The first record of Heterakis gallinarum as a cause of fatal nodular typhlitis in golden pheasants (Chrysolophus pictus) in India.

Background: Heterakidosis is one of the most prevalent parasitic diseases in birds, the caecae of a variety of wild and domestic birds are infected with these nematodes. In pheasants, nodular typhlitis is a lethal disease caused mainly by infection with Heterakis isolonche alone or in conjunction with Heterakis gallinarum. H. gallinarum has long been recognized to infect birds with low pathogenicity, with only a few fatal cases previously reported. Case description: This paper describes a case of fatal nodular typhlitis due to H. gallinarum in a male and female pair of adult golden pheasants (Chrysolophus pictus) from a zoological garden in Uttar Pradesh, India. Findings/treatment and outcome: The caecum had multiple serosal and mucosal nodules, the majority of which were found to contain various stages of parasites embedded in the center along with the free forms in the caecal contents. Histopathologically, these nodules were generally represented by granulomas centered on necrotic parasite debris, with the occasional reactive fibrous hyperplastic tissue reaction. Based on the morphology and nematode-specific internal transcribed spacer (ITS) ITS1-5.8 rRNA-ITS2 region-based PCR, the nematode was identified as H. gallinarum. The presence of H. gallinarum was further confirmed by sequencing the ITS region followed by phylogenetic analysis. According to the author's best knowledge, this is the first instance of H. gallinarum being linked to nodular typhlitis in pheasants in India. Conclusion: Our findings confirm that H. gallinarum, other than H. isolonche, can induce severe nodular typhlitis with a fatal outcome in pheasants.

Optimization of state-of-the-art fuzzy-metaheuristic ANFIS-based machine learning models for flood susceptibility prediction mapping in the Middle Ganga Plain, India.

This study is an attempt to quantitatively test and compare novel advanced-machine learning algorithms in terms of their performance in achieving the goal of predicting flood susceptible areas in a low altitudinal range, sub-tropical floodplain environmental setting, like that prevailing in the Middle Ganga Plain (MGP), India. This part of the Ganga floodplain region, which under the influence of undergoing active tectonic regime related subsidence, is the hotbed of annual flood disaster. This makes the region one of the best natural laboratories to test the flood susceptibility models for establishing a universalization of such models in low relief highly flood prone areas. Based on highly sophisticated flood inventory archived for this region, and 12 flood conditioning factors viz. annual rainfall, soil type, stream density, distance from stream, distance from road, Topographic Wetness Index (TWI), altitude, slope aspect, slope, curvature, land use/land cover, and geomorphology, an advanced novel hybrid model Adaptive Neuro Fuzzy Inference System (ANFIS), and three metaheuristic models-based ensembles with ANFIS namely ANFIS-GA (Genetic Algorithm), ANFIS-DE (Differential Evolution), and ANFIS-PSO (Particle Swarm Optimization), have been applied for zonation of the flood susceptible areas. The flood inventory dataset, prepared by collected flood samples, were apportioned into 70:30 classes to prepare training and validation datasets. One independent validation method, the Area-Under Receiver Operating Characteristic (AUROC) Curve, and other 11 cut-off-dependent model evaluation metrices have helped to conclude that the ANIFS-GA has outperformed other three models with highest success rate AUC = 0.922 and prediction rate AUC = 0.924. The accuracy was also found to be highest for ANFIS-GA during training (0.886) & validation (0.883). Better performance of ANIFS-GA than the individual models as well as some ensemble models suggests and warrants further study in this topoclimatic environment using other classes of susceptibility models. This will further help establishing a benchmark model with capability of highest accuracy and sensitivity performance in the similar topographic and climatic setting taking assumption of the quality of input parameters as constant.

