bluuebunny/crossref_metadata_2025 huggingface dataset:
Openness to the Unknown
Authors: Kageyama Yasuyuki
Published: April 2003

From the time of its birth, Popper 's theory of falsifiability has been fiercely criticized from various viewpoints. In the author's view, however, those various criticisms all have the same root in their assumption that a falsification must be certain and conclusive. As the theory of falsifiability has never had such an assumption, it is the source of misunderstanding. By discarding it, we can reply to every criticism and thereby clarify the role of falsifiability in our search for better knowledge; that is, it makes our attitude open to a yet unknown world.
Artificial Societies
Authors: Sawyer R. Keith
Published: April 2003

This article introduces a general sociological readership to multiagent systems (MAS), a new computer simulation technology that has increasingly been used to describe and explain sociological phenomena. The author uses the term artificial societies to refer to social simulations using MAS and he describes MAS technology and contrasts it with other social simulation technologies. The author argues that MAS have attained a level of maturity where they can be useful tools for sociologists, and he shows how MAS provide new perspectives on contemporary discussions of the micro-macro link in sociological theory by focusing on three aspects of the micro-macro link: micro-to-macro emergence, macro-to-micro social causation, and the dialectic between emergence and social causation.
Tobit Models in Social Science Research
Authors: Smith Douglas A. , Brame Robert
Published: April 2003

The use of tobit models to study censored and limited dependent variables has become increasingly common in applied social science research over the past two decades. Importantly, the likelihood function for a tobit model involves two distinct components: (1) the process that determines whether the outcome variable is fully observed or not and (2) the process that determines the score on the dependent variable for individuals whose outcome is fully observed. One limitation of the tobit model is its assumption that the processes in both regimes of the outcome are equal up to a constant of proportionality. In this article, the authors use Monte Carlo simulation evidence and an empirical example to illustrate the restrictive nature of this assumption and the consequences of disproportionality for the tobit model. They conclude that an alternative model proposed by Cragg should replace the tobit model as the estimator of first resort in situations such as those considered here.
Case-Deletion Diagnostics for Factor Analysis Models With Continuous and Ordinal Categorical Data
Authors: Lee Sik-Yum , Xu Liang
Published: April 2003

This article proposes a method to detect influential observations in a factor analysis model with continuous and ordinal categorical variables. The key ideas are to treat the latent factors as hypothetical missing data and then develop the diagnostic measures on the basis of the conditional expectation of the complete-data log-likelihood function in the EM algorithm. A one-step approximation is proposed to reduce the computational burden. Building blocks for achieving the diagnostic measures are computed via observations generated by the Gibbs sampler. Results from a simulation study and an illustrative real example are presented.
Verbal Morphology in Cajun Vernacular English
Authors: Dubois Sylvie , Horvath Barbara M.
Published: April 2003

Cajun English is spoken in French-dominant rural areas of south Louisiana. The authors present morphosyntactic evidence to show that Cajun English is a vernacular originating in the Louisiana Cajun speech communities and is not the result of dialect spread or faulty language learning. The features of Cajun English reported on are (1) -S Absence, (2) -ED Absence, (3) IS Absence, (4) ARE Absence, and (4) WAS Leveling ( was in Standard English were contexts). A comparison of the results of this study with a large number of similar sociolinguistic studies reveals that Cajun English differs both quantitatively and qualitatively from other varieties of Southern English. In many cases, the amount of deletion, especially for the older speakers who learned French as their first language, is well above any other reported results; the qualitative difference is revealed when the authors examine the widespread deletion of final consonants in general.
On Some Serious Next Millennium Rap Ishhh
Authors: Alim H. Samy
Published: April 2003

By examining the Hip Hop poetics on Pharoahe Monch's album, Internal Affairs (1999), this article demonstrates the linguistic inventiveness and innovativeness of contemporary African American lyricists. As poets, Hip Hop MCs (rhymers) have both built on and expanded far beyond the American poetic tradition, using a form that is highly intertextual and that demonstrates multilayered poetic complexity. While Hip Hop MCs draw upon alliteration and assonance and other traditional rhyme forms, they also employ new rhyme strategies that require new categories of knowledge, such as compound internal rhymes, primary and secondary internal rhymes, chain rhymes, back-to-back chain rhymes, and bridge rhymes. Hip Hop MCs also employ various literary techniques, such as wordplay, simile, metaphor, narrativity, flashback, role-play, suspense, irony, and imagery in their lyrical compositions. Often constructing these rhymes in a multirhyme matrix, Hip Hop MCs offer a vast corpus of literary and linguistic texts to be analyzed.
Legislator Of The World? A Rereading of Bentham on Colonies
Authors: Pitts Jennifer
Published: April 2003

It has become almost commonplace to claim that utilitarianism was, from its inception, an imperialist theory. Many writers, from Bentham’s own followers to recent scholars, have suggested that from Bentham onward, utilitarians reveled in the opportunity that they believed despotic power provided for the establishment of perfectly rational laws and institutions. A closer look at Bentham’s own views on empire, however, reveals a sharp break between his position on European colonies and that of followers such as James and John Stuart Mill. For Bentham, the utilitarian doctrine led to criticisms of the empires of his day. Bentham is better understood as a participant in the late-eighteenth-century skepticism about imperial conquests and aspirations than he is as a proto-colonialist or a “Solon” of India. Once he is understood in this light, our picture of his successors, especially J. S. Mill, is revised as well.
Religious Diversity And Democratic Institutional Pluralism
Authors: Bader Veit
Published: April 2003

