bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetic analysis of felodipine–grapefruit juice interaction based on an irreversible enzyme inhibition model
Authors: Takanaga Hitomi , Ohnishi Ayako , Matsuo Hirotami , Murakami Hideyasu , Sata Hiroko , Kuroda Ken , Urae Akinori , Higuchi Shun , Sawada Yasufumi 
Published: March 2003

Aims Ingestion of grapefruit juice (GFJ) alters the pharmacokinetics of various orally administered drugs. Quantitative evaluation of this GFJ–drug interaction is required for the proper clinical management of patients. Methods Using felodipine as a model drug, we constructed a pharmacokinetic model based on irreversible inhibition of intestinal cytochrome P450 3A4 (CYP3A4) by GFJ. We fitted previously publised data [5, 6] for felodipine ER (extended release formulation) to the ratio of CLGI,int before and after grapefruit juice ingestion by nonlinear least‐squares regression analysis to estimate the reaction rate constant between GFJ and CYP3A4 (K) and the elimination rate constant of CYP3A4 (k ). Results The model gave a turnover rate of CYP3A4 of 0.0849 h−1, corresponding to a half‐life of 8.16 h, in agreement with reported values. The AUC‐time profiles of felodipine ER in the case of different amounts and schedules of GFJ ingestion were simulated using the parameter values estimated from the model. Conclusions The modelling leads to the important conclusion that GFJ–felodipine interaction increases with increasing frequency and amount of GFJ ingestion, and that an interval of 2–3 days between GFJ intake and felodipine administration is necessary if GFJ–felodipine interaction is to be avoided.
Single‐ and multiple‐dose pharmacokinetics of ziprasidone under non‐fasting conditions in healthy male volunteers
Authors: Miceli J. J. , Wilner K. D. , Hansen R. A. , Johnson A. C. , Apseloff G. , Gerber N. 
Published: March 2003

Aims  To evaluate the pharmacokinetics and tolerability of single and multiple oral doses of ziprasidone in healthy male volunteers, and to determine the influence of ziprasidone on serum prolactin levels.Methods  Single and multiple doses of ziprasidone were given orally (as two divided daily doses), at fixed dosages of 10 and 40 mg day− 1, and using titrated regimens of 40–80 and 40–120 mg day− 1, for 14 days. All dosages were taken immediately after food. The study adopted a randomized, double‐blind, placebo‐controlled design. Prolactin response, sedative properties, tolerability, and extrapyramidal symptoms were also investigated.Results  Steady‐state exposure to ziprasidone was attained after 1 day of dosing. Mean Cmax and AUC(0,12 h) increased with increasing dose, with apparent dose‐proportionality between the 20 and 60 mg dose levels. Trough‐to‐peak ratios at steady state ranged from 2 to 5. Accumulation ratios for the fixed‐dose regimens were 1.49 and 1.48 at the 5 and 20 mg dose levels, respectively. Ziprasidone was associated with transient prolactin elevation but levels of prolactin returned to baseline within the dosing interval at steady state. There was a marginal, transient increase in serum prolactin levels which was not dose‐related at the 80 and 120 mg day− 1 doses, and which was noted to attenuate with chronic dosing. Ziprasidone was generally well tolerated. The most frequent side‐effect was mild or moderate headache. A minority of patients suffered first‐dose postural hypotension. Ziprasidone was also associated with a mild sedative effect that became less pronounced as treatment continued. There were no drug‐related changes in electrocardiogram or clinical laboratory variables that were of clinical importance.Conclusions  Ziprasidone is characterized by a predictable pharmacokinetic profile resulting in symptoms that reflect its pharmacological action.
The single dose pharmacokinetics of ribavirin in subjects with chronic liver disease
Authors: Glue Paul , Schenker Steven , Gupta Samir , Clement Robert P. , Zambas Demetris , Salfi Margaret 
Published: March 2003

Aims  The primary objective of this study was to describe the single dose pharmacokinetics of ribavirin in subjects with normal liver function and those with various degrees of stable chronic liver disease. Additionally this study assessed the safety and tolerability of ribavirin in this population.Methods  Single oral 600 mg doses of ribavirin were administered to healthy male and female volunteers (n = 6) and patients with stable chronic liver disease (n = 17), in a parallel group study. Pharmacokinetic sampling and tolerability assessments were performed up to 168 h post dose.Results  Single oral doses of 600 mg ribavirin were well tolerated by healthy volunteers and patients with varying degrees of hepatic dysfunction. Although mean Cmax increased with the severity of hepatic dysfunction, there was no change in extent of absorption or renal clearance of ribavirin.Conclusions  There are no pharmacokinetic reasons for initial dose adjustment of ribavirin in patients with hepatic dysfunction.
The completeness of medication histories in hospital medical records of patients admitted to general internal medicine wards
Authors: Lau Hong Sang , Florax Christa , Porsius Arijan J. , De Boer Anthonius 
Published: March 2003

