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Daily Administration (daily + administration)
Selected AbstractsSafety, Efficacy, and Pharmacokinetic Overview of Low-Dose Daily Administration of TadalafilTHE JOURNAL OF SEXUAL MEDICINE, Issue 7 2009Rebecca Wrishko PhD ABSTRACT Introduction., Several phosphodiesterase type 5 (PDE5) inhibitors are commercially available for the treatment of erectile dysfunction (ED). Development of the first once-daily alternative dosing regimen with a PDE5 inhibitor was motivated by the behavioral complexities associated with sexual intimacy. Aim., To provide an alternative dosing option for certain men who may benefit from the removal of the temporal linkage between administration of an ED therapy and sexual intimacy or for men and their partners who anticipate at least twice-weekly sexual activity. Methods., Pharmacokinetic predictions of tadalafil plasma concentrations were generated based upon empirical data following 20-mg, single-dose administration coupled with tadalafil usage patterns from as-needed clinical trials. To support the pharmacokinetic simulations and pharmacodynamic assumptions, clinical trials were conducted to demonstrate the efficacy and safety of once-daily, low-dose tadalafil 2.5 and 5 mg. Main Outcome Measures., Simulated tadalafil plasma concentrations and comparison with safety and efficacy measures from clinical trials. Results., Based upon pharmacodynamic and pharmacokinetic data, once-daily doses of tadalafil 5 mg were predicted to provide therapeutic concentrations that would be maintained throughout the 24-hour dosing interval. Additionally, for a subgroup of men who anticipate at least twice-weekly sexual activity and are currently taking tadalafil 20 mg, a reduction in daily tadalafil exposure was predicted. To support the hypothesis that low-dose, once-daily tadalafil may be a safe and effective treatment alternative, clinical trials were conducted to demonstrate the safety and efficacy of once-daily tadalafil 2.5 and 5 mg. These results were similar to those of historical as-needed studies evaluating tadalafil 10 and 20 mg. Conclusions., Consistent with pharmacokinetic predictions, data from clinical trials indicate that once-daily use of low-dose tadalafil is a safe and effective treatment for men with ED. Wrishko R, Sorsaburu S, Wong D, Strawbridge A, and McGill J. Safety, efficacy, and pharmacokinetic overview of low-dose daily administration of tadalafil. J Sex Med 2009;6:2039,2048. [source] Ecabet sodium promotes the healing of trinitrobenzene-sulfonic-acid-induced ulceration by enhanced restitution of intestinal epithelial cellsJOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY, Issue 7 2010Tomohisa Takagi Abstract Background and Aims:, Ecabet sodium (ES) is a gastric mucosal protective and ulcer-healing agent. Recently enema therapy with ES was found to be effective for the treatment of human ulcerative colitis as well as experimental colitis in an animal model. Whereas ES possesses potential as a novel treatment for ulcerative colitis, its precise mechanism of action remains to be elucidated. In this study, we investigated the therapeutic efficacy of ES in an experimental rat model of colitis, and evaluated the restitution of intestinal epithelial cells treated with ES in vitro. Methods:, Acute colitis was induced with trinitrobenzene sulfonic acid (TNBS) in male Wistar rats. Rats received intrarectal treatment with ES daily starting on day 7 and were sacrificed on day 14 after the administration of TNBS. The distal colon was removed to evaluate various parameters of inflammation. Moreover, wound-healing assays were used to determine the enhanced restitution of rat intestinal epithelial (RIE) cells treated with ES. Results:, Intracolonic administration of ES accelerated TNBS-induced ulcer healing. Increases in the wet weight of the colon after TNBS administration were significantly inhibited by ES treatment. The wound assay revealed ES enhancement of the migration of RIE cells migration through the phosphorylation of extracellular signal-regulated kinase. Conclusion:, Daily administration of an ES enema promoted the healing of intestinal mucosal injury, in part by the enhanced restitution of intestinal epithelial cells via extracellular signal-regulated kinase activation. ES may thus represent a novel therapeutic approach for the treatment of inflammatory bowel disease. [source] Heteropterys aphrodisiaca Infusion Reduces the Collateral Effects of Cyclosporine A on the TestisTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 7 2008Juliana C. Monteiro Abstract Cyclosporine A (CsA) is known to have testicular toxicity, leading to male infertility. Stimulant and aphrodisiac properties have been attributed to the plant, Heteropterys aphrodisiaca. Thus, the present work was undertaken to evaluate the association of the drug and the medicinal herb in Wistar rats, applying testicular morphometry and ultrastructure. Twenty-four rats were used, divided into four groups: I, control; II, CsA; III, simultaneous use of CsA and H. aphrodisiaca; IV, H. aphrodisiaca. Daily administration by gavage was carried out, during 56 days, of water (sham), CsA in a dose of 15 mg/kg per day and/or H. aphrodisiaca in a dose of 0.5 ml of the infusion prepared with 25 g of roots/100 ml of boiling water. Increased body weight was observed for all groups, but the animals that received only CsA showed the smallest body weight gain. Morphometry showed increased connective tissue volumetric proportion and decreased Leydig cell volumetric proportion in CsA-treated rats. Using transmission electron microscopy, it was possible to ascertain that CsA caused