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Sample records for 400-mg single dose

  1. Availability of cefixime 400 mg tablets--United States, April 2008.

    PubMed

    2008-04-25

    The only current CDC-recommended options for treating Neisseria gonorrhoeae infections are from a single class of antibiotics, the cephalosporins. Within this class, ceftriaxone, available only as an injection, is the recommended treatment for all types of gonorrhea infections (i.e., urogenital, rectal, and pharyngeal). The only oral agent recommended currently by CDC for treatment of uncomplicated urogenital or rectal gonorrhea is a single dose of cefixime 400 mg. Availability of cefixime had been limited since July 2002, when Wyeth Pharmaceuticals (Collegeville, Pennsylvania) discontinued manufacturing cefixime tablets in the United States. Beginning in April 2008, cefixime (Suprax) 400 mg tablets are again available in the United States.

  2. Comparison of single-dose oral grepafloxacin with cefixime for treatment of uncomplicated gonorrhea in men. The STD Study Group.

    PubMed Central

    Hook, E W; McCormack, W M; Martin, D; Jones, R B; Bean, K; Maroli, A N

    1997-01-01

    In a randomized open study, 351 male patients with uncomplicated gonorrhea were given single oral doses of grepafloxacin (400 mg) or cefixime (400 mg). In the 299 microbiologically evaluable patients, urethral infections were cured in 99% (147 of 149) of those receiving grepafloxacin and 97% (145 of 150) of those given cefixime. Eradication rates for both regimens were 100% in the 16% (47 of 299) of participants who were infected with penicillin-resistant Neisseria gonorrhoeae and 97% in the 21% (62 of 299) of participants infected with tetracycline-resistant strains. Grepafloxacin is a well-tolerated alternative to cefixime for treatment of uncomplicated gonorrhea in males. PMID:9257777

  3. The treatment of pharyngeal gonorrhoea with a single oral dose of cefixime.

    PubMed

    McMillan, A; Young, H

    2007-04-01

    An audit of the efficacy treatment of pharyngeal gonorrhoea with a single oral dose of 400 mg of cefixime was undertaken; 83% of patients also received a single oral dose of azithromycin to treat possible concurrent anogenital chlamydial infection. Of the 54 patients studied, only one of 45 patients who attended for at least one test of cure had a positive culture seven days after treatment; the possibility of reinfection could not have been excluded. Two tests of cure were obtained from 18 patients. Cefixime, therefore, seems to be effective in the treatment of pharyngeal gonorrhoea.

  4. Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia

    PubMed Central

    Gugliotta, Gabriele; Castagnetti, Fausto; Breccia, Massimo; Levato, Luciano; D’Adda, Mariella; Stagno, Fabio; Tiribelli, Mario; Salvucci, Marzia; Fava, Carmen; Martino, Bruno; Cedrone, Michele; Bocchia, Monica; Trabacchi, Elena; Cavazzini, Francesco; Usala, Emilio; Rossi, Antonella Russo; Bochicchio, Maria Teresa; Soverini, Simona; Alimena, Giuliana; Cavo, Michele; Pane, Fabrizio; Martinelli, Giovanni; Saglio, Giuseppe; Baccarani, Michele; Rosti, Gianantonio

    2015-01-01

    Nilotinib is a second-generation tyrosine kinase inhibitor that has been approved for the first-line treatment of chronic-phase chronic myeloid leukemia, based on the results of a prospective randomized study of nilotinib versus imatinib (ENESTnd). Apart from this registration study, very few data are currently available on first-line nilotinib treatment. We report here the long-term, 6-year results of the first investigator-sponsored, GIMEMA multicenter phase 2, single-arm trial with nilotinib 400 mg twice daily as first-line treatment in 73 patients with chronic-phase chronic myeloid leukemia. Six-year overall survival and progression-free survival rates were 96%, with one death after progression to blast phase. At 6 years, 75% of the patients were still on nilotinib. The cumulative incidence of major molecular response was 98%; only one patient had a confirmed loss of major molecular response. The cumulative incidence of deep molecular response (MR 4.0) was 76%. Deep molecular response was stable (≥2 years) in 34% of these patients. Cardiovascular adverse events, mainly due to arterial thrombosis, occurred in 11/73 patients (15%), after 24 to 76 months of therapy. They were more frequent in elderly patients, and in those with baseline cardiovascular risk factors. None was fatal, although there was a relevant morbidity. This is the study with the longest follow-up of a high dose of nilotinib (400 mg twice daily): it highlights the high efficacy and the cardiovascular toxicity of the drug (CTG.NCT.00481052). PMID:26113419

  5. Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia.

    PubMed

    Gugliotta, Gabriele; Castagnetti, Fausto; Breccia, Massimo; Levato, Luciano; D'Adda, Mariella; Stagno, Fabio; Tiribelli, Mario; Salvucci, Marzia; Fava, Carmen; Martino, Bruno; Cedrone, Michele; Bocchia, Monica; Trabacchi, Elena; Cavazzini, Francesco; Usala, Emilio; Russo Rossi, Antonella; Bochicchio, Maria Teresa; Soverini, Simona; Alimena, Giuliana; Cavo, Michele; Pane, Fabrizio; Martinelli, Giovanni; Saglio, Giuseppe; Baccarani, Michele; Rosti, Gianantonio

    2015-09-01

    Nilotinib is a second-generation tyrosine kinase inhibitor that has been approved for the first-line treatment of chronic-phase chronic myeloid leukemia, based on the results of a prospective randomized study of nilotinib versus imatinib (ENESTnd). Apart from this registration study, very few data are currently available on first-line nilotinib treatment. We report here the long-term, 6-year results of the first investigator-sponsored, GIMEMA multicenter phase 2, single-arm trial with nilotinib 400 mg twice daily as first-line treatment in 73 patients with chronic-phase chronic myeloid leukemia. Six-year overall survival and progression-free survival rates were 96%, with one death after progression to blast phase. At 6 years, 75% of the patients were still on nilotinib. The cumulative incidence of major molecular response was 98%; only one patient had a confirmed loss of major molecular response. The cumulative incidence of deep molecular response (MR 4.0) was 76%. Deep molecular response was stable (≥ 2 years) in 34% of these patients. Cardiovascular adverse events, mainly due to arterial thrombosis, occurred in 11/73 patients (15%), after 24 to 76 months of therapy. They were more frequent in elderly patients, and in those with baseline cardiovascular risk factors. None was fatal, although there was a relevant morbidity. This is the study with the longest follow-up of a high dose of nilotinib (400 mg twice daily): it highlights the high efficacy and the cardiovascular toxicity of the drug (CTG.NCT.00481052). PMID:26113419

  6. Long-term outcome of a phase 2 trial with nilotinib 400 mg twice daily in first-line treatment of chronic myeloid leukemia.

    PubMed

    Gugliotta, Gabriele; Castagnetti, Fausto; Breccia, Massimo; Levato, Luciano; D'Adda, Mariella; Stagno, Fabio; Tiribelli, Mario; Salvucci, Marzia; Fava, Carmen; Martino, Bruno; Cedrone, Michele; Bocchia, Monica; Trabacchi, Elena; Cavazzini, Francesco; Usala, Emilio; Russo Rossi, Antonella; Bochicchio, Maria Teresa; Soverini, Simona; Alimena, Giuliana; Cavo, Michele; Pane, Fabrizio; Martinelli, Giovanni; Saglio, Giuseppe; Baccarani, Michele; Rosti, Gianantonio

    2015-09-01

    Nilotinib is a second-generation tyrosine kinase inhibitor that has been approved for the first-line treatment of chronic-phase chronic myeloid leukemia, based on the results of a prospective randomized study of nilotinib versus imatinib (ENESTnd). Apart from this registration study, very few data are currently available on first-line nilotinib treatment. We report here the long-term, 6-year results of the first investigator-sponsored, GIMEMA multicenter phase 2, single-arm trial with nilotinib 400 mg twice daily as first-line treatment in 73 patients with chronic-phase chronic myeloid leukemia. Six-year overall survival and progression-free survival rates were 96%, with one death after progression to blast phase. At 6 years, 75% of the patients were still on nilotinib. The cumulative incidence of major molecular response was 98%; only one patient had a confirmed loss of major molecular response. The cumulative incidence of deep molecular response (MR 4.0) was 76%. Deep molecular response was stable (≥ 2 years) in 34% of these patients. Cardiovascular adverse events, mainly due to arterial thrombosis, occurred in 11/73 patients (15%), after 24 to 76 months of therapy. They were more frequent in elderly patients, and in those with baseline cardiovascular risk factors. None was fatal, although there was a relevant morbidity. This is the study with the longest follow-up of a high dose of nilotinib (400 mg twice daily): it highlights the high efficacy and the cardiovascular toxicity of the drug (CTG.NCT.00481052).

  7. The impact of baseline faecal egg counts on the efficacy of single-dose albendazole against Trichuris trichiura.

    PubMed

    Levecke, B; Mekonnen, Z; Albonico, M; Vercruysse, J

    2012-02-01

    There is considerable variation in the efficacy of single-dose albendazole (400mg) against Trichuris trichiura across human trials. Factors contributing to this variation have not yet been identified. We assessed the impact of mean baseline faecal egg counts (FEC) on the efficacy of single-dose albendazole against T. trichiura in five previously conducted trials. Our results suggest that efficacy measured by reduction in mean FECs decreased significantly (p<0.0001) when mean baseline FECs increased, highlighting that this parameter should be considered as an important confounding factor for drug efficacy.

  8. Pharmacokinetics and Safety of FV-100, a Novel Oral Anti-Herpes Zoster Nucleoside Analogue, Administered in Single and Multiple Doses to Healthy Young Adult and Elderly Adult Volunteers▿

    PubMed Central

    Pentikis, Helen S.; Matson, Mark; Atiee, George; Boehlecke, Brian; Hutchins, Jeff T.; Patti, Joseph M.; Henson, Geoffrey W.; Morris, Amy

    2011-01-01

    FV-100 is the prodrug of the highly potent anti-varicella zoster virus bicyclic nucleoside analogue CF-1743. To characterize the pharmacokinetics and safety of oral FV-100, 3 randomized, double-blind, placebo-controlled clinical trials were conducted: (i) a single-ascending-dose study in 32 healthy subjects aged 18 to 55 years (100-, 200-, 400-, and 800-mg doses) with an evaluation of the food effect in the 400-mg group; (ii) a multiple-ascending-dose study in 48 subjects aged 18 to 55 years (100 mg once daily [QD], 200 mg QD, 400 mg QD, 400 mg twice a day, and 800 mg QD for 7 days); and (iii) a 2-part study in subjects aged 65 years and older with a single 400-mg dose in 15 subjects and a 400-mg QD dosing regimen for 7 days in 12 subjects. FV-100 was rapidly and extensively converted to CF-1743, the concentration of which remained above that required to reduce viral activity by 50% for the 24-hour dosing period. Renal excretion of CF-1743 was very low. A high-fat meal reduced exposure to CF-1743; a low-fat meal did not. Pharmacokinetic parameters for the elderly subjects were comparable to those for the younger subjects. FV-100 was well tolerated by all subjects. The pharmacokinetic and safety profiles of FV-100 support its continued investigation for the treatment of herpes zoster and prevention of postherpetic neuralgia with once-daily dosing and without dose modifications for elderly or renally impaired patients. PMID:21444712

  9. Single-dose pharmacokinetics of oral fleroxacin in bacteremic patients.

    PubMed Central

    Schrenzel, J; Cerruti, F; Herrmann, M; Leemann, T; Weidekamm, E; Portmann, R; Hirschel, B; Lew, D P

    1994-01-01

    Fleroxacin is a new broad-spectrum quinolone which can be given by the oral route. The present study was designed to assess the influence of bacteremia on the pharmacokinetics of a single oral dose of fleroxacin. Thirteen patients with proven bacteremia (one or more pairs of positive blood cultures, no hypotension) were given a single 400-mg fleroxacin dose orally on two occasions while also receiving standard antibiotic therapy. The first dose was administered 12 to 36 h after the last positive blood culture was drawn (day 1), and a second dose was administered 7 days later (day 7 +/- 2) to compare the pharmacokinetics between the acute and the convalescent phases of the disease. Following each administration of fleroxacin, serial plasma samples were collected for up to 72 h and were analyzed for unchanged drug by a reversed phase high-pressure liquid chromatography technique. There were no significant changes in the following pharmacokinetic parameters (mean standard deviation) the maximum concentration of drug in serum (6.4 +/- 1.5 versus 6.7 +/- 1.9 mg/liter), the minimum concentration of drug in serum, defined as the concentration of drug in serum at 24 h postdose (3.0 +/- 1.7 versus 2.5 +/- 1.2 mg/liter), the time to the maximum concentration of drug in serum (2.3 +/- 1.4 versus 2.0 +/- 1.2 h), and the elimination half-life (19.7 +/- 8.0 versus 17.9 +/- 6.9 h). Fleroxacin clearances were compared for each individual patient. A positive correlation (R2 = 0.787) was found between the values measured on day 1 and day 7. Oral clearance of fleroxacin (CL = CL/F, where F is bioavailability was slightly, but not significantly, reduced during the bacteremic phase (oral clearance, 43.8+/- 23.5 versus 48.5 +/- 17.5 ml/min.). When compared with previous results obtained in healthy young subjects, longer times to the maximum concentration of drug in serum and elimination half-lives and higher areas under the curve were observed. This could be due to the bacteremic state

  10. Effect of antacids and ranitidine on the single-dose pharmacokinetics of fosamprenavir.

    PubMed

    Ford, Susan L; Wire, Mary B; Lou, Yu; Baker, Katherine L; Stein, Daniel S

    2005-01-01

    Single doses of MAALOX TC and ranitidine were administered separately with 1,400 mg of fosamprenavir (FPV). MAALOX TC decreased the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) for plasma amprenavir (APV) by 18% and the maximum concentration of drug in serum (C(max)) by 35%; the plasma APV concentration at 12 h (C(12)) increased by 14%. Ranitidine at 300 mg decreased the AUC(0-24) for plasma APV by 30% and C(max) by 51%; C(12) was unchanged. FPV may be coadministered with antacids without concern and without separation in dosing; however, caution is recommended when FPV is coadministered with histamine(2)- receptor antagonists or proton pump inhibitors.

  11. Urinary bactericidal activity and pharmacokinetics of enoxacin versus norfloxacin and ciprofloxacin in healthy volunteers after a single oral dose.

    PubMed

    Well, M; Naber, K G; Kinzig-Schippers, M; Sörgel, F

    1998-04-01

    In an open, randomised monocentric crossover study in six male and six female healthy volunteers, the urinary antibacterial activity and pharmacokinetics of enoxacin, norfloxacin and ciprofloxacin were assessed. Urine was collected up to 6 days, and venous blood samples up to 12 h, after a single oral dose of 400 mg enoxacin, 400 mg norfloxacin and 500 mg ciprofloxacin. Enoxacin (250 mg/l) demonstrated the highest peak concentration (median) in the urine (0-6 h), followed by ciprofloxacin (237 mg/l) and norfloxacin (157 mg/l) as determined by the HPLC assay. The total amount (mean) excreted by the kidneys as parent drugs were as follows: enoxacin 54% of dose, ciprofloxacin 33% of dose, and norfloxacin 22% of dose. The mean plasma concentrations decreased from 1 to 4 h after administration for enoxacin from 1.9 to 1.4 mg/l, for ciprofloxacin from 2.0 to 0.8 mg/l and for norfloxacin from 1.3 to 0.5 mg/l. The antibacterial activity in urine was determined as urinary bactericidal titers (UBT), i.e. the highest 2-fold dilution of urine still bactericidal for the reference organism (E. coli ATCC 25,922) and for five uropathogens with minimal inhibitory (MIC) and bactericidal (MBC) concentrations ranging from highly susceptible to resistant cultured from the urine of patients with complicated urinary tract infections (UTI). For the E. coli ATCC 25,922, the organism with the lowest MIC, median UBTs of ciprofloxacin were present for 4 days, decreasing from 1:512 to 1:2, that of enoxacin for 2 days, decreasing from 1:256 to 1:4, and that of norfloxacin for 2 days, decreasing from 1:128 to 1:2. For the five uropathogens (with increasing MICs: K. pneumoniae, P. mirabilis, E. coli (resistant to nalidixic acid), P. aeruginosa and E. faecalis), the UBTs decreased in general, according to MICs, demonstrating the same relations of UBTs for ciprofloxacin (highest) versus enoxacin (medium) versus norfloxacin (lowest) with one exception (P. mirabilis) for which norfloxacin showed

  12. Guaifenesin Pharmacokinetics Following Single-Dose Oral Administration in Children Aged 2 to 17 Years.

    PubMed

    Thompson, Gary A; Solomon, Gail; Albrecht, Helmut H; Reitberg, Donald P; Guenin, Eric

    2016-07-01

    This study characterized guaifenesin pharmacokinetics in children aged 2 to 17 years (n = 40) who received a single oral dose of guaifenesin (age-based doses of 100-400 mg) 2 hours after breakfast. Plasma samples were obtained before and for 8 hours after dosing and analyzed for guaifenesin using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods, relationships with age were assessed using linear regression, and dose proportionality was assessed on 95% confidence intervals. Based on the upper dose recommended in the monograph (for both children and adolescents), area under the curve from time zero to infinity and maximum plasma concentration both increased with age. However, when comparing the upper dose for children aged 2 to 11 years with the lower dose for adolescents aged 12 to 17 years, similar systemic exposure was observed. As expected due to increasing body size, oral clearance (CLo ) and terminal volume of distribution (Vz /F) increased with age. Due to a larger increase in Vz /F than CLo , an increase in terminal exponential half-life was also observed. Allometric scaling indicated no maturation-related changes in CLo and Vz /F. PMID:26632082

  13. Albendazole and its metabolites in the breast milk of lactating women following a single oral dose of albendazole

    PubMed Central

    Abdel-tawab, Ahmed M; Bradley, Mark; Ghazaly, Essam A; Horton, John; El-Setouhy, Maged

    2009-01-01

    AIMS Albendazole (ABZ) is used in several anthelminthic drug programmws. ABZ side-effects are generally mild, but ABZ-induced pancytopenia may be serious. In filariasis programmes, it may be necessary to administer ABZ to breastfeeding women. Few data are available on safety of ABZ for breastfed infants. In addition, the pharmacokinetics of ABZ and its metabolites in human milk is insufficiently investigated. The aim was to study pharmacokinetics of ABZ and its metabolites [ABZ sulphoxide (ABSX) and ABZ sulphone] in the breast milk lactating women after one single oral dose of ABZ. METHODS Thirty-three lactating women (age 18–40 years) participated in the study. They received a single oral 400-mg dose of ABZ. Five milk samples were taken at 0, 6, 12, 24 and 36 h. One serum sample was taken after 6 h. Samples were analysed using high-performance liquid chromatography and pharmacokinetic analysis was performed. RESULTS ABZ was detectable in milk samples 6 h after the oral dose. The mean concentration of serum ABZ was 63.7 ± 11.9 ng ml−1. The pharmacokinetic parameters for ABSX were calculated as follows: 351.9 ± 32.4 ng ml−1, 6.9 ± 0.5 h, 12.4 ± 2.2 h and 5190.3 ± 482.8 ng*h ml−1 for Cmax, Tmax, t½ and AUC0–36, respectively. The milk-to-serum ratios (range) for ABZ and ABSX were 0.9 (0.2–6.5) and 0.6 (0.1–1.5), respectively. CONCLUSIONS After an oral dose of 400 mg, ABZ and ABSX attain low concentrations in breast milk that are unlikely to be considered harmful for the breastfed infant. PMID:19916998

  14. Evaluation of the pharmacokinetic interaction between repeated doses of rifapentine or rifampin and a single dose of bedaquiline in healthy adult subjects.

    PubMed

    Winter, Helen; Egizi, Erica; Murray, Stephen; Erondu, Ngozi; Ginsberg, Ann; Rouse, Doris J; Severynse-Stevens, Diana; Pauli, Elliott

    2015-02-01

    This study assessed the effects of rifapentine or rifampin on the pharmacokinetics of a single dose of bedaquiline and its M2 metabolite in healthy subjects using a two-period single-sequence design. In period 1, subjects received a single dose of bedaquiline (400 mg), followed by a 28-day washout. In period 2, subjects received either rifapentine (600 mg) or rifampin (600 mg) from day 20 to day 41, as well as a single bedaquiline dose (400 mg) on day 29. The pharmacokinetic profiles of bedaquiline and M2 were compared over 336 h after the administration of bedaquiline alone and in combination with steady-state rifapentine or rifampin. Coadministration of bedaquiline with rifapentine or rifampin resulted in lower bedaquiline exposures. The geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for the maximum observed concentration (Cmax), area under the concentration-time curve to the last available concentration time point (AUC0-t), and AUC extrapolated to infinity (AUC0-inf) of bedaquiline were 62.19% (53.37 to 72.47), 42.79% (37.77 to 48.49), and 44.52% (40.12 to 49.39), respectively, when coadministered with rifapentine. Similarly, the GMRs and 90% CIs for the Cmax, AUC0-t, and AUC0-inf of bedaquiline were 60.24% (51.96 to 69.84), 41.36% (37.70 to 45.36), and 47.32% (41.49 to 53.97), respectively, when coadministered with rifampin. The Cmax, AUC0-t, and AUC0-inf of M2 were also altered when bedaquiline was coadministered with rifapentine or rifampin. Single doses of bedaquiline, administered alone or with multiple doses of rifapentine or rifampin, were well tolerated, with no safety concerns related to coadministration. Daily administration of rifapentine to patients with tuberculosis presents the same drug interaction challenges as rifampin and other rifamycins. Strong inducers of the cytochrome P450 isoenzyme CYP3A4 should be avoided when considering the use of bedaquiline. (This study is registered at clinicaltrials.gov under identifier NCT02216331

  15. Phase III, Randomized, Open-Label Study of Daily Imatinib Mesylate 400 mg Versus 800 mg in Patients With Newly Diagnosed, Previously Untreated Chronic Myeloid Leukemia in Chronic Phase Using Molecular End Points: Tyrosine Kinase Inhibitor Optimization and Selectivity Study

    PubMed Central

    Cortes, Jorge E.; Baccarani, Michele; Guilhot, François; Druker, Brian J.; Branford, Susan; Kim, Dong-Wook; Pane, Fabrizio; Pasquini, Ricardo; Goldberg, Stuart L.; Kalaycio, Matt; Moiraghi, Beatriz; Rowe, Jacob M.; Tothova, Elena; De Souza, Carmino; Rudoltz, Marc; Yu, Richard; Krahnke, Tillmann; Kantarjian, Hagop M.; Radich, Jerald P.; Hughes, Timothy P.

    2010-01-01

    Purpose To evaluate the safety and efficacy of initial treatment with imatinib mesylate 800 mg/d (400 mg twice daily) versus 400 mg/d in patients with newly diagnosed chronic myeloid leukemia in chronic phase. Patients and Methods A total of 476 patients were randomly assigned 2:1 to imatinib 800 mg (n = 319) or 400 mg (n = 157) daily. The primary end point was the major molecular response (MMR) rate at 12 months. Results At 12 months, differences in MMR and complete cytogenetic response (CCyR) rates were not statistically significant (MMR, 46% v 40%; P = .2035; CCyR, 70% v 66%; P = .3470). However, MMR occurred faster among patients randomly assigned to imatinib 800 mg/d, who had higher rates of MMR at 3 and 6 months compared with those in the imatinib 400-mg/d arm (P = .0035 by log-rank test). CCyR also occurred faster in the 800-mg/d arm (CCyR at 6 months, 57% v 45%; P = .0146). The most common adverse events were edema, gastrointestinal problems, and rash, and all were more common in patients in the 800-mg/d arm. Grades 3 to 4 hematologic toxicity also occurred more frequently in patients receiving imatinib 800 mg/d. Conclusion MMR rates at 1 year were similar with imatinib 800 mg/d and 400 mg/d, but MMR and CCyR occurred earlier in patients treated with 800 mg/d. Continued follow-up is needed to determine the clinical significance of earlier responses on high-dose imatinib. PMID:20008622

  16. Prevalence of intestinal protozoa infection among school-aged children on Pemba Island, Tanzania, and effect of single-dose albendazole, nitazoxanide and albendazole-nitazoxanide

    PubMed Central

    2013-01-01

    Background Pathogenic intestinal protozoa infections are common in school-aged children in the developing world and they are frequently associated with malabsorption syndromes and gastrointestinal morbidity. Since diagnosis of these parasites is difficult, prevalence data on intestinal protozoa is scarce. Methods We collected two stool samples from school-aged children on Pemba Island, Tanzania, as part of a randomized controlled trial before and 3 weeks after treatment with (i) single-dose albendazole (400 mg); (ii) single-dose nitazoxanide (1,000 mg); (iii) nitazoxanide-albendazole combination (1,000 mg–400 mg), with each drug given separately on two consecutive days; and (iv) placebo. Formalin-fixed stool samples were examined for the presence of intestinal protozoa using an ether-concentration method to determine the prevalence and estimate cure rates (CRs). Results Almost half (48.7%) of the children were diagnosed with at least one of the (potentially) pathogenic protozoa Giardia intestinalis, Entamoeba histolytica/E. dispar and Blastocystis hominis. Observed CRs were high for all treatment arms, including placebo. Nitazoxanide showed a significant effect compared to placebo against the non-pathogenic protozoon Entamoeba coli. Conclusions Intestinal protozoa infections might be of substantial health relevance even in settings where they are not considered as a health problem. Examination of a single stool sample with the ether-concentration method lacks sensitivity for the diagnosis of intestinal protozoa, and hence, care is indicated when interpreting prevalence estimates and treatment effects. PMID:23289920

  17. Safety and efficacy of switching to nilotinib 400 mg twice daily for patients with chronic myeloid leukemia in chronic phase with suboptimal response or failure on front-line imatinib or nilotinib 300 mg twice daily

    PubMed Central

    Hughes, Timothy P.; Hochhaus, Andreas; Kantarjian, Hagop M.; Cervantes, Francisco; Guilhot, François; Niederwieser, Dietger; le Coutre, Philipp D.; Rosti, Gianantonio; Ossenkoppele, Gert; Lobo, Clarisse; Shibayama, Hirohiko; Fan, Xiaolin; Menssen, Hans D.; Kemp, Charisse; Larson, Richard A.; Saglio, Giuseppe

    2014-01-01

    In a randomized, phase III trial of nilotinib versus imatinib in patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase, more patients had suboptimal response or treatment failure on front-line imatinib than on nilotinib. Patients with suboptimal response/treatment failure on imatinib 400 mg once or twice daily or nilotinib 300 mg twice daily could enter an extension study to receive nilotinib 400 mg twice daily. After a 19-month median follow up, the safety profile of nilotinib 400 mg twice daily in patients switching from imatinib (n=35) was consistent with previous reports, and few new adverse events occurred in patients escalating from nilotinib 300 mg twice daily (n=19). Of patients previously treated with imatinib or nilotinib 300 mg twice daily, respectively, 15 of 26 (58%) and 2 of 6 (33%) without complete cytogenetic response at extension study entry, and 11 of 34 (32%) and 7 of 18 (39%) without major molecular response at extension study entry, achieved these responses at any time on nilotinib 400 mg twice daily. Estimated 18-month rates of freedom from progression and overall survival after entering the extension study were lower for patients switched from imatinib (85% and 87%, respectively) versus nilotinib 300 mg twice daily (95% and 94%, respectively). Nilotinib dose escalation was generally well tolerated and improved responses in about one-third of patients with suboptimal response/treatment failure. Switch to nilotinib improved responses in some patients with suboptimal response/treatment failure on imatinib, but many did not achieve complete cytogenetic response (clinicaltrials.gov identifiers:00718263, 00471497 - extension). PMID:24532039

  18. Safety and efficacy of switching to nilotinib 400 mg twice daily for patients with chronic myeloid leukemia in chronic phase with suboptimal response or failure on front-line imatinib or nilotinib 300 mg twice daily.

    PubMed

    Hughes, Timothy P; Hochhaus, Andreas; Kantarjian, Hagop M; Cervantes, Francisco; Guilhot, François; Niederwieser, Dietger; le Coutre, Philipp D; Rosti, Gianantonio; Ossenkoppele, Gert; Lobo, Clarisse; Shibayama, Hirohiko; Fan, Xiaolin; Menssen, Hans D; Kemp, Charisse; Larson, Richard A; Saglio, Giuseppe

    2014-07-01

    In a randomized, phase III trial of nilotinib versus imatinib in patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase, more patients had suboptimal response or treatment failure on front-line imatinib than on nilotinib. Patients with suboptimal response/treatment failure on imatinib 400 mg once or twice daily or nilotinib 300 mg twice daily could enter an extension study to receive nilotinib 400 mg twice daily. After a 19-month median follow up, the safety profile of nilotinib 400 mg twice daily in patients switching from imatinib (n=35) was consistent with previous reports, and few new adverse events occurred in patients escalating from nilotinib 300 mg twice daily (n=19). Of patients previously treated with imatinib or nilotinib 300 mg twice daily, respectively, 15 of 26 (58%) and 2 of 6 (33%) without complete cytogenetic response at extension study entry, and 11 of 34 (32%) and 7 of 18 (39%) without major molecular response at extension study entry, achieved these responses at any time on nilotinib 400 mg twice daily. Estimated 18-month rates of freedom from progression and overall survival after entering the extension study were lower for patients switched from imatinib (85% and 87%, respectively) versus nilotinib 300 mg twice daily (95% and 94%, respectively). Nilotinib dose escalation was generally well tolerated and improved responses in about one-third of patients with suboptimal response/treatment failure. Switch to nilotinib improved responses in some patients with suboptimal response/treatment failure on imatinib, but many did not achieve complete cytogenetic response (clinicaltrials.gov identifiers: 00718263, 00471497 - extension).

  19. Single dose dipyrone for acute postoperative pain

    PubMed Central

    Derry, Sheena; Faura, Clara; Edwards, Jayne; McQuay, Henry J; Moore, R Andrew

    2014-01-01

    Background Dipyrone (metamizole) is a non-steroidal anti-inflammatory drug used in some countries to treat pain (postoperative, colic, cancer, and migraine); it is banned in others because of an association with life-threatening blood agranulocytosis. This review updates a 2001 Cochrane review, and no relevant new studies were identified, but additional outcomes were sought. Objectives To assess the efficacy and adverse events of single dose dipyrone in acute postoperative pain. Search methods The earlier review searched CENTRAL, MEDLINE, EMBASE, LILACS and the Oxford Pain Relief Database to December 1999. For the update we searched CENTRAL, MEDLINE,EMBASE and LILACS to February 2010. Selection criteria Single dose, randomised, double-blind, placebo or active controlled trials of dipyrone for relief of established moderate to severe postoperative pain in adults. We included oral, rectal, intramuscular or intravenous administration of study drugs. Data collection and analysis Studies were assessed for methodological quality and data extracted by two review authors independently. Summed total pain relief over six hours (TOTPAR) was used to calculate the number of participants achieving at least 50% pain relief. Derived results were used to calculate, with 95% confidence intervals, relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over six hours. Use and time to use of rescue medication were additional measures of efficacy. Information on adverse events and withdrawals was collected. Main results Fifteen studies tested mainly 500 mg oral dipyrone (173 participants), 2.5 g intravenous dipyrone (101), 2.5 g intramuscular dipyrone (99); fewer than 60 participants received any other dose. All studies used active controls (ibuprofen, paracetamol, aspirin, flurbiprofen, ketoprofen, dexketoprofen, ketorolac, pethidine, tramadol, suprofen); eight used placebo controls. Over 70% of participants

  20. Single dose regorafenib-induced hypertensive crisis.

    PubMed

    Yilmaz, B; Kemal, Y; Teker, F; Kut, E; Demirag, G; Yucel, I

    2014-06-01

    Gastrointestinal stromal tumors (GISTs) are uncommon tumors of the gastrointestinal (GI) tract. Regorafenib is a new multikinase inhibitor and is approved for the treatment of GISTs in patients who develop resistance to imatinib and sunitinib. The most common drug-related adverse events with regorafenib are hypertension, hand-foot skin reactions, and diarrhea. Grade IV hypertensive side effect has never been reported after a single dose. In this report, we present a case of Grade IV hypertensive side effect (hypertensive crisis and seizure) after a single dose of regorafenib. A 54-year-old male normotensive GIST patient was admitted to the emergency department with seizure and encephalopathy after the first dosage of regorafenib. His blood pressure was 240/140 mmHg upon admission. After intensive treatment with nitrate and nitroprusside, his blood pressure returned to normal levels in five days. Regorafenib was discontinued, and he did not experience hypertension again. This paper reports the first case of Grade IV hypertension after the first dosage of regorafenib. We can suggest that hypertension is an idiosyncratic side effect unrelated to the dosage.

  1. Evaluation of albendazole, pyrantel, bephenium, pyrantel-praziquantel and pyrantel-bephenium for single-dose mass treatment of necatoriasis.

    PubMed

    Nahmias, J; Kennet, R; Goldsmith, R; Greenberg, Z

    1989-12-01

    An effective drug for single-dose mass treatment of necatoriasis was sought by testing three drugs and two drug combinations in Ethiopian immigrants to Israel found to have light infections. The drugs tested sequentially in single-doses were pyrantel pamoate (20 mg kg-1, 81 subjects); bephenium hydroxynaphthoate (2.5-5 g, 65 subjects); combined pyrantel and bephenium (25 subjects); combined pyrantel (20 mg kg-1) and praziquantel (40 mg kg-1) (16 subjects); and albendazole (400 mg, 77 subjects). Follow-up under conditions without likelihood of reinfection was by one stool examination. Cure rates with albendazole, pyrantel-bephenium and pyrantel-praziquantel were 84, 80 and 81% respectively; these rates were significantly higher than the 49% found for bephenium and the 51% for pyrantel (P less than 0.05). Egg reductions in those not cured were pyrantel (22%), bephenium (6%), pyrantel-bephenium (34%), pyrantel-praziquantel (3%) and albendazole (6%). Albendazole was the most promising single drug treatment; unexpected was the high effectiveness of pyrantel-praziquantel in combination. PMID:2619378

  2. The pharmacokinetics of once-daily oral 400 mg ofloxacin in patients with peritonitis complicating continuous ambulatory peritoneal dialysis.

    PubMed

    McMullin, C M; Brown, N M; Brown, I M; Tomson, C R; White, L O; Reeves, D S; MacGown, A P

    1997-06-01

    Seven patients with end-stage renal disease requiring support by continuous ambulatory peritoneal dialysis received once-daily 400 mg oral ofloxacin for 7 days for the treatment of bacterial peritonitis. Serum and peritoneal dialysis fluid (PDF) were collected for assay throughout the course of the study and for 5 days thereafter. Ofloxacin, desmethyl ofloxacin and ofloxacin-N-oxide accumulated over the course of therapy and could still be detected in serum and PDF 5 days after the end of therapy. The mean elimination half-life of ofloxacin in serum was 32 +/- 7 h, desmethyl ofloxacin 45 +/- 26 h and for ofloxacin-N-oxide 44 +/- 15 h. The total mean recovery of ofloxacin and its metabolites from the PDF was 15.4%. This regimen results in serum and PDF concentrations likely to be effective for the treatment of infection for at least 10 days.

  3. Single dose oral naproxen and naproxen sodium for acute postoperative pain (Review)

    PubMed Central

    Mason, L; Edwards, JE; Moore, RA; McQuay, HJ

    2014-01-01

    Background Postoperative pain is often poorly managed. Treatment options include a range of drug therapies such as non-steroidal anti-inflammatory drugs (NSAIDs) of which naproxen is one. Naproxen is used to treat a variety of painful conditions including acute postoperative pain, and is often combined with sodium to improve its solubility for oral administration. Naproxen sodium 550 mg (equivalent to 500 mg of naproxen) is considered to be an effective dose for treating postoperative pain but to date no systematic review of the effectiveness of naproxen/naproxen sodium at different doses has been published. Objectives To assess the efficacy, safety and duration of action of a single oral dose of naproxen or naproxen sodium for acute postoperative pain in adults. Search strategy We searched The Cochrane Library, MEDLINE, EMBASE and the Oxford Pain Relief Database for relevant studies. Additional studies were identified from the reference list of retrieved reports. The most recent search was undertaken in July 2004. Selection criteria Included studies were randomised, double blind, placebo-controlled trials of a single dose of orally administered naproxen or naproxen sodium in adults with moderate to severe acute postoperative pain. Data collection and analysis Pain relief or pain intensity data were extracted and converted into dichotomous information to give the number of patients with at least 50% pain relief over four to six hours. Relative risk estimates (RR) and the number-needed-to-treat (NNT) for at least 50% pain relief were then calculated. Information was sought on the percentage of patients experiencing any adverse event, and the number-needed-to-harm was derived. Time to remedication was also estimated. Main results Ten trials (996 patients) met the inclusion criteria: nine assessed naproxen sodium; one combined the results from two small trials of naproxen alone. Included studies scored well for methodological quality. Meta-analysis of six trials (500

  4. Effect of single-dose albendazole and vitamin A supplementation on the iron status of pre-school children in Sichuan, China.

    PubMed

    Chen, Ke; Xie, Hu Mina; Tian, Weizheng; Zheng, Xiaoling; Jiang, Alice C

    2016-04-01

    The aim of this study was to explore the effect of single-dose albendazole and vitamin A intervention on the anaemic status and Fe metabolism of pre-school children. This study was a randomised, placebo-controlled and double-blinded intervention trial. All eligible anaemic pre-school children were randomly divided into three groups: group 1 received no intervention, which served as the control group, group 2 received 400 mg single-dose albendazole administration and group 3 received a 60000 μg vitamin A capsule combined with 400 mg single-dose albendazole at the beginning of the study. The follow-up period was for 6 months. Anthropometry and biochemical index about Fe metabolism were measured before and after intervention. A total of 209 pre-school anaemic children were randomly divided into three intervention groups (sixty-four, sixty-two and sixty for groups 1, 2 and 3, respectively). The mean age of the children in the study was 4·4 (sd 0·7) years and 50·5 % of the children were female (94/186). After a follow-up period of 6 months, the levels of serum retinol, ferritin, transferrin receptor-ferritin index and body total Fe content of children in group 3 were significantly higher compared with children in groups 1 and 2 (P<0·05). Moreover, the proportion of vitamin A deficiency, marginal vitamin A deficiency and Fe deficiency among children in group 3 were markedly lower compared with children in groups 1 and 2 (P<0·05). Albendazole plus vitamin A administration showed more efficacy on the improvement of serum retinol and Fe metabolic status.

  5. A Phase 1, Randomized, Single-Dose Crossover Pharmacokinetic Study to Investigate the Effect of Food Intake on Absorption of Orteronel (TAK-700) in Healthy Male Subjects.

    PubMed

    Suri, Ajit; Pham, Theresa; MacLean, David B

    2016-05-01

    This study aimed to determine the impact of food on the pharmacokinetics of orteronel, an investigational nonsteroidal, reversible selective inhibitor of 17,20-lyase. In this open-label, randomized crossover study, healthy subjects received single doses of orteronel 400 mg with a low-fat meal, a high-fat meal, and under fasting conditions in a randomized sequence. Plasma concentrations of orteronel and its primary M-I metabolite were determined by ultra-performance liquid chromatography, and pharmacokinetic parameters were evaluated using mixed-effects analysis of variance model. Compared with fasting conditions, the oral bioavailability of orteronel was increased under fed conditions. The least-squares mean ratio for area under the plasma concentration-time curve after a low-fat breakfast was 135% (90% confidence interval [CI], 126%-145%) compared with fasting conditions. Similarly, after a high-fat breakfast, the corresponding value was 142% (90%CI, 132%-152%). No unexpected safety concerns were raised with orteronel 400 mg administered in the fasted state or after either a high-fat or a low-fat meal; mild adverse events were experienced by 36% of the healthy male subjects. PMID:27163497

  6. Efficacy of single and double doses of albendazole and mebendazole alone and in combination in the treatment of Trichuris trichiura in school-age children in Uganda.

    PubMed

    Namwanje, Harriet; Kabatereine, Narcis B; Olsen, Annette

    2011-10-01

    A randomised clinical trial was conducted in Kabale District, southwestern Uganda, to compare the efficacies of single and double doses of a combination of 400mg albendazole (ALB) and 500mg mebendazole (MBZ) with those of single and double doses of each drug given alone in the treatment of Trichuris trichiura. Infected pupils (n=611) were randomised to six treatment groups. Three groups received either a single dose of ALB, MBZ or the combination (ALB+MBZ). The other three groups received either a double dose of ALB (ALB/ALB), MBZ (MBZ/MBZ) or the combination (ALB+MBZ/ALB+MBZ). All double doses were given 8h apart. Children were followed-up weekly for 1 month. Cure rates were significantly higher using double doses compared with single doses (irrespective of drug; z=-4.02, P<0.0005) as well as using the drug combination compared with single drugs (irrespective of doses; z=-7.64, P<0.0005). Cure rates measured at Day 7 were significantly higher than on Days 14 and 21 after treatment (Day 14, z=9.90, P<0.0005; Day 21, z=7.36, P<0.0005). Geometric mean (GM) intensities of positives were significantly lower on Day 7 compared with all other subsequent days (P<0.00005), and on Day 28 GM intensities reached pre-treatment levels (P=0.096). Whilst there was no difference in egg excretion between single and double doses of the same drug or drug combination (F((df)(1))=0.28, P=0.60), the combination treatment resulted in lower egg excretion than use of single drugs (F((df)(2))=50.90, P<0.00005). All the tested regimens of ALB and MBZ had low cure rates against T. trichiura in Uganda, but both combination treatments showed satisfactory egg reduction rates 3 weeks after treatment.

  7. Single- and multiple-dose pharmacokinetics of biphasic immediate-release/extended-release hydrocodone bitartrate/acetaminophen (MNK-155) compared with immediate-release hydrocodone bitartrate/ibuprofen and immediate-release tramadol HCl/acetaminophen

    PubMed Central

    Devarakonda, Krishna; Kostenbader, Kenneth; Giuliani, Michael J; Young, Jim L

    2015-01-01

    Objective To characterize the single-dose and steady-state pharmacokinetics (PK) of biphasic immediate-release/extended-release hydrocodone bitartrate/acetaminophen (IR/ER HB/APAP), IR HB/ibuprofen, and IR tramadol HCl/APAP. Methods In this single-center, open-label, randomized, four-period crossover study, healthy participants received four treatments under fasted conditions: 1) a single dose of two IR/ER HB/APAP 7.5/325 mg tablets (15/650 mg total dose) on day 1, followed by two tablets every 12 hours (q12h) beginning on day 3; 2) a single dose of IR HB/ibuprofen 15/400 mg (divided as one 7.5/200 mg tablet at hour 0 and 6), followed by one tablet every 6 hours (q6h) beginning on day 3; 3) a single dose of IR tramadol HCl/APAP 75/650 mg (divided as one 37.5/325 mg tablet at hour 0 and 6), followed by one tablet q6h beginning on day 3; and 4) a single dose of three IR/ER HB/APAP 7.5/325 mg tablets (22.5/975 mg total dose) on day 1, a three-tablet initial dose at 48 hours followed by two-tablet doses q12h beginning on day 3. Hydrocodone and APAP single-dose and steady-state PK were assessed. Adverse events were monitored. Results The PK analysis was carried out on 29 of 48 enrolled participants who completed all treatment periods. Single-dose hydrocodone exposure was similar for IR/ER HB/APAP 22.5/975 mg and IR HB/ibuprofen 15/400 mg; time to maximum observed plasma concentration was shorter and half-life was longer for IR/ER HB/APAP (22.5/975 mg and 15/650 mg) vs IR HB/ibuprofen. Single-dose APAP exposure was similar for IR/ER HB/APAP 15/650 mg and IR tramadol HCl/APAP 75/650 mg. Steady-state hydrocodone and APAP exposures were similar between treatments. Adverse events were similar for each treatment and typical of low-dose combination opioid analgesics. With dosing q12h, IR/ER HB/APAP had half as many concentration peaks and troughs as the comparators treated q6h. Conclusion With dosing q12h, IR/ER HB/APAP provided similar peak and total steady-state hydrocodone

  8. Single dose NTBC-treatment of hereditary tyrosinemia type I.

    PubMed

    Schlune, A; Thimm, E; Herebian, D; Spiekerkoetter, U

    2012-09-01

    NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3cyclohexanedione) is the mainstay of treatment in tyrosinemia type 1 (HT 1). The current recommendation is to divide the total daily dose of NTBC into two doses. We monitored the plasma NTBC concentrations in a series of seven patients who were changed from multiple divided doses to a single daily dose of NTBC. Two additional patients were started on a single daily dose of NTBC after the diagnosis of HT 1 was established. In three patients, NTBC kinetics were performed over 6 and 24 hours, respectively. The use of multiple divided doses or a single daily dose did not significantly affect plasma NTBC concentrations or the mean daily dose needed to attain therapeutic plasma NTBC concentrations. Moreover, kinetic studies demonstrated that plasma NTBC concentrations were completely stable over a period of 24 hours with a single dose regimen, as expected given the known NTBC plasma half life of 54 hours. Although these preliminary results need to be confirmed in more patients, our findings show that administration of NTBC in a single daily dose may be as effective as a multiple-dose regimen in reaching therapeutic plasma NTBC concentrations and suppressing succinylacetone formation in patients with HT 1. In fact, single dose treatment may increase patients' compliance with the drug treatment and improve metabolic control.

  9. Single-dose intravenous gammaglobulin can stabilize neutrophil Mac-1 activation in sickle cell pain crisis

    PubMed Central

    Manwani, Deepa; Chen, Grace; Carullo, Veronica; Serban, Stelian; Olowokure, Olugbenga; Jang, Jungeun; Huggins, Matthew; Cohen, Hillel W.; Billett, Henny; Atweh, George F.; Frenette, Paul S.; Shi, Patricia A.

    2015-01-01

    Intravenous immunoglobulin (IVIG) decreases neutrophil adhesion to endothelium and red blood cell-neutrophil interactions in sickle cell mice undergoing vaso-occlusion. In this Phase I clinical trial of sickle cell anemia (SCA) patients admitted with pain crisis, we evaluated the status of adhesion molecules on neutrophils in control and IVIG-treated subjects pre- and post-infusion up to 800 mg/kg, the same dose used in murine studies. Mac-1 function significantly decreased from baseline in the low-dose IVIG (200–400 mg/kg) cohorts. IVIG-related adverse events may have occurred in the high-dose (600–800 mg/kg) cohorts. There were no significant increases in neutrophil and leukocyte counts, suggesting that IVIG may more selectively inhibit Mac-1 function as opposed to neutrophil adhesion. This study provides the first in-human validation of pre-clinical murine studies that IVIG can decrease Mac-1 function. PMID:25616042

  10. Single-dose versus multi-dose vaccine vials for immunization programmes in developing countries.

    PubMed Central

    Drain, Paul K.; Nelson, Carib M.; Lloyd, John S.

    2003-01-01

    Excessive vaccine wastage and safety concerns have prompted the international health community to develop and supply vaccines in formats other than the standard multi-dose vial. This article presents a programmatic and economic comparison of the major differences between the multi-dose vials and single-dose formats used for immunization services in developing countries. Multi-dose vials, in general, sell at a lower per-dose price and occupy less cold-chain capacity than single-dose formats. However, higher wastage rates may offset these benefits, especially for more expensive vaccines. Single-dose formats offer several important programmatic benefits, such as increased vaccination opportunities and improved vaccine safety. One single-dose format, the prefilled auto-disable (AD) device, provides additional injection safety and convenience features because it physically combines the vaccine and AD syringe. Selecting the appropriate vaccine presentation will depend on many factors. However, multi-dose vials are likely to be most appropriate for cheaper vaccines and in settings where cold-chain storage capacity is restricted. Single-dose formats will be most appropriate for more expensive vaccines and where there are problems with unsafe injection practices. Prefilled AD injection devices will be particularly useful in expanding outreach services while eliminating the possibility of needle reuse. PMID:14758432

  11. Seroconversion status after single dose and double doses of varicella vaccination in children with leukemia.

    PubMed

    Cakir, F Betul; Timur, Cetin; Yoruk, Asim; Cakir, Erkan; Ayhan, Aylin Canbolat

    2012-03-01

    Although varicella is a benign self-limiting disease in healthy children, it can be fatal when it occurs in immunocompromised hosts. Despite that immunosuppressed children are suggested to require 2 doses of vaccine to achieve seroconversion, conflicting results are reported in the literature. The aim of this study was to investigate the seroconversion status and mean antibody titers at first year after single dose and double doses of varicella vaccination in acute lymphoblastic leukemia patients. Patients with leukemia in remission for at least 1 year who were seronegative for varicella-zoster virus immunoglobulin G (IgG) were vaccinated. Titers above the cutoff level (0.65) were accepted as seroconversion. Seventeen patients were vaccinated with single dose whereas 24 patients were vaccinated with double doses. Mean prevaccination antibody titers were 0.56 ± 0.05 in patients with single dose and 0.51 ± 0.08 in patients with double doses (P > .05, Student t test). The mean antibody titers at first year were 0.61 ± 0.05 in patients with single-dose vaccination (P > .05, Wilcoxon signed-rank test) and 1.48 ± 0.04 in patients with double doses (P < .001, Wilcoxon signed-rank test). Seroconversion after single-dose vaccination was achieved in 29% of patients (n = 5/17) and in 75% of patients with double doses (n = 18/24) at first year (P = .004, chi-square test). These results suggest that seroconversion after single-dose vaccination might not persist at first year in malignancy patients. Double doses should be applied in order to provide long-term seroconversion.

  12. Effect of steady-state enoxacin on single-dose pharmacokinetics of roflumilast and roflumilast N-oxide.

    PubMed

    Lahu, Gezim; Nassr, Nassr; Herzog, Rolf; Elmlinger, Martin; Ruth, Peter; Hinder, Markus; Huennemeyer, Andreas

    2011-04-01

    Roflumilast is an oral phosphodiesterase 4 (PDE4) inhibitor for the treatment of chronic obstructive pulmonary disease (COPD). It is metabolized by CYP1A2 and CYP3A4 to its primary metabolite, roflumilast N-oxide, through which >90% total PDE4 inhibitory activity (tPDE4i) is mediated. Fluoroquinolones, of which enoxacin is the most potent CYP1A2 inhibitor, are used to treat COPD exacerbations. This phase I, open, nonrandomized, fixed-sequence, 2-period study evaluated the effects of steady-state enoxacin on the single-dose pharmacokinetics of roflumilast and roflumilast N-oxide. Twenty healthy participants received roflumilast, 500 µg once daily, on days 1 and 12, and enoxacin, 400 mg twice daily, on days 7 to 18. Pharmacokinetic profiles were obtained for days 1 to 6 and 12 to 19. The safety and tolerability of all treatments were also assessed. In 19 evaluable participants, coadministration led to 56% higher mean systemic exposure, 20% higher mean peak concentrations, and 36% lower mean apparent oral clearance compared with roflumilast alone. For roflumilast N-oxide, 23% higher mean systemic exposure and 14% lower mean peak concentrations were seen after coadministration. Roflumilast was well tolerated both alone and in combination with enoxacin. A weak interaction was shown between roflumilast and enoxacin, as mean tPDE4i increased by 25%, but is unlikely to have clinical relevance.

  13. Single-dose oral fluconazole versus topical clotrimazole in patients with pityriasis versicolor: A double-blind randomized controlled trial.

    PubMed

    Dehghan, Mohammad; Akbari, Negin; Alborzi, Nazila; Sadani, Somayeh; Keshtkar, Abas A

    2010-08-01

    This study was designed to compare the therapeutic effects of topical clotrimazole and systemic fluconazole in pityriasis versicolor. A double-blind randomized controlled trial was carried out in the dermatological clinic of Gorgan, northern Iran, between April 2006 and May 2007. All consecutive patients with pityriasis versicolor were included and randomly divided into two groups. In the first group (G1), patients underwent treatment with a single dose of fluconazole capsule (400 mg) and placebo cream. In the second group (G2), patients underwent treatment with clotrimazole cream (twice daily) and placebo capsule. The course of treatment was 2 weeks. All subjects were re-evaluated 2, 4 and 12 weeks after the end of the therapeutic course. After 2 weeks, the rate of complete resolution of disease was significantly higher in G2 than G1 (49.1% vs 30%). After 4 weeks, 41 patients (81.2%) of G1 and 52 patients (94.9%) of G2 showed complete resolution. After 12 weeks, 46 patients (92%) in G1 and 45 patients (81.8%) in G2 showed complete resolution. Recurrence rate in G1 and G2 were 6% and 18.2%, respectively. No complications were seen in either group. In this study, clinical response at week 4 was greater in the clotrimazole group than the fluconazole group. Recurrence at week 12 after treatment was less with oral fluconazole than clotrimazole cream. So, for better evaluation, more studies need to be done.

  14. Flurbiprofen interaction with single doses of atenolol and propranolol.

    PubMed Central

    Webster, J; Petrie, J C; McLean, I; Hawksworth, G M

    1984-01-01

    In patients with mild hypertension, flurbiprofen in a dose of 100 mg daily for 7 days attenuated the hypotensive effect of a single dose of propranolol 80 mg but not of atenolol 100 mg. The attenuation was not due to an effect on the pharmacokinetic profile of either propranolol or atenolol. An alternative explanation is required. PMID:6529525

  15. IMATINIB 800MG DAILY INDUCES DEEPER MOLECULAR RESPONSES THAN IMATINIB 400MG DAILY: RESULTS OF SWOG S0325, AN INTERGROUP RANDOMIZED PHASE II TRIAL IN NEWLY DIAGNOSED CHRONIC PHASE CHRONIC MYELOID LEUKAEMIA

    PubMed Central

    Deininger, Michael W.; Kopecky, Kenneth J.; Radich, Jerald P.; Kamel-Reid, Suzanne; Stock, Wendy; Paietta, Elisabeth; Emanuel, Peter D.; Tallman, Martin; Wadleigh, Martha; Larson, Richard A.; Lipton, Jeffrey H.; Slovak, Marilyn L.; Appelbaum, Frederick R.; Druker, Brian J.

    2014-01-01

    The standard dose of imatinib for newly diagnosed patients with chronic phase chronic myeloid leukemia (CP-CML) is 400mg daily (IM400), but the optimal dose is unknown. This randomized phase II study compared the rates of molecular, haematologic and cytogenetic response to IM400 vs. imatinib 400mg twice daily (IM800) in 153 adult patients with CP-CML. Dose adjustments for toxicity were flexible to maximize retention on study. Molecular response (MR) at 12 months was deeper in the IM800 arm (4-log reduction of BCR-ABL1 mRNA: 25% vs. 10% of patients, P=0.038; 3-log reduction: 53% vs. 35%, P=0.049). During the first 12 months BCR-ABL1 levels in the IM800 arm were an average 2.9-fold lower than in the IM400 arm (P=0.010). Complete haematologic response was similar, but complete cytogenetic response was higher with IM800 (85% vs. 67%, P=0.040). Grade 3–4 toxicities were more common for IM800 (58% vs. 31%, P=0.0007), and were most commonly haematologic. Few patients have relapsed, progressed or died, but progression-free (P=0.048) and relapse-free (P=0.031) survival were superior for IM800. In newly diagnosed CP-CML patients, IM800 induced deeper molecular responses than IM400, with a trend for improved progression-free and overall survival, but was associated with more severe toxicity. PMID:24383843

  16. Minimum effective doses of mebendazole in treatment of soil-transmitted helminths.

    PubMed

    Nontasut, P; Waikagul, J; Muennoo, C; Sanguankait, S; Nuamtanong, S; Maipanich, W

    1997-06-01

    Three hundred and fifteen primary school children infected with soil-transmitted helminths were divided into 5 groups. Three groups were treated with 25, 50 and 75 mg mebendazole (MBZ) single dose. One group was given MBZ conventional dose of 100 mg twice daily for 3 days and another group was given albendazole (ABZ) standard dose of 400 mg single dose. Every trial lower MBZ dose 75 mg, 50 mg and 25 mg regimen were highly effective against Ascaris lumbricoides but only moderately effective against Trichuris trichiura and Necator americanus.

  17. Single-dose oral guanidinoacetic acid exhibits dose-dependent pharmacokinetics in healthy volunteers.

    PubMed

    Ostojic, Sergej M; Vojvodic-Ostojic, Aleksandra

    2015-03-01

    Guanidinoacetic acid (GAA), the natural precursor of creatine, has potential as a dietary supplement for human nutrition, yet no data are available regarding its dose-dependent pharmacokinetic (PK) behavior. We hypothesized that a single dose of orally administered GAA exhibited dose-dependent PK behavior in healthy volunteers. Forty-eight young adults were enrolled in a randomized, placebo-controlled, double-blind, parallel-group trial to receive single oral doses of GAA (1.2, 2.4, and 4.8 g) or a placebo. Pharmacokinetic metrics for plasma GAA and creatine were assessed immediately before (0 hours) and at 1, 2, 4, 6, 8, 12, and 24 hours after GAA ingestion. The lag time appeared to be similar after the bolus ingestion of GAA (0.14 ± 0.17 hours for low-dose GAA, 0.31 ± 0.18 hours for medium-dose GAA, and 0.38 ± 0.32 hours for high-dose GAA; P = .05). An increase in the area under the concentration-time curve for plasma GAA was found for the dose range tested, with 2.4- and 9.3-fold increases in the area under the concentration-time curve for every 2-fold increase in the GAA dose (P < .0001). No differences were found for elimination half-time between the low-dose and medium-dose groups (<1.75 hours), whereas the elimination half-time was significantly longer (>2.1 hours) for the high-dose GAA regimen (P = .001). The volume of distribution was affected by the dosage of GAA applied (102.6 ± 17.3 L for low-dose GAA, 97.5 ± 15.7 L for medium-dose GAA, and 61.1 ± 12.7 L for high-dose GAA; P < .0001). Ingestion of GAA elevated plasma creatine by 80%, 116%, and 293% compared with the placebo for the 1.2, 2.4, and 4.8 g doses, respectively (P < .0001). Guanidinoacetic acid single-dose PK metrics were nonlinear with respect to dose size. Across the dose range of 1.2 to 4.8 g, systemic exposure to GAA increased in a greater than dose-proportional manner. PMID:25622538

  18. Prolonged and symptomatic bradycardia following a single dose of fingolimod.

    PubMed

    Faber, Hans; Fischer, Hans-Jörg; Weber, Frank

    2013-01-01

    Fingolimod-related bradycardia is usually asymptomatic, reaches its nadir within 6 hours post-dose and recovers spontaneously. Here we report the case of a 30-year-old MS patient with vagotonia who developed symptomatic bradycardia with 33 beats per minute at nadir 39 hours after a single dose of fingolimod. Bradycardia was responsive to atropine, but returned within 2 hours. Overall, it took a week until the patient recovered. Extended monitoring is advised in patients with symptomatic bradycardia.

  19. No negative symptoms in healthy volunteers after single doses of amisulpride, aripiprazole, and haloperidol: a double-blind placebo-controlled trial.

    PubMed

    Park, Chul-Hyun; Park, Tae-Won; Yang, Jong-Chul; Lee, Keon-Hak; Huang, Guang-Biao; Tong, Zhao; Park, Myung-Sook; Chung, Young-Chul

    2012-03-01

    Noncompliance and poor outcome in patients with schizophrenia are closely related to the negative symptoms secondary to antipsychotics. No controlled study has evaluated whether amisulpride and aripiprazole induce negative symptoms. The aim of this study was to assess the effects of single doses of amisulpride, aripiprazole, haloperidol, and risperidone in healthy volunteers. Seventy-eight young volunteers took part in this double-blind, randomized, placebo-controlled, parallel study of four antipsychotics: 400 mg amisulpride, 10 mg aripiprazole, 3 mg haloperidol, and 2 mg risperidone. Assessments of negative symptoms were done 4 h after administration using both subjective rating scales (Neuroleptic Induced Deficit Syndrome Scale and Subjective Deficit Syndrome Scale) and an objective rating scale (Scale for the Assessment of Negative Symptoms). Risperidone only produced significant increases on the avolition score of the Neuroleptic Induced Deficit Syndrome Scale and blunted affect and alogia scores of the Scale for the Assessment of Negative Symptoms compared with placebo. The effect on blunted affect persisted after controlling for mental sedation. Amisulpride, aripiprazole, and haloperidol did not induce negative symptoms. Aripiprazole and risperidone induced mild extrapyramidal symptoms. The most common adverse events were somnolence and cognitive slowing. These data indicate that a single risperidone dose induces negative symptoms in normal volunteers, whereas amisulpride, aripiprazole, and haloperidol do not. These characteristics of antipsychotics should be considered when choosing optimal drugs for patients with psychosis.

  20. The Global Programme to Eliminate Lymphatic Filariasis: History and achievements with special reference to annual single-dose treatment with diethylcarbamazine in Samoa and Fiji.

    PubMed

    Kimura, Eisaku

    2011-03-01

    Samoa in relation to the annual single-dose MDAs revealed that low density mf carriers, who have a very low mf count of 1-20/ml of venous blood, could not play a significant role in filariasis transmission.From around 1990, studies on spaced low-dose DEC treatments and various types of combination chemotherapy with DEC and ivermectin increased. Albendazole, a well-known anti-intestinal helminths agent, was later added to the combination. The main findings of these studies with W. bancrofti are: (i) a single dose of DEC at 6 mg/kg reduced mean mf density by ca. 90% 1 year after treatment; (ii) the same dose could damage/kill adult worms; (iii) a single dose of ivermectin at ca. 400 µg/kg was more effective than DEC in reducing mf density during the first year and was similarly or less effective in the second year; (iv) ivermectin probably could not kill adult worms; (v) a single combined dose of albendazole (400 mg) and DEC (6 mg/kg) was effective to reduce mf density by 85 to nearly 100% 12-24 months after treatment; and (vi) ivermectin or albendazole included in the combination chemotherapy produced "beyond-filariasis" benefits: clearance/reduction of intestinal helminths, and, additionally, in the case of ivermectin, skin-dwelling ectoparasites.The Global Programme to Eliminate Lymphatic Filariasis (GPELF) started its worldwide activities in 2000, with the target of elimination by 2020. The basic strategy is to conduct annual single-dose MDAs for 4-6 years. In 2000-2007, a minimum of 570 million individuals were treated in 48 of 83 endemic countries. The drugs used are DEC 6 mg/kg plus albendazole 400 mg in most countries, or ivermectin 200-400 µg/kg plus albendazole 400 mg particularly in onchocerciasis endemic countries in Africa. (MDAs with DEC alone had been used in India.)The GPELF achieved impressive results in terms of parasitological cure/improvement, clinical benefits, social and economic impacts, etc. However, the most impressive result of all was the

  1. The Global Programme to Eliminate Lymphatic Filariasis: History and achievements with special reference to annual single-dose treatment with diethylcarbamazine in Samoa and Fiji

    PubMed Central

    Kimura, Eisaku

    2011-01-01

    Samoa in relation to the annual single-dose MDAs revealed that low density mf carriers, who have a very low mf count of 1-20/ml of venous blood, could not play a significant role in filariasis transmission. From around 1990, studies on spaced low-dose DEC treatments and various types of combination chemotherapy with DEC and ivermectin increased. Albendazole, a well-known anti-intestinal helminths agent, was later added to the combination. The main findings of these studies with W. bancrofti are: (i) a single dose of DEC at 6 mg/kg reduced mean mf density by ca. 90% 1 year after treatment; (ii) the same dose could damage/kill adult worms; (iii) a single dose of ivermectin at ca. 400 µg/kg was more effective than DEC in reducing mf density during the first year and was similarly or less effective in the second year; (iv) ivermectin probably could not kill adult worms; (v) a single combined dose of albendazole (400 mg) and DEC (6 mg/kg) was effective to reduce mf density by 85 to nearly 100% 12-24 months after treatment; and (vi) ivermectin or albendazole included in the combination chemotherapy produced “beyond-filariasis” benefits: clearance/reduction of intestinal helminths, and, additionally, in the case of ivermectin, skin-dwelling ectoparasites. The Global Programme to Eliminate Lymphatic Filariasis (GPELF) started its worldwide activities in 2000, with the target of elimination by 2020. The basic strategy is to conduct annual single-dose MDAs for 4-6 years. In 2000-2007, a minimum of 570 million individuals were treated in 48 of 83 endemic countries. The drugs used are DEC 6 mg/kg plus albendazole 400 mg in most countries, or ivermectin 200-400 µg/kg plus albendazole 400 mg particularly in onchocerciasis endemic countries in Africa. (MDAs with DEC alone had been used in India.) The GPELF achieved impressive results in terms of parasitological cure/improvement, clinical benefits, social and economic impacts, etc. However, the most impressive result of all was

  2. Replacing the measles ten-dose vaccine presentation with the single-dose presentation in Thailand.

    PubMed

    Lee, Bruce Y; Assi, Tina-Marie; Rookkapan, Korngamon; Connor, Diana L; Rajgopal, Jayant; Sornsrivichai, Vorasith; Brown, Shawn T; Welling, Joel S; Norman, Bryan A; Chen, Sheng-I; Bailey, Rachel R; Wiringa, Ann E; Wateska, Angela R; Jana, Anirban; Van Panhuis, Willem G; Burke, Donald S

    2011-05-12

    Introduced to minimize open vial wastage, single-dose vaccine vials require more storage space and therefore may affect vaccine supply chains (i.e., the series of steps and processes involved in distributing vaccines from manufacturers to patients). We developed a computational model of Thailand's Trang province vaccine supply chain to analyze the effects of switching from a ten-dose measles vaccine presentation to each of the following: a single-dose measles-mumps-rubella vaccine (which Thailand is currently considering) or a single-dose measles vaccine. While the Trang province vaccine supply chain would generally have enough storage and transport capacity to accommodate the switches, the added volume could push some locations' storage and transport space utilization close to their limits. Single-dose vaccines would allow for more precise ordering and decrease open vial waste, but decrease reserves for unanticipated demand. Moreover, the added disposal and administration costs could far outweigh the costs saved from preventing open vial wastage. PMID:21439313

  3. Antiretroviral Therapies in Women after Single-Dose Nevirapine Exposure

    PubMed Central

    Lockman, S.; Hughes, M.D.; McIntyre, J.; Zheng, Y.; Chipato, T.; Conradie, F.; Sawe, F.; Asmelash, A.; Hosseinipour, M.C.; Mohapi, L.; Stringer, E.; Mngqibisa, R.; Siika, A.; Atwine, D.; Hakim, J.; Shaffer, D.; Kanyama, C.; Wools-Kaloustian, K.; Salata, R.A.; Hogg, E.; Alston-Smith, B.; Walawander, A.; Purcelle-Smith, E.; Eshleman, S.; Rooney, J.; Rahim, S.; Mellors, J.W.; Schooley, R.T.; Currier, J.S.

    2010-01-01

    BACKGROUND Peripartum administration of single-dose nevirapine reduces mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) but selects for nevirapine-resistant virus. METHODS In seven African countries, women infected with HIV-1 whose CD4+ T-cell counts were below 200 per cubic millimeter and who either had or had not taken single-dose nevirapine at least 6 months before enrollment were randomly assigned to receive antiretroviral therapy with tenofovir–emtricitabine plus nevirapine or tenofovir-emtricitabine plus lopinavir boosted by a low dose of ritonavir. The primary end point was the time to confirmed virologic failure or death. RESULTS A total of 241 women who had been exposed to single-dose nevirapine began the study treatments (121 received nevirapine and 120 received ritonavir-boosted lopinavir). Significantly more women in the nevirapine group reached the primary end point than in the ritonavir-boosted lopinavir group (26% vs. 8%) (adjusted P = 0.001). Virologic failure occurred in 37 (28 in the nevirapine group and 9 in the ritonavir-boosted lopinavir group), and 5 died without prior virologic failure (4 in the nevirapine group and 1 in the ritonavir-boosted lopinavir group). The group differences appeared to decrease as the interval between single-dose nevirapine exposure and the start of antiretroviral therapy increased. Retrospective bulk sequencing of baseline plasma samples showed nevirapine resistance in 33 of 239 women tested (14%). Among 500 women without prior exposure to single-dose nevirapine, 34 of 249 in the nevirapine group (14%) and 36 of 251 in the ritonavir-boosted lopinavir group (14%) had virologic failure or died. CONCLUSIONS In women with prior exposure to peripartum single-dose nevirapine (but not in those without prior exposure), ritonavir-boosted lopinavir plus tenofovir–emtricitabine was superior to nevirapine plus tenofovir–emtricitabine for initial antiretroviral therapy. (Funded by the National

  4. Single-dose intrathecal analgesia to control labour pain

    PubMed Central

    Minty, R.G.; Kelly, Len; Minty, Alana; Hammett, D.C.

    2007-01-01

    OBJECTIVE To examine the safety and efficacy of single-dose spinal analgesia (intrathecal narcotics [ITN]) during labour. QUALITY OF EVIDENCE MEDLINE was searched and the references of 2 systematic reviews and a meta-analysis were reviewed to find articles on obstetric analgesia and pain measurement. The 33 articles selected included 14 studies, 1 meta-analysis, and 2 systematic reviews, all providing level I evidence. MAIN MESSAGE The literature supports use of ITN as a safe and effective alternative to epidural anesthesia. The recent decrease in rates of episiotomies and use of forceps during deliveries means patients require less dense perineal anesthesia. The advantageof single-dose ITN is that fewer physicians and nurses are needed to administer it even though its safety and effectiveness are comparable with other analgesics. Use of ITN is associated with a shorter first stage of labour and more rapid cervical dilation. A combination of 2.5 mg of bupivacaine, 25 μg of fentanyl, and 250 μg of morphine intrathecally usually provides a 4-hour window of acceptable analgesia for patients without complications not anticipating protracted labour. The evolution in dosing of ITN warrants a re-examination of its usefulness in modern obstetric practice. CONCLUSION Physicians practising modern obstetrics in rural and small urban centres might find single-dose ITN a useful alternative to parenteral or epidural analgesia for appropriately selected patients. PMID:17872679

  5. Single oral dose safety of D-allulose in dogs

    PubMed Central

    NISHII, Naohito; NOMIZO, Toru; TAKASHIMA, Satoshi; MATSUBARA, Tatsuya; TOKUDA, Masaaki; KITAGAWA, Hitoshi

    2016-01-01

    Healthy dogs were administered acute oral doses of D-allulose (also called D-psicose) to evaluate its toxicity. Six dogs received oral doses of either a placebo or D-allulose solution (1 and 4 g/kg) on three different study days. One dog experienced vomiting, and five dogs showed transient diarrhea when 4 g/kg of D-allulose was administered. All dogs were active and had a good appetite throughout the study period. Blood glucose concentration slightly decreased without a rise in plasma insulin concentration 2 hr after D-allulose administration. Plasma alkaline phosphatase activities showed a mild increase between 12 and 48 hr after D-allulose administration. These data suggested that a single oral dose of D-allulose does not show severe toxicity in dogs. PMID:26972334

  6. Single dose mebendazole therapy for soil-transmitted nematodes.

    PubMed

    Abadi, K

    1985-01-01

    Four hundred and fifty subjects were included in a study of the prevalence of soil-transmitted nematodes in Ujung Pandang, South-Sulawesi, Indonesia. Trichuriasis was the most prevalent infection (93.3%), followed by ascariasis (80.2%) and hookworm infection (19.5%). Among 156 subjects who were given 500 mg of mebendazole in a single dose, treatment resulted in cure rates of 93.4%, 77.6%, and 91.1%, and average egg-count reduction rates of 99.0%, 92.8%, and 98.3%, for ascariasis, trichuriasis, and hookworm infections, respectively. Mebendazole appeared to be equally effective against necatoriasis and ancylostomiasis. The drug was well tolerated and almost no side effects were observed. Single dose mebendazole treatment appears to be relatively inexpensive, convenient, and effective in mass treatment for the control of intestinal nematode infections, especially in highly infected communities.

  7. Single-Dose Radiation-Induced Oral Mucositis Mouse Model

    PubMed Central

    Maria, Osama Muhammad; Syme, Alasdair; Eliopoulos, Nicoletta; Muanza, Thierry

    2016-01-01

    The generation of a self-resolved radiation-induced oral mucositis (RIOM) mouse model using the highest possibly tolerable single ionizing radiation (RT) dose was needed in order to study RIOM management solutions. We used 10-week-old male BALB/c mice with average weight of 23 g for model production. Mice were treated with an orthovoltage X-ray irradiator to induce the RIOM ulceration at the intermolar eminence of the animal tongue. General anesthesia was injected intraperitoneally for proper animal immobilization during the procedure. Ten days after irradiation, a single RT dose of 10, 15, 18, 20, and 25 Gy generated a RIOM ulcer at the intermolar eminence (posterior upper tongue surface) with mean ulcer floor (posterior epithelium) heights of 190, 150, 25, 10, and 10 μm, respectively, compared to 200 μm in non-irradiated animals. The mean RIOM ulcer size % of the total epithelialized upper surface of the animal tongue was RT dose dependent. At day 10, the ulcer size % was 2, 5, 27, and 31% for 15, 18, 20, and 25 Gy RT, respectively. The mean relative surface area of the total epithelialized upper surface of the tongue was RT dose dependent, since it was significantly decreased to 97, 95, 88, and 38% with 15, 18, 20, and 25 Gy doses, respectively, at day 10 after RT. Subcutaneous injection of 1 mL of 0.9% saline/6 h for 24 h yielded a 100% survival only with 18 Gy self-resolved RIOM, which had 5.6 ± 0.3 days ulcer duration. In conclusion, we have generated a 100% survival self-resolved single-dose RIOM male mouse model with long enough duration for application in RIOM management research. Oral mucositis ulceration was radiation dose dependent. Sufficient hydration of animals after radiation exposure significantly improved their survival. PMID:27446800

  8. Radiation damage in single-particle cryo-electron microscopy: effects of dose and dose rate

    PubMed Central

    Karuppasamy, Manikandan; Karimi Nejadasl, Fatemeh; Vulovic, Milos; Koster, Abraham J.; Ravelli, Raimond B. G.

    2011-01-01

    combined with an improved understanding of the effects of dose and dose rate will aid single-particle cryo-electron microscopists to have better control of the outcome of their experiments. PMID:21525648

  9. Radiation damage in single-particle cryo-electron microscopy: effects of dose and dose rate.

    PubMed

    Karuppasamy, Manikandan; Karimi Nejadasl, Fatemeh; Vulovic, Milos; Koster, Abraham J; Ravelli, Raimond B G

    2011-05-01

    an improved understanding of the effects of dose and dose rate will aid single-particle cryo-electron microscopists to have better control of the outcome of their experiments. PMID:21525648

  10. Single dose oral paracetamol (acetaminophen) for postoperative pain in adults

    PubMed Central

    Toms, Laurence; McQuay, Henry J; Derry, Sheena; Moore, R Andrew

    2014-01-01

    Background This is an updated version of the original Cochrane review published in Issue 1, 2004 - this original review had been split from a previous title on ‘Single dose paracetamol (acetaminophen) with and without codeine for postoperative pain’. The last version of this review concluded that paracetamol is an effective analgesic for postoperative pain, but additional trials have since been published. This review sought to evaluate the efficacy and safety of paracetamol using current data, and to compare the findings with other analgesics evaluated in the same way. Objectives To assess the efficacy of single dose oral paracetamol for the treatment of acute postoperative pain. Search methods We searched The Cochrane Library, MEDLINE, EMBASE, the Oxford Pain Relief Database and reference lists of articles to update an existing version of the review in July 2008. Selection criteria Randomised, double-blind, placebo-controlled clinical trials of paracetamol for acute postoperative pain in adults. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Area under the “pain relief versus time” curve was used to derive the proportion of participants with paracetamol or placebo experiencing at least 50% pain relief over four to six hours, using validated equations. Number-needed-to-treat-to-benefit (NNT) was calculated, with 95% confidence intervals (CI). The proportion of participants using rescue analgesia over a specified time period, and time to use, were sought as measures of duration of analgesia. Information on adverse events and withdrawals was also collected. Main results Fifty-one studies, with 5762 participants, were included: 3277 participants were treated with a single oral dose of paracetamol and 2425 with placebo. About half of participants treated with paracetamol at standard doses achieved at least 50% pain relief over four to six hours, compared with about 20% treated with placebo. NNTs for at

  11. Plasma bupivacaine levels following single dose intraarticular instillation for arthroscopy.

    PubMed

    Meinig, R P; Holtgrewe, J L; Wiedel, J D; Christie, D B; Kestin, K J

    1988-01-01

    Arthroscopy of the knee was performed using 30 ml single dose intraarticular instillations of 0.5% or 0.25% solutions of bupivacaine (Marcaine). A total of 18 patients (mean age, 34 years), divided into two groups, participated in this study. Venous plasma levels were measured at 0, 10, 20, 30, 45, 60, 90, 120, and 240 minute intervals following a single instillation into the knee joint. All patients had suspected traumatic internal derangement of the knee. Electrocardiogram tracings, blood pressure, and neurologic assessment were monitored at each venous sampling interval or more often if clinically indicated. The type and amount of supplemental anesthesia were also recorded. None of our 18 patients required a general anesthetic because of pain although the following procedures were performed: meniscectomy, plica release, abrasion chondroplasty, loose body retrieval, and limited meniscal repair. A new methodology for the measurement of plasma bupivacaine using the gas chromatograph mass spectrometer is described. Monitoring specific molecular mass fragments allows the measurement of picogram per milliliter levels of bupivacaine. The highest peak plasma concentration occurred 20 minutes after instillation of 30 ml of 0.5% bupivacaine. The 625 +/- 225 ng/ml level was well below the 2,500 to 4,000 ng/ml reported to elicit early subjective CNS symptoms of bupivacaine toxicity. Thus, a single dose intraarticular instillation of 30 ml 0.5% or 0.25% bupivacaine is convenient, efficacious, and pharmacologically safe for routine clinical arthroscopy.

  12. Pharmacokinetic Comparison of a Single Oral Dose of Polymorph Form I versus Form V Capsules of the Antiorthopoxvirus Compound ST-246 in Human Volunteers

    PubMed Central

    Chinsangaram, Jarasvech; Honeychurch, Kady M.; Tyavanagimatt, Shanthakumar R.; Bolken, Tove' C.; Jordan, Robert; Jones, Kevin F.; Marbury, Thomas; Lichtenstein, Israel; Pickens, Margaret; Corrado, Michael; Landis, Patrick; Clarke, Jean M.; Frimm, Annie M.

    2012-01-01

    ST-246, a novel compound that inhibits egress of orthopoxvirus from mammalian cells, is being tested as a treatment for pathogenic orthopoxvirus infections in humans. This phase I, double-blind, randomized, crossover, exploratory study was conducted to compare the pharmacokinetics (PK) of a single daily 400-mg oral dose of ST-246 polymorph form I versus polymorph form V administered to fed, healthy human volunteers. Both forms appeared to be well tolerated, with no serious adverse events. The order of administration of the two forms had no effect on the results of the PK analyses. Form I and form V both exhibited comparable plasma concentration versus time profiles, but complete bioequivalence between the two forms was not found. Maximum drug concentration (Cmax) met the bioequivalence criteria, as the 90% confidence interval (CI) was 80.6 to 96.9%. However, the area under the concentration-time curve from time zero to time t (AUC0-t) and AUC0-∞ did not meet the bioequivalence criteria (CIs of 67.8 to 91.0% and 73.9 to 104.7%, respectively). The extent of absorption of form I, as defined by AUC0-∞, was 11.7% lower than that of form V. Since ST-246 form I is more thermostable than form V, form I was selected for further development and use in all future studies. PMID:22526314

  13. Single dose oral flurbiprofen for acute postoperative pain in adults

    PubMed Central

    Sultan, Asquad; McQuay, Henry J; Moore, R Andrew; Derry, Sheena

    2014-01-01

    Background Flurbiprofen is a non-selective non-steroidal anti-inflammatory drug (NSAID), related to ibuprofen and naproxen, used to treat acute and chronic painful conditions. There is no systematic review of its use in acute postoperative pain. Objectives To assess efficacy, duration of action, and associated adverse events of single dose oral flurbiprofen in acute postoperative pain in adults. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to January 2009. Selection criteria Randomised, double blind, placebo-controlled trials of single dose orally administered flurbiprofen in adults with moderate to severe acute postoperative pain. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk (RR) and number needed to treat to benefit (NNT) were calculated. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected. Main results Eleven studies compared flurbiprofen (699 participants) with placebo (362 participants) in studies lasting 6 to 12 hours. Studies were of adequate reporting quality, and most participants had pain following dental extractions. The dose of flurbiprofen used was 25 mg to 100 mg, with most information for 50 mg and 100 mg. The NNT for at least 50% pain relief over 4 to 6 hours for flurbiprofen 50 mg compared with placebo (692 participants) was 2.7 (2.3 to 3.3) and for 100 mg (416 participants) it was 2.5 (2.0 to 3.1). With flurbiprofen 50 mg and 100 mg 65% to 70% of participants experienced at least 50% pain relief, compared with 25% to 30% with placebo. Rescue medication was used by 25

  14. Absorption, Distribution, and Excretion of the Investigational Agent Orteronel (TAK-700) in Healthy Male Subjects: A Phase 1, Open-Label, Single-Dose Study.

    PubMed

    Suri, Ajit; Pusalkar, Sandeepraj; Li, Yuexian; Prakash, Shimoga

    2016-05-01

    This study evaluated the absorption, distribution, and excretion of orteronel, an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. Six healthy male subjects received a single 400-mg dose of radiolabeled [(14) C]-orteronel (18.5 kBq). The pharmacokinetics of [(14) C]-radioactivity, orteronel, and the primary metabolite M-I were characterized by ultra-performance liquid chromatography-tandem mass spectrometry, and mass balance recovery of [(14) C]-radioactivity was determined by liquid scintillation counting and accelerator mass spectrometry. Median time to maximum observed concentration of [(14) C]-radioactivity was 2.5 hours (plasma/whole blood) and of orteronel was 1 hour (plasma). Mean terminal half-life for [(14) C]-radioactivity in plasma and whole blood was 9.46 and 7.39 hours, respectively. For [(14) C]-radioactivity, the geometric mean whole blood-to-plasma ratios for maximum observed plasma/whole-blood concentration, area under the plasma concentration-time curve from time 0 to last quantifiable concentration (AUC0-last ), and AUC0-inf (AUC from time 0 to infinity) were 1.04, 0.92, and 0.93, respectively. Dose recovery accounted for 95.9% of the administered orteronel dose; the majority of excretion occurred by 96 hours postdose. The principal excretion route was via urine (mean, 77.5%; including 49.7% unchanged drug and 16.3% M-I) compared with 18.4% via feces. Three mild adverse events were reported; none were considered serious or related to orteronel. PMID:27163496

  15. Pharmacokinetic and Pharmacodynamic Comparison of Once-Daily Efavirenz (400 mg vs. 600 mg) in Treatment-Naïve HIV-Infected Patients: Results of the ENCORE1 Study.

    PubMed

    Dickinson, L; Amin, J; Else, L; Boffito, M; Egan, D; Owen, A; Khoo, S; Back, D; Orrell, C; Clarke, A; Losso, M; Phanuphak, P; Carey, D; Cooper, D A; Emery, S; Puls, R

    2015-10-01

    Daily efavirenz 400 mg (EFV400) was virologically noninferior to 600 mg (EFV600) at 48 weeks in treatment-naïve patients. We evaluated EFV400 and EFV600 pharmacokinetics (NONMEM v. 7.2), assessing patient demographics and genetic polymorphisms (CYP2B6, CYP2A6, CYP3A4, NR1I3) as covariates and explored relationships with efficacy (plasma HIV-RNA (pVL) <200 copies/mL) and safety outcomes at 48 weeks in 606 randomized ENCORE1 patients (female = 32%, African = 37%, Asian = 33%; EFV400 = 311, EFV600 = 295). CYP2B6 516G>T/983T>C/CYP2A6*9B/*17 and weight were associated with efavirenz CL/F. Exposure was significantly lower for EFV400 (geometric mean ratio, GMR; 90% confidence interval, CI: 0.73 (0.68-0.78)) but 97% (EFV400) and 98% (EFV600) of evaluable pVL was <200 copies/mL at 48 weeks (P = 0.802). Four of 20 patients with mid-dose concentrations <1.0 mg/L had pVL ≥200 copies/mL (EFV400 = 1; EFV600 = 3). Efavirenz exposure was similar between those with and without efavirenz-related side effects (GMR; 90% CI: 0.95 (0.88-1.02)). HIV suppression was comparable between doses despite significantly lower EFV400 exposure. Comprehensive evaluation of efavirenz pharmacokinetics/pharmacodynamics revealed important limitations in the accepted threshold concentration.

