bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparison of ciprofloxacin, norfloxacin, ofloxacin, azithromycin and cefixime examined by observational cohort studies
Authors: WILTON L. V. , PEARCE G. L. , MANN R. D. 
Published: October 2003

1 The safety in everyday clinical usage of three 4‐quinolone antibiotics, (ciprofloxacin, norfloxacin and ofloxacin), was compared with similar data for azithromycin and cefixime, each agent being examined by Prescription‐Event Monitoring (PEM) during the early post‐marketing period. 2 In PEM the exposure data are derived from general practitioner prescriptions confidentially provided by the Prescription Pricing Authority. Outcome data are provided by questionnaires (green forms) on which the prescribing medical practitioner records event data. When necessary, further information is obtained from a number of sources which include follow‐up of all pregnancies and the patients' life‐time medical record. 3 The main outcome measures were demographic information, including the patient's date of birth and sex; the indication for prescribing the drug being monitored; the reason for stopping treatment; the start and stop dates of treatment and the events recorded during and after treatment. 4 The final cohort for each of the five antibiotics exceeded 11000 patients. The only event significantly related to the use of all five antibiotics was nausea/vomiting. This was also the most frequent adverse event causing treatment to be discontinued with norfloxacin, ofloxacin and azithromycin (relevant information was not requested in the studies of ciprofloxacin and cefixime). Vaginal candidiasis was significantly more frequently associated with the use of the three 4‐quinolones than with azithromycin and cefixime but it was frequently delayed until the week or two after the cessation of therapy. Within each event, as recorded in these studies, the highest event rates (the number of events per 1000 patients) in the week following the start of therapy were: 9.2 for diarrhoea with cefixime; 4.9 for nausea/vomiting with ofloxacin; 2.4 for rash with azithromycin; 2.2 for abdominal pain with norfloxacin; 1.5 for headache/migraine with ofloxacin; 1.4 for malaise/lassitude with ofloxacin; 1.2 for dizziness with norfloxacin. Uncommon events (reported in less than 1:1000 patients) included rare cases of allergic phenomena, convulsions and pseudomembranous colitis. There were no reports of tendinitis, tenosynovitis or tendon rupture in children but tendon disorders were reported in the two months following the start of treatment in 20 adults. A total of 307 pregnancies were reported. Thirty‐eight of the 55 women who received these drugs during the first trimester of pregnancy gave birth to healthy babies. No congenital abnormalities were reported. Apart from one case of unconfirmed pseudomembranous colitis, none of the other 2468 deaths that occurred in these studies was attributed to the antibiotics. 5 These five antibiotics are acceptably safe antimicrobial agents when used in general medical practice. PEM is an effective method for monitoring the safety of recently introduced antimicrobial agents.
The influence of the sparteine/debrisoquine genetic polymorphism on the disposition of dexfenfluramine
Authors: GROSS A. S. , PHILLIPS A. C. , RIEUTORD A. , SHENFIELD G. M. 
Published: October 2003

