bluuebunny/crossref_metadata_2025_split huggingface dataset:
The pharmacokinetics of morphine and morphine glucuronide metabolites after subcutaneous bolus injection and subcutaneous infusion of morphine
Authors: Stuart‐harris R. , Joel S. P. , McDonald P. , Currow D. , Slevin M. L. 
Published: March 2003

Aims
To investigate the pharmacokinetics of morphine, morphine‐6‐glucuronide (M6G) and morphine‐3‐glucuronide (M3G) in healthy volunteers after the administration of morphine by subcutaneous bolus injection (s.c.b.) and subcutaneous infusion (s.c.i.) over 4 h, and to compare the results with the intravenous bolus (i.v.) administration of morphine.
Methods
Six healthy volunteers each received 5 mg morphine sulphate by i.v., s.c.b. and short s.c.i. over 4 h, on three separate occasions, in random order, each separated by at least 1 week. Plasma samples were assayed for morphine, M6G and M3G.
Results
After i.v. morphine, the concentrations of morphine, M6G and M3G and their pharmacokinetic parameters were similar to those we have observed previously, in other healthy volunteers (when standardized to nmol l− 1, for a 10 mg dose to a 70 kg subject). After s.c.b. morphine, similar results were obtained except that the median tmax values for morphine and M3G were significantly longer than after i.v. morphine (P< 0.001 and P< 0.05, respectively), with a trend to a longer tmax for M6G (P= 0.09). The appearance half‐lives after s.c.b. morphine for M6G and M3G were also significantly longer than after i.v. morphine (P= 0.03 and P< 0.05, respectively). Comparison of log‐transformed AUC values indicated that i.v. and s.c.b. administration of morphine were bioequivalent with respect to morphine, M6G and M3G. In comparison with i.v. morphine, morphine by s.c.i. was associated with significantly longer median tmax values for morphine (P< 0.001), M6G (P< 0.001) and M3G (P< 0.05), and the mean standardized Cmax values significantly lower than after both i.v. and s.c.b. morphine (morphine P< 0.001, M6G P< 0.001 and M3G P< 0.01 for each comparison). Comparison of log‐transformed AUC values after i.v. and s.c.i. morphine indicated that the two routes were not bioequivalent for morphine (log‐transformed AUC ratio 0.78, 90% CI 0.66–0.93), M6G (0.72, 90% CI 0.63–0.82), or M3G (0.65, 90% CI 0.54–0.78). A small stability study indicated no evidence of adsorptive losses from morphine infused over 4 h using the infusion devices from the study.
Conclusions
Although bioequivalence was demonstrated between the s.c.b. and i.v. routes of morphine administration, the bioavailabilities of morphine, M6G and M3G after s.c.i. were significantly lower than after i.v. administration. However, despite this, the study demonstrates that the subcutaneous route is an effective method for the parenteral administration of morphine.
The pharmacokinetics of ziprasidone in subjects with normal and impaired hepatic function
Authors: Everson G. , Lasseter K. C. , Anderson K. E. , Bauer L. A. , Carithens R. L. , Wilner K. D. , Johnson A. , Anziano R. J. , Smolarek T. A. , Turncliff R. Z. 
Published: March 2003