  16. Pharmacokinetic and Pharmacodynamic Comparison of Once‐Daily Efavirenz (400 mg vs. 600 mg) in Treatment‐Naïve HIV‐Infected Patients: Results of the ENCORE1 Study

    PubMed Central

    Amin, J; Else, L; Boffito, M; Egan, D; Owen, A; Khoo, S; Back, D; Orrell, C; Clarke, A; Losso, M; Phanuphak, P; Carey, D; Cooper, DA; Emery, S

    2015-01-01

    Daily efavirenz 400 mg (EFV400) was virologically noninferior to 600 mg (EFV600) at 48 weeks in treatment‐naïve patients. We evaluated EFV400 and EFV600 pharmacokinetics (NONMEM v. 7.2), assessing patient demographics and genetic polymorphisms (CYP2B6, CYP2A6, CYP3A4, NR1I3) as covariates and explored relationships with efficacy (plasma HIV‐RNA (pVL) <200 copies/mL) and safety outcomes at 48 weeks in 606 randomized ENCORE1 patients (female = 32%, African = 37%, Asian = 33%; EFV400 = 311, EFV600 = 295). CYP2B6 516G>T/983T>C/CYP2A6*9B/*17 and weight were associated with efavirenz CL/F. Exposure was significantly lower for EFV400 (geometric mean ratio, GMR; 90% confidence interval, CI: 0.73 (0.68–0.78)) but 97% (EFV400) and 98% (EFV600) of evaluable pVL was <200 copies/mL at 48 weeks (P = 0.802). Four of 20 patients with mid‐dose concentrations <1.0 mg/L had pVL ≥200 copies/mL (EFV400 = 1; EFV600 = 3). Efavirenz exposure was similar between those with and without efavirenz‐related side effects (GMR; 90% CI: 0.95 (0.88–1.02)). HIV suppression was comparable between doses despite significantly lower EFV400 exposure. Comprehensive evaluation of efavirenz pharmacokinetics/pharmacodynamics revealed important limitations in the accepted threshold concentration. PMID:26044067

  17. Pharmacokinetic and Pharmacodynamic Comparison of Once-Daily Efavirenz (400 mg vs. 600 mg) in Treatment-Naïve HIV-Infected Patients: Results of the ENCORE1 Study.

    PubMed

    Dickinson, L; Amin, J; Else, L; Boffito, M; Egan, D; Owen, A; Khoo, S; Back, D; Orrell, C; Clarke, A; Losso, M; Phanuphak, P; Carey, D; Cooper, D A; Emery, S; Puls, R

    2015-10-01

    Daily efavirenz 400 mg (EFV400) was virologically noninferior to 600 mg (EFV600) at 48 weeks in treatment-naïve patients. We evaluated EFV400 and EFV600 pharmacokinetics (NONMEM v. 7.2), assessing patient demographics and genetic polymorphisms (CYP2B6, CYP2A6, CYP3A4, NR1I3) as covariates and explored relationships with efficacy (plasma HIV-RNA (pVL) <200 copies/mL) and safety outcomes at 48 weeks in 606 randomized ENCORE1 patients (female = 32%, African = 37%, Asian = 33%; EFV400 = 311, EFV600 = 295). CYP2B6 516G>T/983T>C/CYP2A6*9B/*17 and weight were associated with efavirenz CL/F. Exposure was significantly lower for EFV400 (geometric mean ratio, GMR; 90% confidence interval, CI: 0.73 (0.68-0.78)) but 97% (EFV400) and 98% (EFV600) of evaluable pVL was <200 copies/mL at 48 weeks (P = 0.802). Four of 20 patients with mid-dose concentrations <1.0 mg/L had pVL ≥200 copies/mL (EFV400 = 1; EFV600 = 3). Efavirenz exposure was similar between those with and without efavirenz-related side effects (GMR; 90% CI: 0.95 (0.88-1.02)). HIV suppression was comparable between doses despite significantly lower EFV400 exposure. Comprehensive evaluation of efavirenz pharmacokinetics/pharmacodynamics revealed important limitations in the accepted threshold concentration. PMID:26044067

  18. Single dose testosterone administration reduces loss chasing in healthy females.

    PubMed

    Wu, Yin; Liu, Jinting; Qu, Lujing; Eisenegger, Christoph; Clark, Luke; Zhou, Xiaolin

    2016-09-01

    Testosterone has been linked to modulation of impulsivity and risky choice, potentially mediated by changes in reward or punishment sensitivity. This study investigated the effect of testosterone on risk-taking and the adjustment of risk-taking on trials following a gain or a loss. Loss chasing is operationalized herein as the propensity to recover losses by increasing risky choice. Healthy female participants (n=26) received a single-dose of 0.5mg sublingual testosterone in a double-blind, placebo-controlled crossover design. At 240min post-administration, participants performed a gambling task with a high and a low risk option. In the placebo condition, participants were more likely to choose the high risk option following losses compared to wins. This effect was abolished on the testosterone session. Ignoring prior outcomes, no overall changes in risk-taking were observed. Our data indicate that testosterone affects human decision-making via diminishing sensitivity to punishment. PMID:27236486

  19. Methyl Selenocysteine: single-dose pharmacokinetics in men

    PubMed Central

    Marshall, James R.; Ip, Clement; Romano, Karen; Fetterly, Gerald; Fakih, Marwan; Jovanovic, Borko; Perloff, Marjorie; Crowell, James; Davis, Warren; French-Christy, Renee; Dew, Alexander; Coomes, Margerie; Bergan, Raymond

    2011-01-01

    The recently published report of the SELECT evaluation of selenium and vitamin E provided strong evidence that selenium 200mcg/day in the form of selenomethionine does not protect selenium-replete men against prostate or any other cancer. This appears to refute the result of the much smaller Nutritional Prevention of Cancer (NPC) trial of selenium. Since SELECT did not test the NPC agent, is possible that the difference between the two trials stems partly from the use of different agents: selenomethionine in SELECT, selenized yeast in the NPC trial. One of the organic selenium forms suspected of having strong chemopreventive effects, and which may have been present in the NPC agent, is methyl selenocysteine. This study characterizes the single-dose pharmacokinetics of methyl selenocysteine. PMID:21846796

  20. Effective, single-dose treatment or porcine cysticercosis with oxfendazole.

    PubMed

    Gonzales, A E; Garcia, H H; Gilman, R H; Gavidia, C M; Tsang, V C; Bernal, T; Falcon, N; Romero, M; Lopez-Urbina, M T

    1996-04-01

    The pig is a vital link in the transmission cycle of Taenia solium, the cestode responsible for human-porcine cysticercosis. Infected pigs also represent an important source of economic loss to farmers in developing countries. Past efforts to find an adequate therapeutic regimen to treat this parasite disease in swine have failed because of low efficacy, high cost, side effects, or the need for multiple doses. In this randomized, no treatment-controlled study, the efficacy and safety of oxfendazole and praziquantel for the treatment of porcine cysticercosis were evaluated in 16 naturally infected pigs. Four groups of four pigs were treated with oxfendazole, praziquantel, oxfendazole plus praziquantel, or untreated. The pigs were humanely killed 12 weeks post-treatment, the number of cyst was counted, and parasite viability was assessed by cyst evagination. No detectable side effects were seen in any of the pigs. Praziquantel treatment alone appeared to reduce the number of cysts, but did not decrease the viability of the remaining parasites. Treatment with oxfendazole alone or oxfendazole plus praziquantel killed all of the parasites, and left only microcalcifications in the meat. Oxfendazole provides, for the first time, a practical, effective, inexpensive, and single-dose therapy for porcine cysticercosis.

  1. Multiple-dose pharmacokinetics and safety of rufloxacin in normal volunteers.

    PubMed Central

    Kisicki, J C; Griess, R S; Ott, C L; Cohen, G M; McCormack, R J; Troetel, W M; Imbimbo, B P

    1992-01-01

    The pharmacokinetics and safety of rufloxacin were evaluated in a double-blind, placebo-controlled study. Two groups of 16 healthy volunteers were given a single oral loading dose of 400 or 600 mg of rufloxacin on day 1 of the study. A single daily maintenance dose of 200 or 300 mg was then administered for a further 9 days; in addition, four subjects in each group received placebos. Rufloxacin levels in plasma and urine were determined by high-performance liquid chromatography. Following the initial dose, the mean (+/- standard error of the mean) peak concentrations of rufloxacin in plasma were 3.35 +/- 0.12 micrograms/ml in the 400-mg group and 4.54 +/- 0.19 micrograms/ml in the 600-mg group. They were generally reached 2 to 3 h after dosing. At the end of treatment, maximum levels in plasma rose to 4.51 +/- 0.15 and 7.20 +/- 0.25 micrograms/ml in the 400-mg and 600-mg groups, with a mean extent of accumulation (fold) of 3.1 +/- 0.1 and 3.3 +/- 0.1. For the 400-mg and 600-mg groups, the elimination half-lives were 40.0 +/- 1.5 and 44.0 +/- 1.3 h, mean residence times were 57.8 +/- 2.2 and 63.7 +/- 1.8 h, apparent volumes of distribution were 132 +/- 4 and 139 +/- 5 liters, and apparent total body clearance were 39 +/- 1 and 44 +/- 4 ml/min, assuming complete bioavailability. Of the total dose administered, the percentages excreted in urine were 49.6 +/- 1.3 and 51.1 +/-2.1%, with renal clearances of 21 +/- 1 and 22 +/- 2 ml/min, for the 400-mg and 600-mg groups. On the whole, the treatments were well tolerated, but some minor adverse events (mainly headache, insomnia, or abdominal discomfort) were reported for 7 subjects on abnormalities were detected in the laboratory examinations or in ocular function tests. This study shows that a 200-mg daily oral dose of rufloxacin preceded by a loading dose of 400 mg are well tolerated and produce steady-state concentrations in plasma above the MIC for most susceptible pathogens. PMID:1329618

  2. Single-Dose Pharmacokinetics and Safety of Ziprasidone in Children and Adolescents

    ERIC Educational Resources Information Center

    Sallee, Floyd R.; Miceli, Jeffrey J.; Tensfeldt, Thomas; Robarge, Lisa; Wilner, Keith; Patel, Nick C.

    2006-01-01

    Objective: The purpose of this study was to provide single-dose pharmacokinetic, safety, and tolerability data for ziprasidone in youths with tic disorder, for comparison to adult studies to discern whether ziprasidone pediatric dosing could be modeled from adult data. Method: A single-dose, open-label study of ziprasidone was conducted in youths…

  3. Serial Myocardial Imaging after a Single Dose of Thallium-201.

    PubMed

    Kamata, Takahiko; Kawasaki, Tatsuya; Kamitani, Tadaaki; Sugihara, Hiroki

    2014-01-01

    Although thallium-201 exercise scintigraphy has been established for the detection of myocardial ischemia and viability, little is known regarding the myocardial thallium-201 kinetics during angioplasty. Herein, we report a 77-year-old man with angina pectoris, in whom serial myocardial imaging after a single dose of thallium-201 was helpful in identifying not only the culprit lesion and myocardial viability, but also the dynamic changes in myocardial perfusion during angioplasty. Thallium-201 images after exercise showed a perfusion defect in the inferior wall, with a trivial redistribution 3 hours after the exercise and a marked improvement 24 hours later. Coronary angiography, performed 27 hours after exercise scintigraphy, showed severe stenosis in the right coronary artery. Guidewire crossing of the lesion interrupted the antegrade flow, which was restored after balloon dilation and stent implantation. Thallium-201 images, 2 hours after angioplasty (i.e., 30 hours after exercise), showed a decreased tracer uptake in the inferior wall, which improved the next day (i.e., 48 hours after exercise). Cardiac biomarkers were negative in the clinical course.

  4. Single-Ascending-Dose Pharmacokinetic Study of Tribendimidine in Opisthorchis viverrini-Infected Patients

    PubMed Central

    Duthaler, Urs; Sayasone, Somphou; Vanobbergen, Fiona; Penny, Melissa A.; Odermatt, Peter; Huwyler, Jörg

    2016-01-01

    Praziquantel is the only drug available for the treatment of Opisthorchis viverrini infections. Tribendimidine has emerged as a potential treatment alternative; however, its pharmacokinetic (PK) properties have not been sufficiently studied to date. Via two phase IIa dose-finding studies, 68 O. viverrini patients were treated with 25- to 600-mg doses of tribendimidine using 50- and 200-mg tablet formulations. Plasma, blood, and dried blood spots (DBS) were sampled at selected time points. The two main metabolites of tribendimidine, active deacetylated amidantel (dADT) and acetylated dADT (adADT), were analyzed in plasma, blood, and DBS. PK parameters were estimated by noncompartmental analysis. An acceptable agreement among plasma and DBS concentrations was observed, with a mean bias of ≤10%, and 60% dADT and 74% adADT concentrations being within ±20% margins. We found that 200-mg tribendimidine tablets possess immediate floating characteristics, which led to variable time to maximal concentration of drug (Tmax) values (2 to 24 h) between individuals. Dose proportionality was observed for dADT from 25 to 200 mg using 50-mg tablets, but at higher dosages (200 to 600 mg), saturation occurred. The median ratio of the area under the plasma concentration-time curve from 0 to 24 h (AUC0–24) of dADT to the AUC0–24 of adADT ranged from 0.8 to 26.4, suggesting substantial differences in acetylation rates. Cure rates ranged from 11% (25-mg dose) to 100% (400-mg dose). Cured patients showed significantly higher dADT maximal serum concentrations (Cmax) and AUC0–24 values than uncured patients. Tribendimidine is a promising drug for the treatment of opisthorchiasis. However, the tablet formulation should be optimized to achieve consistent absorption among patients. Further studies are warranted to assess the large differences between individuals in the rate of metabolic turnover of dADT to adADT. (This study has been registered with the ISRCTN Registry under no. ISRCTN

  5. Biotransformation and pharmacokinetics of ethylmorphine after a single oral dose.

    PubMed Central

    Aasmundstad, T A; Xu, B Q; Johansson, I; Ripel, A; Bjørneboe, A; Christophersen, A S; Bodd, E; Mørland, J

    1995-01-01

    1. The pharmacokinetics of ethylmorphine after administration of a single dose of the cough mixture Cosylan were investigated in 10 healthy subjects. 2. The median urinary recovery of ethylmorphine and measured metabolites was 77% over 48 h. The median tmax of unchanged ethylmorphine was 45 min, and the terminal elimination t1/2 was 2 h. Ethylmorphine-6-glucuronide was found to be the major metabolite. 3. Two subjects had significantly lower urinary recovery (0.48 h) of morphine and morphine-glucuronides than the remainder. Furthermore, these two had urinary metabolic ratios (MRO) and partial metabolic clearances (CLmO) for O-deethylation of ethylmorphine tentatively classifying them phenotypically as poor metabolisers of the debrisoquine/sparteine type. 4. Genotyping for cytochrome P450 (CYP) 2D6 alleles revealed five homozygote (wt/wt) and five heterozygote subjects. Two subjects phenotypically classified as poor metabolisers were genotypically CYP2D6A/wt and CYP2D6D/wt, respectively. 5. Serum and urine samples taken more than 8 and 24 h after administration of ethyl-morphine respectively, contained morphine and morphine-glucuronides, but no ethylmorphine, ethylmorphine-6-glucuronide or (serum only) norethylmorphine. Norethylmorphine could be detected after hydrolysis of urine samples in all subjects. The urinary recovery of the active metabolites morphine and morphine-6-glucuronide after administration of ethylmorphine varied by a factor of 9 between individuals. 6. The wide variation in recovery of morphine and morphine-glucuronides after oral administration of ethylmorphine could not be explained simply by a difference in CYP2D6 genotype. Constitutional variation in other enzymatic pathways involved in ethylmorphine metabolism is probably crucial. Ratios of morphine to parent drug cannot be used to distinguish the source of morphine after administration of ethylmorphine. Norethylmorphine should be included in urine assays for opiates in forensic toxicology

  6. Single daily dosing of gentamicin: pharmacokinetic comparison of two dosing methodologies for postpartum endometritis.

    PubMed Central

    Liu, C; Abate, B; Reyes, M; Gonik, B

    1999-01-01

    OBJECTIVE: We compared the pharmacokinetics of two methods for dosing gentamicin for the treatment of postpartum endometritis with the goal of achieving adequate peak serum concentrations (>12 mg/L) and prolonged trough levels below 2 mg/L. METHODS: Group-I subjects (n = 5) received intravenous gentamicin, 5 mg/kg per total body weight over 60 min., with a maximum dose of 500 mg. Group-II subjects (n = 17) were dosed intravenously according to the following formula: Dose = desired peak concentration (fixed at 14 mg/L) * (volume of distribution, i.e., 0.35 L/kg) * adjusted body weight (in kilograms). Serum gentamicin levels were obtained 1 hr. and 8-12 hr. after infusion of the second dose. Pharmacokinetic parameters for the subjects in each group were calculated according to standard formulas. RESULTS: Subjects in Group I had significantly higher doses and peak drug concentrations (P < 0.01), while in Group II, 76% of patients had peak levels less than desired (<12 mg/L). Both groups maintained trough levels of <2 mg/L in excess of 12 hr. CONCLUSIONS: Changing to the adjusted body weight formula for Group I, while maintaining a dose between 4 and 5 mg/kg, would reduce excessive peak concentrations. Using a calculated volume of distribution of 0.4 L/kg in Group II would improve peak serum concentrations to the desired levels. Both dosing regimens ensure adequate aminoglycoside pharmacokinetic parameters and avoid the need for monitoring serial serum drug concentrations, provided the expected clinical response is also achieved. While the first dosing formula is simpler to calculate, the second dosing formula allows for more individualized dosing considerations. PMID:10371471

  7. Peanut Allergen Threshold Study (PATS): validation of eliciting doses using a novel single-dose challenge protocol

    PubMed Central

    2013-01-01

    Background The eliciting dose (ED) for a peanut allergic reaction in 5% of the peanut allergic population, the ED05, is 1.5 mg of peanut protein. This ED05 was derived from oral food challenges (OFC) that use graded, incremental doses administered at fixed time intervals. Individual patients’ threshold doses were used to generate population dose-distribution curves using probability distributions from which the ED05 was then determined. It is important to clinically validate that this dose is predictive of the allergenic response in a further unselected group of peanut-allergic individuals. Methods/Aims This is a multi-centre study involving three national level referral and teaching centres. (Cork University Hospital, Ireland, Royal Children’s Hospital Melbourne, Australia and Massachusetts General Hospital, Boston, U.S.A.) The study is now in process and will continue to run until all centres have recruited 125 participates in each respective centre. A total of 375 participants, aged 1–18 years will be recruited during routine Allergy appointments in the centres. The aim is to assess the precision of the predicted ED05 using a single dose (6 mg peanut = 1.5 mg of peanut protein) in the form of a cookie. Validated Food Allergy related Quality of Life Questionnaires-(FAQLQ) will be self-administered prior to OFC and 1 month after challenge to assess the impact of a single dose OFC on FAQL. Serological and cell based in vitro studies will be performed. Conclusion The validation of the ED05 threshold for allergic reactions in peanut allergic subjects has potential value for public health measures. The single dose OFC, based upon the statistical dose-distribution analysis of past challenge trials, promises an efficient approach to identify the most highly sensitive patients within any given food-allergic population. PMID:24028324

  8. Single-dose rasburicase 6 mg in the management of tumor lysis syndrome in adults.

    PubMed

    McDonnell, Anne M; Lenz, Kristi L; Frei-Lahr, Debra A; Hayslip, John; Hall, Philip D

    2006-06-01

    Rasburicase is currently approved at a dosage of 0.15-0.2 mg/kg once/day for 5 days in pediatric patients with cancer to lower plasma uric acid concentrations and manage tumor lysis syndrome (TLS). Information on rasburicase dosing in adults is limited, with some data on using rasburicase as a single dose instead of multiple daily doses. Therefore, we evaluated the efficacy of a single dose of rasburicase for preventing or managing TLS in adults. We collected retrospective data for 11 adults with hematologic malignancies who received a single 6-mg dose of rasburicase. All patients received intravenous hydration with urinary alkalinization and allopurinol; however, due to adverse reactions, two patients received short courses of allopurinol. Only patients at high risk for TLS (e.g., large tumor burden, increasing uric acid concentration) or those with TLS received rasburicase. The single dose of rasburicase 6 mg resulted in a median 0.0773-mg/kg dose (range 0.0232-0.1361 mg/kg). The single 6-mg dose rapidly lowered uric acid concentrations in 10 of the 11 patients. The median uric acid concentration of 11.7 mg/dl (range 7.4-17.4 mg/dl) declined to 2.0 mg/dl (range 0.5-15.4 mg/dl) within a day after rasburicase administration (p=0.022). In these 10 patients, uric acid concentrations remained low despite subsequent chemotherapy, and none required additional rasburicase doses. The only patient who did not respond to the single 6-mg rasburicase dose was a morbidly obese man (259 kg, body mass index 87 kg/m2) who subsequently responded to an additional dose of rasburicase 12 mg. These results warrant further investigation of a single 6-mg dose of rasburicase in adults with TLS or at high-risk for developing TLS.

  9. Dose fractionation and single subject studies in PET

    NASA Astrophysics Data System (ADS)

    Balakrishnan, Karthikayan

    Conventional positron emission tomography (PET) for cognitive brain studies typically relies on information collected from the distribution of decays following an injection of 15O-labeled water. The number of injections that can be administered to the subject are constrained by radiation dose to the subject and total length of the PET scan. The standard protocol involves 8--10 injections of H152O separated by approximately 5--7 half-lives of 15O. The number of activation conditions that can be realistically studied in a standard PET session is between 8 and 10. This work investigates the physiological response of a simulated subject to H152O injections that are administered in small doses (1--5 mCi) with short inter-injection intervals (40--180 seconds). A larger number of activation conditions are presented to the subject with a wider variation in the activation paradigm. Repeat conditions are studies. Signal averaging methods are feasible with this method of dose administration. Sinograms from scans with similar activation conditions are summed together before reconstruction. The signal in the primary activation region of the brain is shown to increase while suppressing the contribution of secondary activation regions in the brain. The contrast of the final image is similarly increased which leads to easier identification of the primary activation region. An automated H152O -production unit controlled by a PC running LabView software was developed to produce the dose required for the injection sequence by controlling the flow of H152O -vapor that diffuses across a semi-permeable membrane into saline. The unit is capable of producing H152O rapidly for both the standard and the proposed dose administration methods. The system also detects the bolus arrival time at the subject's lungs using a small external plastic detector. Activation sequence commences with the rise in radioactivity observed by the detector. The simulations indicate that inter-injection intervals

  10. Split-Dose Polyethylene Glycol Is Superior to Single Dose for Colonoscopy Preparation: Results of a Randomized Controlled Trial

    PubMed Central

    Mohamed, Rachid; Hilsden, Robert J.; Dube, Catherine; Rostom, Alaa

    2016-01-01

    Background. The efficacy of colonoscopy in detecting abnormalities within the colon is highly dependent on the adequacy of the bowel preparation. The objective of this study was to compare the efficacy, safety, and tolerability of PEG lavage and split-dose PEG lavage with specific emphasis on the cleanliness of the right colon. Methods. The study was a prospective, randomized, two-arm, controlled trial of 237 patients. Patients between the age of 50 and 75 years were referred to an outpatient university screening clinic for colonoscopy. Patients were allocated to receive either a single 4 L PEG lavage or a split-dose PEG lavage. Results. Overall, the bowel preparation was superior in the split-dose group compared with the single-dose group (mean Ottawa score 3.50 ± 2.89 versus 5.96 ± 3.53; P < 0.05) and resulted in less overall fluid in the colon. This effect was observed across all segments of the colon assessed. Conclusions. The current study supports use of a split-dose PEG lavage over a single large volume lavage for superior bowel cleanliness, which may improve polyp detection. This trial is registered with ClinicalTrials.gov identifier NCT01610856. PMID:27446836

  11. A bounding estimate of neutron dose based on measured photon dose around single pass reactors at the Hanford site.

    PubMed

    Taulbee, Timothy D; Glover, Samuel E; Macievic, Gregory V; Hunacek, Mickey; Smith, Cheryl; DeBord, Gary W; Morris, Donald; Fix, Jack

    2010-07-01

    Neutron and photon radiation survey records have been used to evaluate and develop a neutron to photon (NP) ratio to reconstruct neutron doses to workers around Hanford's single pass reactors that operated from 1945 to 1972. A total of 5,773 paired neutron and photon measurements extracted from 57 boxes of survey records were used in the development of the NP ratio. The development of the NP ratio enables the use of the recorded dose from an individual's photon dosimeter badge to be used to estimate the unmonitored neutron dose. The Pearson rank correlation between the neutron and photon measurements was 0.71. The NP ratio best fit a lognormal distribution with a geometric mean (GM) of 0.8, a geometric standard deviation (GSD) of 2.95, and the upper 95 th % of this distribution was 4.75. An estimate of the neutron dose based on this NP ratio is considered bounding due to evidence that up to 70% of the total photon exposure received by workers around the single pass reactors occurs during shutdown maintenance and refueling activities when there is no significant neutron exposure. Thus when this NP ratio is applied to the total measured photon dose from an individual film badge dosimeter, the resulting neutron dose is considered bounded.

  12. SINGLE VERSUS MULTI-DOSE ANTIBIOTIC PROPHYLAXIS FOR PELVIC ORGAN PROLAPSE SURGERY WITH GRAFT/MESH

    PubMed Central

    Andy, Uduak U.; Harvie, Heidi S.; Ackenbom, Mary F.; Arya, Lily A.

    2015-01-01

    Objective To compare the risk of postoperative infections in women who receive single-dose versus multi-dose prophylactic antibiotic regimen during prolapse surgery with mesh/graft. Study Design Retrospective cohort study of 460 women who underwent prolapse surgery with mesh/graft. We compared women who received a single-dose prophylactic antibiotic regimen to those who received a multi-dose regimen. The primary outcome was the presence of any post-operative infection, defined as the presence of any of the following infections: urinary tract infection (UTI), fever, wound or trocar site infection, mesh infection or pelvic abscess. Associations between prophylactic antibiotic regimen and post-operative infections were estimated using univariable and multivariable analysis. Results Rate of any postoperative infection was similar between the single-dose and multi-dose groups (19% vs. 16%, p=0.50). Rate of UTI was significantly higher in the single-dose compared to the multi-dose group (13% vs. 7%, p=0.03). On multivariable analysis, after controlling for vaginal route of surgery, the odds of UTI was not significantly different between groups (OR 0.59, 95% CI 0.27, 1.26). Conclusion A single dose antibiotic regimen is sufficient for prophylaxis against post-operative infections in women undergoing prolapse surgery with graft/mesh. PMID:25126979

  13. Interoceptive conditioning in rats: effects of using a single training dose or a set of 5 different doses of nicotine.

    PubMed

    Pittenger, Steven T; Bevins, Rick A

    2013-12-01

    Interoceptive conditioning contributes to the tenacity of nicotine dependence. Previous research investigating nicotine as an interoceptive stimulus has typically employed administration of a single training dose of nicotine over an extended time. This approach has allowed for careful study of the nicotine stimulus. In humans, the nicotine stimulus is unlikely to be fixed across learning episodes. Thus, from a translational perspective, systematic variation of nicotine dose in training might better approximate interoceptive conditioning in humans. Notably, training with a class or set of discrete exteroceptive stimuli (e.g., different pictures of cars) produces interesting behavioral differences relative to training with a single stimulus. The present study sought to determine whether similar differences would occur if a set of nicotine stimuli were used in place of a single dose. To investigate this question, one group of male Sprague-Dawley rats was trained on a discriminated goal-tracking task with a set of nicotine doses (0.05, 0.125, 0.2, 0.275, and 0.35mg/kg). A second group received the standard protocol of training with a single nicotine dose (0.2mg/kg). On each nicotine session, there was intermittent access to liquid sucrose (26%) in a conditioning chamber. On intermixed saline sessions, sucrose was withheld. We examined acquisition, subsequent extinction, transfer of extinction, nicotine generalization, and mecamylamine blockade. Both groups reliably discriminated between nicotine and saline sessions, were sensitive to non-reinforcement, displayed transfer of extinction, demonstrated dose-dependent nicotine generalization, and responding was blocked by mecamylamine. There were no significant differences between the two groups. The unique nature of an interoceptive pharmacological stimulus and the challenges posed for studying the impact of training with a set of interoceptive stimuli are discussed.

  14. Marrow toxicity of fractionated vs. single dose total body irradiation is identical in a canine model

    SciTech Connect

    Storb, R.; Raff, R.F.; Graham, T.; Appelbaum, F.R.; Deeg, H.J.; Schuening, F.G.; Shulman, H.; Pepe, M. )

    1993-03-20

    The authors explored in dogs the marrow toxicity of single dose total body irradiation delivered from two opposing [sup 60]Co sources at a rate of 10 cGy/min and compared results to those seen with total body irradiation administered in 100 cGy fractions with minimum interfraction intervals of 6 hr. Dogs were not given marrow transplants. They found that 200 cGy single dose total body irradiation was sublethal, with 12 of 13 dogs showing hematopoietic recovery and survival. Seven of 21 dogs given 300 cGy single dose total body irradiation survived compared to 6 of 10 dogs given 300 cGy fractionated total body irradiation. One of 28 dogs given 400 cGy single dose total body irradiation survived compared to none of six given fractionated radiation. With granulocyte colony stimulating factor (GCSF) administered from day 0-21 after 400 cGy total body irradiation, most dogs survived with hematological recovery. Because of the almost uniform success with GCSF after 400 cGy single dose total body irradiation, a study of GCSF after 400 cGy fractionated total body irradiation was deemed not to be informative and, thus, not carried out. Additional comparisons between single dose and fractionated total body irradiation were carried out with GCSF administered after 500 and 600 cGy of total body irradiation. As with lower doses of total body irradiation, no significant survival differences were seen between the two modes of total body irradiation, and only 3 of 26 dogs studied survived with complete hematological recovery. Overall, therefore, survival among dogs given single dose total body irradiation was not different from that of dogs given fractionated total body irradiation (p = .67). Similarly, the slopes of the postirradiation declines of granulocyte and platelet counts and the rates of their recovery in surviving dogs given equal total doses of single versus fractionated total body irradiation were indistinguishable. 24 refs., 3 figs., 2 tabs.

  15. Single or 2-Dose Micafungin Regimen for Treatment of Invasive Candidiasis: Therapia Sterilisans Magna!

    PubMed

    Gumbo, Tawanda

    2015-12-01

    The time the earth takes to rotate its axis (the day) has dictated how often pharmaceutical compounds are dosed. The scientific link between the 2 events is materia medica arcana. As an example, in the treatment of invasive candidiasis, antifungal therapy with intravenous micafungin is dosed daily. A literature review revealed population pharmacokinetic analyses, in vivo pharmacokinetics/pharmacodynamics studies, and maximum-tolerated-dose studies of micafungin that examined optimal micafungin dosing strategies. The half-life of micafungin in patient blood was 14 hours in several studies, but was even longer in different organs, so that the concentration will persist above minimum inhibitory concentrations of Candida species for several days. Studies in mice and rabbits with persistent neutropenia and disseminated candidiasis, otherwise fatal, demonstrated that a single large dose of micafungin could clear disseminated candidiasis, even though the micafungin half-life in such animals is shorter than in humans. Human pharmacokinetics/pharmacodynamics studies confirmed this link between micafungin efficacy and the ratio of the area under the concentration-time curve, and the optimal exposures initially identified in neutropenic animals. Maximum tolerated dose studies have demonstrated safety of 900 mg administered daily for several weeks, whereas case reports demonstrate efficacy and safety of single 1400-mg doses. Thus, a single dose of micafungin, or 2 such doses within a few days of each other, is not only logical, but might even lead to faster clearance of Candida.

  16. Single or 2-Dose Micafungin Regimen for Treatment of Invasive Candidiasis: Therapia Sterilisans Magna!

    PubMed

    Gumbo, Tawanda

    2015-12-01

    The time the earth takes to rotate its axis (the day) has dictated how often pharmaceutical compounds are dosed. The scientific link between the 2 events is materia medica arcana. As an example, in the treatment of invasive candidiasis, antifungal therapy with intravenous micafungin is dosed daily. A literature review revealed population pharmacokinetic analyses, in vivo pharmacokinetics/pharmacodynamics studies, and maximum-tolerated-dose studies of micafungin that examined optimal micafungin dosing strategies. The half-life of micafungin in patient blood was 14 hours in several studies, but was even longer in different organs, so that the concentration will persist above minimum inhibitory concentrations of Candida species for several days. Studies in mice and rabbits with persistent neutropenia and disseminated candidiasis, otherwise fatal, demonstrated that a single large dose of micafungin could clear disseminated candidiasis, even though the micafungin half-life in such animals is shorter than in humans. Human pharmacokinetics/pharmacodynamics studies confirmed this link between micafungin efficacy and the ratio of the area under the concentration-time curve, and the optimal exposures initially identified in neutropenic animals. Maximum tolerated dose studies have demonstrated safety of 900 mg administered daily for several weeks, whereas case reports demonstrate efficacy and safety of single 1400-mg doses. Thus, a single dose of micafungin, or 2 such doses within a few days of each other, is not only logical, but might even lead to faster clearance of Candida. PMID:26567282

  17. A placebo controlled double-blind evaluation of the pharmacodynamics of fengabine vs amitriptyline following single and multiple doses in elderly volunteers.

    PubMed Central

    Fairweather, D B; Kerr, J S; Hilton, S; Hindmarch, I

    1993-01-01

    1. The effects of fengabine were compared with those of amitriptyline in healthy elderly volunteers. Doses were administered double-blind and assessments were made before and after ingestion. 2. Psychomotor performance and cognitive ability were measured using tests of choice reaction time, tracking, critical flicker fusion threshold, memory scanning and word recognition. Subjective feelings were assessed using the Leeds sleep evaluation questionnaire (LSEQ) and line analogue rating scales (LARS). 3. Pharmacokinetic data suggest that fengabine may induce its own metabolism following repeated dosing. 4. The findings of this study show that fengabine 200 mg and 400 mg does not produce any noticeable behavioural toxicity in elderly volunteers, in contrast to amitriptyline which had a disruptive effect throughout. PMID:8471403

  18. Pharmacokinetics of single ascending doses of the P-glycoprotein inhibitor tariquidar in healthy subjects

    PubMed Central

    Bauer, M.; Zeitlinger, M.; Todorut, D.; Böhmdorfer, M.; Müller, M.; Langer, O.; Jäger, W.

    2013-01-01

    We assessed the pharmacokinetics (PK), tolerability and safety of tariquidar (TQD), a P-glycoprotein (Pgp) inhibitor, after i.v. administration of single ascending doses. Employed doses were up to 4-fold higher than in previous clinical trials in cancer patients and are capable to inhibit Pgp at the blood-brain barrier (BBB). 15 male healthy volunteers were randomised to receive single i.v. doses of TQD at 4, 6 or 8 mg/kg body weight and underwent blood sampling over 24 h. TQD concentrations were determined in plasma samples with high-performance liquid chromatography-mass spectrometry. No dose limiting toxicities of TQD were observed. Area under the plasma concentration-time curve from start until 24 h after end of infusion (AUC0-n) was positively correlated with administered TQD dose (r=0.8981, p<0.0001). Moreover, we found a positive correlation for volume of distribution at steady state Vss (r=0.7129, p=0.0004) with TQD dose. Dose dependency of Vss points to non-linear PK of TQD, which was in all likelihood caused by transporter saturation at high TQD doses. Acceptable safety and tolerability and dose-linear increases in plasma exposure support future use of TQD at doses up to 8 mg/kg to inhibit Pgp at the human BBB. PMID:23146816

  19. Single-dose fentanyl sublingual spray for breakthrough cancer pain.

    PubMed

    Taylor, Donald R

    2013-01-01

    Breakthrough cancer pain (BTCP) is defined as a transient exacerbation of pain that arises in patients with otherwise controlled persistent pain. BTCP typically has a rapid onset and relatively short duration, but it causes a significant amount of physical and psychological distress for patients. Several rapid-onset fentanyl formulations have been introduced in the USA to replace traditional oral opioids for the treatment of BTCP: a transmucosal lozenge, a sublingual orally disintegrating tablet, a buccal tablet, a buccal soluble film, a pectin nasal spray and, the newest formulation to enter the market, a sublingual spray. This article reviews the six rapid-onset formulations of fentanyl approved in the USA for the management of BTCP with emphasis on describing the published literature on fentanyl sublingual spray. The different fentanyl formulations vary in pharmacokinetic properties and ease of use, but all have a rapid onset and a relatively short duration of analgesia. Fentanyl sublingual spray has demonstrated absorption within 5 minutes of administration, with fentanyl plasma concentrations increasing over the first 30 minutes and remaining elevated for 60-90 minutes in pharmacokinetic studies in healthy subjects. Fentanyl sublingual spray shows linear dose proportionality, and changes in the temperature or acidity of the oral cavity do not alter its pharmacokinetic properties. In patients with BTCP, statistically significant pain relief is measurable at 5 minutes after administration of fentanyl sublingual spray, when compared with placebo, with significant pain relief lasting at least 60 minutes after administration. Adverse events are typical of opioid treatment and are considered mild to moderate in intensity. In summary, fentanyl sublingual spray provides rapid onset of analgesia and is a tolerable and effective treatment for BTCP. PMID:23901300

  20. Single-dose fentanyl sublingual spray for breakthrough cancer pain

    PubMed Central

    Taylor, Donald R

    2013-01-01

    Breakthrough cancer pain (BTCP) is defined as a transient exacerbation of pain that arises in patients with otherwise controlled persistent pain. BTCP typically has a rapid onset and relatively short duration, but it causes a significant amount of physical and psychological distress for patients. Several rapid-onset fentanyl formulations have been introduced in the USA to replace traditional oral opioids for the treatment of BTCP: a transmucosal lozenge, a sublingual orally disintegrating tablet, a buccal tablet, a buccal soluble film, a pectin nasal spray and, the newest formulation to enter the market, a sublingual spray. This article reviews the six rapid-onset formulations of fentanyl approved in the USA for the management of BTCP with emphasis on describing the published literature on fentanyl sublingual spray. The different fentanyl formulations vary in pharmacokinetic properties and ease of use, but all have a rapid onset and a relatively short duration of analgesia. Fentanyl sublingual spray has demonstrated absorption within 5 minutes of administration, with fentanyl plasma concentrations increasing over the first 30 minutes and remaining elevated for 60–90 minutes in pharmacokinetic studies in healthy subjects. Fentanyl sublingual spray shows linear dose proportionality, and changes in the temperature or acidity of the oral cavity do not alter its pharmacokinetic properties. In patients with BTCP, statistically significant pain relief is measurable at 5 minutes after administration of fentanyl sublingual spray, when compared with placebo, with significant pain relief lasting at least 60 minutes after administration. Adverse events are typical of opioid treatment and are considered mild to moderate in intensity. In summary, fentanyl sublingual spray provides rapid onset of analgesia and is a tolerable and effective treatment for BTCP. PMID:23901300

  1. Effect of low-dose (single-dose) magnesium sulfate on postoperative analgesia in hysterectomy patients receiving balanced general anesthesia.

    PubMed

    Taheri, Arman; Haryalchi, Katayoun; Mansour Ghanaie, Mandana; Habibi Arejan, Neda

    2015-01-01

    Background and Aim. Aparallel, randomized, double blinded, placebo-controlled trial study was designed to assess the efficacy of single low dose of intravenous magnesium sulfate on post-total abdominal hysterectomy (TAH) pain relief under balanced general anesthesia. Subject and Methods. Forty women undergoing TAH surgery were assigned to two magnesium sulfate (N = 20) and normal saline (N = 20) groups randomly. The magnesium group received magnesium sulfate 50 mg·kg(-1) in 100 mL of normal saline solution i.v as single-dose, just 15 minutes before induction of anesthesia whereas patients in control group received 100 mL of 0.9% sodium chloride solution at the same time. The same balanced general anesthesia was induced for two groups. Pethidine consumption was recorded over 24 hours precisely as postoperative analgesic. Pain score was evaluated with Numeric Rating Scale (NRS) at 0, 6, 12, and 24 hours after the surgeries. Results. Postoperative pain score was lower in magnesium group at 6, 12, and 24 hours after the operations significantly (P < 0.05). Pethidine requirement was significantly lower in magnesium group throughout 24 hours after the surgeries (P = 0.0001). Conclusion. Single dose of magnesium sulfate during balanced general anesthesia could be considered as effective and safe method to reduce postoperative pain and opioid consumption after TAH.

  2. Chemotherapy of onchocerciasis with high doses of diethylcarbamazine or a single dose of ivermectin: microfilaria levels and side effects.

    PubMed

    Albiez, E J; Newland, H S; White, A T; Kaiser, A; Greene, B M; Taylor, H R; Büttner, D W

    1988-03-01

    Fifty adult male subjects with moderate to heavy onchocerciasis from the Liberian rain forest were selected for a double-blind placebo-controlled chemotherapy study. The effects of high doses of diethylcarbamazine (DEC) - 30 mg/kg/d - over one week preceded by a one week initial treatment with normal oral doses of DEC or DEC lotion were compared with a single dose of ivermectin (150 micrograms/kg) and placebo. During the initial treatment DEC tablets or lotion caused distinctly more frequent and severe reactions than did invermectin. The reactions to ivermectin did not differ from those of the placebo patients. High doses of DEC caused, in about half of the patients, headache, dizziness, nausea or vomiting. DEC markedly increased the number of corneal microfilariae and of corneal opacities compared to ivermectin. All changes resolved with a return to pretreatment findings two months after treatment. The three treatment groups showed no differences at the ten months follow-up. In all treated patients skin microfilaria counts fell almost to zero by the end of the two week therapy. In the ivermectin group microfilaria counts remained significantly lower than in the DEC patients at the two and ten months examinations. In summary, ivermectin was much better tolerated than DEC and had a longer lasting effect on the microfilariae in the skin. Since high doses of DEC were less effective and caused more frequent and severe side effects, this approach cannot be recommended for treatment of onchocerciasis.

  3. The maximum single dose of resistant maltodextrin that does not cause diarrhea in humans.

    PubMed

    Kishimoto, Yuka; Kanahori, Sumiko; Sakano, Katsuhisa; Ebihara, Shukuko

    2013-01-01

    The objective of the present study was to determine the maximum dose of resistant maltodextrin (Fibersol)-2, a non-viscous water-soluble dietary fiber), that does not induce transitory diarrhea. Ten healthy adult subjects (5 men and 5 women) ingested Fibersol-2 at increasing dose levels of 0.7, 0.8, 0.9, 1.0, and 1.1 g/kg body weight (bw). Each administration was separated from the previous dose by an interval of 1 wk. The highest dose level that did not cause diarrhea in any subject was regarded as the maximum non-effective level for a single dose. The results showed that no subject of either sex experienced diarrhea at dose levels of 0.7, 0.8, 0.9, or 1.0 g/kg bw. At the highest dose level of 1.1 g/kg bw, no female subject experienced diarrhea, whereas 1 male subject developed diarrhea with muddy stools 2 h after ingestion of the test substance. Consequently, the maximum non-effective level for a single dose of the resistant maltodextrin Fibersol-2 is 1.0 g/kg bw for men and >1.1 g/kg bw for women. Gastrointestinal symptoms were gurgling sounds in 4 subjects (7 events) and flatus in 5 subjects (9 events), although no association with dose level was observed. These symptoms were mild and transient and resolved without treatment.

  4. Pharmacokinetics of eltoprazine in healthy male subjects after single dose oral and intravenous administration.

    PubMed Central

    Raghoebar, M; Mak, M; Cournot, A; Pistorius, M C; Van Harten, J; Roseboom, H

    1990-01-01

    The kinetics, safety and tolerability of eltoprazine hydrochloride were studied in an open, cross-over, partially randomised design after single oral (8 mg) and intravenous (3 and 8 mg) doses to 12 healthy male subjects. After intravenous administration, the mean t1/2 ranged from 7 to 9 h, the MRT was 11 h, CL was 487 +/- 148 (3 mg dose) and 471 +/- 56 (8 mg dose) ml kg-1 h-1, while CLR was 226 +/- 124 (3 mg dose) and 189 +/- 38 (8 mg dose) ml kg-1 h-1. The Vss was 3.3 +/- 0.7 (3 mg dose) and 3.8 +/- 0.5 (8 mg dose) 1 kg-1. Cumulative renal excretion was 40%. The AUC and the cumulative urinary excretion were directly proportional to dose within the range of 3-8 mg. Values of tmax varied from 1 to 4 h after oral administration. The mean Cmax value was 24 ng ml-1 after an oral dose of 8 mg. The plasma elimination half-life after oral administration was 9.8 +/- 3.9 h. Absolute oral bioavailability was 110 +/- 32%. Dose-dependent somnolence was observed. PMID:2288834

  5. Single- and Multiple-Dose Pharmacokinetics and Absolute Bioavailability of Tedizolid

    PubMed Central

    Flanagan, Shawn; Fang, Edward; Muñoz, Kelly A; Minassian, Sonia L; Prokocimer, Philippe G

    2014-01-01

    Objectives Tedizolid phosphate is a novel antibacterial under investigation for the treatment of gram-positive infections. This study was conducted to assess the pharmacokinetics, safety, and tolerability of intravenous tedizolid phosphate as well as the oral bioavailability of tedizolid phosphate. Design Double-blind, single-ascending dose, multiple-dose pharmacokinetics study, as well as tolerability and open-label crossover studies. Setting Single center in the United States (Covance Clinical Research Unit, Madison, WI) between September 2009 and January 2010. Participants Ninety healthy volunteers. Intervention Single intravenous (IV) doses of tedizolid phosphate 50 mg (lead-in) and 100–400 mg. Single oral and IV dose of tedizolid phosphate 200 mg in crossover fashion. Multiple IV doses of tedizolid phosphate 200 and 300 mg for up to 7 days. Measurements and Main Results A dose-dependent increase was observed in the maximum plasma concentration (1.2–5.1 μg/ml) and the area under the concentration-time curve (17.4–58.7 μg × hr/ml) of tedizolid (the microbiologically active moiety of tedizolid phosphate) after single IV doses of tedizolid phosphate 100–400 mg. Administration of IV tedizolid phosphate 200 mg once/day for 7 days resulted in minimal (28%) tedizolid accumulation. The absolute oral bioavailability of tedizolid after a single 200-mg dose of tedizolid phosphate was 91%; pharmacokinetic parameters of tedizolid were similar with oral and IV administration. Treatment-related adverse events occurred in 41% of subjects. Most adverse events were related to infusion site and became more frequent with multiple dosing. In an additional 3-day tolerability study, IV tedizolid phosphate 200 mg and placebo were similarly tolerated, based on visual infusion phlebitis scores. Conclusion These results from a population of healthy volunteers support once/day dosing of tedizolid phosphate 200 mg with both the oral and IV formulations, without the

  6. Variable dose rate single-arc IMAT delivered with a constant dose rate and variable angular spacing

    NASA Astrophysics Data System (ADS)

    Tang, Grace; Earl, Matthew A.; Yu, Cedric X.

    2009-11-01

    Single-arc intensity-modulated arc therapy (IMAT) has gained worldwide interest in both research and clinical implementation due to its superior plan quality and delivery efficiency. Single-arc IMAT techniques such as the Varian RapidArc™ deliver conformal dose distributions to the target in one single gantry rotation, resulting in a delivery time in the order of 2 min. The segments in these techniques are evenly distributed within an arc and are allowed to have different monitor unit (MU) weightings. Therefore, a variable dose-rate (VDR) is required for delivery. Because the VDR requirement complicates the control hardware and software of the linear accelerators (linacs) and prevents most existing linacs from delivering IMAT, we propose an alternative planning approach for IMAT using constant dose-rate (CDR) delivery with variable angular spacing. We prove the equivalence by converting VDR-optimized RapidArc plans to CDR plans, where the evenly spaced beams in the VDR plan are redistributed to uneven spacing such that the segments with larger MU weighting occupy a greater angular interval. To minimize perturbation in the optimized dose distribution, the angular deviation of the segments was restricted to <=± 5°. This restriction requires the treatment arc to be broken into multiple sectors such that the local MU fluctuation within each sector is reduced, thereby lowering the angular deviation of the segments during redistribution. The converted CDR plans were delivered with a single gantry sweep as in the VDR plans but each sector was delivered with a different value of CDR. For four patient cases, including two head-and-neck, one brain and one prostate, all CDR plans developed with the variable spacing scheme produced similar dose distributions to the original VDR plans. For plans with complex angular MU distributions, the number of sectors increased up to four in the CDR plans in order to maintain the original plan quality. Since each sector was delivered

  7. Pharmacokinetics of pholcodine in healthy volunteers: single and chronic dosing studies.

    PubMed Central

    Chen, Z R; Bochner, F; Somogyi, A

    1988-01-01

    1. The pharmacokinetics of pholcodine after two single doses and after chronic administration were studied in healthy human volunteers. 2. Six subjects received single oral doses of 20 and 60 mg of pholcodine according to a balanced cross-over design with an interval of 3 weeks between the two treatments. Blood and saliva samples and all urine were collected over 168 h after each dosage administration. Subsequently, the same subjects received 20 mg pholcodine 8 hourly orally for 10 days. Blood and saliva samples and all urine were collected during an 8 h dosing interval after the last dose on day 11. 3. Plasma, saliva and urine concentrations of pholcodine were determined by a high performance liquid chromatographic assay. 4. After the single doses, pholcodine was absorbed rapidly (tmax = 1.6 +/- 1.2 h) and eliminated slowly with a mean half-life of 50.1 +/- 4.1 h. The renal clearance of pholcodine was 137 +/- 34 ml min-1 and was inversely correlated with urine pH (r = 0.60) but not with urine flow rate. 26.2 +/- 3.3% of the dose was excreted as unchanged pholcodine after both doses. The concentration of pholcodine in saliva was 3.6 times higher than in plasma. 5. After chronic administration, the pharmacokinetics of pholcodine were not statistically different from the single dose parameters. 6. Pholcodine did not appear to undergo conjugation. The plasma protein binding was 23.5%. Morphine, in unconjugated or conjugated form, was not detected in the urine of any subject after pholcodine administration. PMID:3190994

  8. Tumor Induction in Mice After Localized Single- or Fractionated-Dose Irradiation: Differences in Tumor Histotype and Genetic Susceptibility Based on Dose Scheduling

    SciTech Connect

    Edmondson, Elijah F.; Hunter, Nancy R.; Weil, Michael M.; Mason, Kathryn A.

    2015-07-15

    Purpose: To investigate differences in tumor histotype, incidence, latency, and strain susceptibility in mice exposed to single-dose or clinically relevant, fractioned-dose γ-ray radiation. Methods and Materials: C3Hf/Kam and C57BL/6J mice were locally irradiated to the right hindlimb with either single large doses between 10 and 70 Gy or fractionated doses totaling 40 to 80 Gy delivered at 2-Gy/d fractions, 5 d/wk, for 4 to 8 weeks. The mice were closely evaluated for tumor development in the irradiated field for 800 days after irradiation, and all tumors were characterized histologically. Results: A total of 210 tumors were induced within the radiation field in 788 mice. An overall decrease in tumor incidence was observed after fractionated irradiation (16.4%) in comparison with single-dose irradiation (36.1%). Sarcomas were the predominant postirradiation tumor observed (n=201), with carcinomas occurring less frequently (n=9). The proportion of mice developing tumors increased significantly with total dose for both single-dose and fractionated schedules, and latencies were significantly decreased in mice exposed to larger total doses. C3Hf/Kam mice were more susceptible to tumor induction than C57BL/6J mice after single-dose irradiation; however, significant differences in tumor susceptibilities after fractionated radiation were not observed. For both strains of mice, osteosarcomas and hemangiosarcomas were significantly more common after fractionated irradiation, whereas fibrosarcomas and malignant fibrous histiocytomas were significantly more common after single-dose irradiation. Conclusions: This study investigated the tumorigenic effect of acute large doses in comparison with fractionated radiation in which both the dose and delivery schedule were similar to those used in clinical radiation therapy. Differences in tumor histotype after single-dose or fractionated radiation exposures provide novel in vivo evidence for differences in tumor

  9. Prolonged central mu-opioid receptor occupancy after single and repeated nalmefene dosing.

    PubMed

    Ingman, Kimmo; Hagelberg, Nora; Aalto, Sargo; Någren, Kjell; Juhakoski, Auni; Karhuvaara, Sakari; Kallio, Antero; Oikonen, Vesa; Hietala, Jarmo; Scheinin, Harry

    2005-12-01

    The opioid antagonist nalmefene offers an alternative to traditional pharmacological treatments for alcoholism. The present study was designed to investigate the relationship between nalmefene plasma concentration and central mu-opioid receptor occupancy after a clinically effective dose (20 mg, orally). Pharmacokinetics and mu-opioid receptor occupancy of nalmefene after single and repeated dosing over 7 days was studied in 12 healthy subjects. Serial blood samples were obtained after both dosings, and pharmacokinetic parameters for nalmefene and main metabolites were determined. Central mu-opioid receptor occupancy of nalmefene was measured with positron emission tomography (PET) and [(11)C]carfentanil at four time points (3, 26, 50, 74 h) after both dosings. Nalmefene was rapidly absorbed in all subjects. The mean t(1/2) of nalmefene was 13.4 h after single and repeated dosing. The accumulation of nalmefene and its main metabolites in plasma during the repeated dosing period was as expected for a drug with linear pharmacokinetics, and steady-state was reached for all analytes. Both nalmefene dosings resulted in a very high occupancy at mu-opioid receptors (87-100%), and the decline in the occupancy was similar after both dosings but clearly slower than the decline in the plasma concentration of nalmefene or metabolites. High nalmefene occupancy (83-100%) persisted at 26 h after the dosings. The prolonged mu-opioid receptor occupancy by nalmefene indicates slow dissociation of the drug from mu-opioid receptors. These results support the rational of administering nalmefene when needed before alcohol drinking, and they additionally suggest that a high mu-opioid receptor occupancy can be maintained when nalmefene is taken once daily.

  10. Pharmacokinetics of Memantine after a Single and Multiple Dose of Oral and Patch Administration in Rats.

    PubMed

    Lee, Soo-Han; Kim, Seung-Hyun; Noh, Yook-Hwan; Choi, Byung-Moon; Noh, Gyu-Jeong; Park, Woo-Dae; Kim, Eun-Jung; Cho, Ik-Hyun; Bae, Chun-Sik

    2016-02-01

    Memantine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist used to treat Alzheimer's disease. We investigated memantine pharmacokinetics after oral, IV and patch administration in rats, and compared memantine pharmacokinetics after multiple- or single-dose oral and transdermal administration. Venous blood was collected at preset intervals in single- and multiple-dose studies. Non-compartmental pharmacokinetics was analysed for all formulations. The oral, IV and patch memantine doses were 10 mg/kg, 2 mg/kg and 8.21 ± 0.89 mg/kg, respectively. The maximum plasma concentration was lower and the half-life longer after patch administration than oral and IV administration. Memantine bioavailability was 41 and 63% for oral and patch administration, respectively. Steady state was achieved around 24 hr for oral and patch administration. The mean AUC increased after oral or patch administration from single to multiple dose. The memantine patch formulation displayed a longer duration of action and lower peak plasma concentration. However, drug exposure was similar to the oral formulation at each dose. Additionally, the memantine patch formulation displayed a smaller interindividual variability and lower accumulation than the oral formulation.

  11. Impact of dose size in single fraction spatially fractionated (grid) radiotherapy for melanoma

    SciTech Connect

    Zhang, Hualin E-mail: hualinzhang@yahoo.com; Zhong, Hualiang; Barth, Rolf F.; Cao, Minsong; Das, Indra J.

    2014-02-15

    Purpose: To evaluate the impact of dose size in single fraction, spatially fractionated (grid) radiotherapy for selectively killing infiltrated melanoma cancer cells of different tumor sizes, using different radiobiological models. Methods: A Monte Carlo technique was employed to calculate the 3D dose distribution of a commercially available megavoltage grid collimator in a 6 MV beam. The linear-quadratic (LQ) and modified linear quadratic (MLQ) models were used separately to evaluate the therapeutic outcome of a series of single fraction regimens that employed grid therapy to treat both acute and late responding melanomas of varying sizes. The dose prescription point was at the center of the tumor volume. Dose sizes ranging from 1 to 30 Gy at 100% dose line were modeled. Tumors were either touching the skin surface or having their centers at a depth of 3 cm. The equivalent uniform dose (EUD) to the melanoma cells and the therapeutic ratio (TR) were defined by comparing grid therapy with the traditional open debulking field. The clinical outcomes from recent reports were used to verify the authors’ model. Results: Dose profiles at different depths and 3D dose distributions in a series of 3D melanomas treated with grid therapy were obtained. The EUDs and TRs for all sizes of 3D tumors involved at different doses were derived through the LQ and MLQ models, and a practical equation was derived. The EUD was only one fifth of the prescribed dose. The TR was dependent on the prescribed dose and on the LQ parameters of both the interspersed cancer and normal tissue cells. The results from the LQ model were consistent with those of the MLQ model. At 20 Gy, the EUD and TR by the LQ model were 2.8% higher and 1% lower than by the MLQ, while at 10 Gy, the EUD and TR as defined by the LQ model were only 1.4% higher and 0.8% lower, respectively. The dose volume histograms of grid therapy for a 10 cm tumor showed different dosimetric characteristics from those of conventional

  12. Dose Control System in the Optima XE Single Wafer High Energy Ion Implanter

    SciTech Connect

    Satoh, Shu; Yoon, Jongyoon; David, Jonathan

    2011-01-07

    Photoresist outgassing can significantly compromise accurate dosimetry of high energy implants. High energy implant even at a modest beam current produces high beam powers which create significantly worse outgassing than low and medium energy implants and the outgassing continues throughout the implant due to the low dose in typical high energy implant recipes. In the previous generation of high energy implanters, dose correction by monitoring of process chamber pressure during photoresist outgassing has been used. However, as applications diversify and requirements change, the need arises for a more versatile photoresist correction system to match the versatility of a single wafer high energy ion implanter. We have successfully developed a new dosimetry system for the Optima XE single wafer high energy ion implanter which does not require any form of compensation due to the implant conditions. This paper describes the principles and performance of this new dose system.

  13. Single-dose radiation therapy for prevention of heterotopic ossification after total hip arthroplasty

    SciTech Connect

    Healy, W.L.; Lo, T.C.; Covall, D.J.; Pfeifer, B.A.; Wasilewski, S.A. )

    1990-12-01

    Single-dose radiation therapy was prospectively evaluated for its efficacy in prevention of heterotopic ossification in patients at high risk after total hip arthroplasty. Thirty-one patients (34 hips) were treated between 1981 and 1988. Risk factors for inclusion in the protocol included prior evidence of heterotopic ossification, ankylosing spondylitis, and diffuse idiopathic skeletal hyperostosis. Patients with hypertrophic osteoarthritis or traumatic arthritis with osteophytes were not included. Operations on 34 hips included 19 primary total and 11 revision total hip arthroplasties and 4 excisions of heterotopic ossification. All patients received radiotherapy to the hip after operation with a single dose of 700 centigray. Radiotherapy is recommended on the first postoperative day. After this single-dose radiation treatment, no patient had clinically significant heterotopic ossification. Recurrent disease developed in two hips (6%), as seen on radiography (grades 2 and 3). This series documents a 100% clinical success rate and a 94% radiographic success rate in preventing heterotopic ossification in patients at high risk after total hip arthroplasty. Single-dose radiotherapy is as effective as other radiation protocols in preventing heterotopic ossification after total hip arthroplasty. It is less expensive and easier to administer than multidose radiotherapy.

  14. Single dose testosterone administration alleviates gaze avoidance in women with Social Anxiety Disorder.

    PubMed

    Enter, Dorien; Terburg, David; Harrewijn, Anita; Spinhoven, Philip; Roelofs, Karin

    2016-01-01

    Gaze avoidance is one of the most characteristic and persistent social features in people with Social Anxiety Disorder (SAD). It signals social submissiveness and hampers adequate social interactions. Patients with SAD typically show reduced testosterone levels, a hormone that facilitates socially dominant gaze behavior. Therefore we tested as a proof of principle whether single dose testosterone administration can reduce gaze avoidance in SAD. In a double-blind, within-subject design, 18 medication-free female participants with SAD and 19 female healthy control participants received a single dose of 0.5mg testosterone and a matched placebo, at two separate days. On each day, their spontaneous gaze behavior was recorded using eye-tracking, while they looked at angry, happy, and neutral facial expressions. Testosterone enhanced the percentage of first fixations to the eye-region in participants with SAD compared to healthy controls. In addition, SAD patients' initial gaze avoidance in the placebo condition was associated with more severe social anxiety symptoms and this relation was no longer present after testosterone administration. These findings indicate that single dose testosterone administration can alleviate gaze avoidance in SAD. They support theories on the dominance enhancing effects of testosterone and extend those by showing that effects are particularly strong in individuals featured by socially submissive behavior. The finding that this core characteristic of SAD can be directly influenced by single dose testosterone administration calls for future inquiry into the clinical utility of testosterone in the treatment of SAD.

  15. Single intravenous and oral dose pharmacokinetics of florfenicol in the channel catfish Ictalurus punctatus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plasma distribution and elimination of florfenicol in channel catfish were investigated after a single dose (10mg/kg) of intravenous i.v.) or oral administration in freshwater at a mean water temperature of 25.4°C. Florfenicol concentrations in plasma were analyzed by means of liquid chromatography...

  16. MIND+ system; More universal dose patterns by single-step ion implantation

    NASA Astrophysics Data System (ADS)

    Okamoto, Yasuharu; Ninomiya, Shiro; Ochi, Akihiro; Ueno, Yusuke; Yamada, Tatsuya; Kimura, Yasuhiko; Kudo, Tetsuya; Koike, Masazumi; Suetsugu, Noriyuki; Ookita, Yoshiaki; Tsukihara, Mitsukuni; Sato, Fumiaki; Fuse, Genshu; Ueno, Kazuyoshi; Sugitani, Michiro

    2012-11-01

    Electrical characteristics of semi-conductor devices within a wafer are expected to be uniform based on control of the dose pattern during the ion implant process. SEN developed the MIND system (Mapping of Intentional Non-uniform Dosage), to provide such dose pattern control. This capability has been enhanced with MIND+. The new system provides improved two-dimensional dose pattern control with more degrees of freedom and greater accuracy than the original MIND system. In addition, MIND+ can generate practical dose patterns (see below) while using a single step implant. As a result, MIND+ provides a very powerful tool for yield enhancement without sacrificing throughput. This paper will provide more detail on the capabilities and practical applications of the MIND+ system.

  17. A pilot open label, single dose trial of fenobam in adults with fragile X syndrome

    PubMed Central

    Berry-Kravis, E; Hessl, D; Coffey, S; Hervey, C; Schneider, A; Yuhas, J; Hutchison, J; Snape, M; Tranfaglia, M; Nguyen, D V; Hagerman, R

    2009-01-01

    Objective: A pilot open label, single dose trial of fenobam, an mGluR5 antagonist, was conducted to provide an initial evaluation of safety and pharmacokinetics in adult males and females with fragile X syndrome (FXS). Methods: Twelve subjects, recruited from two fragile X clinics, received a single oral dose of 50–150 mg of fenobam. Blood for pharmacokinetic testing, vital signs and side effect screening was obtained at baseline and numerous time points for 6 h after dosing. Outcome measures included prepulse inhibition (PPI) and a continuous performance test (CPT) obtained before and after dosing to explore the effects of fenobam on core phenotypic measures of sensory gating, attention and inhibition. Results: There were no significant adverse reactions to fenobam administration. Pharmacokinetic analysis showed that fenobam concentrations were dose dependent but variable, with mean (SEM) peak values of 39.7 (18.4) ng/ml at 180 min after the 150 mg dose. PPI met a response criterion of an improvement of at least 20% over baseline in 6 of 12 individuals (4/6 males and 2/6 females). The CPT did not display improvement with treatment due to ceiling effects. Conclusions: Clinically significant adverse effects were not identified in this study of single dose fenobam across the range of dosages utilised. The positive effects seen in animal models of FXS treated with fenobam or other mGluR5 antagonists, the apparent lack of clinically significant adverse effects, and the potential beneficial clinical effects seen in this pilot trial support further study of the compound in adults with FXS. PMID:19126569

  18. Interdisciplinary science and the design of a single-dose antibiotic therapy.

    PubMed

    Curatolo, William

    2011-09-01

    Azithromycin is a unique antibiotic due to its serum half-life of 69 h. This half-life is long enough to permit administration of an entire course of therapy in a single dose, if the gastrointestinal (GI) side effects of such a high dose can be minimized. A series of exploratory clinical pharmacology studies were carried out to understand the site-specific absorption and toleration constraints involved in delivering a 2 g oral single-dose regimen. These studies demonstrated that (a) GI side effects were locally mediated in the GI tract, (b) the duodenum was more sensitive than the ileocecal region, and (c) colonic absorption was limited. A novel controlled release suspension dosage form was designed to meet these constraints, and was shown to deliver the desired systemic dose with acceptable toleration. This dosage form, Zmax®, is an oral powder-for-constitution which possesses two major features: (a) 200 μm controlled release microspheres which release the drug as they transit down the small intestine, and (b) alkalizing agents which raise the pH of the gastric milieu for ~20 min to minimize gastric release of the drug (which has high solubility at low pH), in order to minimize exposure of the drug to the sensitive duodenal region. The ability to provide a high single dose of azithromycin results in "front-loading" the mononuclear and polymorphonuclear leukocytes which concentrate the drug and carry it to sites of infection. This provides high drug concentrations early on at infection sites, when the bacterial burden is greatest, potentially improving efficacy and potentially overcoming resistant bacterial strains. Finally, this revolutionary single dose formulation gives 100% compliance, which maximizes the likelihood of therapeutic success.

  19. Single Intramuscular-dose Toxicity of Anti-inflammatory Pharmacopuncture in Rats

    PubMed Central

    Jung, Da-jung; Kim, Sung-chul; Lee, Hyung-geol; Choi, Yoo-min; Sin, Min-seop; Choi, Seok-woo; Hong, Seung-won; Song, Beom-yong; Kim, Jong-uk; Yook, Tae-han

    2013-01-01

    Objectives: This study was performed to analyze the toxicity of the test substance, anti-inflammatory pharmacopuncture (AIP), when used as a single intramuscular-dose in 6-week-old, male and female Sprague-Dawley rats and to find the lethal dose. Methods: The experiment was conducted at Biotoxtech according to Good Laboratory Practices. Twenty (20) female and 20 male Spague-Dawley rats were divided into 4 groups of five 5 female and 5 male animals per group. The rats in the three experimental groups received single intramuscular injections with 0.1-㎖, 0.5-㎖ and 1.0-㎖/animal doses of AIP, Groups 2, 3, and 4, respectively, and the control group, Group 1, received a single intramuscular injection with a 1.0-㎖ dose of normal saline. Clinical signs were observed and body weight measurements were carried out for 14 days following the injections. At the end of the observation period, hematology, clinical chemistry, histopathological tests and necropsy were performed on the injected parts. Results: No deaths occurred in any of the groups. Also, histopathological tests showed that AIP had no effect on the injected parts in terms of clinical signs, body weight, hematology, clinical chemistry, and necropsy. Conclusions: As a result of single intramuscular-dose tests of the test substance AIP in 4 groups of rats, the lethal dose for both males and females exceeded 1.0㎖/animal. Therefore, AIP is a relatively safe pharmacopuncture that can be used for treatment, but further studies should be performed. PMID:25780679

  20. Acute and chronic bioeffects of single and multiple doses of piezoelectric shockwaves (EDAP LT.01).

    PubMed

    Ryan, P C; Jones, B J; Kay, E W; Nowlan, P; Kiely, E A; Gaffney, E F; Butler, M R

    1991-02-01

    Piezoelectric second generation lithotriptors are an established means of administering extracorporeal shockwave lithotripsy (ESWL) enabling treatment to be performed without anaesthesia or analgesia, but higher shockwave doses and multiple or staged treatment are frequently required. The bioeffects of this modality of ESWL, therefore, require further assessment. Seven experimental groups of adult male rabbits were treated using the EDAP LT.01 in order to determine the acute and chronic bioeffects of clinical dose, excess dose, divided excess dose, high frequency and multiple treatment (X10) piezoelectric shockwaves (PSW). Renal function was measured before and after treatment using mercaptoacetyltriglycine (MAG 3) scans. Gross and histological morphological changes were assessed at one and 30 days following application of PSW. Application of single clinical dose PSW was not associated with any significant functional or morphological renal injury. Excess dose PSW caused transient gross renal contusion, which resolved in the majority of animals with no persistent microscopic abnormality. Divided excess dose PSW resulted in no gross or microscopic damage. High frequency PSW was associated with mild histological abnormality. Multiple PSW treatments caused small discrete fibrotic lesions in all cases, without any change in renal function.

  1. Acute tolerance to rate-decreasing effects of single doses of ethanol.

    PubMed

    Ginsburg, Brett C; Martinez, Gerardo; Friesenhahn, Gregory; Javors, Martin; Lamb, R J

    2008-06-01

    Acute tolerance occurs when behavioral impairment is greater at a given blood ethanol concentration (BAC) on the ascending versus descending limb of the BAC-time curve following administration of a single dose of ethanol, however studies utilizing learned behaviors have not been widely reported. We assessed acute tolerance to single doses of ethanol in five Lewis rats responding under a fixed-ratio (FR8) schedule of food presentation. Response rates for food during 1-min components (ending 2, 4, 11, 18, 33, and 57 min after ethanol administration) were determined, and BAC was measured immediately after each component using a rat breathalyzer. Ethanol (0.4, 0.6, 0.8, and 1.2 g/kg, i.p.) produced dose-related decreases in responding for food that tended to recover over time for all but the highest dose tested. Similarly, dose-related increases in BAC were also observed. Using either an analysis that expressed impairment per unit BAC on the ascending limb versus the descending limb (by assessing the area under the curve (AUC) for behavior and BAC on each limb), the slope of the function that relates the behavioral effect to BAC (each expressed as percent maximum effect), or a variant of the Mellanby method (hysteresis), acute tolerance was observed following a dose of 0.4 g/kg ethanol. Though behavior appeared to recover on the descending limb following higher doses (especially 0.6 and 0.8 g/kg), acute tolerance to these doses was not present. PMID:18328511

  2. Intravenous Single-Dose Toxicity of Redaporfin-Based Photodynamic Therapy in Rodents

    PubMed Central

    Rocha, Luis B.; Schaberle, Fábio; Dąbrowski, Janusz M.; Simões, Sérgio; Arnaut, Luis G.

    2015-01-01

    We assessed the tolerability and safety in rodents of a single intravenous (i.v.) dose of redaporfin, a novel photosensitizer for Photodynamic Therapy (PDT) of cancer. Two approaches were used to evaluate acute toxicity: (i) a dose escalation study in BALB/c mice to evaluate the maximum tolerated dose of redaporfin; and (ii) a safety toxicology study in Wistar rats, of a single dose of redaporfin, with or without illumination, to evaluate possible signs of systemic toxicity. Redaporfin formulation was well tolerated by mice, with no signs of adverse reactions up to 75 mg/kg. In rats, there were no relevant changes, except for a significant, but transient, increase in the blood serum markers for hepatic function and muscle integrity, and also on neutrophil counts, observed after the application of light. The overall results showed that redaporfin-PDT is very well tolerated. No abnormalities were observed, including reactions at the injection site or skin phototoxicity, although the animals were maintained in normal indoor lighting. Redaporfin also showed a high efficacy in the treatment of male BALB/c mice with subcutaneously implanted colon (CT26) tumours. Vascular-PDT with 1.5 mg/kg redaporfin and a light dose of 74 J/cm2 led to the complete tumour regression in 83% of the mice. PMID:26670231

  3. SINGLE- VERSUS DOUBLE-DOSE RABIES VACCINATION IN CAPTIVE AFRICAN WILD DOGS (LYCAON PICTUS).

    PubMed

    Connolly, Maren; Thomas, Patrick; Woodroffe, Rosie; Raphael, Bonnie L

    2015-12-01

    The immune responses of 35 captive African wild dogs (Lycaon pictus) to an inactivated rabies virus vaccine were evaluated. Seventeen animals received one 1-ml dose of inactivated rabies vaccine administered intramuscularly, while 18 received two 1-ml doses given simultaneously but at different injection sites. Sera were collected from all animals prior to vaccination and intermittently from a subset of animals between 3 and 49 mo postvaccination. Rabies neutralizing serum antibody titers were measured by rapid fluorescent focus inhibition testing. Within 3 mo postvaccination, all 28 animals that were tested within that time period had seroconverted. Overall, titers were significantly higher among animals given two doses of vaccine than among those given a single dose, although this difference was no longer significant by 15 mo postvaccination. Regardless of initial dose, a single administration of inactivated rabies virus vaccine resulted in long-term elevation of titers in the African wild dogs in this study. In the two individuals followed for greater than 36 mo, both (one from each group) maintained detectable titers.

  4. SINGLE- VERSUS DOUBLE-DOSE RABIES VACCINATION IN CAPTIVE AFRICAN WILD DOGS (LYCAON PICTUS).

    PubMed

    Connolly, Maren; Thomas, Patrick; Woodroffe, Rosie; Raphael, Bonnie L

    2015-12-01

    The immune responses of 35 captive African wild dogs (Lycaon pictus) to an inactivated rabies virus vaccine were evaluated. Seventeen animals received one 1-ml dose of inactivated rabies vaccine administered intramuscularly, while 18 received two 1-ml doses given simultaneously but at different injection sites. Sera were collected from all animals prior to vaccination and intermittently from a subset of animals between 3 and 49 mo postvaccination. Rabies neutralizing serum antibody titers were measured by rapid fluorescent focus inhibition testing. Within 3 mo postvaccination, all 28 animals that were tested within that time period had seroconverted. Overall, titers were significantly higher among animals given two doses of vaccine than among those given a single dose, although this difference was no longer significant by 15 mo postvaccination. Regardless of initial dose, a single administration of inactivated rabies virus vaccine resulted in long-term elevation of titers in the African wild dogs in this study. In the two individuals followed for greater than 36 mo, both (one from each group) maintained detectable titers. PMID:26667524

  5. Efficacy of a single high oxfendazole dose against gastrointestinal nematodes in naturally infected pigs.

    PubMed

    Alvarez, Luis; Saumell, Carlos; Fusé, Luis; Moreno, Laura; Ceballos, Laura; Domingue, Gilbert; Donadeu, Meritxell; Dungu, Baptiste; Lanusse, Carlos

    2013-05-01

    The goal of the current experiment was to assess the clinical efficacy of oxfendazole (OFZ) administered as a single oral dose (30 mg/kg) to pigs naturally parasitized with Ascaris suum, Oesophagostomum spp., Metastrongylus spp. and Trichuris suis. Thirty-six local ecotype piglets were divided into three independent experiments, named I, II and III (n=12 each), respectively. Each experiment involved two different groups (n=6): Untreated Control and OFZ treated. Animals were naturally parasitized with A. suum (Experiments I, II and III), Oesophagostomum spp. (Experiments I and II), T. suis (Experiments II and III) and Metastrongylus spp. (Experiment I). Pigs in the treated group received OFZ (Synanthic(®), Merial Ltd., 9.06% suspension) orally at 30 mg/kg dose. At five (5) days post-treatment, animals were sacrificed and the clinical efficacy of the OFZ treatment was established following the currently available WAAVP guidelines for a controlled efficacy test. None of the animals involved in this experiment showed any adverse events during the study. OFZ treatment given as a single 30 mg/kg oral dose showed a 100% efficacy against all the nematode parasites present in the three experiments. In conclusion, under the current experimental conditions, OFZ orally administered to naturally parasitized piglets at a single dose of 30 mg/kg was safe and highly efficacious (100%) against adult stages of A. suum, Oesophagostomum spp., T. suis and Metastrongylus spp. PMID:23357598

  6. Efficacy of a single high oxfendazole dose against gastrointestinal nematodes in naturally infected pigs.

    PubMed

    Alvarez, Luis; Saumell, Carlos; Fusé, Luis; Moreno, Laura; Ceballos, Laura; Domingue, Gilbert; Donadeu, Meritxell; Dungu, Baptiste; Lanusse, Carlos

    2013-05-01

    The goal of the current experiment was to assess the clinical efficacy of oxfendazole (OFZ) administered as a single oral dose (30 mg/kg) to pigs naturally parasitized with Ascaris suum, Oesophagostomum spp., Metastrongylus spp. and Trichuris suis. Thirty-six local ecotype piglets were divided into three independent experiments, named I, II and III (n=12 each), respectively. Each experiment involved two different groups (n=6): Untreated Control and OFZ treated. Animals were naturally parasitized with A. suum (Experiments I, II and III), Oesophagostomum spp. (Experiments I and II), T. suis (Experiments II and III) and Metastrongylus spp. (Experiment I). Pigs in the treated group received OFZ (Synanthic(®), Merial Ltd., 9.06% suspension) orally at 30 mg/kg dose. At five (5) days post-treatment, animals were sacrificed and the clinical efficacy of the OFZ treatment was established following the currently available WAAVP guidelines for a controlled efficacy test. None of the animals involved in this experiment showed any adverse events during the study. OFZ treatment given as a single 30 mg/kg oral dose showed a 100% efficacy against all the nematode parasites present in the three experiments. In conclusion, under the current experimental conditions, OFZ orally administered to naturally parasitized piglets at a single dose of 30 mg/kg was safe and highly efficacious (100%) against adult stages of A. suum, Oesophagostomum spp., T. suis and Metastrongylus spp.

  7. Effects of single-dose and fractionated cranial irradiation on rat brain accumulation of methotrexate

    SciTech Connect

    Kamen, B.A.; Moulder, J.E.; Kun, L.E.; Ring, B.J.; Adams, S.M.; Fish, B.L.; Holcenberg, J.S.

    1984-11-01

    The effects of single-dose and fractionated whole-brain irradiation on brain methotrexate (MTX) has been studied in a rat model. The amount of MTX present in the brain 24 hr after a single i.p. dose (100 mg/kg) was the same whether animals were sham irradiated or given a single dose of 2000 rads 6 or 48 hr prior to the drug (6.9, 8.3, and 6.8 pmol MTX/g, wet weight, respectively). Animals sham irradiated or given 2000 rads in 10 fractions over 11 days and treated with an average dose of 1.2 mg MTX/kg i.p. twice a week for 24 weeks did not differ significantly in their brain MTX concentration (7.9 and 8.3 pmol MTX/g, wet weight, respectively). Chronically MTX-treated animals became folate deficient whether they were irradiated or not (450 and 670 pmol folate/g, wet weight, brain in MTX-treated and control animals). Thus, MTX accumulates in the brain with acute or chronic administration, and this accumulation is not altered by this amount of brain irradiation.

  8. Single-dose Intravenous Toxicology Testing of Daebohwalryeok Pharmcopuncture in Sprague-Dawley Rats

    PubMed Central

    Sun, Seung-Ho; Park, Sunju; Jeong, Jong-Jin; Lee, Kwang-Ho; Yu, Jun-Sang; Seo, Hyung-Sik; Kwon, Ki-Rok

    2015-01-01

    Objectives: The aims of the study were to test the single-dose intravenous toxicity of Daebohwalryeok pharmacopuncture (DHRP) in Sprague-Dawley (SD) rats and to estimate the crude lethal dose. Methods: The experiments were conducted at Biotoxtech Co., a Good Laboratory Practice (GLP) laboratory, according to the GLP regulation and were approved by the Institutional Animal Care and Use Committee of Biotoxtech Co. (Approval no: 110156). The rats were divided into three groups: DHRP was injected into the rats in the two test groups at doses of 10 mL/kg and 20 mL/kg, respectively, and normal saline solution was injected into the rats in the control group. Single doses of DHRP were injected intravenously into 6 week old SD rats (5 male and 5 female rats per group). General symptoms were observed and weights were measured during the 14 day observation period after the injection. After the observation period, necropsies were done. Then, histopathological tests were performed. Weight data were analyzed with a one-way analysis of variance (ANOVA) by using statistical analysis system (SAS, version 9.2). Results: No deaths and no statistical significant weight changes were observed for either male or female SD rats in either the control or the test groups during the observation period. In addition, no treatment related general symptoms or necropsy abnormalities were observed. Histopathological results showed no DHRP related effects in the 20 mL/kg DHRP group for either male or female rats. Conclusion: Under the conditions of this study, the results from single-dose intravenous injections of DHRP showed that estimated lethal doses for both male and female rats were above 20 mL/kg. PMID:26120487

  9. Sequential morphologic analysis of the nephrotoxicity produced in rats by single doses of chlorozotocin.

    PubMed

    Dees, J H; Kramer, R A

    1986-01-01

    Chlorozotocin is a chloroethylnitrosourea antitumor agent that is in clinical trial for a variety of human tumors. Renal failure has been a reported side effect of treatment with several of the chloroethylnitrosoureas, including chlorozotocin. To better understand the pathogenesis of this target organ toxicity, we have studied the nephrotoxicity of a single high, intermediate, or low dose of chlorozotocin in male F344 rats. We report here the sequence of histopathologic changes seen over a 1-10-day (high dose) or 1-28-day (intermediate or low dose) period. The single high dose (40 mg/kg, s.c.) produced an acute cortical necrosis involving the proximal tubules, followed by later necrotic changes in the collecting ducts in the inner medulla. Karyomegaly was noted at 10 days in occasional cells of the papillary collecting ducts and urinary epithelium lining the papilla. A single intermediate dose (25 mg/kg, s.c.) caused a similar but less severe injury of later onset. Proximal tubule injury was less severe and more limited. Necrosis of papillary collecting ducts was not seen; however, karyomegaly was pronounced in cells of the collecting ducts in the inner stripe of the outer medulla and inner medulla, and in the urinary epithelium covering the papilla. No discernible histopathology was present following the low dose (12.5 mg/kg, s.c.) of chlorozotocin. The histopathology was correlated with biochemical parameters. Our findings have possible implications for monitoring the severity of nephrotoxic side effects in patients, as well as provide preliminary evidence that this antineoplastic agent may itself cause preneoplastic changes, a finding with important long term implications.

  10. Safety and Efficacy of Single Dose versus Multiple Doses of AmBisome® for Treatment of Visceral Leishmaniasis in Eastern Africa: A Randomised Trial

    PubMed Central

    Khalil, Eltahir A. G.; Weldegebreal, Teklu; Younis, Brima M.; Omollo, Raymond; Musa, Ahmed M.; Hailu, Workagegnehu; Abuzaid, Abuzaid A.; Dorlo, Thomas P. C.; Hurissa, Zewdu; Yifru, Sisay; Haleke, William; Smith, Peter G.; Ellis, Sally; Balasegaram, Manica; EL-Hassan, Ahmed M.; Schoone, Gerard J.; Wasunna, Monique; Kimutai, Robert; Edwards, Tansy; Hailu, Asrat

    2014-01-01

    Background Anti-leishmanial drug regimens that include a single dose AmBisome® could be suitable for eastern African patients with symptomatic visceral leishmaniasis (VL) but the appropriate single dose is unknown. Methodology A multi-centre, open-label, non-inferiority, randomized controlled trial with an adaptive design, was conducted to compare the efficacy and safety of a single dose and multiple doses of AmBisome® for the treatment of VL in eastern Africa. The primary efficacy endpoint was definitive cure (DC) at 6 months. Symptomatic patients with parasitologically-confirmed, non-severe VL, received a single dose of AmBisome® 7.5 mg/kg body weight or multiple doses, 7 times 3 mg/kg on days 1–5, 14, and 21. If interim analyses, evaluated 30 days after the start of treatment following 40 or 80 patients, showed the single dose gave significantly poorer parasite clearance than multiple doses at the 5% significance level, the single dose was increased by 2·5 mg/kg. In a sub-set of patients, parasite clearance was measured by quantitative reverse transcriptase (qRT) PCR. Principal Findings The trial was terminated after the third interim analysis because of low efficacy of both regimens. Based on the intention-to-treat population, DC was 85% (95%CI 73–93%), 40% (95%CI 19–64%), and 58% (95%CI 41–73%) in patients treated with multiple doses (n = 63), and single doses of 7·5 (n = 21) or 10 mg/kg (n = 40), respectively. qRT-PCR suggested superior parasite clearance with multiple doses as early as day 3. Safety data accorded with the drug label. Conclusions The tested AmBisome® regimens would not be suitable for VL treatment across eastern Africa. An optimal single dose regimen was not identified. Trials Registration www.clinicaltrials.gov NCT00832208 PMID:24454970

  11. The effect of a single oral dose of pergolide on intraocular pressure and pupil diameter.

    PubMed Central

    al-Sereiti, M R; Quik, R F; Turner, P

    1989-01-01

    1. The ocular hypotensive effect of a single oral dose of 25 micrograms pergolide, a dopamine 2-receptor agonist, was studied in 12 normal human volunteers, using a non-invasive method. 2. An oral dose of timolol 20 mg was used as a positive control. 3. The effects of both drugs on pupil diameter were also studied, using a photographic method. 4. Considering the first 6 h post-dosing measurements, using multiple linear regression analysis comparing drug with placebo and including the baseline values as continuous independent variables, both pergolide and timolol had a significant ocular hypotensive effect in both eyes (P less than 0.0001) with no significant effects on pupil diameter. 5. Further topical application studies in normal and glaucomatous eyes are needed to evaluate the usefulness of pergolide in the treatment of glaucoma. PMID:2789919

  12. Single high dose intraoperative electrons for advanced stage pancreatic cancer: Phase I pilot study

    SciTech Connect

    Goldson, A.L.; Ashaveri, E.; Espinoza, M.C.

