bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of duration of dose delivery with patient‐controlled analgesia on the incidence of nausea and vomiting after hysterectomy
Authors: Woodhouse Annie , Mather Laurence E. 
Published: March 2003

Aims
Postoperative nausea and vomiting (PONV) may be exacerbated by postoperative opioid analgesics and may limit patients’ successful use of these medications when used with patient controlled analgesia (PCA). We tested the hypothesis that the rapid change in blood morphine concentration associated with PCA bolus delivery contributed to PONV, and that prolonging its delivery to a brief infusion would result in decreased PONV.
Methods
Patients, who were receiving morphine for pain relief via patient‐controlled analgesia (PCA) after total abdominal hysterectomy, received 1 mg morphine sulphate incremental doses either over 40 s with a 5 min lockout interval or over 5 min delivery with a 1 min lockout interval. Episodes of nausea, retching and vomiting, along with the use of morphine and the pain relief obtained, were recorded.
Results
Data from 20 patients in each group were analysed. Contrary to expectations, most patients in both groups reported nausea postoperatively. Those patients receiving morphine over 5 min experienced more episodes of emesis (36) than those receiving the dose over 40 s (17). Most patients receiving the 40 s doses vomited in the first 12 h (median time 8 h), while those receiving the 5 min doses vomited between 12 and 24 h (median time 19 h) (P=0.01). There were no differences between groups in the visual analogue pain scores or use of morphine between groups.
Conclusions
Reasons for these unexpected findings remain speculative. The high incidence of PONV appears to be inherently high in gynaecological surgery patients and standard antiemetic medication regimens appear to be poorly efficacious. Reasons for the differences in the time‐course of emetic episodes between the two groups may be related to differences in the time‐course of central opioid receptor occupancy.
Gastrointestinal tolerability of meloxicam and piroxicam: a double‐blind placebo‐controlled study
Authors: Lipscomb G. R. , Wallis N. , Armstrong G. , Rees W. D. W. 
Published: March 2003

Aims
The aim of the study was to compare the effects of meloxicam and piroxicam on the gastroduodenal mucosa in healthy adults.
Methods
Forty‐four healthy volunteers were given a 28 day course of either meloxicam 15 mg, piroxicam 20 mg or placebo. Damage to the oesophageal, gastric and duodenal mucosa was assessed, mucosal blood flow (MBF) measured at endoscopy and biopsies taken for prostaglandin content and microscopic assessment of damage before NSAID administration and during days 1, 7 and 28 of continued intake.
Results
Maximal macroscopic gastric mucosal damage (median grade+IQR) occurred within 24 h of piroxicam administration, the damage score increasing from 0 to 2.5 (0–3) (P=0.02) at day 1 before falling to 2.0 (0–2) at day 7 and 0 (0–1) at day 28 with resolution of damage observed in six out of the seven subjects who sustained acute injury. No significant macroscopic gastric damage occurred in either of the two other groups although some minor damage was observed in seven subjects taking placebo and five taking meloxicam. There was a trend towards piroxicam causing more acute gastric damage than meloxicam (P=0.06). Baseline antral, body and duodenal MBF were similar in all three groups. No significant changes occurred in any of the groups on any of the visits. There were also no changes in gastric mucosal prostaglandin content in any group.
Conclusions
These observations suggest that meloxicam causes little acute damage to the upper gastrointestinal tract and piroxicam causes some acute gastric injury but such damage resolves in most subjects by 28 days.
Cardiovascular effects of melatonin in hypertensive patients well controlled by nifedipine: a 24‐hour study
Authors: Lusardi Paola , Piazza Elena , Fogari Roberto 
Published: March 2003