Effectiveness of Pentoxifylline in the treatment of oral submucous fibrosis patients: a case-control study

Background: Oral submucous fibrosis (OSMF) is a potentially malignant disorder largely seen in the South-Asian countries where areca nut is found to be the main predisposing factor. Pentoxifylline, a methylxanthine derivative, has vasodilating properties and is believed to increase the vascularity of the mucosal layer. This study was designed to determine the effect of pentoxifylline (Trental) on the clinical progression of oral submucous fibrosis. Aim: The present study was aimed to evaluate the effectiveness of drug pentoxifylline in the management of OSMF and to correlate the clinical parameters evaluated before and after treatment. Methods: Study Design: This investigation was conducted as a case-control study incorporating a Control Group in comparison to a Study Group where pentoxifylline 400 mg was administered 3 times daily, as coated, sustainedrelease tablets for prescribed for 3 months. The stipulated period for the study was 8 months and a total of 80 cases of oral submucous fibrosis (40 test subjects and 40 controls) were included in this study and 100% acquiescence was reported at the end of the test period. Results: Mild dizziness and gastric irritation were the only untoward symptoms reported in 2 of the volunteers in the study group during this trial. These were managed by diet protocols. A review of the patients and controls was done at an interval of every 4 weeks for 3 months. The subjective and objective measurements were recorded. The follow-up data at each visit concerning each other and to base-line values were calibrated using nonparametric tests of the Chi-Square test and Mann-Whitney. Significant comparisons with regard to improvement were recorded as objective criteria of mouth opening (u value =1.137, p = 0.260), tongue protrusion (u value = 0.262, p = 0.794 and cheek flexibility (u value =0.990, p = 0.326). Subjective symptoms of burning sensation of mouth (U value = 2.673, p = 0.008), pain on opening the mouth (U value = 4.320, p < 0.0001), difficulty in swallowing and difficulty in the speech were also recorded. Conclusion: This study showed the effectiveness of pentoxifylline as an additional therapy in the routine management of oral submucous fibrosis.

Crocodilian Nest in a Late Cretaceous Sauropod Hatchery from the Type Lameta Ghat Locality, Jabalpur, India.

The well-known Late Cretaceous Lameta Ghat locality (Jabalpur, India) provides a window of opportunity to study a large stable, near shore sandy beach, which was widely used by sauropod dinosaurs as a hatchery. In this paper, we revisit the eggs and eggshell fragments previously assigned to lizards from this locality and reassign them to crocodylomorphs. Several features point to a crocodilian affinity, including a subspherical to ellipsoidal shape, smooth, uneven external surface, discrete trapezoid shaped shell units with wide top and narrow base, basal knobs and wedge shaped crystallites showing typical inverted triangular extinction under crossed nicols. The crocodylomorph eggshell material presented in this paper adds to the skeletal data of these most probably Cretaceous-Eocene dryosaurid crocodiles.

Methods to evaluate and improve the injection site tolerability of intravenous formulations prior to first-in-human testing.

INTRODUCTION: Evaluation of infusion site tolerability is required for the development of intravenous formulations of New Molecular Entities and is of particular importance for investigational drugs that have the potential to precipitate on contact with the blood stream. Based on a comprehensive set of in vitro and in vivo studies conducted with JNJ-X, a development stage small molecule investigational drug, with a pH-dependent solubility that showed potential to cause infusion site irritation at high concentrations, we have developed a systematic approach for evaluating and selecting suitable intravenous formulations for compounds that show potential to precipitate at the infusion site. METHODS: Aqueous formulations containing a range of concentrations of JNJ-X with different excipients, and buffering agents at different pHs (3.9-7.4) were evaluated in an in vitro solubility assay, a modified hen's egg test-chorioallantoic membrane assay (HET-CAM(VT)) and in vivo in rabbit, rat, and dog intravenous infusion toxicity studies. RESULTS: The data obtained with JNJ-X in the different in vitro and in vivo studies were compared and used to support the development of an in silico model and to create a systematic approach to screen and identify candidate intravenous formulations with improved tolerability. DISCUSSION/CONCLUSION: This approach provides a framework that can be used to assess the risk for infusion site irritation and identify better tolerated formulations with a reduced need for in vivo testing.

Sperm donor recruitment, attitudes and provider practices--5 years after the removal of donor anonymity.