    1981-07-01

    Phase I toxicity studies with intraoperative radiotherapy proved to be a feasible adjunct to surgery for unresectable malignancies of the pancreas at Howard University Hospital. There have been minimal side effects or complications related to the combination of limited surgical decompression and intraoperative radiotherapy alone. The toxic effects of intraoperative radiotherapy on normal tissues is being assessed on a dose volume basis. Doses of 2000 to 2500 rad in a single exposure to include the pancreas, regional nodes and duodenum are acceptable if the total treatment volume is less than or equal to 100 cm. The tumoricidal effects on the cancer are demonstratable when one reviews the pathological specimens that illustrate massive tumor necrosis and fibros replacement, but in all cases reviewed, viable cancer was noted. Intraoperative radiotherapy, therefore, represents a significant boost dose for resectable, partially resectable or non-resectable tumors when added to conventional external beam irradiation and/or chemotherapy. Preliminary clinical data and minimal toxicity justifies further investigation.

  13. Single-dose Intramuscular Injection Toxicology of Danggui Pharmacopuncture (DGP) in Sprague-Dawley Rats

    PubMed Central

    Sun, SeungHo; Jeong, JongJin; Park, Sunju; Lee, KwangHo; Yu, JunSang; Seo, Hyung-Sik; Kwon, KiRok

    2015-01-01

    Objectives: The purpose of the study is to assess both the approximate lethal dose and the single dose intramuscular injection toxicity of Danggui (Angelica gigantis radix) pharmacopuncture (DGP) in Sprague-Dawley (SD) rats. Methods: The experiments were conducted at the good laboratory practice (GLP) laboratory, Biotoxtech Co., which is a laboratory approved by the ministry of food and drug safety (MFDS). The study was performed according to the GLP regulation and the toxicity test guidelines of the MFDS (2009) after approval of the institutional animal care and use committee of Biotoxtech. Single doses of DGP were injected intramuscularly into the rats in three test groups of 6 week old SD rats (5 male and 5 female rats per groups) in the amounts of 0.1, 0.5, and 1.0 mL/animal for groups 2, 3, and 4, respectively, and normal saline solution in the amount of 1.0 mL/animal was injected intramuscularly into the rats (5 male and 5 female rats) in the control group. Observations of the general symptoms and weight measurements were performed during the 14 day observation period after the injection. Hematologic and serum biochemical examination, necropsy, and a local tolerance test at the injection site were done after the observation period. Results: No death was observed in three test groups (0.1, 0.5 and 1.0 mL/animal group). In addition, the injection of DGP had no effect on general symptoms, weights, hematologic and serum biochemical examination, and necropsy. The results from the local tolerance tests at injection site showed no treatment related effects in the SD rats. Conclusion: The results of single dose intramuscular injection of DGP suggest that the approximate lethal dose is above 1.0 mL/animal for both male and female SD rats and that intramuscular injection of DGP may be safe. PMID:25830059

  14. Single-dose monomeric HA subunit vaccine generates full protection from influenza challenge

    PubMed Central

    Mallajosyula, Jyothi K; Hiatt, Ernie; Hume, Steve; Johnson, Ashley; Jeevan, Trushar; Chikwamba, Rachel; Pogue, Gregory P; Bratcher, Barry; Haydon, Hugh; Webby, Richard J; McCormick, Alison A

    2014-01-01

    Recombinant subunit vaccines are an efficient strategy to meet the demands of a possible influenza pandemic, because of rapid and scalable production. However, vaccines made from recombinant hemagglutinin (HA) subunit protein are often of low potency, requiring high dose or boosting to generate a sustained immune response. We have improved the immunogenicity of a plant-made HA vaccine by chemical conjugation to the surface of the Tobacco mosaic virus (TMV) which is non infectious in mammals. We have previously shown that TMV is taken up by mammalian dendritic cells and is a highly effective antigen carrier. In this work, we tested several TMV-HA conjugation chemistries, and compared immunogenicity in mice as measured by anti-HA IgG titers and hemagglutination inhibition (HAI). Importantly, pre-existing immunity to TMV did not reduce initial or boosted titers. Further optimization included dosing with and without alum or oil-in water adjuvants. Surprisingly, we were able to stimulate potent immunogenicity and HAI titers with a single 15µg dose of HA as a TMV conjugate. We then evaluated the efficacy of the TMV-HA vaccine in a lethal virus challenge in mice. Our results show that a single dose of the TMV-HA conjugate vaccine is sufficient to generate 50% survival, or 100% survival with adjuvant, compared with 10% survival after vaccination with a commercially available H1N1 vaccine. TMV-HA is an effective dose-sparing influenza vaccine, using a single-step process to rapidly generate large quantities of highly effective flu vaccine from an otherwise low potency HA subunit protein. PMID:24378714

  15. Pharmacokinetics of Single- and Multiple-Dose Oral Clarithromycin in Soft Tissues Determined by Microdialysis▿

    PubMed Central

    Traunmüller, Friederike; Zeitlinger, Markus; Zeleny, Petra; Müller, Markus; Joukhadar, Christian

    2007-01-01

    The antimicrobial spectrum of clarithromycin renders this antibiotic a frequently used option in the treatment of skin and soft-tissue infections. In most cases, these infections are caused by extracellularly proliferating microorganisms. Thus, clarithromycin concentrations achieved in the interstitial space are considered particularly important for clinical efficacy. In the present study, clarithromycin concentrations in plasma and interstitial-space fluid of subcutaneous adipose tissue and skeletal muscle of six healthy male volunteers were assessed by means of the microdialysis technique after oral single-dose administration of 250 mg and multiple doses of 500 mg of clarithromycin twice a day (b.i.d.). The ratios of the area under the concentration-time curve of free clarithromycin from 0 to 24 h calculated for a single dose of 250 mg (fAUC0-24) in interstitial-space fluid to the fAUC0-24 in plasma were 0.29 ± 0.17 and 0.42 ± 0.18 for subcutis and skeletal muscle, respectively. For 500 mg of clarithromycin at the steady state (3 to 5 days of intake twice daily), the fAUC0-24(b.i.d.) ratios at the steady state were 0.39 ± 0.04 and 0.41 ± 0.19 for subcutis and skeletal muscle, respectively. The half-life was around 2 h after a single dose but increased to approximately 4 h in plasma and tissues after repetitive clarithromycin administration. Based on subsequently performed pharmacokinetic-pharmacodynamic calculations, a dosing regimen of 500 mg b.i.d. may be ineffective in the treatment of soft-tissue infections caused by pathogens with a drug MIC higher than 0.125 mg/liter. PMID:17606673

  16. Pharmacokinetics of single- and multiple-dose oral clarithromycin in soft tissues determined by microdialysis.

    PubMed

    Traunmüller, Friederike; Zeitlinger, Markus; Zeleny, Petra; Müller, Markus; Joukhadar, Christian

    2007-09-01

    The antimicrobial spectrum of clarithromycin renders this antibiotic a frequently used option in the treatment of skin and soft-tissue infections. In most cases, these infections are caused by extracellularly proliferating microorganisms. Thus, clarithromycin concentrations achieved in the interstitial space are considered particularly important for clinical efficacy. In the present study, clarithromycin concentrations in plasma and interstitial-space fluid of subcutaneous adipose tissue and skeletal muscle of six healthy male volunteers were assessed by means of the microdialysis technique after oral single-dose administration of 250 mg and multiple doses of 500 mg of clarithromycin twice a day (b.i.d.). The ratios of the area under the concentration-time curve of free clarithromycin from 0 to 24 h calculated for a single dose of 250 mg (fAUC(0-24)) in interstitial-space fluid to the fAUC(0-24) in plasma were 0.29 +/- 0.17 and 0.42 +/- 0.18 for subcutis and skeletal muscle, respectively. For 500 mg of clarithromycin at the steady state (3 to 5 days of intake twice daily), the fAUC(0-24(b.i.d.)) ratios at the steady state were 0.39 +/- 0.04 and 0.41 +/- 0.19 for subcutis and skeletal muscle, respectively. The half-life was around 2 h after a single dose but increased to approximately 4 h in plasma and tissues after repetitive clarithromycin administration. Based on subsequently performed pharmacokinetic-pharmacodynamic calculations, a dosing regimen of 500 mg b.i.d. may be ineffective in the treatment of soft-tissue infections caused by pathogens with a drug MIC higher than 0.125 mg/liter. PMID:17606673

  17. Single-dose monomeric HA subunit vaccine generates full protection from influenza challenge.

    PubMed

    Mallajosyula, Jyothi K; Hiatt, Ernie; Hume, Steve; Johnson, Ashley; Jeevan, Trushar; Chikwamba, Rachel; Pogue, Gregory P; Bratcher, Barry; Haydon, Hugh; Webby, Richard J; McCormick, Alison A

    2014-01-01

    Recombinant subunit vaccines are an efficient strategy to meet the demands of a possible influenza pandemic, because of rapid and scalable production. However, vaccines made from recombinant hemagglutinin (HA) subunit protein are often of low potency, requiring high dose or boosting to generate a sustained immune response. We have improved the immunogenicity of a plant-made HA vaccine by chemical conjugation to the surface of the Tobacco mosaic virus (TMV) which is non infectious in mammals. We have previously shown that TMV is taken up by mammalian dendritic cells and is a highly effective antigen carrier. In this work, we tested several TMV-HA conjugation chemistries, and compared immunogenicity in mice as measured by anti-HA IgG titers and hemagglutination inhibition (HAI). Importantly, pre-existing immunity to TMV did not reduce initial or boosted titers. Further optimization included dosing with and without alum or oil-in water adjuvants. Surprisingly, we were able to stimulate potent immunogenicity and HAI titers with a single 15 µg dose of HA as a TMV conjugate. We then evaluated the efficacy of the TMV-HA vaccine in a lethal virus challenge in mice. Our results show that a single dose of the TMV-HA conjugate vaccine is sufficient to generate 50% survival, or 100% survival with adjuvant, compared with 10% survival after vaccination with a commercially available H1N1 vaccine. TMV-HA is an effective dose-sparing influenza vaccine, using a single-step process to rapidly generate large quantities of highly effective flu vaccine from an otherwise low potency HA subunit protein. PMID:24378714

  18. Efficacy of a single oral dose of oxfendazole against Fasciola hepatica in naturally infected sheep.

    PubMed

    Gomez-Puerta, Luis A; Gavidia, Cesar; Lopez-Urbina, Maria T; Garcia, Hector H; Gonzalez, Armando E

    2012-03-01

    The efficacy of a single oral dose of 30 mg/kg of oxfendazole against Fasciola hepatica was evaluated in a controlled study in naturally infected sheep. Sheep were diagnosed by stool microscopy after sedimentation, and positive animals were randomized to oxfendazole (N = 20) or no treatment (N = 20). A new stool exam was performed 10 days after treatment. All stool microscopies were performed masked to the treatment group. No side effects were noticed. All sheep in the control group remained infected with similar counts of eggs per gram of stools. None of the animals in the treatment group showed Fasciola eggs in stools after 10 days of treatment. A single dose of oxfendazole is highly effective against F. hepatica, providing a new drug alternative for the control of fascioliasis or integrated zoonosis control.

  19. Efficacy of a Single Oral Dose of Oxfendazole against Fasciola hepatica in Naturally Infected Sheep

    PubMed Central

    Gomez-Puerta, Luis A.; Gavidia, Cesar; Lopez-Urbina, Maria T.; Garcia, Hector H.; Gonzalez, Armando E.

    2012-01-01

    The efficacy of a single oral dose of 30 mg/kg of oxfendazole against Fasciola hepatica was evaluated in a controlled study in naturally infected sheep. Sheep were diagnosed by stool microscopy after sedimentation, and positive animals were randomized to oxfendazole (N = 20) or no treatment (N = 20). A new stool exam was performed 10 days after treatment. All stool microscopies were performed masked to the treatment group. No side effects were noticed. All sheep in the control group remained infected with similar counts of eggs per gram of stools. None of the animals in the treatment group showed Fasciola eggs in stools after 10 days of treatment. A single dose of oxfendazole is highly effective against F. hepatica, providing a new drug alternative for the control of fascioliasis or integrated zoonosis control. PMID:22403323

  20. Pharmacokinetics of marbofloxacin after a single oral dose to loggerhead sea turtles (Caretta caretta).

    PubMed

    Marín, P; Lai, O R; Laricchiuta, P; Marzano, G; Di Bello, A; Cárceles, C M; Crescenzo, G

    2009-10-01

    The single-dose disposition kinetics of marbofloxacin (MBX) were determined in clinically healthy loggerhead sea turtles (n=5) after oral (PO) administration of 2 mg kg(-1) bodyweight. Marbofloxacin plasma concentrations were determined by DAD-HPLC (LOD/LOQ 0.015/0.05 microg ml(-1)). Data were subjected to non-compartmental analysis. Following PO administration, marbofloxacin achieved maximum plasma concentrations of 11.66+/-2.53 mg L(-1) at 15.00+/-3.00 h. The absence of general adverse reactions in the turtles of the study, and the favourable pharmacokinetic properties (long half-life and high maximum plasma concentration) of MBX administered PO at the single-dose of 2 mg kg(-1) suggest the possibility of its safe and effective clinical use in loggerhead sea turtles.

  1. A therapeutic response to a single diagnostic dose of luteinising hormone-releasing hormone.

    PubMed

    Distiller, L A; Sagel, J; Polakow, E S; Morley, J E

    1975-01-11

    Luteinising hormone-releasing hormone (LH-RH) administration is a useful provocative test for the evaluation of the hypothalamic-pituitary-gonadal axis. Seven cases with oligomenorrhoea or amenorrhoea are reported, in which a single diagnostic injection of LH-RH produced an apparent therapeutic response. Six patients converted to a regular normal menstrual cycle, and 4 of these had evidence of ovulation. The seventh patient conceived. It is postulated that in some cases of hypothalamic menstrual dysfunction the gonadotrophic imbalance may be corrected by a single intravenous dose of LH-RH.

  2. Lack of protective effect of thromboxane synthetase inhibitor (CGS-13080) on single dose radiated canine intestine

    SciTech Connect

    Barter, J.F.; Marlow, D.; Kamath, R.K.; Harbert, J.; Torrisi, J.R.; Barnes, W.A.; Potkul, R.K.; Newsome, J.T.; Delgado, G. )

    1991-03-01

    The effect of a thromboxane A2 synthetase inhibitor (CGS-13080) on canine intestine was studied using a single dose of radiation, and radioactive microspheres were used to determine resultant blood flow. Thromboxane A2 causes vasospasm and platelet aggregation and may play a dominant role in radiation injury. However, there was no effect on the intestinal blood flow diminution occurring after radiation in this laboratory model using this thromboxane A2 synthetase inhibitor.

  3. [Measuring reaction times in healthy probands before and following a single dose of psychotropic drugs].

    PubMed

    Fischer, W; Streubel, F R; Herzer, H; Rabending, G

    1986-10-01

    A single dose of Clomipramin, 50 mg; Amitriptylin, 50 mg; Desipramin, 50 mg; Imipramin, 50 mg; Diazepam, 10 mg; Carbamazepin, 200 mg; Haloperidol, 3 mg; were each administered orally, and Clomipramin, 25 mg was administered intravenously, and reaction times were measured and compared with those obtained after administering a placebo. The statistical examination was conducted using Wilcoxon's test. In the case of Amitriptylin, Diazepam, and Haloperidol, there was a statistically significant reduction in the reaction times.

  4. A clinical pharmacokinetic study comparing two azelastine hydrochloride nasal formulations in a single-dose design.

    PubMed

    Du, Daniel; Targett, Darren; Stolberg, Erhard; Canali, Alessandra

    2014-03-01

    Azelastine hydrochloride is a potent second-generation antihistamine, available in Europe and the USA as a nasal spray formulation for the treatment of allergic rhinitis symptoms. GlaxoSmithKline (GSK) Consumer Healthcare has developed a new nasal formulation of azelastine hydrochloride. The present study was aimed at comparing the clinical pharmacokinetic profiles and assessing the bioequivalence of the new formulation of azelastine hydrochloride with a marketed reference nasal spray product. This was a randomized, two-way crossover, two-stage, single-dose pharmacokinetic study with 2 weeks washout between the two treatment periods. A dosage of 0.28 mg of the test and reference products was administered as a single dose to healthy volunteers according to the crossover design. Twenty-three subjects (15 subjects from stage 1 and 8 subjects from stage 2) were enrolled in the study. Adjusted mean values for AUC0-t were 1,526.8 h pg/mL for the test drug and 1,441.5 h pg/mL for the reference drug; for C max the values were 61.59 pg/mL for the test drug and 58.21 pg/mL for the reference drug. The 94.12 % CI of geometric mean ratios (test/reference) were 0.99-1.13 and 0.95-1.18 for AUC0-t and C max. This met the predefined criteria for bioequivalence between test and reference drugs. Secondary pharmacokinetic parameters for azelastine and for the metabolite desmethyl azelastine, AUC(0-∞) and t max, were numerically similar between the two study treatments. Both test and reference azelastine hydrochloride formulations were well tolerated at single dose. This study demonstrated the bioequivalence between the new azelastine hydrochloride nasal spray formulation and the marketed reference Allergodil(®) after single-dose administration. PMID:23681835

  5. Induction of lymphoma and osteosarcoma in mice by single and protracted low alpha doses

    SciTech Connect

    Mueller, W.A.L.; Luz, A.; Murray, A.B.; Linzner, U. )

    1990-09-01

    Internal doses from the short-lived alpha-emitter 22Ra were given to 4-wk-old female mice. One group of about 300 animals received a single injection of 18.5 kBq 22Ra kg-1 body weight, corresponding to a mean skeletal alpha dose of 0.15 Gy. A second group of about 300 animals received the same total amount of 224Ra in the form of 72 fractions of 257 Bq kg-1 each, applied twice weekly during 36 wk. The fractionated group received the same final mean total skeletal dose of 0.15 Gy as the single injected group, but with a mean skeletal dose rate of 1 mGy d-1. A rather high incidence, 13.5% (40/296), of early malignant lymphomas was observed in the fractionated group during and shortly after the injection period, followed by a 7% incidence (21/296) of osteosarcomas during the second half of the animals' lifetime. The group with a single injection did not develop early lymphomas but did develop osteosarcomas later with an incidence of 5.8% (17/295). The occurrence of osteosarcomas was similar up to day 800 in the two experimental groups. Surprisingly, however, after this period no additional case of osteosarcoma was observed in the single-injected group, whereas one-third of all osteosarcomas occurred after day 800 in the protracted group. The additional later occurrence of osteosarcomas occurred after indicates a longer lasting induction effect on osteosarcomas, or a promoting effect in older age, for this kind of treatment.

  6. A single subcutaneous dose of tramadol for mild to moderate musculoskeletal trauma in the emergency department

    PubMed Central

    Cardozo, Alejandro; Silva, Carlos; Dominguez, Luis; Botero, Beatriz; Zambrano, Paulo; Bareno, Jose

    2014-01-01

    BACKGROUND: Mild to moderate musculoskeletal trauma is a common cause for an emergency room visit, and frequent pain is one of the cardinal symptoms of consultation. The objective of this study is to assess the perception of a single subcutaneous dose of 50 mg tramadol for pain management in patients with mild to moderate musculoskeletal trauma, likewise to appraise the perception of pain by subcutaneous injection. METHODS: A total of 77 patients, who met inclusion criteria, received a single subcutaneous dose of tramadol. Pain control was evaluated based on the verbal numerical pain scale (0–10) at baseline, 20 and 60 minutes; similarly, pain perception was evaluated secondary to subcutaneous injection of the analgesic. RESULTS: On admission, the average pain perceived by patients was 8; twenty minutes later, 89% of the patients reported five or less, and after sixty minutes, 94% had three or less on the verbal numerical pain scale. Of the patients, 88% reported pain perception by verbal numeric scale of 3 or less by injection of the drug, and 6.5% required a second analgesic for pain control. Two events with drug administration (soft tissue infection and mild abdominal rectus injection) were reported. CONCLUSION: We conclude that a single subcutaneous dose of tramadol is a safe and effective option for the management of patients with mild to moderate pain and musculoskeletal disease in the emergency department. PMID:25548601

  7. Single Dose Propranolol Does Not Affect Physiologic or Emotional Reactivity to Smoking Cues

    PubMed Central

    Pachas, Gladys N.; Gilman, Jodi; Orr, Scott P.; Hoeppner, Bettina; Carlini, Sara V.; Loebl, Tsafrir; Nino, Johanna; Pitman, Roger K.; Evins, A. Eden

    2015-01-01

    Background Smoking cue exposure reactivates salient smoking-related memories, triggering craving to smoke, a phenomenon associated with maintenance of smoking behavior and relapse after periods of abstinence. Acute β-adrenergic blockade with propranolol reduces physiologic reactivity during subsequent recollection of traumatic events by inhibiting reconsolidation of reactivated memories in a process called memory reconsolidation blockade. Objective To determine whether a single dose of propranolol prior to retrieval of smoking-related memories reduces subsequent physiologic reactivity to personally salient smoking imagery scripts in current smokers. Methods Fifty-four overnight-abstinent, adult smokers received single dose propranolol or placebo prior to reactivation of smoking-related memories in a randomized, double-blind, placebo-controlled trial and resumed smoking afterward. One week later, skin conductance (SC), heart rate (HR) left corrugator electromyogram (EMG), self-reported emotional state and craving were assessed following script driven imagery with neutral and personalized smoking-related scripts. Results Smoking scripts were associated with increased physiologic activation (SC, HR, EMG), craving and negative emotional state compared with neutral scripts. Propranolol did not moderate the effect of script type on any outcome. Conclusion Personalized smoking script-driven imagery robustly increased physiologic activation, negative emotional state and craving, and a single dose of propranolol prior to memory reactivation did not moderate this effect. PMID:25413896

  8. A single-dose of oral nattokinase potentiates thrombolysis and anti-coagulation profiles

    PubMed Central

    Kurosawa, Yuko; Nirengi, Shinsuke; Homma, Toshiyuki; Esaki, Kazuki; Ohta, Mitsuhiro; Clark, Joseph F.; Hamaoka, Takafumi

    2015-01-01

    Our aim was to determine the quantitative effects of a single-dose of Nattokinase (NK) administration on coagulation/fibrinolysis parameters comprehensively in healthy male subjects. A double-blind, placebo-controlled cross-over NK intervention study was carried out in 12 healthy young males. Following the baseline blood draw, each subject was randomized to receive either a single-dose of 2,000 FU NK (NSK-SD, Japan Bio Science Laboratory Co., Ltd) or placebo with subsequent cross-over of the groups. Subjects donated blood samples at 2, 4, 6 and 8 hours following administration for analysis of coagulation/fibrinolysis parameters. As a result, D-dimer concentrations at 6, and 8 hours, and blood fibrin/fibrinogen degradation products at 4 hours after NK administration elevated significantly (p < 0.05, respectively). Factor VIII activity declined at 4 and 6 hours (p < 0.05, respectively), blood antithrombin concentration was higher at 2 and 4 hours (p < 0.05, respectively), and the activated partial thromboplastin time prolonged significantly at 2 and 4 hours following NK administration (p < 0.05 and p < 0.01, respectively). All the changes, however, were within the normal range. In conclusion, thus, a single-dose of NK administration appears enhancing fibrinolysis and anti-coagulation via several different pathways simultaneously. PMID:26109079

  9. A single-dose of oral nattokinase potentiates thrombolysis and anti-coagulation profiles.

    PubMed

    Kurosawa, Yuko; Nirengi, Shinsuke; Homma, Toshiyuki; Esaki, Kazuki; Ohta, Mitsuhiro; Clark, Joseph F; Hamaoka, Takafumi

    2015-06-25

    Our aim was to determine the quantitative effects of a single-dose of Nattokinase (NK) administration on coagulation/fibrinolysis parameters comprehensively in healthy male subjects. A double-blind, placebo-controlled cross-over NK intervention study was carried out in 12 healthy young males. Following the baseline blood draw, each subject was randomized to receive either a single-dose of 2,000 FU NK (NSK-SD, Japan Bio Science Laboratory Co., Ltd) or placebo with subsequent cross-over of the groups. Subjects donated blood samples at 2, 4, 6 and 8 hours following administration for analysis of coagulation/fibrinolysis parameters. As a result, D-dimer concentrations at 6, and 8 hours, and blood fibrin/fibrinogen degradation products at 4 hours after NK administration elevated significantly (p < 0.05, respectively). Factor VIII activity declined at 4 and 6 hours (p < 0.05, respectively), blood antithrombin concentration was higher at 2 and 4 hours (p < 0.05, respectively), and the activated partial thromboplastin time prolonged significantly at 2 and 4 hours following NK administration (p < 0.05 and p < 0.01, respectively). All the changes, however, were within the normal range. In conclusion, thus, a single-dose of NK administration appears enhancing fibrinolysis and anti-coagulation via several different pathways simultaneously.

  10. Salbutamol Residues in Plasma, Urine and Hair of Heifers After a Single Dose and Throughout.

    PubMed

    Zhang, Kai; Liang, Xiaowei; Su, Chuanyou; Tang, Chaohua; Zhao, Qingyu; Zhang, Junmin; Meng, Qingshi

    2016-07-01

    The objective of this study was to evaluate the salbutamol residues in the plasma, urine and hair of heifers after a single dose. Three heifers were given a single oral dose of salbutamol hydrochloride (150 μg/kg bodyweight). The salbutamol concentrations were measured in the plasma, urine (before and after hydrolysis with β-glucuronidase/arylsulfatase) and hair samples with ultra-performance liquid chromatography-tandem mass spectrometry. In the unhydrolyzed samples, the peak concentrations of salbutamol occurred in the plasma and urine at 12 and 8 h after drug administration, respectively, but were below the limit of quantification (LOQ = 0.2 ng/mL) at 48 and 120 h after administration, respectively. However, in the hydrolyzed samples, the salbutamol concentration was 1.1 ng/mL in the plasma 72 h after its administration and 0.7 ng/mL in the urine 168 h after its administration. Thus, the concentrations of salbutamol were significantly higher in the hydrolyzed samples than that in the unhydrolyzed samples (P < 0.01). The concentrations of salbutamol in the black and white hair 24 h after its administration were 1.7 and 1.0 ng/g, respectively. These results indicate that hair may be a target tissue for detecting the misuse of salbutamol after a single dose and that the primary forms of salbutamol in the plasma and urine samples from heifers are its sulfate and glucuronide conjugates. PMID:27165803

  11. Single-neuron axonal pathfinding under geometric guidance: low-dose-methylmercury developmental neurotoxicity test.

    PubMed

    Wei, Lina; Sweeney, Andrew J; Sheng, Liyuan; Fang, Yu; Kindy, Mark S; Xi, Tingfei; Gao, Bruce Z

    2014-09-21

    Because the nervous system is most vulnerable to toxicants during development, there is a crucial need for a highly sensitive developmental-neurotoxicity-test model to detect potential toxicants at low doses. We developed a lab-on-chip wherein single-neuron axonal pathfinding under geometric guidance was created using soft lithography and laser cell-micropatterning techniques. After coating the surface with L1, an axon-specific member of the Ig family of cell adhesion molecules (CAMs), and optimizing microunit geometric parameters, we introduced low-dose methylmercury, a well-known, environmentally significant neurotoxicant, in the shared medium. Its developmental neurotoxicity was evaluated using a novel axonal pathfinding assay including axonal turning and branching rates at turning points in this model. Compared to the conventional neurite-outgrowth assay, this model's detection threshold for low-dose methylmercury was 10-fold more sensitive at comparable exposure durations. These preliminary results support study of developmental effects of known and potential neurotoxicants on axon pathfinding. This novel assay model would be useful to study neuronal disease mechanisms at the single-cell level. To our knowledge, the potential of methylmercury chloride to cause acute in vitro developmental neurotoxicity (DNT) at such a low dosage has not been reported. This is the first DNT test model with high reproducibility to use single-neuron axonal pathfinding under precise geometric guidance. PMID:25041816

  12. Cognitive effects of methylphenidate in healthy volunteers: a review of single dose studies.

    PubMed

    Linssen, A M W; Sambeth, A; Vuurman, E F P M; Riedel, W J

    2014-06-01

    Methylphenidate (MPH), a stimulant drug with dopamine and noradrenaline reuptake inhibition properties, is mainly prescribed in attention deficit hyperactivity disorder, is increasingly used by the general population, intending to enhance their cognitive function. In this literature review, we aim to answer whether this is effective. We present a novel way to determine the extent to which MPH enhances cognitive performance in a certain domain. Namely, we quantify this by a percentage that reflects the number of studies showing performance enhancing effects of MPH. To evaluate whether the dose-response relationship follows an inverted-U-shaped curve, MPH effects on cognition are also quantified for low, medium and high doses, respectively. The studies reviewed here show that single doses of MPH improve cognitive performance in the healthy population in the domains of working memory (65% of included studies) and speed of processing (48%), and to a lesser extent may also improve verbal learning and memory (31%), attention and vigilance (29%) and reasoning and problem solving (18%), but does not have an effect on visual learning and memory. MPH effects are dose-dependent and the dose-response relationship differs between cognitive domains. MPH use is associated with side effects and other adverse consequences, such as potential abuse. Future studies should focus on MPH specifically to adequately asses its benefits in relation to the risks specific to this drug.

  13. Penetration of Linezolid into Soft Tissues of Healthy Volunteers after Single and Multiple Doses

    PubMed Central

    Dehghanyar, Pejman; Bürger, Cornelia; Zeitlinger, Markus; Islinger, Florian; Kovar, Florian; Müller, Markus; Kloft, Charlotte; Joukhadar, Christian

    2005-01-01

    The present study tested the ability of linezolid to penetrate soft tissues in healthy volunteers. Ten healthy volunteers were subjected to linezolid drug intake at a dose of 600 mg twice a day for 3 to 5 days. The first dose was administered intravenously. All following doses were self-administered orally. The tissue penetration of linezolid was assessed by use of in vivo microdialysis. In the single-dose experiments the ratios of the area under the concentration-time curve from 0 to 8 h (AUC0-8) for tissue to the AUC0-8 for free plasma were 1.4 ± 0.3 (mean ± standard deviation) and 1.3 ± 0.4 for subcutaneous adipose and muscle tissue, respectively. After multiple doses, the corresponding mean ratios were 0.9 ± 0.2 and 1.0 ± 0.5, respectively. The ratios of the AUC from 0 to 24 h (AUC0-24) for free linezolid in tissues to the MIC were between 50 and 100 for target pathogens with MICs between 2 and 4 mg/liter. In conclusion, the present study showed that linezolid penetrates rapidly into the interstitial space fluid of subcutaneous adipose and skeletal muscle tissues in healthy volunteers. On the basis of pharmacokinetic-pharmacodynamic calculations, we suggest that linezolid concentrations in soft tissues can be considered sufficient to inhibit the growth of many clinically relevant bacteria. PMID:15917535

  14. Beyond Gaussians: a study of single spot modeling for scanning proton dose calculation

    PubMed Central

    Li, Yupeng; Zhu, Ronald X.; Sahoo, Narayan; Anand, Aman; Zhang, Xiaodong

    2013-01-01

    Active spot scanning proton therapy is becoming increasingly adopted by proton therapy centers worldwide. Unlike passive-scattering proton therapy, active spot scanning proton therapy, especially intensity-modulated proton therapy, requires proper modeling of each scanning spot to ensure accurate computation of the total dose distribution contributed from a large number of spots. During commissioning of the spot scanning gantry at the Proton Therapy Center in Houston, it was observed that the long-range scattering protons in a medium may have been inadequately modeled for high-energy beams by a commercial treatment planning system, which could lead to incorrect prediction of field-size effects on dose output. In the present study, we developed a pencil-beam algorithm for scanning-proton dose calculation by focusing on properly modeling individual scanning spots. All modeling parameters required by the pencil-beam algorithm can be generated based solely on a few sets of measured data. We demonstrated that low-dose halos in single-spot profiles in the medium could be adequately modeled with the addition of a modified Cauchy-Lorentz distribution function to a double-Gaussian function. The field-size effects were accurately computed at all depths and field sizes for all energies, and good dose accuracy was also achieved for patient dose verification. The implementation of the proposed pencil beam algorithm also enabled us to study the importance of different modeling components and parameters at various beam energies. The results of this study may be helpful in improving dose calculation accuracy and simplifying beam commissioning and treatment planning processes for spot scanning proton therapy. PMID:22297324

  15. Dose rate effect on micronuclei induction in human blood lymphocytes exposed to single pulse and multiple pulses of electrons.

    PubMed

    Acharya, Santhosh; Bhat, N N; Joseph, Praveen; Sanjeev, Ganesh; Sreedevi, B; Narayana, Y

    2011-05-01

    The effects of single pulses and multiple pulses of 7 MV electrons on micronuclei (MN) induction in cytokinesis-blocked human peripheral blood lymphocytes (PBLs) were investigated over a wide range of dose rates per pulse (instantaneous dose rate). PBLs were exposed to graded doses of 2, 3, 4, 6, and 8 Gy of single electron pulses of varying pulse widths at different dose rates per pulse, ranging from 1 × 10(6) Gy s(-1) to 3.2 × 10(8) Gy s(-1). Different dose rates per pulse were achieved by changing the dose per electron pulse by adjusting the beam current and pulse width. MN yields per unit absorbed dose after irradiation with single electron pulses were compared with those of multiple pulses of electrons. A significant decrease in the MN yield with increasing dose rates per pulse was observed, when dose was delivered by a single electron pulse. However, no reduction in the MN yield was observed when dose was delivered by multiple pulses of electrons. The decrease in the yield at high dose rates per pulse suggests possible radical recombination, which leads to decreased biological damage. Cellular response to the presence of very large numbers of chromosomal breaks may also alter the damage.

  16. A Single-Dose Bioequivalence and Food Effect Study With Aprepitant and Fosaprepitant Dimeglumine in Healthy Young Adult Subjects.

    PubMed

    Shadle, Craig R; Murphy, M Gail; Liu, Yang; Ho, Maureen; Tatosian, Daniel; Li, Susie Xiujiang; Blum, Robert A

    2012-07-01

    Fosaprepitant dimeglumine, a lyophilized prodrug, is rapidly converted to aprepitant, a substance P/neurokinin 1 (NK1 ) receptor antagonist. Intravenous (IV) fosaprepitant and oral aprepitant are used in combination with other antiemetics to prevent chemotherapy-induced nausea and vomiting. This randomized, phase 1 study was designed to assess the aprepitant area under the curve (AUC0-∞ ) equivalence of a single, oral 165-mg or 185-mg dose of aprepitant to a single 150-mg fosaprepitant IV dose infused over 20 minutes, and to evaluate the effect of food on the bioavailability of the oral 165-mg and 185-mg aprepitant doses. Plasma samples were analyzed for aprepitant, and linear mixed-effects models were applied to natural log-transformed aprepitant AUC data. A 2 one-sided tests procedure was used to evaluate bioequivalence; the adjusted P values for the AUC0-∞ of both oral doses versus the IV dose were < .05, supporting the hypothesis that each single, oral dose of aprepitant is equivalent to the AUC0-∞ of a single IV infusion of fosaprepitant. Food effect results suggest that dose adjustment would not be necessary with a single oral dose of aprepitant. Single-dose administration of oral 165 mg and 185 mg aprepitant and IV 150 mg fosaprepitant was generally well tolerated. PMID:27121336

  17. Application of optically stimulated luminescence technique to evaluate simultaneously accumulated and single doses with the same dosimeter

    NASA Astrophysics Data System (ADS)

    Malthez, Anna Luiza M. C.; Freitas, Marcelo B.; Yoshimura, Elisabeth M.; Button, Vera L. S. N.

    2014-02-01

    Optically stimulated luminescence dosimeters (OSLD) can be read several times with a negligible loss (degradation) of signal. In this work, we explore this OSL property to estimate simultaneously the accumulated and single doses using a unique Al2O3 dosimeter, irradiated repeated times along over 4 months. This was done through several irradiations of OSLD (Landauer Luxel Dots) with two energies (28 keV X-rays and 1.25 MeV Co-60 gamma rays) and several doses distributed over time. Thermoluminescent dosimeters (TLD) were used as a reference to compare the estimated doses obtained with OSLD. For each irradiation, and both energies, a calibration curve was evaluated with OSLD and TLD to estimate the dose values. The OSL readouts were made with a MicroStar (Landauer) OSL reader. To estimate background (BG) over time, a set of OSLD and TLD (Bycron TLD100) was not irradiated and BG was monitored at each readout section. After irradiations, the OSL and TL signals were converted to dose and values were compared. As a set of OSLD suffered no bleaching after the readouts, it was possible to estimate simultaneously the accumulated and single doses with a unique OSLD. Each single dose was estimated through the subtraction of successive accumulated doses determined for each single OSLD. We concluded that the single doses determined by OSL and TL techniques were compatible, and that the accumulated dose, obtained with OSL technique was comparable to the sum of single doses determined with TLD. We can conclude that using OSL technique and Al2O3 dosimeters it is possible to estimate simultaneously accumulated and single doses with the same dosimeter irradiated with low or high energy photons.

  18. Single dose pharmacokinetics of the novel transdermal donepezil patch in healthy volunteers

    PubMed Central

    Kim, Yo Han; Choi, Hee Youn; Lim, Hyeong-Seok; Lee, Shi Hyang; Jeon, Hae Sun; Hong, Donghyun; Kim, Seong Su; Choi, Young Kweon; Bae, Kyun-Seop

    2015-01-01

    Background Donepezil is an acetylcholinesterase inhibitor indicated for Alzheimer’s disease. The aim of this randomized, single-blind, placebo-controlled, single-dose, dose-escalation study was to investigate the safety, tolerability, and pharmacokinetics of the donepezil patch in healthy male subjects. Methods Each healthy male subject received a single transdermal donepezil patch (72 hours patch-on periods) of 43.75 mg/12.5 cm2, 87.5 mg/25 cm2, or 175 mg/50 cm2. Serial blood samples were collected up to 312 hours after patch application. The plasma concentrations of donepezil were determined by using a validated liquid chromatography–tandem mass spectrometry method. Pharmacokinetic parameters were obtained by noncompartmental analysis. Tolerability of the patches and performance of the patches (adhesion, skin irritation, residual donepezil content in the patch) were assessed throughout the study. Results The study was completed by 36 healthy subjects. After patch application, the maximal plasma donepezil concentration (Cmax) and the area under the curve (AUC) increased in a dose-proportional manner. Median time to Cmax was ~74–76 hours (~2–4 hours after patch removal), and mean t1/2β was ~63.77–93.07 hours. The average donepezil residue in the patch after 72 hours was ~73.9%–86.7% of the loading dose. There were neither serious adverse events nor adverse events that lead to discontinuation. Skin adhesion of the patch was good in 97.2% of the subjects. All skin irritations after patch removal were mild and were resolved during the study period. Conclusion The donepezil patch appeared to be generally well tolerated and adhesive. Pharmacokinetic analysis of the donepezil patch demonstrated linear kinetics. PMID:25792802

  19. Esophageal Toxicity From High-Dose, Single-Fraction Paraspinal Stereotactic Radiosurgery

    SciTech Connect

    Cox, Brett W.; Jackson, Andrew; Hunt, Margie; Bilsky, Mark; Yamada, Yoshiya

    2012-08-01

    Purpose: To report the esophageal toxicity from single-fraction paraspinal stereotactic radiosurgery (SRS) and identify dosimetric and clinical risk factors for toxicity. Methods and Materials: A total of 204 spinal metastases abutting the esophagus (182 patients) were treated with high-dose single-fraction SRS during 2003-2010. Toxicity was scored using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4.0. Dose-volume histograms were combined to generate a comprehensive atlas of complication incidence that identifies risk factors for toxicity. Correlation of dose-volume factors with esophageal toxicity was assessed using Fisher's exact test and logistic regression. Clinical factors were correlated with toxicity. Results: The median dose to the planning treatment volume was 24 Gy. Median follow-up was 12 months (range, 3-81). There were 31 (15%) acute and 24 (12%) late esophageal toxicities. The rate of grade {>=}3 acute or late toxicity was 6.8% (14 patients). Fisher's exact test resulted in significant median splits for grade {>=}3 toxicity at V12 = 3.78 cm{sup 3} (relative risk [RR] 3.7, P=.05), V15 = 1.87 cm{sup 3} (RR 13, P=.0013), V20 = 0.11 cm{sup 3} (RR 6, P=0.01), and V22 = 0.0 cm{sup 3} (RR 13, P=.0013). The median split for D2.5 cm{sup 3} (14.02 Gy) was also a significant predictor of toxicity (RR 6; P=.01). A highly significant logistic regression model was generated on the basis of D2.5 cm{sup 3}. One hundred percent (n = 7) of grade {>=}4 toxicities were associated with radiation recall reactions after doxorubicin or gemcitabine chemotherapy or iatrogenic manipulation of the irradiated esophagus. Conclusions: High-dose, single-fraction paraspinal SRS has a low rate of grade {>=}3 esophageal toxicity. Severe esophageal toxicity is minimized with careful attention to esophageal doses during treatment planning. Iatrogenic manipulation of the irradiated esophagus and systemic agents classically associated with radiation

  20. Five-Year Outcomes of High-Dose Single-Fraction Spinal Stereotactic Radiosurgery

    SciTech Connect

    Moussazadeh, Nelson; Lis, Eric; Katsoulakis, Evangelia; Kahn, Sweena; Svoboda, Marek; DiStefano, Natalie M.; McLaughlin, Lily; Bilsky, Mark H.; Yamada, Yoshiya; Laufer, Ilya

    2015-10-01

    Purpose: To characterize local tumor control and toxicity risk in very long-term survivors (>5 years) after high-dose spinal image guided, intensity modulated radiation therapy delivered as single-dose stereotactic radiosurgery (SRS). Previously published spinal SRS outcome analyses have included a heterogeneous population of cancer patients, mostly with short survival. This is the first study reporting the long-term tumor control and toxicity profiles after high-dose single-fraction spinal SRS. Methods and Materials: The study population included all patients treated from June 2004 to July 2009 with single-fraction spinal SRS (dose 24 Gy) who had survived at least 5 years after treatment. The endpoints examined included disease progression, surgical or radiation retreatment, in-field fracture development, and radiation-associated toxicity, scored using the Radiation Therapy Oncology Group radiation morbidity scoring criteria and the Common Terminology Criteria for Adverse Events, version 4.0. Local control and fracture development were assessed using Kaplan-Meier analysis. Results: Of 278 patients, 31 (11.1%), with 36 segments treated for spinal tumors, survived at least 5 years after treatment and were followed up radiographically and clinically for a median of 6.1 years (maximum 102 months). The histopathologic findings for the 5-year survivors included radiation-resistant metastases in 58%, radiation-sensitive metastases in 22%, and primary bone tumors in 19%. In this selected cohort, 3 treatment failures occurred at a median of 48.6 months, including 2 recurrences in the radiation field and 1 patient with demonstrated progression at the treatment margins. Ten lesions (27.8%) were associated with acute grade 1 cutaneous or gastrointestinal toxicity. Delayed toxicity ≥3 months after treatment included 8 cases (22.2%) of mild neuropathy, 2 (5.6%) of gastrointestinal discomfort, 8 (22.2%) of dermatitides, and 3 (8.3%) of myalgias/myositis. Thirteen

  1. Evidence for CVD 103-HgR as an effective single-dose oral cholera vaccine.

    PubMed

    Jackson, Sarah S; Chen, Wilbur H

    2015-01-01

    We propose the ideal oral cholera vaccine (OCV) should be an inexpensive, single, oral dose that rapidly confers immunity for a long duration, and is well tolerated by individuals vulnerable to cholera. Vaccine trials in industrialized countries of a single oral dose of 5 × 10(8) colony forming units (CFU) of the live, attenuated cholera strain CVD 103-HgR have shown 88-97% serum vibriocidal antibody seroconversion rates, a correlate of protection and documented vaccine efficacy of ≥80% using volunteer challenge studies with wild-type cholera. For individuals of developing countries, a 5 × 10(9) CFU dose of CVD 103-HgR is necessary to elicit similar antibody responses. Presently, a reformulation of CVD 103-HgR is in late-stage clinical development for prospective US FDA licensure; making a cholera vaccine for US travelers potentially accessible in 2016. The availability of CVD 103-HgR should be a welcome addition to the currently available OCVs.

  2. Evidence for CVD 103-HgR as an effective single-dose oral cholera vaccine.

    PubMed

    Jackson, Sarah S; Chen, Wilbur H

    2015-01-01

    We propose the ideal oral cholera vaccine (OCV) should be an inexpensive, single, oral dose that rapidly confers immunity for a long duration, and is well tolerated by individuals vulnerable to cholera. Vaccine trials in industrialized countries of a single oral dose of 5 × 10(8) colony forming units (CFU) of the live, attenuated cholera strain CVD 103-HgR have shown 88-97% serum vibriocidal antibody seroconversion rates, a correlate of protection and documented vaccine efficacy of ≥80% using volunteer challenge studies with wild-type cholera. For individuals of developing countries, a 5 × 10(9) CFU dose of CVD 103-HgR is necessary to elicit similar antibody responses. Presently, a reformulation of CVD 103-HgR is in late-stage clinical development for prospective US FDA licensure; making a cholera vaccine for US travelers potentially accessible in 2016. The availability of CVD 103-HgR should be a welcome addition to the currently available OCVs. PMID:26228388

  3. Comparative single dose and steady-state pharmacokinetics of bevantolol in young and elderly subjects.

    PubMed

    Selen, A; Kinkel, A W; Darke, A C; Greene, D S; Welling, P G

    1986-01-01

    The pharmacokinetics of bevantolol were examined following single and repeated oral doses to young and elderly volunteers. Following administration of a single 200-mg bevantolol tablet mean maximum plasma bevantolol concentrations in young and elderly subjects were 1690 ng/ml and 1810 ng/ml, respectively. Maximum bevantolol concentrations occurred approximately 1.1 h postdose in both young and elderly subjects. There were no significant differences in mean steady state bevantolol concentrations on Day 14 between young and elderly subjects. However, disproportionate increases in Cmax, and in AUC, but not in tmax values were observed between Days 1 and 14. On Days 1 and 14, most young and elderly subjects exhibited monoexponential decline in bevantolol plasma concentrations after absorption phase. In those subjects Day 14 elimination half-lives in young and elderly were 1.9 and 2.2 h, respectively. In subjects who exhibited biexponential decline in bevantolol, an age effect in elimination became apparent, on Day 14 elimination half-lives were 5.7 and 11.2 h in young and elderly subjects, respectively. Bevantolol Metabolite III concentrations were observed in plasma of some subjects during the first 6 h after dosing. At steady-state AUC (0-ldc) values for the metabolite were less than 2% those of bevantolol. Bevantolol plasma levels accumulate to a small extent with repeated 200 mg daily doses. This is probably due to the contribution of a late and more persistent terminal elimination phase that was discernable in only certain individuals.

  4. Single dose toxicity study of IRDye 800CW in Sprague-Dawley rats

    NASA Astrophysics Data System (ADS)

    Marshall, Milton V.; Draney, Daniel; Sevick-Muraca, Eva M.; Olive, D. Michael

    2010-02-01

    Fluorophore-labeled contrast imaging agents are moving toward clinical use as aids in nodal staging and intraoperative resection of tumors. Near-infrared fluorophores with defined toxicity properties will be needed before these agents can be translated to the clinic. The near-infrared dye IRDye 800CW is frequently used in its N-hydroxysuccinamide (NHS) ester form for labeling these agents. Following conjugation or breakdown of a labeled ligand, excess NHS ester is converted to the carboxylate form. We report here the results of a preliminary toxicity study on IRDye 800CW carboxylate in preparation for its use as a labeling moiety for targeted contrast agents. Male and female Sprague Dawley rats were given a single intravenous or intradermal administration of IRDye 800CW carboxylate; indocyanine green was used as a comparative control. Following administration of varying doses of either the dyes or saline, animals were observed for up to fourteen days during which time, hematological, clinical chemistry, enzymological, and histological testing was performed on animal subgroups. Under the conditions tested, a single administration of IRDye 800CW carboxylate intravenously at dose levels of 1, 5 and 20 mg/kg or 20 mg/kg intradermally produced no pathological evidence of toxicity. A dose of 20 mg/kg was identified as the NOAEL (no observed adverse effect level) following IV or ID routes of administration of IRDye 800CW.

  5. Ovarian development in Wistar rat treated prenatally with single dose diisobutyl phthalate.

    PubMed

    Ray, B; D'Souza, A S; Kumar, V; Pugazhandhi, B; D'Souza, M R; Nayak, D; Sushma, R K; Shetty, P; Singh, H; Krishna, L; Bhat, K M; Rao, A C; Chakraborti, S; Kumar, N; Saxena, A

    2012-01-01

    Phthalates are a class of industrial compounds with an array of toxicological properties used in day to day life. Diisobutyl phthalate on (DIBP) is used as an additive to keep the plastics soft or flexible (plasticizer) in nitrocellulose plastic, nail polish, explosives, lacquer manufacturing etc. Although DIBP exposure in humans is generally low, people in adhesive industries and pharmaceutical industries are exposed to higher levels. The aim of this study was to determine the effect of single dose of DIBP on developing ovary of Wistar rat. One hundred and eight adult pregnant Wistar rats were divided into control and experimental groups. Rats in experimental group were given DIBP on day 10, 12 and 14 of gestation at 0.375, 0.75 and 1.25 ml/kg body weight dose intraperitoneally in a single dose. Sections of ovaries collected on day 21 of gestation were stained with hematoxylin and eosin and examined and Masson's trichrome histologically. Sections belonging to the control group showed the presence of oocytes in clusters separated by thin fibrous septa. Degeneration oocytes, empty follicles surrounded by follicular cells without gonocytes in the center were observed in ovarian stroma. Blood vessels in the ovarian stroma were prominent and congested. Around a bunch of follicles total architectural disarray was observed although on special staining fibrosis was not evident. As pregnant women are constantly exposed, effect of DIBP on ovary of a developing fetus would denote the long term consequence in future generations (Fig. 5, Ref. 39). PMID:23094893

  6. Pharmacokinetics of marbofloxacin in loggerhead sea turtles (Caretta caretta) after single intravenous and intramuscular doses.

    PubMed

    Lai, Olimpia R; Marín, Pedro; Laricchiuta, Pietro; Marzano, Giacomo; Crescenzo, Giuseppe; Escudero, Elisa

    2009-09-01

    The disposition kinetics of marbofloxacin at a single dose of 2 mg/kg bodyweight were determined in a crossover trial with five clinically healthy loggerhead sea turtles (Caretta caretta) after i.v. and i.m. administration. Marbofloxacin plasma concentrations were determined by high-performance liquid chromatography (LOD/LOQ 0.05 microg/ml). Data were subjected to noncompartmental analysis. The integrated pharmacokinetic/pharmacodynamic variables showed that optimal area under the curve (AUC(0-24 h)): minimal inhibitory concentration (MIC) (>125) and Cmax: MIC (>8) ratios, as reported for concentration-dependent bactericidal antimicrobials (e.g., fluoroquinolones), were achievable with both a once daily i.v. or i.m. dose for microorganisms with MIC < or = 0.5 microg/ml, while a Cmax: MIC > 8 for MIC > or = 1 microg/ml was achievable only after the i.v. administration. The absence of adverse reactions in the animals after i.v. or i.m. administration of marbofloxacin and the favorable pharmacokinetic/pharmacodynamic properties after a single dose of 2 mg/kg suggest the possibility of its safe and effective clinical use in loggerhead sea turtles.

  7. Preliminary single-dose pharmacokinetics of marbofloxacin in ball pythons (Python regius).

    PubMed

    Coke, Rob L; Isaza, Ramiro; Koch, David E; Pellerin, Marie A; Hunter, Robert P

    2006-03-01

    Pharmacokinetics of marbofloxacin in two male and four female adult ball pythons (Python regius) was determined after i.v. and p.o. administration of a single dose. Using a crossover design, each snake was given a single 10 mg/kg dose of marbofloxacin i.v. and p.o. Blood samples were collected prior to and 0.5, 1, 1.5, 3, 6, 12, and 24 hr after marbofloxacin administration. Marbofloxacin was quantitated by use of liquid chromatography-mass spectrometry. Following p.o. administration, marbofloxacin had a peak plasma concentration (Cmax) of 9.40 microg/ml and a time to Cmax (Tmax) of 9.0 hr. Based on the plasma pharmacokinetics generated in this study and pending any further studies to evaluate potential toxicity and multi-dose pharmacokinetics, we suggest a dosage for marbofloxacin in ball pythons of 10 mg/kg p.o. at least every 48 hr, depending on the sensitivity of the pathogen and as a basis for further research.

  8. Comparative disposition of codeine and pholcodine in man after single oral doses.

    PubMed Central

    Findlay, J W; Fowle, A S; Butz, R F; Jones, E C; Weatherley, B C; Welch, R M; Posner, J

    1986-01-01

    Four healthy male subjects received single oral doses of 15, 30 and 60 mg of codeine and pholcodine according to a balanced cross-over design with an interval of 7 days between the six treatments. Blood samples were collected for 8 h after each drug administration. In phase 2 of the study six different male volunteers received single oral doses of 60 mg of codeine and pholcodine with a 14 day interval between successive drug treatments. Blood was sampled for 12 h after codeine and 121 h after pholcodine administration. Plasma concentrations of free (unconjugated) and total (unconjugated plus conjugated) codeine, pholcodine and morphine were determined by radioimmunoassay and selected pharmacokinetic parameters were derived from these data. Pharmacokinetics of both drugs were independent of dose. Codeine was absorbed and eliminated relatively rapidly [elimination t1/2 = 2.3 +/- 0.4 h (mean +/- s.d.)]. While codeine kinetics were adequately described by a one-compartment open model with first-order absorption, a two-compartment model was required to describe pholcodine elimination from plasma (t1/2,z = 37.0 +/- 4.2 h). Plasma concentrations of conjugated codeine were much greater than those of the unconjugated alkaloid. By contrast, pholcodine appeared to undergo little conjugation. Biotransformation of codeine to morphine was evident in all subjects, although the extent of this metabolic conversion varied considerably between subjects. Morphine was not detectable in the plasma of any subject after pholcodine administration. PMID:3741728

  9. Pharmacokinetics of a single subcutaneous dose of sustained release buprenorphine in northern elephant seals (Mirounga angustirostris).

    PubMed

    Molter, Christine M; Barbosa, Lorraine; Johnson, Shawn; Knych, Heather K; Chinnadurai, Sathya K; Wack, Raymund F

    2015-03-01

    Information regarding analgesics in pinnipeds is limited. This study aimed to establish the pharmacokinetic parameters of a single subcutaneous dose of sustained release buprenorphine (Buprenorphine SR) in juvenile northern elephant seals (Mirounga angustirostris) with regard to its potential to provide long-lasting analgesia that requires infrequent dosing. Seals (n=26) were administered a single dose of sustained release buprenorphine at 0.12 mg/kg s.c. Blood samples were collected from the extradural intervertebral vein at 0 hr and at three or four of the following time points: 0.5, 1, 2, 6, 12, 24, 36, 48, 60, 96, 120, and 144 hr. Seals were examined daily for systemic and local adverse reactions. Plasma was analyzed by liquid chromatography tandem-mass spectrometry for buprenorphine and norbuprenorphine concentrations. A noncompartmental analysis for pharmacokinetic parameters was calculated using standard methods and equations. An average maximum concentration of 1.21 ng/ml (0.3-2.9 ng/ml) was detected 12 hr postadministration. Concentrations were quantifiable up to 144 hr postadministration but were below those expected to provide analgesia in some other species. No systemic adverse effects were noted in healthy seals receiving sustained release buprenorphine. Cellulitis or abscesses at the injection site were observed in 6/26 (23%) seals between 24 and 168 hr postadministration. Adverse local effects suggest that this drug should be used with caution in northern elephant seals. PMID:25831576

  10. Pharmacokinetics of a single subcutaneous dose of sustained release buprenorphine in northern elephant seals (Mirounga angustirostris).

    PubMed

    Molter, Christine M; Barbosa, Lorraine; Johnson, Shawn; Knych, Heather K; Chinnadurai, Sathya K; Wack, Raymund F

    2015-03-01

    Information regarding analgesics in pinnipeds is limited. This study aimed to establish the pharmacokinetic parameters of a single subcutaneous dose of sustained release buprenorphine (Buprenorphine SR) in juvenile northern elephant seals (Mirounga angustirostris) with regard to its potential to provide long-lasting analgesia that requires infrequent dosing. Seals (n=26) were administered a single dose of sustained release buprenorphine at 0.12 mg/kg s.c. Blood samples were collected from the extradural intervertebral vein at 0 hr and at three or four of the following time points: 0.5, 1, 2, 6, 12, 24, 36, 48, 60, 96, 120, and 144 hr. Seals were examined daily for systemic and local adverse reactions. Plasma was analyzed by liquid chromatography tandem-mass spectrometry for buprenorphine and norbuprenorphine concentrations. A noncompartmental analysis for pharmacokinetic parameters was calculated using standard methods and equations. An average maximum concentration of 1.21 ng/ml (0.3-2.9 ng/ml) was detected 12 hr postadministration. Concentrations were quantifiable up to 144 hr postadministration but were below those expected to provide analgesia in some other species. No systemic adverse effects were noted in healthy seals receiving sustained release buprenorphine. Cellulitis or abscesses at the injection site were observed in 6/26 (23%) seals between 24 and 168 hr postadministration. Adverse local effects suggest that this drug should be used with caution in northern elephant seals.

  11. Fixed-dose combinations of drugs versus single-drug formulations for treating pulmonary tuberculosis

    PubMed Central

    Gallardo, Carmen R; Rigau Comas, David; Valderrama Rodríguez, Angélica; Roqué i Figuls, Marta; Parker, Lucy Anne; Caylà, Joan; Bonfill Cosp, Xavier

    2016-01-01

    Background People who are newly diagnosed with pulmonary tuberculosis (TB) typically receive a standard first-line treatment regimen that consists of two months of isoniazid, rifampicin, pyrazinamide, and ethambutol followed by four months of isoniazid and rifampicin. Fixed-dose combinations (FDCs) of these drugs are widely recommended. Objectives To compare the efficacy, safety, and acceptability of anti-tuberculosis regimens given as fixed-dose combinations compared to single-drug formulations for treating people with newly diagnosed pulmonary tuberculosis. Search methods We searched the Cochrane Infectious Disease Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL, published in the Cochrane Library, Issue 11 2015); MEDLINE (1966 to 20 November 2015); EMBASE (1980 to 20 November 2015); LILACS (1982 to 20 November 2015); the metaRegister of Controlled Trials; and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), without language restrictions, up to 20 November 2015. Selection criteria Randomized controlled trials that compared the use of FDCs with single-drug formulations in adults (aged 15 years or more) newly diagnosed with pulmonary TB. Data collection and analysis Two review authors independently assessed studies for inclusion, and assessed the risk of bias and extracted data from the included trials. We used risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data with 95% confidence intervals (CIs). We attempted to assess the effect of treatment for time-to-event measures with hazard ratios and their 95% CIs. We used the Cochrane 'Risk of bias' assessment tool to determine the risk of bias in included trials. We used the fixed-effect model when there was little heterogeneity and the random-effects model with moderate heterogeneity. We used an I² statistic value of 75% or greater to denote significant heterogeneity, in which case we did not perform a

  12. Efficacy and safety of single doses of intramuscular ketorolac tromethamine compared with meperidine for postoperative pain.

    PubMed

    Stanski, D R; Cherry, C; Bradley, R; Sarnquist, F H; Yee, J P

    1990-01-01

    Ketorolac tromethamine, a potent nonnarcotic prostaglandin synthetase-inhibiting analgesic, was compared with meperidine for relief of moderate to severe postoperative pain. In a double-blind, randomized study, 125 patients received single intramuscular doses of ketorolac 30 or 90 mg or meperidine 50 or 100 mg. The degree of pain and pain relief were quantified verbally and with visual analog scales at baseline and 30 minutes, then hourly for 6 hours. Ketorolac 30 and 90 mg were significantly superior to meperidine 50 mg in six of nine efficacy measures. The onset of and peak analgesic effect of both doses of ketorolac and of meperidine were equivalent. Compared with both doses of meperidine, the two doses of ketorolac exhibited significantly longer duration of analgesic effect, as measured by the percentage of patients who terminated the study because of inadequate pain relief. The frequency of side effects was not significantly different between the drugs. The prolonged efficacy of intramuscular ketorolac combined with the reduced risk of respiratory depression suggest an important use of this drug for the relief of postoperative pain.

  13. Bayesian adaptive designs in single ascending dose trials in healthy volunteers

    PubMed Central

    Guédé, David; Reigner, Bruno; Vandenhende, Francois; Derks, Mike; Beyer, Ulrich; Jordan, Paul; Worth, Eric; Diack, Cheikh; Frey, Nicolas; Peck, Richard

    2014-01-01

    Aim Recent publications indicate a strong interest in applying Bayesian adaptive designs in first time in humans (FTIH) studies outside of oncology. The objective of the present work was to assess the performance of a new approach that includes Bayesian adaptive design in single ascending dose (SAD) trials conducted in healthy volunteers, in comparison with a more traditional approach. Methods A trial simulation approach was used and seven different scenarios of dose–response were tested. Results The new approach provided less biased estimates of maximum tolerated dose (MTD). In all scenarios, the number of subjects needed to define a MTD was lower with the new approach than with the traditional approach. With respect to duration of the trials, the two approaches were comparable. In all scenarios, the number of subjects exposed to a dose greater than the actual MTD was lower with the new approach than with the traditional approach. Conclusions The new approach with Bayesian adaptive design shows a very good performance in the estimation of MTD and in reducing the total number of healthy subjects. It also reduces the number of subjects exposed to doses greater than the actual MTD. PMID:24528176

  14. Continuous DOPA synthesis from a single AAV: dosing and efficacy in models of Parkinson's disease

    PubMed Central

    Cederfjäll, Erik; Nilsson, Nathalie; Sahin, Gurdal; Chu, Yaping; Nikitidou, Elisabeth; Björklund, Tomas; Kordower, Jeffrey H.; Kirik, Deniz

    2013-01-01

    We used a single adeno-associated viral (AAV) vector co-expressing tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) to investigate the relationship between vector dose, and the magnitude and rate of recovery in hemi-parkinsonian rats. Intrastriatal injections of >1E10 genomic copies (gc) of TH-GCH1 vector resulted in complete recovery in drug-naïve behavior tests. Lower vector dose gave partial to no functional improvement. Stereological quantification revealed no striatal NeuN+ cell loss in any of the groups, whereas a TH-GCH1 dose of >1E11 gc resulted in cell loss in globus pallidus. Thus, a TH-GCH1 dose of 1E10 gc gave complete recovery without causing neuronal loss. Safety and efficacy was also studied in non-human primates where the control vector resulted in co-expression of the transgenes in caudate-putamen. In the TH-GCH1 group, GCH1 expression was robust but TH was not detectable. Moreover, TH-GCH1 treatment did not result in functional improvement in non-human primates. PMID:23831692

  15. Disposition of marbofloxacin in vulture (Gyps fulvus) after intravenous administration of a single dose.

    PubMed

    Garcia-Montijano, Marino; Waxman, Samanta; de Lucas, J Julio; Luaces, I; de San Andrés, María Dolores; Rodríguez, Casilda

    2011-04-01

    The pharmacokinetics properties of marbofloxacin were studied in adult Eurassian Griffon vulture after single-dose intravenous (IV) administration of 2mg/kg. Drug concentration in plasma was determined by high-performance liquid chromatography and the data obtained were subjected to compartmental and non-compartmental kinetic analysis. Marbofloxacin presented a volume of distribution at steady-state (Vdss) of 1.51±0.22L and total plasma clearance (Cl) of 0.109±0.023L/hkg. The permanence of this drug was long in vultures (T(1/2)(λ)=12.51±2.52h; MRT(∞)=13.54±2.29h). The optimal dose of marbofloxacin estimated is 2.73mg/kg per day for the treatment of infections in vultures with MIC(90)=0.2μg/mL.

  16. Arteether toxicokinetics and pharmacokinetics in rats after 25 mg/kg/day single and multiple doses.

    PubMed

    Li, Q G; Brueckner, R P; Peggins, J O; Trotman, K M; Brewer, T G

    1999-01-01

    Multiple doses of arteether (ARTE) at 25 mg/kg cause CNS and anorectic toxicities in rats. The same dose of ARTE was used to study the toxicokinetics (TK) after multiple injections and the pharmacokinetics (PK) following single administration. Animals were administered ARTE in sesame oil for 7 days, blood samples were collected using destructive sampling for up to 192 h after dosing and assayed by HPLC-ECD. Two other groups of rats were administered either a single 25 mg/kg i.v. or i.m. dose. In addition, the drug remaining in the i.m. injection site was measured. During the 7 day treatments, anorectic toxicity of ARTE was observed, and that caused significant reductions in food consumption and body weight after day 2. TK data on days 2-7 revealed marked changes compared to the PK parameters estimated on day 1. AUC (4367 ng x h/ml) on day 7 was 5-fold higher than AUC (905 ng x h/ml) on day 1. The volume of distribution at steady state (V(SS)) on day 7 (41.8 l) was 40% of the day 1 value of the V(SS) (104.3 l). Clearance (CL) was increased by 89% of the day 1 value, from 0.98 l/h to 1.85 l/h on day 7. The elimination t(1/2) of ARTE was also prolonged from 13.7 h (day 1) to 31.2 h (day 7). These data suggest that ARTE may have altered its distribution and elimination in rats as a result of the systemic toxicity. Analysis of the injection sites showed that 38% and 91% of the total amount of ARTE single dose remained in the muscles at 24 h (after first injection) and 168 h (at 24 h after 7 daily multiple doses), respectively. Fast and slow absorption phases from muscle were seen with t(1/2) of 0.97 h and 26.3 h, respectively. The apparent elimination t(1/2) of ARTE after i.m. injection (13.7 h) was much longer than that after i.v. dosing (0.67 h) due to the prolonged muscle absorption phase. Acute toxicity data of artemisinin drugs demonstrated that animals receiving a high single ARTE dose in sesame oil died between days 5-11, similar to artemether. When animals

  17. PHARMACOKINETICS OF SINGLE-DOSE ORALLY ADMINISTERED CIPROFLOXACIN IN CALIFORNIA SEA LIONS (ZALOPHUS CALIFORNIANUS).

    PubMed

    Barbosa, Lorraine; Johnson, Shawn P; Papich, Mark G; Gulland, Frances

    2015-06-01

    Ciprofloxacin is commonly selected for clinical use due to its broad-spectrum efficacy and is a frequently administered antibiotic at The Marine Mammal Center, a marine mammal rehabilitation facility. Ciprofloxacin is used for treatment of California sea lions ( Zalophus californianus ) suffering from a variety of bacterial infections at doses extrapolated from other mammalian species. However, as oral absorption is variable both within and across species, a more accurate determination of appropriate dosage is needed to ensure effective treatment and avoid emergence of drug-resistant bacterial strains. A pharmacokinetic study was performed to assess plasma concentrations of ciprofloxacin in California sea lions after a single oral dose. Twenty healthy California sea lions received a single 10-mg/kg oral dose of ciprofloxacin administered in a herring fish. Blood was then collected at two of the following times from each individual: 0.5, 0.75, 1, 2, 4, 8, 10, 12, 18, and 24 hr postingestion. Plasma ciprofloxacin concentration was assessed via high-performance liquid chromatography. A population pharmacokinetics model demonstrated that an oral ciprofloxacin dose of 10 mg/kg achieved an area under the concentration vs. time curve of 6.01 μg hr/ml. Absorption was rapid, with ciprofloxacin detectable in plasma 0.54 hr after drug administration; absorption half-life was 0.09 hr. A maximum plasma concentration of 1.21 μg/ml was observed at 1.01 hr, with an elimination half-life of 3.09 hr. Ciprofloxacin administered orally at 10 mg/kg produced therapeutic antibacterial exposure for only some of the most susceptible bacterial organisms commonly isolated from California sea lions. PMID:26056878

  18. PHARMACOKINETICS OF SINGLE-DOSE ORALLY ADMINISTERED CIPROFLOXACIN IN CALIFORNIA SEA LIONS (ZALOPHUS CALIFORNIANUS).

    PubMed

    Barbosa, Lorraine; Johnson, Shawn P; Papich, Mark G; Gulland, Frances

    2015-06-01

    Ciprofloxacin is commonly selected for clinical use due to its broad-spectrum efficacy and is a frequently administered antibiotic at The Marine Mammal Center, a marine mammal rehabilitation facility. Ciprofloxacin is used for treatment of California sea lions ( Zalophus californianus ) suffering from a variety of bacterial infections at doses extrapolated from other mammalian species. However, as oral absorption is variable both within and across species, a more accurate determination of appropriate dosage is needed to ensure effective treatment and avoid emergence of drug-resistant bacterial strains. A pharmacokinetic study was performed to assess plasma concentrations of ciprofloxacin in California sea lions after a single oral dose. Twenty healthy California sea lions received a single 10-mg/kg oral dose of ciprofloxacin administered in a herring fish. Blood was then collected at two of the following times from each individual: 0.5, 0.75, 1, 2, 4, 8, 10, 12, 18, and 24 hr postingestion. Plasma ciprofloxacin concentration was assessed via high-performance liquid chromatography. A population pharmacokinetics model demonstrated that an oral ciprofloxacin dose of 10 mg/kg achieved an area under the concentration vs. time curve of 6.01 μg hr/ml. Absorption was rapid, with ciprofloxacin detectable in plasma 0.54 hr after drug administration; absorption half-life was 0.09 hr. A maximum plasma concentration of 1.21 μg/ml was observed at 1.01 hr, with an elimination half-life of 3.09 hr. Ciprofloxacin administered orally at 10 mg/kg produced therapeutic antibacterial exposure for only some of the most susceptible bacterial organisms commonly isolated from California sea lions.

  19. Single dose oral mefenamic acid for acute postoperative pain in adults

    PubMed Central

    Moll, Rachel; Derry, Sheena; Moore, R Andrew; McQuay, Henry J

    2014-01-01

    Background Mefenamic acid is a non-steroidal anti-inflammatory drug (NSAID). It is most often used for treating pain of dysmenorrhoea in the short term (seven days or less), as well as mild to moderate pain including headache, dental pain, postoperative and postpartum pain. It is widely available in many countries worldwide. Objectives To assess the efficacy of single dose oral mefenamic acid in acute postoperative pain, and any associated adverse events. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to December 2010. Selection criteria Single oral dose, randomised, double-blind, placebo-controlled trials of mefenamic acid for relief of established moderate to severe postoperative pain in adults. Data collection and analysis Studies were assessed for methodological quality and the data extracted by two review authors independently. Summed total pain relief (TOTPAR) or pain intensity difference (SPID) over 4 to 6 hours was used to calculate the number of participants achieving at least 50% pain relief. These derived results were used to calculate, with 95% confidence intervals, the relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over 4 to 6 hours. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals was collected. Main results Four studies with 842 participants met the inclusion criteria; 126 participants were treated with mefenamic acid 500 mg, 67 with mefenamic acid 250 mg, 197 with placebo, and 452 with lignocaine, aspirin, zomepirac or nimesulide. Participants had pain following third molar extraction, episiotomy and orthopaedic surgery. The NNT for at least 50% pain relief over 6 hours with a single dose of mefenamic acid 500 mg compared to placebo was 4.0 (2

  20. Single-ion microbeam as a tool for low-dose radiation effects investigations

    NASA Astrophysics Data System (ADS)

    Gerardi, Silvia; Galeazzi, Giuseppe; Cherubini, Roberto

    2006-05-01

    Practical assessment of human radiation exposure risk deserves particular attention especially for low doses (and low dose rates), which concern environmental and occupational exposure. At these dose levels ionizing radiation exposures involve mainly isolated charged particle tracks, which strike individual cells at time intervals averaging from weeks to several years apart. Accelerator-based microbeam irradiation technique offers a unique tool to mimic such an exposure, allowing irradiating single cells individually with micrometer precision and with a preset number of charged particles down to one particle per cell. A horizontal single-ion microbeam facility for single-cell irradiations has been designed and set up at the INFN-LNL 7MV CN Van de Graaff accelerator. The light ion beam is collimated in air down to a section of 2-3µm in diameter by means of appropriate pinholes. Semi-automatic cell visualization and automatic cell positioning and revisiting system, based on an inverted phase contrast optical microscope and on X-Y translation stages with 0.1µm positioning precision, has been developed. An in-house-written software allows to control remotely the irradiation protocol. As a distinctive feature of the facility, cell recognition is performed without using fluorescent staining and UV light. Particle detection in air, behind the biological sample, is based on a silicon detector while in-air beam profile and precise hit position measurements are accomplished by a custom-made cooled-CCD camera and Solid State Nuclear Track detectors, respectively. A particle counting rate of less than 1 ion/sec can be reached.

  1. Long-term follow-up analysis of zolpidem in fingernails after a single oral dose.

    PubMed

    Hang, Chen; Ping, Xiang; Min, Shen

    2013-09-01

    The determination of xenobiotics in keratinized matrices, such as nails and hair, has received considerable attention because of the relatively long detection window for compounds. The distribution of xenobiotics in fingernails, unlike hair, was equivocal. The main aim of this study was to use follow-up surveys to measure zolpidem profiles in nails after subjects consumed a single dose of the drug. In addition, the zolpidem concentrations in nails were compared with data for different biosamples, such as hair and blood from previous work. With these preconditions, a high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the determination of zolpidem in nails. Nails underwent alkaline hydrolysis and were extracted with diethyl ether. A Capcell Pak C18 MGII column was used to separate the target compound, and an API 4000 Qtrap mass spectrometer was used as a detector. The results for nail samples from seven subjects who had taken a single 10 mg zolpidem dose were significant: two relatively high zolpidem concentrations were observed in the long-term follow-up analysis of nails. The zolpidem concentration was less than 1.74 pg/mg and less than 3.29 pg/mg in fingernails and toenails, respectively. The subsequent peak concentration of zolpidem was observed between 10 and 15 weeks after each subject took a single dose of the drug. This result suggested that the germinal matrix area was a primary in vivo pathway for zolpidem secretion into the nail. The analysis of biosamples, such as nails, may be a useful adjunct to conventional methods of drug testing and hair analysis. Further research is needed concerning the contamination risk in analysis of nail biosamples.

  2. [Pharmacokinetics and relative bioavailability of THC and THC-solid dispersion orally to mice at single dose].

    PubMed

    Liao, Li; Hua, Hua; Zhao, Jun-Ning; Luo, Heng; Yang, An-Dong

    2014-03-01

    To establish a fast sensitive, reproducible LC-MS/MS method to study pharmacokinetic properties of THC, and compare relative bioavailability of THC and its solid dispersion in mice. 200 mice were divided randomly into two groups, and administered orally with THC and THC-solid dispersion after fasting (calculate on THC:400 mg x kg(-1)), used HPLC-MS/MS method to determine the THC concentration of each period at the following times: baseline ( predose ), 15, 30, 45 min, 1, 1.5, 2, 3, 4, 6, 24 h after dosing. Calculating the pharmacokinetic parameters according to the C-t curv, and then use the Phoenix WinNonlin software for data analysis. The calibration curves were linear over the range 9.06-972 microg x L(-1) for THC (R2 = 0.999). The limit of detection (LOD) was 0.7 microg x L(-1), respectively. The average extraction recoveries for THC was above 75%, The methodology recoveries were between 79% and 108%. The intra-day and inter-day RSD were less than 13%, the stability test showed that the plasma samples was stable under different conditions (RSD < 15%). The precision, accuracy, recovery and applicability were found to be adequate for pharmacokinetic studies. Pharmacokinetic parameters of THC and THC-solid dispersion orally to mice shows as fllows: T(max), were 60 and 15 min, AUC(0-t) were 44 500.43 and 57 497.81 mg x L(-1) x min, AUC(0-infinity) were 51 226.00 and 68 031.48 mg x L(-1) x min, MRT(0-infinity) were 596.915 6, 661.747 7 min, CL(z)/F were 0.007 809 and 0.005 88 L x min(-1) x kg(-1). Compared with THC, the MRT and t1/2 of the THC-solid dispersion were all slightly extended, the t(max) was significantly reduced, AUC(0-24 h), AUC(0-infinity) and C(max) were all significantly higher, the relative bioavailability of THC-solid dispersion is 1.34 times of THC. The results of the experiment shows that the precision, accuracy, recovery and applicability were found to be adequate for the pharmacokinetic studies. After oral administration to mice, the relative

  3. [Pharmacokinetics and relative bioavailability of THC and THC-solid dispersion orally to mice at single dose].

    PubMed

    Liao, Li; Hua, Hua; Zhao, Jun-Ning; Luo, Heng; Yang, An-Dong

    2014-03-01

    To establish a fast sensitive, reproducible LC-MS/MS method to study pharmacokinetic properties of THC, and compare relative bioavailability of THC and its solid dispersion in mice. 200 mice were divided randomly into two groups, and administered orally with THC and THC-solid dispersion after fasting (calculate on THC:400 mg x kg(-1)), used HPLC-MS/MS method to determine the THC concentration of each period at the following times: baseline ( predose ), 15, 30, 45 min, 1, 1.5, 2, 3, 4, 6, 24 h after dosing. Calculating the pharmacokinetic parameters according to the C-t curv, and then use the Phoenix WinNonlin software for data analysis. The calibration curves were linear over the range 9.06-972 microg x L(-1) for THC (R2 = 0.999). The limit of detection (LOD) was 0.7 microg x L(-1), respectively. The average extraction recoveries for THC was above 75%, The methodology recoveries were between 79% and 108%. The intra-day and inter-day RSD were less than 13%, the stability test showed that the plasma samples was stable under different conditions (RSD < 15%). The precision, accuracy, recovery and applicability were found to be adequate for pharmacokinetic studies. Pharmacokinetic parameters of THC and THC-solid dispersion orally to mice shows as fllows: T(max), were 60 and 15 min, AUC(0-t) were 44 500.43 and 57 497.81 mg x L(-1) x min, AUC(0-infinity) were 51 226.00 and 68 031.48 mg x L(-1) x min, MRT(0-infinity) were 596.915 6, 661.747 7 min, CL(z)/F were 0.007 809 and 0.005 88 L x min(-1) x kg(-1). Compared with THC, the MRT and t1/2 of the THC-solid dispersion were all slightly extended, the t(max) was significantly reduced, AUC(0-24 h), AUC(0-infinity) and C(max) were all significantly higher, the relative bioavailability of THC-solid dispersion is 1.34 times of THC. The results of the experiment shows that the precision, accuracy, recovery and applicability were found to be adequate for the pharmacokinetic studies. After oral administration to mice, the relative

  4. Interstitial pregnancy treated with a single-dose of systemic methotrexate: A successful management

    PubMed Central

    Corioni, Serena; Perelli, Federica; Bianchi, Claudia; Cozzolino, Mauro; Maggio, Luana; Masini, Giulia; Coccia, Maria Elisabetta

    2015-01-01

    Interstitial pregnancy is an ectopic pregnancy at high hemorrhagic risk. It often poses a diagnostic and therapeutic challenge to the clinician, with a significant risk of morbidity and mortality. It presents a difficult management problem with no absolute standard of care; the most appropriate treatment technique for these pregnancies remains controversial. We describe a case of unruptured interstitial pregnancy successfully treated with a single-dose of systemic methotrexate with subsequent ultrasound and serum beta human chorionic gonadotropin monitoring. Medical management can be a safe and successful option in selected cases that satisfy specific criteria and in women who are able to be monitored after treatment. PMID:26109980

  5. Toxicokinetics of acrylamide in rats and humans following single oral administration of low doses

    SciTech Connect

    Kopp, Eva Katharina; Dekant, Wolfgang

    2009-03-01

    The rodent carcinogen acrylamide (AA) is formed during preparation of starch-containing foods. AA is partly metabolized to the genotoxic epoxide glycidamide (GA). After metabolic processing, the mercapturic acids N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA), rac-N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine (GAMA) and rac-N-acetyl-S-(1-carbamoyl-moyl-2-hydroxyethyl)-L-cysteine (iso-GAMA) are excreted with urine. In humans, AAMA can be sulfoxidized to AAMA-sulfoxide. The aim of this study was to assess potential species-differences in AA-toxicokinetics in rats and humans after single oral administration of doses similar to the daily human dietary exposure. Male Fischer 344 rats (n = 5/dose group) were administered 20 and 100 {mu}g/kg b.w. {sup 13}C{sub 3}-AA in deionized water via oral gavage. Human subjects (n = 3/gender) were orally administered 0.5 and 20 {mu}g/kg b.w. {sup 13}C{sub 3}-AA with drinking water. Urine samples were collected in intervals for 96 and 94 h, respectively. Urinary concentrations of {sup 13}C{sub 3}-AAMA, {sup 13}C{sub 3}-GAMA and {sup 13}C{sub 3}-AAMA-sulfoxide were monitored by liquid chromatography-tandem mass spectrometry. The recovered urinary metabolites accounted for 66.3% and 70.5% of the 20 and 100 {mu}g/kg b.w. doses in rats and for 71.3% and 70.0% of the 0.5 and 20 {mu}g/kg b.w. doses in humans. In rats, {sup 13}C{sub 3}-AAMA accounted for 33.6% and 38.8% of dose and 32.7% and 31.7% of dose was recovered as {sup 13}C{sub 3}-GAMA; {sup 13}C{sub 3}-AAMA-sulfoxide was not detected in rat urine. In humans, {sup 13}C{sub 3}-AAMA, {sup 13}C{sub 3}-GAMA and {sup 13}C{sub 3}-AAMA-sulfoxide accounted for 51.7% and 49.2%, 6.3% and 6.4% and 13.2% and 14.5% of the applied dose, respectively. The obtained results suggest that the extent of AA bioactivation to GA in humans is lower than in rodents.

  6. Fixed-Dose Combination Drug Approvals, Patents and Market Exclusivities Compared to Single Active Ingredient Pharmaceuticals

    PubMed Central

    Hao, Jing; Rodriguez-Monguio, Rosa; Seoane-Vazquez, Enrique

    2015-01-01

    Introduction Fixed-dose combinations (FDC) contain two or more active ingredients. The effective patent and exclusivity life of FDC compared to single active ingredient has not been assessed. Objectives Trends in FDA approved FDC in the period 1980–2012 and time lag between approval of FDC and single active ingredients in the combination were assessed, and the effective patent and exclusivity life of FDC was compared with their single active ingredients. Materials and Methods New molecular entities (NMEs), new therapeutic biologics license applications (BLAs) and FDC data were collected from the FDA Orange Book and Drugs@FDA. Analysis included FDC containing one or more NMEs or BLAs at first FDA approval (NMEs-FDC) and only already marketed drugs (Non-NMEs-FDC). Descriptive, Kruskal-Wallis and Wilcoxon Rank Sum analyses were performed. Results During the study period, the FDA approved 28 NMEs-FDC (3.5% of NMEs) and 117 non-NMEs-FDC. FDC approvals increased from 12 in the 1980s to 59 in the 2000s. Non-NMEs-FDC entered the market at a median of 5.43 years (interquartile range 1.74, 10.31) after first FDA approval of single active ingredients in the combination. The Non-NMEs-FDC entered the market at a median of 2.33 years (-7.55, 2.39) before approval of generic single active ingredient. Non-NME-FDC added a median of 9.70 (2.75, 16.24) years to the patent and exclusivity life of the single active ingredients in the combination. Conclusion FDC approvals significantly increased over the last twenty years. Pharmaceutical companies market FDC drugs shortly before the generic versions of the single ingredients enter the market extending the patent and exclusivity life of drugs included in the combination. PMID:26469277

  7. Focal and segmental glomerulosclerosis following a single intravenous dose of puromycin aminonucleoside.

    PubMed Central

    Diamond, J. R.; Karnovsky, M. J.

    1986-01-01

    Focal and segmental glomerulosclerosis (FSGS) represents a final pathologic pattern of a number of human renal disorders. Among laboratory models, repeated intraperitoneal injections of the aminonucleoside of puromycin (PA) produces a histologic pattern not unlike the human process. A single intravenous dose of this drug usually results in glomerular morphologic changes in rats resembling those in human nephrotic syndrome with minimal changes. This report describes acute and chronic glomerular injury that begins as early as 8 days after a single central administration of PA and progresses to FSGS within an 18-week period. It seems likely that minimal change disease and FSGS are two pathologic processes in the same continuum of disease. In this model, the severity and persistence of the glomerular lesion may represent irreversible glomerular epithelial cell (GEC) injury secondary to the toxic effects of PA. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:3953770

  8. Dissociable effects of a single dose of ecstasy (MDMA) on psychomotor skills and attentional performance.

    PubMed

    Lamers, C T J; Ramaekers, J G; Muntjewerff, N D; Sikkema, K L; Samyn, N; Read, N L; Brookhuis, K A; Riedel, W J

    2003-12-01

    Ecstasy (3,4-methylenedioxymethamphetamine, MDMA) is a psychoactive recreational drug widely used by young people visiting dance parties, and has been associated with poor cognitive function. The current study assessed the influence of a single dose of MDMA 75 mg and alcohol 0.5 g/kg on cognition, psychomotor performance and driving-related task performance. Twelve healthy recreational ecstasy users participated in an experimental study conducted according to a double-blind, double-dummy, placebo-controlled three-way cross-over design. MDMA improved psychomotor performance, such as movement speed and tracking performance in a single task, as well as in a divided attention task. MDMA impaired the ability to predict object movement under divided attention. However, the inability to accurately predict object movement after MDMA may indicate impairment of particular performance skills relevant to driving. There was no effect of MDMA on visual search, planning or retrieval from semantic memory.