Aims
As melatonin has been found to play a role in the mechanisms of cardiovascular regulation, we designed the present study to evaluate whether the evening ingestion of the pineal hormone might interfere with the antihypertensive therapy in hypertensive patients well‐controlled by nifedipine monotherapy.
Methods
Forty‐seven mild to moderate essential hypertensive outpatients taking nifedipine GITS 30 or 60 mg monotherapy at 08.30 h for at least 3 months, were given placebo or melatonin 5 mg at 22.30 h for 4 weeks according to a double‐blind cross‐over study. At the end of each treatment period patients underwent a 24 h noninvasive ambulatory blood pressure monitoring (ABPM) during usual working days; sleeping period was scheduled to last from 23.00 to 07.00 h.
Results
The evening administration of melatonin induced an increase of blood pressure and heart rate throughout the 24 h period (ΔSBP = + 6.5 mmHg, P < 0.001; ΔDBP = + 4.9 mmHg, P < 0.01; ΔHR = + 3.9 beats min−1, P < 0.01). The DBP as well as the HR increase were particularly evident during the morning and the afternoon hours.
Conclusions
We hypothesize that competition between melatonin and nifedipine, is able to impair the antihypertensive efficacy of the calcium channel blocker. This suggests caution in uncontrolled use of melatonin in hypertensive patients. As the pineal hormone might interfere with calcium channel blocker therapy, it cannot be considered simply a dietary supplement.
Compliance with tricyclic antidepressants: the value of four different methods of assessment
Authors: George C. F. , Peveler R. C. , Heiliger S. , Thompson C. 
Published: March 2003

Aims
To assess the advantages and disadvantages of four methods for studying compliance with antidepressants: self‐report scores, tablet counts, a microprocessor (MEMS) container system and the assay of nordothiepin and dothiepin concentrations in plasma.
Methods
The techniques were used in 88 patients commencing tricyclic antidepressants in the setting of UK general practice.
Results
The MEMS system proved to be the most informative technique allowing identification of the precise time of container opening, the demonstration of ‘drug holidays’ and early cessation of therapy. Self‐report scores (Morisky) proved a useful screening technique with a sensitivity of 72.2% and specificity of 74.1% for ≥ 80% compliance. Although tablet counts were possible in 84 patients (95.5%) they were unreliable in 19 (21.6%). Blood concentration assays proved the least acceptable method to patients and were possible in only 53 (60.2%). A ratio of nordothiepin:dothiepin ≥ 1.1 claimed, by others, to identify noncompliance was only reliable when concentrations were low.
Conclusions
Both the MEMS system and self‐report scores proved useful methods for identifying noncompliant patients in the setting of UK general practice. Although compliance was higher than reported in previous studies with 70 patients (79.5%) completing 6 weeks treatment, general practitioners tended to prescribe subtherapeutic doses.
Pharmacokinetic interactions between sildenafil and saquinavir/ritonavir
Authors: Muirhead Gary J. , Wulff Maria B. , Fielding Anitra , Kleinermans Diane , Buss Neil 
Published: March 2003