STUDY QUESTION: Has the change in donor anonymity legislation in UK affected the recruitment of men wanting to be sperm donors and also affected the attitudes of the practitioners who provide donor sperm treatment? SUMMARY ANSWER: We have performed fewer IUI and IVF treatments using donor sperm following the change in legislation in April 2005 than before. However, we have seen an overall increase in men wanting to donate their sperm, including a small increase in men from ethnic minorities. WHAT IS KNOWN ALREADY: Sweden, which removed donor anonymity in 1985, had an initial drop in men wanting to donate and then 10 years later started to have an increase. The Human Fertilisation and Embryology Authority (HFEA) and other studies in the UK have shown an overall downward trend, but have not been able to compare large time scales either side of the change in legislation. STUDY DESIGN, SIZE, DURATION: This was a retrospective descriptive study that looked at all men who approached the clinic between the years 2000 and 2010, i.e. 5 years either side of the change in legislation (April 2005). Overall, we had 24 men wanting to be donors prior to the rule change and 65 men after the rule change. We also investigated the total number of all treatments with donor sperm, and this included a total of 1004 donor sperm treatments prior to the change in legislation and 403 donor sperm treatments after the change in legislation. PARTICIPANTS, SETTING, METHODS: The study was set in an NHS IVF clinic in South East London. We compared the indicators of service provision, provider practices and donor attitudes, in the period between April 2000 and March 2005 (Group A) with those between April 2005 and March 2010 (Group B), i.e. 5 years either side of the change in legislation. MAIN RESULTS: There were 875 IUI treatments and 129 IVF or ICSI treatments in Group A and 325 IUI and 78 IVF/ICSI treatments in Group B with the use of donor sperm, of which, 11.9% (119 out of 1004) in Group A and 39.5% (159 out of 403) in Group B were with donor sperm recruited by our unit. The clinical pregnancy rate per cycle of treatment in Group A was (86 out of 875) 9.8% for IUI and (27 out of 129) 20.9% for IVF/ICSI and in Group B (32/325) 9.8% and (28 out of 78) 35.9%, respectively. There was a sharp yearly fall in donor sperm treatments from 2004. Twenty-four men were screened in Group A, of which 18 (75.0%) were recruited for long-term storage and 12 (50%) were registered as donors with the HFEA when the sperm was used, whereas in Group B, 65 men were screened, 53 (82.0%) were recruited and 24 (36.92%) were registered as donors. Six (24.0%) men in Group A failed in screening because of poor semen analysis when compared with 9 (13.8%) men in Group B. The majority of post-recruitment dropouts were because of loss of follow-up or withdrawal of consent. More donors in Group A were white (92.0 versus 77.0%) and born in UK (92.0 versus 68.0%) when compared with those in Group B. Donors in Group B were more likely to be single (46.0 versus 4.0%) and to have informed their relevant partner of donation (71.0 versus 54.0%) when compared with those in Group A. 83.0% of donors in Group A were heterosexual when compared with 69.0% in Group B. The primary reason for donating in both groups of potential donors was 'wanting to help' (46.0% 'altruistic donors' in Group A versus 72.0% in Group B). Fewer donors in Group B (37%) had specific restrictions about the use of their sperm when compared with 46.0% in Group A. LIMITATIONS, REASONS FOR CAUTION: As this was a retrospective study, there is a chance for the introduction of bias. WIDER IMPLICATIONS OF THE FINDINGS: We have shown that despite no active in-house recruitment procedures, we are managing to recruit more potential sperm donors after the change in UK legislation, and we are able to meet the demand for treatments with in-house recruited donor sperm that is a reassuring finding for donor sperm treatment services in the wider UK. FUNDING/COMPETING INTERESTS: No external funds were sought for this work. None of the authors have any competing interests to declare.

Role of mixed ion channel effects in the cardiovascular safety assessment of the novel anti-MRSA fluoroquinolone JNJ-Q2.

BACKGROUND AND PURPOSE: JNJ-Q2, a novel broad-spectrum fluoroquinolone with anti-methicillin-resistant Staphylococcus aureus activity, was evaluated in a comprehensive set of non-clinical and clinical cardiovascular safety studies. The effect of JNJ-Q2 on different cardiovascular parameters was compared with that of moxifloxacin, sparfloxacin and ofloxacin. Through comparisons with these well-known fluoroquinolones, the importance of effects on compensatory ion channels to the cardiovascular safety of JNJ-Q2 was investigated. EXPERIMENTAL APPROACH: JNJ-Q2 and comparator fluoroquinolones were evaluated in the following models/test systems: hERG-transfected HEK293 cells sodium channel-transfected CHO cells, guinea pig right atria, arterially perfused rabbit left ventricular wedge preparations and in vivo studies in anaesthetized guinea pigs, anaesthetized and conscious telemetered dogs, and a thorough QT study in humans. KEY RESULTS: The trend for effects of JNJ-Q2 on Tp-Te, QT, QRS and PR intervals in the non-clinical models and the plateau in QTc with increasing plasma concentration in humans are consistent with offsetting sodium and calcium channel activities that were observed in the non-clinical studies. These mixed ion channel activities result in the less pronounced or comparable increase in QTc interval for JNJ-Q2 compared with moxifloxacin and sparfloxacin despite its greater in vitro inhibition of I(Kr). CONCLUSIONS AND IMPLICATIONS: Based on the non-clinical and clinical cardiovascular safety assessment, JNJ-Q2 has a safe cardiovascular profile for administration in humans with comparable or reduced potential to prolong QT intervals, compared with moxifloxacin. The results demonstrate the importance of compensatory sodium and calcium channel activity in offsetting potassium channel activity for compounds with a fluoroquinolone core.

