Compatibility studies of nevirapine in physical mixtures with excipients for oral HAART

International Nuclear Information System (INIS)

Oliveira, G.G.G. de; Ferraz, H.G.; Severino, P.; Souto, E.B.

2013-01-01

Nevirapine is a hydrophobic non-nucleoside reverse transcriptase inhibitor, used in first line regimens of highly active antiretroviral therapy (HAART). The drug has more than one crystalline form, which may have implications for its behaviour during production and also for its in vivo performance. This study was aimed at exploring the suitability of thermoanalytical methods for the solid-state characterization of commercial crystalline forms of nevirapine. The drug powder was characterized by ultraviolet spectrophotometry, stereoscopy, scanning electron microscopy, wide-angle X-ray diffraction, measurements of density, flowability, solubility and intrinsic dissolution rate (IDR), differential scanning calorimetry, thermogravimetric analysis, and photostability measurements. The results showed that nevirapine has high stability and is not susceptible to degradation under light exposure. The drug showed compatibility with the excipients tested (lactose, microcrystalline cellulose, polyvinylpyrrolidone and polyvinyl acetate copolymer (PVP/PVA), and hydroxypropylmethylcellulose (HPMC)). Nevirapine has low solubility, an acid medium being the most appropriate medium for assessing the release of the drug from dosage forms. However, the data obtained from IDR testing indicate that dissolution is the critical factor for the bioavailability of this drug. - Graphical abstract: Bulk nevirapine powder analysed by scanning electron microscopy and the drug solubility profile in various buffer solutions. The pH values of the media in which the tests were conducted are also presented. Highlights: ► Nevirapine shows more than one crystalline form, that influence its in vivo and in vitro behaviour. ► DSC and TGA were used for solid-state characterization of crystalline forms of nevirapine. ► Nevirapine is compatible with lactose, microcrystalline cellulose, PVP/PVA copolymers and HPMC. ► The acid form of nevirapine is the most appropriate for assessing release profile from

a study of nevirapine toxicity in hiv infected pregnant women

African Journals Online (AJOL)

Esem

HIV infected women commenced on nevirapine-based regimen in the current pregnancy with CD4 counts up to. 3. 350 cells/mm at the University Teaching Hospital,. Lusaka, Zambia. Design: Longitudinal observational study with 2 arms. Group 1 (low CD4 count arm): HIV infected pregnant. 3 women with CD4 counts less ...

The antiretroviral efficacy of highly active antiretroviral therapy and plasma nevirapine concentrations in HIV-TB co-infected Indian patients receiving rifampicin based antituberculosis treatment

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Sinha Sanjeev

2011-11-01

Full Text Available Abstract Background Rifampicin reduces the plasma concentrations of nevirapine in human immunodeficiency virus (HIV and tuberculosis (TB co-infected patients, who are administered these drugs concomitantly. We conducted a prospective interventional study to assess the efficacy of nevirapine-containing highly active antiretroviral treatment (HAART when co-administered with rifampicin-containing antituberculosis treatment (ATT and also measured plasma nevirapine concentrations in patients receiving such a nevirapine-containing HAART regimen. Methods 63 cases included antiretroviral treatment naïve HIV-TB co-infected patients with CD4 counts less than 200 cells/mm3 started on rifampicin-containing ATT followed by nevirapine-containing HAART. In control group we included 51 HIV patients without tuberculosis and on nevirapine-containing HAART. They were assessed for clinical and immunological response at the end of 24 and 48 weeks. Plasma nevirapine concentrations were measured at days 14, 28, 42 and 180 of starting HAART. Results 97 out of 114 (85.1% patients were alive at the end of 48 weeks. The CD4 cell count showed a mean increase of 108 vs.113 cells/mm3 (p=0.83 at 24 weeks of HAART in cases and controls respectively. Overall, 58.73% patients in cases had viral loads of less than 400 copies/ml at the end of 48 weeks. The mean (± SD Nevirapine concentrations of cases and control at 14, 28, 42 and 180 days were 2.19 ± 1.49 vs. 3.27 ± 4.95 (p = 0.10, 2.78 ± 1.60 vs. 3.67 ± 3.59 (p = 0.08, 3.06 ± 3.32 vs. 4.04 ± 2.55 (p = 0.10 respectively and 3.04 μg/ml (in cases. Conclusions Good immunological and clinical response can be obtained in HIV-TB co-infected patients receiving rifampicin and nevirapine concomitantly despite somewhat lower nevirapine trough concentrations. This suggests that rifampicin-containing ATT may be co administered in resource limited setting with nevirapine-containing HAART regimen without substantial reduction in

Virological failure of staggered and simultaneous treatment interruption in HIV patients who began Efavirenz-based regimens after allergic reactions to nevirapine

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Siripassorn Krittaecho

2013-01-01

Full Text Available Abstract Objective The objective of this work was to study the virological outcomes associated with two different types of treatment interruption strategies in patients with allergic reactions to nevirapine (NVP. We compared the virological outcomes of (1 HIV-1-infected patients who discontinued an initial NVP-based regimen because of cutaneous allergic reactions to NVP; different types of interruption strategies were used, and second-line regimen was based on efavirenz (EFV; and (2 HIV-1-infected patients who began an EFV-based regimen as a first-line therapy (controls. Methods This retrospective cohort included patients who began an EFV-based regimen, between January 2002 and December 2008, as either an initial regimen or as a subsequent regimen after resolving a cutaneous allergic reaction against an initial NVP-based regimen. The study ended in March 2010. The primary outcome was virological failure, which was defined as either (a two consecutive plasma HIV-1 RNA levels >400 copies/mL or (b a plasma HIV-1 RNA level >1,000 copies/mL plus any genotypic resistance mutation. Results A total of 559 patients were stratified into three groups: (a Simultaneous Interruption, in which the subjects simultaneously discontinued all the drugs in an NVP-based regimen following an allergic reaction (n=161; (b Staggered Interruption, in which the subjects discontinued NVP treatment while continuing nucleoside reverse transcriptase inhibitor (NRTI backbone therapy for a median of 7 days (n=82; and (c Control, in which the subjects were naïve to antiretroviral therapy (n=316. The overall median follow-up time was 43 months. Incidence of virological failure in Simultaneous Interruption was 12.9 cases per 1,000 person-years, which trended toward being higher than the incidences in Staggered Interruption (5.4 and Control (6.6. However, differences were not statistically significant. Conclusions Among the patients who had an acute allergic reaction to first

Once-daily dose regimen of ribavirin is interchangeable with a twice-daily dose regimen: randomized open clinical trial

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Balk JM

2015-08-01

Full Text Available Jiska M Balk,1 Guido RMM Haenen,1 Özgür M Koc,2 Ron Peters,3 Aalt Bast,1 Wim JF van der Vijgh,1 Ger H Koek,4 1Department of Toxicology, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre, 2Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, 3DSM Resolve, Geleen, 4Department of Internal Medicine, Division of Gastroenterology and Hepatology, Maastricht University Medical Centre, Maastricht, the Netherlands Background: The combination of ribavirin (RBV and pegylated interferon (PEG-IFN is effective in the treatment of chronic hepatitis C infection. Reducing the frequency of RBV intake from twice to once a day will improve compliance and opens up the opportunity to combine RBV with new and more specific direct-acting agents in one pill. Therefore, the purpose of this study was to evaluate the pharmacokinetic profile of RBV in a once-daily to twice-daily regimen. The secondary aim was to determine tolerability as well as the severity and differences in side effects of both treatment regimens. Methods: In this randomized open-label crossover study, twelve patients with chronic type 1 hepatitis C infection and weighing more than 75 kg were treated with 180 µg of PEG-IFN weekly and 1,200 mg RBV daily for 24 weeks. The patients received RBV dosed as 1,200 mg once-daily for 12 weeks followed by RBV dosed as 600 mg twice-daily for 12 weeks, or vice versa. In addition to the pharmacokinetic profile, the hematological profile and side effects were recorded. The RBV concentrations in plasma were determined using liquid chromatography-tandem mass spectrometry. Results: Eight of twelve patients completed the study. Neither the time taken for RBV to reach peak plasma concentration nor the AUC0-last (adjusted for difference in dose was significantly different between the two groups (P>0.05. Furthermore, the once-daily regimen did not give more side effects than the twice-daily regimen (P>0

Comparison of genotypic resistance profiles and virological response between patients starting nevirapine and efavirenz in EuroSIDA

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Bannister, Wendy P; Ruiz, Lidia; Cozzi-Lepri, Alessandro

2008-01-01

OBJECTIVE: To compare virological outcome and genotypic resistance profiles in HIV-1-infected patients starting non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens. METHODS: NNRTI-naive patients were included who started treatment with nevirapine (NVP) or efavirenz (EFV) wi...

The impact of nevirapine- versus protease inhibitor-based regimens on virological markers of HIV-1 persistence during seemingly suppressive ART.

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Kiselinova, Maja; Anna, Maria; Malatinkova, Eva; Vervish, Karen; Beloukas, Apostolos; Messiaen, Peter; Bonczkowski, Pawel; Trypsteen, Wim; Callens, Steven; Verhofstede, Chris; De Spiegelaere, Ward; Vandekerckhove, Linos

2014-01-01

The source and significance of residual plasma HIV-1 RNA detection during suppressive ART remain controversial. It has been proposed that nevirapine (NVP)-based regimens achieve a greater HIV-1 RNA suppression than regimens containing a protease inhibitor (PI). The aim of this study was to compare the effect of receiving NVP- vs PI-based ART on the virological markers of HIV persistence in peripheral blood. The study population comprised 161 HIV-1 infected patients receiving either NVP-based (n=81) or PI-based (n=80) ART and showing a HIV-1 RNA load stably suppressed ART, with median (IQR) levels of 5 (3-6) and 5 (3-8) copies/mL, respectively. HIV-1 RNA detection was associated with shorter duration of suppressive ART regardless of treatment arm (p=0.007), and lower CD4 nadir (p=0.015). HIV-1 DNA levels were median 282 (120-484) and 213 (87-494) copies/106 PBMCs in the two groups respectively, and were lowest (ART HIV-1 RNA load (p=0.0001). In this comprehensive characterization of patients on long-term suppressive ART, we did not observe evidence for a greater suppressive activity of NVP-based over PI-based therapy on plasma and intracellular markers of virus persistence. Overall excellent correlation was observed between the markers, allowing the identification of a subset of treated patients with low HIV-1 expression as an important cohort for future HIV cure studies.

Evaluation of nevirapine and/or hydroxyurea with nucleoside reverse transcriptase inhibitors in treatment-naive HIV-1-infected subjects

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Blanckenberg, Daniel H.; Wood, Robin; Horban, Andrzej; Beniowski, Marek; Boron-Kaczmarska, Anna; Trocha, Hanna; Halota, Waldemar; Schmidt, Reinhold E.; Fatkenheuer, G.; Jessen, Heiko; Lange, Joep M. A.

2004-01-01

Objective: To examine the effect of adding nevirapine (NVP) and/or hydroxyurea (HU) to a triple nucleoside analogue reverse transcriptase inhibitor (NRTI) regimen in terms of efficacy and tolerability. Methods: HIV-1-infected, treatment-naive adults were randomized, using a factorial design, to add

Effect of Lopinavir and Nevirapine Concentrations on Viral Outcomes in Protease Inhibitor-experienced HIV-infected Children.

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Moholisa, Retsilisitsoe R; Schomaker, Michael; Kuhn, Louise; Castel, Sandra; Wiesner, Lubbe; Coovadia, Ashraf; Strehlau, Renate; Patel, Faeezah; Pinillos, Francoise; Abrams, Elaine J; Maartens, Gary; McIlleron, Helen

2016-12-01

Adequate exposure to antiretroviral drugs is necessary to achieve and sustain viral suppression. However, the target antiretroviral concentrations associated with long-term viral suppression have not been adequately defined in children. We assessed the relationship between plasma lopinavir or nevirapine concentrations and the risk of subsequent viremia in children initially suppressed on antiretroviral therapy. After an induction phase of antiretroviral treatment, 195 children with viral suppression (viral load ≤400 copies/mL) were randomized to continue a lopinavir/ritonavir-based regimen or to switch to a nevirapine-based regimen (together with lamivudine and stavudine). Viral load and lopinavir or nevirapine concentrations were measured at clinic visits 4, 8, 12, 16, 20, 24, 36, 52, 64 and 76 weeks post randomization. Cox multiple failure event models were used to estimate the effects of drug concentrations on the hazard of viremia (viral load >50 copies/mL) RESULTS:: At randomization, the median (interquartile range) age, CD4 T-Lymphocyte percentage, weight-for-age and weight-for-height z scores were 19 (16-24) months, 29% (23-37), -0.6 (-1.3 to 0.2) and -3.2 (-4.1 to -2.1), respectively. The proportion of children with viral load 51-400 copies/mL at randomization was 43%. The hazard of subsequent viremia during follow-up was increased for lopinavir concentrations <1 versus ≥1 mg/L [adjusted hazard ratio 0.62 (95% confidence interval, 0.40-0.94)] and for children with viral loads 51-400 copies/mL at randomization. Nevirapine concentrations were not significantly associated with subsequent viremia. Plasma lopinavir concentrations predicted viral outcomes in children receiving lopinavir-based antiretroviral therapy. Our findings support a minimum target concentration of ≥1 mg/L of lopinavir to ensure sustained viral suppression.