Aims
To investigate the effect of the antiretroviral protease inhibitors saquinavir (soft gelatin capsule) and ritonavir on the pharmacokinetic properties and tolerability of sildenafil and to investigate the effect of sildenafil on the steady‐state pharmacokinetics of saquinavir and ritonavir.
Methods
Two independent, 8 day, open, randomized, placebo‐controlled, parallel‐group studies (containing a double‐blind crossover phase) were conducted at Pfizer Clinical research units (Canterbury, UK. and Brussels, Belgium). Twenty‐eight healthy male volunteers entered each study. In each study, volunteers were randomized (n = 14 per group) to receive sildenafil on day 1 followed by a 7‐day treatment period (days 2–8) with saquinavir or placebo (Study I) or ritonavir or placebo (Study II). Sildenafil or placebo (Study I and Study II) was administered alternately on day 7 or day 8, depending on initial randomization. The effect of saquinavir and ritonavir on the pharmacokinetics of sildenafil and its primary circulating metabolite (UK‐103, 320) and the effect of single‐dose sildenafil on the steady‐state pharmacokinetics of saquinavir (1200 mg three times daily) and ritonavir (500 mg twice daily) were determined. The safety and tolerability of sildenafil coadministered with saquinavir or ritonavir were also assessed.
Results
Both protease inhibitors significantly increased Cmax, AUC, tmax and t½ values for both sildenafil and UK‐103, 320. Ritonavir showed a significantly greater effect than saquinavir with increases in sildenafil AUC and Cmax of 11‐fold (95% CI: 9.0, 12.0) and 3.9‐fold (95% CI: 3.2, 4.9), respectively. This compared with increases of 3.1‐fold (95% CI: 2.5, 4.0) and 2.4‐fold (95% CI: 1.8, 3.3) for coadministration with saquinavir. In contrast, the steady‐state pharmacokinetics of saquinavir and ritonavir were unaffected by sildenafil. The increases in systemic exposure to sildenafil and UK‐103, 320 were not associated with an increased incidence of adverse events or clinically significant changes in blood pressure, heart rate or ECG parameters.
Conclusions
These results indicate that both saquinavir and ritonavir modify the pharmacokinetics of sildenafil presumably through inhibition of CYP3A4. The more pronounced effect of ritonavir may be attributed to its additional potent inhibition of CYP2C9. No change in safety or tolerability was observed when sildenafil was coadministered with either protease inhibitor. However, given the extent of the interactions, a lower sildenafil starting dose (25 mg) should be considered for patients receiving saquinavir and it is recommended not to exceed a maximum single dose of 25 mg in a 48 h period for patients receiving ritonavir.
Lack of effect of grapefruit juice on the pharmacokinetics and pharmacodynamics of amlodipine
Authors: Vincent John , Harris Stuart I. , Foulds George , Dogolo Lisa C. , Willavize Susan , Friedman Hylar L. 
Published: March 2003

Aims
To determine whether repeated once daily administration of grapefruit juice altered the pharmacokinetics or pharmacodynamics of the calcium antagonist amlodipine.
Methods
The effects of grapefruit juice on the pharmacokinetics and pharmacodynamics of oral and intravenous amlodipine were assessed in 20 healthy men in a placebo‐controlled, open, randomized, four‐way crossover study using single doses of amlodipine 10 mg. For 9 days beginning with the day of administration of amlodipine, grapefruit juice (or water control) was given once daily, and blood samples, blood pressure and heart rate measures were obtained. Plasma concentrations of amlodipine and its enantiomers were determined in separate assays by GC‐ECD.
Results
Oral amlodipine had high systemic availability (grapefruit juice: 88%; water: 81%). Pharmacokinetic parameters of racemic amlodipine (AUC, Cmax, tmax, and kel) were not markedly changed with grapefruit juice coadministration. Total plasma clearance and volume of distribution, calculated after intravenous amlodipine, were essentially unchanged by grapefruit juice (CL 6.65 ml min−1 kg−1, juice vs 6.93 ml min−1 kg−1, water; Vdss 22.7 l kg−1, juice vs 21.0 l kg−1, water). Grapefruit juice coadministration did not greatly alter the stereoselectivity in amlodipine oral or intravenous kinetics. The sum of S(–) and R(+) enantiomer concentrations correlated well with total racemic amlodipine concentration (r2 = 0.957; P = 0.0001). Coadministration of grapefruit juice with either route of amlodipine administration did not significantly alter blood pressure changes vs control.
Conclusions
Grapefruit juice has no appreciable effect on amlodipine pharmacodynamics or pharmacokinetics, including its stereoselective kinetics. Bioavailability enhancement by grapefruit juice, noted with other dihydropyridine calcium antagonists, does not occur with amlodipine. Once daily grapefruit juice administration with usual oral doses of amlodipine is unlikely to alter the profile of response in clinical practice.
Clinical risk factors for venous thromboembolus in users of the combined oral contraceptive pill
Authors: Black Corri , Kaye James A. , Jick Hershel 
Published: March 2003