Hydrogeochemistry for the assessment of groundwater quality in Varanasi: a fast-urbanizing center in Uttar Pradesh, India.

The hydrogeochemical parameters for groundwater samples of the Varanasi area, a fast-urbanizing region in India, were studied to evaluate the major ion chemistry, weathering and solute acquisition processes controlling water composition, and suitability of water quality for domestic and irrigation uses. Sixty-eight groundwater samples were collected randomly from dug wells and hand pumps in the urban Varanasi area and analyzed for various chemical parameters. Geologically, the study area comprises Quaternary alluvium made up of an alternating succession of clay, silty clay, and sand deposits. The Total dissolved solids classification reveals that except two locations, the groundwater samples are desirable for drinking, and all are useful for irrigation purposes. The cationic and anionic concentrations indicated that the majority of the groundwater samples belong to the order of Na>Ca>Mg>K and HCO3>Cl>SO4 types, respectively. Geochemical classification of groundwater based on the Chadha rectangular diagram shows that the majority (81%) of groundwater samples belong to the calcium-bicarbonate type. The HCO3/(HCO3+SO4) ratio (0.87) indicates mostly carbonic acid weathering process due to presence of kankar carbonate mixed with clay/fine sand. The high nitrate concentration (>45 mg/l) of about 18% of the groundwater samples may be due to the local domestic sewage, leakage of septic tanks, and improper management of sanitary landfills. In general, the calculated values of sodium adsorption ratio, percent sodium, residual sodium carbonate, and permeability index indicate good to permissible use of water for irrigation, and only a few locations demand remedial measures for better crop yields.

Combined effect of ultraviolet-B radiation and cadmium contamination on nutrient uptake and photosynthetic pigments in Brassica campestris L. seedlings.

Environmental and industrial pollution along with increase in ground level UV-B radiation, because of stratospheric ozone depletion, present multiple stresses, which may affect crop photosynthesis and productivity. The present study was undertaken to see interactive effects of heavy metal contamination (Cd(2+)) and UV-B exposure on essential nutrient (Ca(2+), Mg(2+), K(+)) uptake, biomass, and chlorophyll content in mustard (Brassica campestris L.) seedlings. Plants grown in 0.5, 1.0, 2.5, and 5.0 mg L(-1) Cd(2+) supplemented medium were exposed to UV-B for 30 min (0.4 mW cm(-2)) per day. The interactive effect of two stresses measured after 5 and 10 days showed an overall decline in biomass. Under dual stress (5 mg Cd(2+) L(-1)) significant (P < 0.001) decrease in chlorophyll a (43%), chlorophyll b (23%), and carotenoid (53%) was observed. Ca(2+) uptake was reduced by 51% in roots under high doses of Cd(2+) (5 mg L(-1)) and simultaneous exposure to 0.4 mW cm(-2) UV-B for 10 days. Mg(2+) content was reduced by 48% and K(+) by 62% under similar exposure conditions. Decline in nutrient uptake in Brassica campestris L. seedlings was observed both in root and shoot leaf in the initial growth period under controlled lab conditions. Cadmium ion (Cd(2+)) uptake was significantly enhanced by 33% (P < 0.001) in the presence of UV-B. The findings are significant as multiple stress conditions prevalent in the environment play an important role during the early growth period, a period critical for crop yield.

Effect of bioaccumulation of cadmium on biomass productivity, essential trace elements, chlorophyll biosynthesis, and macromolecules of wheat seedlings.

