bluuebunny/crossref_metadata_2025 huggingface dataset:
Persistence with Antihypertensives Related to Formulation: The Case of Nifedipine
Authors: Breekveldt-Postma Nancy S , Herings Ron MC
Published: December 2004

BACKGROUND:

Controlled-release dosage forms may enhance persistence with therapy because of reduced dosing frequency and fewer adverse effects.

OBJECTIVE:

To assess the differences in persistent use of nifedipine between once-daily nifedipine gastrointestinal therapeutic system (GITS) and twice-daily nifedipine retard formulations.

METHODS:

Incident nifedipine users were selected from January 1992 to December 2001 from the PHARMO database, including drug-dispensing records and hospital records of more than one million subjects in the Netherlands. Patients with unaltered formulation and dosing frequency of nifedipine in the first year of follow-up with at least 2 prescriptions were included in the cohort. Persistence with different formulations was assessed using Cox's proportional hazard analyses. Covariates included in the analysis were, among others, hospitalizations and comedication for cardiovascular diseases.

RESULTS:

In total, 5889 incident users of nifedipine were included. The median duration of the first treatment episode was 133 days for nifedipine retard and 262 days for nifedipine GITS. One-year persistence with nifedipine increased from 32% in patients using retard formulations to 44% in patients using nifedipine GITS. Multivariate analyses showed that patients using nifedipine GITS were 1.3 times (RR 1.33; 95% CI 1.22 to 1.46) more persistent than those using retard formulations of nifedipine. Persistent patients more often used other antihypertensive drugs and were more often hospitalized for cardiovascular diseases.

CONCLUSIONS:

Patients using once-daily nifedipine GITS are more persistent with therapy than patients using twice-daily retard formulations.
Photoreceptor Differentiation during Retinal Development, Growth, and Regeneration in a Metamorphic Vertebrate
Authors: Mader Michelle M. , Cameron David A.
Published: December 2004

To test the hypothesis that growth and regeneration of the adult retina involves a mechanistic recapitulation of retinal development, the patterns of photoreceptor differentiation were investigated in the developing retina, as well as growing and regenerating adult retina, of a metamorphic vertebrate, the winter flounder. Only one opsin, of type RH2 (a “green” cone opsin), was expressed in premetamorphic (developing) retina, and a corresponding middle-wavelength visual pigment was observed. In premetamorphic retinas there was no evidence for any other cone opsins or pigments, rods, rod opsin expression, or rod visual pigment. In contrast, a rod opsin (RH1) and three cone opsins (SWS2, RH2, and LWS) were expressed in postmetamorphic (adult) retina, and these opsins were consistent with the observed repertoire of visual pigments. During postmetamorphic retinal growth and regeneration, cones were always produced before rods, but the different cone types were apparently produced simultaneously, suggesting that cone differentiation mechanisms might change after metamorphosis. The results support the hypothesis that photoreceptor differentiation during growth and regeneration of the adult retina involves a recapitulation of mechanisms that control the sequence of photoreceptor production during retinal development.
Somatostatin Receptor 2 Is Activated in Cortical Neurons and Contributes to Neurodegeneration after Focal Ischemia
Authors: Stumm Ralf K. , Zhou Chun , Schulz Stefan , Endres Matthias , Kronenberg Golo , Allen Jeremy P. , Tulipano Giovanni , Höllt Volker
Published: December 2004

Somatostatin receptor 2 (SSTR2) mediates neuromodulatory signals of somatostatin and cortistatin in the cerebral cortex. Recently, SSTR2 has been shown to enhance conserved death ligand- and mitochondria-mediated apoptotic pathways in non-neuronal cells. Whether somatostatin receptors are activated in cerebrocortical neurons and contribute to neurodegeneration after experimental focal ischemia was unknown until now. Here we examined internalization of SSTR2 in a rat model of middle cerebral artery occlusion (MCAO) by confocal microscopy. At 3 and 6 hr after MCAO, SSTR2 was internalized excessively in cerebrocortical neurons adjacent to the infarct, which was prevented by intracerebroventricular application of the SSTR2-selective antagonist BIM-23627. SSTR2 internalization was associated with a transient depletion of somatostatin from axonal terminals and increased expression of SSTR2 mRNA. The initial loss of somatostatin was followed by an increase in somatostatin mRNA levels, whereas cortistatin mRNA expression was decreased. In SSTR2-deficient mice with lacZ under the control of the SSTR2 promoter, MCAO-induced upregulation of SSTR2 gene expression was less pronounced than in wild types. SSTR2-deficient mice exhibited a 40% reduction of infarct size after permanent distal MCAO and a 63% reduction after transient proximal MCAO. In summary, we provide direct evidence for activation of SSTR2 by an endogenous ligand after focal ischemia. Activation of functional SSTR2 receptors contributes to increased SSTR2 gene expression and postischemic neurodegeneration.
A Gly/Ala switch contributes to high affinity binding of benzoxazinone‐based non‐peptide oxytocin receptor antagonists
Authors: Hawtin Stuart R. , Ha Sookhee N. , Pettibone Douglas J. , Wheatley Mark
Published: December 2004

Non‐peptide antagonists of the oxytocin receptor (OTR) have been developed to prevent pre‐term labour. The benzoxazinone‐based antagonists L‐371,257 and L‐372,662 display pronounced species‐dependent pharmacology with respect to selectivity for the OTR over the V1a vasopressin receptor. Examination of receptor sequences from different species identified Ala318 in helix 7 of the human OTR as a candidate discriminator required for high affinity binding. The mutant receptor [A318G]OTR was engineered and characterised using ligands representing many different chemical classes. Of all the ligands investigated, only the benzoxazinone‐based antagonists had decreased affinity for [A318G]OTR. Molecular modelling revealed that Ala318 provides a direct hydrophobic contact with a methoxy group of L‐371,257 and L‐372,662.
AtNTRB is the major mitochondrial thioredoxin reductase in Arabidopsis thaliana
Authors: Reichheld Jean-Philippe , Meyer Etienne , Khafif Mehdi , Bonnard Géraldine , Meyer Yves
Published: December 2004