Comparison of adherence to generic multi-tablet regimens vs. brand multi-tablet and brand single-tablet regimens likely to incorporate generic antiretroviral drugs by breaking or not fixed-dose combinations in HIV-infected patients.

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Rwagitinywa, Joseph; Lapeyre-Mestre, Maryse; Bourrel, Robert; Montastruc, Jean-Louis; Sommet, Agnès

2018-03-05

Adherence to antiretroviral (ARV) is crucial to achieve viral load suppression in HIV-infected patients. This study aimed to compare adherence to generic multi-tablet regimens (MTR) vs. brand MTR likely to incorporate ARV drugs without breaking fixed-dose combinations (FDC) and brand single-tablet regimens (STR) likely to incorporate generics by breaking the FDC. Patients aged of 18 years or over exposed to one of the generic or the brand of lamivudine (3TC), zidovudine/lamivudine (AZT/TC), nevirapine (NVP), or efavirenz (EFV), or the brand STR of efavirenz/emtricitabine/tenofovir (EFV/FTC/TDF). Adherence was measured by medication possession ratio (MPR) using both defined daily dose (DDD) and daily number of tablet recommended for adults (DNT). Adherence to generic MTR vs. brand MTR and brand STR was compared using Kruskal-Wallis. The overall median adherence was 0.97 (IQR 0.13) by DNT method and 0.97 (0.14) by DDD method. Adherence in patients exposed to generic MTR (n = 165) vs. brand MTR (n = 481) and brand STR (n = 470) was comparable by DNT and DDD methods. In conclusion, adherence to generic MTR was high and comparable with adherence to brand MTR and to STR. Utilization of DDD instead DNT to measure the MPR led to small but nonsignificant difference that has no clinical impact. © 2018 Société Française de Pharmacologie et de Thérapeutique.

Efficacy and safety of weight-based insulin glargine dose titration regimen compared with glucose level- and current dose-based regimens in hospitalized patients with type 2 diabetes: a randomized, controlled study.

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Li, Xiaowei; Du, Tao; Li, Wangen; Zhang, Tong; Liu, Haiyan; Xiong, Yifeng

2014-09-01

Insulin glargine is widely used as basal insulin. However, published dose titration regimens for insulin glargine are complex. This study aimed to compare the efficacy and safety profile of a user-friendly, weight-based insulin glargine dose titration regimen with 2 published regimens. A total of 160 hospitalized patients with hyperglycemia in 3 medical centers were screened. Our inclusion criteria included age 18 to 80 years and being conscious. Exclusion criteria included pregnancy or breast-feeding and hepatic or renal dysfunction. A total of 149 patients were randomly assigned to receive weight-based, glucose level-based, or dose-based insulin glargine dose titration regimen between January 2011 and February 2013. The initial dose of insulin glargine was 0.2 U/kg. In the weight-based regimen (n = 49), the dose was titrated by increments of 0.1 U/kg daily. In the glucose level-based regimen (n = 51), the dose was titrated by 2, 4, 6, or 8 U daily when fasting blood glucose (FBG) was, respectively, between 7.0 and 7.9, 8.0 and 8.9, 9.0 and 9.9, or ≥10 mmol/L. In the current dose-based regimen (n = 49), titration was by daily increments of 20% of the current dose. The target FBG in all groups was ≤7.0 mmol/L. The incidence of hypoglycemia was recorded. One-way ANOVA and χ(2) test were used to compare data between the 3 groups. All but 1 patient who required additional oral antidiabetic medication completed the study. The mean (SD) time to achieve target FBG was 3.2 (1.2) days with the weight-based regimen and 3.7 (1.5) days with the glucose level-based regimen (P = 0.266). These times were both shorter than that achieved with the current dose-based regimen (4.8 [2.8] days; P = 0.0001 and P = 0.005, respectively). The daily doses of insulin glargine at the study end point were 0.43 (0.13) U/kg with the weight-based regimen, 0.50 (0.20) U/kg with the glucose level-based regimen, and 0.47 (0.23) U/kg with the current dose-based regimen (P = 0.184). The incidence

Pregnancy rates in HIV-positive women using contraceptives and efavirenz-based or nevirapine-based antiretroviral therapy in Kenya: a retrospective cohort study.

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Patel, Rena C; Onono, Maricianah; Gandhi, Monica; Blat, Cinthia; Hagey, Jill; Shade, Starley B; Vittinghoff, Eric; Bukusi, Elizabeth A; Newmann, Sara J; Cohen, Craig R

2015-11-01

Concerns have been raised about efavirenz reducing the effectiveness of contraceptive implants. We aimed to establish whether pregnancy rates differ between HIV-positive women who use various contraceptive methods and either efavirenz-based or nevirapine-based antiretroviral therapy (ART) regimens. We did this retrospective cohort study of HIV-positive women aged 15-45 years enrolled in 19 HIV care facilities supported by Family AIDS Care and Education Services in western Kenya between Jan 1, 2011, and Dec 31, 2013. Our primary outcome was incident pregnancy diagnosed clinically. The primary exposure was a combination of contraceptive method and efavirenz-based or nevirapine-based ART regimen. We used Poisson models, adjusting for repeated measures, and demographic, behavioural, and clinical factors, to compare pregnancy rates among women receiving different contraceptive and ART combinations. 24,560 women contributed 37,635 years of follow-up with 3337 incident pregnancies. In women using implants, adjusted pregnancy incidence was 1.1 per 100 person-years (95% CI 0.72-1.5) for nevirapine-based ART users and 3.3 per 100 person-years (1.8-4.8) for efavirenz-based ART users (adjusted incidence rate ratio [IRR] 3.0, 95% CI 1.3-4.6). In women using depot medroxyprogesterone acetate, adjusted pregnancy incidence was 4.5 per 100 person-years (95% CI 3.7-5.2) for nevirapine-based ART users and 5.4 per 100 person-years (4.0-6.8) for efavirenz-based ART users (adjusted IRR 1.2, 95% CI 0.91-1.5). Women using other contraceptive methods, except for intrauterine devices and permanent methods, had 3.1-4.1 higher rates of pregnancy than did those using implants, with 1.6-2.8 higher rates in women using efavirenz-based ART. Although HIV-positive women using implants and efavirenz-based ART had a three-times higher risk of contraceptive failure than did those using nevirapine-based ART, these women still had lower contraceptive failure rates than did those receiving all other

Outcomes for efavirenz versus nevirapine-containing regimens for treatment of HIV-1 infection: a systematic review and meta-analysis.

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Prinitha Pillay

Full Text Available There is conflicting evidence and practice regarding the use of the non-nucleoside reverse transcriptase inhibitors (NNRTI efavirenz (EFV and nevirapine (NVP in first-line antiretroviral therapy (ART.We systematically reviewed virological outcomes in HIV-1 infected, treatment-naive patients on regimens containing EFV versus NVP from randomised trials and observational cohort studies. Data sources include PubMed, Embase, the Cochrane Central Register of Controlled Trials and conference proceedings of the International AIDS Society, Conference on Retroviruses and Opportunistic Infections, between 1996 to May 2013. Relative risks (RR and 95% confidence intervals were synthesized using random-effects meta-analysis. Heterogeneity was assessed using the I(2 statistic, and subgroup analyses performed to assess the potential influence of study design, duration of follow up, location, and tuberculosis treatment. Sensitivity analyses explored the potential influence of different dosages of NVP and different viral load thresholds.Of 5011 citations retrieved, 38 reports of studies comprising 114 391 patients were included for review. EFV was significantly less likely than NVP to lead to virologic failure in both trials (RR 0.85 [0.73-0.99] I(2 = 0% and observational studies (RR 0.65 [0.59-0.71] I(2 = 54%. EFV was more likely to achieve virologic success than NVP, though marginally significant, in both randomised controlled trials (RR 1.04 [1.00-1.08] I(2 = 0% and observational studies (RR 1.06 [1.00-1.12] I(2 = 68%.EFV-based first line ART is significantly less likely to lead to virologic failure compared to NVP-based ART. This finding supports the use of EFV as the preferred NNRTI in first-line treatment regimen for HIV treatment, particularly in resource limited settings.

Extended prophylaxis with nevirapine and cotrimoxazole among HIV-exposed uninfected infants is well tolerated.

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Aizire, Jim; Fowler, Mary Glenn; Wang, Jing; Shetty, Avinash K; Stranix-Chibanda, Lynda; Kamateeka, Moreen; Brown, Elizabeth R; Bolton, Steve G; Musoke, Philippa M; Coovadia, Hoosen

2012-01-28

Nevirapine and cotrimoxazole are associated with hematologic toxicities and skin-rash. Safety of their concurrent use for prophylaxis over extended periods among HIV-exposed uninfected infants has not been previously assessed. Secondary data analysis of the 'HIV Prevention Trials Network-046 protocol' (version 2.0), a phase-III, randomized, placebo-controlled trial that assessed efficacy and safety of nevirapine prophylaxis against breast milk transmission of HIV-1. Trial infants received 6-month study nevirapine/placebo, and standard-of-care peripartum single-dose nevirapine+/- zidovudine 'tail', and cotrimoxazole prophylaxis from 6 weeks through breastfeeding cessation. Adverse events were monitored using United States Division of AIDS Toxicity Tables (2004). Risk of neutropenia, anemia and skin-rash in the cotrimoxazole + nevirapine and the cotrimoxazole + placebo groups were compared using negative-binomial regression. Incidence of neutropenia and/or anemia, and skin-rash was highest during the first 6 weeks of life and declined, thereafter, regardless of study group. Time to first adverse event after 6 weeks was similar in cotrimoxazole + nevirapine and cotrimoxazole + placebo groups: hazard ratio (95% confidence interval) was 1.26 (0.96-1.66) for neutropenia and/or anemia (all grades), 1.27 (0.80-2.03) for neutropenia and/or anemia (grade ≥3) and 1.16 (0.46-2.90) for skin-rash (grade ≥2). There were no statistically significant differences in immediate (6 weeks-6 months) and long-term (6-12 months) adverse event risk among infants on cotrimoxazole + nevirapine versus cotrimoxazole + placebo. Extended nevirapine and cotrimoxazole prophylaxis through 6 months of age among HIV-exposed uninfected infants did not appear to increase the immediate or long-term risk of neutropenia, anemia or skin-rash. Concurrent use beyond 6 months, however, needs to be evaluated.

Differences in Lipid Measurements by Antiretroviral Regimen Exposure in Cohorts from Asia and Australia

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Amit C. Achhra

2012-01-01

Full Text Available We explored the mean differences in routinely measured lipids (total cholesterol, triglycerides, and high-density lipoprotein cholesterol according to exposure to different combination antiretroviral regimens in Asian (n=2051 and Australian (predominantly Caucasian, n=794 cohorts. The regimen was defined as at least 3 antiretroviral drugs with at least 2 nucleoside-reverse transcriptases (NRTIs and either of at least one protease inhibitor (PI or non-nucleoside-reverse transcriptases (NNRTIs. We categorised cART regimens as: NRTIs as tenofovir based or not; NNRTIs as nevirapine or efavirenz (but not both; and PI as atazanavir based or not. We found that the impact of various antiretroviral regimens on lipids in Asian and Australian cohorts was only different by cohort for total cholesterol (P for interaction between regimen and cohort: 0.05. The differences in total cholesterol were however small and unlikely to be of clinical significance. Overall, tenofovir with nevirapine or atazanavir was associated with the most favorable lipids, while the PI regimens without tenofovir and atazanavir were associated with least favorable lipids. We conclude that the impact of various ART regimens on lipids is largely similar in Asian and Australian cohorts and that the newer drugs such as tenofovir and atazanavir are likely to provide similar benefit in terms of lipid profiles in both populations.