Strict separation of church from a presumed ‘religion-blind’and strictly ‘neutral’state still is the preferred model in liberal, democratic, feminist, and socialist political theory. Focusing on the full, reciprocal relationships between society-culture-politics-nation-state and (organized) religions, this article makes a case in favor of ‘nonconstitutional pluralism’ in general, associative democracy in particular. Associative democracy recognizes religious diversity both individually and organizationally; it stimulates legitimate religious diversity; it prevents a hidden majority bias; and it provides a legitimate role for organized religions in the provision of a wide range of services, including education, on one hand, and in the political process, on the other hand. That organized religions should be informed, heard, and consulted in contested issues should be a crucial component of democratic participation. This also might help prevent the development of religious fundamentalism.
Concordance between Tramadol and Dextromethorphan Parent/Metabolite Ratios: The Influence of CYP2D6 and Non‐CYP2D6 Pathways on Biotransformation
Authors: Abdel‐Rahman S. M. , Leeder J. S. , Wilson J. T. , Gaedigk A. , Gotschall R. R. , Medve R. , Liao S. , Spielberg S. P. , Kearns G. L.
Published: April 2003

Cytochrome P4502D6 (CYP2D6) activity has been shown to be a determinant of both the pharmacokinetics and pharmacodynamics of tramadol in adults. This study evaluated the association between CYP2D6 activity, as determined by dextromethorphan (DM) urinary metabolite ratio, and tramadol biotransformation in 13 children (7–16 years). CYP2D6 genotype was determined by XL‐PCR and PCR/RFLP. Phenotype was assessed by HPLC quantitation of DM and its metabolites from a 12‐ to 24‐hour urine collection following a single oral dose of DM. There was only a modest correlation between tramadol/M1 (metabolite 1)plasma concentration or AUC and the DM/dextrorphan (DX) urinary molar ratio in the study cohort; however, when subjects were segregated based on the number of functional CYP2D6 alleles, a much stronger relationship was observed for subjects with two functional alleles, with essentially no relationship evident in those individuals with one functional allele. Further evaluation of these data suggested that the CYP2D6‐mediated metabolite (M1) is formed to a lesser extent, and the formation of the non‐CYP2D6 product (M2) is more pronounced in subjects with one versus two functional alleles. Thus, the number of functional CYP2D6 alleles and the availability of alternative cytochromes P450 capable of metabolizing tramadol may explain the poor association between DM, a well‐characterized CYP2D6 probe, and tramadol in a population of CYP2D6 extensive metabolizers.
Schizonepeta tenuifolia: Chemistry, Pharmacology, and Clinical Applications
Authors: Fung Dennis , Lau Clara B. S.
Published: April 2003

This article presents an up‐to‐date review of the plant Schizonepeta tenuifolia (Jingjie), of family Labiatae, with respect to its traditional uses, chemical constituents, various pharmacological activities, and clinical effects. Nonetheless, its mechanism of actions, adverse effects, drug interactions, and contraindications remain unclear. With the global growth on the use of herbal products, Jingjie has been commonly marketed for the treatment of common cold and fever in Chinese proprietary medicines. Hence, further studies will be warranted to show its efficacy and safety.
Population Pharmacodynamic Modeling without Plasma Concentrations of Rocuronium in Children
Authors: Velázquez‐Armenta Elvia Y. , Nava‐Ocampo Alejandro A.
Published: April 2003

Using the pharmacodynamic model without plasma concentrations described by Bragg et al, an individual approach resulted in highly variable parameters for rocuronium. Using a population approach of the model, the time course of the effect of an IV bolus dose of 400, 600, and 800 μ/kg of rocuronium was studied. Response was measured by accelerometry (TOF‐Guard) in 45 low‐risk surgical children, ages 2 to 14 years, who were receiving general anesthesia with isoflurane. Using a Bayesian approach and the software P‐PHARM, response (the first twitch of the TOF) was modeled. The apparent rate constant of elimination, the rate constant for equilibrium between plasma and the effect compartment, the sigmoidicity factor of the relationship between drug concentration in the effect compartment and the effect, and the infusion rate that produces 50% of the effect at steady state were obtained. Population and individual post hoc parameters were similar among groups and variability was reduced.
Pharmacodynamics and Safety of a New Calcium Sensitizer, Levosimendan, and Its Metabolites during an Extended Infusion in Patients with Severe Heart Failure
Authors: Kivikko Matti , Antila Saila , Eha Jaan , Lehtonen Lasse , Pentikäinen Pertti J.
Published: April 2003