  9. Total Dose Effects on Single Event Transients in Digital CMOS and Linear Bipolar Circuits

    NASA Technical Reports Server (NTRS)

    Buchner, S.; McMorrow, D.; Sibley, M.; Eaton, P.; Mavis, D.; Dusseau, L.; Roche, N. J-H.; Bernard, M.

    2009-01-01

    This presentation discusses the effects of ionizing radiation on single event transients (SETs) in circuits. The exposure of integrated circuits to ionizing radiation changes electrical parameters. The total ionizing dose effect is observed in both complementary metal-oxide-semiconductor (CMOS) and bipolar circuits. In bipolar circuits, transistors exhibit grain degradation, while in CMOS circuits, transistors exhibit threshold voltage shifts. Changes in electrical parameters can cause changes in single event upset(SEU)/SET rates. Depending on the effect, the rates may increase or decrease. Therefore, measures taken for SEU/SET mitigation might work at the beginning of a mission but not at the end following TID exposure. The effect of TID on SET rates should be considered if SETs cannot be tolerated.

  10. Inhibitory effect of single and repeated doses of nilotinib on the pharmacokinetics of CYP3A substrate midazolam.

    PubMed

    Zhang, Hefei; Sheng, Jennifer; Ko, Jin H; Zheng, Cheng; Zhou, Wei; Priess, Petra; Lin, Wen; Novick, Steven

    2015-04-01

    Effects of single and repeated doses of nilotinib on the pharmacokinetics of midazolam, a cytochrome P450 3A (CYP3A) substrate, were assessed in 2 separate studies. In the single-dose nilotinib study, 18 healthy subjects were randomized to 6 treatment sequences to receive single dose of nilotinib 600 mg, midazolam 4 mg, and coadministration of both in a crossover manner. In the repeated-dose nilotinib study, 19 chronic myeloid leukemia patients took a single dose of midazolam 2 mg on days 1 and 13, and nilotinib 400 mg twice daily from days 2-13. In the single-dose study, the geometric mean ratio of the area under the plasma concentration time curve extrapolated to infinity (AUC(inf)) of midazolam plus nilotinib vs. midazolam was 1.3 (90%CI, 1.2-1.5) and the maximum observed serum concentration (C(max)) was 1.2 (90%CI, 1.0-1.4). In the repeated-dose study, the values for AUC(inf) and C(max) were 2.6 (90%CI, 2.1-3.3) and 2.0 (90%CI, 1.7-2.4), respectively. These results indicate that single-dose and repeated-dose administration of nilotinib results in weak and moderate inhibition of CYP3A, respectively. Therefore, appropriate monitoring and dose adjustment may be needed for drugs that are mainly metabolized by CYP3A, and have narrow therapeutic index, when coadministered with nilotinib.

  11. Synergistic effects of total ionizing dose on single event upset sensitivity in static random access memory under proton irradiation

    NASA Astrophysics Data System (ADS)

    Xiao, Yao; Guo, Hong-Xia; Zhang, Feng-Qi; Zhao, Wen; Wang, Yan-Ping; Zhang, Ke-Ying; Ding, Li-Li; Fan, Xue; Luo, Yin-Hong; Wang, Yuan-Ming

    2014-11-01

    Synergistic effects of the total ionizing dose (TID) on the single event upset (SEU) sensitivity in static random access memories (SRAMs) were studied by using protons. The total dose was cumulated with high flux protons during the TID exposure, and the SEU cross section was tested with low flux protons at several cumulated dose steps. Because of the radiation-induced off-state leakage current increase of the CMOS transistors, the noise margin became asymmetric and the memory imprint effect was observed.

  12. Single Intramuscular-dose Toxicity of Samgihwalryeok-Pharmacopuncture in Sprague-Dawley Rats

    PubMed Central

    Kim, Sung-Chul; Ahn, Seong-Hun

    2014-01-01

    Objectives: This study was performed to examine the single-dose toxicity of Samgihwalryeok pharmacopuncture. Methods: Forty six-week-old Sprague-Dawley (SD) rats were divided into four groups of 10 rats each; each group was then sub-divided into two smaller groups, one of five males and the other of five females. Group 1 (G1, control) received 1.0 mL of normal saline solution, while group 2 (G2, low-dose group), group 3 (G3, mid-does group, and group 4 (G4, high-dose group) received 0.1, 0.5, and 1.0 mL of Samgihwalryeok pharmacopuncture, respectively. Results: No mortalities or clinical signs were observed in the four groups. Also, no significant changes in body weights were observed among the group, and no significant differences in hematology/biochemistry, necropsy, or histopathology results were noted. Conclusion: The above findings suggest that treatment with Samgihwalryeok pharmacopuncture is relatively safe. Further studies on this subject are needed. PMID:25780699

  13. Effect of Single-dose Rifampin on the Pharmacokinetics of Warfarin in Healthy Volunteers

    PubMed Central

    Frymoyer, A; Shugarts, S; Browne, M; Wu, AHB; Frassetto, L; Benet, LZ

    2011-01-01

    Based on in vitro rat and human hepatocyte uptake studies showing inhibition of warfarin uptake in the presence of the non-specific organic anion transporting polypeptide (OATP) inhibitor rifampin, a clinical study was conducted in 10 healthy volunteers. In a randomized, single-dose, two-period, crossover design, subjects received a 7.5 mg dose of warfarin alone or immediately following a 600 mg intravenous dose of rifampin. Rifampin did not significantly alter R- or S- warfarin area under the concentration-time curve (AUC) from 0–12 hours (period of hepatic OATP inhibition by rifampin) or Cmax (maximum plasma concentration). AUC0–∞ was decreased on rifampin days for both R- (25% reduction; p < 0.001) and S-warfarin (15% reduction; p < 0.05). No differences were seen on the area under the INR-time curve. Our study suggests hepatic uptake via OATPs may not be clinically important in the pharmacokinetics of warfarin. PMID:20703222

  14. Ivermectin effect on microfilariae of Onchocerca volvulus after a single oral dose in humans.

    PubMed

    Soboslay, P T; Newland, H S; White, A T; Erttmann, K D; Albiez, E J; Taylor, H R; Williams, P N; Greene, B M

    1987-03-01

    Ivermectin is a broad spectrum anti-helminthic agent which is currently being tested for use in human onchocerciasis. Its activity is believed to result from its effect on GABA-mediated neurotransmission. We examined the effects of ivermectin on motility of microfilariae of O. volvulus following administration to humans. When ivermectin was given in dosages of 100, 150 and 200 mcg/kg on day 1 there was a clear reduction in motility of microfilariae obtained on day 3 when compared to microfilariae from the placebo group. The mean motility scores in microfilariae from ivermectin recipients were 3.1, 2.3, and 2.2 at 0, 12, and 24 hours of incubation compared to 3.3, 2.9, and 2.5, respectively, in microfilariae from placebo recipients (p less than 0.003, p less than 0.005, and p less than 0.012, respectively). Examination of the effect according to dose suggested a dose-response relationship. Microfilariae in the anterior chamber of the eye 2 days after a single oral dose of ivermectin showed abnormal and reduced winding and coiling. Microfilariae in 50% of ivermectin recipients showed abnormal motility compared to no such effects in subjects examined concurrently who received oral DEC, DEC lotion or placebo. These observations indicate that ivermectin has an effect on motility of microfilariae of O. volvulus following administration to humans.

  15. Amitriptyline pharmacokinetics. Single doses of Lentizol compared with ordinary amitriptyline tablets.

    PubMed

    Burch, J E; Hullin, R P

    1981-01-01

    Two separate single doses of Lentizol (W. R. Warner, Pontypool, U.K.), a sustained-release preparation of amitriptyline (AT) were taken by each of six healthy subjects. Plasma concentrations of AT and of nortriptyline (NT) were determined at intervals over a period of 48 or 72 h. Faeces were collected and their drug content measured. Results were compared with those obtained when the same subjects took ordinary AT tablets. AT was found in the faeces after the ingestion of Lentizol or of ordinary AT tablets. However, after NT tablets negligible amounts of NT appeared in the faeces. AT was sometimes absorbed slowly from Lentizol, but on other occasions it was absorbed as rapidly as from ordinary tablets. Plasma levels of AT 24 h after the dose were usually not higher after Lentizol than after an equal dose of ordinary tablets. The systemic bioavailability of Lentizol as judged by areas under the plasma concentration-time curves, both for AT and for the NT formed metabolically, was on average lower than that of the ordinary tablets. However, the amounts of AT found in the faeces were not large enough to account for the AT area reduction by simple failure of absorption. Possible explanations of the discrepancy are discussed. PMID:6791203

  16. Single-dose Intramuscular Toxicity of Neutral Natured Blood Stasis Pharmacopuncture in Sprague-Dawley Rats

    PubMed Central

    Yeo, In Ho; Lee, Eun Yong

    2014-01-01

    Objectives: This study was performed to analyze the single-dose toxicity of neutral natured blood stasis pharmacopuncture extracts. Methods: All experiments were conducted at Biotoxtech, an institution authorized to perform non-clinical studies, under the regulations of Good Laboratory Practice (GLP). Sprague-Dawley rats were chosen for the pilot study. Doses of neutral natured blood stasis pharmacopuncture extracts, 0.1, 0.5 and 1.0 mL, were administered to the experimental group, and the same doses of normal saline solution were administered to the control group. This study was conducted under the approval of the Institutional Animal Ethics Committee. Results: In all 4 groups, no deaths occurred, and the neutral natured blood stasis pharmacopuncture extracts administered by intramuscular (IM) injection was over 1.0 mL/animal. No significant changes in the body weights between the control group and the experimental group were observed. To check for abnormalities in organs and tissues, we used microscopy to examine representative histological sections of each specified organ; the results showed no significant differences in any organs or tissues. Conclusion: The above findings suggest that treatment with neutral natured blood stasis pharmacopuncture extracts is relatively safe. Further studies on this subject should be conducted to yield more concrete evidence. PMID:25780698

  17. Compendium of Single-Event Latchup and Total Ionizing Dose Test Results of Commercial Analog to Digital Converters

    NASA Technical Reports Server (NTRS)

    Irom, Farokh; Agarwal, Shri G.

    2012-01-01

    This paper reports single-event latchup and total dose results for a variety of analog to digital converters targeted for possible use in NASA spacecraft's. The compendium covers devices tested over the last 15 years.

  18. Response to single dose of aspartame or saccharin by NIDDM patients.

    PubMed

    Horwitz, D L; McLane, M; Kobe, P

    1988-03-01

    Twelve normal subjects and 10 subjects with non-insulin-dependent diabetes mellitus were given, in random order at intervals of greater than or equal to 1 wk, three drinks of the same beverage: one unsweetened, one sweetened with 400 mg aspartame, and one sweetened with 135 mg saccharin. The amount of sweetener approximated that in 1 L of sugar-free soft drink. Plasma glucose, insulin, and glucagon were measured for 3 h after ingestion of the test beverage. Plasma glucose declined slightly throughout the test period, probably due to fasting, with no differences between the three treatments. Neither sweetener affected peak insulin levels in subjects with or without diabetes. Analysis of area under the curve showed that mean insulin levels were statistically significantly higher after aspartame than after saccharin or unsweetened beverage in normal subjects only, but the magnitude of the difference was small and unlikely to be of physiological importance in the absence of differences in glucose levels. Furthermore, the differences could largely be accounted for by a decrease in insulin values after both unsweetened beverage and saccharin, with no change from baseline after aspartame. Glucagon levels showed time-to-time variation but no overall differences. We conclude that ingestion of aspartame- or saccharin-sweetened beverages by fasting subjects, with or without diabetes, did not affect blood glucose homeostasis.

  19. A single dose of oxytocin nasal spray improves higher-order social cognition in schizophrenia.

    PubMed

    Guastella, Adam J; Ward, Philip B; Hickie, Ian B; Shahrestani, Sara; Hodge, Marie Antoinette Redoblado; Scott, Elizabeth M; Langdon, Robyn

    2015-11-01

    Schizophrenia is associated with significant impairments in both higher and lower order social cognitive performance and these impairments contribute to poor social functioning. People with schizophrenia report poor social functioning to be one of their greatest unmet treatment needs. Recent studies have suggested the potential of oxytocin as such a treatment, but mixed results render it uncertain what aspects of social cognition are improved by oxytocin and, subsequently, how oxytocin might best be applied as a therapeutic. The aim of this study was to determine whether a single dose of oxytocin improved higher-order and lower-order social cognition performance for patients with schizophrenia across a well-established battery of social cognition tests. Twenty-one male patients received both a single dose of oxytocin nasal spray (24IU) and a placebo, two weeks apart in a randomized within-subjects placebo controlled design. Following each administration, participants completed the social cognition tasks, as well as a test of general neurocognition. Results revealed that oxytocin particularly enhanced performance on higher order social cognition tasks, with no effects on general neurocognition. Results for individual tasks showed most improvement on tests measuring appreciation of indirect hints and recognition of social faux pas. These results suggest that oxytocin, if combined to enhance social cognition learning, may be beneficial when targeted at higher order social cognition domains. This study also suggests that these higher order tasks, which assess social cognitive processing in a social communication context, may provide useful markers of response to oxytocin in schizophrenia.

  20. Single high-dose vitamin D at birth corrects vitamin D deficiency in infants in Mexico.

    PubMed

    Moodley, Amaran; Spector, Stephen A

    2015-05-01

    This study examined the prevalence of vitamin D deficiency in mothers and infants in Tijuana, Mexico and determined the effect of a single oral dose of 50,000 IU vitamin D3 at birth on 25-hydroxyvitamin D (25[OH]D) levels during infancy. Healthy infants were randomized to receive vitamin D3 or placebo at birth. At birth 23% of infants were vitamin D deficient and 77% had vitamin D insufficiency (mean 25[OH]D level 18.9 ng/ml); 10% of mothers were vitamin D deficient and 61% were insufficient. Infants receiving vitamin D3 had higher 25(OH)D levels at two months (N = 29; 33.9 versus 24.2 ng/ml) and six months (N = 21; 36.5 versus 27.4 ng/ml). Exclusively breastfed infants had lower 25(OH)D levels at two months (14.9 versus 33.4 ng/ml). Vitamin D deficiency is common in infants and mothers in Tijuana, Mexico. A single dose of vitamin D3 at birth was safe and significantly increased 25(OH)D levels during infancy.

  1. Bioengineered Magnetoferritin Nanoprobes for Single-Dose Nuclear-Magnetic Resonance Tumor Imaging.

    PubMed

    Zhao, Yanzhao; Liang, Minmin; Li, Xiao; Fan, Kelong; Xiao, Jie; Li, Yanli; Shi, Hongcheng; Wang, Fei; Choi, Hak Soo; Cheng, Dengfeng; Yan, Xiyun

    2016-04-26

    Despite all the advances in multimodal imaging, it remains a significant challenge to acquire both magnetic resonance and nuclear imaging in a single dose because of the enormous difference in sensitivity. Indeed, nuclear imaging is almost 10(6)-fold more sensitive than magnetic resonance imaging (MRI); thus, repeated injections are generally required to obtain sufficient MR signals after nuclear imaging. Here, we show that strategically engineered magnetoferritin nanoprobes can image tumors with high sensitivity and specificity using SPECT and MRI in living mice after a single intravenous injection. The magnetoferritin nanoprobes composed of (125)I radionuclide-conjugated human H-ferritin iron nanocages ((125)I-M-HFn) internalize robustly into cancer cells via a novel tumor-specific HFn-TfR1 pathway. In particular, the endocytic recycling characteristic of TfR1 transporters solves the nuclear signal blocking issue caused by the high dose nanoprobes injected for MRI, thus enabling simultaneous functional and morphological tumor imaging without reliance on multi-injections.

  2. Successful comeback of the single-dose live oral cholera vaccine CVD 103-HgR.

    PubMed

    Herzog, Christian

    2016-01-01

    Effective and easy to administer cholera vaccines are in need more than ever, for at risk populations and travellers alike. In many parts of the world cholera is still endemic, causing outbreaks and constituting repeatedly serious public health problems. The oral live cholera vaccine CVD 103-HgR (Orochol, Mutachol), the first genetically modified organism (GMO) used as vaccine, was in its time (launched 1993, Switzerland) the ideal cholera vaccine: single-dose, protective efficacy of 80-100% against moderate to severe cholera, acting within 8 days and exhibiting excellent safety, indiscernible from placebo. However, there were strong headwinds: In the 1990s the indication for cholera vaccines was generally downplayed by experts and in 1997 the European Commission called for a moratorium of GMOs which blocked the registration in the European Union. Thus, demand for this vaccine remained low and in 2003 it was taken off the market for economic reasons. After a decade in obscurity it (Vaxchora) has resurfaced again, now produced in the U.S. and equipped with a U.S. FDA license (June 10, 2016). What had happened? This commentary gives a critical account of an almost unbelievable string of misadventures, emerging adverse circumstances and man-made failures which nearly killed this single-dose live oral cholera vaccine. The good news is that patience and persistence lead to success in the end, allowing good science to prevail for the benefit of those in need. PMID:27425792

  3. Prescription Opioids. IV: Disposition of Hydrocodone in Oral Fluid and Blood Following Single-Dose Administration.

    PubMed

    Cone, Edward J; DePriest, Anne Z; Heltsley, Rebecca; Black, David L; Mitchell, John M; LoDico, Charles; Flegel, Ron

    2015-09-01

    The Substance Abuse and Mental Health Services Administration (SAMHSA) is currently evaluating hydrocodone (HC) for inclusion in the Mandatory Guidelines for Federal Workplace Drug Testing Programs. This study evaluated the time course of HC, norhydrocodone (NHC), dihydrocodeine (DHC) and hydromorphone (HM) in paired oral fluid and whole blood specimens by liquid chromatography-tandem mass spectrometry (limit of quantitation = 1 ng/mL of oral fluid, 5 ng/mL of blood) over a 52-h period. A single dose of HC bitartrate, 20 mg, was administered to 12 subjects. Analyte prevalence was as follows: oral fluid, HC > NHC > DHC; and blood, HC > NHC. HM was not detected in any specimen. HC was frequently detected within 15 min in oral fluid and 30 min in blood. Mean oral fluid to blood (OF : BL) ratios and correlations were 3.2 for HC (r = 0.73) and 0.7 for NHC (r = 0.42). The period of detection for oral fluid exceeded blood at all evaluated thresholds. At a 1-ng/mL threshold for oral fluid, mean detection time was 30 h for HC and 18 h for NHC and DHC. This description of HC and metabolite disposition in oral fluid following single-dose administration provides valuable interpretive guidance of HC test results.

  4. Effect of Single Dose Administration of Methylsulfonylmethane on Oxidative Stress Following Acute Exhaustive Exercise

    PubMed Central

    Nakhostin-Roohi, Babak; Niknam, Zahra; Vaezi, Nasrin; Mohammadi, Sadollah; Bohlooli, Shahab

    2013-01-01

    Methylsulfonylmethane (MSM) is a sulfur-containing compound commonly found in diet and known to reduce oxidative stress. This trial was conducted to determine whether single dose supplementation with MSM attenuates post-exercise oxidative stress in healthy untrained young men. Sixteen untrained men volunteered for this study. Participants were randomized in a double-blind placebo-controlled fashion into 2 groups: Methylsulfonylmethane (MSM) (n = 8) and placebo (n = 8). The participants took supplementation or placebo before running on treadmill for 45 min at 75% VO2max. The MSM supplementation was prepared in water as 100 mg/ kg body weight. The placebo group received water. Serum Malondealdehyde (MDA), uric acid, bilirubin, protein carbonyl (PC) and plasma vitamin E levels were determined as the markers of oxidative stress. Plasma GSH (reduced Glutathione) and total antioxidant capacity (TAC) were measured as markers of plasma antioxidant system. MSM supplementation successfully lowered serum PC 2 and 24 h after exercise. Plasma TAC in MSM group was higher at 24 h after exercise. Serum level of uric acid and bilirubin were significantly low immediately after exercise in MSM supplemented group. There was no significant difference between groups in terms of plasma GSH level. These results complement earlier studies showing anti-oxidant effect of MSM and suggest that single dose oral supplementation with MSM lowers exercise induced oxidative stress in healthy untrained young men, but is not adequate to significantly affect plasma GSH level. PMID:24523764

  5. Effect of single oral dose of tramadol on gastric secretions pH

    PubMed Central

    Ullah, Khan Mueen; Aqil, Mansoor; Hussain, Altaf; Al Zahrani, Tariq; Hillis, Marwan

    2015-01-01

    Background: Tramadol is an atypical analgesic agent. It has been shown that intramuscular or intravenous injection tramadol is able to inhibit M3 muscarinic receptors. Tramadol is able to mediate smooth muscles contraction and glandular secretions. We have evaluated the effects of single oral dose of tramadol given preoperatively on gastric juices pH in patients electively scheduled for laparoscopic cholecystectomy. Materials and Methods: Sixty adult, American Society of Anesthesiologist I and II patients scheduled for laparoscopic cholecystectomy were included in the study. Patients were randomly assigned to receive either placebo (n = 30) or oral tramadol 50 mg (n = 30). General anesthesia was induced using propofol, fentanyl and cisatracurium. After induction of anesthesia 5 ml of gastric fluid was aspirated through orogastric tube. The gastric fluid pH was measured using pH meter. Result: There was no significant difference in the pH between the groups. Gastric pH of the placebo and tramadol groups was 1.97 versus 1.98 (P = 0.092) respectively. Conclusion: Preoperatively single oral dose of tramadol was unable to elevate the desired level of gastric acid secretions pH (>2.5). This may be due to pharmacokinetic disparity between the analgesic and pH elevating properties of tramadol. PMID:25558191

  6. A single dose of citalopram increases fear recognition in healthy subjects.

    PubMed

    Browning, M; Reid, C; Cowen, P J; Goodwin, G M; Harmer, C J

    2007-09-01

    We have previously shown that a single dose of intravenous citalopram in healthy volunteers enhances the detection of fearful facial expressions, suggesting an effect of acute selective serotonin re-uptake inhibitor (SSRI) treatment on the processing of anxiety-related stimuli. The aim of the present study was to confirm and extend this finding by studying the effects of a single dose of oral citalopram on a range of tasks designed to assess different aspects of emotional processing. A total of 32 healthy volunteers were randomly allocated to double-blind treatment with either citalopram 20 mg orally or placebo. Participants then completed a series of tasks assessing emotional aspects of attention (visual-probe task), perception (categorization of facial affect), memory (emotional memory task) and reactivity to threat (emotion potentiated startle). Relative to placebo-treated subjects, participants treated with citalopram demonstrated improved recognition of fearful faces and increased baseline startle response. However, the citalopram group also showed an attentional bias towards positive words. Our data suggest that acute oral citalopram increases the processing of anxiety-related stimuli in healthy volunteers. This mechanism could underlie the known tendency of SSRIs to increase anxiety in patients early in treatment. Our data also suggests that some of the positive biases in emotional processing produced by SSRI treatment might be detectable at the beginning of treatment.

  7. Single dose intravenous methyl prednisolone versus oral prednisolone in Bell's palsy: A randomized controlled trial

    PubMed Central

    Giri, Prithvi; Garg, Ravindra Kumar; Singh, Maneesh Kumar; Verma, Rajesh; Malhotra, Hardeep Singh; Sharma, Praveen Kumar

    2015-01-01

    Objectives: Corticosteroids have been used in the treatment of Bell's palsy and several other postinfectious neurological conditions. We hypothesized that administration of a single dose of intravenous (IV) methylprednisolone might be an effective alternative to oral prednisolone. Materials and Methods: In this open label, randomized trial, patients with acute Bell's palsy were randomized into two groups. One group received single dose (500 mg) of IV methylprednisolone while the other group received 10 days of oral prednisone. Outcome was assessed at 1 and 3 months with House–Brackmann scale. Results: At 3 months, 93 (79.48%) patients had completely recovered. IV methylprednisolone and oral prednisolone groups had similar recovery rates (80% vs. 78.33%, P > 0.05). Patients with Grade 2 and 3 recovered completely. In patients with Grade 6, the recovery rate was 20%. A better outcome was observed if corticosteroids were administered within 3 days of onset of palsy. Conclusion: Intravenous methylprednisolone and oral prednisolone showed equivalent benefit in patients with acute Bell's palsy. PMID:25878371

  8. Successful comeback of the single-dose live oral cholera vaccine CVD 103-HgR.

    PubMed

    Herzog, Christian

    2016-01-01

    Effective and easy to administer cholera vaccines are in need more than ever, for at risk populations and travellers alike. In many parts of the world cholera is still endemic, causing outbreaks and constituting repeatedly serious public health problems. The oral live cholera vaccine CVD 103-HgR (Orochol, Mutachol), the first genetically modified organism (GMO) used as vaccine, was in its time (launched 1993, Switzerland) the ideal cholera vaccine: single-dose, protective efficacy of 80-100% against moderate to severe cholera, acting within 8 days and exhibiting excellent safety, indiscernible from placebo. However, there were strong headwinds: In the 1990s the indication for cholera vaccines was generally downplayed by experts and in 1997 the European Commission called for a moratorium of GMOs which blocked the registration in the European Union. Thus, demand for this vaccine remained low and in 2003 it was taken off the market for economic reasons. After a decade in obscurity it (Vaxchora) has resurfaced again, now produced in the U.S. and equipped with a U.S. FDA license (June 10, 2016). What had happened? This commentary gives a critical account of an almost unbelievable string of misadventures, emerging adverse circumstances and man-made failures which nearly killed this single-dose live oral cholera vaccine. The good news is that patience and persistence lead to success in the end, allowing good science to prevail for the benefit of those in need.

  9. Significant Increase in Salivary Substance P Level after a Single Oral Dose of Cevimeline in Humans

    PubMed Central

    Suzuki, Yosuke; Itoh, Hiroki; Amada, Kohei; Yamamura, Ryota; Sato, Yuhki; Takeyama, Masaharu

    2013-01-01

    Cevimeline is a novel muscarinic acetylcholine receptor agonist currently being developed as a therapeutic agent for xerostomia. We examined the effects of cevimeline on salivary and plasma levels of substance-P- (SP-), calcitonin-gene-related-peptide- (CGRP-), and vasoactive-intestinal-polypeptide- (VIP-) like immunoreactive substances (ISs) in humans. An open-labeled crossover study was conducted on seven healthy volunteers. Saliva volume was measured, and saliva and venous blood samples were collected before and 30–240 min after a single oral dose of cevimeline or placebo. Salivary and plasma levels of SP-, CGRP-, and VIP-IS were measured using a highly sensitive enzyme immunoassay. A single oral dose of cevimeline resulted in significant increases in salivary but not plasma SP-IS level compared to placebo. Cevimeline administration did not alter the salivary or plasma levels of CGRP-IS or VIP-IS compared to placebo. Significant increases in salivary volume were observed after cevimeline administration compared to placebo. A significant correlation was observed between the total release of SP-IS and that of salivary volume. These findings suggest an association of SP with the enhancement of salivary secretion by cevimeline. PMID:23589717

  10. Prescription Opioids. IV: Disposition of Hydrocodone in Oral Fluid and Blood Following Single-Dose Administration.

    PubMed

    Cone, Edward J; DePriest, Anne Z; Heltsley, Rebecca; Black, David L; Mitchell, John M; LoDico, Charles; Flegel, Ron

    2015-09-01

    The Substance Abuse and Mental Health Services Administration (SAMHSA) is currently evaluating hydrocodone (HC) for inclusion in the Mandatory Guidelines for Federal Workplace Drug Testing Programs. This study evaluated the time course of HC, norhydrocodone (NHC), dihydrocodeine (DHC) and hydromorphone (HM) in paired oral fluid and whole blood specimens by liquid chromatography-tandem mass spectrometry (limit of quantitation = 1 ng/mL of oral fluid, 5 ng/mL of blood) over a 52-h period. A single dose of HC bitartrate, 20 mg, was administered to 12 subjects. Analyte prevalence was as follows: oral fluid, HC > NHC > DHC; and blood, HC > NHC. HM was not detected in any specimen. HC was frequently detected within 15 min in oral fluid and 30 min in blood. Mean oral fluid to blood (OF : BL) ratios and correlations were 3.2 for HC (r = 0.73) and 0.7 for NHC (r = 0.42). The period of detection for oral fluid exceeded blood at all evaluated thresholds. At a 1-ng/mL threshold for oral fluid, mean detection time was 30 h for HC and 18 h for NHC and DHC. This description of HC and metabolite disposition in oral fluid following single-dose administration provides valuable interpretive guidance of HC test results. PMID:25962610

  11. Single-dose metronidazole clears Opalina sp. from juvenile Bufo woodhousii.

    PubMed

    Nickol, Devin R; Tufts, Danielle M

    2013-06-01

    Protozoans of the family Opalinidae are intestinal commensals in amphibians. To test the hypothesis that these organisms are susceptible to the antiprotozoal antibiotic metronidazole, we randomly assigned 60 juvenile Woodhouse's toads ( Bufo woodhousii ) to receive a single oral dose of metronidazole or water. In pilot trials, the prevalence of opalinids in untreated members of this population was over 70%. One-third of the study population was dissected at each of 3 time points: 18 hr, 1 wk, and 2 wk post-treatment. An examiner blinded to the toad's treatment history determined the presence or absence of opalinids using a dissecting microscope. Opalinids were found in 3/10 toads in the treatment group and 9/10 in the control group after 18 hr (P < 0.02), in none of the treatment group and 8/10 in the control group after 1 wk (P < 0.001), and in none of the treatment group and 10/10 in the control group after 2 wk (P < 0.0001). These results suggest that a single-dose of metronidazole quickly and reliably clears opalinids from juvenile Woodhouse's toads with no evidence of short-term recurrence. The treatment was well tolerated, with no apparent morbidity and no mortality in either group. Future exploration of opalinid-related host fitness consequences may be facilitated by this simple method of developing a protozoan-free host population. PMID:23339344

  12. Miltefosine Lipid Nanocapsules for Single Dose Oral Treatment of Schistosomiasis Mansoni: A Preclinical Study

    PubMed Central

    Eissa, Maha M.; El-Moslemany, Riham M.; Ramadan, Alyaa A.; Amer, Eglal I.; El-Azzouni, Mervat Z.; El-Khordagui, Labiba K.

    2015-01-01

    Miltefosine (MFS) is an alkylphosphocholine used for the local treatment of cutaneous metastases of breast cancer and oral therapy of visceral leishmaniasis. Recently, the drug was reported in in vitro and preclinical studies to exert significant activity against different developmental stages of schistosomiasis mansoni, a widespread chronic neglected tropical disease (NTD). This justified MFS repurposing as a potential antischistosomal drug. However, five consecutive daily 20 mg/kg doses were needed for the treatment of schistosomiasis mansoni in mice. The present study aims at enhancing MFS efficacy to allow for a single 20mg/kg oral dose therapy using a nanotechnological approach based on lipid nanocapsules (LNCs) as oral nanovectors. MFS was incorporated in LNCs both as membrane-active structural alkylphospholipid component and active antischistosomal agent. MFS-LNC formulations showed high entrapment efficiency (EE%), good colloidal properties, sustained release pattern and physical stability. Further, LNCs generally decreased MFS-induced erythrocyte hemolytic activity used as surrogate indicator of membrane activity. While MFS-free LNCs exerted no antischistosomal effect, statistically significant enhancement was observed with all MFS-LNC formulations. A maximum effect was achieved with MFS-LNCs incorporating CTAB as positive charge imparting agent or oleic acid as membrane permeabilizer. Reduction of worm load, ameliorated liver pathology and extensive damage of the worm tegument provided evidence for formulation-related efficacy enhancement. Non-compartmental analysis of pharmacokinetic data obtained in rats indicated independence of antischistosomal activity on systemic drug exposure, suggesting possible gut uptake of the stable LNCs and targeting of the fluke tegument which was verified by SEM. The study findings put forward MFS-LNCs as unique oral nanovectors combining the bioactivity of MFS and biopharmaceutical advantages of LNCs, allowing targeting

  13. Dose painting to treat single-lobe prostate cancer with hypofractionated high-dose radiation using targeted external beam radiation: Is it feasible?

    PubMed

    Amini, Arya; Westerly, David C; Waxweiler, Timothy V; Ryan, Nicole; Raben, David

    2015-01-01

    Targeted focal therapy strategies for treating single-lobe prostate cancer are under investigation. In this planning study, we investigate the feasibility of treating a portion of the prostate to full-dose external beam radiation with reduced dose to the opposite lobe, compared with full-dose radiation delivered to the entire gland using hypofractionated radiation. For 10 consecutive patients with low- to intermediate-risk prostate cancer, 2 hypofractionated, single-arc volumetric-modulated arc therapy (VMAT) plans were designed. The first plan (standard hypofractionation regimen [STD]) included the entire prostate gland, treated to 70 Gy delivered in 28 fractions. The second dose painting plan (DP) encompassed the involved lobe treated to 70 Gy delivered in 28 fractions, whereas the opposing, uninvolved lobe received 50.4 Gy in 28 fractions. Mean dose to the opposing neurovascular bundle (NVB) was considerably lower for DP vs STD, with a mean dose of 53.9 vs 72.3 Gy (p < 0.001). Mean penile bulb dose was 18.6 Gy for DP vs 19.2 Gy for STD (p = 0.880). Mean rectal dose was 21.0 Gy for DP vs 22.8 Gy for STD (p = 0.356). Rectum V70 (the volume receiving ≥70 Gy) was 2.01% for DP vs 2.74% for STD (p = 0.328). Bladder V70 was 1.69% for DP vs 2.78% for STD (p = 0.232). Planning target volume (PTV) maximum dose points were 76.5 and 76.3 Gy for DP and STD, respectively (p = 0.760). This study demonstrates the feasibility of using VMAT for partial-lobe prostate radiation in patients with prostate cancer involving 1 lobe. Partial-lobe prostate plans appeared to spare adjacent critical structures including the opposite NVB.

  14. Dose painting to treat single-lobe prostate cancer with hypofractionated high-dose radiation using targeted external beam radiation: Is it feasible?

    SciTech Connect

    Amini, Arya; Westerly, David C.; Waxweiler, Timothy V.; Ryan, Nicole; Raben, David

    2015-10-01

    Targeted focal therapy strategies for treating single-lobe prostate cancer are under investigation. In this planning study, we investigate the feasibility of treating a portion of the prostate to full-dose external beam radiation with reduced dose to the opposite lobe, compared with full-dose radiation delivered to the entire gland using hypofractionated radiation. For 10 consecutive patients with low- to intermediate-risk prostate cancer, 2 hypofractionated, single-arc volumetric-modulated arc therapy (VMAT) plans were designed. The first plan (standard hypofractionation regimen [STD]) included the entire prostate gland, treated to 70 Gy delivered in 28 fractions. The second dose painting plan (DP) encompassed the involved lobe treated to 70 Gy delivered in 28 fractions, whereas the opposing, uninvolved lobe received 50.4 Gy in 28 fractions. Mean dose to the opposing neurovascular bundle (NVB) was considerably lower for DP vs STD, with a mean dose of 53.9 vs 72.3 Gy (p < 0.001). Mean penile bulb dose was 18.6 Gy for DP vs 19.2 Gy for STD (p = 0.880). Mean rectal dose was 21.0 Gy for DP vs 22.8 Gy for STD (p = 0.356). Rectum V{sub 70} (the volume receiving ≥70 Gy) was 2.01% for DP vs 2.74% for STD (p = 0.328). Bladder V{sub 70} was 1.69% for DP vs 2.78% for STD (p = 0.232). Planning target volume (PTV) maximum dose points were 76.5 and 76.3 Gy for DP and STD, respectively (p = 0.760). This study demonstrates the feasibility of using VMAT for partial-lobe prostate radiation in patients with prostate cancer involving 1 lobe. Partial-lobe prostate plans appeared to spare adjacent critical structures including the opposite NVB.

  15. SU-E-T-568: Neutron Dose Survey of a Compact Single Room Proton Machine

    SciTech Connect

    Chen, Y; Prusator, M; Islam, M; Johnson, D; Ahmad, S

    2015-06-15

    Purpose: To ensure acceptable radiation limits are maintained for those working at and near the machine during its operation, a comprehensive radiation survey was performed prior to the clinical release of Mevion S250 compact proton machine at Stephenson Oklahoma Cancer Center. Methods: The Mevion S250 proton therapy system consists of the following: a superconducting cyclotron to accelerate the proton particles, a passive double scattering system for beam shaping, and paired orthogonal x-ray imaging systems for patient setup and verification via a 6D robotic couch. All equipment is housed within a single vault of compact design. Two beam delivery applicators are available for patient treatment, offering field sizes of as great as 14 cm and 25 cm in diameter, respectively. Typical clinical dose rates are between 1 and 2 Gy/min with a fixed beam energy of 250 MeV. The large applicator (25 cm in diameter) was used in conjunction with a custom cut brass aperture to create a 20 cm x 20 cm field size at beam isocenter. A 30 cm − 30 cm − 35 cm high density plastic phantom was placed in the beam path to mimic the conditions creating patient scatter. Measurements integrated-ambient-neutron-dose-equivalence were made with a SWENDII detector. Gantry angles of 0, 90 and 180 degrees, with a maximum dose rate of 150 MU/min (for large applicator) and beam configuration of option 1 (range 25 cm and 20 cm modulation), were selected as testing conditions. At each point of interest, the highest reading was recorded at 30 cm from the barrier surface. Results: The highest neutron dose was estimated to be 0.085 mSv/year at the console area. Conclusion: All controlled areas are under 5 mSv/year and the uncontrolled areas are under 1 mSv/year. The radiation protection provided by the proton vault is of sufficient quality.

  16. Predictors of Local Control After Single-Dose Stereotactic Image-Guided Intensity-Modulated Radiotherapy for Extracranial Metastases

    SciTech Connect

    Greco, Carlo; Zelefsky, Michael J.; Lovelock, Michael; Fuks, Zvi; Hunt, Margie; Rosenzweig, Kenneth; Zatcky, Joan; Kim, Balem; Yamada, Yoshiya

    2011-03-15

    Purpose: To report tumor local control after treatment with single-dose image-guided intensity-modulated radiotherapy (SD-IGRT) to extracranial metastatic sites. Methods and Materials: A total of 126 metastases in 103 patients were treated with SD-IGRT to prescription doses of 18-24 Gy (median, 24 Gy) between 2004 and 2007. Results: The overall actuarial local relapse-free survival (LRFS) rate was 64% at a median follow-up of 18 months (range, 2-45 months). The median time to failure was 9.6 months (range, 1-23 months). On univariate analysis, LRFS was significantly correlated with prescription dose (p = 0.029). Stratification by dose into high (23 to 24 Gy), intermediate (21 to 22 Gy), and low (18 to 20 Gy) dose levels revealed highly significant differences in LRFS between high (82%) and low doses (25%) (p < 0.0001). Overall, histology had no significant effect on LRFS (p = 0.16). Renal cell histology displayed a profound dose-response effect, with 80% LRFS at the high dose level (23 to 24 Gy) vs. 37% with low doses ({<=}22 Gy) (p = 0.04). However, for patients who received the high dose level, histology was not a statistically significant predictor of LRFS (p = 0.90). Target organ (bone vs. lymph node vs. soft tissues) (p = 0.5) and planning target volume size (p = 0.55) were not found to be associated with long-term LRFS probability. Multivariate Cox regression analysis confirmed prescription dose to be a significant predictor of LRFS (p = 0.003). Conclusion: High-dose SD-IGRT is a noninvasive procedure resulting in high probability of local tumor control. Single-dose IGRT may be effectively used to locally control metastatic deposits regardless of histology and target organ, provided sufficiently high doses (> 22 Gy) of radiation are delivered.

  17. QMRA for Drinking Water: 2. The Effect of Pathogen Clustering in Single-Hit Dose-Response Models.

    PubMed

    Nilsen, Vegard; Wyller, John

    2016-01-01

    Spatial and/or temporal clustering of pathogens will invalidate the commonly used assumption of Poisson-distributed pathogen counts (doses) in quantitative microbial risk assessment. In this work, the theoretically predicted effect of spatial clustering in conventional "single-hit" dose-response models is investigated by employing the stuttering Poisson distribution, a very general family of count distributions that naturally models pathogen clustering and contains the Poisson and negative binomial distributions as special cases. The analysis is facilitated by formulating the dose-response models in terms of probability generating functions. It is shown formally that the theoretical single-hit risk obtained with a stuttering Poisson distribution is lower than that obtained with a Poisson distribution, assuming identical mean doses. A similar result holds for mixed Poisson distributions. Numerical examples indicate that the theoretical single-hit risk is fairly insensitive to moderate clustering, though the effect tends to be more pronounced for low mean doses. Furthermore, using Jensen's inequality, an upper bound on risk is derived that tends to better approximate the exact theoretical single-hit risk for highly overdispersed dose distributions. The bound holds with any dose distribution (characterized by its mean and zero inflation index) and any conditional dose-response model that is concave in the dose variable. Its application is exemplified with published data from Norovirus feeding trials, for which some of the administered doses were prepared from an inoculum of aggregated viruses. The potential implications of clustering for dose-response assessment as well as practical risk characterization are discussed. PMID:26812258

  18. Single dose oral indometacin for the treatment of acute postoperative pain

    PubMed Central

    Moore, R Andrew; Derry, Sheena; Mason, Lorna; McQuay, Henry J; Edwards, Jayne

    2014-01-01

    Background This is an updated version of the original Cochrane review published in Issue 4, 2004. Indometacin is a non-steroidal anti-inflammatory drug (NSAID) used most commonly for the treatment of inflammation and pain resulting from rheumatic disease (arthritis), and less commonly in postoperative pain management. When taken for chronic pain conditions, indometacin has been associated with a high incidence of adverse events. The benefits and harms of orally-administered indometacin for postoperative pain are not clear. Objectives To determine the efficacy of a single dose of oral indometacin compared with placebo in treating acute postoperative pain in adults, and to analyse information relating to adverse events. Search methods We searched the Cochrane CENTRAL Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE and the Oxford Pain Relief Database for relevant studies in January 2002 and for the updated search in December 2007. Additional studies were sought from the reference lists of retrieved studies. Selection criteria Studies were included in the review if they were randomised, double blind, placebo-controlled clinical trials using a single oral dose of indometacin in adults with acute postoperative pain. Data collection and analysis Studies were assessed independently by two review authors. Pain relief or pain intensity data were extracted and converted into dichotomous information to give the number of participants with at least 50% pain relief over four to six hours. The relative benefit for at least 50% pain relief was calculated. Main results In the original review one study of 59 women with post-episiotomy pain met the inclusion criteria. The dose of indometacin assessed against placebo was 50 mg, and the results concluded that indometacin was not significantly better than placebo for relieving postoperative pain at four to six hours. There was insufficient information to conduct further efficacy analyses or assess adverse events

  19. Measurement of gallbladder emptying sequentially using a single dose of /sup 99m/Tc-labeled hepatobiliary agent

    SciTech Connect

    Krishnamurthy, G.T.; Bobba, V.R.; Kingston, E.; Turner, F.

    1982-10-01

    The gallbladder emptying response to a single large (20 ng/kg) and four equally divided sequential small (5 ng/kg each) doses of octapeptide of cholecystokinin at 20-min intervals was measured in a paired study in six normal subjects noninvasively and quantitatively by a nongeometric method using a gamma camera, computer, and /sup 99m/Tc labeled hepatobiliary agent. The gallbladder mean (+/- SD) ejection fraction after a single large dose (20 ng/kg) of octapeptide of cholecystokinin was 34 +/- 24% and after four sequential small (5 ng/kg each) doses was 42 +/- 14%, 45 +/- 28%, 37 +/- 22%, and 32 +/- 27%, respectively (p greater than 0.05). The results of this study indicate that the first part of the 5 ng/kg sequential octapeptide of cholecystokinin dose is as effective as the single 20-ng/kg dose. The gallbladder emptying requires continued presence of high levels of octapeptide of cholecystokinin in the serum closer to levels that initiate contraction and in the absence of which the gallbladder ceases to empty further despite the fact it has inherent capacity to do so. Each of four equal octapeptide of cholecystokinin doses given sequentially elicits, on the average, an equal degree of emptying response. The method has potential for application in the study of the pharmacological effects of drugs on the biliary dynamics using a single dose of /sup 99/mTc-labeled hepatobiliary radiopharmaceutical.

  20. Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain in adults

    PubMed Central

    Toms, Laurence; Derry, Sheena; Moore, R Andrew; McQuay, Henry J

    2014-01-01

    Background This is an updated version of the Cochrane review published in Issue 4, 1998. Combining drugs from different classes with different modes of action may offer opportunity to optimise efficacy and tolerability, using lower doses of each drug to achieve the same degree of pain relief. Previously we concluded that addition of codeine to paracetamol provided additional pain relief, but at expense of additional adverse events. New studies have been published since. This review sought to evaluate efficacy and safety of paracetamol plus codeine using current data, and compare findings with other analgesics evaluated similarly. Objectives Assess efficacy of single dose oral paracetamol plus codeine in acute postoperative pain, increase in efficacy due to the codeine component, and associated adverse events. Search methods We searched CENTRAL, MEDLINE, EMBASE, the Oxford Pain Relief Database in October 2008 for this update. Selection criteria Randomised, double-blind, placebo-controlled trials of paracetamol plus codeine, compared with placebo or the same dose of paracetamol alone, for relief of acute postoperative pain in adults. Data collection and analysis Two authors assessed trial quality and extracted data. The area under the “pain relief versus time” curve was used to derive proportion of participants with paracetamol plus codeine and placebo or paracetamol alone experiencing least 50% pain relief over four-to-six hours, using validated equations. Number-needed-to-treat-to-benefit (NNT) was calculated using 95% confidence intervals (CIs). Proportion of participants using rescue analgesia over a specified time period, and time to use of rescue analgesia, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected. Main results Twenty-six studies, with 2295 participants, were included comparing paracetamol plus codeine with placebo. Significant dose response was seen for the outcome of at least 50% pain

  1. Patient Radiation Dose in Diagnostic and Interventional Procedures for Intracranial Aneurysms: Experience at a Single Center

    PubMed Central

    Chun, Chang Woo; Lee, Cheol Hyoun; Ihn, Yon Kwon; Shin, Yong-Sam

    2014-01-01

    Objective To assess patient radiation doses during cerebral angiography and embolization of intracranial aneurysms in a large sample size from a single center. Materials and Methods We studied a sample of 439 diagnostic and 149 therapeutic procedures for intracranial aneurysms in 480 patients (331 females, 149 males; median age, 57 years; range, 21-88 years), which were performed in 2012 with a biplane unit. Parameters including fluoroscopic time, dose-area product (DAP), and total angiographic image frames were obtained and analyzed. Results Mean fluoroscopic time, total mean DAP, and total image frames were 12.6 minutes, 136.6 ± 44.8 Gy-cm2, and 251 ± 49 frames for diagnostic procedures, 52.9 minutes, 226.0 ± 129.2 Gy-cm2, and 241 frames for therapeutic procedures, and 52.2 minutes, 334.5 ± 184.6 Gy-cm2, and 408 frames for when both procedures were performed during the same session. The third quartiles for diagnostic reference levels (DRLs) were 14.0, 61.1, and 66.1 minutes for fluoroscopy time, 154.2, 272.8, and 393.8 Gy-cm2 for DAP, and 272, 276, and 535 for numbers of image frames in diagnostic, therapeutic, and both procedures in the same session, respectively. The proportions of fluoroscopy in DAP for the procedures were 11.4%, 50.5%, and 36.1%, respectively, for the three groups. The mean DAP for each 3-dimensional rotational angiographic acquisition was 19.2 ± 3.2 Gy-cm2. On average, rotational angiography was used 1.4 ± 0.6 times/session (range, 1-4; n = 580). Conclusion Radiation dose in our study as measured by DAP, fluoroscopy time and image frames did not differ significantly from other reported DRL studies for cerebral angiography, and DAP was lower with fewer angiographic image frames for embolization. A national registry of radiation-dose data is a necessary next step to refine the dose reference level. PMID:25469098

  2. Dose-Volume Response Relationship for Brain Metastases Treated with Frameless Single-Fraction Linear Accelerator-Based Stereotactic Radiosurgery

    PubMed Central

    Pan, Jianmin; Yusuf, Mehran B; Dragun, Anthony; Dunlap, Neal; Guan, Timothy; Boling, Warren; Rai, Shesh; Woo, Shiao

    2016-01-01

    Background: Our aim was to identify a dose-volume response relationship for brain metastases treated with frameless stereotactic radiosurgery (SRS). Methods: We reviewed patients who underwent frameless single-fraction linear accelerator SRS for brain metastases between 2007 and 2013 from an institutional database. Proportional hazards modeling was used to identify predictors of outcome. A ratio of maximum lesion dose per mm-diameter (Gy/mm) was constructed to establish a dose-volume relationship. Results: There were 316 metastases evaluated in 121 patients (2 - 33 mm in the largest diameter). The median peripheral dose was 18.0 Gy (range: 10.0 – 24.0 Gy). Local control was 84.8% for all lesions and was affected by location, peripheral dose, maximum dose, and lesion size (p values < 0.050). A dose-volume response relationship was constructed using the maximum dose and lesion size. A unit increase in Gy/mm was associated with decreased local failure (p = 0.005). Local control of 80%, 85%, and 90% corresponded to maximum doses per millimeter of 1.67 Gy/mm, 2.86 Gy/mm, and 4.4 Gy/mm, respectively. Toxicity was uncommon and only 1.0% of lesions developed radionecrosis requiring surgery. Conclusions: For brain metastases less than 3 cm, a dose-volume response relationship exists between maximum radiosurgical dose and lesion size, which is predictive of local control. PMID:27284495

  3. Disposition of chloroquine in man after single intravenous and oral doses.

    PubMed

    Gustafsson, L L; Walker, O; Alván, G; Beermann, B; Estevez, F; Gleisner, L; Lindström, B; Sjöqvist, F

    1983-04-01

    1 Chloroquine was given in 300 mg single doses as an i.v. infusion, an oral solution and as tablets at intervals of at least 56 days to 11 healthy volunteers. Concentrations of chloroquine and its metabolite desethylchloroquine were measured in plasma, erythrocytes and urine using h.p.l.c. 2 Chloroquine was detectable in all plasma samples up to 23 days and occasionally up to 52 days after dosage. Urinary concentrations were monitored up to 119 days. The disposition pattern was multiexponential reflecting extensive tissue binding of the drug. 3 After i.v. dosing the volume of distribution ranged from 116 to 285 l/kg and the apparent terminal half-life from 146 to 333 h. Total plasma clearance +/- s.d. was 712 +/- 166 ml/min and renal clearance 412 +/- 139 ml/min. The mean estimated urinary recovery of chloroquine was 47%, 42% and 46% after i.v., oral solution and tablets indicating nearly complete bioavailability. The corresponding figures for the metabolite were 7%, 10% and 12%. 4 The disposition of chloroquine in erythrocytes was parallel to that in plasma. The concentrations in erythrocytes were consistently 2 to 5 times higher than in plasma. 5 Subjective side effects like difficulties with swallowing and accommodation, diplopia and fatigue occurred during intravenous infusion and were closely related to plasma concentrations. No effect was seen on the electrocardiogram, mean arterial blood pressure and pulse rate. No adverse reactions were observed after the oral doses. High frequency audiometry did not reveal any significant hearing impairment for the group as a whole.

  4. Single-Dose Pharmacokinetic Study of Tramadol Extended-Release Tablets in Children and Adolescents.

    PubMed

    Vandenbossche, Joris; Van Peer, Achiel; Richards, Henry

    2016-09-01

    Combined analyses from 2 open-label, phase-1 studies-the pharmacokinetic profile of tramadol and its metabolite (M1) following a single oral dose of tramadol extended release (ER) (25 to 100 mg) in children (7 to 11 years old; study 1: n = 37) and adolescents (12 to 17 years old; study 2: n = 38) with painful conditions-were historically compared with that of healthy adults following similar dosing. The dose-normalized area under the curve (DN AUC0-24h ) and maximum concentration (DN Cmax ) of tramadol and of M1 in children and in adolescents were lower than those in adults (children vs adults: tramadol, DN AUC0-24h 82.19%; DN Cmax 80.38%, P = .0031; M1, DN AUC0-24h 51.19%, DN Cmax 52.68%, P < .0001; adolescents vs adults: tramadol, DN AUC0-24h 89.56%, DN Cmax 84.01%; M1, DN AUC0-24h 85.28%, DN Cmax 83.03%, P = .0004). The arithmetic mean terminal elimination t1/2 of tramadol in children and adolescents was comparable to that in adults (children 8.4 hours; adolescents 8.5 hours; adults 7.9 hours). The most frequently reported (≥5% of participants) treatment-emergent adverse events in children included headache, upper abdominal pain and constipation, and in adolescents were headache, nausea, dizziness, and stomach discomfort. Multiple factors may have contributed to these observations, including a higher proportion of children (56%) who may have a lower activity of CYP2D6, resulting in reduced clearance of tramadol.

  5. Tumor lysis syndrome in metastatic breast cancer after a single dose of paclitaxel.

    PubMed

    Vaidya, Gaurang Nandkishor; Acevedo, Russell

    2015-02-01

    Tumor lysis syndrome (TLS) is an oncologic emergency characterized by spillage of intracellular material into the blood caused by disruption of massive load of tumor cells. It is more commonly reported in hematological cancers and can have fatal consequences due to renal and multi-organ failure and arrhythmias due to electrolyte imbalance. We describe a case with metastatic breast cancer who presented with TLS after a single dose of paclitaxel, second such case in literature. The development of a risk stratification score to assess the need for hospitalization or close observation of these patients and the documentation of appropriate preventive strategies could help prevent such fatal occurrences. TLS should be included in the differential when cancer patients on treatment present with acute decompensation. PMID:25178848

  6. Research design considerations for single-dose analgesic clinical trials in acute pain: IMMPACT recommendations.

    PubMed

    Cooper, Stephen A; Desjardins, Paul J; Turk, Dennis C; Dworkin, Robert H; Katz, Nathaniel P; Kehlet, Henrik; Ballantyne, Jane C; Burke, Laurie B; Carragee, Eugene; Cowan, Penney; Croll, Scott; Dionne, Raymond A; Farrar, John T; Gilron, Ian; Gordon, Debra B; Iyengar, Smriti; Jay, Gary W; Kalso, Eija A; Kerns, Robert D; McDermott, Michael P; Raja, Srinivasa N; Rappaport, Bob A; Rauschkolb, Christine; Royal, Mike A; Segerdahl, Märta; Stauffer, Joseph W; Todd, Knox H; Vanhove, Geertrui F; Wallace, Mark S; West, Christine; White, Richard E; Wu, Christopher

    2016-02-01

    This article summarizes the results of a meeting convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) on key considerations and best practices governing the design of acute pain clinical trials. We discuss the role of early phase clinical trials, including pharmacokinetic-pharmacodynamic (PK-PD) trials, and the value of including both placebo and active standards of comparison in acute pain trials. This article focuses on single-dose and short-duration trials with emphasis on the perioperative and study design factors that influence assay sensitivity. Recommendations are presented on assessment measures, study designs, and operational factors. Although most of the methodological advances have come from studies of postoperative pain after dental impaction, bunionectomy, and other surgeries, the design considerations discussed are applicable to many other acute pain studies conducted in different settings. PMID:26683233

  7. Research design considerations for single-dose analgesic clinical trials in acute pain: IMMPACT recommendations.

    PubMed

    Cooper, Stephen A; Desjardins, Paul J; Turk, Dennis C; Dworkin, Robert H; Katz, Nathaniel P; Kehlet, Henrik; Ballantyne, Jane C; Burke, Laurie B; Carragee, Eugene; Cowan, Penney; Croll, Scott; Dionne, Raymond A; Farrar, John T; Gilron, Ian; Gordon, Debra B; Iyengar, Smriti; Jay, Gary W; Kalso, Eija A; Kerns, Robert D; McDermott, Michael P; Raja, Srinivasa N; Rappaport, Bob A; Rauschkolb, Christine; Royal, Mike A; Segerdahl, Märta; Stauffer, Joseph W; Todd, Knox H; Vanhove, Geertrui F; Wallace, Mark S; West, Christine; White, Richard E; Wu, Christopher

    2016-02-01

    This article summarizes the results of a meeting convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) on key considerations and best practices governing the design of acute pain clinical trials. We discuss the role of early phase clinical trials, including pharmacokinetic-pharmacodynamic (PK-PD) trials, and the value of including both placebo and active standards of comparison in acute pain trials. This article focuses on single-dose and short-duration trials with emphasis on the perioperative and study design factors that influence assay sensitivity. Recommendations are presented on assessment measures, study designs, and operational factors. Although most of the methodological advances have come from studies of postoperative pain after dental impaction, bunionectomy, and other surgeries, the design considerations discussed are applicable to many other acute pain studies conducted in different settings.

  8. Single-dose cefuroxime axetil in the treatment of uncomplicated gonorrhea: a controlled trial.

    PubMed

    Reichman, R C; Nolte, F S; Wolinsky, S M; Greisberger, C A; Trupei, M A; Nitzkin, J

    1985-01-01

    One hundred eighty-four patients were enrolled in a randomized study that evaluated the efficacy and toxicity of a single dose of orally administered cefuroxine axetil in the treatment of men and women with uncomplicated gonorrhea. Sixty-two patients received cefuroxine axetil alone, 62 received cefuroxine axetil and probenecid, and 60 received amoxicillin plus probenecid. Cure rates in the three groups were 98%, 98%, 96%, respectively. Only 2% of patients who received cefuroxine axetil alone complained of nausea, as compared with 11% of those who received a regimen that contained probenecid (P less than .05). The results show that cefuroxime axetil is effective and nontoxic in the treatment of uncomplicated gonococcal infections in adults.

  9. Single high dose-large field irradiation in drug resistant non-Hodgkin's lymphoma

    SciTech Connect

    Scarantino, C.W.; Greven, K.M.; Buss, D.H.

    1988-05-01

    Single high dose-large field irradiation (SHD-LFI), also described as half-body irradiation (HBI), has previously been reported as an effective modality for the palliation of symptoms in a number of solid tumors. This report concerns the ability of SHD-LFI to produce palliation of symptoms and/or objective response in patients with drug resistant non-Hodgkin's lymphoma (NHL). From 1981 to 1984, 34 patients with advanced drug resistant NHL were treated with SHD-LFI either to the whole abdomen (24 patients) or to the upper half body (10 patients). Overall, 19 of 23 patients achieved symptomatic improvement, while objective response was noted in 23 of 30 patients. We noted subjective and objective response in all histologies, and duration of response was not significantly different. Our results suggest a beneficial role for the early and judicious use of SHD-LFI in NHL.

  10. Catastrophic brain relapse in seronegative NMO after a single dose of natalizumab.

    PubMed

    Kitley, Joanna; Evangelou, Nikos; Küker, Wilhelm; Jacob, Anu; Leite, M Isabel; Palace, Jackie

    2014-04-15

    Natalizumab, an effective treatment for MS, has been shown to exacerbate neuromyelitis optica (NMO) with aquaporin-4 antibodies, but whether this is the case in antibody negative NMO and atypical MS/NMO spectrum disorder overlap syndromes is unknown. We describe a patient with a relapsing optico-spinal demyelinating syndrome, negative for aquaporin-4 antibodies, who experienced a catastrophic brain relapse shortly after a single dose of natalizumab, highlighting that MS immunomodulatory drugs may worsen demyelination in patients with seronegative NMO and atypical MS/NMO overlap syndromes even if they are aquaporin-4 antibody negative. We summarise the treatments considered safe and effective in NMO, and those with potential to exacerbate disease. PMID:24576801

  11. Pharmacokinetics of A40926 in rats after single intravenous and subcutaneous doses.

    PubMed Central

    Bernareggi, A; Danese, A; Cavenaghi, L

    1988-01-01

    A40926 is a new glycopeptide antibiotic with unique activity against Neisseria gonorrhoeae and high and prolonged levels in mouse blood (B. P. Goldstein, E. Selva, L. Gastaldo, M. Berti, R. Pallanza, F. Ripamonti, P. Ferrari, M. Denaro, V. Arioli, and G. Cassani, Antimicrob. Agents Chemother., 31:1961-1966, 1987). We studied the pharmacokinetics of A40926 in rats after single intravenous and subcutaneous 10-mg/kg (body weight) doses. Concentrations in plasma and urine were determined by microbiological assay. After intravenous administration, high concentrations of A40926, ranging from 132 mg/liter at 3 min to 0.7 mg/liter at 96 h, were found in plasma. Concentrations declined with a three-exponential decay correlated with a prolonged, biphasic distribution and a slow elimination (terminal half-life, 61.22 h). After completion of the distribution, the compound was widely distributed to the extravascular space. The rate-limiting step in the elimination of A40926 from the body appears to be the slow return from the deep compartment into the central one. A40926 was rapidly absorbed from the injection site after subcutaneous administration, and its availability was close to 90%. The percentage of the dose excreted in urine in 120 h was 35.9%. PMID:3364946

  12. Clinical trial with Secnidazole in a single dose in Venezuelan children infected by Giardia intestinalis.

    PubMed

    Di Prisco, M C; Jiménez, J C; Rodríguez, N; Costa, V; Villamizar, J; Silvera, A; Carrillo, M; Lira, C; Zerpa, E; López, Y

    2000-09-01

    The aim of this work was to evaluate in an open, noncomparative study the use of secnidazole in oral suspension given to Venezuelan children infected with Giardia intestinalis, from a community in Carapita, a slum area in Caracas. Seventy children from 2 to 11 years old (38 males and 32 females) were treated with a single oral dose of secnidazole (30 mg/Kg of body weight), after clinical and parasitological evaluation to make the diagnosis of active giardiasis. The effectiveness of treatment was determined by clinical examination and parasitological evaluation of feces samples 15 days after treatment. The results showed 95% of clinical cure with a significant decrease of the frequency of gastrointestinal symptoms. The parasitological cure was 98%, there were 4 failures at the end of treatment. Side effects observed after treatment were of mild intensity, lasting only few hours. These results show that a simple dose of secnidazole in an oral suspension is an effective, safe and well tolerated treatment for giardiasis in children and that this drug may be used as a mass treatment in risk populations. PMID:11029834

  13. Fixed-dose combinations of drugs versus single-drug formulations for treating pulmonary tuberculosis

    PubMed Central

    Gallardo, Carmen R; Rigau Comas, David; Valderrama Rodríguez, Angélica; Roqué i Figuls, Marta; Parker, Lucy Anne; Caylà, Joan; Bonfill Cosp, Xavier

    2016-01-01

    Background People who are newly diagnosed with pulmonary tuberculosis (TB) typically receive a standard first-line treatment regimen that consists of two months of isoniazid, rifampicin, pyrazinamide, and ethambutol followed by four months of isoniazid and rifampicin. Fixed-dose combinations (FDCs) of these drugs are widely recommended. Objectives To compare the efficacy, safety, and acceptability of anti-tuberculosis regimens given as fixed-dose combinations compared to single-drug formulations for treating people with newly diagnosed pulmonary tuberculosis. Search methods We searched the Cochrane Infectious Disease Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL, published in the Cochrane Library, Issue 11 2015); MEDLINE (1966 to 20 November 2015); EMBASE (1980 to 20 November 2015); LILACS (1982 to 20 November 2015); the metaRegister of Controlled Trials; and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), without language restrictions, up to 20 November 2015. Selection criteria Randomized controlled trials that compared the use of FDCs with single-drug formulations in adults (aged 15 years or more) newly diagnosed with pulmonary TB. Data collection and analysis Two review authors independently assessed studies for inclusion, and assessed the risk of bias and extracted data from the included trials. We used risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data with 95% confidence intervals (CIs). We attempted to assess the effect of treatment for time-to-event measures with hazard ratios and their 95% CIs. We used the Cochrane 'Risk of bias' assessment tool to determine the risk of bias in included trials. We used the fixed-effect model when there was little heterogeneity and the random-effects model with moderate heterogeneity. We used an I² statistic value of 75% or greater to denote significant heterogeneity, in which case we did not perform a

  14. A Single Dose of Kudzu Extract Reduces Alcohol Consumption in a Binge Drinking Paradigm

    PubMed Central

    Penetar, David M.; Toto, Lindsay H.; Lee, David Y.-W.; Lukas, Scott E.

    2015-01-01

    Background Overconsumption of alcohol has significant negative effects on an individual's health and contributes to an enormous economic impact on society as a whole. Pharmacotherapies to curb excessive drinking are important for treating alcohol use disorders. Methods Twenty (20) men participated in a placebo-controlled, double-blind, between subjects design experiment (n=10/group) that tested the effects of kudzu extract (Alkontrol-Herbal™) for its ability to alter alcohol consumption in a natural settings laboratory. A single dose of kudzu extract (2 grams total with an active isoflavone content of 520 mg) or placebo was administered 2.5 hours before the onset of a 90 minute afternoon drinking session during which participants had the opportunity to drink up to 6 beers ad libitum; water and juice were always available as alternative beverages. Results During the baseline session, the placebo-randomized group consumed 2.7 ± 0.78 beers before treatment and increased consumption to 3.4 ± 1.1 beers after treatment. The kudzu group significantly reduced consumption from 3.0 ± 1.7 at baseline to 1.9 ± 1.3 beers after treatment. The placebo-treated group opened 33 beers during baseline conditions and 38 following treatment whereas the kudzu-treated group opened 32 beers during baseline conditions and only 21 following treatment. Additionally, kudzu-treated participants drank slower. Conclusion This is the first demonstration that a single dose of kudzu extract quickly reduces alcohol consumption in a binge drinking paradigm. These data add to the mounting clinical evidence that kudzu extract may be a safe and effective adjunctive pharmacotherapy for alcohol abuse and dependence. PMID:26048637

  15. A single dose of oxytocin nasal spray improves higher-order social cognition in schizophrenia.

    PubMed

    Guastella, Adam J; Ward, Philip B; Hickie, Ian B; Shahrestani, Sara; Hodge, Marie Antoinette Redoblado; Scott, Elizabeth M; Langdon, Robyn

    2015-11-01

    Schizophrenia is associated with significant impairments in both higher and lower order social cognitive performance and these impairments contribute to poor social functioning. People with schizophrenia report poor social functioning to be one of their greatest unmet treatment needs. Recent studies have suggested the potential of oxytocin as such a treatment, but mixed results render it uncertain what aspects of social cognition are improved by oxytocin and, subsequently, how oxytocin might best be applied as a therapeutic. The aim of this study was to determine whether a single dose of oxytocin improved higher-order and lower-order social cognition performance for patients with schizophrenia across a well-established battery of social cognition tests. Twenty-one male patients received both a single dose of oxytocin nasal spray (24IU) and a placebo, two weeks apart in a randomized within-subjects placebo controlled design. Following each administration, participants completed the social cognition tasks, as well as a test of general neurocognition. Results revealed that oxytocin particularly enhanced performance on higher order social cognition tasks, with no effects on general neurocognition. Results for individual tasks showed most improvement on tests measuring appreciation of indirect hints and recognition of social faux pas. These results suggest that oxytocin, if combined to enhance social cognition learning, may be beneficial when targeted at higher order social cognition domains. This study also suggests that these higher order tasks, which assess social cognitive processing in a social communication context, may provide useful markers of response to oxytocin in schizophrenia. PMID:26150070

  16. Single dose pharmacokinetics of atorvastatin oral formulations using a simple HPLC-UV method.

    PubMed

    Sohail, Muhammad; Ahmad, Mahmood; Minhas, Muhammad Usman

    2016-07-01

    The study was aimed to assess pharmacokinetics of atorvastatin (40 mg) in healthy fasted human subjects by a simple and inexpensive high performance liquid chromatography. Experimental design of the study was a randomized, two way, two periods, crossover study (single dose in fasted conditions). Eighteen (18) healthy male volunteers were enrolled according to FDA guidelines. The plasma samples were assayed using an isocratic High Performance Liquid Chromatography (HPLC) system of Agilent technologies USA consisted of an isocratic pump with column of Thermo Electron Corporation USA (ODS hypersil C(18) 4.6 mm x 250 mm), a UV-visible detector set at λ(max) 237 nm. Maximum plasma concentrations (C(max)) of atorvastatin (Mean ± SEM) for the reference product (A) found to be 13.739±0.210ng/ml & 13.374±0.145ng/ml for test product (B). T(max) values (Mean±SEM) of atorvastatin were 1.222 ±0.060 hours and 1.167±0.057 hours for reference and test products, respectively. The values of AUC(0-oo) (Mean ± SEM) for the reference (A) and test product (B) were 73.955 ± 1.715ng.h/ml and 77.773 ± 1.858ng. h/ml, respectively. Other pharmacokinetic parameters of both products were also determined. A statistical non-significant difference between pharmacokinetic parameters has been found and both brands of atorvastatin showed the same rate and extent of absorption in healthy fasted human volunteers after single dose. A simple and cost effective HPLC method was developed and applied. PMID:27393428

  17. Effect of single-dose amoxicillin on rat incisor odontogenesis: a morphological study.

    PubMed

    Kumazawa, Kaido; Sawada, Takashi; Yanagisawa, Takaaki; Shintani, Seikou

    2012-06-01

    The effect of exposure to amoxicillin on tooth development remains to be elucidated. The purpose of this study was to investigate the effect of amoxicillin on rat incisor odontogenesis. Male Wistar rats weighing approximately 100 g were given a single intraperitoneal injection of 3.0 g/kg body weight amoxicillin. One week after injection, the rats were fixed, and the lower incisors were demineralized and prepared into paraffin sections for light microscopy (LM) and immunohistochemistry. Undemineralized samples were embedded in resin and ground for processing for contact microradiography (CMR) and scanning electron microscopy (SEM). Serum calcium, phosphate, and magnesium concentrations were measured. At 1 week after amoxicillin administration, LM, CMR, and SEM revealed a clear increase in the area of interglobular dentin, representing disruption of mineralization by odontoblasts. Immunohistochemistry demonstrated moderate levels of the small integrin-binding ligand N-linked glycoprotein family dentin matrix protein 1 in large areas of interglobular dentin. On the other hand, no morphological alteration or hypomineralization was observed in the enamel. Serum calcium values showed no significant differences between the control and experimental rats during the experimental period although both serum phosphate and magnesium levels increased at day 1 after amoxicillin injection. The results suggest that a single dose of amoxicillin specifically affects normal tooth dentin mineralization, but not enamel mineralization in rat incisor odontogenesis. The present results further our understanding of the clinical association between dentin abnormality and amoxicillin exposure during tooth development.

  18. Pharmacokinetic properties of single-dose primaquine in Papua New Guinean children: feasibility of abbreviated high-dose regimens for radical cure of vivax malaria.

    PubMed

    Moore, Brioni R; Salman, Sam; Benjamin, John; Page-Sharp, Madhu; Robinson, Leanne J; Waita, Elizabeth; Batty, Kevin T; Siba, Peter; Mueller, Ivo; Davis, Timothy M E; Betuela, Inoni

    2014-01-01

    Since conventional 14-day primaquine (PMQ) radical cure of vivax malaria is associated with poor compliance, and as total dose, not therapy duration, determines efficacy, a preliminary pharmacokinetic study of two doses (0.5 and 1.0 mg/kg of body weight) was conducted in 28 healthy glucose-6-phosphate dehydrogenase-normal Papua New Guinean children, aged 5 to 12 years, to facilitate development of abbreviated high-dose regimens. Dosing was with food and was directly observed, and venous blood samples were drawn during a 168-h postdose period. Detailed safety monitoring was performed for hepatorenal function and hemoglobin and methemoglobin concentrations. Plasma concentrations of PMQ and its metabolite carboxyprimaquine (CPMQ) were determined by liquid chromatography-mass spectrometry and analyzed using population pharmacokinetic methods. The derived models were used in simulations. Both single-dose regimens were well tolerated with no changes in safety parameters. The mean PMQ central volume of distribution and clearance relative to bioavailability (200 liters/70 kg and 24.6 liters/h/70 kg) were within published ranges for adults. The median predicted maximal concentrations (Cmax) for both PMQ and CPMQ after the last dose of a 1.0 mg/kg 7-day PMQ regimen were approximately double those at the end of 14 days of 0.5 mg/kg daily, while a regimen of 1.0 mg/kg twice daily resulted in a 2.38 and 3.33 times higher Cmax for PMQ and CPMQ, respectively. All predicted median Cmax concentrations were within ranges for adult high-dose studies that also showed acceptable safety and tolerability. The present pharmacokinetic data, the first for PMQ in children, show that further studies of abbreviated high-dose regimens are feasible in this age group. PMID:24189254

  19. Single fraction multimodal image guided focal salvage high-dose-rate brachytherapy for recurrent prostate cancer

    PubMed Central

    Rischke, Hans-Christian; Meyer, Philipp Tobias; Knobe, Sven; Volgeova-Neher, Natalja; Kollefrath, Michael; Jilg, Cordula Annette; Grosu, Anca Ligia; Baltas, Dimos; Kroenig, Malte

    2016-01-01

    Purpose We present a novel method for treatment of locally recurrent prostate cancer (PCa) following radiation therapy: focal, multimodal image guided high-dose-rate (HDR) brachytherapy. Material and methods We treated two patients with recurrent PCa after primary (#1) or adjuvant (#2) external beam radiation therapy. Multiparametric magnetic resonance imaging (mpMRI), choline, positron emission tomography combined with computed tomography (PET/CT), or prostate-specific membrane antigen (PSMA)-PET combined with CT identified a single intraprostatic lesion. Positron emission tomography or magnetic resonance imaging – transrectal ultrasound (MRI-TRUS) fusion guided transperineal biopsy confirmed PCa within each target lesion. We defined a PET and mpMRI based gross tumor volume (GTV). A 5 mm isotropic margin was applied additionally to each lesion to generate a planning target volume (PTV), which accounts for technical fusion inaccuracies. A D90 of 18 Gy was intended in one fraction to each PTV using ultrasound guided HDR brachytherapy. Results Six month follow-up showed adequate prostate specific antygen (PSA) decline in both patients (ΔPSA 83% in patient 1 and ΔPSA 59.3% in patient 2). Follow-up 3-tesla MRI revealed regressive disease in both patients and PSMA-PET/CT showed no evidence of active disease in patient #1. No acute or late toxicities occurred. Conclusions Single fraction, focal, multimodal image guided salvage HDR brachytherapy for recurrent prostate cancer is a feasible therapy for selected patients with single lesions. This approach has to be evaluated in larger clinical trials. PMID:27504134

  20. Efficacy of Single-Dose Azithromycin in Treatment of Acute Otitis Media in Children after a Baseline Tympanocentesis

    PubMed Central

    Dunne, Michael W.; Khurana, Chandra; Mohs, Adriano Arguedas; Rodriguez, Adib; Arrieta, Antonio; McLinn, Samuel; Krogstad, Judy A.; Blatter, Mark; Schwartz, Richard; Vargas, Sergio L.; Emparanza, Paz; Fernandez, Pilar; Gooch III, Willis M.; Aspin, Mary; Podgore, John; Roine, Irmeli; Blumer, Jeffrey L.; Ehrlich, Garth D.; Chow, Jean

    2003-01-01

    Children with acute otitis media underwent tympanocentesis and were given a single dose of 30 mg of azithromycin/kg of body weight. At day 28, the overall clinical cure rate was 206 of 242 (85%). Clinical cure rates for patients infected with Streptococcus pneumoniae (67 of 76; 88%) and Haemophilus influenzae (28 of 44; 64%) were consistent with historical rates for the 5-day dosing regimen. PMID:12878537

  1. A case of acute psychosis in a patient following exposure to a single high dose of styrene.

    PubMed

    Moon, Eunsoo; Suh, Hwagyu; Lee, Byung Dae; Park, Je Min; Lee, Young Min; Jeong, Hee Jeong

    2015-09-01

    We report a case of acute psychotic symptoms following exposure to a single high dose of styrene monomer. The 24-year-old male patient showed psychotic and cognitive symptoms immediately after exposure. His psychotic symptoms included auditory hallucinations and delusions of reference. Brain magnetic resonance imaging, electroencephalography, and laboratory examinations were performed to evaluate any other causes. The clinical, neuroimaging, and laboratory review in this case suggested that the suddenly developed psychotic symptoms that led to chronic deterioration were caused by the single exposure to styrene monomer. This is the first recent report in which acute psychotic symptoms developed from a single high dose of styrene suffocation compared with previous findings showing symptoms because of long-term low-dose exposure.

  2. Clinical evaluation of a single daily dose of phenylpropanolamine in the treatment of urethral sphincter mechanism incompetence in the bitch

    PubMed Central

    Claeys, Stéphanie; Rustichelli, Frederico; Noël, Stéphanie; Hamaide, Annick

    2011-01-01

    The objective of this retrospective study was to determine the efficacy of a single daily oral dose of phenylpropanolamine (PPA) in the treatment of urethral sphincter mechanism incompetence (USMI) in bitches. Nine bitches diagnosed with USMI were treated with a single daily dose [1.5 mg/kg body weight (BW)] of PPA for at least 1 month. Urethral pressure profiles (UPP) were performed in 7 dogs before treatment and repeated in 4 of them after treatment. Treatment with PPA resulted in long-term continence in 8/9 bitches. One dog did not respond to PPA and was treated surgically later. Recheck UPPs showed a significant increase in maximal urethral closure pressure in the 4 bitches after treatment with PPA compared to before treatment. In conclusion, long-term continence can be achieved in bitches affected with USMI after administration of a single daily dose of PPA (1.5 mg/kg BW). PMID:22043069

  3. PHARMACOKINETICS OF A SINGLE DOSE OF METRONIDAZOLE AFTER RECTAL ADMINISTRATION IN CAPTIVE ASIAN ELEPHANTS (ELEPHAS MAXIMUS).

    PubMed

    Sander, Samantha J; Siegal-Willott, Jessica L; Ziegler, Jessie; Lee, Elizabeth; Tell, Lisa; Murray, Suzan

    2016-03-01

    Metronidazole is a nitroimidazole antibacterial and antiprotozoal drug with bacteriocidal activity against a broad range of anaerobic bacteria. It is a recognized treatment for elephants diagnosed with anaerobic bacterial infection or protozoal disease or exhibiting signs of colonic impaction, diarrhea, and colic. This study evaluated the pharmacokinetics of rectally administered metronidazole (15 mg/kg) in five adult female Asian elephants (Elephas maximus). Serum samples were collected from each animal for 96 hr after rectal administration of metronidazole. Serum concentrations of metronidazole and its primary metabolite, hydroxymetronidazole, were measured via ultraperformance liquid chromatography. Data were analyzed via a noncompartmental pharmacokinetic approach. Results indicated that serum levels of metronidazole were quantifiable at the 0.25 hr time point and absent in all elephants by the 96 hr time point. The serum peak concentration (mean ± SD, 13.15 ± 2.59 μg/ml) and area under the curve from time 0 to infinity (mean ± SD, 108.79 ± 24.77 hr × μg/ml) were higher than that reported in domestic horses after similar usage. Concurrently, the time of maximum serum concentration (mean ± SD, 1.2 ± 0.45 hr) and terminal elimination half-life (harmonic mean ± pseudo-SD, 7.85 ± 0.93 hr) were longer when compared to equine reports. Rectal administration of metronidazole was well tolerated and rapidly absorbed in all study elephants. Based on the findings in this study, metronidazole administered at a single dose of 15 mg/kg per rectum in the Asian elephant is likely to result in serum concentrations above 4 μg/ml for 8 hr and above 2 μg/ml for 24 hr after treatment is administered. Dosing recommendations should reflect the mean inhibitory concentration of metronidazole for each pathogen.

  4. PHARMACOKINETICS OF A SINGLE DOSE OF METRONIDAZOLE AFTER RECTAL ADMINISTRATION IN CAPTIVE ASIAN ELEPHANTS (ELEPHAS MAXIMUS).

    PubMed

    Sander, Samantha J; Siegal-Willott, Jessica L; Ziegler, Jessie; Lee, Elizabeth; Tell, Lisa; Murray, Suzan

    2016-03-01

    Metronidazole is a nitroimidazole antibacterial and antiprotozoal drug with bacteriocidal activity against a broad range of anaerobic bacteria. It is a recognized treatment for elephants diagnosed with anaerobic bacterial infection or protozoal disease or exhibiting signs of colonic impaction, diarrhea, and colic. This study evaluated the pharmacokinetics of rectally administered metronidazole (15 mg/kg) in five adult female Asian elephants (Elephas maximus). Serum samples were collected from each animal for 96 hr after rectal administration of metronidazole. Serum concentrations of metronidazole and its primary metabolite, hydroxymetronidazole, were measured via ultraperformance liquid chromatography. Data were analyzed via a noncompartmental pharmacokinetic approach. Results indicated that serum levels of metronidazole were quantifiable at the 0.25 hr time point and absent in all elephants by the 96 hr time point. The serum peak concentration (mean ± SD, 13.15 ± 2.59 μg/ml) and area under the curve from time 0 to infinity (mean ± SD, 108.79 ± 24.77 hr × μg/ml) were higher than that reported in domestic horses after similar usage. Concurrently, the time of maximum serum concentration (mean ± SD, 1.2 ± 0.45 hr) and terminal elimination half-life (harmonic mean ± pseudo-SD, 7.85 ± 0.93 hr) were longer when compared to equine reports. Rectal administration of metronidazole was well tolerated and rapidly absorbed in all study elephants. Based on the findings in this study, metronidazole administered at a single dose of 15 mg/kg per rectum in the Asian elephant is likely to result in serum concentrations above 4 μg/ml for 8 hr and above 2 μg/ml for 24 hr after treatment is administered. Dosing recommendations should reflect the mean inhibitory concentration of metronidazole for each pathogen. PMID:27010257

  5. Total Dose Effects on Single Event Transients in Linear Bipolar Systems

    NASA Technical Reports Server (NTRS)

    Buchner, Stephen; McMorrow, Dale; Bernard, Muriel; Roche, Nicholas; Dusseau, Laurent

    2008-01-01

    Single Event Transients (SETs) originating in linear bipolar integrated circuits are known to undermine the reliability of electronic systems operating in the radiation environment of space. Ionizing particle radiation produces a variety of SETs in linear bipolar circuits. The extent to which these SETs threaten system reliability depends on both their shapes (amplitude and width) and their threshold energies. In general, SETs with large amplitudes and widths are the most likely to propagate from a bipolar circuit's output through a subsystem. The danger these SET pose is that, if they become latched in a follow-on circuit, they could cause an erroneous system response. Long-term exposure of linear bipolar circuits to particle radiation produces total ionizing dose (TID) and/or displacement damage dose (DDD) effects that are characterized by a gradual degradation in some of the circuit's electrical parameters. For example, an operational amplifier's gain-bandwidth product is reduced by exposure to ionizing radiation, and it is this reduction that contributes to the distortion of the SET shapes. In this paper, we compare SETs produced in a pristine LM124 operational amplifier with those produced in one exposed to ionizing radiation for three different operating configurations - voltage follower (VF), inverter with gain (IWG), and non-inverter with gain (NIWG). Each configuration produces a unique set of transient shapes that change following exposure to ionizing radiation. An important finding is that the changes depend on operating configuration; some SETs decrease in amplitude, some remain relatively unchanged, some become narrower and some become broader.

  6. Single dose rasburicase in the management of tumor lysis syndrome in childhood acute lymphoblastic leukemia: A case series.

    PubMed

    Latha, S M; Krishnaprasadh, D; Murugapriya, P; Scott, J X

    2015-01-01

    Tumor lysis syndrome (TLS) occurs in malignancies with high proliferative potential and tumor burden, such as lymphomas and leukemias. TLS syndrome is an oncologic emergency, requiring prompt intervention. The metabolic derangements cause acute kidney failure and may lead to cardiac arrhythmias, seizures, and death. With the advent of rasburicase, a recombinant urate oxidase, there has been a decline in the TLS-mediated renal failure and the need for dialysis. The recommended regimen and doses pose a heavy financial burden for patients in developing countries like India. With data and studies proving a similar efficacy for the reduced dose and lesser number of rasburicase, we report here a case series of seven children with acute leukemias, whose TLS was managed by a single dose of rasburicase. A retrospective analysis of case records of seven children with acute lymphoblastic leukemia and TLS, admitted to our Pediatric Oncology Unit of our Hospital between the period 2011 and 2013, was done. All our patients responded to a single dose, indicating that in appropriately monitored patients, single dose followed by as-needed dosing can be cost-saving. PMID:25838646

  7. A comparison of the dose distributions from three proton treatment planning systems in the planning of meningioma patients with single-field uniform dose pencil beam scanning.