NADPH‐dependent thioredoxin reductases (NTR) are homodimeric enzymes that reduce thioredoxins. Two genes encoding NADPH‐dependent thioredoxin reductases (AtNTRA and AtNTRB) were found in the genome of Arabidopsis thaliana. These originated from a recent duplication event and the encoded proteins are highly homologous. Previously, AtNTRA was shown to encode a dual targeted cytosol and mitochondrial protein. Here, we show that the AtNTRB gene encodes two mRNAs, presumably by initiating transcription at two different sites. The longer mRNA encodes a precursor polypeptide that is actively imported into mitochondria by a cleavage‐associated mechanism, while the shorter mRNA encodes a cytosolic isoform. Isolation of Arabidopsis mutants with knocked‐out AtNTRA or AtNTRB genes allowed us to prove that both genes encode cytosolic and mitochondrial isoforms. Interestingly, AtNTRB appeared to express the major mitochondrial NTR, while AtNTRA expresses as the major cytosolic isoform, suggesting that these two recently duplicated genes are evolving towards a specific function.
Disabilities of the Arm, Shoulder and Hand (Dash) Questionnaire: Determining Functional Activity Profiles in Patients with Upper Extremity Disorders
Authors: JESTER A. , HARTH A. , WIND G. , GERMANN G. , SAUERBIER M.
Published: December 2004

The Disability of Arm, Shoulder and Hand (DASH) questionnaire is a standardized measure which captures the patients’ own perspective of their upper extremity health status. Based on the scores of the DASH modules: symptoms, function and sport, this follow-up study of 590 hand-injured subjects from 11 diagnostic groups evaluated impairments and disabilities perceived 2 to 5 years postoperatively. Secondly, we explored the relationships between the diagnostic groups at the individual DASH item level.

Exploratory testing of statistical significance showed that the DASH modules differentiated well among the groups (ANOVA P-value 0.001) and further differences existed at the item level, so that functional activity problem profiles could be developed for each diagnostic group. Our findings confirm that the DASH is a useful instrument for outcome evaluation. Moreover, in view of the continuing challenge to provide comprehensive care which meets patients’ needs in the shortest space of time, we consider that DASH has potential in the development of patient-centred treatment programmes which are tailored to the individual patients’ requirements and have relevance to their daily activities.
New geological framework for Western Amazonia (Brazil) and implications for biogeography and evolution
Authors: de Fátima Rossetti Dilce , Mann de Toledo Peter , Góes Ana Maria
Published: December 2004

Although many of the current hypotheses to explain the origin and distribution of the Amazon biodiversity has been based directly or indirectly on geological data, the reconstruction of the geological history of the Amazon region is still inadequate to analyze its relationship with the biodiversity. This work has the main goal to characterize the sedimentary successions formed in the Brazilian Amazon in the Neogene-Quaternary discussing the evolution of the depositional systems through time and analyzing their main controlling mechanisms in order to fill up this gap. Radar image interpretation, sedimentological studies, and radiocarbon dating allowed the mapping of Plio-Pleistocene to Holocene units along the Solimões-Amazonas River, Brazil. This integrated work led to the characterization of five sedimentary successions overlying Miocene deposits of the Solimões/Pebas Formation, which include the following: Içá Formation (Plio-Pleistocene), deposits Q1 (37,400–43,70014C yr B.P.), deposits Q2 (27,20014C yr B.P.), deposits Q3 (6730–248014C yr B.P.), and deposits Q4 (280–13014C yr B.P.). These deposits occur mostly to the west of Manaus, forming NW–SE elongated belts that are progressively younger from SW to NE, indicating a subsiding basin with a depocenter that migrated to the NE. The reconstruction of the depositional history is consistent with significant changes in the landscapes. Hence, the closure of a large lake system at the end of the Miocene gave rise to the development of a Plio-Pleistocene fluvial system. This was yet very distinct from the modern drainage, with shallow, energetic, highly migrating, braided to anastomosed channels having an overall northeast outlet. This fluvial system formed probably under climatic conditions relatively drier than today's. During the early Pleistocene, there was pronounced erosion, followed by a renewed depositional phase ca. 40,00014C yr B.P., with the development of prograding lobes and/or crevasse splays associated with a lake system (i.e., fan-delta) and/or fluvial flood plain areas. After a period of erosion, a fluvial system with eastward draining channels started to develop at around 27,00014C yr B.P. The fluvial channels were overflooded in mid-Holocene time. This flooding is attributed to an increased period of humidity, with a peak between 5000 and 250014C yr B.P. The data presented herein support that, rather than being a monotonous area, the Amazonia was a place with frequent changes in landscape throughout the Neogene-Quaternary, probably as a result of climatic and tectonic factors. We hypothesize that these changes in the physical environment stressed the biota, resulting in speciation and thus had a great impact on modern biodiversity.
Ibuprofen pharmacokinetics in preterm infants with patent ductus arteriosus
Authors: Van Overmeire Bart , Touw Daan , Schepens Paul J. C. , Kearns Gregory L. , van den Anker John N.
Published: December 2004

Objective

Our objective was to study the pharmacokinetics of ibuprofen in premature infants with patent ductus arteriosus on day 3 and day 5 after birth.

Methods

Ibuprofen was administered on days 3, 4, and 5 by a 15‐minute intravenous infusion of 10, 5, and 5 mg/kg, respectively, with the aim of closing the ductus arteriosus. Blood samples were drawn at time zero and at 0.5, 1, 2, 4, 12, and 24 hours after the first and third doses. Ibuprofen plasma concentrations were assayed by HPLC.