Levosimendan is a new calcium sensitizer developed for the short‐term intravenous treatment of congestive heart failure. The aims of the present open‐label, nonrandomized study were to determine the tolerability, hemodynamic effects, and the basic pharmacokinetics of levosimendan and its metabolites during an extended continuous infusion of levosimendan. Twenty‐four patients with New York Heart Association (NYHA) III‐IV heart failure in two groups of 12 patients were exposed to either 0.05 μg/kg/min or 0.1 μg/kg/min of levosimendan for 7 days. Heart rate and blood pressure were measured, and blood samples for the determination of plasma concentrations of the parent drug and its metabolites were drawn daily during the infusion and the 10 to 15 days' follow‐up. The 7‐day infusion was well tolerated and no premature discontinuations occurred. Both systolic and diastolic blood pressure decreased maximally by 6 mmHg in the lower and by 11 mmHg in the higher levosimendan dose groups during the infusion period (p < 0.05 for both groups). The mean heart rate values increased maximally by 18 and 26 beats/min in the lower and higher levosimendan dose groups, respectively (p < 0.001 for both groups). The hemodynamic effects peaked at the end of the infusion period and thereafter slowly declined during the follow‐up. After the recommended infusion period of 24 hours, the mean heart rate increase was only 2 and 6 beats/min in the lower and higher levosimendan dose groups, respectively. The elimination half‐life of levosimendan was approximately 1 hour and of the metabolites 70 to 80 hours. It can be concluded that levosimendan, even administered considerably longer than the recommended 24 hours, was well tolerated. The 7‐day infusion induced a prolonged increase in heart rate and a minor decrease in blood pressure. The long‐lasting effects are probably explained by the active metabolite.
Concentration‐Effect Relationships for Intravenous Alfentanil and Ketamine Infusions in Human Volunteers: Effects on Acute Thresholds and Capsaicin‐Evoked Hyperpathia
Authors: Wallace Mark S. , Ridgeway Beri , Leung Albert , Schulteis Gery , Yaksh Tony L.
Published: April 2003

The authors have extended preclinical studies on pain to human volunteers by examining the effects of intravenous alfentanil and ketamine on acute sensory thresholds and facilitated processing induced by intradermal capsaicin. Eleven healthy subjects received targeted plasma concentrations of alfentanil, ketamine, and placebo followed by neurosensory testing (thermal and von Frey hair thresholds). After completing the tests at the highest plasma level, intradermal capsaicin was injected into the volar aspect of the left forearm, and the flare response and hyperalgesia to von Frey hair, stroking, and heat were assessed. Alfentanil significantly elevated cool and warm thresholds and decreased capsaicin‐induced stroking hyperalgesia. Ketamine significantly decreased capsaicin‐induced von Frey hair hyperalgesia. Both drugs resulted in a significant elevation of von Frey hair‐induced pain thresholds and a decrease in capsaicin‐induced pain. These studies suggest that experimental human pain models may be used to study analgesic pharmacology and may serve as important methods for defining the analgesic efficacy of drugs in phase I clinical trials.
Insulin‐Metformin Combination Therapy in Obese Patients with Type 2 Diabetes
Authors: Jaber Linda A. , Nowak Sandra N. , Slaughter Richard R.
Published: April 2003

The aim of the study was to evaluate the effects of insulinmetformin combination therapy compared to insulin monotherapy in obese, insulin‐requiring patients with type 2 diabetes mellitus. Eighteen patients uncontrolled on ≥ 70 U/day of insulin monotherapy were investigated in this prospective, open‐label study. Patients continued their previous insulin and dietary regimens for 4 weeks, after which metformin was added with doses titrated to achieve a fasting plasma glucose (FPG) < 7.8 mmol/l or until the maximum daily dose was reached. Insulin‐metformin combination therapy was continued for an additional 8 weeks. Insulin‐metformin combination therapy resulted in a significant decrease in glycated hemoglobin values with a final mean reduction of 1.5% ± 1.2% (p = 0.001). FPG decreased significantly (p < 0.005) by week4 of insulin‐metformin therapy, but the change was not statistically significant by week 12, and daily insulin requirements were significantly reduced during combination therapy (p < 0.05). These results suggest that in obese patients with type 2 diabetes mellitus receiving ≥ 70 U of daily insulin, the addition of metformin leads to improved glycemic control with lower daily doses of insulin and without adverse effects.
Differential Influence of Two Cyclosporine Formulations on Everolimus Pharmacokinetics: A Clinically Relevant Pharmacokinetic Interaction
Authors: Kovarik John M. , Kalbag Jyoti , Figueiredo Joaquim , Rouilly Marisel , O'Bannon Larita Frazier , Rordorf Christiane
Published: April 2003

Everolimus is an immunosuppressant intended for use with cyclosporine in acute‐rejection prophylaxis following organ transplantation. The possibility of a drug interaction of cyclosporine on everolimus was assessed. In this randomized, two‐period, crossover study, 24 healthy subjects received a single oral dose of 2 mg everolimus alone and with one of two cyclosporine formulations: either 175 mg Neoral or 300 mg Sandimmune. The single doses of Neoral and Sandimmune were chosen to yield similar average areas under the concentration‐time curve (AUC). Treatments were separated by a 14‐day washout period. Cyclosporine AUCs were similar for both formulations (p = 0.53), whereas the peak concentration (Cmax) was significantly higher for Neoral (p = 0.02). Simultaneous administration of Neoral with everolimus increased everolimus Cmax and AUC by 82% and 168%, respectively (p = 0.0001). Coadministration of Sandimmune with everolimus did not affect everolimus Cmax (p = 0.59) but increased everolimus AUC by 74% on average (p = 0.0001). Everolimus elimination half‐lives were unchanged in the presence of both cyclosporine formulations. The everolimus AUC increase with Neoral coadministration was significantly greater than the AUC increase with Sandimmune (p = 0.008). However, there was no apparent association between cyclosporine Cmax and the change in everolimus AUC with cyclosporine coadministration. If Neoral or Sandimmune is removed from an everolimuscyclosporine immunosuppressive regimen, a two‐ to threefold decrease in everolimus exposure is expected. Therapeutic monitoring of everolimus concentrations would be helpful after the removal of cyclosporine to individually titrate everolimus exposure.
Carbamazepine Decreases Antihypertensive Effect of Nilvadipine
Authors: Yasui‐Furukori Norio , Tateishi Tomonori
Published: April 2003