1 To determine whether dexfenfluramine is a substrate of cytochrome P450 2D6 (CYP2D6), its disposition has been studied in nine extensive (EM) and eight poor metabolizers (PM) of debrisoquine. 2 Following a 30 mg dose of dexfenfluramine hydrochloride, urine was collected in all subjects for 96 h post‐dose and plasma samples were collected in 11 subjects (six EMs and five PMs). Dexfenfluramine and nordexfenfluramine were measured in urine by h.p.l.c. and in plasma by g.c. 3 Urinary recovery of dexfenfluramine was greater in PMs than EMs (4136±1509 μg vs 1986±792 μg; 95% CI of difference 926–3374; P<0.05) whereas that of nordexfenfluramine was similar in both phenotypes (PM: 1753±411 μg vs 1626±444 μg). 4 Dexfenfluramine AUC was higher in PMs (677±348 μg l−1 h) than EMs (359±250 μg l−1 h). The apparent oral clearance of dexfenfluramine was greater in EMs than PMs (93.6±42.4 l h−1vs 45.6±19.5 l h−1; 95% CI of difference 1.2–94.7; P<0.05). The renal clearance was similar in both phenotypes (EMs: 5.88±2.83 l h−1; PMs 6.60±2.01 l h−1), indicating that the higher urinary recovery of dexfenfluramine in PMs reflects higher plasma concentrations, rather than phenotype differences in the renal handling, of dexfenfluramine. 5 The apparent nonrenal clearance of dexfenfluramine was substantially lower (P<0.05; 95% CI of difference 3.0–94.1) in PMs (39.0±19.5 l h−1) than EMs (87.6±41.2 l h−1). 6 There was a significant inverse correlation (rs=−0.776 95% CI −0.31–−0.94; n=11; P=0.005) between the debrisoquine metabolic ratio and the apparent nonrenal clearance of dexfenfluramine. 7 PMs had a higher incidence of adverse effects (nausea and vomiting) than EMs. 8 In conclusion, the metabolism of dexfenfluramine is impaired in PMs. Thus CYP2D6, the isoenzyme deficient in poor metabolizers of debrisoquine, must catalyse at least one pathway of dexfenfluramine biotransformation.
Pre‐ and afterload reduction in chronic mitral regurgitation: a double‐blind randomized placebo‐controlled trial of the acute and 2 weeks' effect of nifedipine or isosorbide dinitrate treatment on left ventricular function and the severity of mitral regurgitation
Authors: KELBÆK HENNING , ALDERSHVILE JAN , SKAGEN KNUD , HILDEBRANDT PER , NIELSEN STEEN L. 
Published: October 2003

1The acute effect and effect of 14 days' treatment with isosorbide dinitrate (ISDN) and nifedipine (NIF) was evaluated by radionuclide cardiography in patients with chronic mitral regurgitation and sinus rhythm. 2In 23 patients with clinically stable disease blood pressure was lowered by 15% and left ventricular volume was reduced by 16–20% after 20 mg sublingual ISDN causing combined pre‐and afterload reduction. Afterload reduction alone induced by 10 mg NIF resulted in an acute 9% decrease in left ventricular endsystolic volume, whereas forward stroke volume increased by 30%, and regurgitation fraction tended to decrease. No haemodynamic effects could be detected after 14 days' treatment with 20 mg ISDN orally twice daily (preload reduction), whereas 20 mg NIF twice daily (afterload reduction) caused an increase in forward stroke volume (18%) and a decrease in both regurgitant volume (20%) and regurgitation fraction (22%) without affecting blood pressure or heart rate. 3ISDN and NIF have beneficial acute haemodynamic effects in patients with chronic mitral regurgitation probably due to their pre‐ and afterload reducing properties. The reduction in regurgitation induced by NIF appears to be sustained after 14 days therapy.
Morphine, morphine‐6‐glucuronide and morphine‐3‐glucuronide pharmacokinetics in newborn infants receiving diamorphine infusions
Authors: BARRETT D. A. , BARKER D. P. , RUTTER N. , PAWULA M. , SHAW P. N. 
Published: October 2003