Results

A total of 27 premature infants were included (gestational age, 28.6 ±1.9 weeks; birth weight, 1250 ±460 g; values are mean ±standard deviation). Ibuprofen pharmacokinetics followed a 2‐compartment open model. Between the first and third doses (day 3 and day 5) there was a significant decrease of the volume of distribution of the central compartment (Vdc) (0.244 versus 0.171 L/kg; P = .03) and area under the plasma concentration‐time curve (524 versus 447 mg · h/L; P = .01). The decrease in Vdc was most pronounced in patients with a closing ductus. Total body clearance and plasma half‐life did not change significantly. No significant differences were observed in ibuprofen peak plasma concentrations after the first and third doses in relation to ductal status after treatment.

Conclusion

Ibuprofen pharmacokinetics showed a large interindividual variation in premature infants during treatment for patent ductus arteriosus, and significant changes may occur between day 3 and day 5 after birth in those infants with a closing ductus. These findings may have implications for the treatment schedule with ibuprofen in patients with patent ductus arteriosus.

Clinical Pharmacology & Therapeutics (2001) 70, 336–343; doi: 10.1016/S0009‐9236(01)13478‐8
The human pharmacology of monocyte cyclooxygenase 2 inhibition by cortisol and synthetic glucocorticoids
Authors: Santini Giovanna , Patrignani Paola , Sciulli Maria G. , Seta Francesca , Tacconelli Stefania , Panara Maria R. , Ricciotti Emanuela , Capone Marta L. , Patrono Carlo
Published: December 2004

Background

We studied the concentration dependence of the inhibitory effects of cortisol, 6‐methylprednisolone, and dexamethasone on cyclooxygenase‐2 (COX‐2) expression and activity in human monocytes in response to lipopolysaccharide (LPS) in vitro. Moreover, we characterized the time and dose dependence of the inhibitory effects of 6‐methylprednisolone, administered to healthy subjects, on LPS‐inducible prostaglandin E2 (PGE2) biosynthesis in whole blood ex vivo.

Methods

Heparinized whole‐blood samples obtained from healthy subjects and patients with rheumatoid arthritis were incubated with LPS (10 μg/ml) for 24 hours at 37°C, and PGE2 was measured in plasma as an index of monocyte COX‐2 activity. Comparative experiments were performed in LPS‐stimulated isolated monocytes. The levels of COX‐2‐like immunoreactivity in monocyte lysates were measured by a specific Western blot technique. PGE2 was evaluated by radioimmunoassay.

Results

Nanomolar concentrations of cortisol, 6‐methylprednisolone, and dexamethasone suppressed LPS‐induced PGE2 biosynthesis both in whole blood and in isolated monocytes in vitro with relative potencies similar to those reported for their anti‐inflammatory effects in vivo. The administration of single oral doses (4, 8, or 16 mg) of 6‐methylprednisolone caused a dose‐ and time‐dependent inhibition of whole‐blood COX‐2 activity. Whole‐blood samples obtained from patients with rheumatoid arthritis treated with comparable maintenance doses of glucocorticoids produced significantly lower levels of LPS‐inducible PGE2 than were found in untreated patients.

Conclusions

Therapeutic plasma levels of synthetic glucocorticoids down‐regulate inducible prostanoid biosynthesis in circulating monocytes. This effect may represent a readily measurable surrogate marker of their clinical efficacy for dose‐finding studies.

Clinical Pharmacology & Therapeutics (2001) 70, 475–483; doi: 10.1016/S0009‐9236(01)14130‐5
Influence of hepatic impairment on everolimus pharmacokinetics: Implications for dose adjustment
Authors: Kovarik John M. , Sabia Helene D. , Figueiredo Joaquim , Zimmermann Heidrun , Reynolds Christine , Dilzer Stacy C. , Lasseter Kenneth , Rordorf Christiane
Published: December 2004

Objective

We assessed the influence of hepatic impairment on the pharmacokinetics of the immunosuppressant everolimus to provide dose recommendations for clinical use.

Methods

In this open‐label, single‐dose, case‐control study, 8 subjects with liver cirrhosis classed as moderate hepatic impairment (Child‐Pugh score, 7–9) and 8 demographically matched healthy control subjects received a single oral 2‐mg dose of everolimus. Routine safety assessments were made, and blood samples were taken for determination of everolimus concentrations and protein binding.

Results

The apparent clearance of everolimus was significantly reduced by 53% in subjects with moderate hepatic impairment compared with healthy subjects (9.1 ± 3.1 versus 19.4 ± 5.8 L/h). This was manifested by a 115% higher area under the blood concentration‐time curve (AUC) (245 ± 91 versus 114 ± 45 ng · h/ml) and 84% prolonged half‐life (79 ±42 versus 43 ± 18 hours) in subjects with hepatic impairment. The rate of absorption of everolimus was not altered by hepatic impairment on the basis of the maximum blood concentration (Cmax) and time to reach Cmax (tmax). Protein binding was similar in the two groups (73.8% ± 3.6% versus 73.5% ± 2.4%). A significant positive correlation of the everolimus AUC with bilirubin level (r = 0.86) and a significant negative correlation with albumin concentration (r = 0.72) was observed.

Conclusions

The dose of everolimus should initially be reduced by half in patients with mild and moderate hepatic impairment on the basis of the Child‐Pugh classification. Therapeutic monitoring would be a helpful adjunct to subsequent titration of everolimus exposure in this subpopulation. Everolimus has not been assessed in patients with severe hepatic impairment.

Clinical Pharmacology & Therapeutics (2001) 70, 425–430; doi: 10.1016/S0009‐9236(01)15633‐X
Pharmacokinetics and metabolism of intravenous midazolam in preterm infants
Authors: de Wildt S. N. , Kearns G. L. , Hop W. C. J. , Murry D. J. , Abdel‐Rahman S. M. , van den Anker J. N.
Published: December 2004

Background

Midazolam, a benzodiazepine, is finding expanded use in neonatal intensive care units. We studied the pharmacokinetics and metabolism of midazolam after a single intravenous dose in preterm infants.