Aims  To assess whether hepatic impairment influences the pharmacokinetics of ziprasidone.Methods  Thirty subjects with normal hepatic function or a primary diagnosis of clinically significant cirrhosis (Child‐Pugh A or B) were enrolled into an open‐label, multicentre, multiple‐dose study. The subjects with chronic, stable hepatic impairment and the matched control subjects received ziprasidone 40 mg day− 1, given orally with food, as two divided daily doses for 4 days and a single 20 mg dose on the morning of day 5. Pharmacokinetic variables were determined from multiple venous blood samples collected on days 1 and 5. Liver function was evaluated quantitatively using antipyrine.Results  On day1 there were no statistically significant differences in the pharmacokinetics (AUC(0,12 h), Cmax, tmax) of ziprasidone between the two groups. On day 5 there were no statistically significant differences in the Cmax or tmax for ziprasidone between the two groups. The mean AUC(0,12 h) for ziprasidone was statistically significantly greater in the hepatically impaired subjects compared with the normal subjects (590 ng ml− 1 h vs 467 ng ml− 1 h, P= 0.042). However, the AUC(0,12 h) increased by only 26% in the cirrhotic group compared with the matched control group. The ziprasidone λz in the subjects with normal hepatic function was statistically significantly greater than that in the hepatically impaired subjects (P< 0.001). There was no correlation between antipyrine λz and ziprasidone λz in the subjects with normal hepatic function or in those with hepatic impairment.Conclusions  The findings of this study indicate that mild to moderate hepatic impairment does not result in clinically significant alteration of ziprasidone pharmacokinetics.
Interaction between the LMWH reviparin and aspirin in healthy volunteers
Authors: Klinkhardt, Ute , Breddin, Hans Klaus , Esslinger, Heinz Ulrich , Haas Silvia , Kalatzis Andreas , Harder Sebastian 
Published: March 2003

Aims
To investigate potential interactions between reviparin and acetylsalicylic acid (ASA 300 mg o.d. from day 1–5).
Methods
In an open, randomized, three‐way‐cross over study nine healthy volunteers received reviparin (s.c. injection of 6300 anti‐Xa units) or placebo from days 3 to 5 and acetylsalicylic acid (ASA 300 mg) or placebo from days 1 to 5. Assessments included bleeding time (BT), collagen (1 µg ml−1) induced platelet aggregation (CAG), heptest, plasma antifactor Xa‐activity and activated partial thromboplastin time (aPTT).
Results
Median bleeding time at day 5 was 5.5 min after reverparin alone and after ASA alone and was 9.6 min after the combination of reviparin and ASA. ASA treatment reduced CAG from 84% to 40 to 50% of Amax; values after combined treatment of reviparin with ASA were not different from those after ASA alone. aPTT was prolonged to 32 s after reviparin; this effect was not modified if subjects received ASA. Combined treatment with ASA and reviparin had no effect on plasma anti‐Xa‐activity and heptest compared with reviparin alone.
Conclusions
We could not entirely exclude a small interaction between reviparin and ASA on bleeding time, but the effect is probably without clinical significance.
Nonprescription medicine use in a multiple sclerosis clinic population
Authors: Tremlett H. L. , Wiles C. M. , Luscombe D. K. 
Published: March 2003

Aims
To determine the use of nonprescription medicines in a cohort of multiple sclerosis (MS) patients and to identify a subgroup of patients liable to spend more on nonprescription medicines
Methods
A questionnaire was given to MS patients attending a neurology out‐patients clinic during the previous year. Medicines from a General Practitioner (GP), pharmacy and ‘other’ sources utilized in the last month were determined, along with demographic data. Additional information was obtained from hospital notes.
Results
One hundred and seventeen MS patients responded to the questionnaire, giving a response rate of 79% (117/148). Responders differed from nonresponders only in age, with responders being significantly older than nonresponders (P = 0.011). Over one‐third of medicines taken in the last month were nonprescription medicines (35%; 219/627). A gamolenic acid containing preparation was the most popular, purchased by 28% of patients. Fifteen percent (17/117) of MS patients had exceeded the recommended daily allowance of a vitamin (frequently vitamins A, D and E), and one exceeded the upper safe level for daily self‐supplementation of vitamin A and D. Females spent significantly more than males in the previous month (£10.09 compared with £5.53, respectively; P = 0.022). Patients who were older, reported worsening MS symptoms in the last year and those who exhibited greater disability were more likely to have been prescribed medicines by a GP (P < 0.0005), although they were not more likely to self‐prescribe or take alternative remedies (P > 0.05). However, those with poorer mobility were significantly less likely to have purchased a pharmacy medicine in the last month (P = 0.033).
Conclusions
MS patients were high users of nonprescription medicines. A typical subgroup of MS patients that spent more on nonprescription medicines could not be identified, aside from females. Furthermore, the strong predictors for increased use of prescription medicines (increasing age, severity of symptoms in the last year and poorer mobility) were not found for nonprescription medicines. Excessive intake of the fat soluble vitamins could lead to hypervitaminosis, the effects of which could exacerbate or mimic MS symptoms. Health professionals should be aware of these issues and counsel the MS patient accordingly, particularly as the majority purchased products from ‘other’ sources where typically there is no health‐professional available to give advice. The limited use of pharmacy medicines by the more disabled patient could indicate a problem with access to the pharmacy, or could reflect the greater use of prescription medicines.
The rates of common adverse events reported during treatment with proton pump inhibitors used in general practice in England: cohort studies
Authors: Martin Richard M. , Dunn Nicholas R. , Freemantle Shayne , Shakir Saad 
Published: March 2003