seminiferous epithelium degeneration, resulting in Sertoli cell vacuolization, abnormal round and elongated spermatids and large accumulation of residual cytoplasm at the epithelium border next to the lumen. Expanded intercellular spaces between germ cells were still observed in H. aphrodisiaca -treated rat testes. The administration of H. aphrodisiaca infusion to CsA-treated rats diminished nearly all the CsA-induced damage to the testis ultrastructure, suggesting that H. aphrodisiaca infusion may be used combined with CsA to reduce CsA-induced injuries in the testis. Anat Rec, 291:809-817, 2008. © 2008 Wiley-Liss, Inc. [source] Maintenance of pregnancy in ovariectomized Mongolian gerbils (Meriones unguiculatus)ANIMAL SCIENCE JOURNAL, Issue 5 2002Osamu KAI ABSTRACT Bilateral ovariectomy (Ovx) was carried out on day 20 of pregnancy in Mongolian gerbils (Meriones unguiculatus). The body weights of all groups tended to decrease on the day after the operation, and the decrease was significant in the group that was ovariectomized and given vehicle (Ovx + vehicle group). The body weight in this group never recovered until autopsy on day 24, which is normally 1 day before parturition. No fetuses survived to the time of autopsy in any of the animals of the Ovx + vehicle group. Daily administration of 4 mg of progesterone (P4) prevented the termination of pregnancy in Ovx animals, but 1 mg did not. Treatment with estradiol 17, (E2) in addition to 4 mg of P4 tended to result in a lower rate of fetal survival than that of the Ovx group treated with 4 mg of P4 alone. With regard to fetal weight, treatment with 4 mg of P4 resulted in the same weight as in the sham-operated controls, but the addition of 0.2 or 1 ,g of E2 to the 4 mg of P4 resulted in a significantly lower weight than that of fetuses in the 4 mg of P4 group. The present study suggests that adequate maintenance of pregnancy in ovariectomized gerbils can be achieved by daily treatment with 4 mg of P4 alone. Moreover, treatment with 0.2 or 1 ,g of E2 in addition to 4 mg of P4 caused a deterioration in the maintenance of gestation, in contrast to the effects in rats, mice and hamsters. [source] Combined counseling and bupropion therapy for smoking cessation: identification of outcome predictorsDRUG DEVELOPMENT RESEARCH, Issue 3 2006Maria Caterina Grassi Abstract Because some smoking-induced pathologies improve upon discontinuation, strategies have been developed to help smokers quit. The aim of this study was to measure the rate of smokers still abstinent one year after one cycle of a six-week group counseling given alone or in combination with a seven-week period of daily administration of bupropion. We also evaluated the predictor validity of nicotine dependence intensity at enrollment, administering both the Fageström Tolerance Questionnaire (FTQ) and the Severity of Dependence Scale (SDS). Visual Analogue Scale (VAS), to measure the intensity of "smoke craving," was also administered. Two hundred twenty-nine subjects trying to quit smoking were enrolled. Bupropion therapy was accepted by 110 subjects, but only 50 completed the 7-week cycle of therapy. Abstinence rates at one year were 68.0 and 56.6%, respectively, in the group that used bupropion for the scheduled 7 weeks and in the group that discontinued bupropion, and 35.3% in the group with counseling therapy alone. SDS (but not FTQ) scores at enrollment, VAS values for craving at the end of the program, and bupropion therapy were the variables selected by Linear Discriminant Analysis to assign subjects to the Smoker or Non-smoker group, with a global correctness of 70.9%. In conclusion, the efficacy of bupropion largely depends upon its interaction with psychological factors, such as the level of nicotine dependence, craving for nicotine, and the subject's commitment to quit smoking. Drug Dev. Res. 67:271,279, 2006. © 2006 Wiley-Liss, Inc. [source] Once-per-cycle pegfilgrastim in breast cancer patients treated with docetaxel/epidoxorubicin/cyclophosphamideEUROPEAN JOURNAL OF CANCER CARE, Issue 2 2010L. MONTELLA md MONTELLA L., ADDEO R., GUARRASI R., CENNAMO G., FAIOLA V., CAPASSO E., CARAGLIA M. & DEL PRETE S. (2010) European Journal of Cancer Care19, 200,204 Once-per-cycle pegfilgrastim in breast cancer patients treated with docetaxel/epidoxorubicin/cyclophosphamide The incidence of neutropenia following combination chemotherapy is significant in breast cancer and impairs patients' quality of life. Colony-stimulating factors significantly decrease the risk of febrile neutropenia (FN). Aim of the present study was to assess the efficacy and safety profile of once-per-cycle pegfilgrastim in reducing FN in breast cancer patients treated with docetaxel (75 mg/m2), epidoxorubicin (75 mg/m2), cyclophosphamide (500 mg/m2) administered every 3 weeks. Thirty-five breast cancer patients were enrolled. Chemotherapy was administered in adjuvant, neoadjuvant and metastatic setting respectively in 26, 4 and 5 patients. Toxicity was monitored with programmed clinical evaluation and blood sampling. All patients completed the therapeutic programme consisting of six cycles for overall 210 cycles. The FN appeared in 6 out of 35 patients (17%), requiring dose reduction in 3 patients. Hypertransaminasemia was registered in two patients. In one patient pegfilgrastim administration was stopped because of skin hypersensititivity reaction. In conclusion, pegfilgrastim was able to maintain doses and timing of docetaxel/epidoxorubicin/cyclophosphamide in almost all breast cancer patients treated in this series. The reduced need for daily administration of colony-stimulating factors, blood sampling, antibiotic therapy and hospitalization