Methods

The pharmacokinetics of midazolam and its hydroxylated metabolite (1‐OH‐midazolam) after a single 0.1 mg/kg intravenous dose of midazolam were determined in 24 preterm infants (gestational age, 26 to 34 weeks; postnatal age, 3 to 11 days). Blood samples were obtained before drug administration and at 0.5, 1, 2, 4, 6, 12, and 24 hours after the start of the infusion. Midazolam and 1‐OH‐midazolam concentrations were determined by use of gas chromatography‐mass spectrometry.

Results

Total body clearance, apparent volume of distribution, and plasma half‐life of midazolam were (median [range]): 1.8 (0.7–6.7) ml/kg per min, 1.1 (0.4–4.2) L/kg, and 6.3 (2.6–17.7) h, respectively. In 19 of 24 preterm infants, 1‐OH‐midazolam concentrations could be detected: 1‐OH‐midazolam (1‐OH‐M) maximal concentration of drug in plasma (Cmax), time to reach Cmax (Tmax), and 1‐OH‐M/M area under the concentration‐time curve from time zero to the last sampling time point (AUC0−t) ratio were [median (range)]: 8.2 (<0.5–68.2) ng/ml, 6 (1–12) h, and 0.09 (<0.001–1), respectively. Midazolam plasma clearance was increased in those infants who had indomethacin (INN, indometacin) exposure.

Discussion

Consequent to immature hepatic cytochrome P450 3A4 (CYP3A4) activity, midazolam clearance and 1‐OH‐midazolam concentrations are reduced markedly in preterm infants as compared to concentrations in previous reports from studies in older children and adults. Indomethacin exposure and its apparent impact on midazolam clearance support alteration of drug disposition produced by a patent ductus arteriosus or by the direct effects of indomethacin on hemodynamic or renal function.

Clinical Pharmacology & Therapeutics (2001) 70, 525–531; doi: 10.1016/S0009‐9236(01)15882‐0
Pathogenetic role of cyclooxygenase‐2 in hyperprostaglandin E syndrome/antenatal bartter syndrome: Therapeutic use of the cyclooxygenase‐2 inhibitor nimesulide
Authors: Nüsing Rolf M. , Reinalter Stephan C. , Peters Melanie , Kömhoff Martin , Seyberth Hannsjörg W.
Published: December 2004

Patients with hyperprostaglandin E syndrome/antenatal Bartter syndrome typically have renal salt wasting, hypercalciuria with nephrocalcinosis, and secondary hyperaldosteronism. Antenatally, these patients have fetal polyuria, leading to polyhydramnios and premature birth. Hyperprostaglandin E syndrome/antenatal Bartter syndrome is accompanied by a pathologically elevated synthesis of prostaglandin E2, thought to be responsible for aggravation of clinical symptoms such as salt and water loss, vomiting, diarrhea, and failure to thrive. In this study administration of the cyclooxygenase‐2 (COX‐2) specific inhibitor nimesulide to patients with hyperprostaglandin E syndrome/antenatal Bartter syndrome blocked renal prostaglandin E2 formation and relieved the key parameters hyperprostaglandinuria, secondary hyperaldosteronism, and hypercalciuria. Partial suppression of serum thromboxane B2 synthesis resulting from platelet COX‐1 activity and complete inhibition of urinary 6‐keto‐prostaglandin F1α, reflecting endothelial COX‐2 activity, indicate preferential inhibition of COX‐2 by nimesulide. Amelioration of the clinical symptoms by use of nimesulide indicates that COX‐2 may play an important pathogenetic role in hyperprostaglandin E syndrome/antenatal Bartter syndrome. Moreover, on the basis of our data we postulate that COX‐2‐derived prostaglandin E2 is an important mediator for stimulation of the renin‐angiotensin‐aldosterone system in the kidney.

Clinical Pharmacology & Therapeutics (2001) 70, 384–390; doi: 10.1016/S0009‐9236(01)21861‐X
A pilot evaluation of alfentanil‐induced miosis as a noninvasive probe for hepatic cytochrome P450 3A4 (CYP3A4) activity in humans
Authors: Phimmasone Somphane , Kharasch Evan D.
Published: December 2004

Objective

The opioid alfentanil is a CYP3A4 substrate whose plasma clearance depends exclusively on hepatic CYP3A4 activity. Alfentanil clearance is an excellent in vivo probe for hepatic CYP3A4 activity and drug interactions in humans. However, such pharmacokinetic studies are invasive and time‐consuming, and they require extensive analytical effort. This investigation tested the hypothesis that alfentanil‐induced miosis (drug effect) can be used as a surrogate measure for alfentanil plasma concentrations and that alfentanil effect clearance will reflect plasma clearance; thus alfentanil can serve as a noninvasive probe for hepatic CYP3A4.

Methods

Six healthy volunteers were studied in a 3‐way randomized crossover design. Each volunteer received 1 mg intravenous midazolam, followed 1 hour later by 15 μg/kg intravenous alfentanil, after CYP3A4 induction (rifampin [INN, rifampicin]), CYP3A4 inhibition (troleandomycin), and control. Dark‐adapted pupil diameter and dynamic light response were measured coincident with venous blood sampling for up to 8 hours. Midazolam and alfentanil were quantified by gas chromatography‐mass spectrometry. Plasma concentrations of alfentanil and midazolam (an additional CYP3A4 probe) and pupil diameter versus time data were analyzed by use of noncompartmental modeling. Pupil diameter change was analyzed analogously to determine the area under the alfentanil effect (miosis)‐time curve (AUEC), effect clearance (CLmiosis), and effect half‐time.