Aims
To estimate the rates of common adverse events in patients treated with the proton pump inhibitors omeprazole, lansoprazole and pantoprazole in general practice in England.
Methods
In prescription‐event monitoring cohort studies, data on dispensed prescriptions prescribed by general practitioners in England soon after each drug was launched were linked to subsequent clinical events recorded by the prescriber. 16 205 patients prescribed omeprazole between June 1989 and June 1990, 17 329 patients prescribed lansoprazole between May and November 1994, and 11 541 patients prescribed pantoprazole between December 1996 and June 1997 were studied.
Results
The commonest adverse events in the omeprazole, lansoprazole and pantoprazole cohorts were diarrhoea (incidence: 0.18, 0.39 and 0.23 per 1000 days of exposure, respectively); nausea/vomiting (incidence: 0.16, 0.22 and 0.18 per 1000 days of exposure, respectively); abdominal pain (incidence: 0.17, 0.21 and 0.17 per 1000 days of exposure, respectively); and headache (incidence rates: 0.10, 0.17 and 0.15 per 1000 days of exposure, respectively). The remaining adverse events occurred at rates of less than 0.11 per 1000 days of exposure. There were little absolute differences in the rates of most events between the three proton pump inhibitors. However, diarrhoea was more commonly associated with lansoprazole compared with omeprazole (rate difference: 0.21 per 1000 days of exposure; 95% CI 0.17, 0.25; rate ratio: 2.11; 1.78, 2.51), and there was a clear age‐response relationship.
Conclusions
Adverse events occurred relatively infrequently in all three cohorts. There were only small absolute differences in event rates between the three drugs, although these data suggest the hypothesis that lansoprazole is associated with more frequent occurrence of diarrhoea, particularly in the elderly.
Effects of high ambient temperature on parasympathetically mediated cardiovascular reflexes in normal man
Authors: Banjar W. M. A. , Gazzaz J. , Langley R. W. , Bradshaw C. M. , Szabadi E. 
Published: March 2003