Frequency of Antiretroviral Resistance Mutations among Infants Exposed to Single-Dose Nevirapine and Short Course Maternal Antiretroviral Regimens: ACTG A5207.

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Hitti, Jane; Halvas, Elias K; Zheng, Lu; Panousis, Constantinos G; Kabanda, Joseph; Taulo, Frank; Kumarasamy, Nagalingeswaran; Pape, Jean William; Lalloo, Umesh; Sprenger, Heather; Klingman, Karin L; Chan, Ellen S; McMahon, Deborah; Mellors, John W

2014-11-01

Intrapartum single-dose nevirapine (sdNVP) reduces HIV-1 perinatal transmission but selects NVP resistance among mothers and infants. We evaluated the frequency of antiretroviral resistance among infants with intrauterine HIV-1 infection exposed to sdNVP and maternal antenatal or breastfeeding antiretroviral therapy. This analysis included 429 infants from sub-Saharan Africa, India and Haiti whose 422 mothers received sdNVP plus maternal study treatment. At entry mothers had CD4>250/μL and were ART-naïve except for antenatal ZDV per local standard of care. Maternal study treatment started intrapartum and included ZDV/3TC, TDF/FTC or LPV/r for 7 or 21 days in a randomized factorial design. Infants received sdNVP study treatment and ZDV if local standard of care. Infant HIV RNA or DNA PCR and samples for genotype were obtained at birth and weeks 2, 4 and 12; infants who ever breast-fed were also tested at weeks 16, 24, 48 and 96. Samples from HIV-1-infected infants were tested for drug resistance by population genotype (ViroSeq). NVP or NRTI resistance mutations were assessed using the IAS-USA mutation list. Perinatal HIV-1 transmission occurred in 17 (4.0%) infants including 12 intrauterine infections. Resistance mutations were detected among 5 (42%) intrauterine-infected infants; of these, 3 had mutations conferring resistance to NVP alone, 1 had resistance to NRTI alone, and 1 had dual-class resistance mutations. Among the 2 infants with NRTI mutations, one (K70R) was likely maternally transmitted and one (K65R) occurred in the context of breastfeeding exposure to maternal antiretroviral therapy. Infants with intrauterine HIV infection are at risk of acquiring resistance mutations from exposure to maternal antiretroviral medications intrapartum and/or during breastfeeding. New approaches are needed to lower the risk of antiretroviral resistance in these infants.

Economic evaluation of 3-drug antiretroviral regimens for the prevention of mother-to-child HIV transmission in Thailand.

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Werayingyong, Pitsaphun; Phanuphak, Nittaya; Chokephaibulkit, Kulkunya; Tantivess, Sripen; Kullert, Nareeluk; Tosanguan, Kakanang; Butchon, Rukmanee; Voramongkol, Nipunporn; Boonsuk, Sarawut; Pilasant, Songyot; Kulpeng, Wantanee; Teerawattananon, Yot

2015-03-01

The current program for prevention of mother-to-child HIV transmission in Thailand recommends a 2-drugs regimen for HIV-infected pregnant women with a CD4 count >200 cells/mm(3). This study assesses the value for money of 3 antiretroviral drugs compared with zidovudine (AZT)+single-dose nevirapine (sd-NVP). A decision tree was constructed to predict costs and outcomes using the governmental perspective for assessing cost-effectiveness of 3-drug regimens: (1) AZT, lamivudine, and efavirenz and (2) AZT, 3TC, and lopinavir/ritonavir, in comparison with the current protocol, AZT+sd-NVP. The 3-drug antiretroviral regimens yield lower costs and better health outcomes compared with AZT+sd-NVP. Although these 3-drug regimens offer higher program costs and health care costs for premature birth, they save money significantly in regard to pediatric HIV treatment and treatment costs for drug resistance in mothers. The 3-drug regimens are cost-saving interventions. The findings from this study were used to support a policy change in the national recommendation. © 2013 APJPH.

A comparison of the long-term durability of nevirapine, efavirenz and lopinavir in routine clinical practice in Europe: a EuroSIDA study

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Reekie, J; Reiss, P; Ledergerber, B

2011-01-01

The durability of combination antiretroviral therapy (cART) regimens can be measured as time to discontinuation because of toxicity or treatment failure, development of clinical disease or serious long-term adverse events. The aim of this analysis was to compare the durability of nevirapine, efav...

Late effects of various dose-fractionation regimens

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Turesson, I.; Notter, G.

1983-01-01

These clinical investigations of various dose-fractionation regimens on human skin show that: The late reactions cannot be predicted from the early reactions; The dose-response curves for late reactions are much steeper than for early reactions; Equivalent doses for various fractionation schedules concerning late effects can be calculated by means of a corrected CRE (NSD) formula; the correction must be considered preliminary because further follow-up is needed. A clinical fractionation study of this type requires: Extremely careful dosimetry; Study of the same anatomical region; Very long follow-up; Studies at different effect levels; Skin reaction is the only end point we have studied systematically for different fractionation regimens. Experience with the CRE formula as a model for calculating isoeffect doses for different fractionation schedules in routine clinical use can be summarized as follows: The CRE formula has been used prospectively since 1972 in all patients; CRE-equivalent weekly doses to 5 x 2.0 Gy per week has been used. (Although the fractionation schedule is changed, the overall treatment time is still the same); The CRE range was 18 to 21 for curative radiotherapy on carcinomas; No irradiation was applied during pronounced acute reactions. No unexpected complications have been observed under these conditions

Effect of Moringa oleifera Lam. leaf powder on the pharmacokinetics of nevirapine in HIV-infected adults: a one sequence cross-over study.

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Monera-Penduka, Tsitsi G; Maponga, Charles C; Wolfe, Alan R; Wiesner, Lubbe; Morse, Gene D; Nhachi, Charles F B

2017-01-01

Moringa oleifera Lam., an herb commonly consumed by HIV-infected people on antiretroviral therapy, inhibits cytochrome P450 3A4, 1A2 and 2D6 activity in vitro; and may alter the pharmacokinetics (PK) of antiretroviral drugs metabolized via the same pathways. However, in vitro drug interaction activity may not translate to a clinically significant effect. Therefore, the effect of moringa leaf powder on the PK of nevirapine in HIV-infected people was investigated. Adult patients at steady-state dosing with nevirapine were admitted for 12-h intensive PK sampling following a 21-day herbal medicine washout. Blood sampling was repeated after 14 days of nevirapine and moringa (1.85 g leaf powder/day) co-administration. Nevirapine plasma concentrations were determined by liquid chromatography-tandem mass spectrometry. To assess the effect of moringa on nevirapine PK, the change in nevirapine area under the plasma concentration-time curve (AUC) was determined. The mean difference in pre- and post-moringa nevirapine, maximum concentration (C max ) and concentration at 12 h (C 12h ) were also calculated. The PK parameters were compared by assessing the post/pre geometric mean ratios (GMRs) and associated 90% confidence intervals (CIs). Pharmacokinetics analyses were performed on the results from 11 participants for whom complete data were obtained. The post/pre GMRs and associated 90% CIs for nevirapine were 1.07 (1.00-1.14) for the AUC; 1.06 (0.98-1.16) for C max and 1.03 (0.92-1.16) for C 12h . Co-administration of Moringa oleifera Lam. leaf powder at the traditional dose did not significantly alter the steady-state PK of nevirapine. Trial registration number NCT01410058 (ClinicalTrials.gov).

Renal histoarchitectural changes in nevirapine therapy: possible ...

African Journals Online (AJOL)

This study investigates the attenuating effect of kolaviron in nevirapine- therapy on the histological structure ... virapine and vitamin C; Group G was given nevirapine and kolaviron ..... may be better explained using stereological techniques in.

131-I treatment in patients with hyperthyroidism using low fixed dose regimen

International Nuclear Information System (INIS)

Bochev, P.; Klisarova, A.; Chaushev, B.; Hristozov, K.; Tsvetanova, B.

2007-01-01

Treatment of hyperthyroidism is one of the major problems in thyroidology. The well known and widely exploited treatment modalities in patients with hyperthyroidism are antithyroid drugs, radioiodine treatment and thyroid surgery, the latter two being considered definitive. Radioiodine treatment is effective and well tolerated treating modality, which major disadvantage is the impossibility of exact calculation of the dose needed. Lots of dosage regimens are approved, including empirically chosen fixed dose regimen. The aim of the study is to define the overall success rate in patients with hyperthyroidism in subgroups Grave's disease and toxic nodular goiter treated with fixed dose 185MBq regimen. Of all treated patients a low fixed dose regimen was chosen in 43. All the patients were followed up clinically, with ultrasonography and hormone levels for a period of minimum 1 year. Part of the patients with persistent hyperthyroidism 6 months after the initial treatment receive a second dose of 185MBq 131-1. The overall success rate in the subgroup with Grave's disease was 87% by the time of the study, compared to a considerably lower success of 62% in patients with toxic nodular goiter. (authors)

Extended high dose letrozole regimen versus short low dose letrozole regimen as an adjuvant to gonadotropin releasing hormone antagonist protocol in poor responders undergoing IVF-ET.

Science.gov (United States)

Fouda, Usama M; Sayed, Ahmed M

2011-12-01

To compare the efficacy and cost-effectiveness of extended high dose letrozole regimen/HPuFSH-gonadotropin releasing hormone antagonist (GnRHant) protocol with short low dose letrozole regimen/HPuFSH-GnRHant protocol in poor responders undergoing IVF-ET. In this randomized controlled trial, 136 women who responded poorly to GnRH agonist long protocol in their first IVF cycle were randomized into two equal groups using computer generated list and were treated in the second IVF cycle by either extended letrozole regimen (5 mg/day during the first 5 days of cycle and 2.5 mg/day during the subsequent 3 days) combined with HPuFSH-GnRHant protocol or short letrozole regimen (2.5 mg/day from cycle day 3-7) combined with HPuFSH-GnRHant protocol. There were no significant differences between both groups with regard to number of oocytes retrieved and clinical pregnancy rate (5.39 ± 2.08 vs. 5.20 ± 1.88 and 22.06% vs. 16.18%, respectively).The total gonadotropins dose and medications cost per cycle were significantly lower in extended letrozole group (44.87 ± 9.16 vs. 59.97 ± 14.91 ampoules and 616.52 ± 94.97 vs. 746.84 ± 149.21 US Dollars ($), respectively).The cost-effectiveness ratio was 2794 $ in extended letrozole group and 4616 $ in short letrozole group. Extended letrozole regimen/HPuFSH-GnRHant protocol was more cost-effective than short letrozole regimen/HPuFSH-GnRHant protocol in poor responders undergoing IVF-ET.

A retrospective cohort analysis comparing pregnancy rates among HIV-positive women using contraceptives and efavirenz- or nevirapine-based antiretroviral therapy in Kenya

Science.gov (United States)

PATEL, Rena C.; ONONO, Maricianah; GANDHI, Monica; BLAT, Cinthia; HAGEY, Jill; SHADE, Starley B.; VITTINGHOFF, Eric; BUKUSI, Elizabeth A.; NEWMANN, Sara J.; COHEN, Craig R.

2015-01-01

SUMMARY Background Given recent concerns of efavirenz reducing the efficacy of contraceptive implants, we sought to determine if pregnancy rates differ among HIV-positive women using various contraceptive methods and efavirenz- or nevirapine-based antiretroviral therapy (ART) regimens. Methods We conducted a retrospective cohort analysis of HIV-positive women aged 15–45 years enrolled in HIV care facilities in western Kenya from January 2011 to December 2013. Pregnancy was diagnosed clinically and the primary exposure was a combination of contraceptive method and ART regimen. We used Poisson models, adjusting for repeated measures, as well as demographic, behavioral and clinical factors, to compare pregnancy rates among women on different contraceptive/ART combinations. Findings 24,560 women contributed 37,635 years of follow-up with 3,337 incident pregnancies. Among women using implants, adjusted pregnancy incidence for nevirapine- and efavirenz-based ART users were 1·1 (95% CI 0·72–1·5) and 3·3 (95% CI 1·8–4·8) per 100 women-years (w-y), respectively (adjusted incidence rate ratio (aIRR) 3·0, 95% CI 1·3–4·6). Among women using depomedroxyprogesterone acetate (DMPA), adjusted pregnancy incidence for nevirapine- and efavirenz-based ART users were 4·5 (95% CI 3·7–5·2) and 5·4 (95% CI 4·0–6·8) per 100 w-y, respectively (aIRR 1·2, 95% CI 0·91–1·5). Women using other contraceptive methods, except for intrauterine devices and permanent methods, experienced 3·1–4·1 higher rates of pregnancy than women using implants, with 1·6–2·8 higher rates specifically among women using efavirenz-based ART. Interpretation While HIV-positive women using implants on efavirenz-based ART faced three times higher risk of contraceptive failure than those on nevirapine-based ART, these women still experienced lower contraceptive failure rates than women on all other contraceptive methods, except for intrauterine devices and permanent methods

Therapeutic drug monitoring of nevirapine in resource-limited settings.