1The pharmacokinetics of morphine, morphine‐6‐glucuronide (M6G) and morphine‐3‐glucuronide (M3G) were studied in 19 ventilated newborn infants(24–41 weeks gestation) who were given a loading dose of 50 μg kg−1 or 200 μg kg−1 of diamorphine followed by an intravenous infusion of 15 μg kg−1 h−1 of diamorphine. Plasma concentrations of morphine, M3G and M6G were measured during the accrual to steady‐state and at steady state of the diamorphine infusion. 2Following both the 50 μg kg−1 or 200 μg kg−1 loading doses the mean steady‐state plasma concentration (±s.d.) of morphine, M3G and M6G were 86±52 ng ml−1, 703±400 ng ml−1 and 48±28 ng ml−1 respectively and morphine clearance was found to be 4.6±3.2 ml min−1 kg−1. 3M3G formation clearance was estimated to be 2.5±1.8 ml min−1 kg−1, and the formation clearance of M6G was estimated to be 0.46±0.32 ml min−1 kg−1. 4M3G metabolite clearance was 0.46±0.60 ml min−1 kg−1, the elimination half‐life was 11.1±11.3 h and the volume of distribution was 0.55±1.13 l kg−1. M6G metabolite clearance was 0.71±0.36 ml min−1 kg−1, the elimination half‐life was 18.2±13.6 h and the volume of distribution was 1.03±0.88 l kg−1. 5No significant effect of the loading dose (50 μg kg−1 or 200 μg kg−1) on the plasma morphine or metabolite concentrations or their derived pharmacokinetic parameters was found. 6We were unable to identify correlations between gestational age of the infants and any of the determined pharmacokinetic parameters. 7M3G:morphine and M6G:morphine steady‐state plasma concentration ratios were 11.0±10.8 and 0.8±0.8, respectively. 8The metabolism of morphine in neonates, in terms of the respective contributions of each glucuronide pathway, was similar to that in adults.
Disposition of diazepam in young and elderly subjects after acute and chronic dosing
Authors: HERMAN ROBERT J. , WILKINSON GRANT R. 
Published: October 2003

1The pharmacokinetics of diazepam were examined in seven young (20–30 years) and six elderly (60–75 years) males prior to and also after chronic oral dosing of diazepam.2Following intravenous administration, the half‐life and volume of distribution of 14C‐labelled diazepam in the elderly were approximately twofold greater than corresponding estimates in younger subjects (mean ±s.d., 71.5±27.6 vs 44.5±16.5 h and 1.39±0.32 vs 0.88±0.30 1 kg−1, respectively). Clearance did not differ between the two groups (0.26±0.09 vs 0.29±0.09 ml min−1 kg−1).3The accumulation of diazepam and its major metabolite, desmethyldiazepam, were extensive during chronic administration. A radioreceptor assay that measured total benzodiazepine activity, including diazepam and its active metabolites, indicated that the accumulation of ‘benzodiazepine equivalents’ was similar to the sum of the accumulated diazepam and desmethyldiazepam concentration levels. However, the level of ‘benzodiazepine equivalents’ on multiple‐dosing was about double that of the predicted steady‐state ‘equivalent’ concentration from single‐dose studies. This was due to the insensitivity of the radioreceptor assay for desmethyldiazepam following single‐dose diazepam administration.4There were no age‐ or dosing‐related differences in diazepam clearance (0.37±0.22 vs 0.32±0.18 ml min−1 kg−1, young vs elderly, single‐dose; 0.37± 0.11 vs 0.27±0.12 ml min−1 kg−1, young vs elderly, multiple‐dose) and no age‐related differences in the levels of accumulated ‘benzodiazepine equivalents’ (243.7±60.1 vs 288.0±125.8 ng ml−1, young vs elderly).5Thus, changes that occur in diazepam disposition with ageing after acute administration do not appear to be important during chronic dosing. On the other hand, accumulation of diazepam and desmethyldiazepam are considerable and would be expected to be clinically relevant.
A clinical pharmacologist's view of drug toxicity
Authors: BRECKENRIDGE ALASDAIR 
Published: October 2003

1Our ability to understand the basis of adverse drug reactions has improved progressively, and with it, the ability to prevent their occurrence; one aim of the clinical pharmacologist is to identify patients at special risk. 2Four examples of clinical drug toxicity which illustrate how the subject has advanced over the past 20 years are described. These illustrate how a combination of clinical and laboratory medicine can be used to help our understanding of the basis of adverse drug reactions. With a fair degree of certainty one can also predict that advances in bioinformatics, genomics and combinatorial chemistry will progressively contribute to clinical toxicology in the future.
The clinical pharmacologist in drug regulation: a European perspective
Authors: RAWLINS MICHAEL D. 
Published: October 2003