Aims
To examine the effects of high ambient temperature (‘heat stressor’) on parasympathetically mediated cardiovascular reflexes (power of respiratory sinus dysrhythmia; change in heart rate elicited by change in posture from lying to standing [‘30 : 15 ratio’]).
Methods
Twelve healthy male volunteers participated in four weekly sessions, each of which was associated with one treatment condition (placebo at an ambient temperature of 22 °C; propranolol 40 mg at 22 °C; placebo at 40 °C; propranolol 40 mg at 40 °C), according to a balanced double‐blind design. Heart rate was recorded by ECG, finger tremor (7–12 Hz) with an accelerometer strapped to the middle finger of the nondominant hand, and sublingual temperature by a mercury thermometer. Power of finger tremor and the variations of the R‐R intervals of the ECG were obtained from Fourier transformations of the data. Data were analysed by analysis of variance, with repeated measures using a significance criterion of P < 0.05; individual comparisons of active treatment with placebo and of data obtained at 40 °C with those obtained at 22 °C were made with Fisher's Least Significant Difference test.
Results
Heart rate was increased by the heat stressor, and this increase was abolished by propranolol. The heat stressor reduced the power of respiratory sinus dysrhythmia and the 30 : 15 ratio, and increased the power of physiological finger tremor. Propranolol did not affect heat stressor‐induced changes in the parasympathetic cardiac reflexes, but reduced the heat stressor‐induced enhancement of finger tremor.
Conclusions
The increase in the power of physiological finger tremor at high ambient temperature is consistent with sympathetic activation, whereas the reduction in the power of respiratory sinus dysrhythmia and 30 : 15 ratio indicates a decrease in parasympathetic activity. These results demonstrate that high ambient temperature may induce vagal withdrawal in the heart.
Population modelling of the effect of inogatran, at thrombin inhibitor, on ex vivo coagulation time (APTT) in healthy subjects and patients with coronary artery disease
Authors: Cullberg Marie , Eriksson Ulf G. , Larsson Marita , Karlsson Mats O. 
Published: March 2003

Aims  The purpose of this study was to characterize the relationship between the degree of anticoagulation, assessed by APTT, and the plasma concentration of inogatran in healthy subjects and in patients with coronary artery disease.Methods  Data from five phase I studies in 78 healthy males and two phase II multicentre studies in 948 patients of both sexes with unstable angina pectoris or non‐Q‐wave myocardial infarction were evaluated. A total of 3296 pairs of concentration‐APTT samples were obtained before, during, and after intravenous infusions of inogatran. Mixed effects modelling was used for population pharmacodynamic analysis of the drug effect and for describing the variability in baseline APTT.Results  The population mean baseline APTT was 29 s, but large variations between individuals (s.d. 3.6 s) were observed. The variability between studies (1.3 s) and centres (1.8 s) were of less importance, though statistically significant. APTT increased in a nonlinear manner with increasing inogatran concentration and the relationship was well described by a combined linear and Emax model. A significant part of the overall variability could be ascribed to the APTT reagent and equipment used at the different study centres. These method‐dependent differences were compensated for by including the lower limit of the normal reference range as a covariate, affecting both baseline and Emax, in the model. For the typical healthy subject and patient, the method‐corrected population mean parameters were: APTTbaseline 35 and 31 s, slope 8.0 and 5.8 s l µmol−1, Emax 36 and 34 s, and EC50 0.54 and 0.72 µmol l−1, respectively. The model predicted plasma concentration needed to double the APTT from the baseline value was 1.25 and 1.45 µmol l−1 in the healthy volunteer and patient, respectively.Conclusions  The nonlinear relationship between APTT and inogatran concentration in plasma was well described by a combined linear and Emax model. Pooling of data was made possible by incorporating a centre‐specific characteristic of the assay method in the model. Patients had lower baseline APTT and appeared to have less pronounced effect of inogatran than young healthy subjects.
Effects of nociceptin and endomorphin 1 on the electrically stimulated human vas deferens
Authors: Bigoni Raffaella , Calo Girolamo , Guerrini Remo , Strupish James W. , Rowbotham David J. , Lambert David G. 
Published: March 2003

Aims  To examine the effects of nociceptin (NC) and endomorphin 1 (EM1) on electrical field stimulation (EFS)‐induced contractions of the human vas deferens (hVD).Methods  Concentration‐response curves to NC and EM1 were constructed in the absence and in presence of peptidase inhibitors (PI). In some experiments a NC receptor antagonist, [Phe1ψ(CH2‐NH)Gly2]NC(1–13)NH2 [F/G], 10 µm) or naloxone (1 µm) were included.Results  All data are mean(95%CI). In the presence of PI, NC inhibited twitches (Emax=67(44,90)%; pEC50 = 7.28(6.95,7.61)). NC inhibition was sensitive to [F/G]. EM1 also inhibited twitches both in the absence (Emax=82(73,91)% pEC50 = 7.07(6.92,7.22)) and presence (Emax=83(76,90)%; pEC50 = 7.00(6.91, 7.09)) of PI. EM1 inhibition was sensitive to naloxone.Conclusions  These data suggest that hVD express NC and opioid receptors that inhibit neurogenic contractions.
Frequencies of thiopurine S‐methyltransferase mutant alleles (TPMT*2, *3A, *3B and *3C) in 151 healthy Japanese subjects and the inheritance of TPMT*3C in the family of a propositus
Authors: Kubota T. , Chiba K. 
Published: March 2003