A 59‐year‐old male who had suffered from hypertension for 21 years was admitted because of manic and delusional symptoms. He was treated with 12 mg/day of haloperidol for psychotic symptoms and 8 mg/day of nilvadipine for hypertension. Due to insufficient effect of haloperidol on the patient's manic symptoms, carbamazepine was added to these medications. Abnormally high blood pressure was observed during carbamazepine coadministration, and it returned gradually to normal range after its discontinuation. Retrospective analyses revealed that the plasma concentrations of nilvadipine were undetectable during carbamazepine treatment. The clinical course and laboratory findings suggest that carbamazepine decreased the plasma concentration and hence the antihypertensive effect of nilvadipine probably via CYP3A induction. This interaction between nilvadipine and carbamazepine should be kept in mind when these drugs are administered concomitantly.
Hypotension and Bradycardia in a Healthy Volunteer following a Single 5 mg Dose of Olanzapine
Authors: Markowitz John S. , DeVane C. Lindsay , Boulton David W , Liston Heidi L. , Risch S. Craig
Published: April 2003

Olanzapine is an atypical antipsychotic medication indicated for the treatment of schizophrenia and other manifestations of psychotic illness. Common side effects include somnolence, constipation, weight gain, and postural hypotension. The authors report a case of hypotension accompanied by bradycardia in a normal, healthy volunteer participating in an olanzapine pharmacokinetic study following a single 5 mg dose. A venous catheter allowed for serial blood sampling of olanzapine concentrations before, during, and after the adverse event. The subject experienced a rapid absorption of the drug and higher than anticipated maximum plasma concentrations. This case suggests that atypical antipsychotics, although generally better tolerated than conventional agents, may still result in untoward reactions that may be partially due to individual differences in drug absorption and metabolism.
Clinical Manifestation of Atherosclerotic Peripheral Arterial Disease and the Role of Cilostazol in Treatment of Intermittent Claudication
Authors: Crouse John Robert , Allan Michael C. , Elam Marshall B.
Published: April 2003

Intermittent claudication (IC) is the symptomatic expression of peripheral arterial disease (PAD), which itself is a manifestation of systemic atherosclerosis. Like other forms of atherosclerosis, PAD is associated with elevated rates of cardiovascular and cerebrovascular morbidity and mortality. Until recently, therapeutic options for the treatment of the symptoms of IC have been limited, and the efficacy of available treatment has been questioned. Cilostazol, a selective phosphodiesterase IIIinhibitor with vasodilator, antiplatelet, and antiproliferative properties, has recently been approved for the treatment of IC symptoms in the United States. Cilostazol significantly improves maximal and pain‐free walking distances. Clinical studies have also demonstrated that cilostazol favorably alters plasma lipids (elevates HDL‐cholesterol, lowers triglycerides). These properties may contribute to the benefit of this drug in IC and in other diseases secondary to atherosclerosis.
Absolute Bioavailability, Pharmacokinetics, and Urinary Excretion of the Novel Antimigraine Agent Almotriptan in Healthy Male Volunteers
Authors: Jansat Josep M. , Costa Joan , Salvà Pau , Fernandez Francisco J. , Martinez‐Tobed Antonio
Published: April 2003

Absolute bioavailability, pharmacokinetics, and urinary excretion of almotriptan, a novel 5‐HT1B/1D receptor agonist, were studied in 18 healthy males following single intravenous (i.v.) (3 mg), subcutaneous (s.c.) (6 mg), and oral (25 mg) doses. Volunteers received each dose in a randomized sequence separated by a 7‐day washout. Blood and urine samples for pharmacokinetic evaluations were taken for up to 24 hours after dosing. The disposition kinetics of almotriptan after i.v. and s.c. administration showed biphasic decline described by a two‐compartment model. The fastest disposition phase was well observed, although estimates of the rate constant showed high variability. After s.c. administration of almotriptan, the bioavailability was 100% with a time to maximum plasma concentration (tmax) of 5 to 15 minutes, whereas after oral administration, the bioavailability was about 70% with a tmax of 1.5 to 3.0 hours. No significant differences were observed between administration routes in the elimination half‐life (t1/2), obtaining mean values ranging from 3.4 to 3.6 hours. The volume of distribution, total clearance, and t1/2 indicated that almotriptan was extensively distributed and rapidly cleared from the body irrespective of dose or route of administration. The primary route of elimination was renal clearance (approximately 50%‐60% of total body clearance). About 65% of the i.v. and s.c. dose and 45% of the oral dose were excreted unchanged in urine in 24 hours, with nearly 90% of this in the first 12 hours. Renal clearance was approximately 2‐ to 3‐fold that of the glomerular filtration rate in man, suggesting that almotriptan is eliminated in part by renal tubular secretion.
Microsomal Enzyme Induction and Clinical Aggravation of Porphyria: The Evaluation of Human Urinary 6β‐Hydroxycortisol/Cortisol Ratio as the Index of Hepatic CYP3A4 Activity
Authors: Uejima Etsuko , Takahashi Kyoko , Morisaki Tomoko , Takahashi Koichi , Ohno Masako , Nishida Yuko , Moriya Masayuki , Kaido Misako , Abe Kazuo , Sakoda Saburo , Yanagihara Takehiko , Kurokawa Nobuo , Azuma Junichi
Published: April 2003