has a significant impact in terms of both quality of life and pharmaco-economic evaluations. [source] PRECLINICAL STUDY: Is withdrawal hyperalgesia in morphine-dependent mice a direct effect of a low concentration of the residual drug?ADDICTION BIOLOGY, Issue 4 2009Vardit Rubovitch ABSTRACT Withdrawal of opioid drugs leads to a cluster of unpleasant symptoms in dependent subjects. These symptoms are stimulatory in nature and oppose the acute, inhibitory effects of opiates. The conventional theory that explains the opioid withdrawal syndrome assumes that chronic usage of opioid drugs activates compensatory mechanisms whose stimulatory effects are revealed upon elimination of the inhibitory opioid drug from the body. Based on previous studies that show a dose-dependent dual activity of opiates, including pain perception, we present here an alternative explanation to the phenomenon of withdrawal-induced hyperalgesia. According to this explanation, the residual low concentration of the drug that remains after cessation of its administration elicits the stimulatory withdrawal hyperalgesia. The goal of the present study was to test this hypothesis. In the present study we rendered mice dependent on morphine by a daily administration of the drug. Cessation of morphine application elicited withdrawal hyperalgesia that was completely blocked by a high dose of the opiate antagonist naloxone (100 mg/kg). Similarly, naloxone (2 mg/kg)-induced withdrawal hyperalgesia was also blocked by 100 mg/kg of naloxone. The blockage of withdrawal hyperalgesia by naloxone suggested the involvement of opioid receptors in the phenomenon and indicated that withdrawal hyperalgesia is a direct effect of a residual, low concentration of morphine. Acute experiments that show morphine- and naloxone-induced hyperalgesia further verified our hypothesis. Our findings offer a novel, alternative approach to opiate detoxifications that may prevent withdrawal symptoms by a complete blockage of the opioid receptors using a high dose of the opioid antagonist. [source] Anti-tumor efficacy of the nucleoside analog 1-(2-deoxy-2-fluoro-4-thio-,-D-arabinofuranosyl) cytosine (4,-thio-FAC) in human pancreatic and ovarian tumor xenograft modelsINTERNATIONAL JOURNAL OF CANCER, Issue 6 2005Deborah A. Zajchowski Abstract 1-(2-Deoxy-2-fluoro-4-thio-,- D -arabinofuranosyl) cytosine (4,-thio-FAC) is a deoxycytidine analog that has been shown previously to have impressive anti-proliferative and cytotoxic effects in vitro and in vivo toward colorectal and gastric tumors. In our present studies, the pharmacokinetic behavior in nude mice and the effectiveness of 4,-thio-FAC against human pancreatic and ovarian tumor growth were assessed in comparison with standard chemotherapeutic agents. Potent in vitro anti-proliferative effects were observed against pancreatic (Capan-1, MIA-PaCa-2, BxPC-3) and ovarian (SK-OV-3, OVCAR-3, ES-2) cancer cell lines with IC50 of 0.01,0.2 ,M. In vivo anti-tumor activity was evaluated in nude mice bearing subcutaneously (s.c.) implanted human pancreatic tumor xenografts or intraperitoneally (i.p.) disseminated human ovarian xenografted tumors. Oral daily administration of 4,-thio-FAC for 8,10 days significantly inhibited the growth of gemcitabine-resistant BxPC-3 pancreatic tumors and induced regression of gemcitabine-refractory Capan-1 tumors. 4,-Thio-FAC was also a highly effective inhibitor of ovarian peritoneal carcinomatosis. In the SK-OV-3 and ES-2 ovarian cancer models, 4,-thio-FAC prolonged survival to a greater extent than that observed with gemcitabine. Furthermore, the superiority of 4,-thio-FAC to carboplatin and paclitaxel was demonstrated in the ES-2 clear cell ovarian carcinoma model. Studies provide evidence that 4,-thio-FAC is a promising new alternative to gemcitabine and other chemotherapeutic drugs in the treatment of a variety of tumor indications, including pancreatic and ovarian carcinoma. © 2004 Wiley-Liss, Inc. [source] The role of melatonin in immuno-enhancement: potential application in cancerINTERNATIONAL JOURNAL OF EXPERIMENTAL PATHOLOGY, Issue 2 2006Sandra C. Miller Summary Melatonin, a neurohormone produced mainly by the pineal gland, is a modulator of haemopoiesis and of immune cell production and function, both in vivo and in vitro. Physiologically, melatonin is associated with T-helper 1 (Th1) cytokines, and its administration favours Th1 priming. In both normal and leukaemic mice, melatonin administration results in quantitative and functional enhancement of natural killer (NK) cells, whose role is to mediate defenses against virus-infected and cancer cells. Melatonin appears to regulate cell dynamics, including the proliferative and maturational stages of virtually all haemopoietic and immune cells lineages involved in host defense , not only NK cells but also T and B lymphocytes, granulocytes and monocytes , in both bone marrow and tissues. In particular, melatonin is a powerful antiapoptotic signal promoting the survival of normal granulocytes and B lymphocytes. In mice bearing mid-stage leukaemia, daily administration of melatonin results in a survival index of 30,40% vs. 0% in untreated mice. Thus, melatonin seems to have a fundamental role as a system regulator in haemopoiesis and immuno-enhancement, appears to be closely involved in several fundamental aspects of host defense and has the potential to be useful as an adjuvant tumour immunotherapeutic agent. [source] Pilot randomised controlled trial of community pharmacy administration of buprenorphine versus methadoneINTERNATIONAL JOURNAL OF PHARMACY PRACTICE, Issue 4 2006Isobel M Cameron research fellow Objectives The established regime for opiate