Aims  To determine the frequencies of four thiopurine S‐methyltransferase (TPMT) mutant alleles, TPMT*2, *3A, *3B and *3C in a normal Japanese population.Methods  Genotypes were determined in 151 Japanese subjects and in six family members of a propositus using polymerase chain reaction (PCR)‐restriction fragment length polymorphism and allele‐specific PCR assays.Results  Only one TPMT*3C heterozygote was identified (gene frequency 0.3%). TPMT*2,*3A and *3B were not detected. In addition, TPMT*3C was found to have been inherited from the mother and passed on to the son of the propositus.Conclusions  TPMT*3C appears to be most prevalent among the known mutant allele of TPMT in a Japanese population which may have some relevance for the treatment of Japanese patients with thiopurine drugs.
Oral bioavailability of dihydroartemisinin in Vietnamese volunteers and in patients with falciparum malaria
Authors: Binh Tran Quang , Ilett Kenneth F. , Batty Kevin T. , Davis Timothy M. E. , Hung Nguyen Canh , Powell Shane M. , Thu Le Thi Anh , Van Thien Huynh , Phuöng Hoang Lan , Phuong Vu Duong Bich 
Published: March 2003

Aims  To obtain comprehensive bioavailability data for artesunate (ARTS) and its active metabolite dihydroartemisinin (DHA) following their separate oral administration to Vietnamese volunteers and to patients with acute, uncomplicated falciparum malaria.Methods  Volunteers were randomized to receive either i.v. ARTS (120 mg) followed by oral ARTS (150 mg) 8 h later (Group 1, n = 10), or i.v. ARTS (120 mg) followed by oral DHA (120 mg) 8 h later. Patients, also received oral ARTS (150 mg; Group 3, n = 8) or DHA (120 mg; Group 2, n = 7), in a randomized cross‐over study design. Multiple blood samples were collected after each administration and plasma ARTS and/or DHA concentrations were determined by h.p.l.c. Pharmacokinetic descriptors were obtained from noncompartmental analysis and bioavailability was calculated from AUC data. In the patients, the time to 50% parasite clearance (PCT50) and fever clearance time (FCT) also were measured.Results  In Group 1 (volunteers), the mean (95% CI) absolute bioavailability of oral ARTS was 80% (62,98%), while in Group 2 (volunteers), the bioavailability of oral DHA was 45% (34,56%). In the patients (Group 3), the bioavailability of oral DHA relative to oral ARTS was 88% (49,127%). The median PCT50 and FCT were 2.3 and 28 h, respectively.Conclusions  The study shows that the absolute bioavailability of DHA was significantly lower than that for ARTS in healthy volunteers. The bioavailability of ARTS in volunteers was consistent with previous studies in patients with uncomplicated falciparum malaria. The dose‐normalized Cmax and AUC(0,∞) for DHA were significantly greater in patients with falciparum malaria than in healthy volunteers. The high relative bioavailability of DHA in the patients may have been due to lower first‐pass clearance. We conclude that, for the treatment of malaria, DHA is likely to be a suitable oral substitute for ARTS. Based on our mean AUC measurements, it appears that equal doses of DHA and ARTS (mg basis) should give equivalent systemic exposure to bioactive DHA in uncomplicated falciparum malaria.
What knowledge and skills are essential for specialists in Clinical Pharmacology and Therapeutics? Results of a Delphi study
Authors: Mucklow J. C. 
Published: March 2003