Aims  To estimate the risk of venous thromboembolism among women prescribed the oral contraceptive pill who have acute clinical conditions such as lower limb fractures, compared with women with idiopathic venous thromboembolism.Methods  A nested case‐control analysis using the General Practice Research Database, January 1993 to December 1999 was carried out. The participants were women aged 15–39 years, prescribed third generation oral contraceptives (gestodene and desogestrel) or oral contraceptives containing levonorgestrel. The main outcome measures were odds ratios as a measure of the relative risk estimate for venous thromboembolism in women with clinical conditions that predispose to VTE.Results  The adjusted relative risk estimate for venous thromboembolism among patients with the acute clinical conditions, compared with those without such illness, and adjusted for oral contraceptive use, was 17 (95% CI 6.5, 46).Conclusions  This paper documents the strong independent association between certain acute clinical conditions and venous thromboembolism in women prescribed oral contraceptives. Failure to accurately identify and exclude such patients from a study of the effect of oral contraceptives on the risk of venous thromboembolism would result in an underestimate of the risk of venous thromboembolism associated with oral contraceptives.
Oxidation of celecoxib by polymorphic cytochrome P450 2C9 and alcohol dehydrogenase
Authors: Sandberg Mia , Yasar Ümit , Strömberg Patrik , Höög Jan‐Olov , Eliasson Erik 
Published: March 2003

Aims
Celecoxib is a novel selective cyclooxygenase‐2 inhibitor, which is subject to extensive hepatic metabolism. The aims of the present in vitro investigation were 1) to compare the rate of celecoxib hydroxylation by different genetic variants of cytochrome P450 2C9 (CYP2C9), and 2) to identify the enzyme(s) involved in the formation of the major metabolite carboxycelecoxib.
Methods
Hydroxycelecoxib formation was studied in human liver microsomes from 35 genotyped livers, as well as in yeast microsomes with recombinant expression of different P450 variants. Carboxycelecoxib formation was studied in liver microsomes incubated in the absence or presence of liver cytosol. The metabolites were identified and quantified by h.p.l.c. In addition, hydroxycelecoxib oxidation by different variants of recombinant human alcohol dehydrogenase (ADH1–3) was analysed by spectrophotometric monitoring of NADH generation from NAD+.
Results
The  intrinsic  clearance  of  celecoxib  hydroxylation  was  significantly  lower for yeast‐expressed CYP2C9.3 (0.14 ml min−1 nmol−1 enzyme) compared with CYP2C9.1  (0.44 ml min−1 nmol−1 enzyme).  In  human  liver  microsomes,  a  signifi­cant 2‐fold decrease in the rate of hydroxycelecoxib formation was evident in CYP2C9*1/*3 samples compared with CYP2C9*1/*1 samples. There was also a marked reduction (up to 5.3 times) of hydroxycelecoxib formation in a liver sample genotyped as CYP2C9*3/*3. However, the CYP2C9*2 samples did not differ significantly from CYP2C9*1 in any of the systems studied. Inhibition experiments with sulphaphenazole (SPZ) or triacetyloleandomycin indicated that celecoxib hydroxylation in human liver microsomes was mainly dependent on CYP2C9 and not CYP3A4. The further oxidation of hydroxycelecoxib to carboxycelecoxib was completely dependent on liver cytosol and NAD+. Additional experiments showed that ADH1 and ADH2 catalysed this reaction in vitro with apparent Km values of 42 µm and 10 µm, respectively, whereas ADH3 showed no activity.
Conclusions
The results confirm that CYP2C9 is the major enzyme for celecoxib hydroxylation in vitro and further indicate that the CYP2C9*3 allelic variant is associated with markedly slower metabolism. Furthermore, it was shown for the first time that carboxycelecoxib formation is dependent on cytosolic alcohol dehydrogenase, presumably ADH1 and/or ADH2.
Quinine pharmacokinetics in chronic haemodialysis patients
Authors: Roy Louise ,   Martine Leblanc,, Bannon Pierre , Villeneuve Jean‐Pierre 
Published: March 2003