Results

Compared with control, CYP3A4 induction and inhibition significantly altered the clearances of alfentanil (2.8 ±1.4, 5.3 ±1.0, and 0.42 ±0.1 ml/kg/min, respectively;P < .05 versus control) and midazolam. Dark‐adapted resting diameter (in millimeters) was the best measure of alfentanil pupil effects. Alfentanil‐dependent miosis was significantly altered by CYP3A4 modulation, and log(diameter0 — diametert) versus time curves resembled alfentanil plasma disposition. AUEC∞ values after control, CYP3A4 induction, and inhibition were 280 ±150, 120 ±22, and 1030 ±240 mm · min, respectively (P < .05 versus control). Effect clearances (CLmiosis) were 4.2 ±1.3, 8.8 ±2.4, and 1.2 ±0.8 μg/mm · min, respectively, and effect half‐times were 62 ±23, 34 ±27, and 211 ±35 minutes, respectively (P < .05 versus control). CLmiosis was significantly correlated with plasma clearances of alfentanil (r = 0.77, P < .001) and midazolam (r = 0.80; P < .001).

Conclusions

Alfentanil effect (miosis) may be a sensitive and reliable surrogate for plasma alfentanil concentrations. Alfentanil effect kinetics may be used as a noninvasive surrogate for conventional pharmacokinetics. CLmiosis appears to be a suitable noninvasive in vivo probe for hepatic CYP3A4 activity, and it merits further investigation.

Clinical Pharmacology & Therapeutics (2001) 70, 505–517; doi: 10.1016/S0009‐9236(01)23711‐4
Low sodium and furosemide‐induced stimulation of the renin system in man is mediated by cyclooxygenase 2
Authors: Kammerl Martin C. , Nüsing Rolf M. , Schweda Frank , Endemann Dierk , Stubanus Mike , Kees Frieder , Lackner Karl J. , Fischereder Michael , Krämer Bernhard K.
Published: December 2004

The aim of this study was to examine the effects of highly selective inhibition of cyclooxygenase 2 (COX‐2) with rofecoxib on the renin system during long‐term stimulation and after short‐term stimulation. Six healthy male volunteers received, in a randomized crossover design, a low‐sodium diet for days 1 through 9 with or without 25 mg rofecoxib twice daily on days 5 through 9 and, in addition, 20 mg of furosemide intravenously on day 8. Plasma renin activity increased 2 to 3 times over baseline with a low‐sodium diet and 5 times over baseline 30 minutes after intravenous furosemide; it was still elevated nearly 5 times on day 9. These effects were completely blocked by rofecoxib. Plasma aldosterone and urinary aldosterone concentrations basically reflected the findings with plasma renin activity. Urinary sodium excretion decreased during a low‐sodium diet and increased after intravenous furosemide without being significantly affected by rofecoxib. We have concluded that low‐sodium and furosemide‐stimulated renin and aldosterone secretion is completely blocked in healthy volunteers during COX‐2 inhibition with rofecoxib, suggesting that intact COX‐2 is of major importance for stimulation of the renin system under these conditions in man.

Clinical Pharmacology & Therapeutics (2001) 70, 468–474; doi: 10.1016/S0009‐9236(01)49789‐X
Ethnicity influences morphine pharmacokinetics and pharmacodynamics
Authors: Cepeda M. Soledad , Farrar John T. , Roa Jairo H. , Boston Ray , Meng Qing C. , Ruiz Franklin , Carr Daniel B. , Strom Brian L.
Published: December 2004

Objective

Our objective was to evaluate ethnic differences in response to morphine and to determine whether any detectable differences were pharmacokinetically based.

Methods

This cohort study was carried out in a teaching hospital. Sixty‐six young, healthy male subjects from 3 ethnic groups (Caucasians, native Indians, and Latinos; n = 22 in each group) consented to participate. All subjects received an intravenous morphine bolus of 0.08 mg/kg followed by 0.002 mg/kg · min infused for 30 minutes. Respiratory response was evaluated with the carbon dioxide rebreathing method before and at 25, 95, 180, and 360 minutes after morphine administration. Vital signs and opioid side effects were recorded, and serial blood samples were analyzed for morphine, morphine‐3‐glucuronide, and morphine‐6‐glucuronide (M6G).

Results

All 3 groups had suppression of the ventilatory response to hypercapnia, but the degree of blunting of the ventilatory response differed among groups. Compared with Caucasians, native Indians had an additional 18% reduction in ventilatory response after morphine administration (95% confidence interval, −35% to −2%). The incidence of side effects was similar in all groups (P = .18). Caucasians had higher plasma levels of M6G than did native Indians or Latinos. M6G areas under 6‐hour concentration‐versus‐time curve were as follows: Caucasians, 12,065 ± 4354; native Indians, 8464 ± 4809; and Latinos, 9156 ± 3764 ng · min/mL (P = .03).

Conclusions

Ethnicity influences the response to morphine. Native Indians are more susceptible to morphine depression of the ventilatory response than Caucasians, despite the higher serum M6G levels in Caucasians.

Clinical Pharmacology & Therapeutics (2001) 70, 351–361; doi: 10.1016/S0009‐9236(01)51508‐8
A population pharmacokinetic‐pharmacodynamic analysis and model validation of azimilide
Authors: Phillips Luann , Grasela Thaddeus H. , Agnew Jeffrey R. , Ludwig Elizabeth A. , Thompson Gary A.
Published: December 2004

Background

Pharmacokinetic (PK) and pharmacodynamic (PD) models for azimilide were developed and validated with sparse blood sampling and QTc interval data obtained during three clinical trials of azimilide for prevention of supraventricular arrhythmia recurrence.

Methods

Patients were orally administered placebo or azimilide dihydrochloride, 35, 50, 75, 100, or 125 mg/d, for 6 to 9 months. NONMEM was used for data fitting and assessment of selected patient covariates and concomitant medication classes for PK/PD relationships.