substitute prescribing for drug misusers is daily methadone administered under supervision in community pharmacies. Buprenorphine has recently been introduced as an alternative. However there is a lack of evidence of the effectiveness of buprenorphine maintenance therapy (BMT) in the UK treatment setting. This study aimed to assess methods for a randomised controlled trial (RCT) and the feasibility of pharmacy-based supervised self-administration (SSA) of buprenorphine compared to methadone. Setting Specialist substance misuse service, general practices and community pharmacies in Aberdeen, Scotland. Method The design was a pilot RCT. Opiate-dependent drug misusers, newly referred for maintenance treatment were randomised to receive BMT or methadone maintenance therapy (MMT). Clients and pharmacists were interviewed at baseline and at the end of a 12-week intervention period. Clients completed the quality of life measure EQ-5D. Pharmacy activities were timed. Key findings Twenty-one opiate-dependent clients were recruited (BMT = 11, MMT = 10). Recruitment levels improved as the trial progressed. Clients' treatment preferences were evident. Withdrawals occurred early with BMT. Clients found SSA of buprenorphine acceptable, but found daily administration more manageable than three times weekly. Pharmacists found the dispensing of buprenorphine to be an acceptable role, but felt less certain of ensuring against diversion with buprenorphine than they were with methadone. Pharmacy activities associated with buprenorphine took longer than those associated with methadone (mean = 7 min 25 s versus mean = 3 min 27 s, respectively). Conclusion Recruitment to a trial comparing MMT to BMT for opiate-dependent clients within a UK treatment setting is feasible. Clients and pharmacists found buprenorphine acceptable. [source] Monthly Oral Ibandronate Therapy in Postmenopausal Osteoporosis: 1-Year Results From the MOBILE StudyJOURNAL OF BONE AND MINERAL RESEARCH, Issue 8 2005Paul D Miller MD Abstract Once-monthly (50/50, 100, and 150 mg) and daily (2.5 mg; 3-year vertebral fracture risk reduction: 52%) oral ibandronate regimens were compared in 1609 women with postmenopausal osteoporosis. At least equivalent efficacy and similar safety and tolerability were shown after 1 year. Introduction: Suboptimal adherence to daily and weekly oral bisphosphonates can potentially compromise therapeutic outcomes in postmenopausal osteoporosis. Although yet to be prospectively shown in osteoporosis, evidence from randomized clinical trials in several other chronic conditions shows that reducing dosing frequency enhances therapeutic adherence. Ibandronate is a new and potent bisphosphonate with antifracture efficacy proven for daily administration and also intermittent administration with a dose-free interval of >2 months. This report presents comparative data on the efficacy and safety of monthly and daily oral ibandronate regimens. Materials and Methods: MOBILE is a 2-year, randomized, double-blind, phase III, noninferiority trial. A total of 1609 women with postmenopausal osteoporosis were assigned to one of four oral ibandronate regimens: 2.5 mg daily, 50 mg/50 mg monthly (single doses, consecutive days), 100 mg monthly, or 150 mg monthly. Results: After 1 year, lumbar spine BMD increased by 3.9%, 4.3%, 4.1%, and 4.9% in the 2.5, 50 /50, 100, and 150 mg arms, respectively. All monthly regimens were proven noninferior, and the 150 mg regimen superior, to the daily regimen. All monthly regimens produced similar hip BMD gains, which were larger than those with the daily regimen. All regimens similarly decreased serum levels of C-telopeptide, a biochemical marker of bone resorption. Compared with the daily regimen, a significantly larger proportion of women receiving the 100 and 150 mg monthly regimens achieved predefined threshold levels for percent change from baseline in lumbar spine (6%) or total hip BMD (3%). All regimens were similarly well tolerated. Conclusions: Monthly ibandronate is at least as effective and well tolerated as the currently approved daily ibandronate regimen in postmenopausal osteoporosis. [source] Matrix-assisted laser desorption/ionization tissue profiling of secretoneurin in the nucleus accumbens shell from cocaine-sensitized ratsJOURNAL OF MASS SPECTROMETRY (INCORP BIOLOGICAL MASS SPECTROMETRY), Issue 1 2010Joachim D. Uys Abstract Proteins in the nucleus accumbens mediate many cocaine-induced behaviors. In an effort to measure changes in nucleus accumbens protein expression as potential biomarkers for addiction, coronal tissue sections were obtained from rats that developed behavioral sensitization after daily administration of cocaine, or from daily saline-treated controls. The tissue sections were subjected to matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MS) profiling and tissue imaging. For profiling experiments, brain sections were manually spotted with matrix over the nucleus accumbens, a brain region known to regulate cocaine sensitization. Summed mass spectra (10 000 laser shots, grid) were acquired and spectra were aligned to reference peaks. Using bioinformatics tools, eight spectral features were found to be altered by cocaine treatment. Based on additional sequencing experiments with MALDI tandem MS and database searches of measured masses, secretoneurin (m/z 3653) was identified as having an increased expression. In addition, the distribution of m/z 3653 in the nucleus accumbens was determined by MALDI tissue imaging, and the increased expression of its precursor protein, secretogranin II, was verified by immunoblotting. Copyright © 2009 John Wiley & Sons, Ltd. [source] Neuroprotective effects of