NARCIS (Netherlands)

L'homme, R.F.A.; Muro, E.P.; Droste, J.A.H.; Wolters, L.R.; Ewijk-Beneken Kolmer, E.W.J. van; Schimana, W.; Burger, D.M.

2008-01-01

BACKGROUND: We developed a simple and inexpensive thin-layer chromatography (TLC) assay for semiquantitative detection of saliva concentrations of nevirapine in resource-limited settings. The method was validated in an African target population. METHODS: Paired plasma and saliva nevirapine

A randomized, double-blind trial comparing combinations of nevirapine, didanosine, and zidovudine for HIV-infected patients: the INCAS Trial. Italy, The Netherlands, Canada and Australia Study.

Science.gov (United States)

Montaner, J S; Reiss, P; Cooper, D; Vella, S; Harris, M; Conway, B; Wainberg, M A; Smith, D; Robinson, P; Hall, D; Myers, M; Lange, J M

1998-03-25

were 23% (11/47), 25% (13/53), and 12% (6/51) for the zidovudine plus nevirapine, zidovudine plus didanosine, and triple drug therapy groups, respectively (P=.08). Triple drug therapy with zidovudine, didanosine, and nevirapine led to a substantially greater and sustained decrease in plasma viral load than the 2-drug regimens studied. Our results also suggest that suppression of viral replication, as demonstrated by a decrease in the plasma HIV-1 RNA load below the level of quantitation of the most sensitive test available, may at least forestall the development of resistance.

Foetal loss and enhanced fertility observed in mice treated with Zidovudine or Nevirapine.

Science.gov (United States)

Onwuamah, Chika K; Ezechi, Oliver C; Herbertson, Ebiere C; Audu, Rosemary A; Ujah, Innocent A O; Odeigah, Peter G C

2014-01-01

Health concerns for HIV-infected persons on antiretroviral therapy (ART) have moved from morbidity to the challenges of long-term ART. We investigated the effect of Zidovudine or Nevirapine on reproductive capacity across two mouse generations. A prospective mouse study with drugs administered through one spermatogenic cycle. Mouse groups (16 males and 10 females) were given Zidovudine or Nevirapine for 56 days. Males were mated to untreated virgin females to determine dominant lethal effects. Twenty females (10 treated and 10 untreated) mated with the treated males per dose and gave birth to the F1 generation. Parental mice were withdrawn from drugs for one spermatogenic cycle and mated to the same dams to ascertain if effects are reversible. The F1 generation were exposed for another 56 days and mated to produce the F2 generation. Foetal loss was indicated in the dominant lethal assay as early as four weeks into drug administration to the males. At the first mating of the parental generation to produce the F1 generation, births from 10 dams/dose when the 'father-only' was exposed to Zidovudine (10, 100 and 250 mg/kg) was 3, 2 and 1 while it was 7, 1 and 4 respectively when 'both-parents' were exposed. Similarly births from the parental generation first mating when the 'father-only' was exposed to Nevirapine (5, 50 and 150 mg/kg) was 2, 2 and 0 while it was 6, 5 and 9 respectively when 'both-parents' were exposed. However, fertility was not significantly different neither by dose nor by the parental exposure. The F1 mice mated to produce the F2 generation recorded only one birth. The dominant lethal analysis showed foetal loss occurred when the "fathers-only" were treated while fertility was enhanced when "both-parents" were on therapy at the time of mating.

Foetal loss and enhanced fertility observed in mice treated with Zidovudine or Nevirapine.

Directory of Open Access Journals (Sweden)

Chika K Onwuamah

Full Text Available Health concerns for HIV-infected persons on antiretroviral therapy (ART have moved from morbidity to the challenges of long-term ART. We investigated the effect of Zidovudine or Nevirapine on reproductive capacity across two mouse generations.A prospective mouse study with drugs administered through one spermatogenic cycle. Mouse groups (16 males and 10 females were given Zidovudine or Nevirapine for 56 days. Males were mated to untreated virgin females to determine dominant lethal effects. Twenty females (10 treated and 10 untreated mated with the treated males per dose and gave birth to the F1 generation. Parental mice were withdrawn from drugs for one spermatogenic cycle and mated to the same dams to ascertain if effects are reversible. The F1 generation were exposed for another 56 days and mated to produce the F2 generation.Foetal loss was indicated in the dominant lethal assay as early as four weeks into drug administration to the males. At the first mating of the parental generation to produce the F1 generation, births from 10 dams/dose when the 'father-only' was exposed to Zidovudine (10, 100 and 250 mg/kg was 3, 2 and 1 while it was 7, 1 and 4 respectively when 'both-parents' were exposed. Similarly births from the parental generation first mating when the 'father-only' was exposed to Nevirapine (5, 50 and 150 mg/kg was 2, 2 and 0 while it was 6, 5 and 9 respectively when 'both-parents' were exposed. However, fertility was not significantly different neither by dose nor by the parental exposure. The F1 mice mated to produce the F2 generation recorded only one birth.The dominant lethal analysis showed foetal loss occurred when the "fathers-only" were treated while fertility was enhanced when "both-parents" were on therapy at the time of mating.

Pharmacokinetic Modeling of Voriconazole To Develop an Alternative Dosing Regimen in Children.

Science.gov (United States)

Gastine, Silke; Lehrnbecher, Thomas; Müller, Carsten; Farowski, Fedja; Bader, Peter; Ullmann-Moskovits, Judith; Cornely, Oliver A; Groll, Andreas H; Hempel, Georg

2018-01-01

The pharmacokinetic variability of voriconazole (VCZ) in immunocompromised children is high, and adequate exposure, particularly in the first days of therapy, is uncertain. A population pharmacokinetic model was developed to explore VCZ exposure in plasma after alternative dosing regimens. Concentration data were obtained from a pediatric phase II study. Nonlinear mixed effects modeling was used to develop the model. Monte Carlo simulations were performed to test an array of three-times-daily (TID) intravenous dosing regimens in children 2 to 12 years of age. A two-compartment model with first-order absorption, nonlinear Michaelis-Menten elimination, and allometric scaling best described the data (maximal kinetic velocity for nonlinear Michaelis-Menten clearance [ V max ] = 51.5 mg/h/70 kg, central volume of distribution [ V 1 ] = 228 liters/70 kg, intercompartmental clearance [ Q ] = 21.9 liters/h/70 kg, peripheral volume of distribution [ V 2 ] = 1,430 liters/70 kg, bioavailability [ F ] = 59.4%, K m = fixed value of 1.15 mg/liter, absorption rate constant = fixed value of 1.19 h -1 ). Interindividual variabilities for V max , V 1 , Q , and F were 63.6%, 45.4%, 67%, and 1.34% on a logit scale, respectively, and residual variability was 37.8% (proportional error) and 0.0049 mg/liter (additive error). Monte Carlo simulations of a regimen of 9 mg/kg of body weight TID simulated for 24, 48, and 72 h followed by 8 mg/kg two times daily (BID) resulted in improved early target attainment relative to that with the currently recommended BID dosing regimen but no increased rate of accumulation thereafter. Pharmacokinetic modeling suggests that intravenous TID dosing at 9 mg/kg per dose for up to 3 days may result in a substantially higher percentage of children 2 to 12 years of age with adequate exposure to VCZ early during treatment. Before implementation of this regimen in patients, however, validation of exposure, safety, and tolerability in a carefully designed

Population pharmacokinetics and dosing regimen design of milrinone in preterm infants

Science.gov (United States)

Paradisis, Mary; Jiang, Xuemin; McLachlan, Andrew J; Evans, Nick; Kluckow, Martin; Osborn, David

2007-01-01

Aims To define the pharmacokinetics of milrinone in very preterm infants and determine an optimal dose regimen to prevent low systemic blood flow in the first 12 h after birth. Methods A prospective open‐labelled, dose‐escalation pharmacokinetic study was undertaken in two stages. In stage one, infants received milrinone at 0.25 μg/kg/min (n = 8) and 0.5 μg/kg/min (n = 11) infused from 3 to 24 h of age. Infants contributed 4–5 blood samples for concentration–time data which were analysed using a population modelling approach. A simulation study was used to explore the optimal dosing regimen to achieve target milrinone concentrations (180–300 ng/ml). This milrinone regimen was evaluated in stage two (n = 10). Results Infants (n = 29) born before 29 weeks gestation were enrolled. Milrinone pharmacokinetics were described using a one‐compartment model with first‐order elimination rate, with a population mean clearance (CV%) of 35 ml/h (24%) and volume of distribution of 512 ml (21%) and estimated half‐life of 10 h. The 0.25 and 0.5 μg/kg/min dosage regimens did not achieve optimal milrinone concentration‐time profiles to prevent early low systemic blood flow. Simulation studies predicted a loading infusion (0.75 μg/kg/min for 3 h) followed by maintenance infusion (0.2 μg/kg/min until 18 h of age) would provide an optimal milrinone concentration profile. This was confirmed in stage two of the study. Conclusion Population pharmacokinetic modelling in the preterm infant has established an optimal dose regimen for milrinone that increases the likelihood of achieving therapeutic aims and highlights the importance of pharmacokinetic studies in neonatal clinical pharmacology. PMID:16690639

Nevirapine, sodium concentration and HIV-1 RNA in breast milk and plasma among HIV-infected women receiving short-course antiretroviral prophylaxis

DEFF Research Database (Denmark)

Salado-Rasmussen, Kirsten; Theilgaard, Zahra Persson; Chiduo, Mercy G.

2015-01-01

and breast milk after intrapartum single-dose nevirapine combined with either 1-week tail of Combivir (zidovudine/lamivudine) or single-dose Truvada (tenofovir/emtricitabine). Methods Maternal plasma and bilateral breast milk samples were collected between April 2008 and April 2011 at 1, 4 and 6 weeks...... postpartum from HIV-infected Tanzanian women. Moreover, plasma samples were collected at delivery from mother and infant. Results HIV-1 RNA was quantified in 1,212 breast milk samples from 273 women. At delivery, 96% of the women and 99% of the infants had detectable nevirapine in plasma with a median...... (interquartile range, IQR) of 1.5 μg/mL (0.75–2.20 μg/mL) and 1.04 μg/mL (0.39–1.71 μg/mL), respectively (P women had detectable nevirapine in plasma and breast milk, with a median (IQR) of 0.13 μg/mL (0.13–0.39 μg/mL) and 0.22 μg/mL (0.13–0.34 μg...

Hepatic adverse events during highly active antiretroviral therapy containing nevirapine: a case report

Directory of Open Access Journals (Sweden)

Yamazhan Tansu

2002-09-01

Full Text Available Abstract Background Hepatotoxicity is one of the most serious complications of highly active antiretroviral therapy (HAART. The aim of this report is to analyse an HIV infected patient on HAART including nevirapine and taking antidepressive agents, with acute toxic hepatitis. Case presentation A 39 year old patient diagnosed as HIV positive one month ago administered to the clinical ward of the Department of Infectious Diseases and Clinical Microbiology in Ege University Medical School with high fever, malaise, nausea, diarrheae and elevated liver enzymes (ALT 1558 U/L, AST 4288 U/L. He has been using HAART including zidovudine+lamivudine (2 × 1/day and nevirapine (2 × 200 mg/day, following dose escalation for 22 days, sertralin and diazepam for 12 days and lithium for 10 days. The patient was hospitalized. Antiretroviral and antidepressant treatments were stopped. The day after admission, his fever dropped and his symptoms improved. Clinical improvement continued on the following days. The patient was discharged upon his request on the 14th day of hospitalization. The liver function tests returned to normal levels in two weeks following discharge. Conclusion Close monitoring of liver enzymes during the first 12 weeks of nevirapine therapy is critical to prevent life threatening events.