Soil contamination with heavy metals has become a worldwide problem, leading to losses in agricultural yield and hazardous human health effects as they enter the food chain. The present investigation was undertaken to examine the influence of cadmium (Cd2+) on the wheat (Triticum aestivum L.) plant. Cd2+ accumulation and distribution in 3-wk-old seedlings grown in nutrient medium containing varying concentrations of Cd2+ (control, 0.25, 0.50, 1.0, 2.5, and 5.0 mg/L) was monitored. The effect of varying Cd2+ concentrations up to 21 d on biomass productivity, plant growth, photosynthetic pigments, protein, amino acids, starch, soluble sugars, and essential nutrients uptake was studied in detail to explore the level up to which the plant can withstand the stress of heavy metal. Plants treated with 0.5, 1.0, 2.5, and 5.0 mg/L Cd2+ showed symptoms of heavy-metal toxicity as observed by various morphological parameters which were recorded with the growth of plants. The root, shoot-leaf length and the root, shoot-leaf biomass progressively decreased with increasing Cd2+ concentration in the nutrient medium. Cd2+ uptake and accumulation was found to be maximum during the initial growth period. Cd2+ also interfered with the nutrients uptake, especially calcium (Ca2+), magnesium (Mg2+), potassium (K+), iron (Fe2+), zinc (Zn2+), and manganese (Mn2+) from the growth medium. Growth reduction and altered levels of major biochemical constituents such as chlorophyll, protein, free amino acids, starch, and soluble sugars that play a major role in plant metabolism were observed in response to varying concentrations of Cd2+ in the nutrient medium. In the present study, the effects of Cd2+ on growth, biomass productivity, mineral nutrients, chlorophyll biosynthesis, protein, free amino acid, starch, and soluble sugars in wheat plants was estimated to establish an overall picture of the Cd2+ toxicity at structural and functional levels.

Biotransformation of insulin glargine after subcutaneous injection in healthy subjects.

OBJECTIVE: It is important to establish pharmacokinetic or pharmacodynamic differences between novel insulin analogues and human insulin. This study examined the primary metabolic degradation products of insulin glargine (LANTUS) in humans. DESIGN: In this single dose, open-label study, insulin glargine was administered subcutaneously at a dose of 0.6 IU/kg; placebo was administered to one control subject. PATIENTS: Four healthy male subjects, plus one control subject, aged 18-50 years were enrolled in this study. MEASUREMENTS: Following insulin glargine administration, blood glucose levels were clamped at the subjects' fasting concentration for 6 h and the amount of 20% glucose infused to maintain this baseline concentration was recorded. Metabolite profiling was performed in plasma and injection site tissue using HPLC and radioimmunoassay (RIA). Pharmacokinetics were evaluated by RIA of serum and plasma immunoreactive insulin levels. The primary pharmacodynamic measure was the glucose infusion rate (GIR). Safety was evaluated by measuring blood glucose concentrations during the clamp and adverse events were observed by the investigator or reported by the subject. RESULTS: Metabolic profiling revealed a clear pattern: insulin glargine is metabolised by sequential cleavage at the carboxy terminus of the B chain, to yield products M1 and M2, which are both structurally similar to human insulin. These degradation products are present both at the injection site and in plasma. CONCLUSION: Thus, during treatment with a subcutaneous injection of insulin glargine, metabolic degradation is likely to be initiated at the injection site and continued within the circulatory system.

One site fits both: a model for the ternary complex of folate + NADPH in R67 dihydrofolate reductase, a D2 symmetric enzyme.