atorvastatin against glutamate-induced excitotoxicity in primary cortical neuronesJOURNAL OF NEUROCHEMISTRY, Issue 6 2005Julian Bösel Abstract Statins [3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors] exert cholesterol-independent pleiotropic effects that include anti-thrombotic, anti-inflammatory, and anti-oxidative properties. Here, we examined direct protective effects of atorvastatin on neurones in different cell damage models in vitro. Primary cortical neurones were pre-treated with atorvastatin and then exposed to (i) glutamate, (ii) oxygen,glucose deprivation or (iii) several apoptosis-inducing compounds. Atorvastatin significantly protected from glutamate-induced excitotoxicity as evidenced by propidium iodide staining, nuclear morphology, release of lactate dehydrogenase, and mitochondrial tetrazolium metabolism, but not from oxygen,glucose deprivation or apoptotic cell death. This anti-excitototoxic effect was evident with 2,4 days pre-treatment but not with daily administration or shorter-term pre-treatment. The protective properties occurred independently of 3-hydroxy-3-methylglutaryl-CoA reductase inhibition because co-treatment with mevalonate or other isoprenoids did not reverse or attenuate neuroprotection. Atorvastatin attenuated the glutamate-induced increase of intracellular calcium, which was associated with a modulation of NMDA receptor function. Taken together, atorvastatin exerts specific anti-excitotoxic effects independent of 3-hydroxy-3-methylglutaryl-CoA reductase inhibition, which has potential therapeutic implications. [source] Histometric evaluation of the effect of nicotine administration on periodontal breakdown: an in vivo studyJOURNAL OF PERIODONTAL RESEARCH, Issue 6 2001Francisco H. Nociti Jr The present study investigated the effect of nicotine administration on periodontal breakdown resulting from ligature-induced periodontitis in rats. Twenty adult male Wistar rats were used. After anesthesia, a mandibular first molar was randomly assigned to receive a cotton ligature in the sulcular area while the contralateral tooth was left unligated. The animals were randomly assigned to one of the following treatments, of daily intraperitoneal injections: A , saline solution, B , 0.37 mg of nicotine/kg, C , 0.57 mg of nicotine/kg and D , 0.73 mg of nicotine/kg. Thirty days later, the animals were sacrificed and the specimens routinely processed for serial decalcified sections. Statistical analysis (ANOVA) revealed greater bone loss (p<0.05) in the ligated teeth of animals which received nicotine (groups B/C/D) than in the ligated teeth of animals which received saline solution (group A). In addition, a dose-dependent response was observed among the nicotine groups. A negative effect of nicotine was observed in the unligated teeth of the experimental groups (p<0.05). Therefore, daily administration of nicotine enhanced, in a dose-dependent manner, the effects of local factors in producing periodontal breakdown. Furthermore, the nicotine seemed to have a direct deleterious effect on the periodontal tissues. [source] Hippocampal adult neurogenesis is enhanced by chronic eszopiclone treatment in ratsJOURNAL OF SLEEP RESEARCH, Issue 3 2010MELVI METHIPPARA Summary The adult hippocampal dentate gyrus (DG) exhibits cell proliferation and neurogenesis throughout life. We examined the effects of daily administration of eszopiclone (Esz), a commonly used hypnotic drug and ,-aminobutyric acid (GABA) agonist, compared with vehicle, on DG cell proliferation and neurogenesis, and on sleep,wake patterns. Esz was administered during the usual sleep period of rats, to mimic typical use in humans. Esz treatment for 7 days did not affect the rate of cell proliferation, as measured by 5-bromo-2,-deoxyuridine (BrdU) immunostaining. However, twice-daily Esz administration for 2 weeks increased survival of newborn cells by 46%. Most surviving cells exhibited a neuronal phenotype, identified as BrdU,neuronal nuclei (NeuN) double-labeling. NeuN is a marker of neurons. Non-rapid eye movement sleep was increased on day 1, but not on days 7 or 14 of Esz administration. Delta electroencephalogram activity was increased on days 1 and 7 of treatment, but not on day 14. There is evidence that enhancement of DG neurogenesis is a critical component of the effects of antidepressant treatments of major depressive disorder (MDD). Adult-born DG cells are responsive to GABAergic stimulation, which promotes cell maturation. The present study suggests that Esz, presumably acting as a GABA agonist, has pro-neurogenic effects in the adult DG. This result is consistent with evidence that Esz enhances the antidepressant treatment response of patients with MDD with insomnia. [source] Clinical efficacy and safety of a once-daily formulation of carbimazole in cats with hyperthyroidismJOURNAL OF SMALL ANIMAL PRACTICE, Issue 10 2009R. Frénais Objective:Evaluation of efficacy and safety of a novel controlled-release formulation of carbimazole in feline hyperthyroidism. Methods:A multicentre, self-controlled study in 44 client-owned cats with history and clinical signs of hyperthyroidism, and total thyroxine concentration greater than or equal to 50 nmol/l. Treatment was started at 15 mg once daily, response assessed after 10 days, and 3, 5, 8, 26 and 53 weeks and dose adjusted as required. Results:The median dose of carbimazole was 10 mg (range 10 to 15 mg) and 15 mg (5 to 25 mg) once daily after 3 and 53 weeks, respectively. Median total thyroxine concentration dropped significantly from 118 nmol/l (50 to 320 nmol/l) at presentation to 33 nmol/l (n=40) after 10 days, 31 nmol/l (n=34) at 3 weeks and 21 nmol/l (n=18) at 53 