Aims
Accurate recording of medication histories in hospital medical records (HMR) is important when patients are admitted to the hospital. Lack of registration of drugs can lead to unintended discontinuation of drugs and failure to detect drug related problems. We investigated the comprehensiveness of medication histories in HMR with regard to prescription drugs by comparing the registration of drugs in HMR with computerized pharmacy records obtained from the community pharmacy.
Methods
Patients admitted to the general ward of two acute care hospitals were included in the study after obtaining informed consent. We conducted an interview on drugs used just prior to hospitalization and extracted the medication history from the HMR. Pharmacy records were collected from the community pharmacists over a 1 year period before the admission. Drugs in the pharmacy records were defined as possibly used (PU‐drugs) when they were dispensed before the admission date and had a theoretical enddate of 7 days before the admission date or later. If any PU‐drug was not recorded in the HMR, we asked the patient whether they were using that drug or not.
Results
Data were obtained from 304 patients who had an average age of 71 (range 40–92) years. The total number of drugs according to the HMR was 1239, 43 of which were not used. When compared with the pharmacy records we found an extra 518 drugs that were not recorded in the HMR but were possibly in use. After verification with the patients, 410 of these were indeed in use bringing the total number of drugs in use to 1606. The type of drugs in use but not recorded in the HMR covered a broad spectrum and included many drugs considered to be important such as cardiovascular drugs (n = 67) and NSAIDs (n = 31). The percentages of patients with 0, 1, 2, 3, 4, 5–11 drugs not recorded in the HMR were 39, 28, 16, 8, 3.6 and 5.5, respectively. Of the 1606 drugs in use according to information from all sources, only 38 (2.4%) were not retrievable in the pharmacy records when the complete year prior to hospitalization was evaluated.
Conclusions
The medication history in the hospital medical record is often incomplete, as 25% of the prescription drugs in use is not recorded and 61% of all patients has one of more drugs not registered. Pharmacy records from the community pharmacist can be used to obtain more complete information on the medication history of patients admitted to the hospital.
Intracranial haemorrhage and use of selective serotonin reuptake inhibitors
Authors: De Abajo Francisco J. , Jick Hershel , Derby Laura , Jick Susan , Schmitz Stephen 
Published: March 2003

Aims
In the past few years an increasing number of bleeding disorders have been reported in association with the use of selective serotonin reuptake inhibitors (SSRIs), including serious cases of intracranial haemorrhage, raising concerns about the safety of this class of drugs. The present study was performed to test the hypothesis of an increased risk of intracranial haemorrhage associated with the use of SSRIs.
Methods
We carried out a case‐control study nested in a cohort of antidepressants users with the UK‐based General Practice Research Database (GPRD) as the primary source of information. The study cohort encompassed subjects aged between 18 and 79 years who received a first‐time prescription for any antidepressant from January, 1990 to October, 1997. Patients with presenting conditions or treatments that could be associated with an increased risk of intracranial haemorrhage were excluded from the cohort. Patients were followed‐up until the occurrence of an idiopathic intracranial haemorrhage. Up to four controls per case, matched on age, sex, calendar time and practice were randomly selected from the study cohort. We estimated adjusted odds ratios and 95% confidence intervals of intracranial haemorrhage with current use of SSRIs and other antidepressants as compared with nonuse using conditional logistic regression.
Results
We identified 65 cases of idiopathic intracranial haemorrhage and 254 matched controls. Current exposure to SSRIs was ascertained in 7 cases (10.8%) and 24 controls (9.7%) resulting in an adjusted OR (95%CI) of 0.8 (0.3,2.3). The estimate for ‘other antidepressants’ was 0.7 (0.3,1.6). The effect measures were not modified by gender or age. No effect related to dose or treatment duration was detected. The risk estimates did not change according to the location of bleeding (intracerebral or subarachnoid).
Conclusions
Our results are not compatible with a major increased risk of intracranial haemorrhage among users of SSRIs or other antidepressants at large. However, smaller but still relevant increased risks cannot be ruled out.
A double‐blind placebo‐controlled study of the effectiveness and tolerability of oral stevioside in human hypertension
Authors: Chan Paul , Tomlinson Brian , Chen Yi‐Jen , Liu Ju‐Chi , Hsieh Ming‐Hsiung , Cheng Juei‐Tang 
Published: March 2003