The clinical aspect of porphyria has been investigated, and it is well known that porphyrinogens such as estrogens and alcohol or other inducers of P450 isoenzymes exacerbate the porphyric state. However, there can be a delay in diagnosing porphyria and a difficulty in selecting safe medicine for it even today. A 21‐year‐old woman developed epilepsy, disturbance of mental state, and spastic tetraparesis during the convalescent period after acute viral encephalitis. She was diagnosed with porphyria after the fifth hospitalization. In the course of modifying her anticonvulsant regimen, the authors examined the 6β‐hydroxycortisol/cortisol ratio (6β‐OHF/F) in her urine, which can be the index of hepatic CYP3A4 activity, with electrospray ionization/mass spectrometry/mass spectrometry (ESI/MS/MS). Generalized and partial complex seizures, other neurological signs and symptoms, and laboratory data were improved after modification of her anticonvulsant regimen. This is the first report of evaluating the urinary 6β‐hydroxycortisol/cortisol ratio in a case of porphyria.
No Effect of the Novel Antidiabetic Agent Nateglinide on the Pharmacokinetics and Anticoagulant Properties of Warfarin in Healthy Volunteers
Authors: Anderson Denise M. , Shelley Sarah , Crick Nina , Buraglio Mauro
Published: April 2003

The novel hypoglycemic agent nateglinide is pharmacologically distinct from oral hypoglycemic agents such as sulfonylureas and repaglinide. The present study investigated the effects in healthy volunteers of multiple doses of nateglinide on the pharmacokinetics and pharmacodynamics of warfarin. The study comprised a randomized two‐group, two‐way crossover, open‐label design in 12 healthy male subjects. One group of 6 subjects initially received a single oral dose of warfarin 30 mg and then, after a 7‐ to 14‐day washout, received both warfarin and nateglinide (120 mg nateglinide, 10 min before meals for 4 days and a single dose of 30 mg warfarin on the second day). The alternate group of 6 subjects received treatments in the opposite order. Pharmacokinetic profiles were derived from plasma warfarin and nateglinide concentrations. Prothrombin measurements were evaluated in both periods as a measure of warfarin activity. When administered alone or in combination, there were no statistically significant differences in mean warfarin (R‐ and S‐enantiomers) or nateglinide pharmacokinetic parameters. The concurrent administration of nateglinide and warfarin did not affect the maximal change in prothrombin time that follows warfarin administration. In this study, there was no evidence of an effect of coadministration of nateglinide on the pharmacodynamic action of warfarin or any pharmacokinetic interaction between warfarin and nateglinide.
Pharmacokinetics and Safety of a Single Oral Dose of Once‐Daily Alfuzosin, 10 mg, in Male Subjects with Mild to Severe Renal Impairment
Authors: Marbury Thomas C. , Blum Robert A. , Rauch Clémence , Pinquier Jean‐Louis
Published: April 2003

The effect of renal impairment on the safety and pharmacokinetics of a once‐daily formulation of alfuzosin, 10 mg, was evaluated. In an open, single‐dose study, 26 volunteers, ages 18 to 65 years, were classified as having normal renal function (n = 8) or mild (n = 6), moderate (n = 6), or severe (n = 6) renal impairment. Mean Cmax values increased by a factor of 1.20, 1.52, and 1.20 in subjects with mild, moderate, or severe renal impairment, respectively, compared with controls. Values for AUC0‐∞ were 1.46,1.47, and 1.44, respectively. The t1/2z was increased only in the group with severe renal impairment. Emergent vasodilatory adverse events were reported by 4 of 26 subjects. No discontinuations due to adverse events occurred. Laboratory parameters were satisfactory in all groups. In conclusion, once‐daily alfuzosin, 10 mg, could be safely administered to patients with impaired renal function, and dosage adjustment does not seem necessary.
Bleeding Associated with Eptifibatide Targeting Higher Risk Patients with Acute Coronary Syndromes: Incidence and Multivariate Risk Factors
Authors: Rasty Saeed , Borzak Steven , Tisdale James E.
Published: April 2003

The objective of this study was to determine the safety of the glycoprotein Ilb/IIa receptor inhibitor eptifibatide in patients at high risk for adverse clinical outcomes and to determine risk factors for eptifibatide‐associated bleeding. Consecutive patients (n =175) who presented with an acute coronary syndrome and who were at high risk for adverse clinical outcomes were prospectively observed for eptifibatide‐associated bleeding, which was classified according to Thrombolysis in Myocardial Infarction (TIMI) and Global Use of Strategies to Open Occluded arteries (GUSTO) criteria. High risk was defined as unstable angina or non‐Q‐wave myocardial infarction with at least one of the following: left ventricular ejection fraction < 40%, diabetes mellitus, ST segment depression or transient ST segment elevation, serum [troponin I] > 2.5 ng/mL, and recurrent angina symptoms after initiation of conventional antianginal therapy Bleeding incidences in thepatients in this study were compared with those in the 4722 eptifibatide‐treated patients in the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) trial. Compared to PURSUIT patients, the population in this study was similar in age but had a higher proportion of females, African Americans, hypertension, diabetes, prior myocardial infarction, heart failure, and revascularization. Bleeding incidences in this study's patients were similar to or lower than those in the PURSUIT population: TIMI major 1.1% versus 10.8%, TIMI minor 12.6% versus 13.1%, GUSTO severe 1.7% versus 1.5%, GUSTO moderate 3.9% versus 11.3%, and GUSTO mild 19.7% versus 26.1%. Renal dysfunction was an independent risk factor for TIMI (odds ratio = 9.1 [95% CI= 1.6–52.5]) and GUSTO (odds ratio = 6.1 [95% CI = 1.2–30.0]) bleeding. In conclusion, despite being at higher risk for adverse outcomes, patients administered eptifibatide according to this study's institutional guidelines had comparable or lower bleeding rates than in the PURSUIT trial. Renal dysfunction is an independent risk factor for eptifibatide‐induced bleeding.
Influence of Mild Liver Impairment on the Pharmacokinetics and Metabolism of Bosentan, a Dual Endothelin Receptor Antagonist
Authors: van Giersbergen Paul L. M. , Popescu Gabriela , Bodin Frédéric , Dingemanse Jasper
Published: April 2003