    PubMed

    Doolan, Paul J; Alshaikhi, Jailan; Rosenberg, Ivan; Ainsley, Chris G; Gibson, Adam; D'Souza, Derek; Bentefour, El Hassane; Royle, Gary

    2015-01-01

    With the number of new proton centers increasing rapidly, there is a need for an assessment of the available proton treatment planning systems (TPSs). This study compares the dose distributions of complex meningioma plans produced by three proton TPSs: Eclipse, Pinnacle3, and XiO. All three systems were commissioned with the same beam data and, as best as possible, matched configuration settings. Proton treatment plans for ten patients were produced on each system with a pencil beam scanning, single-field uniform dose approach, using a fixed horizontal beamline. All 30 plans were subjected to identical dose constraints, both for the target coverage and organ at risk (OAR) sparing, with a consistent order of priority. Beam geometry, lateral field margins, and lateral spot resolutions were made consistent across all systems. Few statistically significant differences were found between the target coverage and OAR sparing of each system, with all optimizers managing to produce plans within clinical tolerances (D2 < 107% of prescribed dose, D5 < 105%, D95 > 95%, D99 > 90%, and OAR maximum doses) despite strict constraints and overlapping structures.

  8. A comparison of the dose distributions from three proton treatment planning systems in the planning of meningioma patients with single-field uniform dose pencil beam scanning.

    PubMed

    Doolan, Paul J; Alshaikhi, Jailan; Rosenberg, Ivan; Ainsley, Chris G; Gibson, Adam; D'Souza, Derek; Bentefour, El Hassane; Royle, Gary

    2015-01-01

    With the number of new proton centers increasing rapidly, there is a need for an assessment of the available proton treatment planning systems (TPSs). This study compares the dose distributions of complex meningioma plans produced by three proton TPSs: Eclipse, Pinnacle3, and XiO. All three systems were commissioned with the same beam data and, as best as possible, matched configuration settings. Proton treatment plans for ten patients were produced on each system with a pencil beam scanning, single-field uniform dose approach, using a fixed horizontal beamline. All 30 plans were subjected to identical dose constraints, both for the target coverage and organ at risk (OAR) sparing, with a consistent order of priority. Beam geometry, lateral field margins, and lateral spot resolutions were made consistent across all systems. Few statistically significant differences were found between the target coverage and OAR sparing of each system, with all optimizers managing to produce plans within clinical tolerances (D2 < 107% of prescribed dose, D5 < 105%, D95 > 95%, D99 > 90%, and OAR maximum doses) despite strict constraints and overlapping structures. PMID:25679158

  9. Oral contraception does not alter single dose saquinavir pharmacokinetics in women

    PubMed Central

    Fröhlich, Margit; Burhenne, Jürgen; Martin-Facklam, Meret; Weiss, Johanna; von Wolff, Michael; Strowitzki, Thomas; Walter-Sack, Ingeborg; Haefeli, Walter E

    2004-01-01

    Aims Women experience more adverse drug reactions (ADR) to antiretroviral therapy than men. This may be attributed to higher plasma concentrations of protease inhibitors due to pharmacokinetic interactions with hormonal preparations. Thus, in the present study we aimed to investigate the influence of oral contraceptives (OC) on the pharmacokinetics of the protease inhibitor saquinavir. Methods Saquinavir was administered in a hard gelatin capsule formulation (Invirase®) to rule out confounding by pharmaceutical aids of the more frequently used soft gelatin capsule. After an overnight fast, eight healthy female participants ingested a single oral dose of 600 mg saquinavir immediately before and after the 19th dose of a combined, low dose OC (0.03 mg ethinylestradiol, 0.075 mg gestodene) in a prospective, fixed sequence study design. The first saquinavir application was scheduled on day 1, 2, or 3 of the individual menstrual cycle. Plasma concentrations of saquinavir and relative concentrations of its M2&M3-hydroxy metabolites were determined by LC/MS/MS for 48 h. Results Intake of OC resulted in a significant decrease in morning serum concentrations (before intake of OC, compared to day 19 of OC therapy) of 17β-estradiol by −23.4 pg ml−1 (57%, 95%CI: −76% to −37.4%); progesterone by −0.25 ng ml−1 (33%, 95%CI: −45.3% to −21.5%); follicle-stimulating hormone by −4.06 U l−1 (82%, 95%CI: −96.5% to −67.7%); and luteinizing hormone by −3.49 U l−1 (74%, 95%CI: −93 to −54.6%). Conversely, sexual hormone binding globulin serum concentrations increased by 83.6 nmol l−1 (205%, 95%CI: 32.2% to 377%). Pharmacokinetic parameters of saquinavir (AUC, Cmax, tmax, t1/2, CLR) were not affected by OC, nor was the relative metabolic ratio of saquinavir/M2&M3-hydroxy saquinavir. Furthermore, there was no association of serum hormone concentrations or MDR1-polymorphisms (C3435T and G2677T) with pharmacokinetic parameters of saquinavir. Conclusions There

  10. Marbofloxacin disposition after intravenous administration of a single dose in wild mallard ducks (Anas platyrhynchos).

    PubMed

    Garcia-Montijano, Marino; de Lucas, J Julio; Rodríguez, Casilda; González, Fernando; San Andrés, Manuel Ignacio; Waxman, Samanta

    2012-03-01

    Marbofloxacin, a fluoroquinolone developed specifically for veterinary use, has demonstrated considerable pharmokinetic variation among avian species. The goal of this study was to determine the disposition kinetics of marbofloxacin in mallard ducks (Anas platyrhynchos) after a single intravenous injection. Six wild mallard ducks were used in the study. Marbofloxacin was injected at a dose of 2 mg/kg into the basilic vein, and blood was subsequently collected at regular intervals from each bird. Plasma marbofloxacin concentrations were determined by using high-performance liquid chromatography. The volume of distribution at steady state was 1.78 +/- 0.37 L/kg, and the total plasma clearance was 0.59 +/- 0.08 L/kg per hour. Marbofloxacin had a relatively short permanence, with a elimination half-life of 2.81 +/- 1.20 hours, a terminal half-life of 2.43 +/- 0.61 hours, and a mean residence time of 2.99 +/- 0.52 hour. The maximum observed concentration (Cmax) and area under the curve (AUC) were 1.34 +/- 0.27 microg/mL and 3.75 +/- 0.56 microg x h/mL, respectively. Values of minimum inhibitory concentration (MIC), Cmax, and AUC have been used to predict the clinical efficacy of a drug in treating bacterial infections, with a Cmax: MIC value of 10 and an AUC: MIC ratio of 125-250 associated with optimal bactericidal effects. By using the study data and MIC breakpoints of 0.125 microg/mL or 0.2 microg/mL, values derived for Cmax: MIC were 9.37 +/- 0.99 and 5.85 +/- 0.62, respectively, and for AUC: MIC were 29.99 +/- 4.51 and 18.74 +/- 2.82, respectively. By using MIC values of 0.125 and 0.2 microg/mL and a target AUC: MIC = 125, the calculated optimal daily marbofloxacin dosages for mallard ducks were 9.24 and 14.78 mg/kg, respectively. These results suggest that, primarily because of the high total plasma clearance observed, the marbofloxacin dose for treatment of bacterial diseases in mallard ducks should be increased after intravenous administration. Intravenous doses

  11. Single-dose intrapulmonary pharmacokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefuroxime in volunteer subjects.

    PubMed

    Conte, J E; Golden, J; Duncan, S; McKenna, E; Lin, E; Zurlinden, E

    1996-07-01

    The intrapulmonary pharmacokinetics of azithromycin, clarithromycin, ciprofloxacin, and cefuroxime were studied in 68 volunteers who received single, oral doses of azithromycin (0.5 g), clarithormycin (0.5 g), ciprofloxacin (0.5 g), or cefuroxime (0.5 g). In subgroups of four subjects each, the subjects underwent bronchoscopy and bronchoalveolar lavage at timed intervals following drug administration. Drug concentrations, including those of 14-hydroxyclarithromycin (14H), were determined in serum, bronchoalveolar lavage fluid, and alveolar cells (ACs) by high-pressure liquid chromatography. Concentrations in epithelial lining fluid (ELF) were calculated by the urea diffusion method. The maximum observed concentrations (mean +/- standard deviation) of azithromycin, clarithromycin, 14H, ciprofloxacin, and cefuroxime in serum were 0.13 +/- 0.07, 1.0 +/- 0.6, 0.60 +/- 0.41, 0.95 +/- 0.32, and 1.1 +/- 0.3 microgram/ml, respectively (all at 6 h). None of the antibiotics except clarithromycin (39.6 +/- 41.1 micrograms/ml) was detectable in ELF at the 6-h bronchoscopy. The movement into and persistence in cells was different for azithromycin and clarithromycin. In ACs azithromycin was not detectable at 6 h, reached its highest concentration at 120 h, and exhibited the greatest area under the curve (7,403 micrograms.hr ml-1). The peak concentration of clarithromycin (181 +/- 94.1 micrograms/ml) was greater and occurred earlier (6 h), but the area under the curve (2,006 micrograms.hr ml-1) was less than that observed for azithromycin. 14H was detectable in ACs at 6 h (40.3 +/- 5.2 micrograms/ml) and 12 h (32.8 +/- 57.2 micrograms/ml). The peak concentration of ciprofloxacin occurred at 6 h (4.3 +/- 5.2 micrograms/ml), and the area under the curve was 35.0 micrograms.hr ml-1. The data indicate that after the administration of a single dose, azithromycin, clarithromycin, and ciprofloxacin penetrated into ACs in therapeutic concentrations and that only clarithromycin was

  12. Acute effect of pretreatment with single conventional dose of salmeterol on dose-response curve to oxitropium bromide in chronic obstructive pulmonary disease

    PubMed Central

    Cazzola, M.; Di, P; Centanni, S.; Califano, C.; Donner, C. F.; D'Amato, M.; D'Amato, G.

    1999-01-01

    BACKGROUND—An earlier study documented that, in patients with chronic obstructive pulmonary disease (COPD), addition of ipratropium bromide at the clinically recommended dose (40 µg) does not produce any further bronchodilation than that achieved with salmeterol 50 µg alone. However, the dose of ipratropium bromide needed to produce near maximal bronchodilation is several times higher than the customary dosage. The full therapeutic potential of combined salmeterol plus an anticholinergic drug can therefore only be established using doses higher than those currently recommended in the marketing of these agents. A study was undertaken to examine the possible acute effects of higher than conventional doses of an anticholinergic agent on the single dose salmeterol induced bronchodilation in patients with stable and partially reversible COPD.
METHODS—Thirty two outpatients received 50 µg salmeterol or placebo. Two hours after inhalation a dose-response curve to inhaled oxitropium bromide (100 µg/puff) or placebo was constructed using one puff, one puff, two puffs, and two puffs—that is, a total cumulative dose of 600 µg oxitropium bromide. Dose increments were given at 20 minute intervals with measurements being made 15 minutes after each dose. On four separate days all patients received one of the following: (1) 50 µg salmeterol + 600 µg oxitropium bromide; (2) 50 µg salmeterol + placebo; (3) placebo + 600 µg oxitropium bromide; (4) placebo +placebo.
RESULTS—Salmeterol induced a good bronchodilation (mean increase 0.272 l; 95% CI 0.207 to 0.337) two hours after its inhalation. Oxitropium bromide elicited an evident dose-dependent increase in forced expiratory volume in one second (FEV1) and this occurred also after pretreatment with salmeterol with a further mean maximum increase of 0.152 l (95% CI of differences 0.124 to 0.180).
CONCLUSIONS—This study shows that acute pretreatment with 50 µg salmeterol does not block the possibility of

  13. Effect of single-dose radiation on cell survival and growth hormone secretion by rat anterior pituitary cells

    SciTech Connect

    Hochberg, Z.; Kuten, A.; Hertz, P.; Tatcher, M.; Kedar, A.; Benderly, A.

    1983-06-01

    Cranial irradiation has been shown to impair growth hormone secretion in children. In this study a cell culture of dispersed rat anterior pituitary cells was exposed to single doses of radiation in the range of 100 to 1500 rad. Survival curves were obtained for the different anterior pituitary cell lines, and growth hormone secretion was measured in the tissue culture medium. Both survival and growth hormone secretion curves showed an initial shoulder in the range of 0 to 300 rad, followed by a decline between 300 to 750 rad. It is concluded that growth hormone secreting acidophilic pituicytes are sensitive to radiation at single doses greater than 300 rad.

  14. Guaifenesin Pharmacokinetics Following Single‐Dose Oral Administration in Children Aged 2 to 17 Years

    PubMed Central

    Thompson, Gary A.; Solomon, Gail; Albrecht, Helmut H.; Reitberg, Donald P.

    2016-01-01

    Abstract This study characterized guaifenesin pharmacokinetics in children aged 2 to 17 years (n = 40) who received a single oral dose of guaifenesin (age‐based doses of 100‐400 mg) 2 hours after breakfast. Plasma samples were obtained before and for 8 hours after dosing and analyzed for guaifenesin using liquid chromatography‐tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods, relationships with age were assessed using linear regression, and dose proportionality was assessed on 95% confidence intervals. Based on the upper dose recommended in the monograph (for both children and adolescents), area under the curve from time zero to infinity and maximum plasma concentration both increased with age. However, when comparing the upper dose for children aged 2 to 11 years with the lower dose for adolescents aged 12 to 17 years, similar systemic exposure was observed. As expected due to increasing body size, oral clearance (CLo) and terminal volume of distribution (Vz/F) increased with age. Due to a larger increase in Vz/F than CLo, an increase in terminal exponential half‐life was also observed. Allometric scaling indicated no maturation‐related changes in CLo and Vz/F. PMID:26632082

  15. Compendium of Single Event Effects, Total Ionizing Dose, and Displacement Damage for Candidate Spacecraft Electronics for NASA

    NASA Technical Reports Server (NTRS)

    LaBel, Kenneth A.; OBryan, Martha V.; Chen, Dakai; Campola, Michael J.; Casey, Megan C.; Pellish, Jonathan A.; Lauenstein, Jean-Marie; Wilcox, Edward P.; Topper, Alyson D.; Ladbury, Raymond L.; Berg, Melanie D.; Gigliuto, Robert A.; Boutte, Alvin J.; Cochran, Donna J.; Buchner, Stephen P.; Violette, Daniel P.

    2014-01-01

    We present results and analysis investigating the effects of radiation on a variety of candidate spacecraft electronics to proton and heavy ion induced single event effects (SEE), proton-induced displacement damage (DD), and total ionizing dose (TID). Introduction: This paper is a summary of test results.NASA spacecraft are subjected to a harsh space environment that includes exposure to various types of ionizing radiation. The performance of electronic devices in a space radiation environment is often limited by its susceptibility to single event effects (SEE), total ionizing dose (TID), and displacement damage (DD). Ground-based testing is used to evaluate candidate spacecraft electronics to determine risk to spaceflight applications. Interpreting the results of radiation testing of complex devices is quite difficult. Given the rapidly changing nature of technology, radiation test data are most often application-specific and adequate understanding of the test conditions is critical. Studies discussed herein were undertaken to establish the application-specific sensitivities of candidate spacecraft and emerging electronic devices to single-event upset (SEU), single-event latchup (SEL), single-event gate rupture (SEGR), single-event burnout (SEB), single-event transient (SET), TID, enhanced low dose rate sensitivity (ELDRS), and DD effects.

  16. Randomized dose-ranging study of the 14-day early bactericidal activity of bedaquiline (TMC207) in patients with sputum microscopy smear-positive pulmonary tuberculosis.

    PubMed

    Diacon, Andreas H; Dawson, Rodney; Von Groote-Bidlingmaier, Florian; Symons, Gregory; Venter, Amour; Donald, Peter R; Conradie, Almari; Erondu, Ngozi; Ginsberg, Ann M; Egizi, Erica; Winter, Helen; Becker, Piet; Mendel, Carl M

    2013-05-01

    Bedaquiline is a new antituberculosis agent targeting ATP synthase. This randomized, double-blinded study enrolling 68 sputum smear-positive pulmonary tuberculosis patients evaluated the 14-day early bactericidal activity of daily doses of 100 mg, 200 mg, 300 mg, and 400 mg bedaquiline, preceded by loading doses of 200 mg, 400 mg, 500 mg, and 700 mg, respectively, on the first treatment day and 100 mg, 300 mg, 400 mg, and 500 mg on the second treatment day. All groups showed activity with a mean (standard deviation) daily fall in log10 CFU over 14 days of 0.040 (0.068), 0.056 (0.051), 0.077 (0.064), and 0.104 (0.077) in the 100-mg, 200-mg, 300-mg, and 400-mg groups, respectively. The linear trend for dose was significant (P = 0.001), and activity in the 400-mg dose group was greater than that in the 100-mg group (P = 0.014). All of the bedaquiline groups showed significant bactericidal activity that was continued to the end of the 14-day evaluation period. The finding of a linear trend for dose suggests that the highest dose compatible with safety considerations should be taken forward to longer-term clinical studies. PMID:23459487

  17. Randomized Dose-Ranging Study of the 14-Day Early Bactericidal Activity of Bedaquiline (TMC207) in Patients with Sputum Microscopy Smear-Positive Pulmonary Tuberculosis

    PubMed Central

    Dawson, Rodney; Von Groote-Bidlingmaier, Florian; Symons, Gregory; Venter, Amour; Donald, Peter R.; Conradie, Almari; Erondu, Ngozi; Ginsberg, Ann M.; Egizi, Erica; Winter, Helen; Becker, Piet; Mendel, Carl M.

    2013-01-01

    Bedaquiline is a new antituberculosis agent targeting ATP synthase. This randomized, double-blinded study enrolling 68 sputum smear-positive pulmonary tuberculosis patients evaluated the 14-day early bactericidal activity of daily doses of 100 mg, 200 mg, 300 mg, and 400 mg bedaquiline, preceded by loading doses of 200 mg, 400 mg, 500 mg, and 700 mg, respectively, on the first treatment day and 100 mg, 300 mg, 400 mg, and 500 mg on the second treatment day. All groups showed activity with a mean (standard deviation) daily fall in log10 CFU over 14 days of 0.040 (0.068), 0.056 (0.051), 0.077 (0.064), and 0.104 (0.077) in the 100-mg, 200-mg, 300-mg, and 400-mg groups, respectively. The linear trend for dose was significant (P = 0.001), and activity in the 400-mg dose group was greater than that in the 100-mg group (P = 0.014). All of the bedaquiline groups showed significant bactericidal activity that was continued to the end of the 14-day evaluation period. The finding of a linear trend for dose suggests that the highest dose compatible with safety considerations should be taken forward to longer-term clinical studies. PMID:23459487

  18. Randomized dose-ranging study of the 14-day early bactericidal activity of bedaquiline (TMC207) in patients with sputum microscopy smear-positive pulmonary tuberculosis.

    PubMed

    Diacon, Andreas H; Dawson, Rodney; Von Groote-Bidlingmaier, Florian; Symons, Gregory; Venter, Amour; Donald, Peter R; Conradie, Almari; Erondu, Ngozi; Ginsberg, Ann M; Egizi, Erica; Winter, Helen; Becker, Piet; Mendel, Carl M

    2013-05-01

    Bedaquiline is a new antituberculosis agent targeting ATP synthase. This randomized, double-blinded study enrolling 68 sputum smear-positive pulmonary tuberculosis patients evaluated the 14-day early bactericidal activity of daily doses of 100 mg, 200 mg, 300 mg, and 400 mg bedaquiline, preceded by loading doses of 200 mg, 400 mg, 500 mg, and 700 mg, respectively, on the first treatment day and 100 mg, 300 mg, 400 mg, and 500 mg on the second treatment day. All groups showed activity with a mean (standard deviation) daily fall in log10 CFU over 14 days of 0.040 (0.068), 0.056 (0.051), 0.077 (0.064), and 0.104 (0.077) in the 100-mg, 200-mg, 300-mg, and 400-mg groups, respectively. The linear trend for dose was significant (P = 0.001), and activity in the 400-mg dose group was greater than that in the 100-mg group (P = 0.014). All of the bedaquiline groups showed significant bactericidal activity that was continued to the end of the 14-day evaluation period. The finding of a linear trend for dose suggests that the highest dose compatible with safety considerations should be taken forward to longer-term clinical studies.

  19. Incorporating single-side sparing in models for predicting parotid dose sparing in head and neck IMRT

    SciTech Connect

    Yuan, Lulin Wu, Q. Jackie; Yin, Fang-Fang; Yoo, David; Jiang, Yuliang; Ge, Yaorong

    2014-02-15

    Purpose: Sparing of single-side parotid gland is a common practice in head-and-neck (HN) intensity modulated radiation therapy (IMRT) planning. It is a special case of dose sparing tradeoff between different organs-at-risk. The authors describe an improved mathematical model for predicting achievable dose sparing in parotid glands in HN IMRT planning that incorporates single-side sparing considerations based on patient anatomy and learning from prior plan data. Methods: Among 68 HN cases analyzed retrospectively, 35 cases had physician prescribed single-side parotid sparing preferences. The single-side sparing model was trained with cases which had single-side sparing preferences, while the standard model was trained with the remainder of cases. A receiver operating characteristics (ROC) analysis was performed to determine the best criterion that separates the two case groups using the physician's single-side sparing prescription as ground truth. The final predictive model (combined model) takes into account the single-side sparing by switching between the standard and single-side sparing models according to the single-side sparing criterion. The models were tested with 20 additional cases. The significance of the improvement of prediction accuracy by the combined model over the standard model was evaluated using the Wilcoxon rank-sum test. Results: Using the ROC analysis, the best single-side sparing criterion is (1) the predicted median dose of one parotid is higher than 24 Gy; and (2) that of the other is higher than 7 Gy. This criterion gives a true positive rate of 0.82 and a false positive rate of 0.19, respectively. For the bilateral sparing cases, the combined and the standard models performed equally well, with the median of the prediction errors for parotid median dose being 0.34 Gy by both models (p = 0.81). For the single-side sparing cases, the standard model overestimates the median dose by 7.8 Gy on average, while the predictions by the combined

  20. Defect evolution in single crystalline tungsten following low temperature and low dose neutron irradiation

    DOE PAGES

    Hu, Xunxiang; Koyanagi, Takaaki; Fukuda, Makoto; Katoh, Yutai; Wirth, Brian D; Snead, Lance Lewis

    2016-01-01

    The tungsten plasma-facing components of fusion reactors will experience an extreme environment including high temperature, intense particle fluxes of gas atoms, high-energy neutron irradiation, and significant cyclic stress loading. Irradiation-induced defect accumulation resulting in severe thermo-mechanical property degradation is expected. For this reason, and because of the lack of relevant fusion neutron sources, the fundamentals of tungsten radiation damage must be understood through coordinated mixed-spectrum fission reactor irradiation experiments and modeling. In this study, high-purity (110) single-crystal tungsten was examined by positron annihilation spectroscopy and transmission electron microscopy following low-temperature (~90 °C) and low-dose (0.006 and 0.03 dpa) mixed-spectrum neutronmore » irradiation and subsequent isochronal annealing at 400, 500, 650, 800, 1000, 1150, and 1300 °C. The results provide insights into microstructural and defect evolution, thus identifying the mechanisms of different annealing behavior. Following 1 h annealing, ex situ characterization of vacancy defects using positron lifetime spectroscopy and coincidence Doppler broadening was performed. The vacancy cluster size distributions indicated intense vacancy clustering at 400 °C with significant damage recovery around 1000 °C. Coincidence Doppler broadening measurements confirm the trend of the vacancy defect evolution, and the S–W plots indicate that only a single type of vacancy cluster is present. Furthermore, transmission electron microscopy observations at selected annealing conditions provide supplemental information on dislocation loop populations and visible void formation. This microstructural information is consistent with the measured irradiation-induced hardening at each annealing stage. This provides insight into tungsten hardening and embrittlement due to irradiation-induced matrix defects.« less

  1. Defect evolution in single crystalline tungsten following low temperature and low dose neutron irradiation

    SciTech Connect

    Hu, Xunxiang; Koyanagi, Takaaki; Fukuda, Makoto; Katoh, Yutai; Wirth, Brian D; Snead, Lance Lewis

    2016-01-01

    The tungsten plasma-facing components of fusion reactors will experience an extreme environment including high temperature, intense particle fluxes of gas atoms, high-energy neutron irradiation, and significant cyclic stress loading. Irradiation-induced defect accumulation resulting in severe thermo-mechanical property degradation is expected. For this reason, and because of the lack of relevant fusion neutron sources, the fundamentals of tungsten radiation damage must be understood through coordinated mixed-spectrum fission reactor irradiation experiments and modeling. In this study, high-purity (110) single-crystal tungsten was examined by positron annihilation spectroscopy and transmission electron microscopy following low-temperature (~90 °C) and low-dose (0.006 and 0.03 dpa) mixed-spectrum neutron irradiation and subsequent isochronal annealing at 400, 500, 650, 800, 1000, 1150, and 1300 °C. The results provide insights into microstructural and defect evolution, thus identifying the mechanisms of different annealing behavior. Following 1 h annealing, ex situ characterization of vacancy defects using positron lifetime spectroscopy and coincidence Doppler broadening was performed. The vacancy cluster size distributions indicated intense vacancy clustering at 400 °C with significant damage recovery around 1000 °C. Coincidence Doppler broadening measurements confirm the trend of the vacancy defect evolution, and the S–W plots indicate that only a single type of vacancy cluster is present. Furthermore, transmission electron microscopy observations at selected annealing conditions provide supplemental information on dislocation loop populations and visible void formation. This microstructural information is consistent with the measured irradiation-induced hardening at each annealing stage. This provides insight into tungsten hardening and embrittlement due to irradiation-induced matrix defects.

  2. Defect evolution in single crystalline tungsten following low temperature and low dose neutron irradiation

    NASA Astrophysics Data System (ADS)

    Hu, Xunxiang; Koyanagi, Takaaki; Fukuda, Makoto; Katoh, Yutai; Snead, Lance L.; Wirth, Brian D.

    2016-03-01

    The tungsten plasma-facing components of fusion reactors will experience an extreme environment including high temperature, intense particle fluxes of gas atoms, high-energy neutron irradiation, and significant cyclic stress loading. Irradiation-induced defect accumulation resulting in severe thermo-mechanical property degradation is expected. For this reason, and because of the lack of relevant fusion neutron sources, the fundamentals of tungsten radiation damage must be understood through coordinated mixed-spectrum fission reactor irradiation experiments and modeling. In this study, high-purity (110) single-crystal tungsten was examined by positron annihilation spectroscopy and transmission electron microscopy following low-temperature (∼90 °C) and low-dose (0.006 and 0.03 dpa) mixed-spectrum neutron irradiation and subsequent isochronal annealing at 400, 500, 650, 800, 1000, 1150, and 1300 °C. The results provide insights into microstructural and defect evolution, thus identifying the mechanisms of different annealing behavior. Following 1 h annealing, ex situ characterization of vacancy defects using positron lifetime spectroscopy and coincidence Doppler broadening was performed. The vacancy cluster size distributions indicated intense vacancy clustering at 400 °C with significant damage recovery around 1000 °C. Coincidence Doppler broadening measurements confirm the trend of the vacancy defect evolution, and the S-W plots indicate that only a single type of vacancy cluster is present. Furthermore, transmission electron microscopy observations at selected annealing conditions provide supplemental information on dislocation loop populations and visible void formation. This microstructural information is consistent with the measured irradiation-induced hardening at each annealing stage, providing insight into tungsten hardening and embrittlement due to irradiation-induced matrix defects.

  3. Effects of a single dose of menadione on the intestinal calcium absorption and associated variables.

    PubMed

    Marchionatti, Ana M; Díaz de Barboza, Gabriela E; Centeno, Viviana A; Alisio, Arturo E; Tolosa de Talamoni, Nori G

    2003-08-01

    The effect of a single large dose of menadione on intestinal calcium absorption and associated variables was investigated in chicks fed a normal diet. The data show that 2.5 micro mol of menadione/kg of b.w. causes inhibition of calcium transfer from lumen-to-blood within 30 min. This effect seems to be related to oxidative stress provoked by menadione as judged by glutathione depletion and an increment in the total carbonyl group content produced at the same time. Two enzymes presumably involved in calcium transcellular movement, such as alkaline phosphatase, located in the brush border membrane, and Ca(2+)- pump ATPase, which sits in the basolateral membrane, were also inhibited. The enzyme inhibition could be due to alterations caused by the appearance of free hydroxyl groups, which are triggered by glutathione depletion. Addition of glutathione monoester to the duodenal loop caused reversion of the menadione effect on both intestinal calcium absorption and alkaline phosphatase activity. In conclusion, menadione shifts the balance of oxidative and reductive processes in the enterocyte towards oxidation causing deleterious effects on intestinal Ca(2+) absorption and associated variables, which could be prevented by administration of oral glutathione monoester. PMID:12948877

  4. Pharmacokinetics of enrofloxacin after single dose oral and intravenous administration in the African penguin (Spheniscus demersus).

    PubMed

    Wack, Allison N; KuKanich, Butch; Bronson, Ellen; Denver, Mary

    2012-06-01

    The pharmacokinetics of a single dose of enrofloxacin administered orally, both pilled and in fish, and i.v. to African penguins (Spheniscus demersus) at 15 mg/kg were determined. Plasma concentrations of enrofloxacin and its metabolite ciprofloxacin were measured via high-pressure liquid chromatography with mass spectrometry. An i.v. administration of enrofloxacin resulted in an extrapolated mean plasma concentration of 7.86 microg/ml at time zero. Plasma volume of distribution for i.v. administration was 3.00 L/kg, with a mean elimination half-life of 13.67 hr and a mean total body clearance rate of 3.03 ml/min/kg. Oral administration of enrofloxacin achieved a mean maximum plasma concentration of4.38 microg/ml at 4.8 hr after administration when pilled, whereas mean maximum plasma concentration was 4.77 microg/ml at 1.59 hr after administration when given in fish. Mean terminal elimination half-life was 13.79 hr pilled and 11.93 hr when given in fish. Low concentrations of ciprofloxacin were detected after both oral and i.v. enrofloxacin administration. Enrofloxacin administered to African penguins at 15 mg/kg p.o.q. 24 hr, whether in fish or pilled, is expected to achieve the surrogate markers of efficacy for bacteria with a minimum inhibitory concentration of 0.5 microg/ml or less; however, clinical studies are needed to determine efficacy.

  5. A Single Human Papillomavirus Vaccine Dose Improves B Cell Memory in Previously Infected Subjects.

    PubMed

    Scherer, Erin M; Smith, Robin A; Gallego, Daniel F; Carter, Joseph J; Wipf, Gregory C; Hoyos, Manuela; Stern, Michael; Thurston, Tate; Trinklein, Nathan D; Wald, Anna; Galloway, Denise A

    2016-08-01

    Although licensed human papillomavirus (HPV) vaccines are most efficacious in persons never infected with HPV, they also reduce infection and disease in previously infected subjects, indicating natural immunity is not entirely protective against HPV re-infection. The aim of this exploratory study was to examine the B cell memory elicited by HPV infection and evaluate whether vaccination merely boosts antibody (Ab) levels in previously infected subjects or also improves the quality of B cell memory. Toward this end, the memory B cells (Bmem) of five unvaccinated, HPV-seropositive subjects were isolated and characterized, and subject recall responses to a single HPV vaccine dose were analyzed. Vaccination boosted Ab levels 24- to 930-fold (median 77-fold) and Bmem numbers 3- to 27-fold (median 6-fold). In addition, Abs cloned from naturally elicited Bmem were generally non-neutralizing, whereas all those isolated following vaccination were neutralizing. Moreover, Ab and plasmablast responses indicative of memory recall responses were only observed in two subjects. These results suggest HPV vaccination augments both the magnitude and quality of natural immunity and demonstrate that sexually active persons could also benefit from HPV vaccination. This study may have important public policy implications, especially for the older 'catch-up' group within the vaccine's target population. PMID:27423190

  6. Single-dose attenuated Vesiculovax vaccines protect primates against Ebola Makona virus.

    PubMed

    Mire, Chad E; Matassov, Demetrius; Geisbert, Joan B; Latham, Theresa E; Agans, Krystle N; Xu, Rong; Ota-Setlik, Ayuko; Egan, Michael A; Fenton, Karla A; Clarke, David K; Eldridge, John H; Geisbert, Thomas W

    2015-04-30

    The family Filoviridae contains three genera, Ebolavirus (EBOV), Marburg virus, and Cuevavirus. Some members of the EBOV genus, including Zaire ebolavirus (ZEBOV), can cause lethal haemorrhagic fever in humans. During 2014 an unprecedented ZEBOV outbreak occurred in West Africa and is still ongoing, resulting in over 10,000 deaths, and causing global concern of uncontrolled disease. To meet this challenge a rapid-acting vaccine is needed. Many vaccine approaches have shown promise in being able to protect nonhuman primates against ZEBOV. In response to the current ZEBOV outbreak several of these vaccines have been fast tracked for human use. However, it is not known whether any of these vaccines can provide protection against the new outbreak Makona strain of ZEBOV. One of these approaches is a first-generation recombinant vesicular stomatitis virus (rVSV)-based vaccine expressing the ZEBOV glycoprotein (GP) (rVSV/ZEBOV). To address safety concerns associated with this vector, we developed two candidate, further-attenuated rVSV/ZEBOV vaccines. Both attenuated vaccines produced an approximately tenfold lower vaccine-associated viraemia compared to the first-generation vaccine and both provided complete, single-dose protection of macaques from lethal challenge with the Makona outbreak strain of ZEBOV.

  7. Concentrations of gemifloxacin at the target site in healthy volunteers after a single oral dose.

    PubMed

    Islinger, Florian; Bouw, Rene; Stahl, Mathias; Lackner, Edith; Zeleny, Petra; Brunner, Martin; Müller, Markus; Eichler, Hans Georg; Joukhadar, Christian

    2004-11-01

    Free gemifloxacin concentrations in the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue were measured by means of in vivo microdialysis to characterize the ability of gemifloxacin to penetrate human soft tissues. Twelve healthy volunteers received a single oral dose of 320 mg of gemifloxacin. The mean areas under the concentration-time curves from 0 to 10 h (AUC(0-10)) were significantly higher for soft tissue than for unbound gemifloxacin in plasma (P < 0.05). The ratios of the mean AUC(0-10) for tissue to the AUC(0-10) for free gemifloxacin in plasma were 1.7 +/- 0.7 (mean +/- standard deviation) for skeletal muscle and 2.4 +/- 1.0 for adipose tissue. The AUC(0-24) ratios for free gemifloxacin in tissues to the MIC at which 90% of frequently isolated bacteria are inhibited were close to or higher than 100 h. Therefore, based on pharmacokinetic and pharmacodynamic calculations, we conclude that gemifloxacin might be a useful therapeutic option for the treatment of soft tissue infections. PMID:15504848

  8. Concentrations of Gemifloxacin at the Target Site in Healthy Volunteers after a Single Oral Dose

    PubMed Central

    Islinger, Florian; Bouw, Rene; Stahl, Mathias; Lackner, Edith; Zeleny, Petra; Brunner, Martin; Müller, Markus; Eichler, Hans Georg; Joukhadar, Christian

    2004-01-01

    Free gemifloxacin concentrations in the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue were measured by means of in vivo microdialysis to characterize the ability of gemifloxacin to penetrate human soft tissues. Twelve healthy volunteers received a single oral dose of 320 mg of gemifloxacin. The mean areas under the concentration-time curves from 0 to 10 h (AUC0-10) were significantly higher for soft tissue than for unbound gemifloxacin in plasma (P < 0.05). The ratios of the mean AUC0-10 for tissue to the AUC0-10 for free gemifloxacin in plasma were 1.7 ± 0.7 (mean ± standard deviation) for skeletal muscle and 2.4 ± 1.0 for adipose tissue. The AUC0-24 ratios for free gemifloxacin in tissues to the MIC at which 90% of frequently isolated bacteria are inhibited were close to or higher than 100 h. Therefore, based on pharmacokinetic and pharmacodynamic calculations, we conclude that gemifloxacin might be a useful therapeutic option for the treatment of soft tissue infections. PMID:15504848

  9. A comparative study of oral single dose of metronidazole, tinidazole, secnidazole and ornidazole in bacterial vaginosis

    PubMed Central

    Thulkar, Jyoti; Kriplani, Alka; Agarwal, Nutan

    2012-01-01

    Objective: To compare the cure rates of oral single dose of metronidazole (2 g), tinidazole (2 g), secnidazole (2 g), and ornidazole (1.5 g) in cases of bacterial vaginosis. Materials and Methods: This was a prospective, comparative, randomized clinical trial on 344 Indian women (86 women in each group) who attended a gynecology outpatient department with complaint of abnormal vaginal discharge or who had abnormal vaginal discharge on Gynecological examination but they did not complaint of it. For diagnosis and cure rate of bacterial vaginosis, Amsel's criteria were used. Statistical analysis was done by Chi-square test of proportions. The cure rate was compared considering metronidazole cure rate as gold standard. Results: At 1 week, the cure rate of tinidazole and ornidazole was 100% and at 4 weeks, it was 97.7% for both drugs (P<0.001). Secnidazole had cure rate of 80.2% at 4 weeks (P=NS). Metronidazole showed a cure rate of 77.9% at 4 weeks, which is the lowest of all four drugs. Conclusion: Tinidazole and ornidazole have better cure rate as compared to metronidazole in cases of bacterial vaginosis. PMID:22529484

  10. Single-dose pharmacokinetics of bupropion hydrobromide and metabolites in healthy adolescent and adult subjects.

    PubMed

    Oh, D Alexander; Crean, Christopher S

    2015-09-01

    Data from 2 pediatric single-dose studies, conducted at the same center, were combined to evaluate exposure levels of bupropion and metabolites in adolescents 12-17 years old, compared with adults > 18 years. Pharmacokinetic analyses of bupropion and its metabolites were performed using normalization and pharmacological/convulsive weighting methods on exposure. When compared with adults (>18 years), subjects 12-14 years had an increase in weight-normalized exposure to bupropion (ie, Cmax , 78%; AUC0-t , 83%; and AUCinf , 85%). Variability in this younger age group was also higher, with observations of a 3- to 4-fold increase in exposure. When the changes in metabolites were accounted within pharmacological and convulsive-weighted exposures, the relative ratio of 12-14 years to adults in body weight-normalized Cmax was 127% and 110%, respectively. Subjects 15-17 years did not exhibit a difference in exposure compared with adults. The influence of age on bupropion pharmacokinetics demonstrates that, in general, healthy adolescent subjects cannot be considered smaller healthy adult subjects; the increase in exposure is inversely related to age and appears to be solely associated with bupropion, not with its metabolites. Because there are no clinical safety and efficacy data of bupropion in adolescents, this data may shift its risk-benefit profile. PMID:27137143

  11. Effects of a single dose of menadione on the intestinal calcium absorption and associated variables.

    PubMed

    Marchionatti, Ana M; Díaz de Barboza, Gabriela E; Centeno, Viviana A; Alisio, Arturo E; Tolosa de Talamoni, Nori G

    2003-08-01

    The effect of a single large dose of menadione on intestinal calcium absorption and associated variables was investigated in chicks fed a normal diet. The data show that 2.5 micro mol of menadione/kg of b.w. causes inhibition of calcium transfer from lumen-to-blood within 30 min. This effect seems to be related to oxidative stress provoked by menadione as judged by glutathione depletion and an increment in the total carbonyl group content produced at the same time. Two enzymes presumably involved in calcium transcellular movement, such as alkaline phosphatase, located in the brush border membrane, and Ca(2+)- pump ATPase, which sits in the basolateral membrane, were also inhibited. The enzyme inhibition could be due to alterations caused by the appearance of free hydroxyl groups, which are triggered by glutathione depletion. Addition of glutathione monoester to the duodenal loop caused reversion of the menadione effect on both intestinal calcium absorption and alkaline phosphatase activity. In conclusion, menadione shifts the balance of oxidative and reductive processes in the enterocyte towards oxidation causing deleterious effects on intestinal Ca(2+) absorption and associated variables, which could be prevented by administration of oral glutathione monoester.

  12. Termination of pregnancy with reduced doses of mifepristone. World Health Organisation Task Force on Post-ovulatory Methods of Fertility Regulation.

    PubMed Central

    1993-01-01

    OBJECTIVES--To compare the abortifacient efficacy and side effects of three doses of the antiprogestin mifepristone plus prostaglandin for termination of early pregnancy. DESIGN--Randomised, double blind multicentre trial. SETTING--11 departments of obstetrics and gynaecology and of family planning, mostly in university hospitals, in seven countries. SUBJECTS--1182 women with an early pregnancy (menstrual delay of 7-28 days) requesting abortion. INTERVENTIONS--Single doses of 200 mg, 400 mg, or 600 mg mifepristone followed, 48 hours later, by vaginal pessary of 1 mg of the prostaglandin E1 analogue gemeprost. MAIN OUTCOME MEASURES--Outcome of treatment; duration and subjective amount of menstrual bleeding; side effects and complications; and concentrations of haemoglobin. RESULTS--Outcome was similar with the three doses of mifepristone. Of the 1151 women with known outcome, 95.5% had a complete abortion (364 (93.8%) of those given 200 mg mifepristone, 368 (94.1%) of those given 400 mg, and 367 (94.3%) of those given 600 mg), 3.7% had an incomplete abortion (14 (3.6%), 15 (3.8%), and 14 (3.6%)), 0.3% had a missed abortion (three (0.8%), one (0.3%), and none), and 0.4% had a continuing live pregnancy (two (0.5%), two (0.5%), and one (0.3%)). Of the 43 women who had incomplete abortion, 23 underwent emergency uterine curettage (usually for haemostatic purposes) and three of these women were given a blood transfusion. The numbers of reported complaints, bleeding patterns, and changes in blood pressure and haemoglobin concentrations were similar with the three treatments. CONCLUSIONS--For termination of early pregnancy a single dose of 200 mg mifepristone is as effective as the currently recommended dose of 600 mg when used in combination with a vaginal pessary of 1 mg gemeprost. PMID:8400972

  13. Pharmacokinetics, pharmacodynamics and food effect of LB30870, a novel direct thrombin inhibitor, after single oral doses in healthy men.

    PubMed

    Kim, John; Lee, Sung-Hack; Boyce, Malcolm; Warrington, Steve; Cho, Kwan Hyung; Yoon, Suk Kyoon; Park, Hee Dong; Kim, Aeri

    2015-01-01

    1. The safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect of LB30870, a new selective thrombin inhibitor, were studied in 16 healthy men. 2. A double-blind, placebo-controlled single ascending dose study was done at oral doses of 5, 15, 30, 60, 120, and 240 mg under fasting conditions. An open, randomized, balanced cross-over food effect study was done at 60 mg dose. Plasma and urinary concentrations were measured up to 48 h post-dose. Coagulation and thrombin activity markers were measured at selected time points. 3. Cmax of LB30870 was at 1.3-3.0 h post-dose with a mean apparent terminal half-life (t1/2) of 2.8-4.1 h. AUC after doses above 15 mg appeared greater than dose-proportional. In fed state, AUC showed 80% reduction relative to fasting condition. 4. At doses 60 and 120 mg, peak activated partial thromboplastin time (aPTT) increased by 1.5- and 2-fold, respectively, from baseline. The aPTT and international normalized ratio (INR) were concentration-dependent, with less within-individual variability than ecarin clotting time (ECT), prothrombin time (PT), or thrombin time (TT). 5. Single oral doses of LB30870 up to 240 mg were well tolerated. The food effect must be overcome if LB30870 is to be used as an oral anti-coagulant. PMID:25673087

  14. Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial

    PubMed Central

    Todd, John A.; Porter, Linsey; Smyth, Deborah J.; Rainbow, Daniel B.; Ferreira, Ricardo C.; Yang, Jennie H.; Bell, Charles J. M.; Schuilenburg, Helen; Challis, Ben; Clarke, Pamela; Coleman, Gillian; Dawson, Sarah; Goymer, Donna; Kennet, Jane; Brown, Judy; Greatorex, Jane; Goodfellow, Ian; Evans, Mark; Mander, Adrian P.; Bond, Simon; Wicker, Linda S.

    2016-01-01

    Background Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs. Methods and Findings To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = −0

  15. Trophic transfer of nano-TiO2 in a paddy microcosm: A comparison of single-dose versus sequential multi-dose exposures.

    PubMed

    Kim, Jung In; Park, Hyung-Geun; Chang, Kwang-Hyeon; Nam, D H; Yeo, Min-Kyeong

    2016-05-01

    In the present study, replicated paddy microcosm systems were used to investigate the environmental fate and trophic transfer of titanium nanoparticles (NPs) over a period of 14 days. Most TiO2 NPs immediately settled down in the sediment, and high accumulations of nano TiO2 in the sandy loam sediment and biofilm were observed. The test organisms (quillworts, water dropworts, duckweeds, biofilms, river snails, and Chinese muddy loaches) and environmental media (freshwater, sandy loam sediment) were exposed to sequential low doses (2 mg/L at 1 h, 4 days, and 9 days) or a single high-dose (6 mg/L) of TiO2 NPs. The bioconcentration factors (BCFs) of nano-TiO2 in biofilms, quillworts, duckweeds, and Chinese muddy loaches were higher in the sequential multi-dose group than in the single-dose group. Chinese muddy loaches showed higher bioaccumulation factors (BAFs) over their prey than river snails. The difference in the carbon isotope ratios between Chinese muddy loaches and river snails was less than 2‰, and an approximately 4‰ difference in the stable nitrogen isotope ratio was observed in the two aquatic predators from their major prey (e.g., biofilms or particulate organic matter). The trophic levels between biofilms and river snails and between biofilms and Chinese muddy loaches were 2.8 and 2.4 levels, respectively. These results indicate that these two predators consumed biofilm and other alternative preys at a higher level than biofilm. Although the trophic transfer rates of TiO2 are generally low, relatively higher biomagnification factors (BMFs) were found in Chinese muddy loaches (0.04-0.05) than in river snails (0.01-0.02). These results suggest that TiO2 NPs show greater movement in the sediment than in the water and that TiO2 NPs can be retained through aquatic food chains more after a sequential low-dose exposure than after a single high-dose exposure. PMID:26854701

  16. QMRA for Drinking Water: 1. Revisiting the Mathematical Structure of Single-Hit Dose-Response Models.

    PubMed

    Nilsen, Vegard; Wyller, John

    2016-01-01

    Dose-response models are essential to quantitative microbial risk assessment (QMRA), providing a link between levels of human exposure to pathogens and the probability of negative health outcomes. In drinking water studies, the class of semi-mechanistic models known as single-hit models, such as the exponential and the exact beta-Poisson, has seen widespread use. In this work, an attempt is made to carefully develop the general mathematical single-hit framework while explicitly accounting for variation in (1) host susceptibility and (2) pathogen infectivity. This allows a precise interpretation of the so-called single-hit probability and precise identification of a set of statistical independence assumptions that are sufficient to arrive at single-hit models. Further analysis of the model framework is facilitated by formulating the single-hit models compactly using probability generating and moment generating functions. Among the more practically relevant conclusions drawn are: (1) for any dose distribution, variation in host susceptibility always reduces the single-hit risk compared to a constant host susceptibility (assuming equal mean susceptibilities), (2) the model-consistent representation of complete host immunity is formally demonstrated to be a simple scaling of the response, (3) the model-consistent expression for the total risk from repeated exposures deviates (gives lower risk) from the conventional expression used in applications, and (4) a model-consistent expression for the mean per-exposure dose that produces the correct total risk from repeated exposures is developed.

  17. QMRA for Drinking Water: 1. Revisiting the Mathematical Structure of Single-Hit Dose-Response Models.

    PubMed

    Nilsen, Vegard; Wyller, John

    2016-01-01

    Dose-response models are essential to quantitative microbial risk assessment (QMRA), providing a link between levels of human exposure to pathogens and the probability of negative health outcomes. In drinking water studies, the class of semi-mechanistic models known as single-hit models, such as the exponential and the exact beta-Poisson, has seen widespread use. In this work, an attempt is made to carefully develop the general mathematical single-hit framework while explicitly accounting for variation in (1) host susceptibility and (2) pathogen infectivity. This allows a precise interpretation of the so-called single-hit probability and precise identification of a set of statistical independence assumptions that are sufficient to arrive at single-hit models. Further analysis of the model framework is facilitated by formulating the single-hit models compactly using probability generating and moment generating functions. Among the more practically relevant conclusions drawn are: (1) for any dose distribution, variation in host susceptibility always reduces the single-hit risk compared to a constant host susceptibility (assuming equal mean susceptibilities), (2) the model-consistent representation of complete host immunity is formally demonstrated to be a simple scaling of the response, (3) the model-consistent expression for the total risk from repeated exposures deviates (gives lower risk) from the conventional expression used in applications, and (4) a model-consistent expression for the mean per-exposure dose that produces the correct total risk from repeated exposures is developed. PMID:26812257

  18. Voriconazole Disposition After Single and Multiple, Oral Doses in Healthy, Adult Red-tailed Hawks ( Buteo jamaicensis ).

    PubMed

    Gentry, Jordan; Montgerard, Christy; Crandall, Elizabeth; Cruz-Espindola, Crisanta; Boothe, Dawn; Bellah, Jamie

    2014-09-01

    Voriconazole is effective for treatment of aspergillosis, a common disease in captive red-tailed hawks ( Buteo jamaicensis ). To determine the disposition and safety of voriconazole after single and multiple, oral doses, 12 adult red-tailed hawks were studied in 2 phases. In phase 1, each bird received a single dose of voriconazole solution (10 mg/kg) by gavage. Blood samples were collected at 0, 0.5, 1, 3, 6, 9, 12, 16, 24, and 36 hours after treatment. In phase 2, each of 8 birds received voriconazole oral solution at 10 mg/kg PO q12h for 14 days. Plasma samples were collected on days 0, 5, and 10 and after the final dose and were processed as in phase 1. Plasma samples were submitted for analysis of voriconazole levels by high-performance liquid chromatography and ultraviolet spectrophotometry and for measurement of selected plasma biochemical parameters. After single dosing, voriconazole concentrations reached a (mean ± SD) peak (Cmax) of 4.7 ± 1.3 μg/mL at 2.0 ± 1.2 hours. The disappearance half-life (t1/2) was 2.8 ± 0.7 hours, and the mean residence time (MRT) was 4.6 ± 0.9 hours. After the last dose at 14 days, the mean Cmax of voriconazole was 4.5 ± 2.7 μg/mL at 2.4 ± 1.1 hours. The t1/2 was 2.1 ± 0.8 hours, and the MRT was 3.5 ± 1.1 hours. Although concentrations of several plasma biochemical parameters were significantly different at study end compared with prestudy concentrations, only plasma creatine kinase activity was outside the reference range. No adverse reactions were observed in any of the birds. After both single and multiple dosing at 10 mg/kg, voriconazole concentrations exceeded the minimum inhibitory concentration to inhibit 90% (MIC90) of Aspergillus species (1 μg/mL) by at least fourfold and remained above the MIC90 for 8.8 ± 1.1 hours after single dosing versus 6.5 ± 1.5 hours after multiple dosing (P = .003). This difference suggests that more frequent dosing (eg, up to q8h) may be necessary to maintain target

  19. Evaluation of Sphingolipids in Wistar Rats Treated to Prolonged and Single Oral Doses of Fumonisin B1

    PubMed Central

    Direito, Glória M.; Almeida, Adriana P.; Aquino, Simone; dos Reis, Tatiana Alves; Pozzi, Claudia Rodrigues; Corrêa, Benedito

    2009-01-01

    The objective of the present study was to evaluate sphingolipid levels (sphingosine-So and sphinganine-Sa) and to compare the Sa/So ratio in liver, serum and urine of Wistar rats after prolonged administration (21 days) of fumonisin B1 (FB1). In parallel, the kinetics of sphingolipid elimination in urine was studied in animals receiving a single dose of FB1. Prolonged exposure to FB1 caused an increase in Sa levels in urine, serum and liver. The most marked effect on sphingolipid biosynthesis was observed in animals treated with the highest dose of FB1. Animals receiving a single dose of FB1 presented variations in Sa and So levels and in the Sa/So ratio. PMID:19333435

  20. 21 CFR 320.26 - Guidelines on the design of a single-dose in vivo bioavailability or bioequivalence study.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Guidelines on the design of a single-dose in vivo bioavailability or bioequivalence study. 320.26 Section 320.26 Food and Drugs FOOD AND DRUG ADMINISTRATION... test product and the reference material should be administered to subjects in the fasting state,...

  1. 21 CFR 320.26 - Guidelines on the design of a single-dose in vivo bioavailability or bioequivalence study.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Guidelines on the design of a single-dose in vivo bioavailability or bioequivalence study. 320.26 Section 320.26 Food and Drugs FOOD AND DRUG ADMINISTRATION... test product and the reference material should be administered to subjects in the fasting state,...

  2. 21 CFR 320.26 - Guidelines on the design of a single-dose in vivo bioavailability or bioequivalence study.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Guidelines on the design of a single-dose in vivo bioavailability or bioequivalence study. 320.26 Section 320.26 Food and Drugs FOOD AND DRUG ADMINISTRATION... test product and the reference material should be administered to subjects in the fasting state,...

  3. 21 CFR 320.26 - Guidelines on the design of a single-dose in vivo bioavailability or bioequivalence study.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Guidelines on the design of a single-dose in vivo bioavailability or bioequivalence study. 320.26 Section 320.26 Food and Drugs FOOD AND DRUG ADMINISTRATION... test product and the reference material should be administered to subjects in the fasting state,...

  4. 21 CFR 320.26 - Guidelines on the design of a single-dose in vivo bioavailability or bioequivalence study.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Guidelines on the design of a single-dose in vivo bioavailability or bioequivalence study. 320.26 Section 320.26 Food and Drugs FOOD AND DRUG ADMINISTRATION... test product and the reference material should be administered to subjects in the fasting state,...

  5. Compendium of Single Event Effects, Total Ionizing Dose, and Displacement Damage for Candidate Spacecraft Electronics for NASA

    NASA Technical Reports Server (NTRS)

    LaBel, Kenneth A.; O'Bryan, Martha V.; Chen, Dakai; Campola, Michael J.; Casey, Megan C.; Pellish, Jonathan A.; Lauenstein, Jean-Marie; Wilcox, Edward P.; Topper, Alyson D.; Ladbury, Raymond L.; Berg, Melanie D.; Gigliuto, Robert A.; Boutte, Alvin J.; Cochran, Donna J.; Buchner, Stephen P.; Violette, Daniel P.

    2014-01-01

    We present results and analysis investigating the effects of radiation on a variety of candidate spacecraft electronics to proton and heavy ion-induced single-event effects (SEE), proton-induced displacement damage (DD), and total ionizing dose (TID). This paper is a summary of test results.

  6. Reproductive toxicity of a single dose of 1,3-dinitrobenzene in two ages of young adult male rats

    EPA Science Inventory

    These studies evaluated the reproductive response and the possible influence of testicular maturation on the reproductive parameters, in male rats treated with 1,3-dinitrobenzene (m-DNB). Young adult male rats (75 or 105 days of age) were given a single oral dose of 0, 8, 16, 24,...

  7. Single doses of piracetam affect 42-channel event-related potential microstate maps in a cognitive paradigm.

    PubMed

    Michel, C M; Lehmann, D

    1993-01-01

    We examined whether a single administration of piracetam produces dose-dependent effects on brain functions in healthy young men. In 6 subjects, 42-channel event-related EEG potential maps (ERP) were recorded during a task requiring subjects to watch single digits presented in a pseudorandom order on a screen and to press a button after all triplets of three consecutive odd or even digits. The ERP maps to the three digits of the correctly detected triplets were analyzed in terms of their mapped ERP field configuration (landscape). Different landscapes of the maps indicate different configuration of the activated neural population and therefore reflect different functional microstates of the brain. In order to identify these microstates, adaptive segmentation of the map series based on their landscapes was done. Nineteen time segments were found. These segments were tested for direct effects on brain function of three single doses of piracetam (2.9, 4.8 or 9.6 g) and a placebo given double-blind in balanced order. Piracetam mainly affected the map landscape of the time segments following the triplet's last digit. U-shaped dose-dependent effects were found; they were strongest after 4.8 g piracetam. Since these particular ERP segments are recognized to be strongly correlated to cognitive functions, the present findings suggest that single medium doses of piracetam selectively activate differently located or oriented neurons during cognitive steps of information processing.

  8. The pharmacokinetics of methocarbamol and guaifenesin after single intravenous and multiple-dose oral administration of methocarbamol in the horse.

    PubMed

    Rumpler, M J; Colahan, P; Sams, R A

    2014-02-01

    A simple LC/MSMS method has been developed and fully validated to determine concentrations and characterize the concentration vs. time course of methocarbamol (MCBL) and guaifenesin (GGE) in plasma after a single intravenous dose and multiple oral dose administrations of MCBL to conditioned Thoroughbred horses. The plasma concentration-time profiles for MCBL after a single intravenous dose of 15 mg/kg of MCBL were best described by a three-compartment model. Mean extrapolated peak (C0 ) plasma concentrations were 23.2 (± 5.93) μg/mL. Terminal half-life, volume of distribution at steady-state, mean residence time, and systemic clearance were characterized by a median (range) of 2.96 (2.46-4.71) h, 1.05 (0.943-1.21) L/kg, 1.98 (1.45-2.51) h, and 8.99 (6.68-10.8) mL/min/kg, respectively. Oral dose of MCBL was characterized by a median (range) terminal half-life, mean transit time, mean absorption time, and apparent oral clearance of 2.89 (2.21-4.88) h, 2.67 (1.80-2.87) h, 0.410 (0.350-0.770) h, and 16.5 (13.0-20) mL/min/kg. Bioavailability of orally administered MCBL was characterized by a median (range) of 54.4 (43.2-72.8)%. Guaifenesin plasma concentrations were below the limit of detection in all samples collected after the single intravenous dose of MCBL whereas they were detected for up to 24 h after the last dose of the multiple-dose oral regimen. This difference may be attributed to first-pass metabolism of MCBL to GGE after oral administration and may provide a means of differentiating the two routes of administration. PMID:23859819

  9. A novel CRTH2 antagonist: Single- and multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ACT-453859 in healthy subjects.

    PubMed

    Géhin, Martine; Strasser, Daniel S; Zisowsky, Jochen; Farine, Hervé; Groenen, Peter M A; Dingemanse, Jasper; Sidharta, Patricia N

    2015-07-01

    The chemoattractant receptor-homologous molecule expressed on T-helper 2 cells (CRTH2) is a G-protein-coupled receptor for prostaglandin D2 , a key mediator in inflammatory disorders. In this randomized, double-blind, placebo-controlled study we investigated the single- and multiple-dose tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) up to a dose of 800 mg once a day of ACT-453859, a potent and selective CRTH2 antagonist. ACT-453859 was moderately rapidly absorbed and followed a biphasic elimination pattern, with an elimination half-life between 11 and 20 hours. Steady-state conditions were reached after 1 day, and ACT-453859 did not accumulate. Urinary excretion of unchanged ACT-453859 did not exceed 1.4% of the administered dose. Administration of ACT-453859 resulted in a dose-dependent blockadeof CRTH2 on the surface of eosinophils. The maximum PD effect of ACT-453859 was reached about 2.0 hours after dosing, which corresponded to the highest concentration at which PD were assessed. At steady state, 100 and 800 mg ACT-453859 once a day resulted in blockade of CRTH2 over 24 hours. In this entry-into-humans study, ACT-453859 showed good tolerability at all doses and a PK and PD profile compatible with once-daily dosing.

  10. Single-dose safety, tolerability, and pharmacokinetics of the antibiotic GSK1322322, a novel peptide deformylase inhibitor.

    PubMed

    Naderer, Odin J; Dumont, Etienne; Zhu, John; Kurtinecz, Milena; Jones, Lori S

    2013-05-01

    GSK1322322 is a potent inhibitor of peptide deformylase, an essential bacterial enzyme required for protein maturation. GSK1322322 is active against community-acquired skin and respiratory tract pathogens, including methicillin-resistant Staphylococcus aureus, multidrug-resistant Streptococcus pneumoniae, and atypical pathogens. This phase I, randomized, double-blind, placebo-controlled, 2-part, single-dose, dose escalation study (first time in humans) evaluated the safety, tolerability, and pharmacokinetics of GSK1322322 (powder-in-bottle formulation) in healthy volunteers. In part A, dose escalation included GSK1322322 doses of 100, 200, 400, 800, and 1,500 mg under fasting conditions and 800 mg administered with a high-fat meal. In part B, higher doses of GSK1322322 (2,000, 3,000, and 4,000 mg) were evaluated under fasting conditions. Of the 39 volunteers enrolled in the study, 29 and 10 volunteers were treated with GSK1322322 and placebo, respectively. Upon single-dose administration, GSK1322322 was absorbed rapidly, with median times to maximum plasma concentration (T(max)) ranging from 0.5 to 1.0 h. The maximum observed plasma concentration (C(max)) and exposure (area under the concentration-time curve [AUC]) of GSK1322322 were greater than dose proportional between 100 and 1,500 mg and less than dose proportional between 1,500 and 4,000 mg. Administration of the drug with a high-fat meal reduced the rate of absorption (reduced C(max) and delayed T(max)) without affecting the extent of absorption (no effect on AUC). GSK1322322 was generally well tolerated, with all adverse events being mild to moderate in intensity during both parts of the study. The most frequently reported adverse event was headache. Data from this study support further evaluation of GSK1322322. PMID:23403431

  11. Pharmacokinetics of enrofloxacin after single dose oral and intravenous administration in the African penguin (Spheniscus demersus).

    PubMed

    Wack, Allison N; KuKanich, Butch; Bronson, Ellen; Denver, Mary

    2012-06-01

    The pharmacokinetics of a single dose of enrofloxacin administered orally, both pilled and in fish, and i.v. to African penguins (Spheniscus demersus) at 15 mg/kg were determined. Plasma concentrations of enrofloxacin and its metabolite ciprofloxacin were measured via high-pressure liquid chromatography with mass spectrometry. An i.v. administration of enrofloxacin resulted in an extrapolated mean plasma concentration of 7.86 microg/ml at time zero. Plasma volume of distribution for i.v. administration was 3.00 L/kg, with a mean elimination half-life of 13.67 hr and a mean total body clearance rate of 3.03 ml/min/kg. Oral administration of enrofloxacin achieved a mean maximum plasma concentration of4.38 microg/ml at 4.8 hr after administration when pilled, whereas mean maximum plasma concentration was 4.77 microg/ml at 1.59 hr after administration when given in fish. Mean terminal elimination half-life was 13.79 hr pilled and 11.93 hr when given in fish. Low concentrations of ciprofloxacin were detected after both oral and i.v. enrofloxacin administration. Enrofloxacin administered to African penguins at 15 mg/kg p.o.q. 24 hr, whether in fish or pilled, is expected to achieve the surrogate markers of efficacy for bacteria with a minimum inhibitory concentration of 0.5 microg/ml or less; however, clinical studies are needed to determine efficacy. PMID:22779234

  12. The effects of a single dose of concentrated beetroot juice on performance in trained flatwater kayakers.

    PubMed

    Muggeridge, David J; Howe, Christopher C F; Spendiff, Owen; Pedlar, Charles; James, Philip E; Easton, Chris

    2013-10-01

    The aim of the current study was to determine the effects of dietary nitrate ingestion on parameters of submaximal and supramaximal exercise and time trial (TT) performance in trained kayakers. Eight male kayakers completed four exercise trials consisting of an initial discontinuous graded exercise test to exhaustion and three performance trials using a kayak ergometer. The performance trials were composed of 15 min of paddling at 60% of maximum work rate, five 10-s all-out sprints, and a 1 km TT. The second and third trials were preceded by ingestion of either 70 ml nitrate-rich concentrated beetroot juice (BR) or tomato juice (placebo [PLA]) 3 hr before exercise using a randomized crossover design. Plasma nitrate (PLA: 33.8 ± 1.9 μM, BR: 152 ± 3.5 μM) and nitrite (PLA: 519.8 ± 25.8, BR: 687.9 ± 20 nM) were higher following ingestion of BR compared with PLA (both p < .001). VO2 during steady-state exercise was lower in the BR trial than in the PLA trial (p = .010). There was no difference in either peak power in the sprints (p = .590) or TT performance between conditions (PLA: 277 ± 5 s, BR: 276 ± 5 s, p = .539). Despite a reduction in VO2, BR ingestion appears to have no effect on repeated supramaximal sprint or 1 km TT kayaking performance. A smaller elevation in plasma nitrite following a single dose of nitrate and the individual variability in this response may partly account for these findings.

  13. Deposition of 7-aminoflunitrazepam and flunitrazepam in hair after a single dose of Rohypnol.

    PubMed

    Negrusz, A; Moore, C M; Hinkel, K B; Stockham, T L; Verma, M; Strong, M J; Janicak, P G

    2001-09-01

    In recent years, there has been a notable increase in the number of reports on drug-facilitated sexual assault. Benzodiazepines are the most common so-called "date-rape" drugs, with flunitrazepam (Rohypnol) being one of the most frequently mentioned. The aim of this study was to determine whether flunitrazepam and its major metabolite 7-aminoflunitrazepam could be detected in hair collected from ten healthy volunteers after receiving a single 2 mg dose of Rohypnol using solid phase extraction and NCI-GC-MS. Such data would be of great importance to law enforcement agencies trying to determine the best time interval for hair collection from a victim of drug-facilitated sexual assault in order to reveal drug use. Ten healthy volunteers (eight women and two men, 21 to 49 years old) participated in the study. The following hair samples were collected from each volunteer: one before flunitrazepam administration, and 1, 3, 5, 14, 21, and 28 days after. In five volunteers, 7-aminoflunitrazepam was detected 24 h after flunitrazepam administration and remained in hair throughout the entire 28-day study period (0.6-8.0 pg/mg). In two cases, 7-aminoflunitrazepam appeared in hair 21 days after drug intake (0.5-2.7 pg/mg), and in two subjects 14 days later (0.5-5.4 pg/mg). In one volunteer, 7-aminoflunitrazepam was detected on day 14 and 21 but concentrations were below the quantitation limit. Flunitrazepam was detected in some samples but all concentrations were below the quantitation limit (0.5-2.3 pg/mg). PMID:11569557

  14. Single-dose pharmacokinetics of marbofloxacin in Egyptian buffalo (Bubalus bubalis L.) steers.

    PubMed

    Goudah, Ayman; Abd El-Aty, Abd El-Aty M; Regmi, Nanda L; Shin, Ho-Chul; Shimoda, Minoru; Shim, Jae-Han

    2007-01-01

    The objective of this study was to investigate the pharmacokinetics of marbofloxacin (MAR) following intravenous (iv) and intramuscular (im) administration of a 2.0 mg/kg body weight dosage to five healthy Egyptian buffalo steers. A cross-over design was used with a washout period of 2 weeks. Blood samples were obtained at 0, 5,10,15, and 20 min and at 0.5,0.75,1,2,4,6,8,10,12,24,30 and 48 hours after marbofloxacin administration. The serum marbofloxacin concentrations were quantitated using a modified agar diffusion bioassay method. Marbofloxacin exhibited a relatively high volume of distribution at steady-state (Vdss = 1.77 Lkg), which suggests good tissue penetration, and a total body clearance (Cltot) of 0.18 L/kgxh,which is associated with a long elimination half-life (tl/2beta = 7.52 h). Marbofloxacin was rapidly absorbed at a dosage of 2.0 mg/kg after im administration with an observed maximum serum concentration (Cmax) value of 2.004 microg/mL obtained at a time to peak concentration (tmax) of 0.5 h, and an absolute bioavailability (F %) of 86.79 +/- 5.53 %. The protein-binding ranged from 22 to 24.6 % with an average of 23.4 %. In conclusion, single iv and im administered doses of marbofloxacin were well tolerated by Egyptian buffalo steers. A dosage of 2 mg/kg body weight might not be enough to treat infections caused by bacteria with minimum inhibitory concentration (MIC) at or above 0.2 microg/mL, based on the calculated area under the inhibitory concentration (AUIC).

  15. Impact of biplane versus single-plane imaging on radiation dose, contrast load and procedural time in coronary angioplasty.

    PubMed

    Sadick, V; Reed, W; Collins, L; Sadick, N; Heard, R; Robinson, J

    2010-05-01

    Coronary angioplasties can be performed with either single-plane or biplane imaging techniques. The aim of this study was to determine whether biplane imaging, in comparison to single-plane imaging, reduces radiation dose and contrast load and shortens procedural time during (i) primary and elective coronary angioplasty procedures, (ii) angioplasty to the main vascular territories and (iii) procedures performed by operators with various levels of experience. This prospective observational study included a total of 504 primary and elective single-vessel coronary angioplasty procedures utilising either biplane or single-plane imaging. Radiographic and clinical parameters were collected from clinical reports and examination protocols. Radiation dose was measured by a dose-area-product (DAP) meter intrinsic to the angiography system. Our results showed that biplane imaging delivered a significantly greater radiation dose (181.4+/-121.0 Gycm(2)) than single-plane imaging (133.6+/-92.8 Gycm(2), p<0.0001). The difference was independent of case type (primary or elective) (p = 0.862), vascular territory (p = 0.519) and operator experience (p = 0.903). No significant difference was found in contrast load between biplane (166.8+/-62.9 ml) and single-plane imaging (176.8+/-66.0 ml) (p = 0.302). This non-significant difference was independent of case type (p = 0.551), vascular territory (p = 0.308) and operator experience (p = 0.304). Procedures performed with biplane imaging were significantly longer (55.3+/-27.8 min) than those with single-plane (48.9+/-24.2 min, p = 0.010) and, similarly, were not dependent on case type (p = 0.226), vascular territory (p = 0.642) or operator experience (p = 0.094). Biplane imaging resulted in a greater radiation dose and a longer procedural time and delivered a non-significant reduction in contrast load than single-plane imaging. These findings did not support the commonly perceived advantages of using biplane imaging in single

  16. Comparative metabolism studies of hexabromocyclododecane (HBCD) diastereomers in male rats following a single oral dose

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Male Sprague-Dawley rats were dosed orally with 3 mg/kg of one of three hexabromocyclododecane (HBCD) diastereomers. Each diastereomer was well absorbed (73-83%), and distributed preferentially to lipophilic tissues. Feces were the major route of excretion; cumulatively 42% of dose for alpha-HBCD,...

  17. Primary central nervous system lymphoma treated with high-dose methotrexate and rituximab: A single-institution experience

    PubMed Central

    LY, K. INA; CREW, LAURA L.; GRAHAM, CARRIE A.; MRUGALA, MACIEJ M.

    2016-01-01

    Rituximab (RTX) improves the outcome in patients with systemic diffuse large B-cell lymphoma (DLBCL), but its benefit in primary central nervous system lymphoma (PCNSL) is unclear. In the present study, a single-institution retrospective analysis was performed for 12 patients with newly diagnosed PCNSL treated with combined high-dose methotrexate (HD-MTX) and RTX. MTX was administered biweekly at 8 g/m2/dose until a complete response (CR) was achieved or for a maximum of eight doses. RTX was provided for a total of eight weekly doses at 375 mg/m2/dose. Following a median of 11 cycles of MTX, the radiographic overall response rate was 91% and the CR rate was 58%. A CR was achieved after a median 6 cycles of MTX. The median progression-free survival time was 22 months and the median overall survival time has not yet been attained. These results compare favorably to single-agent HD-MTX and suggest a role for immunochemotherapy in the treatment of PCNSL. PMID:27123138

  18. Pharmacokinetics of CGP 6140 (amocarzine) after oral administration of single 100-1600 mg doses to patients with onchocerciasis.

    PubMed Central

    Lecaillon, J B; Dubois, J P; Awadzi, K; Poltera, A A; Ginger, C D

    1990-01-01

    The concentrations of CGP 6140 [4-nitro-4'-(N-methyl-piperazinylthiocarbonylamido)-diphenylamine] and of its N-oxide metabolite, CGP 13,231, were measured in plasma and urine after single oral dose of 100-1600 mg of CGP 6140 to 41 fasted Ghanaian patients with Onchocerca volvulus infections. The absorption of CGP 6140 was rapid and its terminal elimination half-life was about 3 h. The plasma concentrations of CGP 6140 were essentially proportional to the dose. A greater variability in plasma concentrations was apparent after the 800 and 1600 mg doses indicating a poor bioavailability of the drug administered in fasting conditions to several patients. In plasma, the concentrations of CGP 13,231 were similar to those of CGP 6140. The amount of CGP 13,231 excreted in urine was 25-40% of the dose of CGP 6140 whereas only 1.5% was excreted as unchanged drug. If a single dose of drug is used for the treatment, the plasma concentration would be maintained for 3-4 h at a high level. At 8 h, the concentration falls to about 10% of the Cmax. If sustained plasma concentrations of the drug are needed for efficacy, twice daily administration would maintain the minimum concentration at about 10% of the Cmax. PMID:2291876

  19. Single-dose pharmacokinetics and safety of pegylated interferon-alpha2b in patients with chronic renal dysfunction.

    PubMed

    Gupta, Samir K; Pittenger, Amy L; Swan, Suzanne K; Marbury, Thomas C; Tobillo, Emlyn; Batra, Vijay; Sack, Marshall; Glue, Paul; Jacobs, Sheila; Affrime, Melton

    2002-10-01

    This study evaluates the pharmacokinetics and safety of pegylated interferon-alpha2b (PEG-Intron) following a single-dose subcutaneous injection into subjects with normal renal function, subjects with chronic renal impairment, and patients on hemodialysis. In this open-label, single-dose, parallel group study, subjects were divided into five groups according to their degree of renal function: four groups as defined by measured creatinine clearance and a fifth hemodialysis dependent group. They received 1 microg/kg PEG-Intron subcutaneously after a 10-hour fast. Pharmacokinetic and safety assessments were performed up to 168 hours postdose. Hemodialysis patients had a second PEG-Intron dose 12 hours prior to a hemodialysis session. PEG-Intron pharmacokinetic parameters (AUCtf, Cmax, and t1/2) increased progressively as CL(CR) declined. All subjects reported at least one adverse event, which were typical of those reported after alpha-interferon administration (e.g., flu-like symptoms, headache). Single-dose PEG-Intron administration to volunteers with normal renal function and chronic renal impairment was safe and well tolerated. In patients with CL(CR) < 30 ml/min, AUCand Cmax values were increased 90% compared with controls, while half-life was increased by up to 40% over controls. Based on the relationship between PEG-Intron apparent clearance and CL(CR), renal clearance accountsfor less than half of its total clearance. Hemodialysis did not affect PEG-Intron apparent clearance.

  20. A single-dose regimen for antimicrobial prophylaxis to prevent perioperative infection in urological clean and clean-contaminated surgery.

    PubMed

    Higuchi, Yoshihide; Takesue, Yoshio; Yamada, Yusuke; Ueda, Yasuo; Suzuki, Toru; Aihara, Kinue; Maruyama, Takuo; Kondoh, Nobuyuki; Nojima, Michio; Yamamoto, Shingo

    2011-04-01

    A single dose of antimicrobial prophylaxis (AMP) was administered parenterally for the prevention of perioperative infection in a total of 788 patients undergoing urological surgery, including 380 endoscopic-instrumental, 328 clean, and 80 clean-contaminated operations performed at our institute between January 2007 and December 2009. Surgical site infections (SSIs), urinary tract infections (UTIs), and remote infections (RIs) were prospectively surveyed. The definition for a single dose of AMP allowed for the administration of an additional dose of an antimicrobial during surgery if the procedure was longer than 3 h, but not for the parenteral or oral administration at the end of the procedure in the recovery room, or at a later time over a period of more than 24 h. UTI was observed in 12 (3.2%) patients after endoscopic-instrumental operation, 1 (0.3%) after clean operation, and 1 (0.9%) after clean-contaminated operation. SSI was observed in 2 (0.6%) patients after clean operation but in none after clean-contaminated operations. RI was observed in 1 (0.3%) patient after endoscopic-instrumental operation, 3 (0.9%) after clean operation, and none after clean-contaminated operations. A single-dose regimen of AMP was effective and feasible for the prevention of perioperative infections, including SSIs, UTIs, and RIs, in endoscopic-instrumental, clean, and clean-contaminated urological surgical procedures.

  1. Single Oral Dose Pharmacokinetics of Decursin and Decursinol Angelate in Healthy Adult Men and Women

    PubMed Central

    Zhang, Jinhui; Li, Li; Hale, Thomas W.; Chee, Wayne; Xing, Chengguo; Jiang, Cheng; Lü, Junxuan

    2015-01-01

    The ethanol extract of Angelica gigas Nakai (AGN) root has promising anti-cancer and other bioactivities in rodent models. It is currently believed that the pyranocoumarin isomers decursin (D) and decursinol angelate (DA) contribute to these activities. We and others have documented that D and DA were rapidly converted to decursinol (DOH) in rodents. However, our in vitro metabolism studies suggested that D and DA might be metabolized differently in humans. To test this hypothesis and address a key question for human translatability of animal model studies of D and DA or AGN extract, we conducted a single oral dose human pharmacokinetic study of D and DA delivered through an AGN-based dietary supplement Cogni.Q (purchased from Quality of Life Labs, Purchase, NY) in twenty healthy subjects, i.e., 10 men and 10 women, each consuming 119 mg D and 77 mg DA from 4 vegicaps. Analyses of plasma samples using UHPLC-MS/MS showed mean time to peak concentration (Tmax) of 2.1, 2.4 and 3.3 h and mean peak concentration (Cmax) of 5.3, 48.1 and 2,480 nmol/L for D, DA and DOH, respectively. The terminal elimination half-life (t1/2) for D and DA was similar (17.4 and 19.3 h) and each was much longer than that of DOH (7.4 h). The mean area under the curve (AUC0-48h) for D, DA and DOH was estimated as 37, 335 and 27,579 h∙nmol/L, respectively. Gender-wise, men absorbed the parent compounds faster and took shorter time to reach DOH peak concentration. The human data supported an extensive conversion of D and DA to DOH, even though they metabolized DA slightly slower than rodents. Therefore, the data generated in rodent models concerning anti-cancer efficacy, safety, tissue distribution and pharmacodynamic biomarkers will likely be relevant for human translation. Trial Registration ClinicalTrials.gov NCT02114957 PMID:25695490

  2. Pharmacokinetics and systemic endocrine effects of the phyto-oestrogen 8-prenylnaringenin after single oral doses to postmenopausal women

    PubMed Central

    Rad, M; Hümpel, M; Schaefer, O; Schoemaker, R C; Schleuning, W-D; Cohen, A F; Burggraaf, J

    2006-01-01

    Aims Pre-clinical data suggest that the racemic phyto-oestrogen 8-prenylnaringenin (8-PN) may have beneficial effects in postmenopausal women and may become an alternative to classical hormone replacement therapy (HRT) treatment regimes. The aim of this study was to investigate the pharmacokinetics, endocrine effects and tolerability of chemically synthesized 8-PN in postmenopausal women. Methods The study was performed using a randomized, double-blind, placebo-controlled, dose-escalation design with three groups of eight healthy postmenopausal women. In each group six subjects received 8-PN and two subjects placebo. 8-PN was given orally in doses of 50, 250 or 750 mg. Drug concentrations in serum, urine and faeces were measured up to 48 h and follicle-stimulating hormone/luteinizing hormone (LH) concentrations up to 24 h. Results All treatments were well tolerated and associated with a low incidence of (drug unrelated) adverse events. Serum concentrations of free 8-PN showed rapid drug absorption and secondary peaks suggestive of marked enterohepatic recirculation. Independent of the treatment group, approximately 30% of the dose was recovered in excreta as free compound or conjugates over the 48-h observation period. The first Cmax and AUC0–48 h showed dose linearity with ratios of 1 : 4.5 : 13.6 (Cmax) and 1 : 5.2 : 17.1 (AUC). The 750- mg dose decreased LH concentrations by 16.7% (95% confidence interval 0.5, 30.2). Conclusion Single oral doses of up to 750 mg 8-PN were well tolerated by postmenopausal women. The pharmacokinetic profile of 8-PN was characterized by rapid and probably complete enteral absorption, high metabolic stability, pronounced enterohepatic recirculation and tight dose linearity. The decrease in LH serum concentrations found after the highest dose demonstrates the ability of 8-PN to exert systemic endocrine effects in postmenopausal women. PMID:16934044

  3. [Efficacy, safety and tolerability of a single dose of akatinol memantine in comparison to two-doses in patients with moderately expressed and moderately severe dementia in Alzheimer's disease].

    PubMed

    Kolykhalov, I V; Gavrilova, S I; Kalyn, Ia B; Selezneva, N D; Fedorova, Ia B

    2012-01-01

    The compliance of patients with moderately expressed and moderately severe dementia, caused by Alzheimer's disease (AD), to the treatment with two different dose regimes of akatinol memantine was studied. The study included 40 patients with AD and mixed Alzheimer-vascular dementia (AD/VD) aged from 53 to 84 years. Patients were stratified into 2 groups: patients of group 1 received akatinol memantine in a single dose 20 mg in the morning and patients of group 2 received the drug twice in dose 10 mg in the morning and in the afternoon. The treatment duration was 24 weeks. The single dose of drug was as effective and safety as standard treatment with two doses. Therefore, treatment with a single dose of 20 mg akatinol memantine is recommended for clinical practice.

  4. OSL and TL techniques combined in a beryllium oxide detector to evaluate simultaneously accumulated and single doses.

    PubMed

    Malthez, Anna L M C; Freitas, Marcelo B; Yoshimura, Elisabeth M; Umisedo, Nancy K; Button, Vera L S N

    2016-04-01

    Optically stimulated luminescence (OSL) and thermoluminescence (TL) are similar techniques widely used in radiation dosimetry. The main difference between these techniques is the stimulus to induce luminescence emission: TL technique uses thermal stimulation, whereas OSL uses optical stimulation. One of the main intrinsic characteristics of the OSL technique is the possibility of reading several times the dosimetric materials with a negligible loss of signal. In the case of BeO, recent studies have shown that TL stimulation up to 250°C does not affect its OSL signal. Taking the advantages of dosimetric characteristics of BeO combined with both techniques, in this study, we demonstrated the possibility of measuring accumulated and single doses in the same BeO-based detector in order to use it to improve individual monitoring of radiation workers exposed to X-ray or gamma-ray fields. Single doses were measured using TL technique by heating the detector up to 250°C, whereas accumulated doses were estimated using OSL technique in the same detector in a relatively short time of optical stimulation. The detectors were exposed to two energies: 28keV X-rays and 1.25MeV Co-60 gamma rays. The doses estimated by OSL and TL of BeO (Thermalox 995) were compared with those obtained with LiF (TLD-100) and recorded with a calibrated ionization chamber. The results indicate that combined OSL and TL signals of BeO detectors can provide additional information of accumulated dose, with additional exploration of the advantages of both techniques, such as speed in readouts with OSL, and double-check the doses using TL and OSL intensities from BeO. PMID:26784853

  5. The Response of a Mouse Sarcoma to Single and Divided Doses of X-rays and Fast Neutrons

    PubMed Central

    Denekamp, J.

    1974-01-01

    The response of an experimental sarcoma to single doses and two fractions of x-rays and fast neutrons has been investigated to test the hypothesis that slowly shrinking sarcomata will reoxygenate poorly and therefore will benefit more from fractionated neutron treatment than from fractionated x-ray treatment, in contrast with rapidly shrinking carcinomata. Neutrons were approximately three times more effective than x-rays, both for single doses and for two fractions given in 48 hours, when regrowth was used as a measure of response. This observation is closely similar to results previously obtained on a rat fibrosarcoma and contrasts with previous results from a mouse mammary carcinoma, and is in agreement with the hypothesis. PMID:4855057

  6. Duration of immunity engendered by a single dose of a cold-adapted strain of Avian pneumovirus

    PubMed Central

    2006-01-01

    Abstract The duration of immunity after a single dose of a cold-adapted strain of Avian pneumovirus (APV) was studied. Turkeys were vaccinated at 1 wk of age and challenged with virulent virus 3, 7, 10, and 14 wk later. Nonvaccinated groups were also challenged at the same times. No clinical signs were observed in the vaccinated birds after vaccination or after any challenge. No viral RNA was shed by the vaccinated birds after any challenge. The nonvaccinated birds shed viral RNA after all challenges. Avian pneumovirus-specific humoral antibodies were detected in the vaccinated birds until 14 wk after vaccination. The results of this preliminary study indicate that inoculation with a single dose of a cold-adapted strain of APV at 1 wk of age provides protection until 15 wk of age. PMID:16548335

  7. Comparison of the Efficacy and Safety of Oritavancin Front-Loaded Dosing Regimens to Daily Dosing: an Analysis of the SIMPLIFI Trial ▿

    PubMed Central

    Dunbar, Lala M.; Milata, Joe; McClure, Ty; Wasilewski, Margaret M.