weeks. Clinical signs improved or resolved in almost all cats within three weeks after starting treatment. Twenty-one adverse reactions possibly (20) or probably (1) related to treatment were reported. During treatment, increased blood urea nitrogen concentration was observed in 25 per cent of the cats, eosinophilia in 20 per cent and lymphopenia in 16 per cent, while liver enzymes tended to improve. Clinical Significance:Once daily administration of controlled-release carbimazole tablets was effective and had expected tolerance in hyperthyroid cats during short- and long-term treatment. [source] Clinical trial: oral colon-release parnaparin sodium tablets (CB-01-05 MMX®) for active left-sided ulcerative colitisALIMENTARY PHARMACOLOGY & THERAPEUTICS, Issue 3 2010G. CELASCO Aliment Pharmacol Ther 31, 375-386 Summary Background, The administration of parnaparin sodium as oral colon-release tablets (CB-01-05 MMX®) has been proposed as a novel approach for the treatment of ulcerative colitis (UC). Aim, To assess the efficacy and the tolerability of 8 weeks' oral daily administration of 210 mg of parnaparin sodium compared with placebo in subjects treated with stable-doses of oral aminosalicylates. Methods, This multicenter, randomized, double-blind proof of concept trial compared the efficacy of CB-01-05 MMX® 210 mg tablets to placebo in 141 subjects with mild to moderately active left-sided UC treated with stable-doses of aminosalicylates. The efficacy was assessed by clinical activity index (CAI), endoscopic index (EI) and histological score (HS). Results, A total of 121 subjects (61 in test group and 60 in control group) formed the per protocol (PP) population. After 8 weeks of treatment, clinical remission was achieved in 83.6% of the CB-01-05 MMX® group, and in 63.3% in the comparator group (P = 0.011). This effect was also significantly evident in the test group at week 4 (P = 0.028). A significant difference was also detected in rectal bleeding, (disappeared respectively in 75.4% and 55.0%; P = 0.018), and in mucosal friability (recovered respectively in 80.3% and in 56.7%; P = 0.005). Conclusions, CB-01-05 MMX® was safe and significantly effective in treating subjects with mild-to-moderate left-sided UC treated with stable-doses of aminosalicylates. [source] Pharmacokinetics of ceftiofur in red deer (Cervus elaphus)JOURNAL OF VETERINARY PHARMACOLOGY & THERAPEUTICS, Issue 1 2004Mark L. Drew Twelve adult female red deer (Cervus elaphus) were given 250 mg of ceftiofur sodium by intramuscular injection (i.m.) and ballistic implant in a crossover design. Blood samples were taken from an in-dwelling jugular catheter prior to drug administration and at 0.25, 0.5, 1, 2, 4, 8, 12, 24, 36, 48, and 72 h postadministration of the drug. Samples were centrifuged and plasma kept frozen at ,70 °C until analysis for ceftiofur and active metabolites using an HPLC method. The pharmacokinetics of ceftiofur and metabolites after i.m. dosing and following ballistic implant were quite different. Absorption after i.m. injection was rapid; whereas following ballistic implant there was a lag-time until concentrations were detectable in plasma. The maximum concentration reached in plasma was higher following injection compared with ballistic implant, however the AUC calculated after ballistic implant was almost identical to the mean AUC found after i.m. dosing. The results indicate that i.m. administration of ceftiofur maintains adequate plasma levels for most susceptible bacterial pathogens for at least 12 h; therefore twice daily administration is needed in red deer. Ballistic implants produced plasma concentrations above the MIC for most bacterial pathogens from 4 to 24 h in most animals after administration; however, absorption of the drug was variable and some did not maintain effective concentrations for more than a few hours. Ceftiofur is a useful drug in red deer and twice daily i.m. administration dosing should allow treatment for susceptible bacterial pathogens. [source] Safety, Efficacy, and Pharmacokinetic Overview of Low-Dose Daily Administration of TadalafilTHE JOURNAL OF SEXUAL MEDICINE, Issue 7 2009Rebecca Wrishko PhD ABSTRACT Introduction., Several phosphodiesterase type 5 (PDE5) inhibitors are commercially available for the treatment of erectile dysfunction (ED). Development of the first once-daily alternative dosing regimen with a PDE5 inhibitor was motivated by the behavioral complexities associated with sexual intimacy. Aim., To provide an alternative dosing option for certain men who may benefit from the removal of the temporal linkage between administration of an ED therapy and sexual intimacy or for men and their partners who anticipate at least twice-weekly sexual activity. Methods., Pharmacokinetic predictions of tadalafil plasma concentrations were generated based upon empirical data following 20-mg, single-dose administration coupled with tadalafil usage patterns from as-needed clinical trials. To support the pharmacokinetic simulations and pharmacodynamic assumptions, clinical trials were conducted to demonstrate the efficacy and safety of once-daily, low-dose tadalafil 2.5 and 5 mg. Main Outcome Measures., Simulated tadalafil plasma concentrations and comparison with safety and efficacy measures from clinical trials. Results., Based upon pharmacodynamic and pharmacokinetic data, once-daily doses of tadalafil 5 mg were predicted to provide therapeutic concentrations that would be maintained throughout the 24-hour dosing interval. Additionally, for a subgroup of men who anticipate at least twice-weekly sexual activity and are currently taking tadalafil 20 mg, a reduction in daily tadalafil exposure was predicted. To