Aims Quinine is often used to prevent muscle cramps in patients with chronic renal failure. A standard dose of 300 mg at bedtime is usually recommended, but little is known about the pharmacokinetics of quinine in the presence of renal failure.Methods We studied the pharmacokinetics of quinine in eight normal subjects and eight patients with chronic renal failure on haemodialysis after a single oral dose of quinine sulphate (300 mg).Results The concentration of α1‐acid glycoprotein (AAG), the major binding protein for quinine, was increased in haemodialysis patients compared with control subjects (1.52 g l−1vs 0.63 g l−1[mean difference 1.033; 95% CI 0.735, 1.330]) whereas albumin levels were decreased (30 g l−1vs 40 g l−1[mean difference 9.5; 95% CI 3.048, 15.952]). Accordingly, the free fraction of quinine was decreased (0.024 vs 0.063 [mean difference 0.0380; 95% CI 0.0221, 0.0539]) and the apparent volume of distribution tended to decrease (0.95 l kg−1vs 1.43 l kg−1[mean difference 0.480; 95% CI 0.193, 1.154]). The quinine binding ratio correlated with the plasma concentration of AAG but not that of albumin. The clearance of free (unbound) quinine was increased in haemodialysis patients compared with controls (67.9 ml min−1 kg−1vs 41.1 ml min−1 kg−1[mean difference −26.8; 95% CI, –56.994, 3.469]), and the area under the curve (AUC) of the two main metabolites, 3‐hydroxyquinine and 10,11‐dihydroxydihydroquinine were increased.Conclusions In patients with chronic renal failure, there is an increase in plasma protein binding and in the clearance of free drug, resulting in lower plasma concentration of free quinine.
REVIEWCytokines and chemokines in the initiation and regulation of epidermal Langerhans cell mobilization
Authors: Kimber I. , Cumberbatch M. , Dearman R.J. , Bhushan M. , Griffiths C.E.M. 
Published: March 2003

Abstract
Langerhans cells (LC) are members of the wider family of dendritic cells. LC reside in the epidermis where they serve as sentinels of the immune system, their responsibilities being to sample the external environment for changes and challenges and to deliver information (antigen) to responsive T lymphocytes within skin draining lymph nodes. The ability of LC to migrate from the epidermis to regional lymph nodes is therefore of pivotal importance to the induction of cutaneous immune responses. The journey that LC have to make from the skin has a number of requirements. Initially it is necessary that LC disassociate themselves from surrounding keratinocytes and are liberated from other influences that encourage their retention in the epidermis. Subsequently, migrating LC must successfully traverse the basement membrane of the dermal–epidermal junction and make their way, via afferent lymphatics, to draining lymph nodes. Effective entry into lymph nodes is necessary, as is correct positioning of cells within the paracortex. There is increasing evidence that both cytokines and chemokines, and their interaction with appropriate receptors expressed by LC, orchestrate the mobilization and movement of these cells. We here consider the parts played by these molecules, and how collectively they induce and direct LC migration.
Antineutrophil cytoplasmic antibodies and HLA class II alleles in minocycline-induced lupus-like syndrome
Authors: Dunphy J. , Oliver M. , Rands A.L. , Lovell C.R. , Mchugh N.J. 
Published: March 2003