1The clinical pharmacologist in drug regulation has many roles to play. These include responsibilities for the premarketing assessment of a new product's efficacy and safety, for scrutiny of the summary of Product Characteristics, and for monitoring its performance after marketing. Furthermore, the clinical pharmacologist has a subsidiary responsibility in examining the results of preclinical pharmacological and toxicological studies. 2Clinical pharmacologists in regulatory authorities have one further, and crucial, responsibility—humility. From their training and experience they will (or should) know of their own scientific limitations and of the necessity for seeking help and advice from other disciplines.
New therapeutic agents for hypertension
Authors: REID JOHN L. 
Published: October 2003

1Over the last 40 years a range of therapeutic strategies has been introduced for the long term treatment of hypertension. 2Although safe effective agents are available a significant number of patients are unable or unwilling to take these drugs as long term treatment. 3Both insufficient efficacy and adverse effects justify the search for new antihypertensive strategies. 4Recent developments include orally active angiotensin (AT1) receptor antagonists (ARA) which appear to offer the benefits of prevention of angiotensin II effects without the adverse effects of bradykinin potentiation, such as cough, which limit the usefulness of angiotensin converting enzyme (ACE) inhibitors. 5Imidazoline receptor agonists offer the potential of centrally active antihypertensives without the adverse effects of sedation and dry mouth. Further clinical experience is necessary to confirm whether the clinical efficacy and good tolerability are confirmed with long term use. 6Both ARA and imidazoline preferring substances offer the bonus of a desirable haemodynamic profile in patients with heart failure and may open new therapeutic avenues in the management of cardiac failure.
The influence of renal function on the pharmacokinetics of unchanged and acyl‐glucuroconjugated ketoprofen enantiomers after 50 and 100 mg racemic ketoprofen
Authors: SKEITH K.J. , DASGUPTA M. , LANGE R. , JAMALI F. 
Published: October 2003

1To study the effect of renal dysfunction on the pharmacokinetics of ketoprofen (KT), and the possibility of saturation of clearance with elevation of dose, single 50 and 100 mg doses of racemic ketoprofen were administered in a cross‐over fashion to seven patients (creatinine clearance, CLCR, 6–72 ml min−1).2The stereospecific disposition kinetics of KT enantiomers and their acyl‐glucuronide conjugates (KTconj ) were determined in plasma and urine for 24 h post‐dose.3Decreased renal function was associated with a reduced KT oral clearance (CLO) and terminal elimination rate constant (λz). Renal clearance of KTconj (CLrconj) was reduced with diminished renal function.4Following both 50 and 100 mg doses, there was significant stereoselectivity in the AUC of KT (mean S/R, 0.87 and 0.83, respectively), the AUC of KTconj (mean S/R, 3.4 and 5.2, respectively) and the cumulative urinary excretion of KTconj (mean S/R, 2.1 and 2.2, respectively). The stereoselectivity in renal dysfunction in contrast with the observations previously made in healthy subjects may suggest a disease‐related process.5CLO remained constant after increasing the dose, indicating linearity in the pharmacokinetics of KT despite reduced CLCR. CLrconj, however, was significantly reduced after the 100 mg dose suggestive of saturation of the urinary clearance and existence of a compensatory pathway.6Renal impairment reduces CLrconj and this appears to be the rate‐limiting step for clearance of KT due to the observed stronger correlations of CLO with CLrconj than with CLCR.7Dose reduction of ketoprofen is indicated only for patients with CLCR< 20 ml min−1.
A prospective study of adverse drug reactions as a cause of admission to a paediatric hospital
Authors: MARTÍNEZ‐MIR I. , GARCÍA‐LÓPEZ M. , PALOP V. , FERRER J. M. , ESTAÑ L. , RUBIO E. , MORALES‐OLIVAS F. J. 
Published: October 2003