Results

Results indicate that azimilide clearance (CL) was dependent on body weight (WTKG), gender, and current tobacco use, where CL (L/h) = 3.92 × (WTKG − 43)0.208, with a 17% increase for male subjects and a 15.5% increase for current tobacco use. Volume of distribution (V) was also dependent on WTKG and total bilirubin (BIL), where V (L) = 9.88 × (WTKG − 43) + 717 × (BIL)0.348. The PK/PD analysis indicated that the baseline QTc interval was dependent on gender, New York Heart Association Class, digoxin, and paced artificial pacemaker spike, whereas the 50% effective concentration (EC50) was dependent on the serum potassium (K) level, where EC50 = 107 × K. The change in EC50 was not clinically significant within the normal range for potassium. The mean Emax (maximum increase in the QTc interval for the Emax models) was a 61.7 ms increase from baseline. At 125 mg/d the predicted percent increase in the QTc interval at the maximum plasma drug concentration at steady state was 9% and 10% for male and female patients, respectively. The values of the median prediction error were −3% and −0.4% for the PK and PK/PD models, respectively, and the values of the absolute prediction error were 21% and 4% for the PK and PK/PD models, respectively, indicating that both models are essentially unbiased and acceptably accurate.

Conclusions

Azimilide PK parameters are dependent on body weight, gender, smoking status, and bilirubin and are independent of the coadministration of digoxin, warfarin, and cytochrome P4503A4 inhibitors and inducers. The relationship between azimilide concentration and change in QTc is primarily dependent on serum potassium.

Clinical Pharmacology & Therapeutics (2001) 70, 370–383; doi: 10.1016/S0009‐9236(01)56650‐3
Different effects of St John's Wort on the pharmacokinetics of simvastatin and pravastatin
Authors: Sugimoto Koh‐ichi , Ohmori Masami , Tsuruoka Shuichi , Nishiki Kenta , Kawaguchi Atsuhiro , Harada Ken‐ichi , Arakawa Masashi , Sakamoto Koh‐ichi , Masada Mikio , Miyamori Isamu , Fujimura Akio
Published: December 2004

Objective

St John's Wort, a widely used herbal product, is an inducer of CYP3A4 and it decreases blood concentrations of CYP3A4 substrates. The effects of St John's Wort on the pharmacokinetics of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors simvastatin (an inactive lactone pro‐drug) and pravastatin were determined in this study.

Methods

Sixteen healthy male subjects (n = 8 in group 1 and n = 8 in group 2) took a St John's Wort caplet (300 mg) or matching placebo three times a day for 14 days in a double‐blind, crossover study. On day 14, a single oral dose of 10 mg simvastatin and 20 mg pravastatin was given to subjects in group 1 and group 2, respectively. Blood samples were obtained during a 24‐hour period after the administration of each drug.

Results

Repeated St John's Wort treatment tended to lower plasma simvastatin concentration and significantly (P < .05) lowered concentrations of simvastatin hydroxy acid, its active metabolite. The peak concentration in plasma (ratio, 0.72 of placebo) of simvastatin hydroxy acid tended to be decreased and its area under the plasma concentration‐time curve between time zero and 24 hours after administration (ratio, 0.48 of placebo) was significantly decreased (P < .05) by St John's Wort. On the other hand, St John's Wort did not influence plasma pravastatin concentration. No significant differences were observed in the elimination half‐life of simvastatin or pravastatin between the placebo and St John's Wort trials.

Conclusions

This study showed that St John's Wort decreases plasma concentrations of simvastatin but not of pravastatin. Because simvastatin is extensively metabolized by CYP3A4 in the intestinal wall and liver, which are induced by St John's Wort, it is likely that this interaction is partly caused by the enhancement of the CYP3A4‐mediated first‐pass metabolism of simvastatin in the small intestine and liver.

Clinical Pharmacology & Therapeutics (2001) 70, 518–524; doi: 10.1016/S0009‐9236(01)64092‐X
A MESSAGE FROM THE ASCPT MEMBERSHIP COMMITTEE CHAIR
Authors: Kroetz Deanna L.
Published: December 2004

Clinical Pharmacology & Therapeutics (2001) 70, 495–495; doi: 10.1016/S0009‐9236(01)72611‐2
Angioplasty increases target site concentrations of ciprofloxacin in patients with peripheral arterial occlusive disease
Authors: Joukhadar Christian , Klein Nikolas , Frossard Martin , Minar Erich , Stass Heino , Lackner Edith , Herrmann Markus , Riedmüller Eva , Müller Markus
Published: December 2004

Objective

Patients with peripheral arterial occlusive disease are prone to soft tissue infections and frequently require antibiotics. To date, however, it is not known whether improvement of arterial blood flow by angioplasty of stenosis increases antibiotic concentrations in ischemic lesions.

Patients and methods

All patients were scheduled to undergo elective percutaneous transluminal angioplasty (n = 10). Following a single, 400‐mg dose of ciprofloxacin, drug concentrations in plasma, ischemic and healthy soft tissue; arterial peak systolic velocity; and ankle‐brachial pressure index were assessed before and after angioplasty. Unbound ciprofloxacin concentrations were measured at the site of infection with use of in vivo microdialysis.

Results

Angioplasty increased peak systolic velocity and ankle‐brachial pressure index compared with base‐line (P < .002). Before angioplasty area under concentration‐time curve (AUC0–300) values for ciprofloxacin were lower in ischemic tissue than in healthy tissue, with median values of 7.1 mg·h/L (range, 3.5–13.0) and 11.3 mg·h/L (range, 3.4–19.0), respectively (P = .03). After angioplasty AUC0–300 values were identical in ischemic and healthy adipose tissue; median AUC0–300 values were 8.0 mg·h/L (range, 4.0–20.7) and 8.5 mg·h/L (range, 4.4–22.9), respectively (P = .7). A combined in vivo pharmacokinetic/in vitro pharmacodynamic simulation based on tissue concentration data indicates that this difference in pharmacokinetics is also reflected in antimicrobial effect.

Conclusion

Antibiotic concentrations are reduced significantly in ischemic lesions compared to those of healthy adipose tissue in patients with peripheral arterial occlusive disease. From the present data it might be speculated that improvement of arterial blood flow at the affected extremity is associated with increased cure rates of soft tissue infections in these patients.