Incidence of nevirapine-associated hepatitis in an antenatal clinic

African Journals Online (AJOL)

2008-01-22

Jan 22, 2008 ... together with a non-nucleoside reverse transcriptase inhibitor, either efavirenz or nevirapine.1 As efavirenz is thought to be a teratogen and is classified as a Food and Drug Administration. (FDA) category D drug, nevirapine is the preferred agent for use in pregnant women, for women planning a pregnancy ...

CLINICAL AND PHARMACOLOGICAL APPROACHES TO OPTIMIZE THE DOSING REGIMEN OF ANTIBACTERIAL DRUGS IN PEDIATRICS

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Natal’ya B. Lazareva

2018-01-01

Full Text Available The rational use of antibacterial drugs in children implies an adequate choice of the necessary medication, its dosing regimen, and the duration of treatment in order to achieve maximum efficacy and minimize toxic effects. The knowledge of pharmacokinetic and pharmacodynamic profiles of the antibacterial drug plays a crucial role for optimizing the dosing regimen. The strategy of individual choice of the dosing regimen, taking into account the principles of pharmacokinetics and pharmacodynamics, can be especially effective in patients with the expectedly changed parameters of pharmacokinetics and in infections caused by bacteria strains with low sensitivity to antibiotics. The review presents a contemporary view of pharmacokinetic and pharmacodynamic profiles of antibacterial drugs most commonly used in pediatrics and their relationship to the clinical efficacy of the administered therapy.

Possible hepatotoxic consequence of nevirapine use in juvenile albino rats

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Elias Adikwu

2017-08-01

Full Text Available Context: Nevirapine (NVP is used in human immunodeficiency virus exposed neonates. This could present safety concern due to decreased liver metabolizing enzymes activity and renal clearance in neonates. Aims: To determine the hepatotoxic effect of NVP in juvenile albino rats. Methods: Juvenile albino rats were weighed, divided into groups and treated orally with 4-32 mg/kg/day of NVP for 14 days including a recovery group. The control groups were treated with water (placebo and normal saline (solvent. At the end of NVP treatment, rats were weighed and sacrificed, blood was collected and serum extracted. Serum was analyzed for alanine aminotransferase (ALT, aspartate aminotransferase (AST, alkaline phosphatase (ALP, total bilirubin (TB and conjugated bilirubin (CB. The liver was harvested via dissection, weighed and evaluated for AST, ALT, ALP, superoxide dismutase (SOD, catalase (CAT, glutathione (GSH, malondialdehyde (MDA levels and histological damage. Results: The body, absolute and relative liver weights of rats in NVP treated groups were not significantly different (p>0.05 when compared to placebo. However, serum levels of AST, ALT, ALP, TB and CB were significantly increased (p<0.05 in a dose-dependent manner in NVP-treated groups. Furthermore, liver levels of ALT, ALP, AST and MDA were significantly increased (p<0.05 while SOD, CAT, and GSH were decreased in a dose dependent manner in NVP-treated groups. NVP-treated rats were characterized by varying degrees of hepatic morphological alterations. However, in the recovery group, the effects of NVP were reversed. Conclusions: This study observed dose-dependent and reversible hepatotoxicity in nevirapine- treated juvenile albino rats.

Revisiting Dosing Regimen Using Pharmacokinetic/Pharmacodynamic Mathematical Modeling: Densification and Intensification of Combination Cancer Therapy.

Science.gov (United States)

Meille, Christophe; Barbolosi, Dominique; Ciccolini, Joseph; Freyer, Gilles; Iliadis, Athanassios

2016-08-01

Controlling effects of drugs administered in combination is particularly challenging with a densified regimen because of life-threatening hematological toxicities. We have developed a mathematical model to optimize drug dosing regimens and to redesign the dose intensification-dose escalation process, using densified cycles of combined anticancer drugs. A generic mathematical model was developed to describe the main components of the real process, including pharmacokinetics, safety and efficacy pharmacodynamics, and non-hematological toxicity risk. This model allowed for computing the distribution of the total drug amount of each drug in combination, for each escalation dose level, in order to minimize the average tumor mass for each cycle. This was achieved while complying with absolute neutrophil count clinical constraints and without exceeding a fixed risk of non-hematological dose-limiting toxicity. The innovative part of this work was the development of densifying and intensifying designs in a unified procedure. This model enabled us to determine the appropriate regimen in a pilot phase I/II study in metastatic breast patients for a 2-week-cycle treatment of docetaxel plus epirubicin doublet, and to propose a new dose-ranging process. In addition to the present application, this method can be further used to achieve optimization of any combination therapy, thus improving the efficacy versus toxicity balance of such a regimen.

8-MOP PUVA for psoriasis: a comparison of a minimal phototoxic dose-based regimen with a skin-type approach

Energy Technology Data Exchange (ETDEWEB)

Collins, P.; Wainwright, N.J.; Amorim, I.; Lakshmipathi, T.; Ferguson, J. [Ninewells Hospital and Medical School, Dundee (United Kingdom)

1996-08-01

Two ultraviolet A (UVA) regimens for oral 8-methoxypsoralen (8-MOP) photochemotherapy (PUVA) for moderate/severe chronic plaque psoriasis using a half-body study technique were compared. Each patient received both regimens. A higher-dose regimen based on minimal phototoxic dose (MPD) with percentage incremental increases was given to one-half of the body. The other half received a lower dose regimen based on skin type with fixed incremental UVA increases. Patients were treated twice weekly. Symmetrical plaques were scored to determine the rate of resolution with each regimen. In addition, the number of treatments, cumulative UVA dose and number of days in treatment to achieve overall clearance were recorded. Patients were reviewed monthly for one year to record remission data. Thirty-three patients completed the study. Both regimens were effective and well tolerated. With the MPD-based approach, number of exposures was significantly less for patients with skin types I and II but not III. Although the cumulative UVA dose was higher with the MPD regimen for all skin types studied, the reduced number of exposures required for clearance for skin types I and II but not III, combined with the security of individualized MPD testing, has practical attractions. MPD testing also identified five patients who required an increased psoralen dose and six patients who required a reduction of the initial UVA dose with the skin type regimen. Forty-two percent were still clear 1 year after treatment and there was no significant difference in the number of days in remission between the regimens for those whose psoriasis had recurred. The reduction in the number of exposures required for clearance with the MPD-based regimen may be safer and more cost effective in the long term. (author).

Impact of adverse events of antiretroviral treatment on regimen change and mortality in Ugandan children

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Ntambwe Malangu

2010-06-01

Objectives: The purpose of this study was to determine the prevalence of the adverse events of antiretroviral treatment, their impact on mortality and the change in regimens prescribed to children treated at Mildway Centre in Uganda. Method: A retrospective chart review was performed for children younger than 6 years, treated since the Mildway Centre was opened in 1999. In order to achieve a larger sample, the records of children treated from January 2000 to July 2005 were included in the study. A pre-tested data collection form was used to collate socio-demographic and clinical data of the patients. These included the documented adverse events, causes of death, stage of infection, duration of treatment, regimen prescribed, year of enrolment into the treatment program, as well as whether or not they were still alive. Descriptive statistics were used in the analysis of data. Results: Of the 179 children, the majority were males and had a median age of 4 years. The majority (58.8% of children had suffered from severe immune depression since they met the WHO clinical stage III and IV, 73.8% had a baseline CD4T of less than 15%. Four regimens were prescribed to the children. The most common was a regimen containing zidovudine, lamivudine, and nevirapine (34.6%, followed by a regimen containing stavudine, lamivudine, and nevirapine (27.9%. Eleven children (6.1% had their regimen changed, of which six (54.5% were due to adverse events. The prevalence of adverse events was 8%; of the 14 documented adverse events, the most common were severe anaemia (3, vomiting (3, and skin rashes (3. After 12 months on treatment, 8% of the patients had died. The most common causes of death were infectious diseases (28.6%, severe anaemia (21.4%, and severe dehydration (21.4%. Conclusion: The prevalence of adverse events was 8%; they were responsible for 54.5% of regimen changes and 21.4% of deaths in children treated at the study site. These findings suggest the need for incorporating

A prospective randomized study of the efficacy and cost-effectiveness of high and low dose regimens of I-131 treatment in hyperthyroidism.

Science.gov (United States)

Pusuwan, Pawana; Tuntawiroon, Malulee; Sritongkul, Nopamol; Chaudakshetrin, Pachee; Nopmaneejumruslers, Cherdchai; Komoltri, Chulalak; Thepamongkhol, Kullathorn; Khiewvan, Benjapa; Tuchinda, Pongpija; Sriussadaporn, Sutin

2011-03-01

To compare the efficacy and cost-effectiveness of high and low dose regimens of I-131 treatment in patients with hyperthyroidism. One hundred fifty patients with proven hyperthyroidism were randomly allocated into the high (74 patients) and low (76 patients) dose regimen of I-131 treatment. Four patients of the high dose group and one patient of the low dose group were excluded because of lost follow-up. A gland-specific dosage was calculated on the estimated weight of thyroid gland and 24-hour I-131 uptake. The high and low I-131 dose regimens were 150 microCi/gm and 100 microCi/gm, respectively. The first mean radioiodine activity administered to the high and low dose group was 10.2 and 8 mCi, respectively. Repeated treatment was given to 25 patients of the high dose group and 40 patients of the low dose group. Clinical outcome and calculated costs for outpatient attendances, and laboratory tests together with initial and subsequent treatments were evaluated for one year after I-131 treatment. Elimination of hyperthyroidism that resulted in either euthyroidism or hypothyroidism was classified as therapeutic success. The cost effectiveness was also compared. At 6 months after treatment, 45 (64.3%) patients receiving high dose and 59 (78.7%) patients receiving low dose were hyperthyroidism. Clinical outcome at one year showed persistence of hyperthyroidism in 21 (30%) patients of the high dose regimen and 36 (48%) patients of the low dose regimen. At one year post treatment, it was demonstrated that the high dose regimen could eliminate hyperthyroidism in a significantly shorter time than the low dose regimen, i.e., 259.6 days and 305.5 days, respectively, p = 0.008). For the persistent hyperthyroid patients, the average total cost of treatment in the low dose group was significantly higher than that of the high dose group, i.e., 13,422.78 baht and 10,942.79 baht, respectively; p = 0.050). A high dose regimen of radioactive iodine treatment is more effective than

Post-marketing experience with nevirapine extended release (XR) tablets: effectiveness and tolerability in a population-based cohort in British Columbia, Canada.

Science.gov (United States)

Lepik, Katherine J; Yip, Benita; McGovern, Rachel A; Ding, Erin; Nohpal, Adriana; Watson, Birgit E; Toy, Junine; Akagi, Linda; Harrigan, P Richard; Moore, David M; Hogg, Robert S; Montaner, Julio S G; Barrios, Rolando

2015-01-01

Nevirapine 400 mg extended release tablets (nevirapine-XR) are a once-daily alternative to nevirapine 200 mg immediate release tablets (nevirapine-IR). Study objectives were to describe the effectiveness and tolerability of nevirapine-XR in clinical practice and, for patients who switched from once daily 2×200 mg nevirapine-IR to nevirapine-XR, compare virological suppression and plasma nevirapine concentrations during each treatment period. HIV-1-infected adults entered the study cohort if they initiated nevirapine-XR in British Columbia (BC) Canada between 1 April 2012 and 30 September 2012 and were followed until 30 September 2013. Demographic and clinical variables were abstracted from the BC Centre for Excellence in HIV/AIDS databases. Patients who switched from once daily nevirapine-IR to nevirapine-XR were monitored for 6 months pre- and post-switch with comparison of virological suppression (McNeamer's test) and median random plasma nevirapine concentrations (Wilcoxon-Mann-Whitney test) in each period. The 536 nevirapine-XR-treated patients were 96% male, median (IQR) age 49.9 (44.0-56.9) years. Median follow-up was 15.6 (14.7-16.5) months, with 474/536 (88%) maintaining virological suppression. Emergent drug resistance developed in 5/536 (1%), adverse drug reactions in 17/536 (3%) and, although 31/536 (6%) reported 'whole' tablets in their stools, this was not associated with adverse outcomes. Among the 305 patients who switched from nevirapine-IR to nevirapine-XR, median (IQR) random plasma nevirapine concentration was higher during nevirapine-IR 5,000 (3,690-6,090) ng/ml than nevirapine-XR 3,930 (3,050-5,150) ng/ml (Pmarketing study affirms the effectiveness and tolerability of nevirapine-XR as an alternative to nevirapine-IR in adults.