1A total of 512 consecutive paediatric hospital admissions of children 2 years old or less were evaluated to assess the extent and pattern of admission caused by suspected adverse drug reactions (ADRs). The proportion of suspected ADRs related to hospital admissions was 4.3%. 2The organ‐systems most commonly implicated were the central nervous system (40.5%), digestive system (16.7%), and skin and appendages (14.3%). Together, they accounted for 71.5% of admissions attributed to ADRs. The most common clinical manifestations inducing admission were convulsions (4 cases), dizziness (4), vomiting (3), and tremor, fever, itching and apnoea (2 cases each). 3The four classes of drugs most frequently suspected in admissions due to ADRs were respiratory drugs (35%), anti‐infective agents (25%), drugs active on the central nervous system (15%) and drugs used in dermatology (10%). The most common drugs related to ADRs were a combination of chlorpheniramine, diphenhydramine, phenylephrine, guaiphenesin and salicylic acid (4 cases), followed by fenoterol, adrenaline, paracetamol, DTP vaccine and antipolio vaccine (2 cases each). 4There were no significant differences between children older and younger than 1 year (odds ratio 0.89; 95% CI 0.37–2.17) or between the sexes as regards hospital admittance due to suspected ADRs (odds ratio 1.94; 95% CI 0.72–5.42). 5The results of this kind of study may be influenced by patterns of drug utilization. Nevertheless, the lack of specific studies of drug effects in young children makes it desirable to carry out pharmacoepidemiological studies in this age group.
The effect of age on the pharmacokinetics of the opioid antagonist nalmefene
Authors: FRYE R. F. , MATZKE G. R. , JALLAD N. S. , WILHELM J. A. , BIKHAZI G. B. 
Published: October 2003

1The disposition of nalmefene was evaluated in young and elderly normal healthy volunteers. Subjects received either a single 1 mg (n=18 young; n=11 elderly) or 2 mg (n=8 young; n=15 elderly) intravenous bolus dose of nalmefene. 2Following the administration of nalmefene, the initial plasma concentrations were significantly higher in elderly vs young subjects. The higher concentrations were the result of the 30 to 40% smaller central compartment apparent volume of distribution that was observed in the elderly subjects as compared with the young volunteers (2.8±1.1 vs 3.9±1.1 l kg−1 for 1 mg dose). The elderly volunteers also had a significantly shorter distributional half‐life (t1/2λ1) than young volunteers (0.7±0.7 vs 1.3±0.8 h for 1 mg dose). No significant differences between groups were observed for the elimination half‐life, clearance or steady‐state apparent volume of distribution. 3Although transiently higher nalmefene plasma concentrations were observed in the elderly immediately following drug administration, there was no association between this observation and adverse events. We conclude that no dosage alteration is warranted in elderly patients.
The effects of co‐administration of benzhexol on the peripheral pharmacokinetics of oral levodopa in young volunteers
Authors: ROBERTS J. , WALLER D. G. , RENWICK A. G. , O'SHEA N. , MACKLIN B. S. , BULLING M. 
Published: October 2003