AimsStevioside is a natural plant glycoside isolated from the plantStevia rebaudianawhich has been commercialized as a sweetener in Japan for more than 20 years. Previous animal studies have shown that stevioside has an antihypertensive effect. This study was to designed to evaluate the effect of stevioside in human hypertension.MethodsA multicentre, randomized, double‐blind, placebo‐controlled study was undertaken. This study group consisted of 106 Chinese hypertensive subjects with diastolic blood pressure between 95 and 110 mmHg and ages ranging from 28 to 75 years with 60 subjects (men 34, women 26; mean ± s.d., 54.1 ± 3.8 years) allocated to active treatment and 46 (men 19, women 27; mean ± s.d., 53.7 ± 4.1 years) to placebo treatment. Each subject was given capsules containing stevioside (250 mg) or placebo thrice daily and followed‐up at monthly intervals for 1 year.ResultsAfter 3 months, the systolic and diastolic blood pressure of the stevioside group decreased significantly (systolic: 166.0 ± 9.4–152.6 ± 6.8 mmHg; diastolic: 104.7 ± 5.2–90.3 ± 3.6 mmHg,P < 0.05), and the effect persisted during the whole year. Blood biochemistry parameters including lipid and glucose showed no significant changes. No significant adverse effect was observed and quality of life assessment showed no deterioration.ConclusionsThis study shows that oral stevioside is a well tolerated and effective modality that may be considered as an alternative or supplementary therapy for patients with hypertension.
Effect of an oral contraceptive preparation containing ethinylestradiol and gestodene on CYP3A4 activity as measured by midazolam 1′‐hydroxylation
Authors: Palovaara Sanna , Kivistö Kari T. , Tapanainen Pasi , Manninen Pekka , Neuvonen Pertti J. , Laine Kari 
Published: March 2003

Aims
To characterize the effect of an oral contraceptive (OC) containing ethinylestradiol and gestodene on the activity of CYP3A4 in vivo as measured by the 1′‐hydroxylation of midazolam.
Methods
In this randomised, double‐blind, cross‐over trial nine healthy female subjects received either a combined OC (30 µg ethinylestradiol and 75 µg gestodene) or placebo once daily for 10 days. On day 10, a single 7.5 mg dose of midazolam was given orally. Plasma concentrations of midazolam and 1′‐hydroxymidazolam were determined up to 24 h and the effects of midazolam were measured with three psychomotor tests up to 8 h.
Results
The combined OC increased the mean AUC of midazolam by 21% (95% CI 2% to 40%; P = 0.03) and decreased that of 1′‐hydroxymidazolam by 25% (95% CI 10% to 41%; P = 0.01), compared with placebo. The metabolic ratio (AUC of 1′‐hydroxymidazolam/AUC of midazolam) was 36% smaller (95% CI 19% to 53%; P = 0.01) in the OC phase than in the placebo phase. There were no significant differences in the Cmax, tmax, t½ or effects of midazolam between the phases.
Conclusions
A combined OC preparation caused a modest reduction in the activity of CYP3A4, as measured by the 1′‐hydroxylation of midazolam, and slightly increased the AUC of oral midazolam. This study suggests that, at the doses used, ethinylestradiol and gestodene have a relatively small effect on CYP3A4 activity in vivo.
Pharmacokinetics of propionyl‐ l‐carnitine in humans: evidence for saturable tubular reabsorption
Authors: Pace S. , Longo A. , Toon S. , Rolan P. , Evans A. M. 
Published: March 2003

