causes an important proportion of these effects, although its metabolites may also contribute.
Adult↗
Stereoselective cardiotoxic effects of terodiline.
OBJECTIVE: To study the cardiovascular and electrocardiographic (ECG) effects of the R(+)- and S(-)- enantiomers of terodiline. The racemic drug was previously used to treat detrusor instability but was withdrawn after it caused serious ventricular arrhythmias associated with prolongation of the QT interval. METHODS: A double-blind, placebo-controlled, randomized crossover study was performed that involved nine healthy volunteers who were given single oral doses of racemic terodiline hydrochloride (200 mg), R(+)-terodiline hydrochloride (100 mg), S(-)-terodiline tartrate (100 mg), or placebo. Plasma concentrations of each enantiomer and cardiovascular and ECG effects, including QT intervals and QT dispersion, were measured over 14 days after each treatment. RESULTS: Both racemic and R(+)-terodiline significantly increased QT interval, corrected QT interval (QTc), and QRS duration (all p < 0.05), without affecting QT dispersion. S(-)-Terodiline tartrate (100 mg) did not affect QTc. Peak effects occurred 8 hours after dosing when increases in QTc from baseline (95% confidence intervals) were -3 (-20, 13) for placebo, 23 (8, 37) for racemic terodiline, 19 (6, 33) for R(+)-terodiline, and 0 (-10, 9) ms1/2 for S(-)-terodiline. Although differences were observed between the pharmacokinetics of the two enantiomers, these were not sufficient to account for the differences in ECG effects, and elimination half-lives were similar. Elimination of terodiline enantiomers was not significantly delayed in two genotypic poor metabolizers of debrisoquin (CYP2D6). CONCLUSIONS: QT prolongation associated with racemic terodiline is caused exclusively by the R(+)-enantiomer, which therefore appears to be responsible for the ventricular arrhythmias caused by the drug.
Adolescent↗
Cardiac dysrhythmias in severe verapamil overdose: characterization with a canine model.
Verapamil overdose, because of its frequency and severity, represents a significant problem for the emergency physician. With recent search recommending specific therapies for verapamil toxicity, aids to rapid diagnosis hold promise for decreasing morbidity and mortality from overdose of all calcium channel blockers. At this time, diagnosis of verapamil toxicity depends primarily on patient history and identification of cardiac dysrhythmias. This study attempts to improve the diagnostic armamentarium available for verapamil poisoning by analysing cardiac conduction problems seen in a canine model of verapamil toxicity, with the goal of identifying clinically useful dysrhythmia patterns. In 43 verapamil-toxic animals, junctional rhythm without organized atrial activity was the most frequently identified rhythm (55.6%). The next most commonly seen rhythms were tertiary atrioventricular (AV) block (16.3%) and idioventricular rhythm (11.6%); other animals manifested low grade AV block. Of interest, prominent U waves were noted in 25.6% of animals. While these results are subject to the limitations inherent in the use of an animal model, the data generated provide potentially useful patterns of dysrhythmia which may be encountered in humans with verapamil toxicity.
Animals↗
Effect of oxybutynin on the QTc interval in elderly patients with urinary incontinence.
1. Terodiline, an anticholinergic drug with calcium antagonist properties, is associated with QT prolongation and ventricular arrhythmias. It is not known if oxybutynin, a drug with a similar pharmacological profile, causes QT prolongation. ECGs were obtained before and at least 4 weeks after commencement of oxybutynin (mean daily dose 7.6, range 2.5-10 mg), in 21 elderly (mean age 75, range 58-88 years) patients treated for urinary incontinence. Heart rate, (mean +/- s.d.) 74 +/- 11 vs 69 +/- 11 beats min-1, -6 (-13,2), before vs during oxybutynin therapy, mean difference (95% confidence intervals); PR interval, 168 +/- 27 vs 156 +/- 27 ms, -11 (-26,3); QTc 454 +/- 27 vs 447 +/- 31 ms1/2, -9 (-23,5), and QTc dispersion, QTc max-QTc min, 68 +/- 24 vs 63 +/- 26 ms1/2, -1 (-15,14) were all unaltered by oxybutynin therapy. The lack of an effect on resting heart rate suggests that oxybutynin has little anticholinergic action at cardiac M2 receptors at usually administered doses. Oxybutynin therapy is not associated with QTc interval prolongation and is unlikely to produce ventricular arrhythmias.
Aged↗
Systemic absorption of nebulized morphine compared with oral morphine in healthy subjects.
The inhalation of nebulized morphine has been advocated to treat dyspnoea and pain in patients with cancer. We have compared plasma morphine concentrations in healthy volunteers after nebulized (50 mg in 4 ml saline), oral (10 mg solution) and intravenous (5 mg) morphine sulphate. Bioavailability was estimated by dividing the morphine concentration AUC/dose by that obtained after intravenous morphine. Peak plasma morphine concentrations were achieved more rapidly after nebulized than oral morphine, occurring within 10 min in all subjects. The systemic bioavailabilities of morphine (mean +/- s.d.) were 5 +/- 3% and 24 +/- 13% for the nebulized and oral routes respectively. Nebulization is a rapid but inefficient method of administering morphine. It may provide more rapid pain relief compared with oral morphine but clinical studies are needed to confirm this.
Administration, Oral↗
Glucagon and phenylephrine combination vs glucagon alone in experimental verapamil overdose.
OBJECTIVE: To evaluate glucagon and phenylephrine in combination as a treatment for the hemodynamic effects of verapamil overdose. METHODS: Pentobarbital-anesthetized and instrumented dogs were overdosed using a previously developed verapamil overdose model (15 mg/kg IV over 30 minutes). The animals were maintained and observed for 90 minutes or until death. Cardiac output (CO), heart rate (HR), and mean arterial pressure (MAP) were monitored. Following the 30-minute verapamil infusion (toxicity), the control animals received no treatment; the glucagon animals received a 5-mg glucagon bolus and a drip of 5 mg/90 minutes; and the glucagon/phenylephrine animals received the same glucagon therapy plus a phenylephrine drip titrated to 180 micrograms/min over 15 minutes. The groups were compared using analysis of variance: the experimental variables were group and time; the response variables were changes from toxicity for the hemodynamic parameters. Post-hoc comparisons were done with alpha set at 0.05. RESULTS: A significant change in CO was seen in the glucagon group (delta = 2.6 L/min) and the glucagon/phenylephrine group (delta = 1.9 L/min) compared with the control group (delta = 0.8 L/min). The change in CO was significantly larger for the glucagon animals compared with the glucagon/phenylephrine animals. The change in MAP for the glucagon/phenylephrine group (delta = 24 mm Hg) was significant compared with the control group (delta = 14 mm Hg). The MAP change for the glucagon group (delta = 19 mm Hg) was not significantly different from that of either the control or the glucagon/phenylephrine group. The change in glucagon HR (delta = 6 beats/min) was significant compared with the control group (delta = -4 beats/min) and the glucagon/phenylephrine group (delta = -4 beats/min). CONCLUSION: The glucagon/phenylephrine therapy improved MAP compared with the control, but reduced CO and HR compared with glucagon alone. Glucagon/phenylephrine therapy is not as effective as glucagon alone in reversing the hemodynamic effects of experimental verapamil overdose.
Adrenergic alpha-Agonists↗