    2011-01-01

    Oritavancin is a novel lipoglycopeptide with demonstrated effectiveness against complicated skin and skin structure infections (cSSSI) caused by Gram-positive pathogens, including those caused by methicillin-resistant Staphylococcus aureus (MRSA). The pharmacokinetic and pharmacodynamic profile of oritavancin is favorable for single or infrequent dosing. A phase 2, multicenter, randomized, double-blind, parallel, active-comparator study (ClinicalTrials.gov identifier, NCT00514527) of single and infrequent dosing of intravenous (i.v.) oritavancin for the treatment of cSSSI caused by Gram-positive pathogens (wound infections, major abscess, and cellulitis) was undertaken to evaluate the noninferiority of front-loaded dosing regimens compared to a daily-dosing regimen. A total of 302 patients ≥18 years of age were randomized equally to one of three oritavancin treatment groups, receiving either a daily dose (200 mg) administered for 3 to 7 days, a single dose (1,200 mg), or an infrequent dose (800-mg dose, with the option for an additional 400 mg on day 5). The primary efficacy was defined as a clinical response in clinically evaluable (CE) patients assessed at days 21 to 29 (test of cure [TOC]). The cure rates in the CE population were 72.4% (55/76) in the daily-dose group, 81.5% (66/81) in the 1,200-mg-single-dose group, and 77.5% (55/71) in the infrequent-dose group. In patients with MRSA at baseline, the cure rates were 78.3% (18/23), 73.0% (27/37), and 87.0% (20/23) in the daily-, 1,200-mg-single-, and infrequent-dose groups, respectively; however, the study was not powered to assess outcomes in the MRSA subpopulation, and given the heterogeneity of the types of infection and the small sample size, these do not suggest any true differences in efficacy rates for these pathogens. The frequencies of adverse events were similar among treatment groups. The results of this study show that single- and infrequent-dosing schedules of oritavancin were as efficacious as

  8. Further studies on the hematopoietic damage produced by a single dose of T-2 toxin in mice.

    PubMed

    Faifer, G C; Zabal, O; Godoy, H M

    1992-11-01

    Previous studies revealed that a single dose of T-2 toxin produces a strong inhibition of the 59Fe incorporation into circulating erythrocytes in mice. In the present work it is shown that equivalent doses of T-2 toxin (0.30 mg/kg and above) can produce a relative depletion of granulocyte-macrophage colony-forming cells (CFU-GM) in the bone marrow of treated mice. In additional experiments, both the 59Fe uptake into erythrocytes and the bone marrow CFU-GM were measured as a function of dose and time after a single administration of T-2 toxin. It was found that the initial inhibitory effects are reverted between 24 h and 72 h and that in some cases there is even a significant increase over the normal values, indicating that there may be a compensatory activation of the hematopoietic system. The results presented here suggest that extremely small doses of T-2 toxin can produce a significant degree of bone marrow cytotoxicity and therefore even low level dietary contamination may be of concern. PMID:1462353

  9. Single-dose field bioassay for sensitivity testing in sea lice, Lepeophtheirus salmonis: development of a rapid diagnostic tool.

    PubMed

    Helgesen, K O; Horsberg, T E

    2013-03-01

    Sea lice on farmed salmonids are often treated with chemicals. Sensitivity testing of sea lice can reduce the number of treatments by identifying substances the sea lice are susceptible to. This study describes a simpler protocol for field sensitivity testing than today's six-dose bioassay. The protocol, which uses a single dose of the delousing agents deltamethrin, azamethiphos and emamectin benzoate, was developed on four different strains of sea lice and their subsequent generations. A sensitive strain and a strain showing reduced sensitivity were identified for each chemical after performing traditional bioassays and small-scale treatments. The single doses for each chemical were established by modelling dose-response curves from 24-h bioassays on strains with differences in sensitivity. The largest difference between the lower 80% prediction interval for the sensitive strain and the upper 80% prediction interval for the strain showing reduced sensitivity was identified for each delousing agent. The concentration of the chemical and the % mortality corresponding to each of the 80% prediction intervals were subsequently established. To validate the protocol for field use, further studies on both sensitive and resistant strains of sea lice under field conditions are required.

  10. H-ferritin–nanocaged doxorubicin nanoparticles specifically target and kill tumors with a single-dose injection

    PubMed Central

    Liang, Minmin; Fan, Kelong; Zhou, Meng; Duan, Demin; Zheng, Jiyan; Yang, Dongling; Feng, Jing; Yan, Xiyun

    2014-01-01

    An ideal nanocarrier for efficient drug delivery must be able to target specific cells and carry high doses of therapeutic drugs and should also exhibit optimized physicochemical properties and biocompatibility. However, it is a tremendous challenge to engineer all of the above characteristics into a single carrier particle. Here, we show that natural H-ferritin (HFn) nanocages can carry high doses of doxorubicin (Dox) for tumor-specific targeting and killing without any targeting ligand functionalization or property modulation. Dox-loaded HFn (HFn-Dox) specifically bound and subsequently internalized into tumor cells via interaction with overexpressed transferrin receptor 1 and released Dox in the lysosomes. In vivo in the mouse, HFn-Dox exhibited more than 10-fold higher intratumoral drug concentration than free Dox and significantly inhibited tumor growth after a single-dose injection. Importantly, HFn-Dox displayed an excellent safety profile that significantly reduced healthy organ drug exposure and improved the maximum tolerated dose by fourfold compared with free Dox. Moreover, because the HFn nanocarrier has well-defined morphology and does not need any ligand modification or property modulation it can be easily produced with high purity and yield, which are requirements for drugs used in clinical trials. Thus, these unique properties make the HFn nanocage an ideal vehicle for efficient anticancer drug delivery. PMID:25267615

  11. Pulmonary and Systemic Pharmacokinetics of Colistin Following a Single Dose of Nebulized Colistimethate in Mechanically Ventilated Neonates.

    PubMed

    Nakwan, Narongsak; Lertpichaluk, Pichaya; Chokephaibulkit, Kulkanya; Villani, Paola; Regazzi, Mario; Imberti, Roberto

    2015-09-01

    The purpose of this study was to evaluate the pulmonary and systemic pharmacokinetics of colistin following a single dose of nebulized colistimethate sodium (CMS) in mechanically ventilated neonates. We administered a single dose of nebulized CMS (approximately 120,000 IU/kg of CMS, equivalent to 4 mg/kg colistin base activity) to 6 ventilated neonates with ventilator-associated pneumonia. The median gestational age was 39 weeks (range, 32-39 weeks). Mean (± SD) tracheal aspirate colistin maximum concentration (Cmax), area under the concentration-time curve (AUC 0-24) and t1/2 were 24.0 ± 8.2 μg/mL, 147.6 ± 53.5 μg · hours/mL and 9.8 ± 5.5 hours, respectively. The plasma concentrations of colistin were low. In neonates, a single nebulized dose of CMS (120,000 IU) resulted in high local concentrations for at least 12 hours and low systemic concentrations of colistin. Twice daily nebulization might be more appropriate. PMID:26065861

  12. Pulmonary and Systemic Pharmacokinetics of Colistin Following a Single Dose of Nebulized Colistimethate in Mechanically Ventilated Neonates.

    PubMed

    Nakwan, Narongsak; Lertpichaluk, Pichaya; Chokephaibulkit, Kulkanya; Villani, Paola; Regazzi, Mario; Imberti, Roberto

    2015-09-01

    The purpose of this study was to evaluate the pulmonary and systemic pharmacokinetics of colistin following a single dose of nebulized colistimethate sodium (CMS) in mechanically ventilated neonates. We administered a single dose of nebulized CMS (approximately 120,000 IU/kg of CMS, equivalent to 4 mg/kg colistin base activity) to 6 ventilated neonates with ventilator-associated pneumonia. The median gestational age was 39 weeks (range, 32-39 weeks). Mean (± SD) tracheal aspirate colistin maximum concentration (Cmax), area under the concentration-time curve (AUC 0-24) and t1/2 were 24.0 ± 8.2 μg/mL, 147.6 ± 53.5 μg · hours/mL and 9.8 ± 5.5 hours, respectively. The plasma concentrations of colistin were low. In neonates, a single nebulized dose of CMS (120,000 IU) resulted in high local concentrations for at least 12 hours and low systemic concentrations of colistin. Twice daily nebulization might be more appropriate.

  13. Comparative effects of single intraperitoneal or oral doses of sodium arsenate or arsenic trioxide during in utero development.

    PubMed

    Stump, D G; Holson, J F; Fleeman, T L; Nemec, M D; Farr, C H

    1999-11-01

    Numerous studies have suggested that single-day intraperitoneal (IP) injection of inorganic arsenic results in failure of neural tube closure and other malformations in rats, hamsters, and mice. Most of these studies involved treatment of limited numbers of animals with maternally toxic doses of arsenic (generally As(V)), without defining a dose-response relationship. In the present Good Laboratory Practice-compliant study, sodium arsenate (As(V)) was administered IP and arsenic trioxide (As(III)) was administered either IP or orally (by gavage) on gestational day 9 to groups of 25 mated Crl:CD(R)(SD)BR rats. Only at dose levels that caused severe maternal toxicity, including lethality, did IP injection of arsenic trioxide produce neural tube and ocular defects; oral administration of higher doses of arsenic trioxide caused some maternal deaths but no treatment-related fetal malformations. In contrast, IP injection of similar amounts of sodium arsenate (based on the molar amount of arsenic) caused mild maternal toxicity but a large increase in malformations, including neural tube, eye, and jaw defects. In summary, neural tube and craniofacial defects were observed after IP injection of both As(V) and As(III); however, no increase in malformations was seen following oral administration of As(III), even at maternally lethal doses. These results demonstrate that the frequently cited association between prenatal exposure to inorganic arsenic and malformations in laboratory animals is dependent on a route of administration that is not appropriate for human risk assessment.

  14. Pharmacokinetics of Single-Dose Dolutegravir in HIV-Seronegative Subjects With Moderate Hepatic Impairment Compared to Healthy Matched Controls

    PubMed Central

    Song, Ivy H; Borland, Julie; Savina, Paul M; Chen, Shuguang; Patel, Parul; Wajima, Toshihiro; Peppercorn, Amanda F; Piscitelli, Stephen C

    2013-01-01

    This study evaluated dolutegravir pharmacokinetics (PK) in subjects with moderate hepatic impairment compared to matched, healthy controls. In this open-label, parallel-group study, eight adult subjects with moderate hepatic impairment (Child-Pugh Score 7–9) and eight healthy subjects matched for gender, age, and body mass index received a single dolutegravir 50-mg dose. Following dosing, 72-hour PK sampling was performed to determine total and unbound dolutegravir concentrations. PK parameters were calculated using non-compartmental analysis. Geometric least squares mean ratios (GMR) and 90% confidence intervals (CIs) in subjects with hepatic impairment versus healthy subjects were generated by analysis of variance. Results showed that PK parameters of total plasma dolutegravir were similar between subject groups. The unbound fraction was higher in subjects with moderate hepatic impairment than in healthy subjects with GMR (90% CI) of 2.20 (1.62, 2.99) for unbound fraction at 3 hours post-dose and 1.76 (1.23, 2.51) for unbound fraction at 24 hours post-dose; this correlated with lower serum albumin concentrations and was not considered clinically significant. Dolutegravir was well tolerated in both groups; all adverse events were reported as minor. Although free fraction was increased, no dose adjustment is required for patients treated with dolutegravir who have mild to moderate hepatic impairment. PMID:26097786

  15. Tolerance of young infants to a single, large dose of vitamin A: a randomized community trial in Nepal.

    PubMed

    West, K P; Khatry, S K; LeClerq, S C; Adhikari, R; See, L; Katz, J; Shrestha, S R; Pradhan, E K; Pokhrel, R P; Sommer, A

    1992-01-01

    A randomized, double-masked trial was carried out in rural Nepal to investigate the incidence and severity of acute side-effects among neonates ( < 1 month of age) and infants aged 1-6 months who received a large, oral dose of vitamin A (15,000 retinol equivalents (RE) (50,000 IU) and 30,000 RE (100,000 IU), respectively) or placebo (75 RE (250 IU) and 150 RE (500 IU), respectively) in oil. Infants (vitamin A group, n = 1461; controls, n = 1379) were assessed for vomiting, loose stools, fever, and irritability during the 24 hours before and after dosing. Fontanelles were palpated 24 hours after dosing. Neonates exhibited no excess risk of adverse side-effects after receiving 15,000 RE. Compared with controls the older infants who ingested 30,000 RE had a 1.6% excess rate of vomiting (95% confidence interval (CI): 0.2-3.0%) and a 0.5% excess rate (95% CI: -0.1 to 1.1%) in the occurrence of bulging fontanelles. There were no other significant differences in the older infants. The controlled, periodic distribution of a single 15,000 RE dose of vitamin A therefore confers no apparent acute risk to young infants; a 30,000 RE dose is associated with a minimum risk of transient, acute side-effects. PMID:1486669

  16. Hydroxychloroquine sulphate in the treatment of rheumatoid arthritis: a double blind comparison of two dose regimens.

    PubMed Central

    Pavelka, K; Sen, K P; Pelísková, Z; Vácha, J; Trnavský, K

    1989-01-01

    A controlled, double blind, parallel group, long term study of hydroxychloroquine sulphate in the treatment of rheumatoid arthritis, comparing daily doses of 200 mg and 400 mg, is described. The trial involved 54 patients with moderate disease activity who had not previously received antimalarial drugs. Forty three patients completed the one year treatment. The groups receiving different doses were homogeneous and did not differ in any of the 25 monitored indicators. Both dose regimens were effective, and a significant reduction of disease activity was observed after one year's treatment. Of the nine laboratory and 11 clinical indices of efficacy monitored, no statistically significant differences were reported, but in the group of patients treated with the 400 mg daily dose the number of side effects was three times greater. As there have been no reports of retinopathy with hydroxychloroquine at daily doses of 200 mg the effectiveness of this dose is of practical importance. PMID:2673079

  17. Comparison of structural properties of pristine and gamma irradiated single-wall carbon nanotubes: Effects of medium and irradiation dose

    SciTech Connect

    Kleut, D.; Jovanovic, S.; Markovic, Z.; Kepic, D.; Tosic, D.; Romcevic, N.; Marinovic-Cincovic, M.; Dramicanin, M.; Holclajtner-Antunovic, I.; Pavlovic, V.; Drazic, G.; Milosavljevic, M.; Todorovic Markovic, B.

    2012-10-15

    A systematic study of the gamma irradiation effects on single wall carbon nanotube (SWCNT) structure was conducted. Nanotubes were exposed to different doses of gamma irradiation in three media. Irradiation was carried out in air, water and aqueous ammonia. Thermogravimetric analysis (TGA), Fourier transform infrared spectroscopy (FTIR), elemental analysis (EA) and Raman spectroscopy confirmed the changes in the SWCNT structure. TGA measurements showed the highest percentage of introduced groups for the SWCNTs irradiated with 100 kGy. FTIR spectroscopy provided evidence for the attachment of hydroxyl, carboxyl and nitrile functional groups to the SWCNT sidewalls. Those groups were confirmed by EA. All irradiated SWCNTs had hydroxyl and carboxyl groups irrelevant to media used for irradiation, but nitrile functional groups were only identified in SWCNTs irradiated in aqueous ammonia. Raman spectroscopy indicated that the degree of disorder in the carbon nanotube structure correlates with the irradiation dose. For the nanotubes irradiated with the dose of 100 kGy, the Raman I{sub D}/I{sub G} ratio was three times higher than for the pristine ones. Atomic force microscopy showed a 50% decrease in nanotube length at a radiation dose of 100 kGy. Scanning and transmission electron microscopies showed significant changes in the morphology and structure of gamma irradiated SWCNTs. - Highlights: Black-Right-Pointing-Pointer Gamma irradiation causes SWCNT covalent functionalization. Black-Right-Pointing-Pointer Type of covalently attached groups to SWCNT surface depends on irradiation medium. Black-Right-Pointing-Pointer The SWCNT shortening level increases with applied irradiation dose. Black-Right-Pointing-Pointer The average length of carbon nanotubes decreased by 50% at the highest dose. Black-Right-Pointing-Pointer The diameter of SWCNT bundles becomes small as irradiation dose rises.

  18. Influence of Al³⁺ addition on the flocculation and sedimentation of activated sludge: comparison of single and multiple dosing patterns.

    PubMed

    Wen, Yue; Zheng, Wanlin; Yang, Yundi; Cao, Asheng; Zhou, Qi

    2015-05-15

    In this study, the flocculation and sedimentation performance of activated sludge (AS) with single and multiple dosing of trivalent aluminum (Al(3+)) were studied. The AS samples were cultivated in sequencing batch reactors at 22 °C. The dosages of Al(3+) were 0.00, 0.125, 0.5, 1.0, and 1.5 meq/L for single dosing, and 0.1 meq/L for multiple dosing. Under single dosing conditions, as Al(3+) dosage increased, the zeta potential, total interaction energy, and effluent turbidity decreased, whereas the sludge volume index (SVI) increased, indicating that single Al(3+) dosing could enhance sludge flocculation, but deteriorate sedimentation. By comparison, adding an equal amount of Al(3+) through multiple dosing achieved a similar reduction in turbidity, but the zeta potential was higher, while the loosely bound extracellular polymeric substances (LB-EPS) content and SVI remarkably declined. Although the difference in the flocculation performances between the two dosing patterns was not significant, the underlying mechanisms were quite distinct: the interaction energy played a more important role under single dosing conditions, whereas multiple dosing was more effective in reducing the EPS content. Multiple dosing, which allows sufficient time for sludge restructuring and floc aggregation, could simultaneously optimize sludge flocculation and sedimentation.

  19. A single dose of inactivated hepatitis A vaccine promotes HAV-specific memory cellular response similar to that induced by a natural infection.

    PubMed

    Melgaço, Juliana Gil; Morgado, Lucas Nóbrega; Santiago, Marta Almeida; Oliveira, Jaqueline Mendes de; Lewis-Ximenez, Lia Laura; Hasselmann, Bárbara; Cruz, Oswaldo Gonçalves; Pinto, Marcelo Alves; Vitral, Claudia Lamarca

    2015-07-31

    Based on current studies on the effects of single dose vaccines on antibody production, Latin American countries have adopted a single dose vaccine program. However, no data are available on the activation of cellular response to a single dose of hepatitis A. Our study investigated the functional reactivity of the memory cell phenotype after hepatitis A virus (HAV) stimulation through administration of the first or second dose of HAV vaccine and compared the response to that of a baseline group to an initial natural infection. Proliferation assays showed that the first vaccine dose induced HAV-specific cellular response; this response was similar to that induced by a second dose or an initial natural infection. Thus, from the first dose to the second dose, increase in the frequencies of classical memory B cells, TCD8 cells, and central memory TCD4 and TCD8 cells were observed. Regarding cytokine production, increased IL-6, IL-10, TNF, and IFNγ levels were observed after vaccination. Our findings suggest that a single dose of HAV vaccine promotes HAV-specific memory cell response similar to that induced by a natural infection. The HAV-specific T cell immunity induced by primary vaccination persisted independently of the protective plasma antibody level. In addition, our results suggest that a single dose immunization system could serve as an alternative strategy for the prevention of hepatitis A in developing countries.

  20. Distinct histopathological patterns in single lesion leprosy patients treated with single dose therapy (ROM) in the Brazilian Multicentric Study.

    PubMed

    Costa, M B; Cavalcanti Neto, P F; Martelli, C M; Stefani, M M; Maceira, J P; Gomes, M K; Schettini, A P; Rebello, P F; Pignataro, P E; Ueda, E S; Narahashi, K; Scollard, D M

    2001-09-01

    This paper aims to describe the histomorphologic features of skin biopsies of single lesion leprosy patients recruited at outpatient clinics in four Brazilian states in the Northeast (Amazonas and Rondonia), Southeast (Rio de Janeiro) and Center-West (Goiás) between October 1997 and December 1998. Patients clinically diagnosed as single skin lesion paucibacillary (SSL-PB) leprosy had a standard 4-mm punch biopsy taken from the lesion before rifampin, ofloxacin, minocycline (ROM) therapy. The features of the cellular inflammatory infiltrates, the presence of nerve involvement and acid-fast bacilli (AFB) were used to categorize SSL-PB biopsies into different histopathological groups. Two-hundred-seventy-eight (93.0%) out of 299 patients had a skin biopsy available. Seven single lesion patients were diagnosed as BL or LL leprosy types (MB) by the histopathological exams and 12 cases were excluded due to other skin diseases. Therefore, 259 patients had skin lesions with histomorphological features compatible with PB leprosy categorized as follows: 33.6% (N = 87) of the biopsies represented well-circumscribed epithelioid cell granuloma (Group 1); 21.6% (N = 56) less-circumscribed epithelioid cell granuloma (Group 2); 12.0% (N = 31) were described as mononuclear inflammatory infiltrate permeated with epithelioid cells (Group 3), and 29.7% (N = 77) had perivascular/periadnexal mononuclear inflammatory infiltrate (Group 4). Minimal/no morphological alteration in the skin was detected in only 8 (3.1%) SSL-PB patients categorized as Group 5, who were considered to have leprosy by clinical parameters. SSL-PB leprosy patients recruited in a multicentric study presented histomorphology readings comprising the whole PB leprosy spectrum but also a few MB cases. These results indicate heterogeneity among SSL-PB patients, with a predominance of well-circumscribed and less-circumscribed epithelioid cell granulomas (Groups 1 and 2) in the sites studied and the heterogeneity of local

  1. Hyperfractionation versus single dose irradiation in human acute lymphocytic leukemia cells: application to TBI for marrow transplantation.

    PubMed

    Shank, B

    1993-04-01

    A major purpose of total body irradiation (TBI) for bone marrow transplantation in leukemia patients is to help eradicate all leukemia cells; the ideal regimen has not yet been determined. To answer basic questions regarding leukemic cell survival kinetics, a human acute lymphoblastic leukemia (ALL) cell line (Reh), with the common ALL antigen (CALLA-positive), has been used to assess in vitro the efficacy of one widely used hyperfractionated TBI (HTBI) regimen versus single dose TBI (SDTBI). The regimen studied in this model was 1.2-1.25 Gy/fraction, 3 fractions/day, 5 h apart each day, for 5 days (11-12 fractions) for a total dose of 13.2-15.0 Gy. It was found that: (i) cell survival was consistent with the linear-quadratic model for early responding tissues (alpha/beta = 7.0 Gy). (ii) The change in shape of the 'effective' cell survival curve for three fractions/day was consistent with the hypothesis that there was complete repair between fractions. (iii) Cell regrowth between fractions was minimal (< or = 5%). (iv) Division delay between fractions (2.9 h/Gy) could explain the small contribution to the survival curve of regrowth between fractions. (v) For a full HTBI course to 15 Gy, cell survival was predicted to be approximately 5 x 10(-5), compared with approximately 10(-3) for a low dose rate (0.04-0.07 Gy/min) SDTBI to 10 Gy; the latter projected from the initial slope of the high dose rate, single dose survival curve. PMID:8327730

  2. Effect of a single dose of escitalopram on serotonin concentration in the non-human and human primate brain.

    PubMed

    Nord, Magdalena; Finnema, Sjoerd J; Halldin, Christer; Farde, Lars

    2013-08-01

    Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed for treatment of psychiatric disorders. The exact mechanism underlying the clinical effects of SSRIs remains unclear, although increased synaptic serotonin concentrations have been hypothesized to be an initial step. [¹¹C]AZ10419369 is a novel 5-HT(1B) receptor selective radioligand, which is sensitive to changes in endogenous serotonin concentrations. To assess whether a single dose of the SSRI escitalopram affects endogenous serotonin concentrations in serotonergic projection areas and in the raphe nuclei (RN), three cynomolgus monkeys and nine human subjects underwent PET examinations with [¹¹C]AZ10419369 at baseline conditions and after escitalopram administration. In monkeys, the binding potential (BP(ND)) was significantly lower post dose compared to baseline in dorsolateral prefrontal cortex, occipital cortex, thalamus, midbrain and RN (p < 0.05). In humans, the BP(ND) tended to decrease in RN post dose (p = 0.08). In all serotonergic projection areas, the BP(ND) was conversely higher post dose compared to baseline. The increase was significant in a combined region of all projection areas (p = 0.01) and in occipital and temporal cortex (p < 0.05). SSRIs are generally assumed to elevate endogenous serotonin concentrations in projection areas, evoking the antidepressant effect. In the present study, a single, clinically relevant, dose of escitalopram was found to decrease serotonin concentrations in serotonergic projection areas in humans. Hypothetically, desensitization of inhibitory serotonergic autoreceptors will cause the serotonin concentration in projection areas to increase over time with chronic administration. Thus, the findings in the present study might aid in understanding the mechanism of SSRIs' delayed onset of clinical effect.

  3. On the use of a single-fiber multipoint plastic scintillation detector for 192Ir high-dose-rate brachytherapy

    PubMed Central

    Therriault-Proulx, François; Beddar, Sam; Beaulieu, Luc

    2013-01-01

    Purpose: The goal of this study was to prove the feasibility of using a single-fiber multipoint plastic scintillation detector (mPSD) as an in vivo verification tool during 192Ir high-dose-rate brachytherapy treatments. Methods: A three-point detector was built and inserted inside a catheter-positioning template placed in a water phantom. A hyperspectral approach was implemented to discriminate the different optical signals composing the light output at the exit of the single collection optical fiber. The mPSD was tested with different source-to-detector positions, ranging from 1 to 5 cm radially and over 10.5 cm along the longitudinal axis of the detector, and with various integration times. Several strategies for improving the accuracy of the detector were investigated. The device's accuracy in detecting source position was also tested. Results: Good agreement with the expected doses was obtained for all of the scintillating elements, with average relative differences from the expected values of 3.4 ± 2.1%, 3.0 ± 0.7%, and 4.5 ± 1.0% for scintillating elements from the distal to the proximal. A dose threshold of 3 cGy improved the general accuracy of the detector. An integration time of 3 s offered a good trade-off between precision and temporal resolution. Finally, the mPSD measured the radioactive source positioning uncertainty to be no more than 0.32 ± 0.06 mm. The accuracy and precision of the detector were improved by a dose-weighted function combining the three measurement points and known details about the geometry of the detector construction. Conclusions: The use of a mPSD for high-dose-rate brachytherapy dosimetry is feasible. This detector shows great promise for development of in vivo applications for real-time verification of treatment delivery. PMID:23718599

  4. Pharmacokinetics of a Single Dose of Oral and Subcutaneous Meloxicam in Caribbean Flamingos ( Phoenicopterus ruber ruber).

    PubMed

    Lindemann, Dana M; Carpenter, James W; KuKanich, Butch

    2016-03-01

    To determine the pharmacokinetics of meloxicam in Caribbean flamingos ( Phoenicopterus ruber ruber), a pilot study was performed first, followed by a complete pharmacokinetic study. Four healthy birds were divided into 2 groups and administered 1 mg/kg of either oral (n = 2) or subcutaneous (n = 2) meloxicam. Plasma meloxicam concentrations were determined with liquid chromatography-mass spectrometry. Based on the pilot study results, 12 healthy birds were assigned into 2 groups and administered either 3 mg/kg PO (n = 6) or 1.5 mg/kg SC (n = 6) of meloxicam. Blood samples were collected at baseline and at 9 time intervals per group after administration of meloxicam in all flamingos. Plasma concentrations after administration of 3 mg/kg PO meloxicam reached a mean maximum plasma concentration of 1.449 μg/mL at 2.35 hours with a terminal half-life of 1.832 hours. After administration of 1.5 mg/kg SC meloxicam, maximum plasma concentration was 4.059 μg/mL at 0.91 hour with a terminal half-life of 1.104 hours. The plasma profile from the main oral study (3 mg/kg PO) differed markedly from the pilot study (1 mg/kg PO), suggesting a delayed absorption with the higher dose and lack of dose proportionality. The different doses for subcutaneous administration resulted in a proportional change in plasma concentrations. Further studies are needed to evaluate the effects of the drug volume administered and fasting status when oral dosing is used. Future studies are also needed to investigate multiple-dose pharmacokinetics of meloxicam and to determine the therapeutic meloxicam plasma concentration in Caribbean flamingos.

  5. Plasma and intraprostatic concentrations of ertapenem following preoperative single dose administration: a single-centre prospective experience and clinical implications-the ERTAPRO study.

    PubMed

    Dariane, Charles; Amin, Alexandre; Lortholary, Olivier; Lalli, Alexandre; Michel, Constance; Le Guilchet, Thomas; Treluyer, Jean-Marc; Nguyen-Khoa, Thao; De Toma, Claudia; Urien, Saïk; Méjean, Arnaud; Bourget, Philippe; Timsit, Marc-Olivier

    2016-08-01

    The incidence of urinary tract infections caused by extended-spectrum β-lactamase (ESBL)-producing pathogens is increasing. These infections are associated with a long hospital stay in patients undergoing urological procedures. We aimed to demonstrate that significant intraprostatic diffusion of ertapenem is achieved after a single preoperative administration. A referred sample of 19 patients requiring surgery for benign prostatic hyperplasia was prospectively included. Patients received a 1 g intravenous (i.v.) dose of ertapenem 1 h (n = 10, group A) or 12 h (n = 9, group B) before blood and prostatic samples were collected. Plasma and intraprostatic concentrations of ertapenem were measured using LC-MS/MS. Intraprostatic concentrations were considered satisfactory when higher than the MIC90 value of urinary-targeted pathogens perioperatively and for 40% of the dosing interval. The Wilcoxon test and a pharmacokinetic predictive model were used. Median plasma concentrations of ertapenem were 144.3 mg/L (95% CI 126.5-157.9) in group A and 30.7 mg/L (95% CI 22.9-36.4) in group B (P < 0.001); median intraprostatic concentrations were 16.6 mg/L (95% CI 13.3-31.4 mg/L) and 4.2 mg/L (95% CI 3.1-4.9 mg/L), respectively (P < 0.001), which were above the MIC90 values of bacteria, including ESBL-producers, during surgery and for 40% of the dosing interval. The plasma-to-prostate concentration ratio was not significantly different between groups (P = 0.97). Single-dose i.v. ertapenem reached satisfactory intraprostatic concentrations, suggesting that it could be a relevant prophylactic strategy for carriers of ESBL-producing bacteria undergoing prostatic procedures, which needs to be confirmed by further prospective trials. PMID:27324263

  6. SU-E-I-98: Dose Comparison for Pulmonary Embolism CT Studies: Single Energy Vs. Dual Energy

    SciTech Connect

    Mahmood, U; Erdi, Y

    2014-06-01

    Purpose: The purpose of this study was to assess and compare the size specific dose estimate (SSDE), dose length product (DLP) and noise relationship for pulmonary embolism studies evaluated by single source dual energy computed tomography (DECT) against conventional CT (CCT) studies in a busy cancer center and to determine the dose savings provided by DECT. Methods: An IRB-approved retrospective study was performed to determine the CTDIvol and DLP from a subset of patients scanned with both DECT and CCT over the past five years. We were able to identify 30 breast cancer patients (6 male, 24 female, age range 24 to 81) who had both DECT and CCT studies performed. DECT scans were performed with a GE HD 750 scanner (140/80 kVp, 480 mAs and 40 mm) and CCT scans were performed with a GE Lightspeed 16 slice scanner (120 kVp, 352 mAs, 20 mm). Image noise was measured by placing an ROI and recording the standard deviation of the mean HU along the descending aorta. Results: The average DECT patient size specific dose estimate was to be 14.2 ± 1.7 mGy as compared to 22.4 ± 2.7 mGy from CCT PE studies, which is a 37% reduction in the SSDE. The average DECT DLP was 721.8 ± 84.6 mGy-cm as compared to 981.8 ± 106.1 mGy-cm for CCT, which is a 26% decrease. Compared to CCT the image noise was found to decrease by 19% when using DECT for PE studies. Conclusion: DECT SSDE and DLP measurements indicate dose savings and image noise reduction when compared to CCT. In an environment that heavily debates CT patient doses, this study confirms the effectiveness of DECT in PE imaging.

  7. Two-fraction high-dose-rate brachytherapy within a single day combined with external beam radiotherapy for prostate cancer: single institution experience and outcomes

    PubMed Central

    Liu, Junyang; Kaidu, Motoki; Sasamoto, Ryuta; Ayukawa, Fumio; Yamana, Nobuko; Sato, Hiraku; Tanaka, Kensuke; Kawaguchi, Gen; Ohta, Atsushi; Maruyama, Katsuya; Abe, Eisuke; Kasahara, Takashi; Nishiyama, Tsutomu; Tomita, Yoshihiko; Aoyama, Hidefumi

    2016-01-01

    We investigated the outcomes of treatment for patients with localized prostate cancer (PCa) treated with 3D conformal radiation therapy (3D-CRT) followed by two-fraction high-dose-rate brachytherapy within a single day (2-fr.-HDR-BT/day) at a single institution. A total of 156 consecutive Asian males (median age, 67 years) were enrolled. To compare our findings with those of other studies, we analyzed our results using the D'Amico classification, assigning the patients to low- (n =5; 3.2%), intermediate- (n =36; 23.1%) and high-risk (n =115; 73.7%) groups (Stage T3 PCa patients were classified as high-risk). One patient in the D'Amico low-risk group (20%), 13 intermediate-risk patients (36.1%) and 99 high-risk patients (86.1%) underwent androgen deprivation therapy. We administered a prescription dose of 39 Gy in 13 fractions of 3D-CRT combined with 18 Gy of HDR-BT in two 9-Gy fractions delivered within a single day. We did not distinguish between risk groups in determining the prescription dose. The median follow-up period was 38 months. Of the 156 patients, one died from primary disease and five died from other diseases. The 3-year overall survival (OS) rates were 100%, 100% and 93.7%, and the 3-year ‘biochemical no evidence of disease (bNED)’ rates were 100%, 100% and 96.9% for the D'Amico low-, intermediate- and high-risk groups, respectively. No patient developed ≥ Grade 3 early toxicity. The Grade 3 late genitourinary toxicity rate was 2.6%, and no ≥ Grade 3 late gastrointestinal toxicity occurred. The efficacy and safety of this study were satisfactory, and longer-term follow-up is necessary. PMID:26983988

  8. Effects of Pretreatment With Single-Dose or Intermittent Oxygen on Cisplatin-Induced Nephrotoxicity in Rats

    PubMed Central

    Rasoulian, Bahram; Kaeidi, Ayat; Pourkhodadad, Soheila; Dezfoulian, Omid; Rezaei, Maryam; Wahhabaghai, Hannaneh; Alirezaei, Masoud

    2014-01-01

    Background: Renal injury is the main side effect of cisplatin (CP), an anticancer drug. It has been shown that pretreatment with single-dose oxygen (0.5 to six hours) could reduce CP-induced renal toxicity in rats. Objectives: The present study aimed to compare the effects of pretreatment with single-dose and intermittent O2 on CP-induced nephrotoxicity. Materials and Methods: Adult male rats were allocated to seven groups (eight rats in each group). The rats were kept in normal air or hyperoxic environment (O2, 80%) for either a single six-hour period or intermittent six hours per day for seven days and then were subjected to intraperitoneal injection of saline or CP (5 mg/kg) at 48 hours, 72 hours, or seven days after exposure to O2. Three days after CP (or Saline) injection, renal function tests, renal tissue injury scores, and cleaved Caspase-3 and Bax/Bcl-2 genes expression (as markers of renal cell apoptosis) were assessed. Results: Treatment with the 6-hour single-dose O2 reduced renal injury significantly when CP was administrated 48 hours after O2 pretreatment. Pretreatment with intermittent seven days of six hours per day had no protective effects and even relatively worsened renal injury when CP was injected 48 hours or 72 hours after the last session of O2 pretreatment. The beneficial effects of pretreatment with O2 on renal structure and function were seen if CP was administrates seven days after pretreatment with intermittent O2. Conclusions: The pattern of pretreatment with O2 could change this potential and highly protective strategy against CP-induced nephropathy to an ineffective or even mildly deteriorating one. Therefore, O2 administration before CP injection to patients with cancer, for therapeutic purposes or as a preconditioning approach, should be performed and investigated with caution until exact effects of different protocols has been determined in human. PMID:25695032

  9. Pharmacokinetics of oritavancin in plasma and skin blister fluid following administration of a 200-milligram dose for 3 days or a single 800-milligram dose.

    PubMed

    Fetterly, Gerald J; Ong, Christine M; Bhavnani, Sujata M; Loutit, Jeffrey S; Porter, Steven B; Morello, Lisa G; Ambrose, Paul G; Nicolau, David P

    2005-01-01

    Oritavancin is a novel glycopeptide currently being developed for the treatment of complicated skin and skin structure infections (cSSSI), including those caused by multidrug resistant gram-positive pathogens. The disposition of oritavancin in skin structures was investigated using a cantharide-induced blister fluid model. Seventeen healthy male subjects received oritavancin, but only 16 subjects were evaluated after one subject discontinued study drug. Each subject (eight per dose group) received 200 mg of oritavancin once a day for 3 days (group A) or 800 mg as one single dose (group B). Group A plasma samples and exudates from blister fluid were collected on days 3, 4, 7, 9, and 12 and on days 3, 4, 7, and 9, respectively. Group B samples and exudates were collected on days 1, 2, 5, 7, and 10 and on days 1, 2, 5, and 7, respectively. Drug concentrations were determined using a liquid chromatography-tandem mass spectrometry assay and, subsequently, pharmacokinetic analysis was performed. Differences between treatment groups in ratios for area under the concentration-time curve for blister fluid and plasma (AUC(blister fluid)/AUC(plasma) ratios) were evaluated using a t test (alpha = 0.05). Mean maximum concentration of drug in plasma or blister fluid was approximately 8-fold and 11-fold higher in plasma than in blister fluid following the 200- or 800-mg doses of oritavancin, respectively. Mean AUC(blister fluid)/AUC(plasma) ratios at 24 h were 0.190 (standard deviation [SD], 0.052) and 0.182 (SD, 0.062) for groups A and B, respectively (P = 0.791). To place these results in a clinical context, mean drug concentrations in blister fluid exceed the oritavancin MIC at which 90% of strains are inhibited of Staphylococcus aureus (2 microg/ml) by approximately 2- to 5.5-fold at 12 h and 1.5- to 3-fold at 24 h following administration of both dosing regimens. These results support the potential use of oritavancin for the treatment of cSSSI.

  10. A Thorough QTc Study Confirms Early Pharmacokinetics/QTc Modeling: A Supratherapeutic Dose of Omarigliptin, a Once-Weekly DPP-4 Inhibitor, Does Not Prolong the QTc Interval.

    PubMed

    Tatosian, Daniel A; Cardillo Marricco, Nadia; Glasgow, Xiaoli Shirley; DeGroot, Bruce; Dunnington, Katherine; George, Laura; Gendrano, Isaias Noel; Johnson-Levonas, Amy O; Swearingen, Dennis; Kauh, Eunkyung

    2016-09-01

    Omarigliptin is a dipeptidyl peptidase-4 inhibitor being developed as a once-weekly treatment for type 2 diabetes. This double-blind, double-dummy, randomized, 3-period balanced crossover study definitively evaluated the effects of a supratherapeutic omarigliptin dose on QTc interval. Population-specific correction of QT interval (QTcP) was used for the primary analysis. Healthy subjects (n = 60) were enrolled and received treatments separated by a ≥4-week washout: (1) single-dose 25 mg omarigliptin (day 1), single-dose 175 mg omarigliptin (day 2); (2) placebo (day 1) followed by single-dose 400 mg moxifloxacin (day 2); (3) placebo (days 1 and 2). Day 2 QTcP intervals were analyzed. The primary hypothesis was supported if the 90%CIs for the least-squares mean differences between omarigliptin 175 mg and placebo in QTcP interval change from baseline were all < 10 milliseconds at every postdose point on day 2. The upper bounds of the 90%CIs for the differences (omarigliptin-placebo) in QTcP change from baseline for omarigliptin 175 mg were < 10 milliseconds at all postdose times on day 2. In conclusion, a supratherapeutic dose of omarigliptin does not prolong the QTcP interval to a clinically meaningful degree relative to placebo, confirming the results of the earlier concentration-QTc analysis. PMID:27627194

  11. Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria

    PubMed Central

    Charman, Susan A.; Arbe-Barnes, Sarah; Bathurst, Ian C.; Brun, Reto; Campbell, Michael; Charman, William N.; Chiu, Francis C. K.; Chollet, Jacques; Craft, J. Carl; Creek, Darren J.; Dong, Yuxiang; Matile, Hugues; Maurer, Melanie; Morizzi, Julia; Nguyen, Tien; Papastogiannidis, Petros; Scheurer, Christian; Shackleford, David M.; Sriraghavan, Kamaraj; Stingelin, Lukas; Tang, Yuanqing; Urwyler, Heinrich; Wang, Xiaofang; White, Karen L.; Wittlin, Sergio; Zhou, Lin; Vennerstrom, Jonathan L.

    2011-01-01

    Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC50 values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, OZ439 completely cures Plasmodium berghei-infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-containing antimalarial agents, such as the artemisinin derivatives and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concentration versus time profile in three preclinical species. The outstanding efficacy and prolonged blood concentrations of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death. PMID:21300861

  12. Effects of Age, Sex, and Obesity on the Single-Dose Pharmacokinetics of Omarigliptin in Healthy Subjects.

    PubMed

    Addy, Carol; Tatosian, Daniel A; Glasgow, Xiaoli S; Iii, Isaias Noel Gendrano; Sisk, Christine McCrary; Kauh, Eunkyung A; Stoch, S Aubrey; Wagner, John A

    2016-09-01

    Omarigliptin is being developed as a potent, once-weekly, oral dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes. This double-blind, randomized, placebo-controlled study evaluated the effects of age, sex, and obesity on the pharmacokinetics of omarigliptin in healthy subjects. A single oral dose of omarigliptin 10 mg (n = 6/panel) or placebo (n = 2/panel) was administered in the fasted state to elderly nonobese men and women, young obese (30 ≤ body mass index [BMI] ≤ 35 kg/m(2) ) men and women, and young nonobese women of nonchildbearing potential. Plasma was collected at selected postdose times for evaluation of omarigliptin concentrations. Pharmacokinetic parameters were compared with historical data from a previously-conducted single-dose study in young, healthy, nonobese men. There were no clinically significant differences in omarigliptin AUC0-∞ , the primary pharmacokinetic parameter for assessing efficacy and safety, based on age, sex, or BMI (pooled nonobese elderly versus pooled nonobese young, young nonobese female versus young nonobese male, and pooled young obese versus pooled young nonobese). There were no serious adverse events or hypoglycemic events attributable to omarigliptin administration. Demographic factors and BMI had no meaningful effect on omarigliptin pharmacokinetics, suggesting that dose adjustment based on age, sex, or obesity is not required. PMID:27627193

  13. Synthetic ozonide drug candidate OZ439 offers new hope for a single-dose cure of uncomplicated malaria.

    PubMed

    Charman, Susan A; Arbe-Barnes, Sarah; Bathurst, Ian C; Brun, Reto; Campbell, Michael; Charman, William N; Chiu, Francis C K; Chollet, Jacques; Craft, J Carl; Creek, Darren J; Dong, Yuxiang; Matile, Hugues; Maurer, Melanie; Morizzi, Julia; Nguyen, Tien; Papastogiannidis, Petros; Scheurer, Christian; Shackleford, David M; Sriraghavan, Kamaraj; Stingelin, Lukas; Tang, Yuanqing; Urwyler, Heinrich; Wang, Xiaofang; White, Karen L; Wittlin, Sergio; Zhou, Lin; Vennerstrom, Jonathan L

    2011-03-15

    Ozonide OZ439 is a synthetic peroxide antimalarial drug candidate designed to provide a single-dose oral cure in humans. OZ439 has successfully completed Phase I clinical trials, where it was shown to be safe at doses up to 1,600 mg and is currently undergoing Phase IIa trials in malaria patients. Herein, we describe the discovery of OZ439 and the exceptional antimalarial and pharmacokinetic properties that led to its selection as a clinical drug development candidate. In vitro, OZ439 is fast-acting against all asexual erythrocytic Plasmodium falciparum stages with IC(50) values comparable to those for the clinically used artemisinin derivatives. Unlike all other synthetic peroxides and semisynthetic artemisinin derivatives, OZ439 completely cures Plasmodium berghei-infected mice with a single oral dose of 20 mg/kg and exhibits prophylactic activity superior to that of the benchmark chemoprophylactic agent, mefloquine. Compared with other peroxide-containing antimalarial agents, such as the artemisinin derivatives and the first-generation ozonide OZ277, OZ439 exhibits a substantial increase in the pharmacokinetic half-life and blood concentration versus time profile in three preclinical species. The outstanding efficacy and prolonged blood concentrations of OZ439 are the result of a design strategy that stabilizes the intrinsically unstable pharmacophoric peroxide bond, thereby reducing clearance yet maintaining the necessary Fe(II)-reactivity to elicit parasite death. PMID:21300861

  14. Cellular Inflammatory Infiltrate in Pneumonitis Induced by a Single Moderate Dose of Thoracic X Radiation in Rats

    PubMed Central

    Szabo, Sara; Ghosh, Swarajit N.; Fish, Brian L.; Bodiga, Sreedhar; Tomic, Rade; Kumar, Gagan; Morrow, Natalya V.; Moulder, John E.; Jacobs, Elizabeth R.; Medhora, Meetha

    2010-01-01

    The goal of these studies was to characterize the infiltrating inflammatory cells during pneumonitis caused by moderate doses of radiation. Two groups of male rats (WAG/RijCmcr, 8 weeks old) were treated with single 10- or 15-Gy doses of thoracic X radiation; a third group of age-matched animals served as controls. Only 25% rats survived the 15-Gy dose. Bronchoalveolar lavage fluid and whole lung mounts were subjected to cytological and histological evaluation after 8 weeks for distribution of resident macrophages, neutrophils, lymphocytes and mast cells. There was a modest increase in airway and airspace-associated neutrophils in lungs from rats receiving 15 Gy. Mast cells (detected by immunohistochemistry for tryptase) increased over 70% with 10 Gy and over 13-fold after 15 Gy, with considerable leakage of tryptase into blood vessels and airways. Circulating levels of eight inflammatory cytokines were not altered after 10 Gy but appeared to decrease after 15 Gy. In summary, there were only modest increases in cellular inflammatory infiltrate during pneumonitis after a non-lethal dose of 10 Gy, but there was a dramatic rise in mast cell infiltration after 15 Gy, suggesting that circulating levels of mast cell products may be useful markers of severe pneumonitis. PMID:20334527

  15. Substance P-induced skin inflammation is not modulated by a single dose of sitagliptin in human volunteers.

    PubMed

    Grouzmann, Eric; Bigliardi, Paul; Appenzeller, Monique; Pannatier, André; Buclin, Thierry

    2011-03-01

    Substance P (SP), an undecapeptide belonging to the tachykinin family, is released during the activation of sensory nerves, and causes vasodilation, edema and pain through activation of tissular Neurokinin 1 receptors. SP proinflammatory effects are terminated by angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), while the aminopeptidase dipeptidylpeptidase IV (DPPIV) can also play a role. The aim of this randomized, crossover, double-blind study was to assess the cutaneous vasoreactivity (flare and wheal reaction, burning pain sensation) to intradermal injection of ascending doses of SP in six volunteers receiving a single therapeutic dose of the DPPIV inhibitor sitagliptin or a matching placebo. Cutaneous SP challenges produced the expected, dose-dependent flare and wheal response, while eliciting mild to moderate local pain sensation with little dose dependency. However, no differences were shown in the responses observed under sitagliptin compared with placebo, while the study would have been sufficiently powered to detect a clinically relevant increase in sensitivity to SP. The results of this pilot study are in line with proteolytic cleavage of SP by ACE and NEP compensating the blockade of DPPIV to prevent an augmentation of its proinflammatory action.

  16. Single and 14-day repeated dose inhalation toxicity studies of hexabromocyclododecane in rats.

    PubMed

    Song, Naining; Li, Lei; Li, Haishan; Ai, Wenchao; Xie, Wenping; Yu, Wenlian; Liu, Wei; Wang, Cheng; Shen, Guolin; Zhou, Lili; Wei, Changlei; Li, Dong; Chen, Huiming

    2016-05-01

    Limited toxicological information is available for hexabromocyclododecane (HBCD),a widely used additive brominated flame retardant. Inhalation is a major route of human exposure to HBCD. The aim of this study was to determine the acute inhalation toxicity and potential subchronic inhalation toxicity of HBCD in Sprague-Dawley rats exposed to HBCD only through inhalation. The acute inhalation toxicity of HBCD was determined using the limit test method on five male and five female Sprague-Dawley rats at a HBCD concentration of 5000 mg/m(3). Repeated-dose toxicity tests were also performed, with 20 males and 20 females randomly assigned to four experimental groups (five rats of each sex in each group). There were three treatment groups (exposed to HBCD concentrations of 125,500, and 2000 mg/m(3)) and a blank control group (exposed to fresh air). In the acute inhalation toxicity study, no significant clinical signs were observed either immediately after exposure or during the recovery period. Gross pathology examination revealed no evidence of organ-specific toxicity in any rat. The inhalation LC50(4 h) for HBCD was higher than 5312 ± 278 mg/m3 for both males and females. In the repeated dose inhalation study, daily head/nose-only exposure to HBCD at 132 ± 8.8, 545.8 ± 35.3, and 2166.0 ± 235.9 mg/m(3) for 14 days caused no adverse effects. No treatment-related clinical signs were observed at any of the test doses. The NOAEL for 14-day repeated dose inhalation toxicity study of HBCD is 2000 mg/m(3). PMID:26929994

  17. The influence of frame alignment with dose compensation on the quality of single particle reconstructions.

    PubMed

    Spear, John M; Noble, Alex J; Xie, Qing; Sousa, Duncan R; Chapman, Michael S; Stagg, Scott M

    2015-11-01

    As direct electron detection devices in cryo-electron microscopy become ubiquitous, the field is now ripe for new developments in image analysis techniques that take advantage of their increased SNR coupled with their high-throughput frame collection abilities. In approaching atomic resolution of native-like biomolecules, the accurate extraction of structural locations and orientations of side-chains from frames depends not only on the electron dose that a sample receives but also on the ability to accurately estimate the CTF. Here we use a new 2.8Å resolution structure of a recombinant gene therapy virus, AAV-DJ with Arixtra, imaged on an FEI Titan Krios with a DE-20 direct electron detector to probe new metrics including relative side-chain density and ResLog analysis for optimizing the compensation of electron beam damage and to characterize the factors that are limiting the resolution of the reconstruction. The influence of dose compensation on the accuracy of CTF estimation and particle classifiability are also presented. We show that rigorous dose compensation allows for better particle classifiability and greater recovery of structural information from negatively charged, electron-sensitive side-chains, resulting in a more accurate macromolecular model.

  18. Comparative Metabolism Studies of Hexabromocyclododecane (HBCD) Diastereomers in Male Rats Following a Single Oral Dose.

    PubMed

    Hakk, Heldur

    2016-01-01

    Male Sprague-Dawley rats were dosed orally with 3 mg/kg of one of three hexabromocyclododecane (HBCD) diastereomers. Each diastereomer was well absorbed (73-83%), and distributed preferentially to lipophilic tissues. Feces were the major route of excretion; cumulatively accounting for 42% of dose for α-HBCD, 59% for ß-HBCD, and 53% for γ-HBCD. Urine was also an important route of HBCD excretion, accounting for 13% of dose for α-HBCD, 30% for ß-HBCD, and 21% for γ-HBCD. Total metabolism of HBCD diastereomers followed the rank order ß > γ > α, and was >65% of that administered. The metabolites formed were distinct in male rats: α-HBCD did not debrominate or stereoisomerize, but formed two hydroxylated metabolites; ß- and γ-HBCD were both extensively metabolized via pathways of stereoisomerization, oxidation, dehydrogenation, reductive debromination, and ring opening. ß-HBCD was biotransformed to two mercapturic acid pathway metabolites. The metabolites of ß- and γ-HBCD were largely distinct, and could possibly be used as markers of exposure. These isomer-specific data suggest that α-HBCD would be the most dominant HBCD diastereomer in biological tissues because it was metabolized to the lowest degree and also accumulated from the stereoisomerization of the β- and γ- diastereomers. PMID:26629593

  19. The influence of frame alignment with dose compensation on the quality of single particle reconstructions.

    PubMed

    Spear, John M; Noble, Alex J; Xie, Qing; Sousa, Duncan R; Chapman, Michael S; Stagg, Scott M

    2015-11-01

    As direct electron detection devices in cryo-electron microscopy become ubiquitous, the field is now ripe for new developments in image analysis techniques that take advantage of their increased SNR coupled with their high-throughput frame collection abilities. In approaching atomic resolution of native-like biomolecules, the accurate extraction of structural locations and orientations of side-chains from frames depends not only on the electron dose that a sample receives but also on the ability to accurately estimate the CTF. Here we use a new 2.8Å resolution structure of a recombinant gene therapy virus, AAV-DJ with Arixtra, imaged on an FEI Titan Krios with a DE-20 direct electron detector to probe new metrics including relative side-chain density and ResLog analysis for optimizing the compensation of electron beam damage and to characterize the factors that are limiting the resolution of the reconstruction. The influence of dose compensation on the accuracy of CTF estimation and particle classifiability are also presented. We show that rigorous dose compensation allows for better particle classifiability and greater recovery of structural information from negatively charged, electron-sensitive side-chains, resulting in a more accurate macromolecular model. PMID:26391007

  20. Pharmacokinetics of a single intravenous dose of marbofloxacin in adult donkeys.

    PubMed

    González, F; Rodríguez, C; De Lucas, J J; Waxman, S; San Andrés, M D; Serres, C; Nieto, J; San Andrés, M I

    2007-07-28

    Six donkeys each received 2 mg/kg marbofloxacin as a 10 per cent aqueous solution administered intravenously. Principal pharmacokinetic parameters were determined and two efficacy indices were computed by using pharmacokinetic parameters and selected mic90 values of marbofloxacin against pathogenic equine strains to predict the efficacy of the drug at this dose. The pharmacokinetics of marbofloxacin in donkeys was characterised by a large mean volume of distribution at a steady state (1.15 [0.09] l/kg) and a long mean (sd) elimination half-life of 9.24 (1.96) hours. It was also characterised by a relatively slow total body clearance of 0.10 (0.02) l/kg/hour, slower than in horses. Using mic90 values of marbofloxacin against pathogenic equine strains with a daily dose of 2 mg/kg, appropriate values of efficacy indicators were obtained only for Enterobacteriaceae. Daily intravenous doses of 0.33, 2.62 and 20 mg/kg were calculated for evaluation in clinical trials of infections due to Enterobacteriaceae, Staphylococcus aureus and Streptococci, respectively.

  1. Human metabolism and excretion kinetics of aniline after a single oral dose.

    PubMed

    Modick, Hendrik; Weiss, Tobias; Dierkes, Georg; Koslitz, Stephan; Käfferlein, Heiko Udo; Brüning, Thomas; Koch, Holger Martin

    2016-06-01

    Aniline is an important source material in the chemical industry (e.g., rubber, pesticides, and pharmaceuticals). The general population is known to be ubiquitously exposed to aniline. Thus, assessment of aniline exposure is of both occupational and environmental relevance. Knowledge on human metabolism of aniline is scarce. We orally dosed four healthy male volunteers (two fast and two slow acetylators) with 5 mg isotope-labeled aniline, consecutively collected all urine samples over a period of 2 days, and investigated the renal excretion of aniline and its metabolites by LS-MS/MS and GC-MS. After enzymatic hydrolysis of glucuronide and sulfate conjugates, N-acetyl-4-aminophenol was the predominant urinary aniline metabolite representing 55.7-68.9 % of the oral dose, followed by the mercapturic acid conjugate of N-acetyl-4-aminophenol accounting for 2.5-6.1 %. Acetanilide and free aniline were found only in minor amounts accounting for 0.14-0.36 % of the dose. Overall, these four biomarkers excreted in urine over 48 h post-dose represented 62.4-72.1 % of the oral aniline dose. Elimination half-times were 3.4-4.3 h for N-acetyl-4-aminophenol, 4.1-5.5 h for the mercapturic acid conjugate, and 1.3-1.6 and 0.6-1.2 h for acetanilide and free aniline, respectively. Urinary maximum concentrations of N-acetyl-4-aminophenol were reached after about 4 h and maximum concentrations of the mercapturic acid conjugate after about 6 h, whereas concentrations of acetanilide and free aniline peaked after about 1 h. The present study is one of the first to provide reliable urinary excretion factors for aniline and its metabolites in humans after oral dosage, including data on the predominant urinary metabolite N-acetyl-4-aminophenol, also known as an analgesic under the name paracetamol/acetaminophen.

  2. Human metabolism and excretion kinetics of aniline after a single oral dose.

    PubMed

    Modick, Hendrik; Weiss, Tobias; Dierkes, Georg; Koslitz, Stephan; Käfferlein, Heiko Udo; Brüning, Thomas; Koch, Holger Martin

    2016-06-01

    Aniline is an important source material in the chemical industry (e.g., rubber, pesticides, and pharmaceuticals). The general population is known to be ubiquitously exposed to aniline. Thus, assessment of aniline exposure is of both occupational and environmental relevance. Knowledge on human metabolism of aniline is scarce. We orally dosed four healthy male volunteers (two fast and two slow acetylators) with 5 mg isotope-labeled aniline, consecutively collected all urine samples over a period of 2 days, and investigated the renal excretion of aniline and its metabolites by LS-MS/MS and GC-MS. After enzymatic hydrolysis of glucuronide and sulfate conjugates, N-acetyl-4-aminophenol was the predominant urinary aniline metabolite representing 55.7-68.9 % of the oral dose, followed by the mercapturic acid conjugate of N-acetyl-4-aminophenol accounting for 2.5-6.1 %. Acetanilide and free aniline were found only in minor amounts accounting for 0.14-0.36 % of the dose. Overall, these four biomarkers excreted in urine over 48 h post-dose represented 62.4-72.1 % of the oral aniline dose. Elimination half-times were 3.4-4.3 h for N-acetyl-4-aminophenol, 4.1-5.5 h for the mercapturic acid conjugate, and 1.3-1.6 and 0.6-1.2 h for acetanilide and free aniline, respectively. Urinary maximum concentrations of N-acetyl-4-aminophenol were reached after about 4 h and maximum concentrations of the mercapturic acid conjugate after about 6 h, whereas concentrations of acetanilide and free aniline peaked after about 1 h. The present study is one of the first to provide reliable urinary excretion factors for aniline and its metabolites in humans after oral dosage, including data on the predominant urinary metabolite N-acetyl-4-aminophenol, also known as an analgesic under the name paracetamol/acetaminophen. PMID:26233686

  3. Differential sensitivity of two predominant stromal progenitor cell subpopulations in bone marrow to single and fractionated radiation doses

    SciTech Connect

    Kolesnikova, A.I.; Konoplyannikov, A.G.; Hendry, J.H.

    1995-12-01

    The sensitivity of fibroblastoid precursor cells in rat bone marrow to single and fractionated doses of {gamma} rays delivered in vivo was measured. In vitro colonies were classified as being compact or diffuse, and the progenitor cells for both types were slowly cycling in vivo (survival levels after exposure to hydroxyurea were 90 {+-} 6% and 93 {+-} 11%, respectively). The progenitor cells forming diffuse colonies were more resistant (D{sub o} = 1.39 Gy) than those forming compact colonies (D{sub o} = 0.76 Gy). The fractionation sensitivities were characterized by an {alpha}/{beta} ratio of 12.7 {+-} 5.5 Gy for diffuse colonies and 4.5 {+-} 3.0 Gy for compact colonies, respectively. The progenitor cells forming diffuse colonies may contribute more to long-term regeneration after high doses in vivo. 15 refs., 2 figs., 1 tab.

  4. Efficacy of a single dose of mebendazole on prevalence and intensity of soil-transmitted nematodes in Zanzibar.

    PubMed

    Albonico, M; Renganathan, E; Bosman, A; Kisumku, U M; Alawi, K S; Savioli, L

    1994-01-01

    The efficacy of a single-dose of mebendazole to treat intestinal helminths was studied in Pemba Island, Zanzibar, with the view of incorporating it in future control programmes. A single Kato-Katz stool examination was performed on 2,269 individuals from all age groups. 1,883 individuals were treated with 500 mg of mebendazole (250 mg for children below two years) and re-examined one month and four months after therapy. A total of 466 presented themselves for all three surveys and the data has been reported in this study. The overall cure rate for ascariasis was 93.2% and reduction of egg load after treatment was 89.8% in persistent positive cases. Although the cure rates were lower in trichuriasis (25.6%) and hookworm (17.8%) infections, egg reduction was more evident with 47% for Trichuris trichiura and 51.9% for hookworms. A single dose of mebendazole results not only in a high cure rate for ascariasis but also in a decrease in intensity of ascariasis, trichuriasis and hookworm infections, thereby contributing to its incorporation into low-budget control programmes in developing countries.

  5. Dose response studies of bevantolol in hypertensive patients.

    PubMed

    Okawa, K K

    1986-03-01

    This multicenter study, conducted to determine the antihypertensive efficacy of bevantolol at different fixed doses compared with placebo was carried out at four separate institutions using a common protocol. One hundred thirty-nine patients with mild to moderate essential hypertension were enrolled. At doses of 200 to 400 mg/day bevantolol was clearly effective in lowering diastolic blood pressure and in maintaining this effect over the eight weeks of this double-blind study. Twice a day dosing is indicated since efficacy was evident 12 hours post-dosing. Bevantolol was well tolerated.

  6. Treatment of uncomplicated gonococcal urethritis by double-dosing of 200 mg cefixime at a 6-h interval.

    PubMed

    Deguchi, Takashi; Yasuda, Mitsuru; Yokoi, Shigeaki; Ishida, Ken-Ichiro; Ito, Masayasu; Ishihara, Satoshi; Minamidate, Ken; Harada, Yoshimasa; Tei, Kanhin; Kojima, Kentaro; Tamaki, Masayoshi; Maeda, Shin-Ichi

    2003-03-01

    The efficacy of antimicrobial regimens for the treatment of uncomplicated gonococcal urethritis depends partially upon the period of time (therapeutic time) during which the drug concentration in the blood after the concentration peak is greater than four times the minimum inhibitory concentration for 90% of clinical isolates of Neisseria gonorrhoeae (MIC(90)). A therapeutic time of at least 10 h is suggested as an important determinant for elimination of 95% or more of the infection. In this study, therapeutic times for a single 400-mg dose of cefixime at various MIC(90)s were calculated, and pharmacokinetic profiles of double-dosing of 200 mg cefixime at various intervals were simulated. Subsequently, a dosing interval of 6 h was tested in 6 healthy Japanese men, and then 93 Japanese men with gonococcal urethritis were treated with a regimen of two 200-mg doses of cefixime given at a 6-h interval. For a single dose of 400 mg cefixime, therapeutic times were calculated to be 12.8, 9.1, 5.4, and 1.7 h for MIC(90)s of 0.06, 0.125, 0.25, and 0.5 microg/ml, respectively. In the simulation study of double-dosing of 200 mg cefixime at a 6-h interval, the therapeutic times for the MIC(90)s of < or =0.125 microg/ml were longer than 10 h. Of the 93 patients, 68 were evaluated for microbiological outcome, and N. gonorrhoeae was eradicated in 60 (88.2%). The MIC(90) of cefixime for the 61 isolates tested was 0.125 microg/ml. All strains with MICs of < or =0.06 microg/ml were eradicated, whereas 8 of 16 strains with MICs of > or =0.125 microg/ml persisted after treatment. This regimen would not be effective against infection by strains exhibiting cefixime MIC(90)s of > or =0.125 microg/ml. For such strains, a different regimen with a higher dose of cefixime would be required.

  7. Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy

    PubMed Central

    Naviaux, J C; Schuchbauer, M A; Li, K; Wang, L; Risbrough, V B; Powell, S B; Naviaux, R K

    2014-01-01

    Autism spectrum disorders (ASDs) now affect 1–2% of the children born in the United States. Hundreds of genetic, metabolic and environmental factors are known to increase the risk of ASD. Similar factors are known to influence the risk of schizophrenia and bipolar disorder; however, a unifying mechanistic explanation has remained elusive. Here we used the maternal immune activation (MIA) mouse model of neurodevelopmental and neuropsychiatric disorders to study the effects of a single dose of the antipurinergic drug suramin on the behavior and metabolism of adult animals. We found that disturbances in social behavior, novelty preference and metabolism are not permanent but are treatable with antipurinergic therapy (APT) in this model of ASD and schizophrenia. A single dose of suramin (20 mg kg−1 intraperitoneally (i.p.)) given to 6-month-old adults restored normal social behavior, novelty preference and metabolism. Comprehensive metabolomic analysis identified purine metabolism as the key regulatory pathway. Correction of purine metabolism normalized 17 of 18 metabolic pathways that were disturbed in the MIA model. Two days after treatment, the suramin concentration in the plasma and brainstem was 7.64 μM pmol μl−1 (±0.50) and 5.15 pmol mg−1 (±0.49), respectively. These data show good uptake of suramin into the central nervous system at the level of the brainstem. Most of the improvements associated with APT were lost after 5 weeks of drug washout, consistent with the 1-week plasma half-life of suramin in mice. Our results show that purine metabolism is a master regulator of behavior and metabolism in the MIA model, and that single-dose APT with suramin acutely reverses these abnormalities, even in adults. PMID:24937094

  8. Evaluation of continuous low dose rate versus acute single high dose rate radiation combined with oncolytic viral therapy for prostate cancer

    PubMed Central

    LIU, CHUNYAN; ZHANG, YONGGANG; LIU, MINZHI MAGGIE; ZHOU, HAOMING; CHOWDHURY, WASIM H.; LUPOLD, SHAWN E.; DEWEESE, TED L.; RODRIGUEZ, RONALD

    2011-01-01

    Purpose Conditionally Replicative Adenovirus (CRAd) has been previously demonstrated to augment the activity of radiation, resulting in synergy of cell kill. However, previous models combining radiation with CRAd have not focused on the methods of radiation delivery. Materials and methods We model the combination of a novel prostate-specific CRAd, Ad5 PSE/PBN E1A-AR (Ad5: adenovirus 5; PSE: prostate-specific enhancer; PBN: rat probasin promoter; E1A: early region 1A; AR: androgen receptor), with radiation delivered both acutely and continuously, in an effort to better mimic the potential clinical modes of prostate cancer radiotherapy. Results We demonstrate that pre-treatment of cells with acute single high dose rate (HDR) radiation 24 hours prior to viral infection results in significantly enhanced viral replication and virus-mediated cell death. In addition, this combination causes increased level of γ-H2AX (Phosphorylated histone protein H2AX on serine 139), a marker of double-stranded DNA damage and an indirect measure of nuclear fragmentation. In contrast, continuous low dose rate (LDR) radiation immediately following infection of the same CRAd results in no enhancement of viral replication, and only additive effects in virus-mediated cell death. Conclusions These data provide the first direct assessment of the real-time impact of radiation on viral replication and the first comparison of the effect of radiation delivery on the efficacy of CRAd virotherapy. Our data demonstrate substantial differences in CRAd efficacy based on the mode of radiation delivery. PMID:20201650

  9. Preclinical Study of Single-Dose Moxidectin, a New Oral Treatment for Scabies: Efficacy, Safety, and Pharmacokinetics Compared to Two-Dose Ivermectin in a Porcine Model

    PubMed Central

    Bernigaud, Charlotte; Aho, Ludwig Serge; Dreau, Dominique; Kelly, Andrew; Sutra, Jean-François; Moreau, Francis; Lilin, Thomas; Botterel, Françoise; Guillot, Jacques; Chosidow, Olivier

    2016-01-01

    Background Scabies is one of the commonest dermatological conditions globally; however it is a largely underexplored and truly neglected infectious disease. Foremost, improvement in the management of this public health burden is imperative. Current treatments with topical agents and/or oral ivermectin (IVM) are insufficient and drug resistance is emerging. Moxidectin (MOX), with more advantageous pharmacological profiles may be a promising alternative. Methodology/Principal Findings Using a porcine scabies model, 12 pigs were randomly assigned to receive orally either MOX (0.3 mg/kg once), IVM (0.2 mg/kg twice) or no treatment. We evaluated treatment efficacies by assessing mite count, clinical lesions, pruritus and ELISA-determined anti-S. scabiei IgG antibodies reductions. Plasma and skin pharmacokinetic profiles were determined. At day 14 post-treatment, all four MOX-treated but only two IVM-treated pigs were mite-free. MOX efficacy was 100% and remained unchanged until study-end (D47), compared to 62% (range 26–100%) for IVM, with one IVM-treated pig remaining infected until D47. Clinical scabies lesions, pruritus and anti-S. scabiei IgG antibodies had completely disappeared in all MOX-treated but only 75% of IVM-treated pigs. MOX persisted ~9 times longer than IVM in plasma and skin, thereby covering the mite’s entire life cycle and enabling long-lasting efficacy. Conclusions/Significance Our data demonstrate that oral single-dose MOX was more effective than two consecutive IVM-doses, supporting MOX as potential therapeutic approach for scabies. PMID:27732588

  10. Central nervous system effects of the interaction between risperidone (single dose) and the 5-HT6 antagonist SB742457 (repeated doses) in healthy men

    PubMed Central

    Liem-Moolenaar, Marieke; Rad, Mandana; Zamuner, Stefano; Cohen, Adam F; Lemme, Francesca; Franson, Kari L; van Gerven, Joop M A; Pich, Emilio Merlo

    2011-01-01

    AIM Several lines of evidence suggest a possible role of 5-HT6receptor antagonists in cognitive dysfunction of schizophrenia. Atypical antipsychotics, such as risperidone, are currently used in these disorders. Therefore, the pharmacological interactions between the 5-HT6 antagonist SB-742457 and risperidone were investigated in the light of possible co-medication. METHODS A randomized, double-blind, two-way crossover design was used to study the interaction between multiple doses SB-742457 50 mg and a single dose risperidone 2 mg in 18 healthy subjects. RESULTS Treatment was well tolerated. The most common adverse event was somnolence in 83% during the combination vs. 50% of subjects after risperidone, 32% after placebo and 11% after SB-742457. Combination treatment produced a statistically significant increase in the maximum plasma concentration of risperidone and had no effect on SB-742457 pharmacokinetics. Risperidone decreased saccadic peak velocity, finger tapping, adaptive tracking, subjective alertness, delayed word recognition and body sway and increased electroencephalogram (EEG) theta power and prolactin. The only pharmacodynamic interaction of risperidone and SB-742457 was an increase of absolute EEG alpha (ratio = 1.25, 95% CI = 1.11, 1.40, P = 0.0004) and beta power (ratio = 1.14, 95% CI = 1.03, 1.27, P = 0.016). No significant effects of SB-742457 alone were found. CONCLUSION The pharmacokinetic interactions between SB-742457 and risperidone detected in this study were not clinically relevant. The increase in EEG alpha and beta power is incompatible with enhanced risperidone activity, but could point to mild arousing effects of the combination. Most pharmacodynamic changes of risperidone are consistent with previously reported data. The potential cognitive effects of SB-742457 remain to be established. PMID:21223356

  11. Rizatriptan, a novel 5-HT1B/1D agonist for migraine: single- and multiple-dose tolerability and pharmacokinetics in healthy subjects.

    PubMed

    Goldberg, M R; Lee, Y; Vyas, K P; Slaughter, D E; Panebianco, D; Ermlich, S J; Shadle, C R; Brucker, M J; McLoughlin, D A; Olah, T V

    2000-01-01

    Rizatriptan is a novel 5-HT1D/1B agonist for relief of migraine headache. The pharmacokinetics, metabolite profiles, and tolerability of rizatriptan were examined in a multiple-dose study in healthy subjects. Rizatriptan (N = 24) (or placebo, N = 12) was administered as a single 10 mg dose, followed 48 hours later by administration of one 10 mg dose every 2 hours for three doses on 4 consecutive days, corresponding to the maximum daily dose for a migraine attack. The AUC of rizatriptan and its active N-monodesmethyl metabolite after three 10 mg doses was approximately threefold greater than the plasma concentrations following a single 10 mg dose. Metabolite profiles were similar after single and multiple doses. Adverse events during rizatriptan were mild and transient; similar events occurred during placebo, with a somewhat reduced incidence. Diastolic blood pressure tended to increase compared with placebo (approximately 5 mmHg), particularly on the first multiple-dose day (p < .01 vs. placebo). In conclusion, rizatriptan is well tolerated by healthy subjects during multiple-dose administration, with no unexpected accumulation of drug in plasma. PMID:10631625

  12. A cytomegalovirus-based vaccine provides long-lasting protection against lethal Ebola virus challenge after a single dose

    PubMed Central

    Tsuda, Yoshimi; Parkins, Christopher J.; Caposio, Patrizia; Feldmann, Friederike; Botto, Sara; Ball, Susan; Messaoudi, Ilhem; Cicin-Sain, Luka; Feldmann, Heinz; Jarvis, Michael A.

    2015-01-01

    Ebola virus (Zaire ebolavirus; EBOV) is a highly lethal hemorrhagic disease virus that most recently was responsible for two independent 2014 outbreaks in multiple countries in Western Africa, and the Democratic Republic of the Congo, respectively. Herein, we show that a cytomegalovirus (CMV)-based vaccine provides durable protective immunity from Ebola virus following a single vaccine dose. This study has implications for human vaccination against ebolaviruses, as well as for development of a ‘disseminating’ vaccine to target these viruses in wild African great apes. PMID:25820063

  13. Seropositivity among Korean Young Adults Approximately 2 Years after a Single-Dose Vaccination against Hepatitis A Virus.

    PubMed

    Song, Yeong-Jun; Lim, Jiseun; Park, Woong-Sub; Sohn, Haesook; Lee, Moo-Sik; Shin, Dong-Hoon; Kim, Chun-Bae; Kim, Hwasung; Oh, Gyung-Jae; Ki, Moran

    2015-01-01

    We previously observed 80.7% seropositivity and a significant interaction between gender and hepatitis A virus (HAV) vaccine type (Havrix vs. Epaxal) on the seropositivity approximately 11 months after single-dose HAV vaccinations in Korean young adults. Our objective was to evaluate seropositivity approximately 2 years after a single-dose HAV vaccination and the influence of demographic characteristics on seropositivity, including the interaction between gender and vaccine type. Seronegative medical school students were randomly vaccinated with Havrix or Epaxal. Based on a total serum anti-HAV antibody titer cutoff of 20 IU/mL, 338 participants (76.0%) of the 445 vaccinees were seropositive 20-25 months after a single-dose HAV vaccination. The seropositive rates were similar after vaccination with Havrix (77.0%) and Epaxal (74.9%). Univariate analysis indicated that female (p = 0.052) and less obese (p < 0.001) participants had a higher seropositive rate, whereas other characteristics such as age, alcohol use, smoking history, vaccine type, and follow-up duration were not associated with seropositivity. Multivariate analysis indicated that women (p = 0.026) and participants with moderate alcohol use (p < 0.001) showed significantly higher seropositive rates than men and participants with no or low alcohol use, respectively. The seropositive rates after vaccination with Havrix and Epaxal were 70.9% and 67.5% in men and 87.7% and 91.3% in women, respectively (p for interaction = 0.304). Compared with the seropositive rate approximately 11 months after vaccination, the seropositive rate decreased substantially only in men in the Havrix group (11.0% points), and consequently, the interaction between gender and vaccine type disappeared while seropositivity remained high (87.7% and 91.3% in Havrix and Epaxal groups, respectively) among women approximately 2 years after vaccination. Further studies are needed to assess whether the seropositive rate would be maintained in

  14. Response of mouse epidermal cells to single doses of heavy-particles

    NASA Technical Reports Server (NTRS)

    Leith, J. T.; Schilling, W. A.; Welch, G. P.

    1972-01-01

    The survival of mouse epidermal cells to heavy-particles has been studied In Vivo by the Withers clone technique. Experiments with accelerated helium, lithium and carbon ions were performed. The survival curve for the helium ion irradiations used a modified Bragg curve method with a maximum tissue penetration of 465 microns, and indicated that the dose needed to reduce the original cell number to 1 surviving cell/square centimeters was 1525 rads with a D sub o of 95 rads. The LET at the basal cell layer was 28.6 keV per micron. Preliminary experiments with lithium and carbon used treatment doses of 1250 rads with LET's at the surface of the skin of 56 and 193 keV per micron respectively. Penetration depths in skin were 350 and 530 microns for the carbon and lithium ions whose Bragg curves were unmodified. Results indicate a maximum RBE for skin of about 2 using the skin cloning technique. An attempt has been made to relate the epidermal cell survival curve to mortality of the whole animal for helium ions.

  15. Short- and long-term hormonal effects of a single dose of 50 mg tamoxifen administered to normal males.

    PubMed

    Fauser, B C; Dony, J M; Doesburg, W H; Thomas, C M; Rolland, R

    1984-01-01

    To five potentially fertile males, a single dose of 50 mg tamoxifen was administered orally to explore the short- and long-term hormonal effects on the hypothalamic-pituitary-gonadal axis. Blood specimens were obtained through an integrated sampling technique for the first two hours after the intake of the drug. Then, samples were taken daily throughout one week, and twice weekly for the next two weeks. Hormone measurements of luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone and oestradiol were obtained by specific RIA. All the subjects showed different response patterns. No general characteristic of the hormonal changes in the investigated group could be given. A consistent correlation between the within-individual levels of gonadotrophin and sex steroid changes could not be observed. It is concluded, within the limits of the used experimental design, that in healthy males a single administration of tamoxifen does not result in consistent changes in serum levels of either gonadotrophins or sex steroid hormones.

  16. Processing of DNA damage after exposure to a single dose of fission spectrum neutrons takes 40 hours to complete

    SciTech Connect

    Peak, J.G.; Peak, M.J.

    1996-11-01

    We have examined the time course over a period of days of repair of chromosomal single-strand breaks (SSB) induced by a single dose of JANUS fission-spectrum neutrons in the DNA of human P3 epithelial teratocarcinoma cells. When the cells are allowed a period of repair incubation the breaks are totally sealed by 7 hours. But then following these initial repair the DNA is dismantled as evidenced by the reappearance of SSBs. This secondary breakage is almost as extensive as that caused by the original neutron exposure, with a maximum at 16-18 hours. Finally, the DNA is rejoined, regaining its original size by 40 hours after irradiation. The secondary repair phenomenon may have an editing function, or it many represent the processing of residual damage left unrepaired during the initial rejoining of the backbone breaks.

  17. Serum methanol concentrations in rats and in men after a single dose of aspartame.

    PubMed

    Davoli, E; Cappellini, L; Airoldi, L; Fanelli, R

    1986-03-01

    Serum methanol concentrations were measured in rats and in humans given oral aspartame. The dose given to rats was the FDA's projected 99th percentile daily intake for humans, assuming aspartame were to replace all sucrose sweeteners in the diet (34 mg/kg). Four male adult volunteers each received 500 mg, equivalent to 6-8.7 mg/kg, which is approximately the FDA's estimate of mean daily human consumption. Both treatments caused a rise in serum methanol. In rats the mean peak value was 3.1 mg/litre 1 hr after administration; serum methanol returned to endogenous values 4 hr after treatment. In the men, the mean rise over endogenous values was 1.06 mg/litre after 45 min. Two hours after treatment, serum methanol had returned to basal levels. The temporary serum methanol increase showed peak values within the range of individual basal levels.

  18. Safety of Fixed Dose of Antihypertensive Drug Combinations Compared to (Single Pill) Free-Combinations

    PubMed Central

    Nowak, Emmanuel; Happe, André; Bouget, Jacques; Paillard, Francois; Vigneau, Cécile; Scarabin, Pierre-Yves; Oger, Emmanuel

    2015-01-01

    Abstract To compare serious adverse events of fixed-dose dual antihypertensive drug combination (FIXED) to component-based free-combination (FREE). A population-based nationwide cohort from the French Health Insurance System included subjects over 50 years with first time claims (new user) in the second half of 2009 for a calcium-channel blocker or a thiazide-like diuretic in combination with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker as FREE or FIXED. We designed a nested matched case–control analysis with 304 cases, hospitalized for hypotension, syncope, or collapse (n = 224), renal failure (n = 19), hyponatremia, hyper- or hypokalemia (n = 61) and 1394 controls matched for gender, age, date of inclusion in the cohort, and administrative county. Subjects with a medical history of cardiovascular disease, chronic renal failure, or cancer were excluded. The mean age ± SD was 73 ± 10 years and 70% were women. Based on the last delivery preceding the index date, 1414 patients (83%) were exposed to FIXED. Homogeneity of FIXED effect compared to FREE across components of the main composite outcome was rejected (P = 0.0099). FIXED formulation significantly increased the odd of the most frequent component (ie, hypotension, syncope, or collapse): OR = 1.88 (95% CI: 1.15–3.05) compared to FREE after adjusting for confounding factors including dose. Serious adverse event occurring in the early phase of treatment deserves attention of physicians because it could alter the benefit/risk ratio of antihypertensive drug combination. PMID:26656365

  19. Carcinoma of the large bowel after a single massive dose of radiation in healthy teenagers

    SciTech Connect

    Rotmensch, S.; Avigad, I.; Soffer, E.E.; Horowitz, A.; Bar-Meir, S.; Confino, R.; Czerniak, A.; Wolfstein, I.

    1986-02-15

    Three healthy teenagers were exposed to a single pelvic x-ray irradiation as part of sterilization experiments performed in the Auschwitz concentration camp in 1943. Single and multiple carcinomas of the colon and rectum developed 40 years later in the radiation field. Histologic examination of surgical specimens revealed severe radiation-induced changes in all layers of tumor-adjacent areas. In contrast to previous reports of radiation-induced large bowel cancers, these women had not undergone repeated courses of radiation, had no known co-existing disease that might raise the risk for colonic and rectal malignancies, and had an extremely long and remarkably similar latency period. These cases emphasize the need for long-term surveillance in previously radiated patients. Since thousands of teenagers were subjected to similar sterilization experiments, awareness of this association might help in the early diagnosis of additional cases.

  20. Comparative Hazard Identification by a Single Dose Lung Exposure of Zinc Oxide and Silver Nanomaterials in Mice

    PubMed Central

    Gosens, Ilse; Kermanizadeh, Ali; Jacobsen, Nicklas Raun; Lenz, Anke-Gabriele; Bokkers, Bas; de Jong, Wim H.; Krystek, Petra; Tran, Lang; Stone, Vicki; Wallin, Håkan; Stoeger, Tobias; Cassee, Flemming R.