Aims  Propionyl‐
l‐carnitine (PLC) is an endogenous compound which, along with
l‐carnitine (LC) and acetyl‐
l‐carnitine (ALC), forms a component of the endogenous carnitine pool in humans and most, if not all, animal species. PLC is currently under investigation for the treatment of peripheral artery disease, and the present study was conducted to assess the pharmacokinetics of intravenous propionyl‐
l‐carnitine hydrochloride.Methods  This was a placebo‐controlled, double‐blind, parallel group, dose‐escalating study in which 24 healthy males were divided into four groups of six. Four subjects from each group received propionyl‐
l‐carnitine hydrochloride and two received placebo. The doses (1 g, 2 g, 4 g and 8 g) were administered as a constant rate infusion over 2 h and blood and urine were collected for 24 h from the start of the infusion. PLC, ALC and LC in plasma and urine were quantified by h.p.l.c.Results  All 24 subjects successfully completed the study and the infusions were well tolerated. In addition to the expected increase in PLC levels, the plasma concentrations and urinary excretion of LC and ALC also increased above baseline values following intravenous propionyl‐
l‐carnitine hydrochloride administration. At a dose of 1 g, PLC was found to have a mean (± s.d.) half‐life of 1.09 ± 0.15 h, a clearance of 11.6 ± 0.24 l h−1 and a volume of distribution of 18.3 ± 2.4 l. None of these parameters changed with dose. In placebo‐treated subjects, endogenous PLC, LC and ALC underwent extensive renal tubular reabsorption, as indicated by renal excretory clearance to GFR ratios of less than 0.1. The renal‐excretory clearance of PLC, which was 0.33 ± 0.38 l h−1 under baseline condition, increased (P < 0.001) from 1.98 ± 0.59 l h−1 at a dose of 1 g to 5.55 ± 1.50 l h−1 at a dose of 8 g (95% confidence interval for the difference was 2.18,4.97). As a consequence, the percent of the dose excreted unchanged in urine increased (P < 0.001) from 18.1 ± 5.5% (1 g) to 50.3 ± 13.3% (8 g). The renal‐excretory clearance of LC and ALC also increased substantially after PLC administration and there was evidence for renal metabolism of PLC to LC and ALC.Conclusions  Intravenous administration of propionyl‐
l‐carnitine hydrochloride caused significant increases in the renal excretory clearances of PLC, LC and ALC, due to saturation of the renal tubular reabsorption process – as a consequence there was a substantial increase with dose in the fraction excreted unchanged in urine. Despite the marked increase in the renal clearance of PLC, total clearance remained unchanged, suggesting a compensatory reduction in the clearance of the compound by non excretory routes.
Population PK and PK/PD modelling of microencapsulated octreotide acetate in healthy subjects
Authors: Zhou Honghui , Chen Tian‐Ling , Marino Mark , Lau Henry , Miller Thomas , Kalafsky Gaetana , McLeod James F. 
Published: March 2003

Aims
To develop a population model that can describe the pharmacokinetic profile of microencapsulated octreotide acetate in healthy cholecystectomized subjects. To investigate the correlation between serum IGF‐1 and octreotide concentration.Methods  A population pharmacokinetic analysis was performed on octreotide data obtained following a single dose of 30 mg microencapsulated octreotide acetate intramuscularly. The relationship between serum IGF‐1 concentration and octreotide concentration was effectively described by a population pharmacokinetic/pharmacodynamic model.Results  The pharmacokinetic profile of octreotide was characterized by an initial peak of octreotide followed by a sustained‐release of drug. Plateau concentration were sustained up to day 70, and gradually declined to below the detection limit by day 112. A one‐compartment linear model was constructed which consisted of two absorption processes, characterized by KIR and KSR, rate constants for immediate‐release and sustained‐release, respectively, with first‐order elimination (Ke; 1.05 h−1). The surface, unencapsulated drug was immediately absorbed into the central compartment with first‐order absorption (KIR; 0.0312 h−1), while the microencapsulated drug was first released in a zero‐order fashion into a depot before being absorbed into the central compartment with first‐order absorption (KSR; 0.00469 h−1) during a period of τ (1680 h). Body weight and gender were important covariates for the apparent volume of distribution. The type of formulation was an important covariate for KIR but had no effect on KSR. An inhibitory Emax population pharmacokinetic/pharmacodynamic model could adequately describe the relationship between IGF‐1 (expressed as percent baseline) and octreotide concentration. Baseline IGF‐1 concentration was found to be a significant covariate for the baseline effect (E0). A relationship between GH concentration and octreotide concentration was not established.Conclusions  The pharmacokinetic profile of microencapsulated octreotide acetate was effectively described by the derived population model. The relationship between IGF‐1 and drug concentration could be used to guide optimization of therapeutic octreotide dosage regimens.
Responsiveness of human varicose saphenous veins to vasoactive agents
Authors: Brunner Friedrich , Hoffmann Christine , Schuller‐Petrovic Sanja 
Published: March 2003