1 The effects of benzhexol on the absorption and pharmacokinetics of an oral dose of levodopa have been studied in 10 young healthy volunteers. Subjects were given a suspension of levodopa (250 mg) 90 min after either benzhexol (5 mg) or placebo in a randomized cross over design with doses separated by at least 1 week; on each occasion carbidopa was given 1 h before and 5 h after the dose of levodopa. Soluble paracetamol and radiolabelled DTPA were given with the levodopa as markers of gastric emptying. 2 Most subjects showed two peaks in the levodopa plasma concentration–time curve on the placebo day, with the second minor peak occurring 1–2 h after the dose. After benzhexol administration all subjects showed two or more peak levodopa concentrations in plasma. Benzhexol administration caused a significant decrease in the maximum concentration (43%; P<0.05) of the initial peak and an increase (22%; P<0.1) in the maximum concentration of the second peak. This change in absorption profile caused by benzhexol significantly altered the ratios of the second peak compared with the initial peak for both the maximum concentrations (P<0.02) and for the AUC values (P<0.05). Benzhexol administration did not affect the total AUC of levodopa (7.30±1.09 vs 7.19±1.26 μg ml−1 h; means±s.d.). 3 The plasma concentration–time curves for paracetamol showed similar profiles to those for levodopa and the ratios of the peak concentrations and AUC values for the second peak compared with the initial peak were increased significantly by benzhexol administration (P<0.05). The total AUC of paracetamol was not affected by benzhexol administration (39.4±8.2 vs 40.0±8.9 μg ml−1 h; mean±s.d.) 4 Benzhexol altered the gastric emptying profile, shown by γ‐scintigraphy, with a reduced extent of initial emptying prior to the establishment of the plateau which is characteristic of levodopa administration in the fasting state. In consequence the ratio of the second to the initial phase of emptying was significantly higher (P<0.01) following benzhexol treatment. 5 Benzhexol reduces the initial phase of gastric emptying after a dose of levodopa so that there is a decrease in the initial peak and a greater proportion of the dose is absorbed subsequently following the second phase of gastric emptying which occurs approximately 1 h later. Theoretically, this altered concentration‐time profile could be an advantage for some patients with Parkinson's disease.
Clinical efficacy and pharmacokinetics of artemisinin monotherapy and in combination with mefloquine in patients with falciparum malaria
Authors: HASSAN ALIN M. , ASHTON M. , KIHAMIA C. M. , MTEY G. J. B. , BJÖRKMAN A. 
Published: October 2003

1The aim of this study was to assess the pharmacokinetics, clinical efficacy and safety of artemisinin alone and in combination with mefloquine. 2Thirty‐eight adults with symptomatic Plasmodium falciparum malaria were randomly assigned to receive either artemisinin (500 mg single dose followed by another 500 mg on day 1 and then 250 mg twice daily for 4 days) or artemisinin (500 mg single dose followed by 750 mg on day 1 and then 250 mg three times daily for one more day) in co‐administration with mefloquine (250 mg three times daily for the first day). All drug administration was by the oral route. Patients were hospitalized at the Kibaha Designated District Hospital, Kibaha, Tanzania, for 6 days and a follow up for 3 weeks was performed. 3Treatment with the artemisinin/mefloquine combination resulted in a shorter parasite clearance time (PCT) of 24 (22, 27; 95% confidence interval) h vs 31 (27, 36) h and fever subsidence time (FST) of 14 (12, 16) h vs 20 (18, 23) h compared with artemisinin monotherapy. The 95% CI for the difference of the PCT and FST were 1.7, 12 and 3, 10, respectively. Parasites were detected in 7 out of 17 patients (41%) receiving artemisinin monotherapy at the 3rd and 4th week follow up visits. No parasites were detected after the combination therapy. 4The maximum plasma concentrations (Cmax) were similar after artemisinin monotherapy (615.4±387.0 ng ml−1) and in combination with mefloquine (851.8±523.6 ng ml−1). Elimination half‐lives (t1/2) were also identical at 2.2±0.6 h and 2.5±0.7 h, respectively. However, the AUC values were higher (P<0.05) after combination therapy (3252±1873 ng  ml−1 h) than after monotherapy (2234±1502 ng ml−1 h). The oral clearance values were lower (P<0.05) after combination therapy (195.4±86.9 l h−1) than after monotherapy (314.3±189.4 l h−1). PCT and FST normalized to initial parasitaemia correlated with AUC(0, t) (rs=0.56, P=0.02, rs=0.58, P=0.01, respectively) and with Cmax(rs=0.62, P=0.01, rs=0.68, P=0.005, respectively) in the artemisinin monotherapy only. 5One patient on the combination therapy developed a psychiatric condition and two patients on the monotherapy developed skin itch.