ORIGINAL ARTICLES Nevirapine toxicity- implications for ...

African Journals Online (AJOL)

Nevirapine was the first non-nucleoside drug (NNRTI) to be approved by the ... related toxicities in pregnancy were highlighted by a study published in 2004 ..... health, of consumption of scarce financial resources, of concern about doctors ...

Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of African, Asian, and European descent

NARCIS (Netherlands)

Yuan, Jing; Guo, Sheng; Hall, David; Cammett, Anna M.; Jayadev, Supriya; Distel, Manuel; Storfer, Stephen; Huang, Zimei; Mootsikapun, Piroon; Ruxrungtham, Kiat; Podzamczer, Daniel; Haas, David W.; Benetucci, Jorge; Ortega, Gerardo; Cahn, Pedro; Cesar, Carina; Cassetti, Isabel; Bissio, Emiliano; Lupo, Sergio; Chuah, John; Workman, Cassy; Rees, Vanessa; Cooper, David A.; Hickey, Rebecca; Anderson, Jonathan; Moore, Richard; Hoy, Jennifer; Downs, Cath; Finlayson, Robert; Bodsworth, Neil; Eu, Beng; Lau, Helen; Montaner, Julio; Harris, Marianne; Walmsley, Sharon; d'Aquila, Adrianna; Conway, Brian; Tossonian, Harout; Morlat, Philippe; Louis, Isabelle; Yazdanpanah, Yazdan; Ajana, Faiza; Bollens, Diane; Girard, Pierre-Marie; May, Thierry; Pialoux, Gilles; Slama, Laurence; Lyavanc, Thomas; Piketty, Christophe; Reiss, Peter

2011-01-01

Nevirapine is widely prescribed for HIV-1 infection. We characterized relationships between nevirapine-associated cutaneous and hepatic adverse events and genetic variants among HIV-infected adults. We retrospectively identified cases and controls. Cases experienced symptomatic nevirapine-associated

A prospective cohort study comparing the effect of single-dose 2 g metronidazole on Trichomonas vaginalis infection in HIV-seropositive versus HIV-seronegative women.

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Balkus, Jennifer E; Richardson, Barbra A; Mochache, Vernon; Chohan, Vrasha; Chan, Jeannie D; Masese, Linnet; Shafi, Juma; Marrazzo, Jeanne; Farquhar, Carey; McClelland, R Scott

2013-06-01

This analysis compared the frequency of persistent Trichomonas vaginalis (TV) among HIV-seropositive and HIV-seronegative women. Data were obtained from women enrolled in an open cohort study of sex workers in Kenya. Participants were examined monthly, and those diagnosed as having TV by saline microscopy were treated with single-dose 2 g oral metronidazole. All women on antiretroviral therapy (ART) used nevirapine-based regimens. Generalized estimating equations with a logit link were used to compare the frequency of persistent TV (defined as the presence of motile trichomonads by saline microscopy at the next examination visit within 60 days) by HIV status. Three-hundred sixty participants contributed 570 infections to the analysis (282 HIV-seropositive and 288 HIV-seronegative). There were 42 (15%) persistent infections among HIV-seropositive participants versus 35 (12%) among HIV-seronegative participants (adjusted odds ratio, 1.14; 95% confidence interval [CI], 0.70-1.87). Persistent TV was highest among HIV-seropositive women using ART (21/64 [33%]) compared with HIV-seropositive women not using ART (21/217 [10%]). Concurrent bacterial vaginosis (BV) at TV diagnosis was associated with an increased likelihood of persistent TV (adjusted odds ratio, 1.90; 95% confidence interval, 1.16-3.09). The frequency of persistent TV infection after treatment with single-dose 2 g oral metronidazole was similar by HIV status. Alternative regimens including multiday antibiotic treatment may be necessary to improve cure rates for women using nevirapine-based ART and women with TV and concurrent BV.

Comparison of two dose regimens of misoprostol for second-trimester pregnancy termination

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Brouns, Joseph Franciscus Gertrudis Maria; van Wely, Madelon; Burger, Mattheus Petrus Maria; van Wijngaarden, Willem Jacobus

2010-01-01

Objective: The study was conducted to compare the efficacy of two different dose regimens of misoprostol administered vaginally in combination with mifepristone for second trimester termination of viable and non-viable pregnancies. Design: Double-blind randomized controlled trial conducted at the

COMPARISON OF EFFICACY AND FETOMATERNAL OUTCOME WITH LOW DOSE AND STANDARD PRITCHARD’S REGIMEN OF MAGNESIUM SULPHATE IN ECLAMPSIA

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Nirmala Chamakuri

2017-11-01

Full Text Available BACKGROUND Eclampsia, a hypertensive disorder of pregnancy is a common obstetric emergency, which leads to significant maternal morbidity, perinatal morbidity and mortality. The Pritchard’s regimen of magnesium sulphate remains as the standard regimen worldwide. The aim of this study is to compare the effectiveness, side effects and fetomaternal outcome using low-dose magnesium sulphate with the results of Pritchard regime. MATERIALS AND METHODS A comparative prospective study including 120 eclampsia patients designed into group I and group II treated with low-dose magnesium sulphate and Pritchard’s regimen was conducted in the Department of Obstetrics and Gynaecology for a period of 18 months between January 2015 to June 2016. RESULTS In the present study, there was 100% control of seizures in both the groups. No recurrence of seizures were seen in 57 (95% of cases in group II (low-dose regimen and 3 (5% cases showed recurrence, which were controlled by giving additional doses. In group II, loss of patellar reflexes was seen in 6 (10%, reduced urine output was seen in 3 (5% of cases, mild PPH was observed in 3 (5% cases and perinatal mortality in 18 (30% cases, which were lower than that of group I (Pritchard’s regimen. CONCLUSION Low-dose magnesium sulphate is effective in controlling convulsions in eclampsia. This regimen is highly suitable for use in Indian women who are known to have low body mass index

Validation and clinical application of a method to quantify nevirapine in dried blood spots and dried breast-milk spots.

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Olagunju, Adeniyi; Amara, Alieu; Waitt, Catriona; Else, Laura; Penchala, Sujan D; Bolaji, Oluseye; Soyinka, Julius; Siccardi, Marco; Back, David; Owen, Andrew; Khoo, Saye

2015-10-01

The validation and clinical application of an LC-MS/MS method for the quantification of nevirapine in dried blood spots (DBS) and dried breast-milk spots (DBMS) are presented. DBS and DBMS were prepared from 50 and 30 μL of nevirapine-spiked whole blood and human breast milk, respectively. Chromatographic separation was achieved on a reverse-phase C18 column with 0.1% formic acid in water/acetonitrile using a solvent gradient programme at a flow rate of 400 μL/min, and detection was by a TSQ Quantum Access triple quadrupole mass spectrometer. The clinical application was evaluated in HIV-positive nursing mothers and their breastfed infants. The assay was validated over the concentration range 50-10,000 ng/mL. Accuracy ranged from 93.3% to 113.4% and precision ranged from 1.9% to 12.0%. The mean (percentage coefficient of variation) recovery of nevirapine from DBS and DBMS was ≥ 70.7% (≤ 8.2) and the matrix effect was ≤ 1.04 (≤ 6.1). Nevirapine was stable in DBS and DBMS for ≥ 15 months at room temperature and -80°C. Mean (SD) AUC0-12, Cmax and Cmin in maternal plasma versus breast milk were 57,808 ng · h/mL (24,315) versus 55,817 ng · h/mL (22,368), 6140 ng/mL (2605) versus 5231 ng/mL (2215) and 4334 ng/mL (1880) versus 4342 ng/mL (2245), respectively. The milk-to-plasma concentration ratio over the dosing interval was 0.94 (0.15). Infant plasma concentrations 2 and 8 h after maternal dosing were 580.6 ng/mL (464.7-1607) and 584.1 ng/mL (381.5-1570), respectively. These methods further extend opportunities for conducting clinical pharmacokinetic studies in nursing mother-infant pairs, especially in resource-limited settings. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission.

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Kumwenda, Newton I; Hoover, Donald R; Mofenson, Lynne M; Thigpen, Michael C; Kafulafula, George; Li, Qing; Mipando, Linda; Nkanaunena, Kondwani; Mebrahtu, Tsedal; Bulterys, Marc; Fowler, Mary Glenn; Taha, Taha E

2008-07-10

Effective strategies are urgently needed to reduce mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) through breast-feeding in resource-limited settings. Women with HIV-1 infection who were breast-feeding infants were enrolled in a randomized, phase 3 trial in Blantyre, Malawi. At birth, the infants were randomly assigned to one of three regimens: single-dose nevirapine plus 1 week of zidovudine (control regimen) or the control regimen plus daily extended prophylaxis either with nevirapine (extended nevirapine) or with nevirapine plus zidovudine (extended dual prophylaxis) until the age of 14 weeks. Using Kaplan-Meier analyses, we assessed the risk of HIV-1 infection among infants who were HIV-1-negative on DNA polymerase-chain-reaction assay at birth. Among 3016 infants in the study, the control group had consistently higher rates of HIV-1 infection from the age of 6 weeks through 18 months. At 9 months, the estimated rate of HIV-1 infection (the primary end point) was 10.6% in the control group, as compared with 5.2% in the extended-nevirapine group (P<0.001) and 6.4% in the extended-dual-prophylaxis group (P=0.002). There were no significant differences between the two extended-prophylaxis groups. The frequency of breast-feeding did not differ significantly among the study groups. Infants receiving extended dual prophylaxis had a significant increase in the number of adverse events (primarily neutropenia) that were deemed to be possibly related to a study drug. Extended prophylaxis with nevirapine or with nevirapine and zidovudine for the first 14 weeks of life significantly reduced postnatal HIV-1 infection in 9-month-old infants. (ClinicalTrials.gov number, NCT00115648.) 2008 Massachusetts Medical Society

Clinical Implications of Complex Pharmacokinetics for Daratumumab Dose Regimen in Patients With Relapsed/Refractory Multiple Myeloma

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Xu, Xu Steven; Yan, Xiaoyu; Puchalski, Thomas

2017-01-01

New therapeutic strategies are urgently needed to improve clinical outcomes in patients with multiple myeloma (MM). Daratumumab is a first-in-class, CD38 human immunoglobulin G1κ monoclonal antibody approved for treatment of relapsed or refractory MM. Identification of an appropriate dose regimen...... for daratumumab is challenging due to its target-mediated drug disposition, leading to time- and concentration-dependent pharmacokinetics. We describe a thorough evaluation of the recommended dose regimen for daratumumab in patients with relapsed or refractory MM. This article is protected by copyright. All...

Therapeutic drug monitoring of nevirapine in saliva in Uganda using high performance liquid chromatography and a low cost thin-layer chromatography technique.

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Lamorde, Mohammed; Fillekes, Quirine; Sigaloff, Kim; Kityo, Cissy; Buzibye, Allan; Kayiwa, Joshua; Merry, Concepta; Nakatudde-Katumba, Lillian; Burger, David; de Wit, Tobias F Rinke

2014-09-01

In resource limited settings access to laboratory monitoring of HIV treatment is limited and therapeutic drug monitoring is generally unavailable. This study aimed to evaluate nevirapine concentrations in saliva using low-cost thin-layer chromatography (TLC) and nevirapine concentrations in plasma and saliva using high performance liquid chromatography (HPLC) methods; and to correlate nevirapine plasma concentrations to HIV treatment outcomes in Ugandan patients. Paired plasma and stimulated saliva samples were obtained from Ugandan, HIV-infected adults on nevirapine-based ART. Nevirapine concentrations were measured using a validated HPLC method and a novel TLC method. Plasma nevirapine concentrations HPLC were considered subtherapeutic. Negative/positive predictive values of different thresholds for subtherapeutic nevirapine concentrations in saliva were determined. Virologic testing and, if applicable, HIV drug resistance testing was performed. Median (interquartile range, IQR) age of 297 patients was 39.1 (32.8-45.2) years. Three hundred saliva and 287 plasma samples were available for analysis. Attempts failed to determine nevirapine saliva concentrations by TLC. Using HPLC, median (IQR) nevirapine concentrations in saliva and plasma were 3.40 (2.59-4.47) mg/L and 6.17 (4.79-7.96) mg/L, respectively. The mean (coefficient of variation,%) nevirapine saliva/plasma ratio was 0.58 (62%). A cut-off value of 1.60 mg/L nevirapine in saliva was associated with a negative/positive predictive value of 0.99/0.72 and a sensitivity/specificity of 87%/98% for predicting subtherapeutic nevirapine plasma concentrations, respectively. Only 5% (15/287) of patients had subtherapeutic nevirapine plasma concentrations, of which 3 patients had viral load results > 400 copies/mL. Patients with nevirapine concentrations in plasma 400 copies/mL). The low-cost TLC technique for monitoring nevirapine in saliva was unsuccessful but monitoring nevirapine saliva and plasma

ENHANCING PMTCT PROGRAMmeS THROUGH PSYCHOSOCIAL ...