Clinical Pharmacology & Therapeutics (2001) 70, 532–539; doi: 10.1016/S0009‐9236(01)74143‐4
Heavy metals in traditional Chinese medicines: A systematic review
Authors: Ernst E. , Coon J. Thompson
Published: December 2004

Clinical Pharmacology & Therapeutics (2001) 70, 497–504; doi: 10.1016/S0009‐9236(01)79918‐3
Reply
Authors: Abernethy Darrell R.
Published: December 2004

Clinical Pharmacology & Therapeutics (2001) 70, 568–568; doi: 10.1016/S0009‐9236(01)90122‐5
Reply
Authors: Chiou Win L. , Jeong Hyunyoung , Wu Ta C. , Ma Chien
Published: December 2004

Clinical Pharmacology & Therapeutics (2001) 70, 397–399; doi: 10.1016/S0009‐9236(01)90133‐X
Limited sampling approach
Authors: Duvaldestin Philippe
Published: December 2004

Clinical Pharmacology & Therapeutics (2001) 70, 493–493; doi: 10.1016/S0009‐9236(01)90137‐7
Reply
Authors: Penson Richard T. , Joel Simon P.
Published: December 2004

Clinical Pharmacology & Therapeutics (2001) 70, 493–494; doi: 10.1016/S0009‐9236(01)90138‐9
Assessment of cytochrome P450 activity by a five‐drug cocktail approach
Authors: Zhu Bing , Ou‐Yang Dong‐Sheng , Chen Xiao‐Ping , Huang Song‐Lin , Tan Zhi‐Rong , He Nan , Zhou Hong‐Hao
Published: December 2004

Objectives

Our goal was to establish and validate a modified cocktail approach including probe drugs caffeine, chlorzoxazone, mephenytoin, metoprolol, and midazolam for simultaneous phenotyping of CYP1A2, CYP2E1, CYP2C19, CYP2D6, and CYP3A.

Methods

The study was conducted in 14 healthy, nonsmoking male volunteers with a cocktail of 5 drugs consisting of 100 mg caffeine, 200 mg chlorzoxazone, 100 mg mephenytoin, 100 mg metoprolol, and 7.5 mg midazolam in a randomized manner with a 7 × 7 Latin square design. Plasma was obtained at 1, 4, and 6 hours, and urine was collected from 0 to 8 hours after oral drug administration.

Results

The phenotypic indexes determined for caffeine, chlorzoxazone, mephenytoin, metoprolol, and midazolam were not significantly different when the drugs were given in different combinations. There were no metabolic interactions or analytic interference of these probe drugs.

Conclusions

This cocktail approach can simultaneously provide independent in vivo phenotypic measures for the cytochrome P450 (CYP) enzymes CYP1A2, CYP2E1, CYP2C19, CYP2D6, and CYP3A.

Clinical Pharmacology & Therapeutics (2001) 70, 455–461; doi: 10.1016/S0009‐9236(01)92726‐2
Severe phenytoin intoxication in a subject homozygous for CYP2C9*3
Authors: Brandolese Renato , Scordo Maria Gabriella , Spina Edoardo , Gusella Milena , Padrini Roberto
Published: December 2004

A 31‐year‐old woman who had a severe head injury was treated with oral phenytoin (100 mg 3 times a day) to prevent posttraumatic seizures. On day 10 of phenytoin treatment, 3 hours after the morning dose, the patient manifested neurologic signs compatible with phenytoin intoxication. Thus drug serum concentrations were monitored daily for 12 days. The elimination half‐life was 103 hours, namely, about 5 times longer than the mean value generally quoted (22 hours). In the absence of any acquired predisposing factor for phenytoin toxicity, genetic mutations in the cytochrome P450 (CYP) enzymes responsible for phenytoin metabolism (CYP2C9 and CYP2C19) were suspected. Genotyping revealed that the patient was homozygous for the CYP2C9*3 allele (CYP2C9*3/*3) and heterozygous for the CYP2C19*2 allele (CYP2C19*1/*2). In view of the markedly reduced metabolic activity of CYP2C*3 in comparison with the wild‐type enzyme (about one fifth) and of the minor role of CYP2C19 in phenytoin metabolism, it is likely that CYP2C9*3 mutation was largely responsible for drug overdose.

Clinical Pharmacology & Therapeutics (2001) 70, 391–394; doi: 10.1016/S0009‐9236(01)95478‐5
Studies on crystallization behaviors and crystal morphology of polyamide 66/clay nanocomposites
Authors: Kang Xin , He Suqin , Zhu Chengshen , Wang Liuyang , Lüˇ Liyun , Guo Jianguo
Published: December 2004

X‐ray diffraction methods, DSC thermal analysis, and polarized light microscopy (PLM) were used to investigate the structural changes of nylon 66/clay nanocomposites. PA 66/clay nanocomposites were prepared by the method of melt intercalation. The results indicate that the addition of the intercalated organo‐montmorillonite (OMMT) can induce generation of the β‐form crystal of PA 66 and substantially affect the arrangement of molecules in the α‐form crystal, although the crystallinity scarcely changes. Also, the DSC results indicate that the addition of OMMT in the PA 66 matrix leads to increases of crystallization temperatures and the full width at half maximum (FWHM) of the exothermic peaks. Moreover, the viscosity factor is the main influence on FWHM of the exothermic peaks of PA 66/clay nanocomposites. The results of nonisothermal crystallization kinetics show that OMMT has the effect of heterogeneous nucleation and leads to the decrease of the size of the spherocrystal. The heterogeneous nucleation effects of OMMTs influence the mechanism of crystallization and the growth mode of PA 66 crystals. PLM photographs verify that the size of spherocrystal is decreased and visually confirm the theory of crystallization kinetics. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 95: 756–763, 2005
Studies on physico‐mechanical and optical properties, and WAXS of castor oil based polyurethane/polyacrylates interpenetrating polymer networks
Authors: Siddaramaiah  , Mallu P. , Roopa S. , Somashekarappa H. , Somashekar R.
Published: December 2004