The purpose of the study was to investigate the effect of mild liver impairment on the pharmacokinetics and metabolism of bosentan. Eight patients with mild liver impairment and 8 matching healthy subjects were treated with single and multiple oral 125‐mg doses of bosentan. The pharmacokinetic parameters of bosentan and its metabolites were similar in both groups: geometric means for Cmax and AUC for bosentan were 2534 and 1980 ng/ml and 11,957 and 10,781 ng•h/ml after single doses and were 1831 and 1715 ng/ml and 7216 and 7838 ng•h/ml after multiple doses, respectively, in healthy subjects and patients. In both groups, the exposure to the metabolites was low when compared to that to bosentan. The decrease in exposure to bosentan after multiple dosing, indicative of autoinduction, tended to be less pronounced in patients as compared to healthy subjects. Bosentan was well tolerated in this study. In conclusion, the pharmacokinetics, metabolism, and tolerability of bosentan are similar in healthy subjects and patients with mild liver impairment.
Pharmacokinetics of Repaglinide in Healthy Caucasian and Japanese Subjects
Authors: Thomsen M. S. , Chassard D. , Evène E. , Nielsen K. K. , Jørgensen M.
Published: April 2003

The objective of this study was to investigate the pharmacokinetics of three different single doses (0.5, 1.0, and 2.0 mg) of repaglinide in healthy Caucasian and Japanese subjects. In this single‐center, open‐label, randomized, three‐period crossover study, 27 healthy male subjects (15 Caucasian and 12 Japanese) each received three different single doses of repaglinide (0.5, 1.0, and 2.0 mg) at consecutive 24‐hour intervals. Pharmacokinetic profiles, including area under the curve (AUC0‐t), maximum serum concentration (Cmax), time to Cmax (tmax), and half‐life (t1/2), were determined for each dose of repaglinide. The relative change in blood glucose level (RC1h) and area under the blood glucose curve (AUGC0–1) at 1 hour after dose were also measured. After oral dosing, both Cmax and AUC0‐t increased linearly with dose within the 0.5‐ to 2.0‐mg dose range, regardless of ethnic group. Both Cmax and AUC0‐t were significantly higher in Japanese subjects than in Caucasian subjects. At each dose of repaglinide, Cmax and AUC were statistically significantly higher in Japanese than in Caucasian subjects (p = 0.0038 and 0.023, respectively). Discrepancies in body weight and body mass index (BMI) between Caucasian and Japanese subjects could not explain the between‐group differences in Cmax or AUC0‐t. Statistically significant differences in pharmacodynamic parameters (RC1h and AUGC0–1) were found between ethnic groups (p < 0.0001), the difference being more pronounced for RC1h than AUGC0–1. At a dose of 2.0 mg, the mean decrease in RC1h was 41% for Japanese subjects and 24% for Caucasian subjects. Hypoglycemic reactions were more common at the highest dose (2.0 mg), where they were observed more frequently in Japanese (7 cases) than in Caucasian subjects (4 cases). It was concluded that higher serum levels of repaglinide and greater reductions in blood glucose levels are found in Japanese than in Caucasian subjects following a single oral dose of repaglinide within the 0.5‐ to 2.0‐mg dose range. Repaglinide is well tolerated in both ethnic groups. The results indicate that glycemic control targets may be achieved at lower doses within the recommended range (0.5–4.0 mg/meal) when repaglinide is used to treat Japanese patients in comparison to Caucasian patients.
The Influence of Gender and Food on the Pharmacokinetics of Sodium Oxybate Oral Solution in Healthy Subjects
Authors: Borgen Lowell A. , Okerholm Richard , Morrison Dennis , Lai Allen
Published: April 2003

Sodium oxybate (Xyrem®; gamma‐hydroxybutyrate) oral solution was recently approved in the United States for the treatment of cataplexy in patients with narcolepsy. Two single‐center, randomized, open‐label studies in healthy volunteers receiving single oral 4.5‐g doses of sodium oxybate evaluated effects of (1) gender on oxybate pharmacokinetics and (2) food on its oral bioavailability. In the latter study, one dose was administered after an overnight fast, another after a high‐fat meal; 1 week separated treatments. Sodium oxybate pharmacokinetics was not significantly different between sexes. However, food significantly altered the bioavailability of oxybate by decreasing mean peak plasma concentration, increasing median time‐to‐peak concentration, and decreasing the area under the plasma concentration‐time curve. Food did not affect elimination and urinary excretion of unchanged drug. No dose adjustment of sodium oxybate based on sex is indicated. Although significant food effects were observed, these are minimized in patients by the nocturnal dosing of sodium oxybate hours after the evening meal at a consistent time interval following food ingestion.
Tolbutamide, Flurbiprofen, and Losartan as Probes of CYP2C9 Activity in Humans
Authors: Lee Craig R. , Pieper John A. , Hinderliter Alan L. , Frye Reginald F. , Blaisdell Joyce A. , Goldstein Joyce A.
Published: April 2003

