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.

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.

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.

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.

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.

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.

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.

Nonlinear pharmacokinetics of nefazodone after escalating single and multiple oral doses.

The single- and multiple-dose pharmacokinetics of nefazodone and its metabolites, hydroxynefazodone, p-hydroxynefazodone, and m-chlorophenylpiperazine were investigated in two groups of 18 healthy male volunteers, employing three-period complete crossover designs. In one group, single 50-mg, 100-mg, and 200-mg oral doses of nefazodone hydrochloride were administered with a 1-week washout between treatments. In the other group, doses of 50 mg, 100 mg, and 200 mg were administered twice a day (every 12 hours) for 7.5 days (15 doses) with a 1-week washout between treatments. Serial plasma samples were obtained in both groups and assayed for nefazodone, hydroxynefazodone, m-chlorophenylpiperazine, and p-hydroxynefazodone. Cmax plasma levels of nefazodone and hydroxynefazodone were attained within 2 hours of administration of nefazodone; tmax for m-chlorophenylpiperazine was more delayed, and p-hydroxynefazodone levels were generally below the assay limit. On repeated twice-daily dosing of nefazodone, steady-state levels of the drug and its metabolites were reached within 3 days. Mean single-dose plasma half-life (t1/2) values for nefazodone increased from approximately 1 hour at a 50-mg dose to approximately 2 hours at a 200-mg dose; at steady state, t1/2 values increased from approximately 2 hours at 50 mg twice daily to approximately 3.7 hours at 200 mg twice daily. Whereas dose increased in the proportion of 1:2:4, mean single-dose AUC0-infinity for nefazodone increased in the proportion of 1:3.3:8.9 and mean steady-state AUC0-tau for nefazodone increased in the proportion of 1:4.2:16.8. Plasma levels of hydroxynefazodone paralleled those of nefazodone and were approximately 33% of nefazodone levels at each dose level. Plasma levels of m-chlorophenylpiperazine were only approximately 10% those of nefazodone. Within the dosage range of 50-200 mg of nefazodone hydrochloride, nefazodone and hydroxynefazodone exhibited nonlinear pharmacokinetics; m-chlorophenylpiperazine, a minor metabolite, appeared to exhibit linear pharmacokinetics.

Pharmacokinetic interactions of cefprozil with food, propantheline, metoclopramide, and probenecid in healthy volunteers.

Cefprozil, a new oral cephalosporin antibiotic, is composed of cis and trans isomers in an approximate 90:10 ratio. The objectives of this study were: (1) to assess the effects of alterations in gastrointestinal motility by metoclopramide and propantheline on the pharmacokinetics of cis and trans isomers of cefprozil, and to compare them with the effects of food on the pharmacokinetics of cefprozil; (2) to assess the effects of inhibition of renal tubular secretion by probenecid on the pharmacokinetics of cefprozil isomers. In this four-way crossover study, 15 healthy male volunteers received a 1000-mg dose of cefprozil after fasting, pretreatment with metoclopramide or propantheline, after breakfast, or after probenecid in an incomplete, balanced block design. There was a 1-week washout period between each treatment. Blood and urine samples collected over a 24-hour period were assayed for the cis and trans isomers. The concentrations of the trans isomers were generally 1/10 of the cis isomer. The means and variances of the pharmacokinetic parameters of the cis and trans isomers of cefprozil were similar in fasting subjects and were affected in a parallel manner by food, metoclopramide, propantheline, and probenecid. The pharmacokinetics of the cis isomer under the fasting condition were as follows: maximum peak plasma concentration (Cmax), 14.0 +/- 2.7 micrograms/mL; median time to reach Cmax (tmax), 1.5 (range, 1.0-3.5) hours; half-life (t1/2), 1.24 +/- 0.27 hours; area under the concentration (AUC0-infinity), 47.3 +/- 7.7 micrograms.hour/mL; mean residence time after oral administration (MRTpo), 2.9 +/- 0.4 hours; CLR, 219 +/- 60 mL/minute; and Xu% (percent cumulative urinary excretion in 0-24 hours), 68.1 +/- 12.5.(ABSTRACT TRUNCATED AT 250 WORDS)

Safety, tolerance, and preliminary pharmacokinetics of nefazodone after administration of single and multiple oral doses to healthy adult male volunteers: a double-blind, phase I study.

Safety, tolerance, and preliminary pharmacokinetics of nefazodone, a new antidepressant, were assessed in a randomized, double-blind, parallel group study carried out in two sequential segments: a single and a multiple daily dose segment. Nine subjects in the single daily dose segment were divided into three treatment groups and received nefazodone doses in a leapfrog fashion. Each day of treatment with nefazodone was followed by 2 days of placebo treatment and then administration of the next higher drug dose. Single doses ranged from 5-500 mg. 8 subjects enrolled in the multiple daily dose segment were divided into two treatment groups. In each group, 3 subjects received nefazodone and one received placebo 3 times a day. Each dosage level was administered for 2 days before proceeding to the next higher dose from 5 mg or 10 mg 3 times a day to a maximum of 500 mg 3 times a day. After the dose-escalation period, the subjects in the multiple daily dose segment underwent a 3-day washout, after which they received a single dose of nefazodone at the maximum tolerated level. Safety and tolerance assessment involved analyses of adverse events, laboratory tests, vital signs, ophthalmic examinations, and ECGs. Blood and urine samples were obtained only in the multiple daily dose segment and analyzed for nefazodone and its two pharmacologically active metabolites, hydroxynefazodone and mCPP. A single blood sample was collected on 8 different days for assessment of trough levels (Cmin) and serial samples were obtained on days 5, 9, and 22 of dosing for pharmacokinetic profiles. Additional serial samples were also obtained after the last single dose of 500 mg after a 3-day washout. Nefazodone was found to be safe and well-tolerated in total daily doses as high as 1350 mg (450 mg 3 times a day). Nefazodone was rapidly absorbed after oral administration and converted to hydroxynefazodone and mCPP. The pharmacokinetics of nefazodone, hydroxynefazodone, and mCPP were found to be dose-dependent, as evidenced by dose normalized values of Cmin, Cmax, and AUC0-8 that progressively increased with dose. Although exposure of normal subjects to nefazodone and its 2 pharmacologically active metabolites was disproportionately higher than the corresponding increase in dose, the safety and tolerance profiles did not show a parallel increase in adverse events. Nefazodone may be well-tolerated by patients receiving expected therapeutic doses from 200-600 mg per day when administered in divided doses every 8 to 12 hours.