Interpenetrating polymer networks (IPNs) of polyurethane (PU)/polyacrylates have been synthesized by sequential polymerization of castor oil, methylene diisocyanate (MDI), and acrylate monomers such as methyl acrylate (MA), methyl methacrylate (MMA), and ethyl acrylate (EA); with benzoyl peroxide (BPO) and ethylene glycol dimethyl acrylate (EGDM) as an initiator and crosslinker, respectively. The physico‐mechanical properties, such as density, surface hardness, tensile strength, percentage elongation at break, and tear strength; and the optical properties, like total transmittance and haze, of PU/polyacrylate IPNs have been reported. Microcrystalline parameters of IPNs have been computed by using wide angle X‐ray scattering (WAXS) recordings. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 95: 764–773, 2005
KiSS‐1 expression and metastin‐like immunoreactivity in the rat brain
Authors: Brailoiu G. Cristina , Dun Siok L. , Ohsawa Masahiro , Yin Deling , Yang Jun , Chang Jaw Kang , Brailoiu Eugen , Dun Nae J.
Published: December 2004

Metastin, the gene product of metastasis suppressor gene KiSS‐1, is the endogenous ligand for the G‐protein‐coupled receptor GPR54 (or AXOR12, or OT7T175). The expression of KiSS‐1 gene and peptide and the distribution of metastin were studied in the rat central nervous system by reverse transcriptase‐polymerase chain reaction, Western blotting, and immunohistochemical methods. KiSS‐1 gene and peptide expression was higher in the hypothalamus than in the brainstem and spinal cord. In the brain, metastin‐like immunoreactivity (irMT) was found mainly in three groups of cells: dorsomedial hypothalamic nucleus, nucleus of the solitary tract, and caudal ventrolateral medulla. Immunoreactive fibers of varying density were noted in bed nucleus of stria terminalis, septal nuclei, nucleus accumbens, caudate putamen, diagonal band, amygdala, hypothalamus, zona incerta, thalamus, periaqueductal gray, raphe nuclei, lateral parabrachial nucleus, locus coeruleus, spinal trigeminal tract, rostral ventrolateral medulla, and medullary reticular nucleus. Preabsorption of the antiserum with metastin peptide fragment (45–54)‐NH2 (1 μg/ml) resulted in no staining in any of the sections. The biological activity of metastin was assessed by monitoring intracellular calcium [Ca2+]i in cultured hippocampal neurons, which are known to express GPR54. Metastin increased [Ca2+]i in a population of cultured hippocampal neurons. The results show that metastin is biologically active in rat central neurons, and its anatomical distribution suggests a possible role in nociception and autonomic and neuroendocrine functions. J. Comp. Neurol. 481:314–329, 2005. © 2004 Wiley‐Liss, Inc.
Regional, cellular, and subcellular localization of RGS10 in rodent brain
Authors: Waugh Jeff L. , Lou Angela C. , Eisch Amelia J. , Monteggia Lisa M. , Muly E. Chris , Gold Stephen J.
Published: December 2004

Theregulator ofGproteinsignaling type 10 (RGS10) modulates Gαi/o signaling by means of its GTPase accelerating activity and is abundantly expressed in brain and in immune tissues. To elucidate RGS10 function in the nervous system, we mapped RGS10 protein in rat and mouse brain using light microscopic (LM) and electron microscopic (EM) immunohistochemical techniques. The LM showed that RGS10‐like immunoreactivity (LIR) labels all cellular subcompartments of neurons and microglia, including their nuclei. There were several differences between RGS10‐LIR distributions in rat and mouse, the most striking of which were the far denser immunoreactivity in rat dentate gyrus and dorsal raphe. The EM analysis corroborated and extended our findings from LM. Thus, EM confirmed the presence of dense RGS10‐LIR in the euchromatin compartment of nuclei. The EM analysis also resolved dense staining on terminals at symmetric synapses onto pyramidal cell somata. Dual immunofluorescence showed that forebrain interneurons densely labeled with RGS10‐LIR partially colocalized with parvalbumin‐LIR. Dual‐labeling histochemistry in caudoputamen demonstrated that densely labeled striatal cells were biased to the indirect‐projecting output pathway. Dual‐labeling immunofluorescence also showed that densely labeled RGS10‐LIR cells in the dentate gyrus subgranular zone were not proliferating but that newly born cells could differentiate to express RGS10‐LIR. Taken together, these data support a role for RGS10 in diverse processes that include modulation of pre‐ and postsynaptic G‐protein signaling. Moreover, enrichment of RGS10 in transcriptionally active regions of the nucleus suggests an unforeseen role of RGS10 in modulating gene expression. J. Comp. Neurol. 481:299–313, 2005. © 2004 Wiley‐Liss, Inc.
Comparison of the expression patterns of five neural RNA binding proteins in the Xenopus retina
Authors: Amato Marcos A. , Boy Sébastien , Arnault Emilie , Girard Manon , Della Puppa Alice , Sharif Ariane , Perron Muriel
Published: December 2004

An increasing body of evidence indicates that gene expression can be modulated by posttranscriptional mechanisms. RNA binding proteins, for instance, control gene expression at many regulatory levels including RNA splicing, transport, stability, and translation. Although numerous RNA binding proteins have been identified, very few have been studied extensively in the context of developmental processes. We focused our study on five neural RNA binding proteins: one Musashi homolog, Nrp‐1, one member of the Bruno gene family, BruL‐1 (also known as Etr‐1), and three members of the ELAV/Hu family, ElrB, ElrC, and ElrD. As an initial step in addressing their function during Xenopus neurogenesis, we used in situ hybridization to determine their expression patterns during retinal development. We found that RNA binding proteins belonging to different families have distinct spatio‐temporal expression. These combinatorial expression patterns are reminiscent of previously described cell type‐specific expression patterns of transcription factors during retinal development. The distribution of RNA binding proteins within the retina suggests that these regulators of posttranscriptional events may play important roles in multiple steps of retinogenesis. J. Comp. Neurol. 481:331–339, 2005. © 2004 Wiley‐Liss, Inc.