support the hypothesis that low-dose, once-daily tadalafil may be a safe and effective treatment alternative, clinical trials were conducted to demonstrate the safety and efficacy of once-daily tadalafil 2.5 and 5 mg. These results were similar to those of historical as-needed studies evaluating tadalafil 10 and 20 mg. Conclusions., Consistent with pharmacokinetic predictions, data from clinical trials indicate that once-daily use of low-dose tadalafil is a safe and effective treatment for men with ED. Wrishko R, Sorsaburu S, Wong D, Strawbridge A, and McGill J. Safety, efficacy, and pharmacokinetic overview of low-dose daily administration of tadalafil. J Sex Med 2009;6:2039,2048. [source] Evaluations of toxicity of Turraeanthus africanus (Méliaceae) in miceANDROLOGIA, Issue 6 2009D. Massoma Lembè Summary Turraeanthus africanus (Meliacaeae) is known to possess a broad spectrum of pharmacological, medicinal and therapeutic properties. However, no extensive safety studies have been conducted on these extracts to date. The aim of this study was to evaluate toxicity of the aqueous extract of Turraeanthus africanus (Meliacaeae) after oral and intraperitoneal administration in mice. The acute toxicity was evaluated after single daily administration of the aqueous extract orally at doses of 0, 5, 10, 15, 20, 30 g kg,1 or by the intraperitoneal route at doses of 0, 3, 6, 9, 12 g kg,1 of raw material. The subacute toxicity was evaluated only by the intraperitoneal route for 6 weeks at doses of 1.5, 3, 6 g kg,1 of raw material. Oral doses up to 30 g kg,1 of the aqueous extract of Turraeanthus africanus (TA) did not produce mortality or significant changes in the general behaviour and gross appearance of internal organs of rats. However, the intraperitoneal administration of the aqueous extract of Turraeanthus africanus caused dose-dependent lethal effects. The acute intraperitoneal toxicity (LD50) of TA extract in mice was 7.2 g kg,1. In subacute toxicity in mice, after the intraperitoneal administration of TA extract for 6 consecutive weeks, the feed consumption was significantly affected at the dose 3 g kg,1 with P < 0.05 and at the dose 6 g kg,1 with P < 0.001 and consequently had significant effect with P < 0.05 in body weight of animals. Level of triglyceride of treated animals lowered at dose 1.5 g kg,1 with P < 0.001 and at dose 3 g kg,1 and 6 g kg,1 with P < 0.05. Total cholesterol level of treated animals lowered at dose 1.5 g kg,1 with P < 0.005 and at dose 3 and 6 g kg,1 with P < 0.001. HDL cholesterol level of treated animals lowered up to dose 6 g kg,1 with P < 0.05 while levels of LDL cholesterol, serum and tissue creatinine of treated animals lowered at dose 3 g kg,1 and dose 6 g kg,1 with P < 0.05. Serum protein level of treated animal enhanced at dose 1.5 g kg,1 and at dose 6 g kg,1 with P < 0.05 while tissue creatinine level of treated animal enhanced with P < 0.001. The histology of liver, kidney and lung of the treated mice indicated morphological change of these organs (data not shown). No significant difference was observed during treatment concerning the haematological parameters. The results suggest that the plant is not toxic through the oral route in mice and that parenteral administration should be avoided. [source] Hemolymph ecdysteroids during the last three molt cycles of the blue crab, Callinectes sapidus: quantitative and qualitative analyses and regulationARCHIVES OF INSECT BIOCHEMISTRY AND PHYSIOLOGY (ELECTRONIC), Issue 1 2010J. Sook Chung Abstract The profiles of circulating ecdysteroids during the three molt cycles prior to adulthood were monitored from the juvenile blue crab, Callinectes sapidus. Ecdysteroid patterns are remarkably similar in terms of peak concentrations ranging between 210,330,ng/ml hemolymph. Analysis of hemolymph at late premolt stage revealed six different types of ecdysteroids with ponasterone A (PoA) and 20-OH ecdysone (20-OH E) as the major forms. This ecdysteroid profile was consistent in all three molt cycles. Bilateral eyestalk ablation (EA) is a procedure that removes inhibitory neurohormones including crustacean hyperglycemic hormone (CHH) and molt-inhibiting hormone (MIH) and often results in precocious molting in crustaceans. However, the inhibitory roles of these neuropeptides in vivo have not yet been tested in C. sapidus. We determined the regulatory roles of CHH and MIH in the circulating ecdysteroid from ablated animals through daily injection. A daily administration of purified native CHH and MIH at physiological concentration maintained intermolt levels of ecdysteroids in the EA animals. This suggests that Y organs (YO) require a brief exposure to CHH and MIH in order to maintain the low level of ecdysteroids. Compared to intact animals, the EA crabs did not exhibit the level of peak ecdysteroids, and the major ecdysteroid turned out to be 20-OH E, not PoA. These results further underscore the important actions of MIH and CHH in ecdysteroidogenesis, as they not only inhibit, but also control the composition of output of the YO activity. © 2009 Wiley Periodicals, Inc. [source] Active immunization with IL-1 displayed on virus-like particles protects from autoimmune arthritisEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 3 2008Gunther Spohn Abstract IL-1 is an important mediator of inflammation and a major cause of tissue damage in rheumatoid arthritis (RA). Therapeutic administration of recombinant IL-1 receptor antagonist (IL-1Ra) is efficacious in reducing clinical symptoms of disease, but suffers from several drawbacks, including the need for frequent administrations of large amounts. Here, we show that immunization of mice with either