R67 dihydrofolate reductase (DHFR) is a novel enzyme that confers resistance to the antibiotic trimethoprim. The crystal structure of R67 DHFR displays a toroidal structure with a central active-site pore. This homotetrameric protein exhibits 222 symmetry, with only a few residues from each chain contributing to the active site, so related sites must be used to bind both substrate (dihydrofolate) and cofactor (NADPH) in the productive R67 DHFR.NADPH.dihydrofolate complex. Whereas the site of folate binding has been partially resolved crystallographically, an interesting question remains: how can the highly symmetrical active site also bind and orient NADPH for catalysis? To model this ternary complex, we employed DOCK and SLIDE, two methods for docking flexible ligands into proteins using quite different algorithms. The bound pteridine ring of folate (Fol I) from the crystal structure of R67 DHFR was used as the basis for docking the nicotinamide-ribose-Pi (NMN) moiety of NADPH. NMN was positioned by both DOCK and SLIDE on the opposite side of the pore from Fol I, where it interacts with Fol I at the pore's center. Numerous residues serve dual roles in binding. For example, Gln 67 from both the B and D subunits has several contacts with the pteridine ring, while the same residue from the A and C subunits has several contacts with the nicotinamide ring. The residues involved in dual roles are generally amphipathic, allowing them to make both hydrophobic and hydrophilic contacts with the ligands. The result is a 'hot spot' binding surface allowing the same residues to co-optimize the binding of two ligands, and orient them for catalysis.

Investigation of pharmacokinetic and pharmacodynamic interactions after coadministration of nefazodone and haloperidol.

A double-blind, placebo-controlled study using 12 healthy men was designed to evaluate pharmacokinetic and pharmacodynamic interactions when nefazodone and haloperidol are coadministered. Two groups of six subjects each received a 5-mg oral dose of haloperidol or a placebo on study days 1 and 2. Nefazodone, 200 mg, was administered to all 12 subjects twice daily (every 12 hours) on study days 3 to 9; on study day 10, only the morning dose of nefazodone was administered. On study days 9 and 10, all subjects also received 5 mg of haloperidol or a placebo along with the morning dose of nefazodone. Serial blood samples for pharmacokinetic analysis were collected from each subject over a 12-hour period after the morning dose on study days 1, 2, 9, and 10. Plasma samples were assayed for haloperidol, reduced haloperidol, nefazodone, hydroxynefazodone and m-chlorophenylpiperazine by specific, validated high-performance liquid chromatogoraphy methods. Psychomotor performance tests to evaluate haloperidol pharmacodynamics were also performed on days 1, 2, 9, and 10. Reduced haloperidol in the majority of samples was below the limit of quantitation; therefore, the effect of nefazodone on the pharmacokinetics of reduced haloperidol could not be determined. The administration of 5 mg of haloperidol to subjects dosed with nefazodone to steady state led to a modest pharmacokinetic interaction, as indicated by a 36, 13, and 37% increase in mean area under the curve (AUC0-12), highest concentration, and 12-h concentration values for haloperidol, respectively; only the increase in AUC was statistically significant. In contrast, the steady-state pharmacokinetics of nefazodone, hydroxynefazodone, and m-chlorophenylpiperazine were not affected by the administration of haloperidol. Although there were significant differences observed in some psychomotor performance tests, the effects of nefazodone on the pharmacodynamics of haloperidol could not be consistently demonstrated. The results from this study suggest that nefazodone has only modest pharmacokinetic and pharmacodynamic interactions with haloperidol. Although no specific recommendations can be made, dosage adjustment may be necessary for haloperidol when coadministered with nefazodone.

Nefazodone pharmacokinetics: assessment of nonlinearity, intra-subject variability and time to attain steady-state plasma concentrations after dose escalation and de-escalation.

OBJECTIVE: The time required to reach steady-state plasma levels after an increase and a subsequent decrease in the dose of nefazodone, an antidepressant drug with nonlinear pharmacokinetics, was assessed in 24 healthy, male volunteers. METHODS: Each subject was administered 100 mg nefazodone hydrochloride b.i.d. (q 12 h) from study day 1 to 7, 200 mg b.i.d. from study day 8 to 14 and 100 mg b.i.d. from study day 15 to 21. Trough (Cmin blood samples were obtained just prior to the morning dose on days 4-7, 11-14 and 16-21 to evaluate the attainment of steady state. Serial blood samples were collected for 12 h after the morning dose on days 7, 14, 16, 18 and 21 for pharmacokinetic analysis of plasma levels of nefazodone (NEF) and its metabolites, hydroxynefazodone (HO-NEF), m-chlorophenylpiperazine (mCPP) and triazoledione (DIONE), which were determined by validated HPLC/UV assay methods. The Cmin results indicated that when nefazodone was administered at a dose of 100 mg b.i.d., steady-state plasma levels of parent compound and its metabolites were attained by the 4th day (i.e., after six doses) and when the dose was increased from 100 mg b.i.d. to 200 mg b.i.d. and then decreased back to 100 mg b.i.d., new steady-state plasma levels were also reached by the beginning of the 3rd or 4th day of each regimen. Consistent with the attainment of steady-state data, there were no statistically significant differences in Cmax or AUC values for nefazodone or its metabolites between study days 7, 18 and 21. Also consistent with the known nonlinear pharmacokinetics of nefazodone, the mean nefazodone steady-state Cmax and AUC values for the 200-mg dose were three fold and four fold greater, respectively, than those at the 100-mg dose level. Intrasubject variability (% cv) for NEF and its metabolites ranged from 13% to 24% for Cmax and AUC after 100 mg b.i.d.. Intersubject variability was considerably greater and ranged from 29% to 131% for Cmax and AUC after the same dose.