The metabolic activity of CYP2C9 in 16 subjects expressing four different genotypes (CYP2C9*1/*1, *1/*2, *1/*3, and *2/*2) was evaluated. Single oral doses of tolbutamide, flurbiprofen, and losartan were administered in a randomized, crossover design. Plasma and urine were collected over 24 hours. The urinary metabolic ratio and amount of metabolite(s) excreted were correlated with formation clearance. The formation clearance of tolbutamide to its CYP2C9‐mediated metabolites demonstrated a stronger association with genotype compared to flurbiprofen and losartan, respectively (r2 = 0.64 vs. 0.53 vs. 0.42). A statistically significant correlation was observed between formation clearance of tolbutamide and the 0‐ to 12‐hour urinary amount of 4'‐hydroxytolbutamide and carboxytolbutamide (r= 0.84). Compared to tolbutamide, the correlations observed between the respective measures of flurbiprofen and losartan metabolism were not as strong. Tolbutamide is a better CYP2C9 probe than flurbiprofen and losartan, and the 0‐ to 12‐hour amount of 4'‐hydroxytolbutamide and carboxytolbutamide is the best urinary measure of its metabolism.
Lack of Bioequivalence of Gatifloxacin When Coadministered with Calcium‐Fortified Orange Juice in Healthy Volunteers
Authors: Wallace Allison W. , Victory Jennifer M. , Amsden Guy W.
Published: April 2003

Previous work has demonstrated that the chelation interaction seen with ciprofloxacin when it is coadministered with antacids also happens when it is coadministered with calcium‐fortified foods. This study was conducted to study whether this was a drug‐specific finding or whether the interaction occurs with other members of the fluoroquinolone class of drugs. Sixteen healthy volunteers received single 400‐mg oral doses of gatifloxacin with 12 ounces each of water, nonfortified orange juice, and calcium‐fortified orange juice and had plasma samples drawn for assay over the subsequent 48 hours. Results demonstrated significant increases in total oral clearance (15%) and volume of distribution (13%) along with a matching significant decrease (12%) in exposure (AUC) when gatifloxacin was taken with the fortified juice. Although not statistically significant, peak concentrations decreased by 15% and were reached (tmax) approximately 38% later when gatifloxacin was coadministered with the calcium‐fortified juice. Bioavailability testing indicated that although the 90% confidence intervals (CIs) for the ratio of the geometric means of the calcium‐fortified juice and water arms' AUC stayed within the range of 80% to 125%, those for Cmax did not. This study demonstrated a chelation or adsorption interaction between the fortified juice and gatifloxacin that reached regulatory significance. As a result, clinicians may wish to instruct patients to take gatifloxacin either with nonfortified foods or on an empty stomach.
Safety and Tolerability of the Lidocaine Patch 5%, a Targeted Peripheral Analgesic: A Review of the Literature
Authors: Gammaitoni Arnold R. , Alvarez Nancy A. , Galer Bradley S.
Published: April 2003

The safety, tolerability, and efficacy of the lidocaine patch 5% (Lidoderm®), a targeted peripheral analgesic with an FDA‐approved indication for the treatment of postherpetic neuralgia, has been well established. Recent case reports and studies have suggested potential efficacy in other neuropathic and nonneuropathic pain conditions. Several pharmacokinetic studies have demonstrated minimal systemic absorption with 12‐, 18‐, and 24‐hour/day dosing. Mean maximum plasma concentrations have shown the lidocaine patch to possess a minimal risk for systemic toxicities or drug‐drug interactions. The most common adverse events generally involve mild skin reactions. There have been no drug‐drug interactions noted in clinical trials. Recent evidence suggests that extended application does not result in A‐β‐mediated sensory loss at the application site, which is particularly important in patients who already have a degree of sensory loss due to their underlying condition. The lidocaine patch provides a treatment option that carries a relatively low systemic adverse event and drug‐drug interaction risk burden, even with continuous application of up to four patches per day.
Are Coagulation Times Biomarkers? Data from a Phase I Study of the Oral Thrombin Inhibitor LB‐30057 (CI‐1028)
Authors: Stern Ralph , Chanoine Francoise , Criswell Kay
Published: April 2003

Ecarin clotting time and activated partial thromboplastin time are coagulation tests that meet the definition of a biomarker. Prolongation of these coagulation times closely correlated with blood concentrations of the oral thrombin inhibitor LB‐30057 (CI‐1028) during a phase 1 study. But this simply reflects their functioning as enzyme inhibition assays of drug concentration. Directly adding the drug to blood results in the same concentration‐response relationship. Changes in coagulation tests only demonstrate that ex vivo clot formation has been altered, not that an in vivo process has been affected. To be most informative in drug development, biomarker assays should measure in vivo drug effects, not drug concentrations.
Population Pharmacokinetics and Pharmacodynamics of Zidovudine in HIV‐Infected Infants and Children
Authors: Capparelli Edmund V. , Englund Janet A. , Connor James D. , Spector Stephen A. , McKinney Ross E. , Palumbo Paul , Baker Carol J. ,   PACTG 152 Team
Published: April 2003