    2015-01-01

    Comparative hazard identification of nanomaterials (NMs) can aid in the prioritisation for further toxicity testing. Here, we assessed the acute lung, systemic and liver responses in C57BL/6N mice for three NMs to provide a hazard ranking. A silver (Ag), non-functionalised zinc oxide (ZnO) and a triethoxycaprylylsilane functionalised ZnO NM suspended in water with 2% mouse serum were examined 24 hours following a single intratracheal instillation (I.T.). An acute pulmonary inflammation was noted (marked by a polymorphonuclear neutrophil influx) with cell damage (LDH and total protein) in broncho-alveolar lavage fluid (BALF) after administration of both non-functionalised and functionalised ZnO. The latter also induced systemic inflammation measured as an increase in blood neutrophils and a decrease in blood lymphocytes. Exposure to Ag NM was not accompanied by pulmonary inflammation or cytotoxicity, or by systemic inflammation. A decrease in glutathione levels was demonstrated in the liver following exposure to high doses of all three nanomaterials irrespective of any noticeable inflammatory or cytotoxic effects in the lung. By applying benchmark dose (BMD) modeling statistics to compare potencies of the NMs, we rank functionalised ZnO ranked the highest based on the largest number of affected endpoints, as well as the strongest responses observed after 24 hours. The non-functionalised ZnO NM gave an almost similar response, whereas Ag NM did not cause an acute response at similar doses. PMID:25966284

  1. Comparative hazard identification by a single dose lung exposure of zinc oxide and silver nanomaterials in mice.

    PubMed

    Gosens, Ilse; Kermanizadeh, Ali; Jacobsen, Nicklas Raun; Lenz, Anke-Gabriele; Bokkers, Bas; de Jong, Wim H; Krystek, Petra; Tran, Lang; Stone, Vicki; Wallin, Håkan; Stoeger, Tobias; Cassee, Flemming R

    2015-01-01

    Comparative hazard identification of nanomaterials (NMs) can aid in the prioritisation for further toxicity testing. Here, we assessed the acute lung, systemic and liver responses in C57BL/6N mice for three NMs to provide a hazard ranking. A silver (Ag), non-functionalised zinc oxide (ZnO) and a triethoxycaprylylsilane functionalised ZnO NM suspended in water with 2% mouse serum were examined 24 hours following a single intratracheal instillation (I.T.). An acute pulmonary inflammation was noted (marked by a polymorphonuclear neutrophil influx) with cell damage (LDH and total protein) in broncho-alveolar lavage fluid (BALF) after administration of both non-functionalised and functionalised ZnO. The latter also induced systemic inflammation measured as an increase in blood neutrophils and a decrease in blood lymphocytes. Exposure to Ag NM was not accompanied by pulmonary inflammation or cytotoxicity, or by systemic inflammation. A decrease in glutathione levels was demonstrated in the liver following exposure to high doses of all three nanomaterials irrespective of any noticeable inflammatory or cytotoxic effects in the lung. By applying benchmark dose (BMD) modeling statistics to compare potencies of the NMs, we rank functionalised ZnO ranked the highest based on the largest number of affected endpoints, as well as the strongest responses observed after 24 hours. The non-functionalised ZnO NM gave an almost similar response, whereas Ag NM did not cause an acute response at similar doses. PMID:25966284

  2. Population pharmacokinetics of artesunate and dihydroartemisinin following single- and multiple-dosing of oral artesunate in healthy subjects

    PubMed Central

    2009-01-01

    Background The population pharmacokinetics of artesunate (AS) and its active metabolite dihydroartemisinin (DHA) were studied in healthy subjects receiving single- or multiple-dosing of AS orally either in combination with pyronaridine (PYR) or as a monotherapy with or without food. Methods Data from 118 concentration-time profiles arising from 91 healthy Korean subjects were pooled from four Phase I clinical studies. Subjects received 2-5 mg/kg of single- and multiple-dosing of oral AS either in combination with PYR or as a monotherapy with or without food. Plasma AS and DHA were measured simultaneously using a validated liquid chromatography- mass spectrometric method with a lower limit of quantification of 1 ng/mL for both AS and DHA. Nonlinear mixed-effect modelling was used to obtain the pharmacokinetic and variability (inter-individual and residual variability) parameter estimates. Results A novel parent-metabolite pharmacokinetic model consisting of a dosing compartment, a central compartment for AS, a central compartment and a peripheral compartment for DHA was developed. AS and DHA data were modelled simultaneously assuming stoichiometric conversion to DHA. AS was rapidly absorbed with a population estimate of absorption rate constant (Ka) of 3.85 h-1. The population estimates of apparent clearance (CL/F) and volume of distribution (V2/F) for AS were 1190 L/h with 36.2% inter-individual variability (IIV) and 1210 L with 57.4% IIV, respectively. For DHA, the population estimates of apparent clearance (CLM/F) and central volume of distribution (V3/F) were 93.7 L/h with 28% IIV and 97.1 L with 30% IIV, respectively. The population estimates of apparent inter-compartmental clearance (Q/F) and peripheral volume of distribution (V4/F) for DHA were 5.74 L/h and 18.5 L, respectively. Intake of high-fat and high-caloric meal prior to the drug administration resulted in 84% reduction in Ka. Body weight impacted CLM/F, such that a unit change in weight resulted in 1

  3. The effect of a single dose of bupivacaine on donor site pain after anterior iliac crest bone harvesting.

    PubMed

    Barkhuysen, R; Meijer, G J; Soehardi, A; Merkx, M A W; Borstlap, W A; Bergé, S J; Bronkhorst, E M; Hoppenreijs, T J M

    2010-03-01

    Transplants from the anterior iliac crest are used for most reconstructive procedures in cranio-maxillofacial surgery. The advantages are easy accessibility, the ability to work in two teams and the amount of corticocancellous bone available; disadvantages are postoperative pain and gait disturbances. To reduce donor-site pain, the effect of a single dose of bupivacaine (10 cc of 2.5mg/cc with 1:80.000 epinephrine) was studied. 200 consecutive patients, who underwent anterior iliac crest bone harvesting for reconstructive procedures, were randomly divided into those receiving bupivacaine and those not. They completed a standardized questionnaire. Patients scored the intensity of the pain and difficulties walking at different times with a visual analogue scale. They recorded analgesics used. 98 questionnaires were eligible for analysis. No differences between the bupivacaine and the control group were detected for postoperative pain and gait disturbance. There is no support for administration of a single dose of bupivacaine to reduce pain in the first postoperative days. The surface area of the removed bone had a significant influence on pain and walking; pain is related to the local osseous damage or periosteal stripping rather than to the length of incision or the operation time.

  4. Effects of a single bolus intravenous dose of tramadol on minimum alveolar concentration (MAC) of sevoflurane in dogs.

    PubMed

    Itami, Takaharu; Kawase, Kodai; Tamaru, Naomichi; Ishizuka, Tomohito; Tamura, Jun; Miyoshi, Kenjirou; Umar, Mohammed A; Inoue, Hiroki; Yamashita, Kazuto

    2013-01-01

    Tramadol is an atypical opioid analgesic widely used in small animal practice. This study was designed to determine the effect of a single intravenous (IV) dose of tramadol on the minimum alveolar concentration (MAC) of sevoflurane in dogs. Six beagle dogs were anesthetized twice to determine the sevoflurane MAC with or without an administration of tramadol (4 mg/kg, IV) at 7 days interval. The sevoflurane MAC was determined using a tail clamp method in each dog ventilated with positive pressure ventilation. The tramadol administration produced a significant reduction in the sevoflurane MAC by 22.3 ± 12.2% (1.44 ± 0.28% with tramadol versus 1.86 ± 0.30% without tramadol, P=0.010). This MAC reduction had been determined from 122 ± 19 to 180 ± 41 min following the tramadol administration. During this period, the plasma concentrations of tramadol and its metabolite, O-desmethyltramadol (M1), decreased from 429 ± 64 to 332 ± 55 ng/ml and from 136 ± 24 to 114 ± 68 ng/ml, respectively, but these changes were not statistically significant. There was no significant difference in heart rate, mean arterial blood pressure and SpO2 between the control and tramadol treatment. The dogs that received tramadol treatment sometimes breathed spontaneously. Therefore, their respiratory rates significantly increased, and PETCO2 decreased during the MAC determination. In conclusion, the single IV dose of tramadol produced a significant reduction in the sevoflurane MAC in dogs.

  5. A single neurotoxic dose of methamphetamine induces a long-lasting depressive-like behaviour in mice.

    PubMed

    Silva, Carlos D; Neves, Ana F; Dias, Ana I; Freitas, Hugo J; Mendes, Sheena M; Pita, Inês; Viana, Sofia D; de Oliveira, Paulo A; Cunha, Rodrigo A; Fontes Ribeiro, Carlos A; Prediger, Rui D; Pereira, Frederico C

    2014-04-01

    Methamphetamine (METH) triggers a disruption of the monoaminergic system and METH abuse leads to negative emotional states including depressive symptoms during drug withdrawal. However, it is currently unknown if the acute toxic dosage of METH also causes a long-lasting depressive phenotype and persistent monoaminergic deficits. Thus, we now assessed the depressive-like behaviour in mice at early and long-term periods following a single high METH dose (30 mg/kg, i.p.). METH did not alter the motor function and procedural memory of mice as assessed by swimming speed and escape latency to find the platform in a cued version of the water maze task. However, METH significantly increased the immobility time in the tail suspension test at 3 and 49 days post-administration. This depressive-like profile induced by METH was accompanied by a marked depletion of frontostriatal dopaminergic and serotonergic neurotransmission, indicated by a reduction in the levels of dopamine, DOPAC and HVA, tyrosine hydroxylase and serotonin, observed at both 3 and 49 days post-administration. In parallel, another neurochemical feature of depression--astroglial dysfunction--was unaffected in the cortex and the striatal levels of the astrocytic protein marker, glial fibrillary acidic protein, were only transiently increased at 3 days. These findings demonstrate for the first time that a single high dose of METH induces long-lasting depressive-like behaviour in mice associated with a persistent disruption of frontostriatal dopaminergic and serotonergic homoeostasis.

  6. Clinical Efficacy of a Single Two Gram Dose of Azithromycin Extended Release for Male Patients with Urethritis

    PubMed Central

    Takahashi, Satoshi; Kiyota, Hiroshi; Ito, Shin; Iwasawa, Akihiko; Hiyama, Yoshiki; Uehara, Teruhisa; Ichihara, Koji; Hashimoto, Jiro; Masumori, Naoya; Sunaoshi, Kenichi; Takeda, Koichi; Suzuki, Nobukazu; Hosobe, Takahide; Goto, Hirokazu; Suzuki, Hidenori; Onodera, Shoichi

    2014-01-01

    To clarify the clinical efficacy of a single oral 2 g dose of azithromycin extended-release for heterosexual male patients with urethritis, and the current antimicrobial sensitivity of Neisseria gonorrhoeae to azithromycin, a prospective clinical trial was conducted from 2011–2013. In patients with gonococcal urethritis, the eradication rate was 90.9% (30 of 33). The susceptibility rates of isolated Neisseria gonorrhoeae strains to ceftriaxone, spectinomycin, cefixime and azithromycin were 100%, 100%, 95.3% (41/43) and 37.2% (16/43), respectively. In the patients with nongonococcal urethritis, the eradication rate was 90.0% (45 of 50). The microbiological eradication rates for the pathogens were 90.9% (30/33) for Neisseria gonorrhoeae, 91.5% (43/47) for Chlamydia trachomatis, 71.4% (5/7) for Mycoplasma genitalium, and 100% (13/13) for Ureaplasma urealyticum. The main adverse event was diarrhea and its manifestation rate was 35.2% (32 of 120). The symptom of diarrhea was mostly temporary and resolved spontaneously. The conclusion was that the treatment regimen with a single oral 2 g dose of azithromycin extended-release would be effective for patients with urethritis. However, the antimicrobial susceptibilities of Neisseria gonorrhoeae and Mycoplasma genitalium should be carefully monitored because of possible treatment failure. PMID:27025738

  7. Effects of a single, high oral dose of 25-hydroxycholecalciferol on the mineral metabolism markers in hemodialysis patients.

    PubMed

    Merino, Jose Luis; Teruel, Jose Luis; Fernández-Lucas, Milagros; Villafruela, Juan José; Bueno, Blanca; Gomis, Antonio; Paraíso, Vicente; Quereda, Carlos

    2015-06-01

    Vitamin D deficiency is common in dialysis patients with chronic kidney disease. Low levels have been associated with increased cardiovascular risk and mortality. We evaluated the administration of a high, single oral dose of 25-OH cholecalciferol (3 mg of Hidroferol, 180 000 IU) in patients on chronic hemodialysis. The 94 chronic hemodialysis patients with vitamin D deficiency 25 (OH)D <30 ng/mL included in the study were randomized into two groups. Follow-up time was 16 weeks. Neither the usual treatment for controlling Ca/P levels nor the dialysis bath (calcium of 2.5 mEq/L) were modified. Of the 86 patients who finished the study, 42 were in the treated group and 44 in the control group. An increase in 25(OH)D levels was observed in the treated group that persisted after 16 weeks and was associated with a significant decrease in parathyroid hormone (PTH) levels during the 8 weeks post-treatment. Baseline 1,25(OH)2 D levels of the treated group increased two weeks after treatment (5.9 vs. 21.9 pg/mL, P<0.001) but gradually reduced to 8.4 at week 16. The administration of a single 3 mg dose of 25-OH cholecalciferol seems safe in patients on hemodialysis and maintains sufficient levels of 25(OH)D with a decrease in PTH for 3 months.

  8. Effects of a single low-dose acetaminophen on body temperature and running performance in the heat: a pilot project

    PubMed Central

    Burtscher, Martin; Gatterer, Hannes; Philippe, Marc; Krüsmann, Philipp; Kernbeiss, Stefanie; Frontull, Veronica; Kofler, Philipp

    2013-01-01

    Purpose: To examine the effects of a single low-dose (500 mg) acetaminophen on body temperature and running performance in the heat (30 °C). Methods: This is a randomized, cross-over pilot study performed in a climatic chamber at the Department of Sport Science of the University of Innsbruck. Seven male sport students (age, 25.9 ± 2.3 years; VO2max, 67.3 ± 7.1 mL/min/kg) participated in the study. Each participant performed two prolonged exercise tests at a constant intensity on a treadmill at a temperature of 30 °C at an individual intensity corresponding to 70 % VO2max. Two hours before exercising participants were randomly assigned to receive acetaminophen (500 mg) or placebo and performed the same test 2 weeks later with reverse pre-treatment. Results: After 20 min of running in the heat core temperature increase was less under acetaminophen (P = 0.004) and heart rates were higher (P = 0.02) compared to placebo. At the end of exercise neither running time nor body temperature nor ratings of perceived exertion differed between groups. Conclusion: Although the increase in core temperature was slightly reduced by acetaminophen after 20 minutes of running in the heat running performance remained unaffected after pre-treatment with a single low-dose of acetaminophen. PMID:24044039

  9. A Vesicular Stomatitis Virus-Based Hepatitis B Virus Vaccine Vector Provides Protection against Challenge in a Single Dose

    PubMed Central

    Cobleigh, Melissa A.; Buonocore, Linda; Uprichard, Susan L.; Rose, John K.; Robek, Michael D.

    2010-01-01

    As one of the world's most common infectious diseases, hepatitis B virus (HBV) is a serious worldwide public health problem, with HBV-associated liver disease accounting for more than half a million deaths each year. Although there is an effective prophylactic vaccine currently available to prevent infection, it has a number of characteristics that are suboptimal: multiple doses are needed to induce long-lasting immunity, immunity declines over time, it does not elicit protection in some individuals, and it is not effective therapeutically. We produced a recombinant vesicular stomatitis virus (VSV)-based vaccine vector expressing the HBV middle envelope surface protein (MS) and found that this vector was able to efficiently generate a strong HBs-specific antibody response following a single immunization in mice. A single immunization with the VSV-MS vector also induced robust CD8 T-cell activation. The CD8 T-cell response was greater in magnitude and broader in specificity than the response generated by a vaccinia virus-based vaccine vector or by recombinant protein immunization. Furthermore, a single VSV-MS immunization provided protection against virus challenge in mice. Given the similar antibody titers and superior T-cell responses elicited from a single immunization, a VSV-based HBV vaccine may have advantages over the current recombinant protein vaccine. PMID:20504927

  10. Efficacy and safety of a single dose pentamidine (7mg/kg) for patients with cutaneous leishmaniasis caused by L. guyanensis: a pilot study*

    PubMed Central

    Gadelha, Ellen Priscilla Nunes; Talhari, Sinésio; Guerra, Jorge Augusto de Oliveira; Neves, Leandro Ourives; Talhari, Carolina; Gontijo, Bernardo; da Silva Junior, Roberto Moreira; Talhari, Anette Chrusciak

    2015-01-01

    BACKGROUND There have been few studies on pentamidine in the Americas; and there is no consensus regarding the dose that should be applied. OBJECTIVES To evaluate the use of pentamidine in a single dose to treat cutaneous leishmaniasis. METHODS Clinical trial of phase II pilot study with 20 patients. Pentamidine was used at a dose of 7 mg/kg, in a single dose. Safety and adverse effects were also assessed. Patients were reviewed one, two, and six months after the end of treatments. RESULTS there was no difference between the treatment groups in relation to gender, age, number or location of the lesions. Pentamidine, applied in a single dose, obtained an effectiveness of 55%. Mild adverse events were reported by 17 (85%) patients, mainly transient pain at the site of applications (85%), while nausea (5%), malaise (5%) and dizziness (5%) were reported in one patient. No patient had sterile abscess after taking medication at a single dose of 7mg/kg. CONCLUSIONS Clinical studies with larger samples of patients would enable a better clinical response of pent amidine at a single dose of 7mg, allowing the application of more powerful statistical tests, thus providing more evidences of the decrease in the effectiveness of that medication. Hence, it is important to have larger studies with new diagrams and/or new medications. PMID:26734860

  11. Toxico-kinetics, recovery, and metabolism of napropamide in goats following a single high-dose oral administration.

    PubMed

    Pahari, A K; Majumdar, S; Mandal, T K; Chakraborty, A K; Bhattacharyya, A; Chowdhury, A

    2001-04-01

    Toxicokinetic behavior, recovery and metabolism of napropamide (a pre-emergent herbicide) and its effect on Cytochrome P(450) of liver microsomal pellet were studied following a single high-dose oral administration of 2.5 g kg(-1) and continuous (7 days) oral administration of 500 mg kg(-1) in black Bengal goat. Napropamide was detected in blood at 15 min and the maximum quantity was recovered at 3 h after administration. The absorption rate constant (Ka) value was low indicating poor absorption from the gastrointestinal tract. High elimination half-life (t(1/2) beta) and low body clearance (Cl(B)) values coupled with higher transfer of compound from tissue to central compartment (K(21)) suggest that napropamide persisted in the blood for a long time, i.e., after 72 h of oral administration. The recovery percentage of napropamide, including metabolites, from goats varied from 75.94 to 80.08 and excretion of the parent compound through feces varied from 18.86 to 21.59%, indicating that a major portion of the orally administered napropamide was absorbed from the gastrointestinal tract of goat. Napropamide significantly increased the Cytochrome P(450) content of liver microsomal pellet. The recovery of metabolites from feces, urine, and tissues ranged from 4.2--6.2, 40.81--49.42, and 2.7--11.6%, respectively, during a 4--7 day period. The material balance of napropamide (including metabolites) following a single high-dose oral administration at 2.5 g kg(-1) during 4--7 days after dosing was found to be in the range of 75--80%. PMID:11308331

  12. Effect of a single dose of lactase on symptoms and expired hydrogen after lactose challenge in lactose-intolerant subjects.

    PubMed

    Sanders, S W; Tolman, K G; Reitberg, D P

    1992-06-01

    The effect of a single dose or oral lactase on symptoms, breath hydrogen concentration, and glucose absorption in lactose-intolerant subjects challenged with lactose was studied. Volunteers underwent a lactose challenge test; those whose breath hydrogen concentrations increased 20 ppm or more and who met other criteria were admitted as subjects. After fasting, the subjects were given three chewable lactase tablets (total lactase dose, 9900 FCC units) or placebo tablets in a randomized, double-blind, crossover manner. The subjects also consumed 8 oz of whole milk in which 37.5 g of lactose powder was dissolved (total lactose content, 50 g). The washout period between lactose challenges was at least one week. Breath hydrogen and plasma glucose concentrations were measured before and at intervals after the challenges, and the subjects completed symptom-evaluation questionnaires every eight hours for four days. Twenty-four subjects completed the study. The maximum mean breath hydrogen concentration was significantly lower after lactase treatment than after placebo treatment. In 21 subjects, the area under the hydrogen concentration-time curve (AUC) was lower after lactase than after placebo; three subjects had hydrogen AUCs more than 300 ppm.hr lower. There were no significant differences in plasma glucose levels. Subjective ratings of the severity of abdominal cramping, belching, flatulence, and diarrhea were lower during the first eight hours after challenge in lactase-treated subjects; ratings for bloating were lower during the next eight hours. Single doses of a chewable lactase tablet reduced the concentration of expired hydrogen and symptoms of lactose intolerance after a lactose challenge.

  13. Pharmacological Doses of Daily Ascorbate Protect Tumors from Radiation Damage after a Single Dose of Radiation in an Intracranial Mouse Glioma Model

    PubMed Central

    Grasso, Carole; Fabre, Marie-Sophie; Collis, Sarah V.; Castro, M. Leticia; Field, Cameron S.; Schleich, Nanette; McConnell, Melanie J.; Herst, Patries M.

    2014-01-01

    Pharmacological ascorbate is currently used as an anti-cancer treatment, potentially in combination with radiation therapy, by integrative medicine practitioners. In the acidic, metal-rich tumor environment, ascorbate acts as a pro-oxidant, with a mode of action similar to that of ionizing radiation; both treatments kill cells predominantly by free radical-mediated DNA damage. The brain tumor, glioblastoma multiforme (GBM), is very resistant to radiation; radiosensitizing GBM cells will improve survival of GBM patients. Here, we demonstrate that a single fraction (6 Gy) of radiation combined with a 1 h exposure to ascorbate (5 mM) sensitized murine glioma GL261 cells to radiation in survival and colony-forming assays in vitro. In addition, we report the effect of a single fraction (4.5 Gy) of whole brain radiation combined with daily intraperitoneal injections of ascorbate (1 mg/kg) in an intracranial GL261 glioma mouse model. Tumor-bearing C57BL/6 mice were divided into four groups: one group received a single dose of 4.5 Gy to the brain 8 days after tumor implantation, a second group received daily intraperitoneal injections of ascorbate (day 8–45) after implantation, a third group received both treatments and a fourth control group received no treatment. While radiation delayed tumor progression, intraperitoneal ascorbate alone had no effect on tumor progression. Tumor progression was faster in tumor-bearing mice treated with radiation and daily ascorbate than in those treated with radiation alone. Histological analysis showed less necrosis in tumors treated with both radiation and ascorbate, consistent with a radio-protective effect of ascorbate in vivo. Discrepancies between our in vitro and in vivo results may be explained by differences in the tumor microenvironment, which determines whether ascorbate remains outside the cell, acting as a pro-oxidant, or whether it enters the cells and acts as an anti-oxidant. PMID:25566497

  14. Dose Optimization for Single Intradiscal Administration of the Tumor Necrosis Factor-α Inhibitor, Etanercept, in Rat Disc Injury Models

    PubMed Central

    Orita, Sumihisa; Yamauchi, Kazuyo; Suzuki, Takane; Suzuki, Miyako; Sakuma, Yoshihiro; Kubota, Go; Oikawa, Yasuhiro; Sainoh, Takeshi; Sato, Jun; Fujimoto, Kazuki; Shiga, Yasuhiro; Abe, Koki; Kanamoto, Hirohito; Inoue, Masahiro; Kinoshita, Hideyuki; Takahashi, Kazuhisa; Ohtori, Seiji

    2016-01-01

    Study Design Experimental animal study. Purpose We aimed to determine the optimal dose of a single direct injection of the tumor necrosis factor (TNF)-α inhibitor, etanercept, by using the rat model of degenerative intervertebral disc from injury. Overview of Literature The pain-related peptide expression was suppressed in the etanercept (100 µg and 1,000 µg)-administered groups in a dose-dependent manner. Methods The neurotracer FluoroGold (FG) was applied to the surfaces of L4/5 discs to label their innervating dorsal root ganglion (DRG) neurons (n=50). Ten rats were included in the nonpunctured disc sham surgery control group, whereas the other 40 were included in the experimental group in which intervertebral discs were punctured with a 23-gauge needle. Saline or etanercept (10 µg, 100 µg, or 1,000 µg) was injected into the punctured discs (n=10 for each treatment). After 14 days of surgery, DRGs from L1 to L6 were harvested, sectioned, and immunostained for calcitonin gene-related peptide (CGRP). The proportion of FG-labeled CGRP-immunoreactive DRG neurons was evaluated in all the groups. Results There were no significant differences between the puncture+saline group and the puncture+10-µg etanercept group (p >0.05). However, a significant decrease in the percentage of FG and CGRP double-positive cells in FG-positive cells was observed in the etanercept (100 µg and 1,000 µg)-administered groups in a dose-dependent manner (p <0.05). Conclusions When a low dose of the TNF-α inhibitor (10 µg of etanercept) was directly administered to the rat intervertebral disc in the rat model of degenerative intervertebral disc from injury, no suppressive effect on the pain-related peptide expression was observed. However, when a higher dose of etanercept (100 µg and 1,000 µg) was administered, the pain-related peptide expression was suppressed in a dose-dependent manner. PMID:27559439

  15. Recurring Extracorporeal Circuit Clotting During Continuous Renal Replacement Therapy Resolved after Single-Session Therapeutic Plasma Exchange

    PubMed Central

    Fülöp, Tibor; Cosmin, Adrian; Juncos, Luis A.

    2011-01-01

    We report a case of a 17 year old white male with multiple fractures and multi-organ failure who developed oliguric acute renal failure requiring continuous renal replacement therapy. Repeated clotting of the extracorporeal circuit (ECC) prevented delivery of a minimally acceptable dose of renal replacement therapy despite adequate anticoagulation and dialysis catheter exchanges. Evaluation for a primary hypercoagulable state was negative, but his fibrinogen was elevated (1,320 mg/dL, normal range: 150–400 mg/dL), likely induced by his severe inflammatory state. A single session of therapeutic plasma exchange (TPE) with albumin and normal saline replacement was performed with subsequent drop in fibrinogen to 615 mg/dL. No further episodes of premature ECC clotting occurred, suggesting plasma factor(s) removed may have contributed to the clinical hypercoagulable state. TPE may play an adjunctive role in select cases of recurrent ECC clotting refractory to current anticoagulation techniques. PMID:21618596

  16. Changes in spatial cognition and brain activity after a single dose of testosterone in healthy women.

    PubMed

    Pintzka, Carl W S; Evensmoen, Hallvard R; Lehn, Hanne; Håberg, Asta K

    2016-02-01

    Studies have consistently shown that males perform better than females on several spatial tasks. Animal and human literature suggests that sex hormones have an important role in both establishing and maintaining this difference. The aim of the present study was to examine the effects of exogenous testosterone on spatial cognition and brain activity in healthy women. A cross-sectional, double-blind, randomized, placebo-controlled study was performed in 42 healthy young women who either received one dose of 0.5mg sublingual testosterone or placebo. They then learned a virtual environment and performed navigation tasks during functional magnetic resonance imaging (fMRI). Subsequently, their knowledge of the virtual environment, self-reported navigation strategy, and mental rotation abilities were measured. The testosterone group had improved representations of the directions within the environment and performed significantly better on the mental rotation task compared to the placebo group, but navigation success and navigation strategy were similar in the two groups. Nevertheless, the testosterone group had significantly increased activity within the medial temporal lobe during successful navigation compared to the placebo group, and a positive correlation between testosterone load and medial temporal lobe activity was found. Fetal testosterone levels, measured as second-to-fourth digit length ratio, interacted significantly with parahippocampal activity and tended towards giving higher mental rotation task scores. These results demonstrated that testosterone had a limited effect pertaining specifically to spatial cognition involving 3D-visualization in healthy women, while complex behaviors such as navigation, relying more on learned strategies, were not altered despite increased neuronal activity in relevant brain regions. PMID:26542812

  17. Gene Expression Response of Mice after a Single Dose of 137Cs as an Internal Emitter

    PubMed Central

    Paul, Sunirmal; Ghandhi, Shanaz A.; Weber, Waylon; Doyle-Eisele, Melanie; Melo, Dunstana; Guilmette, Raymond; Amundson, Sally A.

    2014-01-01

    Cesium-137 is a radionuclide of concern in fallout from reactor accidents or nuclear detonations. When ingested or inhaled, it can expose the entire body for an extended period of time, potentially contributing to serious health consequences ranging from acute radiation syndrome to increased cancer risks. To identify changes in gene expression that may be informative for detecting such exposure, and to begin examining the molecular responses involved, we have profiled global gene expression in blood of male C57BL/6 mice injected with 137CsCl. We extracted RNA from the blood of control or 137CsCl-injected mice at 2, 3, 5, 20 or 30 days after exposure. Gene expression was measured using Agilent Whole Mouse Genome Microarrays, and the data was analyzed using BRB-ArrayTools. Between 466–6,213 genes were differentially expressed, depending on the time after 137Cs administration. At early times (2–3 days), the majority of responsive genes were expressed above control levels, while at later times (20–30 days) most responding genes were expressed below control levels. Numerous genes were overexpressed by day 2 or 3, and then underexpressed by day 20 or 30, including many Tp53-regulated genes. The same pattern was seen among significantly enriched gene ontology categories, including those related to nucleotide binding, protein localization and modification, actin and the cytoskeleton, and in the integrin signaling canonical pathway. We compared the expression of several genes three days after 137CsCl injection and three days after an acute external gamma-ray exposure, and found that the internal exposure appeared to produce a more sustained response. Many common radiation-responsive genes are altered by internally administered 137Cs, but the gene expression pattern resulting from continued irradiation at a decreasing dose rate is extremely complex, and appears to involve a late reversal of much of the initial response. PMID:25162453

  18. A single dose of hypnotic corrects sleep and EEG abnormalities in symptomatic Huntington's disease mice.

    PubMed

    Kantor, Sandor; Varga, Janos; Morton, A Jennifer

    2016-06-01

    Sleep and electroencephalogram abnormalities are prominent early features of Huntington's disease (HD) that typically appear before the onset of characteristic motor symptoms. The changes in sleep and electroencephalogram seen in HD patients are largely recapitulated in mouse models of HD such as transgenic R6/2 lines. To test whether or not drugs with hypnotic properties can correct the sleep and electroencephalogram abnormalities seen in HD mice, we treated male wild-type (WT; N = 7) and R6/2 mice (N = 9) acutely with intraperitoneal injections of vehicle, zolpidem (5, 10 or 20 mg/kg) or amitriptyline (5, 10 or 20 mg/kg), and then monitored their sleep-wake behavior. In R6/2 mice, both zolpidem and amitriptyline suppressed the abnormally high REM sleep amount and electroencephalographic gamma (30-46 Hz) oscillations in a dose-dependent manner. Amitriptyline's effect on sleep was similar in both genotypes, whereas zolpidem showed significant genotype differences. Zolpidem exerted a strong hypnotic effect in WT mice by increasing electroencephalographic delta power, doubling the mean bout duration and the total amount of non-rapid eye movement sleep. However, no such effect was seen in R6/2 mice. Our study demonstrates that the pathophysiological changes seen in sleep and electroencephalogram are not 'hard-wired' in HD brain and can be reversed even at late stages of the disease. The diminished hypnotic effect of zolpidem suggests that the GABAergic control of sleep-wake states is impaired in HD mice. A better understanding of the neurochemical basis underlying these abnormalities should lead to more effective and rational therapies for HD. PMID:26805423

  19. Pharmacokinetics and intramuscular bioavailability of a single dose of butorphanol in Asian elephants (Elephas maximus).

    PubMed

    Tana, Leann M; Isaza, Ramiro; Koch, David E; Hunter, Robert P

    2010-09-01

    Captive Asian elephants (Elephas maximus) are susceptible to lameness resulting from foot and joint pain, including chronic arthritis. In the past, opioid analgesics, such as butorphanol, have been used clinically for pain management. However, dosages used in treating elephants were often extrapolated from data in horses, with no pharmacokinetic information on the specific agents used in elephant species. In this pharmacokinetic study, six adult captive Asian elephants (5 female, 1 male castrate) were administered a 0.015 mg/kg dose of butorphanol by both i.v. and i.m. routes. A complete crossover design was used with a 3-wk washout period between treatments. Serial blood samples were collected immediately prior to butorphanol administration and at 5, 10, 20, and 40 min and 1, 1.5, 2, 3, 4, 5, 6, 8, 10, and 24 h after administration. The butorphanol analysis was performed using a validated liquid chromatography-mass spectrophotometric assay with a limit of quantitation of 0.025 ng/ml. The mean Cmax after i.m. administration was 7.9 ng/ml, with a corresponding Tmax, of 40 min and t(1/3), of 7.1 h. After i.v. administration, the mean Vd(ss) was 1.4 L/kg and the mean Cl(p) was 0.26 L/kg/h. Mean i.m. bioavailability was 37%. The results indicate that butorphanol used at 0.015 mg/kg i.m. or i.v. could be useful in elephants when given for pain control. PMID:20945638

  20. [Safety Evaluation of Rare Sugar Syrup: Single-dose Oral Toxicity in Rats, Reverse Mutation Assay, Chromosome Aberration Assay, and Acute Non-Effect Level for Diarrhea of a Single Dose in Humans].

    PubMed

    Yamada, Takako; Iida, Tetsuo; Takamine, Satoshi; Hayashi, Noriko; Okuma, Kazuhiro

    2015-01-01

    The safety of rare sugar syrup obtained from high-fructose corn syrup under slightly alkaline conditions was studied. Mutagenicity of rare sugar syrup was assessed by a reverse mutation assay using Salmonella typhimurium and Escherichia coli, and an in vitro chromosomal aberration assay using Chinese hamster lung cell line (CHL/IU). No mutagenicity of rare sugar syrup was detected under these experimental conditions. Oral administration of single dose (15,000 mg/kg) of rare sugar syrup to rats caused no abnormalities, suggesting no adverse effect of rare sugar syrup. In humans, the acute non-effect level of rare sugar syrup for causing diarrhea was estimated as 0.9 g/kg body weight as dry solid base in both males and females. PMID:26537651

  1. An alternative single dose parameter to avoid the need for steady-state studies on oral extended-release drug products.

    PubMed

    Paixão, Paulo; Gouveia, Luís F; Morais, José A G

    2012-02-01

    Use of single and multiple-dose studies is required to establish the bioequivalence between two extended-release oral dosage forms under the current European Guidelines. However, FDA is less strict in this regard and only requires a single-dose study. The objective of this work is to use a computer simulation in order to test the two approaches. Three pharmacokinetic models, representing different release mechanisms, were considered, and Monte Carlo simulations with intra- and inter-individual variabilities were performed. Five different bioequivalence protocols were used and a new pharmacokinetic metric -C(τ), the concentration at the end of the intended dosing interval obtained in the single-dose study - is proposed in order to avoid the need for steady-state studies while keeping the ability to detect differences between formulations. Results have shown that the European requirements are more capable to discriminate between two potentially different formulations but at the cost of the multiple-dose study and with an increased number of subjects when compared to the FDA requirements. However, the use of C(max) and AUC(0-)(t) obtained on a single-dose study with the added C(τ) metric equals the discriminatory ability of the current EMA requirements, without the need of a multiple-dose study. This proposed approach results in the reduction in the number of studies and volunteers enrolled in clinical bioequivalence trials, without compromising the quality assurance of a new extended-release oral formulation.

  2. Processing of DNA damage after exposure to a single dose of fission spectrum neutrons takes 40 hours to complete

    SciTech Connect

    Peak, J.G.; Peak, M.J.

    1994-01-01

    The authors have examined the long-term (days) fate of breaks induced in the DNA of human P3 epithelial teratocarcinoma cells by a single dose of JANUS fission-spectrum neutrons (mean energy 0.85 MeV). We used alkaline-filter elution methods that assay totality of single- and double-strand breaks, generally referred to as single-strand breaks (SSBs). When the cells are allowed a period of repair incubation, these breaks are totally sealed by 7 hours after the original exposure, but following the initial repair the DNA is dismantled, as revealed by the reappearance of SSBS. This secondary breakage is almost as extensive as that caused by the original neutron exposure, with a maximum at 16-18 hours after irradiation. Finally, the DNA is once again rejoined, regaining its original size by 40 hours after irradiation. The secondary repair phenomenon may have an editing function, or it may represent the processing of residual damage left unrepaired during the initial rejoining of the backbone breaks.

  3. Advax delta inulin adjuvant overcomes immune immaturity in neonatal mice thereby allowing single-dose influenza vaccine protection.

    PubMed

    Honda-Okubo, Yoshikazu; Ong, Chun Hao; Petrovsky, Nikolai

    2015-09-11

    Neonates are at high risk for influenza morbidity and mortality due to immune immaturity and lack of priming by prior influenza virus exposure. Inactivated influenza vaccines are ineffective in infants under six months and to provide protection in older children generally require two doses given a month apart. This leaves few options for rapid protection of infants, e.g. during an influenza pandemic. We investigated whether Advax™, a novel polysaccharide adjuvant based on delta inulin microparticles could help overcome neonatal immune hypo-responsiveness. We first tested whether it was possible to use Advax to obtain single-dose vaccine protection of neonatal pups against lethal influenza infection. Inactivated influenza A/H1N1 vaccine (iH1N1) combined with Advax™ adjuvant administered as a single subcutaneous immunization to 7-day-old mouse pups significantly enhanced serum influenza-specific IgM, IgG1, IgG2a and IgG2b levels and was associated with a 3-4 fold increase in the frequency of splenic influenza-specific IgM and IgG antibody secreting cells. Pups immunized with Advax had significantly higher splenocyte influenza-stimulated IFN-γ, IL-2, IL-4, and IL-10 production by CBA and a 3-10 fold higher frequency of IFN-γ, IL-2, IL-4 or IL-17 secreting T cells by ELISPOT. Immunization with iH1N1+Advax induced robust protection of pups against virus challenge 3 weeks later, whereas pups immunized with iH1N1 antigen alone had no protection. Protection by Advax-adjuvanted iH1N1 was dependent on memory B cells rather than memory T cells, with no protection in neonatal μMT mice that are B-cell deficient. Hence, Advax adjuvant overcame neonatal immune hypo-responsiveness and enabled single-dose protection of pups against otherwise lethal influenza infection, thereby supporting ongoing development of Advax™ as a neonatal vaccine adjuvant.

  4. Induction of mammary tumors in virgin female BALB/c mice by single low doses of 7,12-dimethylbenz(a)anthracene

    SciTech Connect

    Ethier, S.P.; Ullrich, R.L.

    1982-11-01

    The induction of mammary tumors in virgin female inbred BALB/c mice after administration of 7,12-dimethylbenz(a)anthracene (DMBA) over a wide range of doses was studied. Mice were exposed at 12 weeks of age to single or multiple doses of DMBA ranging from 0.0025 to 12.0 mg by gastric intubation and were checked regularly for mammary tumors. The experiment was terminated when the mice were 800 days of age. In the dose range of 0.0025-0.125 mg DMBA, the incidence of mammary tumors was dose-dependent. At higher doses, the mammary tumor incidence became less dose-dependent and was nearly independent of doses above the 0.25-mg level. Analysis of the data for the rate of appearance of mammary tumor with age of the animals and for the age at death of non-mammary tumor-bearing animals indicated that in the low dose range induction of mammary tumors was the predominant effect of DMBA exposure, whereas at moderate to high doses the toxic and carcinogenic effects of DMBA on other tissues significantly influenced the final incidence of mammary tumors. Greater than 90% of the tumors that resulted from administration of low doses of DMBA were adenocarcinomas. In contrast, adenocarcinomas and adenoacanthomas were found in approximately equal proportions following administration of high doses of DMBA.

  5. Single, Escalating Dose Pharmacokinetics, Safety and Food Effects of a New Oral Androgen Dimethandrolone Undecanoate in Man: A prototype oral male hormonal contraceptive

    PubMed Central

    Swerdloff, Ronald S.; Nya-Ngatchou, Jean Jacques; Liu, Peter Y.; Amory, John K.; Leung, Andrew; Hull, Laura; Blithe, Diana L.; Woo, Jason; Bremner, William J.; Wang, Christina

    2014-01-01

    The novel androgen, dimethandrolone (DMA) has both androgenic and progestational activities, properties that may maximize gonadotropin suppression. We assessed the pharmacokinetics of dimethandrolone undecanoate (DMAU), an orally bioavailable, longer-acting ester of DMA, for male contraceptive development. Our objective was to examine the safety and pharmacokinetics of single, escalating doses of DMAU (powder in capsule formulation) administered orally with or without food in healthy men. We conducted a randomized, double-blind Phase 1 study. For each dose of DMAU (25 to 800 mg), ten male volunteers received DMAU and two received placebo at two academic medical centers. DMAU was administered both fasting and after a high fat meal (200–800 mg doses). Serial serum samples were collected over 24h following each dose. DMAU was well tolerated without significant effects on vital signs, safety laboratory tests or electrocardiograms. When administered while fasting, serum DMA (active compound) was detectable in only 4/10 participants after the 800mg dose. When administered with a 50% fat meal, serum DMA was detectable in all participants given 200mg DMAU and showed a dose-incremental increase up to 800mg, with peak levels 4 to 8h after taking the dose. Serum gonadotropins and sex hormone concentrations were significantly suppressed 12h after DMAU administration with food at doses above 200mg. This first-in-man study demonstrated that a single, oral dose of DMAU up to 800 mg is safe. A high-fat meal markedly improved DMAU/DMA pharmacokinetics. PMID:24789057

  6. Mycobacterium leprae DNA associated with type 1 reactions in single lesion paucibacillary leprosy treated with single dose rifampin, ofloxacin, and minocycline.

    PubMed

    Sousa, Ana Lucia O M; Stefani, Mariane M A; Pereira, Gisner A S; Costa, Mauricio B; Rebello, Paula F; Gomes, Maria Katia; Narahashi, Kazue; Gillis, Thomas P; Krahenbuhl, James L; Martelli, Celina M T

    2007-11-01

    Leprosy affects skin and peripheral nerves, and acute inflammatory type 1 reactions (reversal reaction) can cause neurologic impairment and disabilities. Single skin lesion paucibacillary leprosy volunteers (N = 135) recruited in three Brazilian endemic regions, treated with single-dose rifampin, ofloxacin, and minocycline (ROM), were monitored for 3 years. Poor outcome was defined as type 1 reactions with or without neuritis. IgM anti-phenolic glycolipid I, histopathology, Mitsuda test, and Mycobacterium leprae DNA polymerase chain reaction (ML-PCR) were performed at baseline. chi(2) test, Kaplan-Meir curves, and Cox proportional hazards were applied. The majority of volunteers were adults with a mean age of 30.5 +/- 15.4 years; 44.4% were ML-PCR positive. During follow-up, 14.8% of the patients had a poor clinical outcome, classified as a type 1 reaction. Older age (> or = 40 years), ML-PCR positivity, and lesion size > 5 cm were associated with increased risk. In multivariate analysis, age (> or = 40 years) and ML-PCR positivity remained baseline predictors of type 1 reaction among monolesion leprosy patients.

  7. Randomized, controlled, assessor-blind clinical trial to assess the efficacy of single- versus repeated-dose albendazole to treat ascaris lumbricoides, trichuris trichiura, and hookworm infection.

    PubMed

    Adegnika, Ayola A; Zinsou, Jeannot F; Issifou, Saadou; Ateba-Ngoa, Ulysse; Kassa, Roland F; Feugap, Eliane N; Honkpehedji, Yabo J; Dejon Agobe, Jean-Claude; Kenguele, Hilaire M; Massinga-Loembe, Marguerite; Agnandji, Selidji T; Mordmüller, Benjamin; Ramharter, Michael; Yazdanbakhsh, Maria; Kremsner, Peter G; Lell, Bertrand

    2014-05-01

    In many regions where soil-transmitted helminth infections are endemic, single-dose albendazole is used in mass drug administration programs to control infections. There are little data on the efficacy of the standard single-dose administration compared to that of alternative regimens. We conducted a randomized, controlled, assessor-blinded clinical trial to determine the efficacies of standard and extended albendazole treatment against soil-transmitted helminth infection in Gabon. A total of 175 children were included. Adequate cure rates and egg reduction rates above 85% were found with a single dose of albendazole for Ascaris infection, 85% (95% confidence interval [CI], 73, 96) and 93.8% (CI, 87.6, 100), respectively, while two doses were necessary for hookworm infestation (92% [CI, 78, 100] and 92% [CI, 78, 100], respectively). However, while a 3-day regimen was not sufficient to cure Trichuris (cure rate, 83% [CI, 73, 93]), this regimen reduced the number of eggs up to 90.6% (CI, 83.1, 100). The rate ratios of two- and three-dose regimens compared to a single-dose treatment were 1.7 (CI, 1.1, 2.5) and 2.1 (CI, 1.5, 2.9) for Trichuris and 1.7 (CI, 1.0, 2.9) and 1.7 (CI, 1.0, 2.9) for hookworm. Albendazole was safe and well tolerated in all regimens. A single-dose albendazole treatment considerably reduces Ascaris infection but has only a moderate effect on hookworm and Trichuris infections. The single-dose option may still be the preferred regimen because it balances efficacy, safety, and compliance during mass drug administration, keeping in mind that asymptomatic low-level helminth carriage may also have beneficial effects. (This study has been registered at ClinicalTrials.gov under registration number NCT01192802.).

  8. Pharmacokinetics and buccal mucosal concentrations of a 15 milligram per kilogram of body weight total dose of liposomal amphotericin B administered as a single dose (15 mg/kg), weekly dose (7.5 mg/kg), or daily dose (1 mg/kg) in peripheral stem cell transplant patients.

    PubMed

    Gubbins, Paul O; Amsden, Jarrett R; McConnell, Scott A; Anaissie, Elias J

    2009-09-01

    The pharmacokinetics and safety of extended-interval dosing of prophylactic liposomal amphotericin B (L-AMB) in peripheral stem cell transplant recipients were evaluated. The patients received L-AMB daily at 1 mg/kg of body weight or weekly at 7.5 mg/kg or received L-AMB as a single dose (15 mg/kg). The buccal mucosal tissue concentrations of L-AMB were measured. Of the 24 patients enrolled, 5 withdrew after the initial dose due to an infusion-related reaction (n = 2) or significant increases in the serum creatinine (Scr) levels (n = 3). Weekly L-AMB dosing (7.5 mg/kg) produced mean plasma concentrations of >0.300 microg/ml for the first 7 days and >0.220 microg/ml for 7 days after the second dose. A single L-AMB dose (15 mg/kg) produced mean plasma concentrations of >0.491 microg/ml for at least 7 seven days. These concentrations are within the range of the MICs reported in the literature for susceptible strains of Candida and are at the lower limits of the MICs for Aspergillus spp. Extended-interval dosing produced buccal mucosal tissue concentrations well in excess of the MICs reported in the literature for susceptible strains of Candida and Aspergillus spp. Infusion-related reactions occurred in 24% of the patients. Baseline and end-of-study Scr, electrolyte (K+, Mg2+, PO4), and serum transaminase levels were similar across the dosage groups. Five (31%) patients met the nephrotoxicity definition prior to completion of the study. Patients in the weekly or single-dose groups experienced nephrotoxicity significantly faster than the patients in the daily dosing cohort. A weekly L-AMB dose (7.5 mg/kg) or a single L-AMB dose (15 mg/kg) produced sufficient concentrations in plasma and highly vascular tissue to warrant further studies of the safety, efficacy, and practicality of the weekly prophylactic administration of L-AMB. PMID:19546359

  9. Pharmacokinetics and Buccal Mucosal Concentrations of a 15 Milligram per Kilogram of Body Weight Total Dose of Liposomal Amphotericin B Administered as a Single Dose (15 mg/kg), Weekly Dose (7.5 mg/kg), or Daily Dose (1 mg/kg) in Peripheral Stem Cell Transplant Patients▿

    PubMed Central

    Gubbins, Paul O.; Amsden, Jarrett R.; McConnell, Scott A.; Anaissie, Elias J.

    2009-01-01

    The pharmacokinetics and safety of extended-interval dosing of prophylactic liposomal amphotericin B (L-AMB) in peripheral stem cell transplant recipients were evaluated. The patients received L-AMB daily at 1 mg/kg of body weight or weekly at 7.5 mg/kg or received L-AMB as a single dose (15 mg/kg). The buccal mucosal tissue concentrations of L-AMB were measured. Of the 24 patients enrolled, 5 withdrew after the initial dose due to an infusion-related reaction (n = 2) or significant increases in the serum creatinine (Scr) levels (n = 3). Weekly L-AMB dosing (7.5 mg/kg) produced mean plasma concentrations of >0.300 μg/ml for the first 7 days and >0.220 μg/ml for 7 days after the second dose. A single L-AMB dose (15 mg/kg) produced mean plasma concentrations of >0.491 μg/ml for at least 7 seven days. These concentrations are within the range of the MICs reported in the literature for susceptible strains of Candida and are at the lower limits of the MICs for Aspergillus spp. Extended-interval dosing produced buccal mucosal tissue concentrations well in excess of the MICs reported in the literature for susceptible strains of Candida and Aspergillus spp. Infusion-related reactions occurred in 24% of the patients. Baseline and end-of-study Scr, electrolyte (K+, Mg2+, PO4), and serum transaminase levels were similar across the dosage groups. Five (31%) patients met the nephrotoxicity definition prior to completion of the study. Patients in the weekly or single-dose groups experienced nephrotoxicity significantly faster than the patients in the daily dosing cohort. A weekly L-AMB dose (7.5 mg/kg) or a single L-AMB dose (15 mg/kg) produced sufficient concentrations in plasma and highly vascular tissue to warrant further studies of the safety, efficacy, and practicality of the weekly prophylactic administration of L-AMB. PMID:19546359

  10. Pharmacokinetics and buccal mucosal concentrations of a 15 milligram per kilogram of body weight total dose of liposomal amphotericin B administered as a single dose (15 mg/kg), weekly dose (7.5 mg/kg), or daily dose (1 mg/kg) in peripheral stem cell transplant patients.

    PubMed

    Gubbins, Paul O; Amsden, Jarrett R; McConnell, Scott A; Anaissie, Elias J

    2009-09-01

    The pharmacokinetics and safety of extended-interval dosing of prophylactic liposomal amphotericin B (L-AMB) in peripheral stem cell transplant recipients were evaluated. The patients received L-AMB daily at 1 mg/kg of body weight or weekly at 7.5 mg/kg or received L-AMB as a single dose (15 mg/kg). The buccal mucosal tissue concentrations of L-AMB were measured. Of the 24 patients enrolled, 5 withdrew after the initial dose due to an infusion-related reaction (n = 2) or significant increases in the serum creatinine (Scr) levels (n = 3). Weekly L-AMB dosing (7.5 mg/kg) produced mean plasma concentrations of >0.300 microg/ml for the first 7 days and >0.220 microg/ml for 7 days after the second dose. A single L-AMB dose (15 mg/kg) produced mean plasma concentrations of >0.491 microg/ml for at least 7 seven days. These concentrations are within the range of the MICs reported in the literature for susceptible strains of Candida and are at the lower limits of the MICs for Aspergillus spp. Extended-interval dosing produced buccal mucosal tissue concentrations well in excess of the MICs reported in the literature for susceptible strains of Candida and Aspergillus spp. Infusion-related reactions occurred in 24% of the patients. Baseline and end-of-study Scr, electrolyte (K+, Mg2+, PO4), and serum transaminase levels were similar across the dosage groups. Five (31%) patients met the nephrotoxicity definition prior to completion of the study. Patients in the weekly or single-dose groups experienced nephrotoxicity significantly faster than the patients in the daily dosing cohort. A weekly L-AMB dose (7.5 mg/kg) or a single L-AMB dose (15 mg/kg) produced sufficient concentrations in plasma and highly vascular tissue to warrant further studies of the safety, efficacy, and practicality of the weekly prophylactic administration of L-AMB.

  11. Search for atoxic cereals: a single blind, cross-over study on the safety of a single dose of Triticum monococcum, in patients with celiac disease

    PubMed Central

    2013-01-01

    Background Cereals of baking quality with absent or reduced toxicity are actively sought as alternative therapy to a gluten-free diet (GFD) for patients with coeliac disease (CD). Triticum monococcum, an ancient wheat, is a potential candidate having no toxicity in in-vitro and ex-vivo studies. The aim of our study was to investigate on the safety of administration of a single dose of gluten of Tm in patients with CD on GFD. Methods We performed a single blind, cross-over study involving 12 CD patients who had been on a GFD for at least 12 months, challenged on day 0, 14 and 28 with a single fixed dose of 2.5 grams of the following (random order): Tm, rice (as reference atoxic protein) and Amygluten (as reference toxic protein) dispersed in a gluten-free pudding. The primary end-point of the study was the change in intestinal permeability, as assessed by changes in the urinary lactulose/rhamnose ratio (L/R ratio) measured by High Pressure Liquid Chromatography. We also assessed the occurrence of adverse gastrointestinal events, graded for intensity and duration according to the WHO scale. Variables were expressed as mean ± SD; paired t-test and χ2 test were used as appropriate. Results The urinary L/R ratio did not change significantly upon challenge with the 3 cereals, and was 0.055 ± 0.026 for Tm Vs 0.058 ± 0.035 for rice (p = 0.6736) and Vs 0.063 ± 0.054 with Amygluten (p = 0.6071). Adverse gastrointestinal events were 8 for Tm, Vs 11 for rice (p = 0.6321) and Vs 31 for Amygluten p = 0.0016), and, in all cases events were graded as “mild” or “moderate” with TM and rice, and as “severe” or “disabling” in 4 cases during Amygluten. Conclusions No definite conclusion can be drawn on the safety of Tm, based on no change in urinary L/R because even Amygluten, a toxic wheat protein, did not cause a significant change in urinary L/R indicating low sensitivity of this methodology in studies on acute toxicity. Tm was

  12. Delivery characteristics and patients' handling of two single-dose dry-powder inhalers used in COPD.

    PubMed

    Chapman, Kenneth R; Fogarty, Charles M; Peckitt, Clare; Lassen, Cheryl; Jadayel, Dalal; Dederichs, Juergen; Dalvi, Mukul; Kramer, Benjamin

    2011-01-01

    For optimal efficacy, an inhaler should deliver doses consistently and be easy for patients to use with minimal instruction. The delivery characteristics, patients' correct use, and preference of two single-dose dry powder inhalers (Breezhaler and HandiHaler) were evaluated in two complementary studies. The first study examined aerodynamic particle size distribution, using inhalation profiles of seven patients with moderate to very severe chronic obstructive pulmonary disease (COPD). The second was an open-label, two-period, 7-day crossover study, evaluating use of the inhalers with placebo capsules by 82 patients with mild to severe COPD. Patients' correct use of the inhalers was assessed after reading written instructions on Day 1, and after training and 7 days of daily use. Patients' preference was assessed after completion of both study periods. Patient inhalation profiles showed average peak inspiratory flows of 72 L/minute through Breezhaler and 36 L/minute through HandiHaler. For Breezhaler and HandiHaler, fine particle fractions were 27% and 10%, respectively. In the second study, correct use of Breezhaler and HandiHaler was achieved by > 77% of patients for any step after 7 days; 61% of patients showed an overall preference for Breezhaler and 31% for HandiHaler (P = 0.01).Breezhaler is a low-resistance inhaler suitable for use by patients with a range of disease severities. Most patients used both inhalers correctly after 7 days, but more patients showed an overall preference for the Breezhaler compared with the HandiHaler. These are important factors for optimum dose delivery and successful COPD management.

  13. Ingestion of chromium(VI) in drinking water by human volunteers: Absorption, distribution, and excretion of single and repeated doses

    SciTech Connect

    Kerger, B.D.; Corbett, G.E.; Dodge, D.G.

    1997-01-01

    This study examines the magnitude of hexavalent chromium [Cr(VI)] absorption, distribution, and excretion following oral exposure to 5 and 10 mg Cr(VI)/L in drinking water administered as a single bolus dose or for 3 d at a dosage of 1 L/d. Adult male volunteers were used. In the bolus dose studies, a fairly consistent pattern of urinary chromium excretion was observed, with an average half life of about 39 h. However, 4-d total urinary chromium excretion and peak concentrations in urine and blood varied considerably among the 5 volunteers. Studies of repeated exposure to small volumes ingested at a more gradual rate showed similar urinary chromium excretion patterns but generally lower chromium uptake/excretion. These data suggest that virtually all of the ingested Cr(VI) at 5 and 10 mg Cr(VI)/L was reduced to Cr(III) before entering the bloodstream. The interindividual differences in total chromium uptake and excretion are plausibly explained by ingestion of appreciable doses on an empty stomach, likely results in the formation of well-absorbed Cr(III) organic complexes. No clinical indications of toxicity in the volunteers and the patterns of blood uptake and urinary excretion of chromium are consistent with a predominant uptake of Cr(III) organic complexes that are excreted more slowly than inorganic forms of Cr(III). Therefore, it appears that the endogenous reducing agents within the upper gastrointestinal tract and the blood provide sufficient reducing potential to prevent any substantial systemic uptake of Cr(VI) following drinking-water exposures at 5-10 mg Cr(VI)/L. Based on these data, the chemical environment in the gastrointestinal tract and the blood is effective even under relative fasting condition in reducing Cr(VI) to one or more forms of Cr(III). 54 refs., 5 figs., 1 tab.

  14. Estimates of dose to systematic organs and GI tract based on data from miniature swine orally intubated with a single dose of Am-241 citrate

    SciTech Connect

    Bernard, S.R.; Nestor, C.W. Jr.; Eisele, G.R.; Eckerman, K.F.

    1982-01-01

    A model is presented for the internal radiation dose to the small intestine wall of miniature swine given Americium 241 citrate by oral intubation. The model incorporates the uptake of the Am-241 by the intestinal wall. About equal contributions of dose to the small intestine were observed from the intestinal contents and the wall itself. (ACR)

  15. Bixin and norbixin in human plasma: determination and study of the absorption of a single dose of Annatto food color.

    PubMed

    Levy, L W; Regalado, E; Navarrete, S; Watkins, R H

    1997-09-01

    A procedure was developed for the detection and determination of bixin and norbixin in human plasma by reversed-phase HPLC with a sensitivity limit of 5 micrograms l-1. A group of seven volunteers ingested a single dose of 1 ml of a commercial Annatto Food Color (16 mg of cis-bixin in soybean oil). The presence of bixin (cis and trans) and norbixin (cis and trans) was demonstrated in the plasma at average levels of 11.6, 10.1, 2.8 and 0 micrograms l-1 of bixin and 48, 58, 53 and 29 micrograms l-1 of norbixin after 2, 4, 6 and 8 h, respectively. Considerable individual variations were observed. Complete plasma clearance generally occurred for bixin by 8 h and for norbixin by 24 h after ingestion of cis-bixin.

  16. The pros and cons of split-dose granulocyte colony-stimulating factor alone rather than a single high dose for hematopoietic progenitor cell mobilization in small children (< 15 kg) with solid tumors.

    PubMed

    Merlin, Etienne; Piguet, Christophe; Auvrignon, Anne; Rubie, Hervé; Deméocq, François; Kanold, Justyna

    2006-07-01

    Hematopoietic progenitor cells were mobilized in 34 children with solid tumors weighing < or = 15 kg using granulocyte colony-stimulating factor alone at the doses of 10, 20 or 2 x 12 microg/kg/day. The mobilization with 2 x 12 microg/kg/day was more efficient than that with 10 mg/kg/day. Although the superiority of the split-dose compared to the single, high daily dose (20 microg/kg/day) was not statistically significant, our results suggest that the 2 x 12 microg/kg/day regimen is interesting.

  17. Achievement of therapeutic goals with low-dose imiglucerase in Gaucher disease: a single-center experience.

    PubMed

    Tukan, Irina; Hadas-Halpern, Irith; Altarescu, Gheona; Abrahamov, Ayala; Elstein, Deborah; Zimran, Ari

    2013-01-01

    Gaucher disease, a lysosomal storage disorder, is a multisystem disorder with variable and unpredictable onset and severity. Disease-specific enzyme replacement therapy (ERT) has been shown to reverse or ameliorate disease-specific hepatosplenomegaly and anemia and thrombocytopenia. ERT also impacts bone manifestations, including bone crises, bone pain, and appearance of new osteonecrosis, and improves bone mineral density to varying degrees. The objective of this study was to assess achievement of predefined therapeutic goals based on international registry outcomes for Israeli patients with Gaucher disease receiving imiglucerase for four consecutive years on a low-dose regimen followed in a single center. All data were taken from patient files. The therapeutic goals were taken from standards published in the literature for disease-specific clinical parameters. Among 164 patients at baseline, values for spleen and liver volumes, hemoglobin and platelet counts, and Z-scores for lumbar spine and femoral were significantly different from the goal. After four years ERT, there was a significant improvement (P = 0.000) in each of the therapeutic goal parameters from baseline. 15.2% of these patients achieved all hematology-visceral goals. In children, there was achievement of linear growth and puberty. This survey highlights the good overall response in symptomatic patients receiving low-dose ERT with imiglucerase in Israel. PMID:24285960

  18. Prescription opioids. III. Disposition of oxycodone in oral fluid and blood following controlled single-dose administration.

    PubMed

    Cone, Edward J; DePriest, Anne Z; Heltsley, Rebecca; Black, David L; Mitchell, John M; LoDico, Charles; Flegel, Ron

    2015-04-01

    Oxycodone (OC) is recommended to be included as an analyte tested in the proposed Substance Abuse and Mental Health Services Administration (SAMHSA's) Mandatory Guidelines for Federal Workplace Drug Testing Programs using Oral Fluid (OF) Specimens. This study demonstrates the time course of OC and metabolites, noroxycodone (NOC), oxymorphone (OM) and noroxymorphone (NOM), in near-simultaneous paired OF and whole blood (BL) specimens by liquid chromatography-tandem mass spectrometry (LC-MS-MS) (limit of detection = 1 ng/mL OF, 5 ng/mL BL). A single dose of OC 20 mg controlled-release was administered to 12 healthy subjects followed by specimen collections for 52 h. Analyte prevalence was as follows: OF, OC > NOC > OM; and BL, OC > NOC > NOM. OC and NOC were frequently detected within 15-30 min in OF and 30 min to 2 h in BL. NOM and OM appeared between 1.5-5 h post-dose. The mean OF-to-BL (OF:BL) ratios and correlations were 5.4 for OC (r = 0.719) and 1.0 for NOC (r = 0.651). The period of detection for OF exceeded BL by ∼2-fold at similar cutoff concentrations. At a 1 ng/mL cutoff for OF, the mean detection time was 34 h for OC and NOC. These data provide new information that should facilitate interpretation of OC test results.

  19. A Single Low Dose of Proton Radiation Induces Long-Term Behavioral and Electrophysiological Changes in Mice.

    PubMed

    Bellone, John A; Rudobeck, Emil; Hartman, Richard E; Szücs, Attila; Vlkolinský, Roman

    2015-08-01

    Astronauts traveling outside Earth's magnetosphere risk exposure to charged particle radiation that may cause neurophysiological changes and behavioral deficits. Although proton particles comprise a large portion of the space radiation environment, little has been published on the effects of low-dose proton radiation on central nervous system function. In the current study, we irradiated young male mice with 0.5 Gy 150 MeV protons and assessed the effects on behavior and hippocampal neurophysiology. Spatial learning ability, a sensitive behavioral marker of hippocampal damage, was assessed using the water maze and Barnes maze before irradiation and repeatedly 3 and 6 months after irradiation. Evoked field excitatory postsynaptic potentials (fEPSPs) and population spikes, long-term potentiation (LTP) and spontaneous oscillations (SOs) triggered by incubation with Mg(2+)-free media (reflecting interictal epileptiform activity) were assessed 9 months after irradiation in vitro in hippocampal slice preparations. Irradiated mice exhibited impaired reversal learning in the water maze compared to control mice 6 months after irradiation. Proton radiation did not affect LTP, but significantly increased fEPSP slopes and reduced the incidence of SOs 9 months after irradiation. These findings suggest that a single exposure to low-dose proton radiation can increase synaptic excitability and suppress the propensity for epileptiform activity. Such findings of functional alterations in the irradiated mouse hippocampus have implications for extended manned space missions planned in the near future. PMID:26207690

  20. Sensitive and specific radioimmunoassay for fialuridine: initial assessment of pharmacokinetics after single oral doses to healthy volunteers.

    PubMed Central

    Bowsher, R R; Compton, J A; Kirkwood, J A; Place, G D; Jones, C D; Mabry, T E; Hyslop, D L; Hatcher, B L; DeSante, K A

    1994-01-01

    Fialuridine (FIAU) is a halogen-substituted analog of thymidine that was undergoing clinical investigation as a drug for the treatment of chronic hepatitis B viral infection. However, clinical trials of FIAU were terminated after adverse events occurred following chronic oral administration. Prior to the termination of clinical trials, a sensitive assay was needed for the measurement of FIAU because of the anticipated low dose administered to patients. We therefore undertook the development of a radioimmunoassay (RIA). A specific antiserum was raised in rabbits following immunization with a 5'-O-hemisuccinate analog of FIAU coupled to keyhole limpet hemocyanin. Radiolabeled FIAU was synthesized by a destannylation procedure by using sodium [125I]iodide. We developed a competitive-binding procedure and used precipitation with polyethylene glycol as the method for separating the bound and free forms of FIAU. The RIA is sensitive (0.2 ng/ml), specific (negligible interference from known metabolites and endogenous nucleosides), and reproducible (interassay coefficients of variation range from 5 to 19.7% for serum controls). We used the RIA to assess the pharmacokinetics of FIAU in healthy adult volunteers following administration of a single 5-mg oral dose. The sensitivity of the RIA permitted the detection of a prolonged elimination phase for FIAU in healthy volunteers and dogs, with mean elimination half-lives of 29.3 and 35.3 h, respectively. We conclude the RIA is a valid method for the quantification of FIAU in biological fluids. PMID:7811032

  1. Development of a novel multi-point plastic scintillation detector with a single optical transmission line for radiation dose measurement*

    PubMed Central

    Therriault-Proulx, François; Archambault, Louis; Beaulieu, Luc; Beddar, Sam

    2013-01-01

    Purpose The goal of this study was to develop a novel multi-point plastic scintillation detector (mPSD) capable of measuring the dose accurately at multiple positions simultaneously using a single optical transmission line. Methods A 2-point mPSD used a band-pass approach that included splitters, color filters, and an EMCCD camera. The 3-point mPSD was based on a new full-spectrum approach, in which a spectrograph was coupled to a CCD camera. Irradiations of the mPSDs and of an ion chamber were performed with a 6-MV photon beam at various depths and lateral positions in a water tank. Results For the 2-point mPSD, the average relative differences between mPSD and ion chamber measurements for the depth-dose were 2.4±1.6% and 1.3±0.8% for BCF-60 and BCF-12, respectively. For the 3-point mPSD, the average relative differences over all conditions were 2.3±1.1%, 1.6±0.4%, and 0.32±0.19% for BCF-60, BCF-12, and BCF-10, respectively. Conclusions This study demonstrates the practical feasibility of mPSDs. This type of detector could be very useful for pre-treatment quality assurance applications as well as an accurate tool for real-time in vivo dosimetry. PMID:23060069

  2. A single dose of alcohol does not meaningfully alter circadian phase advances and phase delays to light in humans.

    PubMed

    Burgess, Helen J; Rizvydeen, Muneer; Fogg, Louis F; Keshavarzian, Ali

    2016-04-15

    Central circadian timing influences mental and physical health. Research in nocturnal rodents has demonstrated that when alcohol is consumed, it reaches the central hypothalamic circadian pacemaker (suprachiasmatic nuclei) and can directly alter circadian phase shifts to light. In two separate studies, we examined, for the first time, the effects of a single dose of alcohol on circadian phase advances and phase delays to light in humans. Two 23-day within-subjects placebo-controlled counterbalanced design studies were conducted. Both studies consisted of 6 days of fixed baseline sleep to stabilize circadian timing, a 2-day laboratory session, a 6-day break, and a repeat of 6 days of fixed sleep and a 2-day laboratory session. In the phase advance study (n= 10 light drinkers, 24-45 yr), the laboratory sessions consisted of a baseline dim light phase assessment, sleep episode, alcohol (0.6 g/kg) or placebo, 2-h morning bright light pulse, and final phase assessment. In the phase-delay study (n= 14 light drinkers, 22-44 yr), the laboratory sessions consisted of a baseline phase assessment, alcohol (0.8 g/kg) or placebo, 2-h late night bright light pulse, sleep episode, and final phase assessment. In both studies, alcohol either increased or decreased the observed phase shifts to light (interaction P≥ 0.46), but the effect of alcohol vs. placebo on phase shifts to light was always on average smaller than 30 min. Thus, no meaningful effects of a single dose of alcohol vs. placebo on circadian phase shifts to light in humans were observed. PMID:26936778

  3. Acute single dose of ketamine relieves mechanical allodynia and consequent depression-like behaviors in a rat model.

    PubMed

    Zhang, Guang-Fen; Wang, Jing; Han, Jin-Feng; Guo, Jie; Xie, Ze-Min; Pan, Wei; Yang, Jian-Jun; Sun, Kang-Jian

    2016-09-19

    Both chronic pain and depression are debilitating diseases, which often coexist in clinic. However, current analgesics and antidepressants exhibit limited efficacy for this comorbidity. The present study aimed to investigate the effect of ketamine on the comorbidity of inflammatory pain and consequent depression-like behaviors in a rat model established by intraplantar administration of complete Freunds adjuvant (CFA). The mechanical withdrawal threshold, thermal withdrawal latency, open field test, forced swimming test, and sucrose preference test were evaluated after the CFA injection and ketamine treatment. The hippocampus was harvested to determine the levels of interleukin (IL)-6, IL-1β, indoleamine 2,3-dioxygenase (IDO), kynurenine (KYN), 5-hydroxytryptamine (5-HT), and tryptophan (TRP). The inflammatory pain-induced depression-like behaviors presented on 7days and lasted to at least 14days after the CFA injection. Single dose of ketamine at 20mg/kg relieved both the mechanical allodynia and the associated depression-like behaviors as demonstrated by the attenuated mechanical withdrawal threshold, reduced immobility time in the forced swim test, and increased sucrose preference after ketamine treatment. The total distance had no significant change after the CFA injection or ketamine treatment in the open field test. Simultaneously, ketamine reduced the levels of IL-6, IL-1β, IDO, and KYN/TRP ratio and increased the 5-HT/TRP ratio in the hippocampus. In conclusion, acute single dose of ketamine can rapidly attenuate mechanical allodynia and consequent depression-like behaviors and down-regulate hippocampal proinflammatory responses and IDO/KYN signal pathway in rats. PMID:27497920

  4. Toxicodynamic effects of ciclosporin are reflected by metabolite profiles in the urine of healthy individuals after a single dose

    PubMed Central

    Klawitter, Jost; Haschke, Manuel; Kahle, Christine; Dingmann, Colleen; Klawitter, Jelena; Leibfritz, Dieter; Christians, Uwe

    2010-01-01

    AIMS The immunosuppressant ciclosporin is an efficient prophylaxis against transplant organ rejection but its clinical use is limited by its nephrotoxicity. Our previous systematic studies in the rat indicated urine metabolite pattern changes to be sensitive indicators of the negative effects of ciclosporin on the kidney. To translate these results, we conducted an open label, placebo-controlled, crossover study assessing the time-dependent toxicodynamic effects of a single oral ciclosporin dose (5 mg kg−1) on the kidney in 13 healthy individuals. METHODS In plasma and urine samples, ciclosporin and 15-F2t-isoprostane concentrations were assessed using HPLC-MS and metabolite profiles using 1H-NMR spectroscopy. RESULTS The maximum ciclosporin concentrations were 1489 ± 425 ng ml−1 (blood) and 2629 ± 1308 ng ml−1 (urine). The increase in urinary 15-F2t-isoprostane observed 4 h after administration of ciclosporin indicated an increase in oxidative stress. 15-F2t-isoprostane concentrations were on average 2.9-fold higher after ciclosporin than after placebo (59.8 ± 31.2 vs. 20.9 ± 19.9 pg mg−1 creatinine, P < 0.02). While there were no conclusive changes in plasma 15-F2t-isoprostane concentrations or metabolite patterns, non-targeted metabolome analysis using principal components analysis and partial least square fit analysis revealed significant changes in urine metabolites typically associated with negative effects on proximal tubule cells. The major metabolites that differed between the 4 h urine samples after ciclosporin and placebo were citrate, hippurate, lactate, TMAO, creatinine and phenylalanine. CONCLUSION Changes in urine metabolite patterns as a molecular marker are sufficiently sensitive for the detection of the negative effects of ciclosporin on the kidney after a single oral dose. PMID:20653677

  5. A single dose of alcohol does not meaningfully alter circadian phase advances and phase delays to light in humans.

    PubMed

    Burgess, Helen J; Rizvydeen, Muneer; Fogg, Louis F; Keshavarzian, Ali

    2016-04-15

    Central circadian timing influences mental and physical health. Research in nocturnal rodents has demonstrated that when alcohol is consumed, it reaches the central hypothalamic circadian pacemaker (suprachiasmatic nuclei) and can directly alter circadian phase shifts to light. In two separate studies, we examined, for the first time, the effects of a single dose of alcohol on circadian phase advances and phase delays to light in humans. Two 23-day within-subjects placebo-controlled counterbalanced design studies were conducted. Both studies consisted of 6 days of fixed baseline sleep to stabilize circadian timing, a 2-day laboratory session, a 6-day break, and a repeat of 6 days of fixed sleep and a 2-day laboratory session. In the phase advance study (n= 10 light drinkers, 24-45 yr), the laboratory sessions consisted of a baseline dim light phase assessment, sleep episode, alcohol (0.6 g/kg) or placebo, 2-h morning bright light pulse, and final phase assessment. In the phase-delay study (n= 14 light drinkers, 22-44 yr), the laboratory sessions consisted of a baseline phase assessment, alcohol (0.8 g/kg) or placebo, 2-h late night bright light pulse, sleep episode, and final phase assessment. In both studies, alcohol either increased or decreased the observed phase shifts to light (interaction P≥ 0.46), but the effect of alcohol vs. placebo on phase shifts to light was always on average smaller than 30 min. Thus, no meaningful effects of a single dose of alcohol vs. placebo on circadian phase shifts to light in humans were observed.

  6. SU-E-T-556: Monte Carlo Generated Dose Distributions for Orbital Irradiation Using a Single Anterior-Posterior Electron Beam and a Hanging Lens Shield

    SciTech Connect

    Duwel, D; Lamba, M; Elson, H; Kumar, N

    2015-06-15

    Purpose: Various cancers of the eye are successfully treated with radiotherapy utilizing one anterior-posterior (A/P) beam that encompasses the entire content of the orbit. In such cases, a hanging lens shield can be used to spare dose to the radiosensitive lens of the eye to prevent cataracts. Methods: This research focused on Monte Carlo characterization of dose distributions resulting from a single A-P field to the orbit with a hanging shield in place. Monte Carlo codes were developed which calculated dose distributions for various electron radiation energies, hanging lens shield radii, shield heights above the eye, and beam spoiler configurations. Film dosimetry was used to benchmark the coding to ensure it was calculating relative dose accurately. Results: The Monte Carlo dose calculations indicated that lateral and depth dose profiles are insensitive to changes in shield height and electron beam energy. Dose deposition was sensitive to shield radius and beam spoiler composition and height above the eye. Conclusion: The use of a single A/P electron beam to treat cancers of the eye while maintaining adequate lens sparing is feasible. Shield radius should be customized to have the same radius as the patient’s lens. A beam spoiler should be used if it is desired to substantially dose the eye tissues lying posterior to the lens in the shadow of the lens shield. The compromise between lens sparing and dose to diseased tissues surrounding the lens can be modulated by varying the beam spoiler thickness, spoiler material composition, and spoiler height above the eye. The sparing ratio is a metric that can be used to evaluate the compromise between lens sparing and dose to surrounding tissues. The higher the ratio, the more dose received by the tissues immediately posterior to the lens relative to the dose received by the lens.

  7. High doses of dextromethorphan, an NMDA antagonist, produce effects similar to classic hallucinogens

    PubMed Central

    Carter, Lawrence P.; Johnson, Matthew W.; Mintzer, Miriam Z.; Klinedinst, Margaret A.; Griffiths, Roland R.

    2013-01-01

    Rationale Although reports of dextromethorphan (DXM) abuse have increased recently, few studies have examined the effects of high doses of DXM. Objective This study in humans evaluated the effects of supratherapeutic doses of DXM and triazolam. Methods Single, acute, oral doses of DXM (100, 200, 300, 400, 500, 600, 700, 800 mg/70 kg), triazolam (0.25, 0.5 mg/70kg), and placebo were administered to twelve healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Subjective, behavioral, and physiological effects were assessed repeatedly after drug administration for 6 hours. Results Triazolam produced dose-related increases in subject-rated sedation, observer-rated sedation, and behavioral impairment. DXM produced a profile of dose-related physiological and subjective effects differing from triazolam. DXM effects included increases in blood pressure, heart rate, and emesis, increases in observer-rated effects typical of classic hallucinogens (e.g. distance from reality, visual effects with eyes open and closed, joy, anxiety), and participant ratings of stimulation (e.g. jittery, nervous), somatic effects (e.g. tingling, headache), perceptual changes, end-of-session drug liking, and mystical-type experience. After 400 mg/70kg DXM, 11 of 12 participants indicated on a pharmacological class questionnaire that they thought they had received a classic hallucinogen (e.g. psilocybin). Drug effects resolved without significant adverse effects by the end of the session. In a 1-month follow up volunteers attributed increased spirituality and positive changes in attitudes, moods, and behavior to the session experiences. Conclusions High doses of DXM produced effects distinct from triazolam and had characteristics that were similar to the classic hallucinogen psilocybin. PMID:22526529

  8. Hypoxia-Inducible Factor Pathway Inhibition Resolves Tumor Hypoxia and Improves Local Tumor Control After Single-Dose Irradiation

    SciTech Connect

    Helbig, Linda; Koi, Lydia; Brüchner, Kerstin; Gurtner, Kristin; Hess-Stumpp, Holger; Unterschemmann, Kerstin; Pruschy, Martin; and others

    2014-01-01

    Purpose: To study the effects of BAY-84-7296, a novel orally bioavailable inhibitor of mitochondrial complex I and hypoxia-inducible factor 1 (HIF-1) activity, on hypoxia, microenvironment, and radiation response of tumors. Methods and Materials: UT-SCC-5 and UT-SCC-14 human squamous cell carcinomas were transplanted subcutaneously in nude mice. When tumors reached 4 mm in diameter BAY-84-7296 (Bayer Pharma AG) or carrier was daily administered to the animals. At 7 mm tumors were either excised for Western blot and immunohistologic investigations or were irradiated with single doses. After irradiation animals were randomized to receive BAY-84-7296 maintenance or carrier. Local tumor control was evaluated 150 days after irradiation, and the dose to control 50% of tumors (TCD{sub 50}) was calculated. Results: BAY-84-7296 decreased nuclear HIF-1α expression. Daily administration of inhibitor for approximately 2 weeks resulted in a marked decrease of pimonidazole hypoxic fraction in UT-SCC-5 (0.5% vs 21%, P<.0001) and in UT-SCC-14 (0.3% vs 19%, P<.0001). This decrease was accompanied by a significant increase in fraction of perfused vessels in UT-SCC-14 but not in UT-SCC-5. Bromodeoxyuridine and Ki67 labeling indices were significantly reduced only in UT-SCC-5. No significant changes were observed in vascular area or necrosis. BAY-84-7296 before single-dose irradiation significantly decreased TCD{sub 50}, with an enhancement ratio of 1.37 (95% confidence interval [CI] 1.13-1.72) in UT-SCC-5 and of 1.55 (95% CI 1.26-1.94) in UT-SCC-14. BAY-84-7296 maintenance after irradiation did not further decrease TCD{sub 50}. Conclusions: BAY-84-7296 resulted in a marked decrease in tumor hypoxia and substantially reduced radioresistance of tumor cells with the capacity to cause a local recurrence after irradiation. The data suggest that reduction of cellular hypoxia tolerance by BAY-84-7296 may represent the primary biological mechanism underlying the observed enhancement of

  9. Preoperative Single-Fraction Partial Breast Radiation Therapy: A Novel Phase 1, Dose-Escalation Protocol With Radiation Response Biomarkers

    SciTech Connect

    Horton, Janet K.; Blitzblau, Rachel C.; Yoo, Sua; Geradts, Joseph; Chang, Zheng; Baker, Jay A.; Georgiade, Gregory S.; Chen, Wei; Siamakpour-Reihani, Sharareh; Wang, Chunhao; Broadwater, Gloria; Groth, Jeff; Palta, Manisha; Dewhirst, Mark; Barry, William T.; Duffy, Eileen A.; and others

    2015-07-15

    Purpose: Women with biologically favorable early-stage breast cancer are increasingly treated with accelerated partial breast radiation (PBI). However, treatment-related morbidities have been linked to the large postoperative treatment volumes required for external beam PBI. Relative to external beam delivery, alternative PBI techniques require equipment that is not universally available. To address these issues, we designed a phase 1 trial utilizing widely available technology to 1) evaluate the safety of a single radiation treatment delivered preoperatively to the small-volume, intact breast tumor and 2) identify imaging and genomic markers of radiation response. Methods and Materials: Women aged ≥55 years with clinically node-negative, estrogen receptor–positive, and/or progesterone receptor–positive HER2−, T1 invasive carcinomas, or low- to intermediate-grade in situ disease ≤2 cm were enrolled (n=32). Intensity modulated radiation therapy was used to deliver 15 Gy (n=8), 18 Gy (n=8), or 21 Gy (n=16) to the tumor with a 1.5-cm margin. Lumpectomy was performed within 10 days. Paired pre- and postradiation magnetic resonance images and patient tumor samples were analyzed. Results: No dose-limiting toxicity was observed. At a median follow-up of 23 months, there have been no recurrences. Physician-rated cosmetic outcomes were good/excellent, and chronic toxicities were grade 1 to 2 (fibrosis, hyperpigmentation) in patients receiving preoperative radiation only. Evidence of dose-dependent changes in vascular permeability, cell density, and expression of genes regulating immunity and cell death were seen in response to radiation. Conclusions: Preoperative single-dose radiation therapy to intact breast tumors is well tolerated. Radiation response is marked by early indicators of cell death in this biologically favorable patient cohort. This study represents a first step toward a novel partial breast radiation approach. Preoperative radiation should

  10. Pharmacokinetics and safety of single doses of drisapersen in non-ambulant subjects with Duchenne muscular dystrophy: Results of a double-blind randomized clinical trial

    PubMed Central

    Flanigan, Kevin M.; Voit, Thomas; Rosales, Xiomara Q.; Servais, Laurent; Kraus, John E.; Wardell, Claire; Morgan, Allison; Dorricott, Susie; Nakielny, Joanna; Quarcoo, Naashika; Liefaard, Lia; Drury, Tom; Campion, Giles; Wright, Padraig

    2014-01-01

    Duchenne muscular dystrophy (DMD) is a progressive, lethal neuromuscular disorder caused by the absence of dystrophin protein due to mutations of the dystrophin gene. Drisapersen is a 2′-O-methyl-phosphorothioate oligonucleotide designed to skip exon 51 in dystrophin pre-mRNA to restore the reading frame of the mRNA. This study assessed safety, tolerability, and pharmacokinetics of drisapersen after a single subcutaneous administration in non-ambulatory subjects. Eligible subjects were non-ambulant boys aged ≥9 years, in wheelchairs for ≥1 to ≤4 years, with a diagnosis of DMD resulting from a mutation correctable by drisapersen treatment. Four dose cohorts were planned (3, 6, 9 and 12 mg/kg), but study objectives were met with the 9 mg/kg dose. Less than proportional increase in exposure was demonstrated over the 3–9 mg/kg dose range, though post hoc analysis showed dose proportionality was more feasible over the 3–6 mg/kg range. Single doses of drisapersen at 3 and 6 mg/kg did not result in significant safety or tolerability concerns; however, at the 9 mg/kg dose, pyrexia and transient elevations in inflammatory parameters were seen. The maximum tolerated dose of 6 mg/kg drisapersen was identified for further characterization in multiple dose studies in the non-ambulant DMD population. PMID:24321374

  11. Quantification of rat retinal growth and vascular population changes after single and split doses of proton irradiation: translational study using stereology methods

    NASA Technical Reports Server (NTRS)

    Mao, Xiao W.; Archambeau, John O.; Kubinova, Lucie; Boyle, Soames; Petersen, Georgia; Grove, Roger; Nelson, G. A. (Principal Investigator)

    2003-01-01

    This study quantified architectural and population changes in the rat retinal vasculature after proton irradiation using stereology. A 100 MeV conformal proton beam delivered 8, 14, 20 and 28 Gy as single and split doses to the whole eye. The vascular networks were prepared from retinal digests. Stereological methods were used to obtain the area of the retina and unbiased estimates of microvessel/artery/vein endothelial, pericyte and smooth muscle population, and vessel length. The retinal area increased progressively in the unirradiated, age-matched controls and in the retinas irradiated with 8 and 14 Gy, indicating uniform progressive retinal growth. No growth occurred after 20 and 28 Gy. Regression analysis of total endothelial cell number in all vessels (arteries, veins and capillaries) after irradiation documented a progressive time- and dose-dependent cell loss occurring over 15 to 24 months. The difference from controls was significant (P<0.01) after 28 Gy given in single and split doses and after 20 Gy given as a split dose (P<0.05). Total vessel length in microvessel was significantly shortened at 20 and 28 Gy compared to that of controls (P<0.05). No evident dose recovery was observed in the endothelial populations after split doses. At 10 Gy, the rate of endothelial cell loss, a dose parameter used to characterize the time- and dose-dependent loss of the endothelial population, was doubled.