African Journals Online (AJOL)

2008-04-04

Apr 4, 2008 ... recommends less complex PMTCT regimens.10 A single dose of nevirapine ... than 10% of women needing PMTCT services received them in 2006.1 ... dened health care facilities often lack the time, training and resources to ...

The impact of a Wastewater Treatment Works in Southern Gauteng, South Africa on efavirenz and nevirapine discharges into the aquatic environment

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C. Schoeman

2017-06-01

Although an order of magnitude lower nevirapine concentrations displayed the opposite behaviour and gradually increased through the various stages of purification in the WWTP. Minor fluctuations occurred but the concentrations of nevirapine were higher at the effluent (between 92 and 473 ng/L than those entering the WWTP. No nevirapine was detected in the PST sludge. The increase in nevirapine concentrations are likely to be the result of the de-conjugation of the hydroxylated metabolites of nevirapine in the WWTP, its resistance to degradation and the lack of binding of the nevirapine to the PST sludge.

Good performance of an immunoassay based method for nevirapine measurements in human breast milk

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Salado-Rasmussen, Kirsten; Persson Theilgaard, Zahra; Chiduo, Mercy

2011-01-01

, developed and validated for plasma use. In this study, the ARK NVP-test was evaluated for measurement of nevirapine concentrations in breast milk. High performance liquid chromatography (HPLC) is the method currently used to determine nevirapine in breast milk. This method, however, requires complicated...

A novel approach to pharmacodynamic assessment of antimicrobial agents: new insights to dosing regimen design.

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Vincent H Tam

Full Text Available Pharmacodynamic modeling has been increasingly used as a decision support tool to guide dosing regimen selection, both in the drug development and clinical settings. Killing by antimicrobial agents has been traditionally classified categorically as concentration-dependent (which would favor less fractionating regimens or time-dependent (for which more frequent dosing is preferred. While intuitive and useful to explain empiric data, a more informative approach is necessary to provide a robust assessment of pharmacodynamic profiles in situations other than the extremes of the spectrum (e.g., agents which exhibit partial concentration-dependent killing. A quantitative approach to describe the interaction of an antimicrobial agent and a pathogen is proposed to fill this unmet need. A hypothetic antimicrobial agent with linear pharmacokinetics is used for illustrative purposes. A non-linear functional form (sigmoid Emax of killing consisted of 3 parameters is used. Using different parameter values in conjunction with the relative growth rate of the pathogen and antimicrobial agent concentration ranges, various conventional pharmacodynamic surrogate indices (e.g., AUC/MIC, Cmax/MIC, %T>MIC could be satisfactorily linked to outcomes. In addition, the dosing intensity represented by the average kill rate of a dosing regimen can be derived, which could be used for quantitative comparison. The relevance of our approach is further supported by experimental data from our previous investigations using a variety of gram-negative bacteria and antimicrobial agents (moxifloxacin, levofloxacin, gentamicin, amikacin and meropenem. The pharmacodynamic profiles of a wide range of antimicrobial agents can be assessed by a more flexible computational tool to support dosing selection.

Vitamin D supplementation in nursing home patients: randomized controlled trial of standard daily dose versus individualized loading dose regimen.

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Wijnen, Hugo; Salemink, Dayenne; Roovers, Lian; Taekema, Diana; de Boer, Hans

2015-05-01

Supplementation of cholecalciferol 800 IU daily appears to be insufficient to raise vitamin D levels to >75 nmol/l in nursing home (NH) patients. Our objective was to compare the efficacy of an individualized cholecalciferol loading dose (LD) regimen and a daily dose (DD) regimen of cholecalciferol 800 IU in reaching 25-OH vitamin D (25OHD) levels >75 nmol/l. A total of 30 NH patients with 25OHD levels 50 nmol/l were included. Patients were randomized using the minimization method in the LD or DD group. The cholecalciferol LD, calculated with an algorithm based on serum 25OHD level and body weight, was administered in divided doses of 50,000 IU twice a week, followed by a monthly maintenance dose of either 50,000 or 25,000 IU. The DD regimen consisted of cholecalciferol 800 IU daily for 26 weeks. Serum 25OHD, calcium, creatinine, phosphate, and parathyroid hormone were measured, and 2-minute walking test, handgrip strength, and timed get up and go test were assessed at baseline (T 0), after 5 weeks (T 5), 12 weeks (T 12), and 26 weeks (T 26). The primary endpoint was the percentage of patients with 25OHD levels >75 nmol/l at T 5. Secondary endpoints were the proportion of patients with 25OHD levels >75 nmol/l at T 26, safety of LD regimen, and improvement of performance tests with normalization of vitamin D levels. Median baseline 25OHD levels (interquartile range) were comparable between the 14 DD and 16 LD patients: 20.9 (15.9-29.6) and 21.7 (16.4-32.8) nmol/l, respectively. Levels of 25OHD >75 nmol/l at T 5 were reached in 79 % of the 14 LD patients, but in none of the 13 DD patients (p 75 nmol/l were reached in 83 % of the 12 LD patients and in 30 % of the ten DD patients (p tests was observed. In NH patients with severe 25OHD deficiency, an individualized calculated cholecalciferol LD is likely to be superior to a DD of cholecalciferol 800 IU in terms of the ability to rapidly normalize vitamin D levels.

[Influence of dose regimen on gentamycin nephrotoxicity in rats].

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Oliveira, V C; Tejos, C R; Hosaka, E M; Andrade, S C; Araújo, M; Vattimo, M F

2001-06-01

The acute renal failure (ARF), that still presents a right mortality rate (50%) can be defined as an abrupt decline of the glomerular filtration, resultant of ischemic or toxicity event. The drugs nephrotoxicity is one of the most frequent cause (27%) of ARF and it is suggested that the interval of administration of the drug can interfere in this side effect, however the best administration regimen is not very well established. This study evaluated the renal function of rats that received gentamicin (100 mg/kg) in one dose or in two doses (2 x 50 mg/kg), by intraperitoneal infusion. The results obtained in this research, indicated that the single infusion of gentamicin determined smaller nephrotoxicity by the reduction of serum concentration of this drug in 24 hours, decreasing the intracellular accumulation of this gentamicin, which is one of the main cellular mechanisms of this renal injury. The single dose treatment regime, otherwise, shows advantages not only related to the nephrotoxicity effect, but also it is relevant to the cost and safety, which can be rationable factors in the administration of this drug.

Electrochemical studies of nevirapine, an anti-HIV drug, and its assay in tablets and biological samples

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JALDAPPAGARI SEETHARAMAPPA

2012-06-01

Full Text Available The electrochemical oxidation of nevirapine, an anti-HIV drug, at a glassy carbon electrode has been studied by voltammetric techniques. Nevirapine showed one well defined irreversible oxidation peak with a potential of 0.749 V in phosphate buffer at pH 10. The effects of different electrolytes, pH and scan rate on the electrochemical behaviour of nevira¬pine were examined to determine the optimum reaction conditions. The oxidation peak current was found to vary linearly with the concentration of nevirapine in the range of 5.0 – 350 µM. The limit of detection and limit of quantification values were calculated and found to be 1.026 µM and 3.420 µM, respectively. The low relative standard deviation values of inter-day and intra-day assays highlighted the good reproducibility of the proposed m¬ethod for assay of nevirapine. Further, a sensitive and accurate differential pulse voltammetric method was developed for the determination of nevirapine concentrations in pharma¬ceutical formulations.

Good performance of an immunoassay based method for nevirapine measurements in human breast milk

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Salado-Rasmussen, Kirsten; Theilgaard, Zahra Persson; Chiduo, Mercy

2011-01-01

from HIV-uninfected women. Clinical samples from HIV-infected women receiving a single-dose of nevirapine were analyzed. Results: Precision and accuracy were evaluated with two concentrations of quality control materials analyzed in three replicates on four different days and was......, requires complicated extraction techniques. The ARK method employs an immunoassay technology and requires a small sample volume (40 μL) and no pre-treatment of the samples. Methods: Commercial enzyme and antibody were used and calibration standards and quality controls were prepared from pooled breast milk...

Estimation of the optimal dosing regimen of escitalopram in dogs: A dose occupancy study with [11C]DASB.

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Olivia Taylor

Full Text Available Although the favourable characteristics of escitalopram as being the most selective serotonin reuptake inhibitor and having an increased therapeutic efficacy via binding on an additional allosteric binding site of the serotonin transporter, its dosing regimen has not yet been optimized for its use in dogs. This study aimed to estimate the optimal dosing frequency and the required dose for achieving 80% occupancy of the serotonin transporters in the basal ganglia. The dosing frequency was investigated by determining the elimination half-life after a four day oral pre-treatment period with 0.83 mg/kg escitalopram (3 administrations/day and a subsequent i.v. injection 0.83 mg/kg. Blood samples were taken up to 12 hours after i.v. injection and the concentration of escitalopram in plasma was analysed via LC-MSMS. The dose-occupancy relationship was then determined by performing two PET scans in five adult beagles: a baseline PET scan and a second scan after steady state conditions were achieved following oral treatment with a specific dose of escitalopram ranging from 0.5 to 2.5 mg/kg/day. As the elimination half-life was determined to be 6.7 hours a dosing frequency of three administrations a day was proposed for the second part of the study. Further it was opted for a treatment period of four days, which well exceeded the minimum period to achieve steady state conditions. The optimal dosing regimen to achieve 80% occupancy in the basal ganglia and elicit a therapeutic effect, was calculated to be 1.85 mg/kg/day, divided over three administrations. Under several circumstances, such as insufficient response to other SSRIs, concurrent drug intake or in research studies focused on SERT, the use of escitalopram can be preferred over the use of the already for veterinary use registered fluoxetine, however, in case of long-term treatment with escitalopram, regularly cardiac screening is recommended.

Estimation of the optimal dosing regimen of escitalopram in dogs: A dose occupancy study with [11C]DASB.

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Taylor, Olivia; Van Laeken, Nick; Polis, Ingeborgh; Dockx, Robrecht; Vlerick, Lise; Dobbeleir, Andre; Goethals, Ingeborg; Saunders, Jimmy; Sadones, Nele; Baeken, Chris; De Vos, Filip; Peremans, Kathelijne

2017-01-01

Although the favourable characteristics of escitalopram as being the most selective serotonin reuptake inhibitor and having an increased therapeutic efficacy via binding on an additional allosteric binding site of the serotonin transporter, its dosing regimen has not yet been optimized for its use in dogs. This study aimed to estimate the optimal dosing frequency and the required dose for achieving 80% occupancy of the serotonin transporters in the basal ganglia. The dosing frequency was investigated by determining the elimination half-life after a four day oral pre-treatment period with 0.83 mg/kg escitalopram (3 administrations/day) and a subsequent i.v. injection 0.83 mg/kg. Blood samples were taken up to 12 hours after i.v. injection and the concentration of escitalopram in plasma was analysed via LC-MSMS. The dose-occupancy relationship was then determined by performing two PET scans in five adult beagles: a baseline PET scan and a second scan after steady state conditions were achieved following oral treatment with a specific dose of escitalopram ranging from 0.5 to 2.5 mg/kg/day. As the elimination half-life was determined to be 6.7 hours a dosing frequency of three administrations a day was proposed for the second part of the study. Further it was opted for a treatment period of four days, which well exceeded the minimum period to achieve steady state conditions. The optimal dosing regimen to achieve 80% occupancy in the basal ganglia and elicit a therapeutic effect, was calculated to be 1.85 mg/kg/day, divided over three administrations. Under several circumstances, such as insufficient response to other SSRIs, concurrent drug intake or in research studies focused on SERT, the use of escitalopram can be preferred over the use of the already for veterinary use registered fluoxetine, however, in case of long-term treatment with escitalopram, regularly cardiac screening is recommended.