Aims  To identify the knowledge and skills that should be considered essential for specialists in Clinical Pharmacology and Therapeutics (CPT) with a commitment to the National Health Service (NHS).Methods  A Delphi study using a sample of current specialists.Results  Members of the expert panel (20 in all, representative of the Clinical Section membership) identified 78 statements for consideration, in four domains (core of knowledge, therapeutic skills, educative skills, and investigative skills), of which 58 (74.4%) were accepted by more than two‐thirds of respondents. Of these, 35 were knowledge items, whereas 23 were skills (11 therapeutic, 4 educative and 8 investigative). The large majority (79.3%) of these statements were endorsed by at least four out of five panel members.Conclusions  Despite the varied work patterns and responsibilities of specialists in CPT, it is possible to identify a core of knowledge and skill that most consider essential for the delivery of their commitment to the NHS. The findings will provide NHS Trusts with a clear idea of what they can expect from these specialists, and will act as a checklist for specialists themselves to direct their Continuing Professional Development within the consultant appraisal process. The results also describe a curriculum for continuing education in CPT, which the BPS Clinical Section can use to develop information resources and training opportunities.
The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antioestrogen Z‐4‐hydroxy‐tamoxifen in human liver
Authors: Coller Janet K. , Krebsfaenger Niels , Klein Kathrin , Endrizzi Karin , Wolbold Renzo , Lang Thomas , Nüssler Andreas , Neuhaus Peter , Zanger Ulrich M. , Eichelbaum Michel , Mürdter Thomas E. 
Published: March 2003

Aims  To investigate in a large panel of 50 human liver samples the contribution of CYP2C9, CYP2D6, and CYP3A4 to the overall formation of the potent antioestrogen Z‐4‐hydroxy‐tamoxifen, and how various genotypes affect its formation from tamoxifen.Methods  The formation of Z‐4‐hydroxy‐tamoxifen from 10 µm tamoxifen was studied in human liver microsomes (n=50), characterized for CYP2B6, CYP2C9, CYP2D6 and CYP3A4 expression, and CYP2B6, CYP2C9 and CYP2D6 genotype. The effect of chemical and monoclonal antibody inhibitors, and the formation in supersomes expressing recombinant CYP isoforms was also investigated. Z‐4‐hydroxy‐tamoxifen was quantified using LC‐MS analysis.Results  Z‐4‐hydroxy‐tamoxifen was formed by supersomes expressing CYP2B6, CYP2C9, CYP2C19 and CYP2D6, but not CYP3A4. In agreement with these data, the mean formation of Z‐4‐hydroxy‐tamoxifen was inhibited 49% by sulphaphenazole (P=0.001), 38% by quinidine (P<0.05) and 13% by monoclonal antibody against CYP2B6 (MAB‐2B6, P<0.05). Furthermore, Z‐4‐hydroxy‐tamoxifen formation significantly correlated with both CYP2C9 expression (rs=0.256, P<0.05) and CYP2D6 expression (rs=0.309, P<0.05). Genotypes of CYP2D6, CYP2B6 and CYP2C9 had an effect on metabolite formation in such a way that samples with two nonfunctional CYP2D6, or two variant CYP2C9 or CYP2B6 alleles, showed lower enzyme activity compared with those with two functional or wild‐type alleles, (5.0 vs 9.9 pmol mg−1 protein min−1, P=0.046, 5.1 vs 9.9 pmol mg−1 protein min−1, P=0.053, and 6.8 vs 9.4 pmol mg−1 protein min−1, P=0.054, respectively). CYP2D6 and CYP2C9 contribute on average 45 and 46%, respectively, to the overall formation of Z‐4‐hydroxy‐tamoxifen.Conclusions  CYP2B6, CYP2C9 and CYP2D6 genotypes all affected Z‐4‐hydroxy‐tamoxifen formation and can predict individual ability to catalyse this reaction.