IL-1, or IL-1, chemically cross-linked to virus-like particles (VLP) of the bacteriophage Q, elicited a rapid and long-lasting autoantibody response. The induced Ab efficiently neutralized the binding of the respective IL-1 molecules to their receptors in vitro and their pro-inflammatory activities in vivo. In the collagen-induced arthritis model, both vaccines strongly protected mice from inflammation and degradation of bone and cartilage. Moreover, immunization with either vaccine showed superior efficacy than daily administrations of high amounts of IL-1Ra. In the T and B cell-independent collagen Ab transfer model, immunization with the IL-1, vaccine strongly protected from arthritis, whereas immunization with the IL-1, vaccine had no effect. Our results suggest that active immunization with IL-1,, and especially IL-1, conjugated to Q, VLP, might become an efficacious and cost-effective new treatment option for RA and other systemic IL-1-dependent inflammatory disorders. [source] PRECLINICAL STUDY: Acquisition and reinstatement of MDMA-induced conditioned place preference in mice pre-treated with MDMA or cocaine during adolescenceADDICTION BIOLOGY, Issue 4 2009Manuel Daza-Losada ABSTRACT Those who take ecstasy are more likely to consume other drugs than non-users with cocaine abuse being reported by 75.5% of high school student MDMA (± 3,4-methylenedioxymetamphetamine hydrochloride) users. The aim of this work was to evaluate the effects of exposure during adolescence to MDMA, cocaine or to both drugs on the MDMA-induced conditioned place preference (CPP) in adult mice. Animals received two daily administrations of saline, 10 mg/kg of MDMA, 25 mg/kg of cocaine or 10 mg/kg of MDMA plus 25 mg/kg of cocaine over 3 days (from PD28 to 30). Three weeks after pre-treatment, the MDMA-induced CPP procedure was initiated (PD52). Acquisition of CPP was induced with a sub-threshold dose of MDMA (1.25 mg/kg) only in animals treated during adolescence with MDMA alone. Preference was established in all the groups after conditioning with 10 mg/kg of MDMA, while the time required to achieve extinction was longer in those pre-treated with cocaine or MDMA alone (46 and 28 sessions, respectively). Moreover, preference was reinstated with progressively lower priming doses of MDMA in mice pre-treated with MDMA or cocaine alone. These results demonstrate that early exposure to MDMA or cocaine induces long-lasting changes that last until adulthood and modify the response of animals to MDMA. [source] Does Dihydrohonokiol, a Potent Anxiolytic Compound, Result in the Development of Benzodiazepine-like Side Effects?JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 8 2000HISASHI KURIBARA The aims of this study were to assess whether dihydrohonokiol, 3,-(2-propenyl)-5-propyl-(1,1,-biphenyl)-2,4,-diol (DHH-B), a potent anxiolytic compound, developed benzodiazepine-like side effects. A 1 mgkg,1 dose of diazepam, almost equivalent to the minimum dose for the anxiolytic effect, disrupted the traction performance, potentiated hexobarbital-induced sleeping and impaired learning and memory performance. DHH-B, even at a dose of 1 mg kg,1 (i.e. five times higher than the minimum dose for significant anxiolytic effect) neither developed diazepam-like side effects nor enhanced the side effects of diazepam. Rather, the potentiation by diazepam of hexobarbital-induced sleeping was reduced by 1 mg kg,1 DHH-B. Furthermore, mice treated with 10 daily administrations of 1 and 5 mg kg,1 diazepam, but not 0.2,5 mg kg,1 DHH-B, showed precipitated withdrawal symptoms characterized by hyper-reactivity, tremor and tail-flick reaction when they were challenged with flumazenil (10 mg kg,1 i.p.). These results suggest that, unlike the benzodiazepine anxiolytic diazepam, DHH-B is less likely to induce motor dysfunction, central depression, amnesia or physical dependence at the effective dose required for the anxiolytic effect. [source] The ,1 -Adrenergic Receptor Antagonist, Prazosin, Reduces Alcohol Drinking in Alcohol-Preferring (P) RatsALCOHOLISM, Issue 2 2009Dennis D. Rasmussen Background:, Preliminary evidence suggest that noradrenergic signaling may play a role in mediating alcohol drinking behavior in both humans and rats. Accordingly, we tested the hypothesis that blockade of ,1 -adrenergic receptors will suppress alcohol drinking in rats selectively bred for alcohol preference (P line). Methods:, Adult male P rats were given 24-hour access to food and water and scheduled access to a 15% (v/v) alcohol solution for 2 hours daily. Rats were injected IP with the ,1 -adrenergic receptor antagonist, prazosin (0, 0.5, 1.0, 1.5, or 2.0 mg/kg body weight), once a day at 15 minutes prior to onset of the daily 2-hour 2-bottle choice, alcohol versus water, access period for 2 consecutive days and then 3 weeks later for 5 consecutive days. Results:, Prazosin significantly reduced (p < 0.01) alcohol intake during the initial 2 daily administrations, and this reduction of alcohol intake was maintained for 5 consecutive days by daily prazosin treatment in the subsequent more prolonged trial (p < 0.05). The prazosin-induced reduction of alcohol intake was not dependent upon drug-induced motor impairment since increases in water drinking (p < 0.05) were exhibited during the 2-hour access periods during both 2- and 5-day prazosin treatment. Conclusions:, The results indicate that the noradrenergic system plays a role in mediating alcohol drinking in rats of the P line and suggest that prazosin,a safe, well-characterized, and well-tolerated drug,may be an effective pharmacotherapeutic agent for the treatment of alcohol use disorders. [source] | |||||||||||||||||||||||||||||||