Absorption and presystemic metabolism of nefazodone administered at different regions in the gastrointestinal tract of humans.

PURPOSE: The absorption and disposition of nefazodone (NEF) and its metabolites hydroxynefazodone (HO-NEF), m-chlorophenylpiperazine (mCPP) and triazole dione (dione) were assessed in 10 healthy subjects following infusion of NEF solution into the proximal and distal regions of the intestine vs administration of NEF solution orally by mouth. METHODS: NEF HCl (400 mg) was infused over 5 hours into the proximal or distal intestine through a nasogastric tube, or orally ingested in 10 divided doses over 4.5 hours. The three treatments in the three-period crossover design were separated by one week. RESULTS: The bioavailability of NEF, based on AUC(INF), from proximal and distal regions relative to that from oral administration was 97% and 106%, respectively. NEF was absorbed equally well from all three treatments with median Tmax of 5.0 hours which coincided with the duration of infusion. Mean Cmax of NEF was not different between proximal and oral administrations, however, mean Cmax after distal instillation was 40% lower than that after oral administration. Exposure to HO-NEF, mCPP and dione, following proximal instillation was also comparable to that after oral administration. AUC(INF) of HO-NEF and dione was significantly lower after distal instillation compared to that after oral administration but AUC(INF) of mCPP was not. Cmax of all metabolites was significantly lower after distal administration in comparison to oral treatment. Terminal half-life for NEF, HO-NEF and mCPP after distal administration was longer than the other two treatments. CONCLUSIONS: NEF is absorbed throughout the length of the gastro-intestinal tract which supports the development of an extended-release formulation of NEF. The exposure to the metabolites (relative to NEF) was lower from the distal intestinal site compared to the proximal and oral site which may be explained by a reduced first pass of NEF by the cytochrome P450 3A4 in the distal intestine.

Single- and multiple-dose pharmacokinetics of nefazodone in patients with hepatic cirrhosis.

OBJECTIVE: To compare the single- and multiple-dose pharmacokinetics of nefazodone and its three pharmacologically active metabolites, hydroxynefazodone, m-chlorophenylpiperazine, and triazoledione, in patients with biopsy-proven cirrhosis and age-, sex-, and weight-matched healthy volunteers. METHODS: Subjects received a single 100 mg dose of nefazodone on day 1 followed by 100 mg nefazodone every 12 hours on days 3 through 10. Serial blood samples were collected on days 1 and 10; blood samples for trough levels were also collected just before the morning doses on days 7, 8, and 9. Plasma samples were assayed for nefazodone and its metabolites by validated chromatographic methods. RESULTS: The blood samples for trough levels indicated that, regardless of hepatic function, steady state for nefazodone and its metabolites was achieved by the fourth day of every-12-hour dosing. Subjects with liver cirrhosis had about a two-fold greater systemic exposure to nefazodone and hydroxynefazodone compared with normal subjects after a single dose of nefazodone, the difference decreasing to approximately 25% at steady state. Exposure to m-chlorophenylpiperazine was twofold to threefold greater and exposure to triazoledione was similar in patients with cirrhosis after a single dose of nefazodone and at steady state. There were no serious or unexpected adverse events observed in this study. CONCLUSIONS: These findings indicate that, although no untoward accumulation is anticipated compared with patients with normal hepatic function, patients with hepatic impairment may be exposed to higher concentrations of nefazodone and its metabolites than would subjects with normal hepatic function. Consequently, a lower daily dose of nefazodone should be considered when treating patients with impairment of hepatic function.