Abstract
We report 14 patients with minocycline-induced lupus-like syndrome (four men, 10 women; mean age 27·8 years) who developed a lupus-like illness after chronic use of minocycline for acne (1–10 years, median 3·8). Clinical features resolved completely on drug withdrawal (mean follow-up 11 months) and reappeared in two patients who were rechallenged. Sera from all 14 patients contained antineutrophil cytoplasmic antibodies (ANCA) giving a perinuclear pattern on indirect immunofluorescence on ethanol-fixed human neutrophils (p-ANCA), whereas 14 control asymptomatic individuals taking minocycline for acne were ANCA-negative. Eleven of the 14 patients had elevated antimyeloperoxidase antibodies and 10 had antielastase antibodies on enzyme-linked immunosorbent assay, which diminished on extended follow-up, as did other serological abnormalities. Major histocompatibility complex class II typing demonstrated that all of the 13 patients tested were either HLA-DR4 (nine of 13) or HLA-DR2 (four of 13) positive, and all had an HLA-DQB1 allele encoding for tyrosine at position 30 of the first domain. Our findings suggest a model whereby the presence of p-ANCA may be a marker for the development of lupus-like symptoms in genetically susceptible individuals taking minocycline for acne.
The clinical spectrum of epidermolysis bullosa simplex
Authors: Horn H.M. , Tidman M.J. 
Published: March 2003

AbstractAs part of the U.K. National Epidermolysis Bullosa Register, we have systematically recorded clinical information on 130 (77%) of the 168 known Scottish epidermolysis bullosa simplex (EBS) sufferers. Three subtypes of EBS were recognized: Dowling–Meara (EBS-DM), Weber–Cockayne (EBS-WC) and Köbner (EBS-Kb), seen in 5%, 42% and 53% of patients, respectively. As there is considerable overlap between EBS-WC and EBS-Kb, with both phenotypes frequently seen within the same pedigree, EBS-WC is best regarded as a milder variant of EBS-Kb rather than a separate disorder. Improvement with age is common in all variants of EBS, but is not invariable. Pain due to acral blistering in EBS-Kb/EBS-WC has a more marked impact on life-style than the blisters of EBS-DM. Oral blistering, nail involvement and aplasia cutis congenita occur in all EBS subtypes and laryngeal involvement is a feature of EBS-DM. Seasonal variation is not seen in EBS-DM but is common in EBS-Kb/EBS-WC.
Acquired immune deficiency syndrome-related hyperkeratotic Kaposi’s sarcoma with severe lymphoedema: report of five cases
Authors: Hengge U.R. , Stocks K. , Goos M. 
Published: March 2003

Abstract
Kaposi’s sarcoma (KS) is the most frequent neoplasm in acquired immune deficiency syndrome (AIDS) patients. Whereas typical cases present as erythematous, plaque or nodular lesions, hyperkeratotic variants of AIDS-associated KS are rare. We describe five patients with AIDS-associated KS with hyperkeratosis and lymphoedema as prominent features. We also speculate on its pathogenesis.
Epidermolysis bullosa acquisita with ultraviolet radiationsensitivity
Authors: Jappe U. , Zillikens D. , Bonnekoh B. , Gollnick H. 
Published: March 2003

Abstract
A 37-year-old male patient developed a bullous eruption and erythematous plaques mainly in exposed areas following prolonged sun exposure. In addition, blisters were noted on oral and nasal mucous membranes. Histopathological examination of a lesional skin biopsy revealed a subepidermal blister. Linear deposition of IgG and C3 at the epidermal basement membrane zone was revealed by direct immunofluorescence microscopy of a perilesional skin biopsy. Indirect immunofluorescence on 1 mol/L salt-split skin showed binding of autoantibodies to the dermal side of the split. Immunoblot analysis of dermal extracts demonstrated that the patient’s serum contained IgG antibodies against type VII collagen, whereas no reaction was seen with epidermal extracts or by enzyme-linked immunosorbent assay using a recombinant form of bullous pemphigoid 180. Standardized ultraviolet (UV) radiation provocation induced blistering with both UVA (13·5 J/cm2) and UVB (0·04 J/cm2) within 24 h clinically and histologically. External and systemic UV-protective medication and nine cycles of high dosage immunoglobulins given intravenously (1·2 g/kg body weight over 2–3 days every 4 weeks) resulted in the cessation of blister formation. To the best of our knowledge, this is the first report of a case of epidermolysis bullosa acquisita with sensitivity to UV.