  12. Single- and multiple-dose pharmacokinetics of genistein capsules in healthy chinese subjects: A phase I, randomized, open-label study

    PubMed Central

    Zeng, Xing; Feng, Yi; Yang, Liu; Huang, Yu; Zhou, Dan; Sun, Jing; Liu, Yiming; Deng, Yuanhui

    2008-01-01

    Background: Genistein capsules are currently being developed to treat osteoporosis in China. Genistein is extracted from the fruit of Sophora japonica Leguminosae. Objective: The objective of this study was to assess the pharmacokinetics of genistein capsules after single and multiple oral doses in healthy Chinese subjects. Methods: This was a Phase I, randomized, open-label, single- and multiple- dose study in healthy Chinese adults (aged 19–40 years). In the single-dose study, subjects were randomly assigned in a 1:1:1 ratio to receive genistein 50, 100, or 300 mg (in 50-mg capsules). To assess the effect of food on the pharmacokinetics, subjects in the 50-mg group were equally randomized again into fasting and postprandial (genistein was administered after a high-fat breakfast) groups according to a 2-way cross-over design. A separate equal-sized group of subjects were administered genistein 50 mg on day 1 (single dose), received no treatment on days 2 and 3, and were administered genistein 50 mg QD for 6 days (days 4–9) to obtain a multiple-dose pharmacokinetic profile. Because genistein is converted so rapidly and completely to glucuronidated genistein after administration, plasma concentrations of glucuronidated genistein were determined using a validated high-performance liquid chromatography/ tandem mass spectrometry method. Drug tolerability was assessed by monitoring adverse events (AEs) and laboratory parameters. Results: The study enrolled 40 healthy subjects (24 men, 16 women; 10 each in the 50-, 100-, and 300-mg single-dose groups and 10 in the multiple-dose group). Three subjects voluntarily withdrew (2 in the 100-mg group and 1 in the 300-mg group) before study drug administration. Thirty-seven subjects (24 men, 13 women) completed the study and were included in the analysis. The mean (SD) values of the single-dose genistein 50-, 100-, and 300-mg groups were as follows: Tmax, 6.0 (2.4), 7.4 (2.4), and 5.6 (1.2) hours, respectively; tl/2, 13.0 (4

  13. Pharmacokinetics and Safety of a Single Intravenous Dose of myo-Inositol in Preterm Infants of 23 to 29 weeks

    PubMed Central

    Phelps, Dale L.; Ward, Robert M.; Williams, Rick L.; Watterberg, Kristi L.; Laptook, Abbot R.; Wrage, Lisa A.; Nolen, Tracy L.; Fennell, Timothy R.; Ehrenkranz, Richard A.; Poindexter, Brenda B.; Cotten, C. Michael; Hallman, Mikko K.; Frantz, Ivan D.; Faix, Roger G.; Zaterka-Baxter, Kristin M.; Das, Abhik; Ball, M. Bethany; O’Shea, T. Michael; Lacy, Conra Backstrom; Walsh, Michele C.; Shankaran, Seetha; Sánchez, Pablo J.; Bell, Edward F.; Higgins, Rosemary D.

    2014-01-01

    Background Myo-inositol given to preterm infants with respiratory distress has reduced death, increased survival without bronchopulmonary dysplasia (BPD) and reduced severe retinopathy of prematurity (ROP) in 2 randomized trials. Pharmacokinetic (PK) studies in extremely preterm infants are needed prior to efficacy trials. Methods Infants of 23–29 weeks gestation were randomized to a single intravenous (IV) dose of inositol at 60 or 120 mg/kg or placebo. Over 96 h, serum levels (sparse sampling population PK) and urine inositol excretion were determined. Population PK models were fit using a nonlinear mixed effects approach. Safety outcomes were recorded. Results A 1-compartment model that included factors for endogenous inositol production, allometric size based on weight, gestational age (GA) strata and creatinine clearance fit the data best. The central volume of distribution was 0.5115 l/kg, the clearance 0.0679 l/kg/h, endogenous production 2.67 mg/kg/h and the half life 5.22 h when modeled without the covariates. During the first 12 h renal inositol excretion quadrupled in the 120 mg/kg group, returning to near baseline after 48 h. There was no diuretic side-effect. No significant differences in adverse events occurred between the 3 groups (p > 0.05). Conclusions A single compartment model accounting for endogenous production satisfactorily described the PK of IV inositol. PMID:24067395

  14. XG-102 administered to healthy male volunteers as a single intravenous infusion: a randomized, double-blind, placebo-controlled, dose-escalating study

    PubMed Central

    Deloche, Catherine; Lopez-Lazaro, Luis; Mouz, Sébastien; Perino, Julien; Abadie, Claire; Combette, Jean-Marc

    2014-01-01

    The aim of the study is to evaluate the safety, tolerability and pharmacokinetics (PK) of the JNK inhibitor XG-102 in a randomized, double blind, placebo controlled, sequential ascending dose parallel group Phase 1 Study. Three groups of male subjects received as randomly assigned ascending single XG-102 doses (10, 40, and 80 μg/kg; 6 subjects per dose) or placebo (2 subjects per dose) as an intravenous (IV) infusion over 60 min. Safety and tolerability were assessed by physical examination, vital signs, electrocardiography, eye examination, clinical laboratory tests and adverse events (AEs). PK was analyzed using noncompartmental methods. All reported AEs were mild to moderate and neither their number nor their distribution by System Organ Class suggest a dose relationship. Only headache and fatigue were considered probably or possibly study drug related. Headache frequency was similar for active and placebo, consequently this was not considered to be drug related but probably to study conditions. The other examinations did not show clinically relevant deviations or trends suggesting a XG-102 relationship. Geometric mean half-life was similar among doses, ranging from 0.36 to 0.65 h. Geometric mean XG-102 AUC0–last increased more than linearly with dose, 90% confidence intervals (CIs) did not overlap for the two highest doses. Geometric mean dose normalized Cmax values suggest a more than linear increase with dose but 90% CIs overlap. It may be concluded that XG-102 single IV doses of 10–80 μg/kg administered over 1 h to healthy male subjects were safe and well tolerated. PMID:25505576

  15. Single-Dose Local Simvastatin Injection Improves Implant Fixation via Increased Angiogenesis and Bone Formation in an Ovariectomized Rat Model

    PubMed Central

    Tan, Jie; Yang, Ning; Fu, Xin; Cui, Yueyi; Guo, Qi; Ma, Teng; Yin, Xiaoxue; Leng, Huijie; Song, Chunli

    2015-01-01

    Background Statins have been reported to promote bone formation. However, taken orally, their bioavailability is low to the bones. Implant therapies require a local repair response, topical application of osteoinductive agents, or biomaterials that promote implant fixation. Material/Methods The present study evaluated the effect of a single local injection of simvastatin on screw fixation in an ovariectomized rat model of osteoporosis. Results Dual-energy X-ray absorptiometry, micro-computed tomography, histology, and biomechanical tests revealed that 5 and 10 mg simvastatin significantly improved bone mineral density by 18.2% and 22.4%, respectively (P<0.05); increased bone volume fraction by 51.0% and 57.9%, trabecular thickness by 16.4% and 18.9%, trabeculae number by 112.0% and 107.1%, and percentage of osseointegration by 115.7% and 126.3%; and decreased trabeculae separation by 34.1% and 36.6%, respectively (all P<0.01). Bone mineral apposition rate was significantly increased (P<0.01). Furthermore, implant fixation was significantly increased (P<0.05), and bone morphogenetic protein 2 (BMP2) expression was markedly increased. Local injection of a single dose of simvastatin also promoted angiogenesis. Vessel number, volume, thickness, surface area, and vascular volume per tissue volume were significantly increased (all P<0.01). Vascular endothelial growth factor (VEGF), VEGF receptor-2, von Willebrand factor, and platelet endothelial cell adhesion molecule-1 expression were enhanced. Conclusions A single local injection of simvastatin significantly increased bone formation, promoted osseointegration, and enhanced implant fixation in ovariectomized rats. The underlying mechanism appears to involve enhanced BMP2 expression and angiogenesis in the target bone. PMID:25982481

  16. Pharmacokinetic study between a bilayer matrix fentalyl patch and a monolayer matrix fentanyl patch: single dose administration in healthy volunteers*

    PubMed Central

    Zecca, Ernesto; Manzoni, Andrea; Centurioni, Fabio; Farina, Alberto; Bonizzoni, Erminio; Seiler, Dan; Perrone, Tania; Caraceni, Augusto

    2015-01-01

    Aims Transdermal fentanyl is a well established treatment for cancer pain. The aim of the present study is to assess the relative bioavailability of fentanyl from two different transdermal systems by evaluating plasma drug concentrations after single administration of Fentalgon® (test), a novel bilayer matrix type patch, and Durogesic SMAT (reference), a monolayer matrix type patch. In the Fentalgon patch the upper 6% fentanyl reservoir layer maintains a stable concentration gradient between the lower 4% donor layer and the skin. The system provides a constant drug delivery over 72 h. Methods This was an open label, single centre, randomized, single dose, two period crossover clinical trial, that included 36 healthy male volunteers. The patches were applied to non-irritated and non-irradiated skin on the intraclavicular pectoral area. Blood samples were collected at different time points (from baseline to 120 h post-removal of the devices) and fentanyl concentrations were determined using a validated LC/MS/MS method. Bioequivalence was to be claimed if the 90% confidence interval of AUC(0,t) and Cmax ratios (test: reference) were within the acceptance range of 80–125% and 75–133%, respectively. Results The 90% confidence intervals of the AUC(0,t) ratio (116.3% [109.6, 123.4%]) and Cmax ratio (114.4% [105.8, 123.8%] were well included in the acceptance range and the Cmax ratio also met the narrower bounds of 80–125%. There was no relevant difference in overall safety profiles of the two preparations investigated, which were adequately tolerated, as expected for opioid-naïve subjects. Conclusions The new bilayer matrix type patch, Fentalgon®, is bioequivalent to the monolayer matrix type Durogesic SMAT fentanyl patch with respect to the rate and extent of exposure of fentanyl (Eudra/CT no. 2005-000046-36). PMID:25612845

  17. Phase I and pharmacological study of the pulmonary cytotoxin 4-ipomeanol on a single dose schedule in lung cancer patients: hepatotoxicity is dose limiting in humans.

    PubMed

    Rowinsky, E K; Noe, D A; Ettinger, D S; Christian, M C; Lubejko, B G; Fishman, E K; Sartorius, S E; Boyd, M R; Donehower, R C

    1993-04-15

    4-Ipomeanol (IPO), a naturally occurring pulmonary toxin, is the first cytotoxic agent to undergo clinical development based on a biochemical-biological rationale as an antineoplastic agent targeted specifically against lung cancer. This rationale is based on preclinical observations that metabolic activation and intracellular binding of IPO, as well as cytotoxicity, occurred selectively in tissues and cancers derived from tissues that are rich in specific P450 mixed function oxidase enzymes. Although tissues capable of activating IPO to cytotoxic intermediates in vitro include liver, lung, and kidney, IPO has been demonstrated in rodents and dogs to undergo in situ activation, bind covalently, and induce cytotoxicity preferentially in lung tissue at doses not similarly affecting liver or kidneys. Although the drug was devoid of antitumor activity in the conventional murine preclinical screening models, cytotoxic activity was observed in human lung cancers in vitro and in human lung cancer xenografts in vivo, adding to the rationale for clinical development. Somewhat unexpectantly, hepatocellular toxicity was the dose-limiting principal toxicity of IPO administered as a 30-min infusion every 3 weeks to patients with lung cancer. In this study, 55 patients received 254 courses at doses almost spanning 3 orders of magnitude, 6.5 to 1612 mg/m2. Transient and isolated elevations in hepatocellular enzymes, predominantly alanine aminotransferase, occurred in the majority of courses of IPO at 1032 mg/m2, which is the recommended IPO dose for subsequent phase II trials. At higher doses, hepatocellular toxicity was more severe and was often associated with right upper quadrant pain and severe malaise. Toxic effects were also noted in other tissues capable of activating IPO, including possible nephrotoxicity in a patient treated with one course of IPO at 154 mg/m2 and severe, reversible pulmonary toxicity in another patient who received nine courses of IPO at doses ranging

  18. Single oral doses of (±) 3,4-methylenedioxymethamphetamine ('Ecstasy') produce lasting serotonergic deficits in non-human primates: relationship to plasma drug and metabolite concentrations.

    PubMed

    Mueller, Melanie; Yuan, Jie; McCann, Una D; Hatzidimitriou, George; Ricaurte, George A

    2013-05-01

    Repeated doses of the popular recreational drug methylenedioxymethamphetamine (MDMA, 'Ecstasy') are known to produce neurotoxic effects on brain serotonin (5-HT) neurons but it is widely believed that typical single oral doses of MDMA are free of neurotoxic risk. Experimental and therapeutic trials with MDMA in humans are underway. The mechanisms by which MDMA produces neurotoxic effects are not understood but drug metabolites have been implicated. The aim of the present study was to assess the neurotoxic potential of a range of clinically relevant single oral doses of MDMA in a non-human primate species that metabolizes MDMA in a manner similar to humans, the squirrel monkey. A secondary objective was to explore the relationship between plasma MDMA and metabolite concentrations and lasting serotonergic deficits. Single oral doses of MDMA produced lasting dose-related serotonergic neurochemical deficits in the brains of squirrel monkeys. Notably, even the lowest dose of MDMA tested (5.7 mg/kg, estimated to be equivalent to 1.6 mg/kg in humans) produced significant effects in some brain regions. Plasma levels of MDMA engendered by neurotoxic doses of MDMA were on the order of those found in humans. Serotonergic neurochemical markers were inversely correlated with plasma concentrations of MDMA, but not with those of its major metabolites, 3,4-dihydroxymethamphetamine and 4-hydroxy-3-methoxymethamphetamine. These results suggest that single oral doses of MDMA in the range of those used by humans pose a neurotoxic risk and implicate the parent compound (MDMA), rather than one of its metabolites, in MDMA-induced 5-HT neural injury.

  19. Pooled post hoc analysis of population pharmacokinetics of oxycodone and acetaminophen following a single oral dose of biphasic immediate-release/extended-release oxycodone/acetaminophen tablets.

    PubMed

    Franke, Ryan M; Morton, Terri; Devarakonda, Krishna

    2015-01-01

    This analysis evaluated the single-dose population pharmacokinetics (PK) of biphasic immediate-release (IR)/extended-release (ER) oxycodone (OC)/acetaminophen (APAP) 7.5/325 mg tablets administered under fasted conditions and the effects of a meal on their single-dose population PK. Data were pooled from four randomized, single-dose crossover trials enrolling healthy adult (18-55 years old) participants (three trials) and nondependent recreational users of prescription opioids (one trial) with a body weight of ≥59 kg. Participants received IR/ER OC/APAP 7.5/325 mg tablets in single doses of 7.5/325 mg (one tablet), 15/650 mg (two tablets), or 30/1,300 mg (four tablets) under fasted or fed conditions. Six variables were examined: sex, race, age, weight, height, and body mass index. Single-dose population PK was analyzed using first-order conditional estimation methods. A total of 151 participants were included in the analysis under fasted conditions, and 31 participants were included in the fed analysis. Under fasted conditions, a 10% change in body weight was accompanied by ~7.5% change in total body clearance (CL/F) and volume of distribution (V/F) of OC and APAP. Black participants had 17.3% lower CL/F and a 16.9% lower V/F of OC compared with white participants. Under fed conditions, the absorption rate constant of OC and APAP decreased significantly, although there was no effect on CL/F and V/F. Considering that the recommended dose for IR/ER OC/APAP 7.5/325 mg tablets is two tablets every 12 hours, adjustments of <50% are not clinically relevant. Dose adjustment may be necessary for large deviations from average body weight, but the small PK effects associated with race and consumption of a meal are not clinically relevant.

  20. Single-Dose CpG Immunization Protects Against a Heterosubtypic Challenge and Generates Antigen-Specific Memory T Cells

    PubMed Central

    Vogel, Alexander J.; Brown, Deborah M.

    2015-01-01

    Despite extensive research, influenza A virus (IAV) remains a major cause of morbidity, mortality, and healthcare expenditure. Emerging pandemics from highly pathogenic IAV strains, such as H5N1 and pandemic H1N1, highlight the need for universal, cross-protective vaccines. Current vaccine formulations generate strain-specific neutralizing antibodies primarily against the outer coat proteins, hemagglutinin and neuraminidase. In contrast to these highly mutable proteins, internal proteins of IAV are more conserved and are a favorable target for developing vaccines that induce strong T cell responses in addition to humoral immunity. Here, we found that intranasal administration with a single dose of CpG and inactivated x31 (H3N2) reduced viral titers and partially protected mice from a heterosubtypic challenge with a lethal dose of PR8 (H1N1). Early after immunization, vaccinated mice showed increased innate immune activation with high levels of MHCII and CD86 expression on dendritic cells in both draining lymph nodes and lungs. Three days after immunization, CD4 and CD8 cells in the lung upregulated CD69, suggesting that activated lymphocytes are present at the site of vaccine administration. The ensuing effector Th1 responses were capable of producing multiple cytokines and were present at least 30 days after immunization. Furthermore, functional memory responses were observed, as antigen-specific IFN-γ+ and GrB+ cells were detected early after lethal infection. Together, this work provides evidence for using pattern recognition receptor agonists as a mucosal vaccine platform for inducing robust T cell responses capable of protecting against heterologous IAV challenges. PMID:26161083

  1. Angiotensin converting enzyme inhibitors mitigate collagen synthesis induced by a single dose of radiation to the whole thorax.

    PubMed

    Kma, Lakhan; Gao, Feng; Fish, Brian L; Moulder, John E; Jacobs, Elizabeth R; Medhora, Meetha

    2012-01-01

    Our long-term goal is to use angiotensin converting enzyme (ACE) inhibitors to mitigate the increase in lung collagen synthesis that is induced by irradiation to the lung, which could result from accidental exposure or radiological terrorism. Rats (WAG/RijCmcr) were given a single dose of 13 Gy (dose rate of 1.43 Gy/min) of X-irradiation to the thorax. Three structurally-different ACE inhibitors, captopril, enalapril and fosinopril were provided in drinking water beginning 1 week after irradiation. Rats that survived acute pneumonitis (at 6-12 weeks) were evaluated monthly for synthesis of lung collagen. Other endpoints included breathing rate, wet to dry lung weight ratio, and analysis of lung structure. Treatment with captopril (145-207 mg/m(2)/day) or enalapril (19-28 mg/m(2)/day), but not fosinopril (19-28 mg/m(2)/day), decreased morbidity from acute pneumonitis. Lung collagen in the surviving irradiated rats was increased over that of controls by 7 months after irradiation. This increase in collagen synthesis was not observed in rats treated with any of the three ACE inhibitors. Analysis of the lung morphology at 7 months supports the efficacy of ACE inhibitors against radiation-induced fibrosis. The effectiveness of fosinopril against fibrosis, but not against acute pneumonitis, suggests that pulmonary fibrosis may not be a simple consequence of injury during acute pneumonitis. In summary, three structurally-different ACE inhibitors mitigate the increase in collagen synthesis 7 months following irradiation of the whole thorax and do so, even when therapy is started one week after irradiation. PMID:22302041

  2. Serum and urine concentrations of flunitrazepam and metabolites, after a single oral dose, by immunoassay and GC-MS.

    PubMed

    Snyder, H; Schwenzer, K S; Pearlman, R; McNally, A J; Tsilimidos, M; Salamone, S J; Brenneisen, R; ElSohly, M A; Feng, S

    2001-01-01

    A clinical study was conducted to assess the ability of commercially available immunoassays to detect flunitrazepam (FNP) in plasma and urine samples and to compare the results with those obtained by gas chromatography-mass spectrometry (GC-MS). The clinical study consisted of four individuals (two male and two female) who had taken a single 2-mg dose of FNP. Serum was collected over a 48-h period and urine was collected over a 72-h period. The serum and urine samples were analyzed by the COBAS INTEGRA Serum Benzodiazepines assay (SBENZ), the TDx serum and urine Benzodiazepines assay, and GC-MS. The GC-MS procedure was developed for analysis of FNP and metabolites in plasma and urine using an acid hydrolysis step resulting in the formation of specific benzophenones corresponding to FNP and its metabolites. The relative sensitivities of the assays for the detection of FNP and metabolites in serum and urine were GC-MS > SBENZ > TDx. The immunoassay results for serum samples showed peak concentrations of FNP metabolites at 8 h after FNP ingestion for three individuals and at about 1 h for the fourth individual. The GC-MS, SBENZ, and TDx urine immunoassays detected drug above the stated limit of detection (LOD) in 44, 41, and 35 serial FNP urine samples, respectively. FNP metabolites were detected in urine samples with all three assays for up to 72 h after a 2-mg dose. The improved detection rate with the SBENZ assay as compared to the TDx assay is likely explained by its higher cross-reactivity with the major metabolite, 7-amino-flunitrazepam (7-amino-FNP), and its lower LOD.

  3. Single dose disposition of chloroquine in kwashiorkor and normal children--evidence for decreased absorption in kwashiorkor.

    PubMed

    Walker, O; Dawodu, A H; Salako, L A; Alván, G; Johnson, A O

    1987-04-01

    The single dose disposition of chloroquine was studied in five children with kwashiorkor and six normal control children after an oral dose of 10 mg kg-1 of chloroquine base. Plasma concentrations of chloroquine and its main metabolite were assayed by high performance liquid chromatography (h.p.l.c.). Chloroquine was detectable for up to 21 days in all the subjects. Chloroquine was detectable in all the subjects within 30 min after giving the drug except in one subject. Peak levels were reached between 0.5 and 8 h in all the subjects (with no significant difference in the tmax between the two groups of children). Peak plasma chloroquine concentrations in the children with kwashiorkor varied from 9 ng ml-1 to 95 ng ml-1 (mean 40 +/- 34 ng ml-1). Peak chloroquine concentrations in the controls varied between 69 ng ml-1 and 330 ng ml-1 (mean 134 +/- 99 ng ml-1). The mean AUC in the kwashiorkor children was significantly lower than the mean AUC in the control children (P less than 0.001). Peak plasma desethylchloroquine concentrations in the children with kwashiorkor varied between 3 and 13 ng ml-1 (mean 6 +/- 9 ng ml-1) while in the controls the concentrations varied between 14 and 170 ng ml-1 (mean 50 +/- 61 ng ml-1). There was no significant difference in the half-life of chloroquine between the kwashiorkor children and the normal control children. The possible influence of a different binding and distribution pattern of chloroquine in kwashiorkor could not be assessed in this study.(ABSTRACT TRUNCATED AT 250 WORDS)

  4. A standard, single dose of inhaled terbutaline attenuates hyperpnea-induced bronchoconstriction and mast cell activation in athletes

    PubMed Central

    Simpson, A. J.; Bood, J. R.; Anderson, S. D.; Romer, L. M.; Dahlén, B.; Dahlén, S.-E.

    2016-01-01

    Release of bronchoactive mediators from mast cells during exercise hyperpnea is a key factor in the pathophysiology of exercise-induced bronchoconstriction (EIB). Our aim was to investigate the effect of a standard, single dose of an inhaled β2-adrenoceptor agonist on mast cell activation in response to dry air hyperpnea in athletes with EIB. Twenty-seven athletes with EIB completed a randomized, double-blind, placebo-controlled, crossover study. Terbutaline (0.5 mg) or placebo was inhaled 15 min prior to 8 min of eucapnic voluntary hyperpnea (EVH) with dry air. Pre- and postbronchial challenge, urine samples were analyzed by enzyme immunoassay for 11β-prostaglandin F2α (11β-PGF2α). The maximum fall in forced expiratory volume in 1 s of 14 (12–20)% (median and interquartile range) following placebo was attenuated to 7 (5–9)% with the administration of terbutaline (P < 0.001). EVH caused a significant increase in 11β-PGF2α from 41 (27–57) ng/mmol creatinine at baseline to 58 (43–72) ng/mmol creatinine at its peak post-EVH following placebo (P = 0.002). The rise in 11β-PGF2α was inhibited with administration of terbutaline: 39 (28–44) ng/mmol creatinine at baseline vs. 40 (33–58) ng/mmol creatinine at its peak post-EVH (P = 0.118). These data provide novel in vivo evidence of mast cell stabilization following inhalation of a standard dose of terbutaline prior to bronchial provocation with EVH in athletes with EIB. PMID:26846550

  5. Evaluation of pharmacokinetics of single-dose chloroquine in malnourished children with malaria- a comparative study with normally nourished children

    PubMed Central

    Kadam, Prashant P.; Gogtay, Nithya Jaideep; Karande, Sunil; Shah, V.; Thatte, Urmila M.

    2016-01-01

    Objectives: Studies on antimalarial kinetics in children or adults who are undernourished or malnourished are both limited and have yielded conflicting results. The present study was carried out with the objectives of evaluating the pharmacokinetics of single dose chloroquine and its metabolite desethylchloroquine in children who were undernourished and compare them with children who were normally nourished. Methods: Children of either gender between the ages of 5 and 12 years, smear positive for P. vivax malaria and classified either as well nourished or undernourished were included. Undernourishment was adjudged based on the Indian Academy of Pediatrics (IAP) classification of protein energy malnutrition [PEM] which in turn was based on Khadilkar's growth charts. All participants received 10 mg/kg on the first day followed by 10 mg/kg on Day 2 and 5 mg/kg on Day 3 along with supportive treatment. Blood samples for the levels of chloroquine [CQ] and desethylchloroquine [DECQ] were collected at 0, 0.5, 1, 2 4, 8, 12, 24, 48, 72 hours and 14 days after the first dose and levels assessed by High Performance Liquid Chromatography. Results: A total of 12 children who were normally nourished and 13 who were undernourished were studied. Wide inter-individual variability was seen in the levels of both drug and metabolite in both groups of patients. However, the differences in Cmax, AUC 0-inf, Clearance, half life and Vd between the two groups were not significantly different. Discussion: Our results indicate that dosage requirement is unlikely to be needed for chloroquine in undernourished children with uncomplicated P. vivax malaria. PMID:27721533

  6. Study of Intravenous Single-Dose Toxicity Test of Bufonis venonum Pharmacopuncture in Sprague-Dawley Rats

    PubMed Central

    Kwon, Ki-Rok; Yu, Jun-Sang; Sun, Seung-Ho; Lee, Kwang-Ho

    2016-01-01

    Objectives: Bufonis venonum (BV) is toad venom and is the dried, white secretions of the auricular and the skin glands of toads. This study was performed to evaluate the toxicity of intravenous injection of Bufonis venonum pharmacopuncture (BVP) through a single- dose test with sprague-dawley (SD) rats. Methods: Twenty male and 20 female 6-week-old SD rats were injected intravenously in the caudal vein with BVP or normal saline. The animals were divided into four groups with five female and five male rats per group: the control group injected with normal saline, the low-dosage group injected with 0.1 mL/animal of BVP, the medium-dosage group injected with 0.5 mL/ animal of BVP and the high-dosage group injected with 1.0 mL/animal of BVP. We performed clinical observations every day and body weight measurements on days 3, 7 and 14 after the injection. We also conducted hematology, serum biochemistry, and histological observations immediately after the observation period. Results: No mortalities were observed in any experimental group. Paleness occurred in the medium- and the high-dosage groups, and congestion on tails was observed in females in the medium- and the high-dosage groups. No significant changes in weight, hematology, serum biochemistry, and histological observations that could be attributed to the intravenous injection of BVP were observed in any experimental group. Conclusion: The lethal dose of intravenously-administered BVP in SD rats is over 1.0 mL/animal. PMID:27386149

  7. Efficacy of a Radiation Absorbing Shield in Reducing Dose to the Interventionalist During Peripheral Endovascular Procedures: A Single Centre Pilot Study

    SciTech Connect

    Power, S.; Mirza, M.; Thakorlal, A.; Ganai, B.; Gavagan, L. D.; Given, M. F.; Lee, M. J.

    2015-06-15

    PurposeThis prospective pilot study was undertaken to evaluate the feasibility and effectiveness of using a radiation absorbing shield to reduce operator dose from scatter during lower limb endovascular procedures.Materials and MethodsA commercially available bismuth shield system (RADPAD) was used. Sixty consecutive patients undergoing lower limb angioplasty were included. Thirty procedures were performed without the RADPAD (control group) and thirty with the RADPAD (study group). Two separate methods were used to measure dose to a single operator. Thermoluminescent dosimeter (TLD) badges were used to measure hand, eye, and unshielded body dose. A direct dosimeter with digital readout was also used to measure eye and unshielded body dose. To allow for variation between control and study groups, dose per unit time was calculated.ResultsTLD results demonstrated a significant reduction in median body dose per unit time for the study group compared with controls (p = 0.001), corresponding to a mean dose reduction rate of 65 %. Median eye and hand dose per unit time were also reduced in the study group compared with control group, however, this was not statistically significant (p = 0.081 for eye, p = 0.628 for hand). Direct dosimeter readings also showed statistically significant reduction in median unshielded body dose rate for the study group compared with controls (p = 0.037). Eye dose rate was reduced for the study group but this was not statistically significant (p = 0.142).ConclusionInitial results are encouraging. Use of the shield resulted in a statistically significant reduction in unshielded dose to the operator’s body. Measured dose to the eye and hand of operator were also reduced but did not reach statistical significance in this pilot study.

  8. Single-Dose Primaquine in a Preclinical Model of Glucose-6-Phosphate Dehydrogenase Deficiency: Implications for Use in Malaria Transmission-Blocking Programs.

    PubMed

    Wickham, Kristina S; Baresel, Paul C; Marcsisin, Sean R; Sousa, Jason; Vuong, Chau T; Reichard, Gregory A; Campo, Brice; Tekwani, Babu L; Walker, Larry A; Rochford, Rosemary

    2016-10-01

    Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency (G6PDd) are at risk for developing hemolytic anemia when given the antimalarial drug primaquine (PQ). The WHO Evidence Review Group released a report suggesting that mass administration of a single dose of PQ at 0.25 mg of base/kg of body weight (mpk) (mouse equivalent of 3.125 mpk) could potentially reduce malaria transmission based on its gametocytocidal activity and could be safely administered to G6PD-deficient individuals, but there are limited safety data available confirming the optimum single dose of PQ. A single-dose administration of PQ was therefore assessed in our huRBC-SCID mouse model used to predict hemolytic toxicity with respect to G6PD deficiency. In this model, nonobese diabetic (NOD)/SCID mice are engrafted with human red blood cells (huRBC) from donors with the African or Mediterranean variant of G6PDd (A-G6PDd or Med-G6PDd, respectively) and demonstrate dose-dependent sensitivity to PQ. In mice engrafted with A-G6PD-deficient huRBC, single-dose PQ at 3.125, 6.25, or 12.5 mpk had no significant loss of huRBC compared to the vehicle control group. In contrast, in mice engrafted with Med-G6PDd huRBC, a single dose of PQ at 3.125, 6.25, or 12.5 mpk resulted in a significant, dose-dependent loss of huRBC compared to the value for the vehicle control group. Our data suggest that administration of a single low dose of 0.25 mpk of PQ could induce hemolytic anemia in Med-G6PDd individuals but that use of single-dose PQ at 0.25 mpk as a gametocytocidal drug to block transmission would be safe in areas where A-G6PDd predominates. PMID:27458212

  9. The margin of safety of a single application of transdermal fentanyl solution when administered at multiples of the therapeutic dose to laboratory dogs.

    PubMed

    Savides, M C; Pohland, R C; Wilkie, D A; Abbott, J A; Newbound, G C; Freise, K J; Clark, T P

    2012-08-01

    Previous studies have demonstrated that a single, topical application of a novel, long-acting transdermal fentanyl solution provides analgesic fentanyl concentrations for at least 4 days. The objective of this study was to describe the margin of safety following application at multiples of the therapeutic dose. Twenty-four laboratory dogs were administered a single placebo or 1×, 3×, or 5× multiple of the dose of 2.6 mg/kg (50 μL/kg) to the ventral abdominal skin and observed for 14 days. Plasma fentanyl concentrations increased in proportion to dose. Adverse reactions in the 1× group were transient and included a low prevalence (≤ 33%) of mild sedation, reduced food intake, modest weight loss, and minimal reductions in heart rate and rectal temperature. Moderate to severe sedation emerged in the 3× and 5× groups, which was associated with a dose-limiting reduction in food and water intake, necessitating maintenance fluid replacement for the first 2 days following application. Also observed in the higher-dose groups were an increased prevalence of abnormal stools and transient lens opacities. All abnormal health observations were completely resolved prior to necropsy on day 14, and there were no histological abnormalities identified. These data support the safe use of the 1× dose and describe the outcome of an overdose of up to 5× dose in the absence of opioid reversal.

  10. Comparison of fluconazole pharmacokinetics in serum, aqueous humor, vitreous humor, and cerebrospinal fluid following a single dose and at steady state.

    PubMed

    Mian, U K; Mayers, M; Garg, Y; Liu, Q F; Newcomer, G; Madu, C; Liu, W; Louie, A; Miller, M H

    1998-10-01

    The objective of this study was to characterize the pharmacokinetic parameters and penetration of fluconazole following a single dose in the serum, aqueous humor, vitreous humor and cerebrospinal fluid (CSF) of non pigmented rabbits using serial sampling techniques and to determine if the pharmacokinetic parameters in the eye and CSF are similar. Twenty healthy male rabbits received intravenous fluconazole 20 mg/kg as a single dose or 20 mg/kg every 12 hours for 4 doses. Serum, aqueous humor, vitreous humor and CSF samples were taken 15 minutes after the initial intravenous injection and hourly thereafter for six hours. Fluconazole concentrations were determined by microbiological assay. Pharmacokinetic analyses were performed using a nonlinear least-square regression program. Fluconazole's penetration in all anatomical compartments was > 70% than in the serum. Similar elimination half-lives and time to reach maximum concentrations were noted in all compartments. While mean concentrations in each anatomical compartment were similar in animals receiving a single dose or among those at serum steady state, the mean concentrations achieved in the serum, aqueous and vitreous humors and CSF were between 1.82 and 2.17 times higher at serum steady state than following a single dose. At serum concentrations that are comparable to those in humans, the penetration of fluconazole into the noninflamed aqueous and vitreous humors and CSF were > or = 70%. The CSF and ocular pharmacokinetic parameters closely resembled each other, so that either could be used as a surrogate for the other.

  11. Lack of an effect of standard and supratherapeutic doses of linezolid on QTc interval prolongation.

    PubMed

    Damle, Bharat; Labadie, Robert R; Cuozzo, Cheryl; Alvey, Christine; Choo, Heng Wee; Riley, Steve; Kirby, Deborah

    2011-09-01

    A double-blind, placebo-controlled, four-way crossover study was conducted in 40 subjects to assess the effect of linezolid on corrected QT (QTc) interval prolongation. Time-matched, placebo-corrected QT intervals were determined predose and at 0.5, 1 (end of infusion), 2, 4, 8, 12, and 24 h after intravenous dosing of linezolid 600 and 1,200 mg. Oral moxifloxacin at 400 mg was used as an active control. The pharmacokinetic profile of linezolid was also evaluated. At each time point, the upper bound of the 90% confidence interval (CI) for placebo-corrected QTcF values (i.e., QTc values adjusted for ventricular rate using the correction methods of Fridericia) for linezolid 600 and 1,200-mg doses were <10 ms, which indicates an absence of clinically significant QTc prolongation. At 2 and 4 h after the moxifloxacin dose, corresponding to the population T(max), the lower bound of the two-sided 90% CI for QTcF when comparing moxifloxacin to placebo was >5 ms, indicating that the study was adequately sensitive to assess QTc prolongation. The pharmacokinetic profile of linezolid at 600 mg was consistent with previous observations. Systemic exposure to linezolid increased in a slightly more than dose-proportional manner at supratherapeutic doses, but the degree of nonlinearity was small. At a supratherapeutic single dose of 1,200 mg of linezolid, no treatment-related increase in adverse events was seen compared to 600 mg of linezolid, and no clinically meaningful effects on vital signs and safety laboratory evaluations were noted. PMID:21709083

  12. Meta-Analysis of Studies Comparing Single and Multi-Tablet Fixed Dose Combination HIV Treatment Regimens

    PubMed Central

    Clay, P.G.; Nag, S.; Graham, C.M.; Narayanan, S.

    2015-01-01

    Abstract Availability of a single source review of once-daily fixed-dose single tablet regimen (STR) and multiple tablet fixed-dose regimen (MTR) would optimally inform healthcare providers and policy makers involved in the management of population with human immunodeficiency virus (HIV). We conducted a meta-analysis of published literature to compare patient adherence, clinical, and cost outcomes of STR to MTR. Published literature in English between 2005 and 2014 was searched using Embase, PubMed (Medline in-process), and ClinicalTrials.Gov databases. Two-level screening was undertaken by 2 independent researchers to finalize articles for evidence synthesis. Adherence, efficacy, safety, tolerability, healthcare resource use (HRU), and costs were assessed comparing STR to MTR. A random-effects meta-analysis was performed and heterogeneity examined using meta-regression. Thirty-five articles were identified for qualitative evidence synthesis, of which 9 had quantifiable data for meta-analysis (4 randomized controlled trials and 5 observational studies). Patients on STR were significantly more adherent when compared to patients on MTR of any frequency (odds ratio [OR]: 2.37 [95% CI: 1.68, 3.35], P < 0.001; 4 studies), twice-daily MTR (OR: 2.53 [95% CI: 1.13, 5.66], P = 0.02; 2 studies), and once-daily MTR (OR: 1.81 [95% CI: 1.15, 2.84], P = 0.01; 2 studies). The relative risk (RR) for viral load suppression at 48 weeks was higher (RR: 1.09 [95% CI: 1.04, 1.15], P = .0003; 3 studies) while RR of grade 3 to 4 laboratory abnormalities was lower among patients on STR (RR: 0.68 [95% CI: 0.49, 0.94], P = 0.02; 2 studies). Changes in CD4 count at 48 weeks, any severe adverse events (SAEs), grade 3 to 4 AEs, mortality, and tolerability were found comparable between STR and MTR. Several studies reported significant reduction in HRU and costs among STR group versus MTR. Study depicted comparable tolerability, safety (All-SAE and Grade 3–4 AE), and

  13. Oral dose of citrus peel extracts promotes wound repair in diabetic rats.

    PubMed

    Ahmad, M; Ansari, M N; Alam, A; Khan, T H

    2013-10-15

    Diabetic patients wound healing is slower than the healthy individuals. Three citrus peel extracts; Lemon (Citrus limon), Grapes fruits (Citrus paradise) and Orange (Citrus sinensis) promote wound healing in experimental animals. This study investigated the effect of oral treatment with citrus peel extracts on wound repair of the skin of diabetic rats. The extracts were estimated for vitamin C and total carotenoid contents prior to animal study. Diabetes mellitus was induced in rats by intraperitoneal injection of a single dose of streptozotocin (STZ, 75 mg kg(-1) b.wt.). One week after diabetes induction, full thickness excision wounds were made in hyperglycemic rats and were divided groups, each containing 6 rats. The different test group animals were treated with different citrus peel extract orally at the dose of 400 mg kg(-1) body weight daily for 12 days. The blood glucose, body weight and rate of wound closure of each rat were measured every 3rd day during the experimental period. At the end of experiment, granular tissues of wounds were removed and estimated for hydroxylproline and total protein content. The results showed significant reduction in blood glucose and time to wound closure. Tissue growth and collagen synthesis were significantly higher as determined by total protein and hydroxyl proline content. From our experimental data, we propose that oral administration of citrus peel extracts has a therapeutic potential in the treatment of chronic wounds in diabetes.

  14. Single-dose oral quercetin improves redox status but does not affect heat shock response in mice.

    PubMed

    Chen, Yifan; Islam, Aminul; Abraham, Preetha; Deuster, Patricia

    2014-07-01

    Inflammation and oxidative stress are considered as likely contributors to heat injury. However, their roles in regulating the heat shock response in vivo remain unclear. We tested the hypothesis that acute quercetin treatment would improve redox status and reduce heat shock responses in mice. Mice underwent two heat tests before and after single oral administration of either quercetin (15 mg/kg) or vehicle. We measured physiologic and biochemical responses in mice during and 18 to 22 hours after heat tests, respectively. There were no significant differences in core temperature, heart rate, or blood pressure between quercetin and vehicle groups during heat exposure. Mice with relatively severe hyperthermia during the pretreatment heat test showed a significant trend toward a lower peak core temperature during the heat test after quercetin treatment. Compared with mice not exposed to heat, quercetin-treated mice had significantly lower interleukin 6 (P < .01) and higher superoxide dismutase levels (P < .01), whereas vehicle-treated mice had significantly lower total glutathione and higher 8-isoprostane levels in the circulation after heat exposure. Heat exposure significantly elevated heat shock proteins (HSPs) 72 and 90 and heat shock factor 1 levels in mouse liver, heart, and skeletal muscles, but no significant differences in tissue HSPs and heat shock factor 1 were found between quercetin- and vehicle-treated mice. These results suggest that a single moderate dose of quercetin is sufficient to alter redox status but not heat stress response in mice. Acute adaptations of peripheral tissues to heat stress may not be mediated by systemic inflammatory and redox state in vivo.

  15. Late gadolinium enhancement magnetic resonance imaging for the assessment of myocardial infarction: comparison of image quality between single and double doses of contrast agents.

    PubMed

    Kim, Yeo Koon; Park, Eun-Ah; Lee, Whal; Kim, Sang Yoon; Chung, Jin Wook

    2014-12-01

    To compare the image quality of late gadolinium enhancement (LGE) cardiac magnetic resonance imaging (CMR) using a single dose of gadolinium contrast agent versus the conventional double dose for assessing myocardial infarction. This retrospective study examined 37 patients with chronic myocardial infarction who underwent LGE CMR using both inversion recovery (IR)-turbo fast low-angle shot magnitude-reconstructed and phase-sensitive images with two different dosages of gadolinium contrast agent: a single dose of 0.1 mmol/kg gadolinium-DTPA in 17 patients and a double dose of 0.2 mmol/kg in 20 patients. The contrast-to-noise ratio (CNR) and visual conspicuity between infarct and normal myocardium (CNRinfarct-normal, conspicuityinfarct-normal) and between infarct and left ventricular cavity (CNRinfarct-LVC, conspicuityinfarct-LVC) were compared. Interobserver agreement for the maximal transmural extent of infarction was also evaluated. CNRinfarct-normal was significantly higher with double-dose gadolinium contrast agent (15.5 ± 20.7 vs. 40.4 ± 16.1 in magnitude images and 9.5 ± 2.8 vs. 11.2 ± 2.7 in phase-sensitive images, P < 0.001) while conspicuityinfarct-normal showed no significant difference between the two groups (P > 0.05). Both CNRinfarct-LVC (7.7 ± 10.7 vs. -6.6 ± 19.0 in magnitude images and 4.1 ± 2.3 vs. -0.4 ± 4.1 in phase-sensitive images, P < 0.05) and conspicuityinfarct-LVC were significantly better with single-dose gadolinium contrast. Interobserver agreement for assessing the transmural extent of infarction was moderate in both groups: 0.591 for single-dose and 0.472 for double-dose. LGE CMR using a single dose of gadolinium contrast agent showed significantly better contrast between infarcted myocardium and left ventricular cavity lumen without a significant decrease in visual contrast between infarcted myocardium and normal myocardium, compared to a double dose.

  16. Single high-dose irradiation aggravates eosinophil-mediated fibrosis through IL-33 secreted from impaired vessels in the skin compared to fractionated irradiation

    SciTech Connect

    Lee, Eun-Jung; Kim, Jun Won; Yoo, Hyun; Kwak, Woori; Choi, Won Hoon; Cho, Seoae; Choi, Yu Jeong; Lee, Yoon-Jin; Cho, Jaeho

    2015-08-14

    We have revealed in a porcine skin injury model that eosinophil recruitment was dose-dependently enhanced by a single high-dose irradiation. In this study, we investigated the underlying mechanism of eosinophil-associated skin fibrosis and the effect of high-dose-per-fraction radiation. The dorsal skin of a mini-pig was divided into two sections containing 4-cm{sup 2} fields that were irradiated with 30 Gy in a single fraction or 5 fractions and biopsied regularly over 14 weeks. Eosinophil-related Th2 cytokines such as interleukin (IL)-4, IL-5, and C–C motif chemokine-11 (CCL11/eotaxin) were evaluated by quantitative real-time PCR. RNA-sequencing using 30 Gy-irradiated mouse skin and functional assays in a co-culture system of THP-1 and irradiated-human umbilical vein endothelial cells (HUVECs) were performed to investigate the mechanism of eosinophil-mediated radiation fibrosis. Single high-dose-per-fraction irradiation caused pronounced eosinophil accumulation, increased profibrotic factors collagen and transforming growth factor-β, enhanced production of eosinophil-related cytokines including IL-4, IL-5, CCL11, IL-13, and IL-33, and reduced vessels compared with 5-fraction irradiation. IL-33 notably increased in pig and mouse skin vessels after single high-dose irradiation of 30 Gy, as well as in irradiated HUVECs following 12 Gy. Blocking IL-33 suppressed the migration ability of THP-1 cells and cytokine secretion in a co-culture system of THP-1 cells and irradiated HUVECs. Hence, high-dose-per-fraction irradiation appears to enhance eosinophil-mediated fibrotic responses, and IL-33 may be a key molecule operating in eosinophil-mediated fibrosis in high-dose-per fraction irradiated skin. - Highlights: • Single high-dose irradiation aggravates eosinophil-mediated fibrosis through IL-33. • Vascular endothelial cells damaged by high-dose radiation secrete IL-33. • Blocking IL-33 suppressed migration of inflammatory cells and cytokine secretion. • IL

  17. Randomized, Placebo-Controlled, Single-Ascending-Dose Study of BMS-791325, a Hepatitis C Virus (HCV) NS5B Polymerase Inhibitor, in HCV Genotype 1 Infection

    PubMed Central

    Lemm, Julie; Eley, Timothy; Liu, Menping; Berglind, Anna; Sherman, Diane; Lawitz, Eric; Vutikullird, Apinya B.; Tebas, Pablo; Gao, Min; Pasquinelli, Claudio; Grasela, Dennis M.

    2014-01-01

    BMS-791325 is a nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B polymerase with low-nanomolar potency against genotypes 1a (50% effective concentration [EC50], 3 nM) and 1b (EC50, 7 nM) in vitro. BMS-791325 safety, pharmacokinetics, and antiviral activity were evaluated in a double-blind, placebo-controlled, single-ascending-dose study in 24 patients (interferon naive and experienced) with chronic HCV genotype 1 infection, randomized (5:1) to receive a single dose of BMS-791325 (100, 300, 600, or 900 mg) or placebo. The prevalence and phenotype of HCV variants at baseline and specific posttreatment time points were assessed. Antiviral activity was observed in all cohorts, with a mean HCV RNA decline of ≈2.5 log10 copies/ml observed 24 h after a single 300-mg dose. Mean plasma half-life among cohorts was 7 to 9 h; individual 24-hour levels exceeded the protein-adjusted EC90 for genotype 1 at all doses. BMS-791325 was generally well tolerated, with no serious adverse events or discontinuations. Enrichment for resistance variants was not observed at 100 to 600 mg. At 900 mg, variants (P495L/S) associated with BMS-791325 resistance in vitro were transiently observed in one patient, concurrent with an observed HCV RNA decline of 3.4 log10 IU/ml, but were replaced with wild type by 48 h. Single doses of BMS-791325 were well tolerated; demonstrated rapid, substantial, and exposure-related antiviral activity; displayed dose-related increases in exposure; and showed viral kinetic and pharmacokinetic profiles supportive of once- or twice-daily dosing. These results support its further development in combination with other direct-acting antivirals for HCV genotype 1 infection. (This trial has been registered at ClinicalTrials.gov under registration no. NCT00664625.) PMID:24733462

  18. Effect of feeding rate on biochemical measures and fate of a single oral dose of PCB in Arctic char

    SciTech Connect

    Delorme, P.D.; Brown, S.B.; Lockhart, W.L.; Metner, D.A.; Vandenbyllaardt, L.

    1995-12-31

    This study was done to determine the effects of reducing lipid stores and the resulting mobilization of associated contaminants. Individually tagged Arctic char (Saivelinus alpinus) were treated with single gavage doses of 6.1 ng/g {sup 14}C-3,3{prime}4,4{prime},5-pentachlorobiphenyl (PCB 126) in gelatin or vehicle (controls). Following treatment, the PCB was allowed 3 weeks to reach equilibrium distribution within the fish. After this 3 week period, treated and control groups of fish were fed one of three rations, (1.5%, 0.75% or 0.25% body wt/d). Fish were sampled at 0, 8, 24 and 48 weeks following the initiation of the different rations. PCB concentrations and lipid levels were measured in 5 tissues (muscle, liver, intestine, spleen and kidney). Biochemical response measured included hepatic EROD, retinoids and tocopherol. Growth was reduced in both treated and control groups fed the lowest ration. EROD activity was negatively correlated with growth and positively correlated with liver concentrations of PCB 126. Declines in mean lipid content were ration dependent. Changes in hepatic retinoids were related to both ration and treatment. The results indicate that a low ration resulted in greater utilization of stored lipids and higher tissue concentrations of contaminants compared to the other rations. These changes altered biochemical measures which are responsive to planar chlorinated aromatic hydrocarbons.

  19. Novel and Distinct Metabolites Identified Following a Single Oral Dose of α- or γ-Hexabromocyclododecane in Mice

    PubMed Central

    Szabo, David T.; Huwe, Janice; Diliberto, Janet; Birnbaum, Linda S.

    2013-01-01

    The metabolism of α- and γ-hexabromocyclododecane (HBCD) was investigated in adult C57BL/6 female mice. α- or γ-[14C]HBCD (3 mg/kg bw) was orally administered with subsequent urine and feces collection for 4 consecutive days; a separate group of mice were dosed and sacrificed 3 hours post-exposure to investigate tissue metabolite levels. Extractable and non-extractable HBCD metabolites were quantitated in liver, blood, fat, brain, bile, urine and feces and characterized by LC/MS (ESI-). Metabolites identified were distinct between the two stereoisomers. In mice exposed to α-HBCD, four hydroxylated metabolites were detected in fecal extracts, and one of these metabolite isomers was consistently characterized in liver, brain, and adipose tissue extracts. In contrast, mice exposed to γ-HBCD contained multiple isomers of monohydroxy-pentabromocyclododecene, dihydroxy-pentabromocyclododecene, and dihydroxy-pentabromocyclododecadiene in the feces while only a single monohydroxy-pentabromocyclododecane metabolite was measured in liver and adipose tissue. Both stereoisomers were transformed to metabolites which formed covalent bonds to proteins and/or lipids in the gut as evidenced by high fecal non-extractables. Although the potential toxicity of these free and bound metabolites remains to be determined, the presence of distinct metabolic products from the two main HBCD stereoisomers should allow biomarkers to be selected that may aid in characterizing sources of HBCD exposure. PMID:23171393

  20. Chronic carcinogenic and toxic effects of a single subcutaneous dose of cadmium in the male Fischer rat

    SciTech Connect

    Waalkes, M.P.; Rehm, S.; Sass, B.; Konishi, N.; Ward, J.M. )

    1991-06-01

    This study determined tumor incidence in various tissues of male Fischer F344 rats after a single dose of cadmium. Cadmium (as CdCl{sub 2}) was given sc in the dorsal thoracic midline at 30 {mu}mole/kg to 70 8-week old male F344 rats while controls received saline. Rats were observed during the next 90 weeks. Early deaths ({much lt} 32 weeks), due mostly to acute cadmium-induced hepatotoxicity, accounted for 37 of the cadmium-treated rats while no control rats died in the same period. A high incidence of injection site sarcomas (ISS) occurred in the cadmium-treated group while only 1/50 occurred in controls (2%). In fact, ISS were the major cause of morbidity after 35 weeks in cadmium-treated rats. These tumors were mostly fibrosarcomas, although histiocytic and osteogenic sarcomas also occurred. Testicular interstitial cell tumors, which show a very high spontaneous incidence in this strain, were not markedly affected by cadmium. This is in sharp contrast to other strains, such as the Wistar, in which cadmium treatment is reported to cause as much as an eightfold increase in interstitial cell (Leydig cell) tumor incidence. The incidence of large granular lymphocyte (LGL) leukemia, which also occurred frequently in control F344 rats was markedly decreased by cadmium in lymphoid tissues of rats, and this may be related to the suppression of the leukemia.

  1. Negligible risk of inducing resistance in Mycobacterium tuberculosis with single-dose rifampicin as post-exposure prophylaxis for leprosy.

    PubMed

    Mieras, Liesbeth; Anthony, Richard; van Brakel, Wim; Bratschi, Martin W; van den Broek, Jacques; Cambau, Emmanuelle; Cavaliero, Arielle; Kasang, Christa; Perera, Geethal; Reichman, Lee; Richardus, Jan Hendrik; Saunderson, Paul; Steinmann, Peter; Yew, Wing Wai

    2016-01-01

    Post-exposure prophylaxis (PEP) for leprosy is administered as one single dose of rifampicin (SDR) to the contacts of newly diagnosed leprosy patients. SDR reduces the risk of developing leprosy among contacts by around 60 % in the first 2-3 years after receiving SDR. In countries where SDR is currently being implemented under routine programme conditions in defined areas, questions were raised by health authorities and professional bodies about the possible risk of inducing rifampicin resistance among the M. tuberculosis strains circulating in these areas. This issue has not been addressed in scientific literature to date. To produce an authoritative consensus statement about the risk that SDR would induce rifampicin-resistant tuberculosis, a meeting was convened with tuberculosis (TB) and leprosy experts. The experts carefully reviewed and discussed the available evidence regarding the mechanisms and risk factors for the development of (multi) drug-resistance in M. tuberculosis with a view to the special situation of the use of SDR as PEP for leprosy. They concluded that SDR given to contacts of leprosy patients, in the absence of symptoms of active TB, poses a negligible risk of generating resistance in M. tuberculosis in individuals and at the population level. Thus, the benefits of SDR prophylaxis in reducing the risk of developing leprosy in contacts of new leprosy patients far outweigh the risks of generating drug resistance in M. tuberculosis. PMID:27268059

  2. A high performance liquid chromatographic assay of Mefloquine in saliva after a single oral dose in healthy adult Africans

    PubMed Central

    2012-01-01

    Background Mefloquine-artesunate is a formulation of artemisinin based combination therapy (ACT) recommended by the World Health Organization and historically the first ACT used clinically. The use of ACT demands constant monitoring of therapeutic efficacies and drug levels, in order to ensure that optimum drug exposure is achieved and detect reduced susceptibility to these drugs. Quantification of anti-malarial drugs in biological fluids other than blood would provide a more readily applicable method of therapeutic drug monitoring in developing endemic countries. Efforts in this study were devoted to the development of a simple, field applicable, non-invasive method for assay of mefloquine in saliva. Methods A high performance liquid chromatographic method with UV detection at 220 nm for assaying mefloquine in saliva was developed and validated by comparing mefloquine concentrations in saliva and plasma samples from four healthy volunteers who received single oral dose of mefloquine. Verapamil was used as internal standard. Chromatographic separation was achieved using a Hypersil ODS column. Results Extraction recoveries of mefloquine in plasma or saliva were 76-86% or 83-93% respectively. Limit of quantification of mefloquine was 20 ng/ml. Agreement between salivary and plasma mefloquine concentrations was satisfactory (r = 0.88, p < 0.001). Saliva:plasma concentrations ratio was 0.42. Conclusion Disposition of mefloquine in saliva paralleled that in plasma, making salivary quantification of mefloquine potentially useful in therapeutic drug monitoring. PMID:22369125

  3. A single dose of lorazepam reduces paired-pulse suppression of median nerve evoked somatosensory evoked potentials.

    PubMed

    Stude, Philipp; Lenz, Melanie; Höffken, Oliver; Tegenthoff, Martin; Dinse, Hubert

    2016-05-01

    Paired-pulse behaviour in the somatosensory cortex is an approach to obtain insights into cortical processing modes and to obtain markers of changes of cortical excitability attributable to learning or pathological states. Numerous studies have demonstrated suppression of the response to the stimulus that follows a first one after a short interval, but the underlying mechanisms remain elusive, although there is agreement that GABAergic mechanisms seem to play a crucial role. We therefore aimed to explore the influence of the GABAA agonist lorazepam on paired-pulse somatosensory evoked potentials (SEPs). We recorded and analysed SEPs after paired median nerve stimulation in healthy individuals before and after they had received a single dose of 2.5 mg of lorazepam as compared with a control group receiving placebo. Paired-pulse suppression was expressed as a ratio of the amplitudes of the second and the first peaks. We found that, after lorazepam application, paired-pulse suppression of the cortical N20 component remained unchanged, but suppression of the N20-P25 complex was significantly reduced, indicative of GABAergic involvement in intracortical processing. Our data suggest that lorazepam most likely enhances inhibition within the cortical network of interneurons responsible for creating paired-pulse suppression, leading to reduced inhibitory drive with a subsequently reduced amount of suppression. The results provide further evidence that GABAA -mediated mechanisms are involved in the generation of median nerve evoked paired-pulse suppression. PMID:26929110

  4. A single dose of lorazepam reduces paired-pulse suppression of median nerve evoked somatosensory evoked potentials.

    PubMed

    Stude, Philipp; Lenz, Melanie; Höffken, Oliver; Tegenthoff, Martin; Dinse, Hubert

    2016-05-01

    Paired-pulse behaviour in the somatosensory cortex is an approach to obtain insights into cortical processing modes and to obtain markers of changes of cortical excitability attributable to learning or pathological states. Numerous studies have demonstrated suppression of the response to the stimulus that follows a first one after a short interval, but the underlying mechanisms remain elusive, although there is agreement that GABAergic mechanisms seem to play a crucial role. We therefore aimed to explore the influence of the GABAA agonist lorazepam on paired-pulse somatosensory evoked potentials (SEPs). We recorded and analysed SEPs after paired median nerve stimulation in healthy individuals before and after they had received a single dose of 2.5 mg of lorazepam as compared with a control group receiving placebo. Paired-pulse suppression was expressed as a ratio of the amplitudes of the second and the first peaks. We found that, after lorazepam application, paired-pulse suppression of the cortical N20 component remained unchanged, but suppression of the N20-P25 complex was significantly reduced, indicative of GABAergic involvement in intracortical processing. Our data suggest that lorazepam most likely enhances inhibition within the cortical network of interneurons responsible for creating paired-pulse suppression, leading to reduced inhibitory drive with a subsequently reduced amount of suppression. The results provide further evidence that GABAA -mediated mechanisms are involved in the generation of median nerve evoked paired-pulse suppression.

  5. Opposite effects of a single versus repeated doses of gabapentin on retention performance of an inhibitory avoidance response in mice.

    PubMed

    Blake, Mariano G; Boccia, Mariano M; Acosta, Gabriela B; Höcht, Christian; Baratti, Carlos M

    2007-02-01

    CF-1 male mice were trained in an inhibitory avoidance (IA) task. A single gabapentin (GBP) administration (50mg/kg, ip) immediately after training enhanced retention performance when mice were tested 8 days after training. On the contrary, when the same dose of the anticonvulsant drug was given twice a day for 7 days (repeated treatment), a significant impairment on retention performance 12h after the last injection of GBP was observed. When the retention test was delayed 7 days after the end of the repeated treatment, the retention performance was not significant different from the control group, whereas if the retention test was delayed 14 days, retention performance was higher than control group but similar to that observed when GBP was administered once immediately after training. The impairment on retention performance was correlated with a significant decrease in the high affinity choline uptake in the hippocampus at the end of the retention test. The pretest administration of the direct muscarinic cholinergic agonist oxotremorine (50 microg/kg, ip) reversed the impairment on retention performance. This reversion was prevented by the muscarinic cholinergic antagonist scopolamine (0.5 mg/kg, ip). Taken together, these results suggest that the impairment on retention performance of an IA task in mice induced by repeated administration of GBP affected memory retrieval but not memory consolidation and that this impairment may be attributable to a reduction on central cholinergic activity.

  6. Single dose oral amoxycillin 3 g with either 125 mg or 250 mg clavulanic acid to treat uncomplicated anogenital gonorrhoea.

    PubMed Central

    Lawrence, A G; Shanson, D C

    1985-01-01

    A single supervised oral dose of amoxycillin 3 g combined with clavulanic acid 125 mg as a suspension (Augmentin 3.125G) plus probenecid 1 g, cured 97 of 100 assessable patients who had uncomplicated anogenital gonorrhoea. Thirteen of the 100 patients were infected with penicillinase producing strains of Neisseria gonorrhoeae (PPNG) and 11 (85%) of these patients were cured, including one infected with a PPNG strain that was also resistant to spectinomycin. Another group of 93 assessable patients was treated with ampicillin 3 g plus probenecid 1 g, and only 85 (91%) patients were cured. Of the eight treatment failures in this group, five were found to be infected with PPNG strains. In a second study 144 assessable patients were treated with amoxycillin 3 g combined with clavulanic acid 250 mg, (Augmentin 3.250G) plus probenecid 1 g, and a 97% cure rate was again obtained. Five of seven (71%) patients infected with PPNG strains were cured. Although both Augmentin regimens were effective for treating gonorrhoea caused by PPNG and non-PPNG strains, side effects were noted in more patients treated with 250 mg clavulanic acid (24%) than with 125 mg clavulanic acid (5%). In addition, a similar cure rate was obtained in the three primary sites of infection, the urethra, cervix, and rectum. PMID:4007860

  7. A Single Dose of Amoxicillin and Dexamethasone for Prevention of Postoperative Complications in Third Molar Surgery: A Randomized, Double-Blind, Placebo Controlled Clinical Trial

    PubMed Central

    Bortoluzzi, Marcelo Carlos; Capella, Diogo Lenzi; Barbieri, Tharzon; Pagliarini, Micheli; Cavalieri, Talita; Manfro, Rafael

    2013-01-01

    Background The aim of this study was to assess the efficacy of a single prophylactic dose of amoxicillin and/or dexamethasone in preventing postoperative complications (PC) after a surgical removal of a single mandibular third molar (M3). Methods This study is a randomized, placebo controlled clinical trial. Four groups were included: Group 1 (G1) included a prophylactic dose of 2 g of amoxicillin and 8 mg of dexamethasone; Group 2 (G2) included a prophylactic dose of 2 g of amoxicillin and 8 mg of placebo; Group 3 (G3) included a prophylactic dose of 8 mg of dexamethasone and 2 g of placebo and; Group 4 (G4) placebo. Results Fifty patients were included. It was observed one case of alveolar infection (2%) and two of alveolar osteitis (4%) resulting in three PC (6%). No statistical differences were observed between therapeutic groups for development of PC, trismus, pain and edema. The use of antibiotics showed an absolute risk reduction (ARR) for PC development of 3.52% and the number needed to treat (NNT) was 29. Conclusion Prophylactic antibiotics and corticoid in a single dose regimen did not bring any benefit on M3 surgeries. PMID:23390473

  8. Nutrition Composition and Single, 14-Day and 13-Week Repeated Oral Dose Toxicity Studies of the Leaves and Stems of Rubus coreanus Miquel.

    PubMed

    Om, Ae-Son; Song, Yu-Na; Noh, GeonMin; Kim, HaengRan; Choe, JeongSook

    2016-01-08

    The leaves and stems of the plant Rubus coreanus Miquel (RCMLS) are rich in vitamins, minerals and phytochemicals which have antioxidant, anti-hemolytic, anti-inflammatory, anti-fatigue and anti-cancer effects. However, RCMLS is not included in the Korean Food Standards Codex due to the lack of safety assurance concerning RCMLS. We evaluated single and repeated oral dose toxicity of RCMLS in Sprague-Dawley rats. RCMLS did not induce any significant toxicological changes in both male and female rats at a single doses of 2500 mg/kg/day. Repeated oral dose toxicity studies showed no adverse effects in clinical signs, body weight, food consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy findings, organ weight, and histopathology at doses of 625, 1250, and 2500 mg/kg/day. The LD50 and LOAEL of RCMLS might be over 2500 mg/kg body weight/day and no target organs were identified. Therefore, this study revealed that single and repeated oral doses of RCMLS are safe.

  9. Nutrition Composition and Single, 14-Day and 13-Week Repeated Oral Dose Toxicity Studies of the Leaves and Stems of Rubus coreanus Miquel.

    PubMed

    Om, Ae-Son; Song, Yu-Na; Noh, GeonMin; Kim, HaengRan; Choe, JeongSook

    2016-01-01

    The leaves and stems of the plant Rubus coreanus Miquel (RCMLS) are rich in vitamins, minerals and phytochemicals which have antioxidant, anti-hemolytic, anti-inflammatory, anti-fatigue and anti-cancer effects. However, RCMLS is not included in the Korean Food Standards Codex due to the lack of safety assurance concerning RCMLS. We evaluated single and repeated oral dose toxicity of RCMLS in Sprague-Dawley rats. RCMLS did not induce any significant toxicological changes in both male and female rats at a single doses of 2500 mg/kg/day. Repeated oral dose toxicity studies showed no adverse effects in clinical signs, body weight, food consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy findings, organ weight, and histopathology at doses of 625, 1250, and 2500 mg/kg/day. The LD50 and LOAEL of RCMLS might be over 2500 mg/kg body weight/day and no target organs were identified. Therefore, this study revealed that single and repeated oral doses of RCMLS are safe. PMID:26760987

  10. Efficacy and Safety of Single Dose Zoledronic Acid for Osteoporosis in Frail Seniors: A Randomized Clinical Trial

    PubMed Central

    Greenspan, Susan L.; Perera, Subashan; Ferchak, Mary Anne; Nace, David A.; Resnick, Neil M.

    2016-01-01

    Importance 85% of institutionalized elderly have osteoporosis, with fracture rates 8–9 fold higher than observed among community-dwelling elderly. Yet most are untreated and excluded from pivotal osteoporosis trials. Objective Determine the efficacy and safety of zoledronic acid in frail elderly women. Design 2-year, randomized, placebo-controlled, double-blinded study conducted between December 2007 and March 2012. Setting Nursing home and assisted living facilities. Participants 181 women ≥ age 65 with osteoporosis including those with cognitive impairment, immobility, and multimorbidity. Intervention One 5 mg dose of zoledronic acid or placebo IV and daily calcium and vitamin D. Main Outcomes (1) Hip and spine bone mineral density (BMD) at 12 and 24 months and (2) adverse events. Results There were no baseline differences in age (mean=85.4±0.6 years), BMD, or functional or cognitive status, but the treatment group included more subjects with frailty, falls history, diabetes, and anticonvulsant use. BMD was available for 87% of participants at 12 months and 73% at 24 months. BMD changes were greater in the treatment group (p< 0.01): 3.2 ± 0.7 and 3.9 ± 0.7 percentage point differences (mean ± SE) in the total hip at 12 and 24 months respectively, and 1.8 ± 0.7 and 3.6 ± 0.7 at the spine (p<0.01); adjusted analyses were similar. The treatment and placebo groups’ fracture rates were 20% and 16%, respectively (OR=1.30; 95% CI=0.61–2.78); mortality rates were 16% and 13% (OR=1.24; 95% CI=0.54–2.86). Groups did not differ in the proportion of single fallers (28% vs. 24%; OR=1.24; 95% CI=0.64–2.42; p=0.52) but more subjects in the treatment group had multiple falls (49% vs. 35%; OR=1.83; 95% CI=1.01–3.33; p=0.047); this was no longer significant when adjusted for baseline frailty. Conclusions and Relevance In this group of frail, osteoporotic women, one dose of zoledronic acid improved BMD over 2 years. The clinical importance of nonsignificant

  11. Oral testosterone-triglyceride conjugate in rabbits: single-dose pharmacokinetics and comparison with oral testosterone undecanoate.

    PubMed

    Amory, J K; Scriba, G K E; Amory, D W; Bremner, W J

    2003-01-01

    Development of a safe and effective oral form of testosterone has been inhibited by the rapid hepatic metabolism of nonalkylated androgens. Since triglycerides are absorbed via lymphatics and bypass the liver, we hypothesized that a testosterone-triglyceride conjugate (TTC) might allow for safe and effective oral testosterone therapy. Therefore, we studied the single-dose pharmacokinetics of oral administration of TTC in rabbits. Female New Zealand rabbits were administered 2, 4, or 8 mg/kg of TTC in sesame oil by gastric lavage. Testosterone undecanoate (TU) by gastric lavage was used as a positive control. Blood was sampled from a catheter in the auricular artery at 0, 15, 30, 60, 90, 120, 180, 240, 360, 480, and 600 minutes after drug administration. Samples were assayed for testosterone by a fluoroimmunoassay. Mean serum testosterone, area under the curve (AUC), and terminal half-life were calculated. Oral TTC administration resulted in rapid and marked increases in serum testosterone. Oral TTC resulted in higher maximum serum testosterone concentrations than oral TU at 8 mg/kg (TTC: 28.6 +/- 7.9 nmol/L vs TU: 11.9 +/- 2.1 nmol/L; P <.001) and 4 mg/kg (TTC: 11.5 +/- 4.2 nmol/L vs TU: 3.6 +/- 1.0 nmol/L; P <.001). In addition, the AUC was 1.8 to 2.6 times greater for TTC than TU at both doses (P <.05). The terminal half-life for both TU and TTC was between 3 and 5 hours and was not significantly different. We conclude that oral TTC is rapidly absorbed from the rabbit intestine and results in elevated concentrations of serum testosterone. The absorption of TTC appears to be superior to that of TU; however, the in vivo persistence of the 2 compounds is similar. TTC may offer an alternative to the use of TU for oral testosterone therapy. Further testing of this compound is warranted. PMID:12954663

  12. A Randomized, Single-Ascending-Dose, Ivermectin-Controlled, Double-Blind Study of Moxidectin in Onchocerca volvulus Infection

    PubMed Central

    Opoku, Nicholas O.; Attah, Simon K.; Lazdins-Helds, Janis; Kuesel, Annette C.

    2014-01-01

    Background Control of onchocerciasis as a public health problem in Africa relies on annual mass ivermectin distribution. New tools are needed to achieve elimination of infection. This study determined in a small number of Onchocerca volvulus infected individuals whether moxidectin, a veterinary anthelminthic, is safe enough to administer it in a future large study to further characterize moxidectin's safety and efficacy. Effects on the parasite were also assessed. Methodology/Principal Findings Men and women from a forest area in South-eastern Ghana without ivermectin mass distribution received a single oral dose of 2 mg (N = 44), 4 mg (N = 45) or 8 mg (N = 38) moxidectin or 150 µg/kg ivermectin (N = 45) with 18 months follow up. All ivermectin and 97%–100% of moxidectin treated participants had Mazzotti reactions. Statistically significantly higher percentages of participants treated with 8 mg moxidectin than participants treated with ivermectin experienced pruritus (87% vs. 56%), rash (63% vs. 42%), increased pulse rate (61% vs. 36%) and decreased mean arterial pressure upon 2 minutes standing still after ≥5 minutes supine relative to pre-treatment (61% vs. 27%). These reactions resolved without treatment. In the 8 mg moxidectin and ivermectin arms, the mean±SD number of microfilariae/mg skin were 22.9±21.1 and 21.2±16.4 pre-treatment and 0.0±0.0 and 1.1±4.2 at nadir reached 1 and 3 months after treatment, respectively. At 6 months, values were 0.0±0.0 and 1.6±4.5, at 12 months 0.4±0.9 and 3.4±4.4 and at 18 months 1.8±3.3 and 4.0±4.8, respectively, in the 8 mg moxidectin and ivermectin arm. The reduction from pre-treatment values was significantly higher after 8 mg moxidectin than after ivermectin treatment throughout follow up (p<0.01). Conclusions/Significance The 8 mg dose of moxidectin was safe enough to initiate the large study. Provided its results confirm those from this study, availability of moxidectin to control

  13. Antimalarial Preclinical Drug Development: A Single Oral Dose of A 5-Carbon-linked Trioxane Dimer Plus Mefloquine Cures Malaria-Infected Mice.

    PubMed

    Moon, Deuk Kyu; Singhal, Vandana; Kumar, Nirbhay; Shapiro, Theresa A; Posner, Gary H

    2009-01-01

    Three new 5-carbon-linked trioxane dimer carboxylate esters have been prepared from the natural trioxane, artemisinin in only 3-steps and 40-50% overall yields. Each one of these new chemical entities is at least as efficacious as the clinically used trioxane antimalarial drug artemether when combined with mefloquine hydrochloride in a low single oral dose cure. PMID:20686674

  14. Efficacy and Immunogenicity of Single-Dose AdVAV Intranasal Anthrax Vaccine Compared to Anthrax Vaccine Absorbed in an Aerosolized Spore Rabbit Challenge Model

    PubMed Central

    Krishnan, Vyjayanthi; Andersen, Bo H.; Shoemaker, Christine; Sivko, Gloria S.; Tordoff, Kevin P.; Stark, Gregory V.; Zhang, Jianfeng; Feng, Tsungwei; Duchars, Matthew

    2015-01-01

    AdVAV is a replication-deficient adenovirus type 5-vectored vaccine expressing the 83-kDa protective antigen (PA83) from Bacillus anthracis that is being developed for the prevention of disease caused by inhalation of aerosolized B. anthracis spores. A noninferiority study comparing the efficacy of AdVAV to the currently licensed Anthrax Vaccine Absorbed (AVA; BioThrax) was performed in New Zealand White rabbits using postchallenge survival as the study endpoint (20% noninferiority margin for survival). Three groups of 32 rabbits were vaccinated with a single intranasal dose of AdVAV (7.5 × 107, 1.5 × 109, or 3.5 × 1010 viral particles). Three additional groups of 32 animals received two doses of either intranasal AdVAV (3.5 × 1010 viral particles) or intramuscular AVA (diluted 1:16 or 1:64) 28 days apart. The placebo group of 16 rabbits received a single intranasal dose of AdVAV formulation buffer. All animals were challenged via the inhalation route with a targeted dose of 200 times the 50% lethal dose (LD50) of aerosolized B. anthracis Ames spores 70 days after the initial vaccination and were followed for 3 weeks. PA83 immunogenicity was evaluated by validated toxin neutralizing antibody and serum anti-PA83 IgG enzyme-linked immunosorbent assays (ELISAs). All animals in the placebo cohort died from the challenge. Three of the four AdVAV dose cohorts tested, including two single-dose cohorts, achieved statistical noninferiority relative to the AVA comparator group, with survival rates between 97% and 100%. Vaccination with AdVAV also produced antibody titers with earlier onset and greater persistence than vaccination with AVA. PMID:25673303

  15. Efficacy and immunogenicity of single-dose AdVAV intranasal anthrax vaccine compared to anthrax vaccine absorbed in an aerosolized spore rabbit challenge model.

    PubMed

    Krishnan, Vyjayanthi; Andersen, Bo H; Shoemaker, Christine; Sivko, Gloria S; Tordoff, Kevin P; Stark, Gregory V; Zhang, Jianfeng; Feng, Tsungwei; Duchars, Matthew; Roberts, M Scot

    2015-04-01

    AdVAV is a replication-deficient adenovirus type 5-vectored vaccine expressing the 83-kDa protective antigen (PA83) from Bacillus anthracis that is being developed for the prevention of disease caused by inhalation of aerosolized B. anthracis spores. A noninferiority study comparing the efficacy of AdVAV to the currently licensed Anthrax Vaccine Absorbed (AVA; BioThrax) was performed in New Zealand White rabbits using postchallenge survival as the study endpoint (20% noninferiority margin for survival). Three groups of 32 rabbits were vaccinated with a single intranasal dose of AdVAV (7.5 × 10(7), 1.5 × 10(9), or 3.5 × 10(10) viral particles). Three additional groups of 32 animals received two doses of either intranasal AdVAV (3.5 × 10(10) viral particles) or intramuscular AVA (diluted 1:16 or 1:64) 28 days apart. The placebo group of 16 rabbits received a single intranasal dose of AdVAV formulation buffer. All animals were challenged via the inhalation route with a targeted dose of 200 times the 50% lethal dose (LD50) of aerosolized B. anthracis Ames spores 70 days after the initial vaccination and were followed for 3 weeks. PA83 immunogenicity was evaluated by validated toxin neutralizing antibody and serum anti-PA83 IgG enzyme-linked immunosorbent assays (ELISAs). All animals in the placebo cohort died from the challenge. Three of the four AdVAV dose cohorts tested, including two single-dose cohorts, achieved statistical noninferiority relative to the AVA comparator group, with survival rates between 97% and 100%. Vaccination with AdVAV also produced antibody titers with earlier onset and greater persistence than vaccination with AVA.

  16. Phase I, Open-Label, Single-Dose Study To Evaluate the Pharmacokinetics and Safety of Telbivudine in Children and Adolescents with Chronic Hepatitis B

    PubMed Central

    Ke, June; Uy, Grace; Bosheva, Miroslava; Qi, Yin; Praestgaard, Jens

    2013-01-01

    Telbivudine is a nucleoside analogue that has been approved for the treatment of chronic hepatitis B virus (HBV) infection in adults at 600 mg/day. We conducted a phase I, open-label, first-in-pediatrics study to investigate the safety and pharmacokinetics of a single dose of telbivudine in HBV-infected children and adolescents. Eligible patients were enrolled sequentially from older to younger groups, with evaluation of safety and available pharmacokinetic data after each stratum. Adolescent patients (>12 to 18 years) received a single dose of 600 mg telbivudine as an oral solution, while children aged 2 to 12 years received a single dose of 15 or 25 mg/kg of body weight up to a maximum of 600 mg. Telbivudine was well tolerated; all adverse events were mild, and none occurred in more than one patient. The plasma telbivudine concentration-versus-time profiles in adolescents given 600 mg were similar to the mean profile of healthy adults receiving the same oral dose. Children aged 2 to <6 and 6 to 12 years receiving a single 15-mg/kg dose showed similar plasma exposures. To predict the steady-state exposure, plasma concentration-versus-time profiles for patients aged 2 to 12 years (15 mg/kg) and >12 to 18 years (600 mg) were fitted to a two-compartment 1st-order, microconstant, lag time, 1st-order elimination pharmacokinetic (PK) model. This analysis predicted the following dosages to mimic exposures in healthy adults receiving 600 mg/day: 20 mg/kg/day for children 2 to 12 years and 600 mg/day for adolescents. Studies are ongoing to evaluate the efficacy of the recommended dose in pediatric patients. (This study has been registered at ClinicalTrials.gov under registration no. NCT00907894.) PMID:23774433

  17. Ultrastructural changes in the parenchymal liver cells of rats treated with high doses of rifampicin.

    PubMed Central

    Piriou, A.; Maissiat, R.; Jacqueson, A.; Warnet, J. M.; Claude, J. R.

    1987-01-01

    Ultrastructural study of hepatic parenchyma was carried out in female Wistar rats after they had received high doses (400 mg X kg-1) of rifampicin for 1, 2, 4, 6 and 8 days. Morphological changes in the endoplasmic reticulum, Golgi apparatus and mitochondria were observed as early as day 1 of intoxication. These changes corroborate the biochemical data available regarding RFP-induced fatty liver. Images Fig. 1 Fig. 2 Fig. 3 & 4 Fig. 5 Fig. 6 Fig. 7 Fig. 8 PMID:3580280

  18. Single-Dose and Fractionated Irradiation Promote Initiation and Progression of Atherosclerosis and Induce an Inflammatory Plaque Phenotype in ApoE{sup -/-} Mice

    SciTech Connect

    Hoving, Saske; Heeneman, Sylvia; Gijbels, Marion J.J.; Poele, Johannes A.M. te; Russell, Nicola S.; Daemen, Mat J.A.P.; Stewart, Fiona A.

    2008-07-01

    Purpose: Increased risk of atherosclerosis and stroke has been demonstrated in patients receiving radiotherapy for Hodgkin's lymphoma and head-and-neck cancer. We previously showed that 14 Gy to the carotid arteries of hypercholesterolemic ApoE{sup -/-} mice resulted in accelerated development of macrophage-rich, inflammatory atherosclerotic lesions. Here we investigate whether clinically relevant fractionated irradiation schedules and lower single doses also predispose to an inflammatory plaque phenotype. Methods and Materials: ApoE{sup -/-} mice were given 8 or 14 Gy, or 20 x 2.0 Gy in 4 weeks to the neck, and the carotid arteries were subsequently examinated for presence of atherosclerotic lesions, plaque size, and phenotype. Results: At 4 weeks, early atherosclerotic lesions were found in 44% of the mice after single doses of 14 Gy but not in age-matched controls. At 22 to 30 weeks after irradiation there was a twofold increase in the mean number of carotid lesions (8-14 Gy and 20 x 2.0 Gy) and total plaque burden (single doses only), compared with age-matched controls. The majority of lesions seen at 30 to 34 weeks after fractionated irradiation or 14-Gy single doses were granulocyte rich (100% and 63%, respectively), with thrombotic features (90% and 88%), whereas these phenotypes were much less common in age-matched controls or after a single dose of 8 Gy. Conclusions: We showed that fractionated irradiation accelerated the development of atherosclerosis in ApoE{sup -/-} mice and predisposed to the formation of an inflammatory, thrombotic plaque phenotype.

  19. The pharmacokinetics of DPH after the administration of a single intravenous or intramuscular dose in healthy dogs.

    PubMed

    Sanchez, A; Valverde, A; Sinclair, M; Mosley, C; Singh, A; Mutsaers, A J; Hanna, B; Gu, Y; Johnson, R

    2016-10-01

    The objective of this study was to determine the pharmacokinetics of diphenhydramine (DPH) in healthy dogs following a single i.v. or i.m. dose. Dogs were randomly allocated in two treatment groups and received DPH at 1 mg/kg, i.v., or 2 mg/kg, i.m. Blood samples were collected serially over 24 h. Plasma concentrations of DPH were determined by high-performance liquid chromatography, and noncompartmental pharmacokinetic analysis was performed with the commercially available software. Cardio-respiratory parameters, rectal temperature and effects on behaviour, such as sedation or excitement, were recorded. Diphenhydramine Clarea , Vdarea and T1/2 were 20.7 ± 2.9 mL/kg/min, 7.6 ± 0.7 L/kg and 4.2 ± 0.5 h for the i.v. route, respectively, and Clarea /F, Vdarea /F and T1/2 20.8 ± 2.7 mL/kg/min, 12.3 ± 1.2 L/kg and 6.8 ± 0.7 h for the i.m. route, respectively. Bioavailability was 88% after i.m. administration. No significant differences were found in physiological parameters between groups or within dogs of the same group, and values remained within normal limits. No adverse effects or changes in mental status were observed after the administration of DPH. Both routes of administration resulted in DPH plasma concentrations which exceeded levels considered therapeutic in humans.

  20. Tamoxifen Forms DNA Adducts In Human Colon After Administration Of A Single [14C]-Labeled Therapeutic Dose.

    SciTech Connect

    Brown, K; Tompkins, E M; Boocock, D J; Martin, E A; Farmer, P B; Turteltaub, K W; Ubick, E; Hemingway, D; Horner-Glister, E; White, I H

    2007-05-23

    Tamoxifen is widely prescribed for the treatment of breast cancer and is also licensed in the U.S. for the prevention of this disease. However, tamoxifen therapy is associated with an increased occurrence of endometrial cancer in women and there is also evidence that it may elevate the risk of colorectal cancer. The underlying mechanisms responsible for tamoxifen-induced carcinogenesis in women have not yet been elucidated but much interest has focussed on the role of DNA adduct formation. We investigated the propensity of tamoxifen to bind irreversibly to colorectal DNA when given to ten women as a single [{sup 14}C]-labeled therapeutic (20 mg) dose, {approx}18 h prior to undergoing colon resections. Using the sensitive technique of accelerator mass spectrometry, coupled with HPLC separation of enzymatically digested DNA, a peak corresponding to authentic dG-N{sup 2}-tamoxifen adduct was detected in samples from three patients, at levels ranging from 1-7 adducts/10{sup 9} nucleotides. No [{sup 14}C]-radiolabel associated with tamoxifen or its major metabolites was detected. The presence of detectable CYP3A4 protein in all colon samples suggests this tissue has the potential to activate tamoxifen to {alpha}-hydroxytamoxifen, in addition to that occurring in the systemic circulation, and direct interaction of this metabolite with DNA could account for the binding observed. Although the level of tamoxifeninduced damage displayed a degree of inter-individual variability, when present it was {approx}10-100 times higher than that reported for other suspect human colon carcinogens such as PhIP. These findings provide a mechanistic basis through which tamoxifen could increase the incidence of colon cancers in women.

  1. Effect of H2 blockade and food on single-dose pharmacokinetics of GSK1322322, a peptide deformylase inhibitor antibacterial.

    PubMed

    Naderer, Odin J; Dumont, Etienne; Zhu, John; Kurtinecz, Milena; Jones, Lori S

    2013-06-01

    GSK1322322 is first in a new class of antibiotics, peptide deformylase inhibitors, and is active against multidrug-resistant respiratory and skin pathogens. Part 1 of this phase 1, randomized, single-dose (1,000 mg) study in 20 healthy volunteers compared the relative bioavailability of three different tablet formulations of GSK1322322 (fast release, intermediate release, and slow release) to that of the previously studied powder-in-bottle formulation to assess the optimal formulation for progression into clinical trials. Part 2 assessed the effect of a high-fat meal and drug interaction with an H2 blocker and an H2 blocker plus vitamin C on the pharmacokinetic profile of GSK1322322. Of the three tablet formulations, fast-release GSK1322322 provided pharmacokinetic profiles similar to those of the powder-in-bottle reference formulation (~93% relative bioavailability) and was selected for progression in part 2. When GSK1322322 was administered with a high-fat meal, the maximum observed plasma concentration (C(max)) was reduced by 20%, and the time to maximum plasma concentration (T(max)) was delayed by 1.9 h. The exposure (area under the concentration-time curve [AUC]) increased by ~20% compared to that in volunteers in the fasted state. Coadministration of GSK1322322 with an H2 blocker resulted in a slight delay in absorption (T(max) ~0.75 h later) and 58 and 38% decreases in the C(max) and AUC0-∞ values, respectively, compared to GSK1322322 alone. This effect was reversed with vitamin C intake (i.e., no delay in T(max) and the C(max) and AUC0-∞ values decreased by only 21 and 12%, respectively). GSK1322322 was generally well tolerated, and most adverse events were mild in intensity during both parts of the study. PMID:23529727

  2. Acute hemolytic vascular inflammatory processes are prevented by nitric oxide replacement or a single dose of hydroxyurea.

    PubMed