Population pharmacokinetic analysis of didanosine (2',3'-dideoxyinosine) plasma concentrations obtained in phase I clinical trials in patients with AIDS or AIDS-related complex.

Plasma didanosine concentration data from 36 patients receiving once-a-day therapy and from 33 patients receiving twice-a-day therapy were subject to population pharmacokinetic analysis with the computer program NONMEM. Once- or twice-a-day regimens of didanosine were administered intravenously (i.v.) (dose: 0.8-33 mg/kg) during the first 2 weeks of therapy, and orally (dose: 1.6-66 mg/kg) for the remaining 4 weeks of therapy. Plasma pharmacokinetics were determined after the first and last (steady-state) i.v. and oral doses. Population pharmacokinetic parameters for the combined i.v. and oral steady-state data were (mean [%CV]): systemic clearance, CL, 0.70 (5.2) L/h/kg; central compartment volume, Vc, 0.18 (32) L/kg; steady-state distribution volume, Vdss, 0.84 (6.8) L/kg; first-order absorption rate constant, Ka, 1.3 (9.5) hr-1; and bioavailable fraction, F, 0.34 (8.5). Interindividual variability (omega) was (%CV) 22.3 and 71.0 for CL and Vc, respectively. Intraindividual (residual) variability (sigma) in plasma concentrations (%CV) was 50.2. Body weight, sex, and age did not account for the variability in either CL or Vc, and the use of alternate pharmacokinetic models did not reduce the value of intraindividual variability. Population parameters for the combined i.v. and oral first-dose data were generally similar to those for the steady-state data. The parameters can be used to design dosing regimens in patients using the Bayesian feedback approach.

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.

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.

Pharmacokinetics of nefazodone in the dog following single oral administration.

The pharmacokinetics of nefazodone (NEF) and two of its pharmacologically active metabolites viz hydroxynefazodone (HO-NEF) and m-chlorophenylpiperazine (mCPP) were determined following single oral administration of 100, 200 and 400 mg NEF to 6 beagle dogs in a three-way crossover study. Blood samples were collected for 48 h and plasma was analyzed for NEF, HO-NEF and mCPP by a validated HPLC assay. NEF was rapidly absorbed after oral administration. Cmax values for all three compounds and AUCinf values for HO-NEF and mCPP were dose-proportional; AUCinf values for NEF were dose-linear but not dose-proportional. The T1/2 values for NEF and HO-NEF following the 400 mg dose were significantly greater than those for the 100 mg dose. No differences in mCPP T1/2 were observed among the doses. The Cmax and AUCinf ratios for metabolite:NEF were about 2-fold lower for the 200 and 400 mg doses than those observed for the 100 mg dose. However, due to extensive variability, the ratios for three doses were not significantly different based on statistical analysis. Overall, these data suggest the pharmacokinetics of NEF are dose-dependent in the beagle dog. Statistical significance for dose-dependency for many of the pharmacokinetic parameters could not be demonstrated due to high variability associated with the plasma concentration vs time profiles.

Pharmacokinetics of nefazodone following multiple escalating oral doses in the dog.

The single and multiple dose pharmacokinetics of nefazodone (NEF) were investigated in a dose-escalating study in which 4 beagle dogs (weighing approximately 10 kg) were orally administered 100 mg nefazodone hydrochloride on days 1-7, 500 mg on days 8-14 and 1000 mg on days 15-20 once daily. Serial blood samples were collected over a 24 h period following administration of the first (day 1) and last (day 7) doses for the 100 mg/day dose and the last dose for the 500 (day 14) and 1000 mg/day (day 20) doses. Blood samples were also collected for trough level (Cmin) determination on the morning of the 5th, 6th and 7th day of 100 and 500 mg/day dosing regimens and the 3rd, 5th and 6th day of 1000 mg/day regimen. Plasma was analyzed for NEF and 3 metabolites [hydroxynefazodone (HO-NEF), m-chlorophenylpiperazine (mCPP) and p-hydroxynefazodone (p-HO-NEF)] by a validated HPLC assay. There were no significant differences between the 100 mg single and 100 mg/day multiple dose pharmacokinetic parameters for NEF, HO-NEF and mCPP. However, for p-HO-NEF, single dose elimination half life (T1/2) and area under the plasma concentration-time curve (AUC) extended to infinity were significantly smaller (P < or = 0.05) than the multiple dose T1/2 and AUCTAU, respectively. Based on Cmin data, steady state was reached by the 5th day of 500 mg/day and 1000 mg/day multiple dosing. Mean multiple dose AUCTAU values for NEF increased in a 1:9:26 ratio for a 1:5:10 increase in dose. Due to extensive variability and small number of animals used in the study, the statistical analysis indicated that AUCTAU values were dose-proportional. However, metabolite formation decreased significantly with increasing dose as indicated by AUCTAU ratios for metabolite:NEF. These data suggest that NEF exhibits nonlinear pharmacokinetics within 100-1000 mg/kg dose range in dogs.

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.

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.

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.