Aims  To test in vitro the constrictor and relaxation responsiveness of variously diseased segments of human saphenous vein from patients with varicose vein disease.Methods  The vein segments were derived (i) from the inguinal saphenous vein (valvularly incompetent and slightly dilated; tissue A); (ii) from the distal end of the lower leg just above the medial ankle (competent; tissue B); (iii) from a tributary to the long saphenous vein just below the knee (dilated, incompetent and overtly varicose; tissue C). The contractile responses were tested with phenylephrine (an α‐adrenergic receptor agonist) and aescin, a clinically used phlebotonic drug derived from horse chestnut extract. Relaxant responses were tested with acetylcholine and sodium nitroprusside.Results  Both contractile agents contracted vein segments from the inguinal and ankle area with similar potency and efficacy, but were virtually without effect in the overtly varicose segments from the calf. EC50 values (molar concentration of the agonist that produces 50% of the maximum effect) in tissues A and B were 2.9 ± 0.3 and 2.5 ± 0.5 µmol l−1 (phenylephrine) and 9.4 ± 1.0 and 15.9 ± 2.5 µmol l−1 (aescin); the corresponding maximum effects (maximum effect, percent of KCl‐induced contraction) were 76 ± 3 and 70 ± 4% (phenylephrine) and 70 ± 2 and 71 ± 3% (aescin) (P = NS in both cases for A vs B). In tissue C, the maximum effects were 5 ± 5% (phenylephrine) and 10 ± 7% (aescin) of KCl‐induced contraction (not significantly different from zero). Acetylcholine‐induced relaxation was similar for vein segments from locations A and B, whereas sodium nitroprusside was more effective in tissue B than A.Conclusions  These findings support the notion that abnormalities within the venous wall affect venous smooth muscle contractility. Since competent and incompetent clinically normal vessels show normal contractile responses, whereas varicose vessels are not responsive to vasoactive drugs, it is likely that pharmacological treatment regimens are effective in early, but not in late stages of the disease.
Effect of α1‐acid glycoprotein on the intracellular accumulation of the HIV protease inhibitors saquinavir, ritonavir and indinavir in vitro
Authors: Jones K. , Hoggard P. G. , Khoo S. , Maher B. , Back D. J. 
Published: March 2003

Aims  Since α1‐acid glycoprotein (AGP) levels may be raised during HIV infection, we have examined in vitro the effect of increasing the concentration of AGP on the intracellular accumulation of the HIV protease inhibitors saquinavir (SQV), ritonavir (RTV) and indinavir (IDV).Methods  U937 cells (5 × 106 cells in 5 ml RPMI growth medium) were incubated at 37 °C for 18 h with [14C]‐SQV (0.1 µCi), [3H]‐RTV and [3H]‐IDV (0.135 µCi) to a final concentration of 1 µm in the presence of 0, 0.5 and 2.0 mg ml−1 AGP. Following extraction in 60% methanol the intracellular drug concentration was determined by liquid scintillation counting.Results  Binding to AGP (2.0 mg ml−1) reduced the mean intracellular concentration of SQV from 31.5 µm to 7.4 µm (P < 0.0001; 95% CI 19.4–28.8). RTV concentration was also reduced (8.8 µm to 1.6 µm; P < 0.0001; 95% CI 5.4–9.0) as was the concentration of IDV (3.0 µm to 1.5 µm; P < 0.0001; 95% CI 1.1–1.9).Conclusions  Reduced intracellular protease inhibitor concentrations in the presence of increasing concentrations of AGP will certainly impact on the antiviral activity in vitro. However, since protease inhibitors are high clearance drugs, free drug concentration will likely remain unaffected in the presence of elevated AGP during chronic oral dosing although there will be an increase in total plasma drug concentration.
Systemic bioavailability of fluticasone propionate administered as nasal drops and aqueous nasal spray formulations
Authors: Daley‐Yates Peter T. , Baker Richard C. 
Published: March 2003

Aims  To measure and compare the systemic bioavailability of fluticasone propionate aqueous nasal spray and a new nasal drop formulation, using a sensitive analytical method and high dose regimen.Methods  Volunteers received four 800 µg doses of fluticasone propionate as a nasal spray or drops over 2 days, separated by an 8 h dose interval. On day 2, blood samples were collected for assay of fluticasone propionate plasma concentrations.Results  The mean systemic exposure, for both formulations was 8.5 pg ml−1 h (drops) and 67.5 pg ml−1 h (spray). Mean absolute bioavailabilities were estimated to be 0.06% (drops) and 0.51% (spray), by reference to historical intravenous data.Conclusions  Both formulations exhibited low systemic bioavailability, even at 12 times the normal daily dose. The bioavailability from the nasal drops was approximately eight times lower than from the nasal spray.