The purpose of this study was to assess the population pharmacokinetics (PK) and pharmacodynamics (PD) of zidovudine (ZDV) in infants and children. This evaluation includes 394 subjects who participated in Pediatric AIDS Clinical Trials Group (PACTG) Study 152 and received either ZDV alone or in combination with didanosine. The most significant PK covariate was age, with infants < 2 years of age having reduced size‐adjusted clearance. ZDV exposure was weakly related to maximal reduction in immune complex‐dissociated (ICD) p24 antigen but not to reduction at 6 months. Mild chronic anemia occurred in 7.6% of subjects with ZDV average concentration < 1.3 μM (350 ng/mL) versus in 23.4% subjects with higher ZDV concentrations (p < 0.001). There was a direct linear relationship between hemoglobin and ZDV levels. It was concluded that ZDV oral clearance is reduced in infants compared to older children. This lower clearance leads to higher ZDV exposure in infants and contributes to increased hematologic toxicity.
Clinical Development of an Everolimus Pediatric Formulation: Relative Bioavailability, Food Effect, and Steady‐State Pharmacokinetics
Authors: Kovarik John M. , Noe Adele , Berthier Stephane , McMahon Louis , Langholff Wayne K. , Marion Alan S. , Hoyer Peter Friedrich , Ettenger Robert , Rordorf Christiane
Published: April 2003

The immunosuppressant everolimus used in organ transplantation is formulated as a conventional tablet for adults and a dispersible tablet that can be administered in water for pediatric use. As part of the pediatric clinical development program, the relative bioavailability and food effect for the dispersible tablet were evaluated in healthy adult subjects as a prelude to characterizing the steady‐state pharmacokinetics in pediatric kidney allograft recipients. In a randomized, open‐label, three‐way crossover study, 24 healthy adults received single 1.5‐mg oral doses of everolimus as (1) six 0.25‐mg dispersible tablets in water, (2) two 0.75‐mg conventional tablets, and (3) six 0.25‐mg dispersible tablets in water after a high‐fat breakfast. Cmax and AUC were evaluated by standard bioequivalence testing to determine relative bioavailability and to quantify the effect of food. In a multicenter open‐label efficacy/safety trial, pediatric renal allograft recipients received 0.8 mg/m2 (maximum 1.5 mg) bid everolimus as dispersible tablets in water. Serial trough concentrations over the first week and a steady‐state pharmacokinetic profile on day 7 posttransplant were collected in 19 patients ranging from ages 2 to 16 years old. The bioavailability of everolimus from the dispersible tablet was 10% lower relative to the conventional tablet, with a ratio (90% confidence interval) of 0.90 (0.76–1.07). After a high‐fat meal, tmax was delayed by a median 2.5 hours, and Cmax was reduced by 50%. Overall absorption, however, was not affected by food inasmuch as the fed/fasting AUC ratio was 0.99 (0.83–1.17). In pediatric patients, steady state was reached between days 3 and 5. The corresponding steady‐state parameters were as follows: Cmin, 4.4 ± 1.7 ng/ml; Cmax, 13.6 ± 4.2 ng/ml; and AUC, 87 ± 27 ng•h/ml. Steady‐state concentration‐time profiles in pediatric transplant patients receiving the dispersible tablet were comparable to those of adult patients receiving the conventional tablet when both were dosed to yield similar trough concentrations. If a pediatric patient is converted from the everolimus dispersible tablet to the conventional tablet, this should be based on a 1:1 milligram switch with subsequent therapeutic drug monitoring to further individualize the dose as needed. The dispersible tablet formulation should be taken consistently either with or without food to minimize fluctuations in exposure over time.
The Bioequivalence of Nizatidine (Axid®) in Two Extemporaneously and One Commercially Prepared Oral Liquid Formulations Compared with Capsule
Authors: Abdel‐Rahman Susan M. , Johnson Franklin K. , Gauthier‐Dubois Ginette , Weston Irving E. , Kearns Gregory L.
Published: April 2003

Nizatidine (Axid®) is an H2‐receptor antagonist used for the treatment of acid‐related gastrointestinal disorders. Given the frequency of these conditions in children and the potential for pediatric use of nizatidine, an oral liquid dosage formulation would provide an alternative treatment option for patients unable to swallow solid oral dosage forms. This study was designed as an open‐label, single‐dose, four‐way crossover trial to investigate the bioequivalence of 150 mg nizatidine administered in three oral liquid formulations (a commercially prepared oral syrup, an extemporaneous solution in apple juice, and an extemporaneous suspension in infant formula) relative to the marketed capsule formulation. Twenty‐four adult subjects (ages 31.2 ± 7.5 years; weight 71.1 ± 11.8 kg) were enrolled, and blood samples for determination of plasma nizatidine concentrations were collected prior to drug administration and at 19 discrete intervals over a 24‐hour postdose interval. Nizatidine was quantitated from plasma using a validated HPLC‐MS assay, and a noncompartmental approach was used to describe nizatidine biodisposition in all subjects. Significant treatment effects were observed for log‐normalized Cmax, AUC0‐n, and AUC0‐∞ (p < 0.001). Further evaluation revealed that nizatidine prepared in apple juice was markedly less bioavailable than the reference capsule, with 90% confidence intervals (CIs) of 0.518–0.626, 0.682–0.751, and 0.696–0.763 for Cmax, AUC0‐n, and AUC0–∞, respectively. The remaining two oral formulations demonstrated 90% CI within the guidelines established by the Food and Drug Administration (e.g., 0.80–1.25). Thus, nizatidine in infant formula and the commercially prepared oral syrup can be considered bioequivalent to the reference capsule.