Population Pharmacokinetic Model for Vancomycin Used in Open Heart Surgery: Model-Based Evaluation of Standard Dosing Regimens.

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Alqahtani, Saeed A; Alsultan, Abdullah S; Alqattan, Hussain M; Eldemerdash, Ahmed; Albacker, Turki B

2018-04-23

The purpose of this study was to investigate the population pharmacokinetics of vancomycin in patients undergoing open heart surgery. In this observational pharmacokinetic study, multiple blood samples were drawn over a 48-h period of intravenous vancomycin in patients who were undergoing open heart surgery. Blood samples were analysed using the Architect i4000SR Immunoassay Analyzer. Population pharmacokinetic models were developed using Monolix 4.4 software. Pharmacokinetic-pharmacodynamic (PK-PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. One-hundred and sixty-eight blood samples were analysed from 28 patients. The pharmacokinetics of vancomycin was best described by a two-compartment model with between-subject variability in CL, V of the central compartment, and V of the peripheral compartment. CL and central compartment V of vancomycin were related to CL CR , body weight, and albumin concentration. Dosing simulations showed that standard dosing regimens of 1 and 1.5 g failed to achieve the PK-PD target of AUC 0--24 /MIC > 400 for an MIC of 1 mg/L, while high weight-based dosing regimens were able to achieve the PK-PD target. In summary, administration of standard doses of 1 and 1.5 g of vancomycin two times daily provided inadequate antibiotic prophylaxis in patients undergoing open heart surgery. The same findings were obtained when 15 mg/kg and 20 mg/kg doses of vancomycin were administered. Achieving the PK-PD target required higher doses (25 mg/kg and 30 mg/kg) of vancomycin. Copyright © 2018 American Society for Microbiology.

Investigating the continuous synthesis of a nicotinonitrile precursor to nevirapine

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Ashley R. Longstreet

2013-11-01

Full Text Available 2-Chloro-3-amino-4-picoline (CAPIC is a strategic building block for the preparation of nevirapine, a widely-prescribed non-nucleosidic reverse transcriptase inhibitor for the treatment of HIV-infected patients. A continuous synthesis to the bromo derivative of a CAPIC intermediate, 2-bromo-4-methylnicotinonitrile, that terminates in a dead-end crystallization is described. The route uses inexpensive, acyclic commodity-based raw materials and has the potential to enable lower cost production of nevirapine as well as other value added structures that contain complex pyridines. The route terminates in a batch crystallization yielding high purity CAPIC. This outcome is expected to facilitate regulatory implementation of the overall process.

Pharmacokinetic/pharmacodynamic modeling for the determination of a cimicoxib dosing regimen in the dog.

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Jeunesse, Elisabeth C; Schneider, Marc; Woehrle, Frederique; Faucher, Mathieu; Lefebvre, Herve P; Toutain, Pierre-Louis

2013-12-11

Cimicoxib is a new coxib anti-inflammatory drug for use in the dog. To determine a preclinical dosage regimen for cimicoxib in dog, a reversible model of kaolin-induced paw inflammation was used. Dosage regimens were established using pharmacokinetic/pharmacodynamic (PK/PD) modeling approach (indirect response model). Analgesic, anti-inflammatory and antipyretic endpoints investigated with the inflammation model established the efficacy of cimicoxib at a dose of 2 mg/kg administered orally (single dose) in 12 beagle dogs.For both the oral and IV route of administration two groups of dogs to be identified namely Poor Metabolizers (PM) and Extensive Metabolizers (EM).The terminal half-life after oral administration was 8.0 ± 0.6 h for the PM and 4.6 ± 2.6 h for the EM groups, with the corresponding values after the IV route being 5.6 ± 1.7 h and 2.7 ± 0.9 h (mean ± SD).The main pharmacodynamic parameters (potency, efficacy, and sensitivity) were estimated for four endpoints (body temperature, creeping speed, ground vertical reaction force and clinical lameness score). The plasma concentration corresponding to half the maximum of the indirect effect were 239 μg/L for creeping speed, 284 μg/L for the lameness score, 161 μg/L for the ground reaction vertical force and 193 μg/L for the body temperature.To document possible polymorphism of the cimicoxib disposition in the target dog population, cimicoxib was administered by the intravenous route to 40 dogs (four different sized breeds). The cimicoxib half-lives in these 40 dogs were of same order of the magnitude as those of the EM beagle dogs. Thus pharmacokinetic and pharmacodynamic parameters obtained from the EM beagle dogs were selected to simulate the dose-effect relationship of cimicoxib after an oral administration allowing a dosage regimen to be selected for confirmation by a clinical trial. Cimicoxib was an efficacious anti-inflammatory, antipyretic and analgesic drug and a dosage regimen of 2 mg

New dosing strategies for an old antibiotic: pharmacodynamics of front-loaded regimens of colistin at simulated pharmacokinetics in patients with kidney or liver disease.

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Rao, Gauri G; Ly, Neang S; Haas, Curtis E; Garonzik, Samira; Forrest, Alan; Bulitta, Jurgen B; Kelchlin, Pamela A; Holden, Patricia N; Nation, Roger L; Li, Jian; Tsuji, Brian T

2014-01-01

Increasing evidence suggests that colistin monotherapy is suboptimal at currently recommended doses. We hypothesized that front-loading provides an improved dosing strategy for polymyxin antibiotics to maximize killing and minimize total exposure. Here, we utilized an in vitro pharmacodynamic model to examine the impact of front-loaded colistin regimens against a high bacterial density (10(8) CFU/ml) of Pseudomonas aeruginosa. The pharmacokinetics were simulated for patients with hepatic (half-life [t1/2] of 3.2 h) or renal (t1/2 of 14.8 h) disease. Front-loaded regimens (n=5) demonstrated improvement in bacterial killing, with reduced overall free drug areas under the concentration-time curve (fAUC) compared to those with traditional dosing regimens (n=14) with various dosing frequencies (every 12 h [q12h] and q24h). In the renal failure simulations, front-loaded regimens at lower exposures (fAUC of 143 mg · h/liter) obtained killing activity similar to that of traditional regimens (fAUC of 268 mg · h/liter), with an ∼97% reduction in the area under the viable count curve over 48 h. In hepatic failure simulations, front-loaded regimens yielded rapid initial killing by up to 7 log10 within 2 h, but considerable regrowth occurred for both front-loaded and traditional regimens. No regimen eradicated the high bacterial inoculum of P. aeruginosa. The current study, which utilizes an in vitro pharmacodynamic infection model, demonstrates the potential benefits of front-loading strategies for polymyxins simulating differential pharmacokinetics in patients with hepatic and renal failure at a range of doses. Our findings may have important clinical implications, as front-loading polymyxins as a part of a combination regimen may be a viable strategy for aggressive treatment of high-bacterial-burden infections.

Use of an integrated modelling and simulation approach to develop a simplified peginterferon alfa-2a dosing regimen for children with hepatitis C.

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Brennan, Barbara J; Lemenuel-Diot, Annabelle; Snoeck, Eric; McKenna, Michael; Solsky, Jonathan; Wat, Cynthia; Mallalieu, Navita L

2016-04-01

The aim of the study was to simplify the dosing regimen of peginterferon alfa-2a in paediatric patients with chronic hepatitis C. A population pharmacokinetic (PK) model was developed using PK data from 14 children aged 2-8 years and 402 adults. Simulations were produced to identify a simplified dosing regimen that would provide exposures similar to those observed in the paediatric clinical trials and in the range known to be safe/efficacious in adults. Model predictions were evaluated against observed adult and paediatric data to reinforce confidence of the proposed dosing regimen. The final model was a two compartment model with a zero order resorption process. Covariates included a linear influence of body surface area (BSA) on apparent oral clearance (CL/F) and a linear influence of body weight on apparent volume of distribution of the central compartment (V1 /F). A simplified dosing regimen was developed which is expected to provide exposures in children aged ≥5 years similar to the dosing formula used in the paediatric clinical trial and within the range that is safe/efficacious in adults. This simplified regimen is approved in the EU and in other countries for the treatment of chronic hepatitis C in treatment-naive children/adolescents aged ≥5 years in combination with ribavirin. Pre-existing adult PK data were combined with relatively limited paediatric PK data to develop a PK model able to predict exposure in both populations adequately. This provided increased confidence in characterizing PK in children and helped in the development of a simplified dosing regimen of peginterferon alfa-2a in paediatric patients. © 2015 The British Pharmacological Society.

Risk of nevirapine-associated Stevens-Johnson syndrome among ...

African Journals Online (AJOL)

Background. Stevens-Johnson syndrome (SJS) is an acute life-threatening condition often elicited by drugs. The government's indecisiveness in deciding to stop the use of nevirapine (NVP) in HIV-infected pregnant women owing to the increase of SJS among this population group in South Africa prompted this investigation ...

Antioxidant modulation of nevirapine induced hepatotoxicity in rats

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Awodele Olufunsho

2015-03-01

Full Text Available HIV/AIDS related mortality has been dramatically reduced by the advent of antiretroviral therapy (ART. However, ART presents with associated adverse effects. One of such adverse effects is hepatotoxicity observed with nevirapine (NVP containing ART. Since previous studies showed that NVP hepatotoxicity may be due to oxidative stress via generation of oxidative radicals, this study sought to evaluate the protective effects of antioxidants in alleviating NVP induced hepatotoxicity. Rats were divided into 6 groups with 8 animals per group and received doses of the antioxidants jobelyn (10.7 mg/kg/day, vitamin C (8 mg/kg/day, vitamin E (5 mg/kg/day and/or NVP (6 mg/kg/day for 60 days. The animals were sacrificed on day 61 by cervical dislocation, blood samples were collected for biochemical and hematological examination. The liver of the sacrificed animals was weighed and subjected to histopathological examination. There was a statistically significant (p<0.05 elevation in MDA level observed in the NVP group as compared with control. The results further showed non-significant decreases in the levels of MDA in the NVP plus antioxidant groups, except vitamin C, when compared with the NVP alone group. Vitamin E and Vitamin E plus C treated groups showed significantly (p<0.05 higher levels of SOD, CAT and GSH. The results also showed statistically significantly (p<0.05 lower levels of ALT and AST in the antioxidant treated groups There was an observed significantly (p<0.05 higher level of TP and urea in the antioxidant treated rats. A significantly (p<0.05 higher white blood cell count was observed in the antioxidant groups. Histopathological assessment of the liver extracted from the rats showed no visible pathology across the groups. Observations from this study suggest a potentially positive modulatory effect of antioxidants and may be indicative for the inclusion of antioxidants in nevirapine containing ART.

Effectiveness and tolerance of long-term malaria prophylaxis with mefloquine. Need for a better dosing regimen.

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Lobel, H O; Bernard, K W; Williams, S L; Hightower, A W; Patchen, L C; Campbell, C C

1991-01-16

To measure the effectiveness and tolerance of long-term malaria prophylaxis with mefloquine, the incidence of Plasmodium falciparum malaria and of adverse reactions was compared in Peace Corps volunteers in West Africa who took mefloquine every 2 weeks and in volunteers who took chloroquine phosphate weekly. Mefloquine was only 63% more effective than chloroquine; the monthly incidence of P falciparum infections was one case per 100 volunteers who took mefloquine and 2.7 cases per 100 volunteers who took chloroquine. Using daily proguanil (chloroguanide) hydrochloride in addition to chloroquine did not provide additional protection. All mefloquine prophylaxis failures occurred during the second week of the every-2-weeks dosing regimen in volunteers who had used mefloquine for more than 2 months. Blood concentrations of mefloquine were lower during the second week of the alternate-week regimen than during the first week, suggesting that blood levels are too low during the second week to suppress parasitemia. No serious adverse reactions were observed. The results indicate that a dosing regimen of 250 mg of mefloquine weekly should be considered for travelers to areas with chloroquine-resistant P falciparum malaria.

The effect of dosing regimen on the pharmacokinetics of risedronate

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Mitchell, David Y; Heise, Mark A; Pallone, Karen A; Clay, Marian E; Nesbitt, John D; Russell, Darrell A; Melson, Chad W

1999-01-01

Aims To examine the effect of timing of a risedronate dose relative to food intake on the rate and extent of risedronate absorption following single-dose, oral administration to healthy male and female volunteers. Methods A single-dose, randomized, parallel study design was conducted with volunteers assigned to four treatment groups (31 or 32 subjects per group, 127 subjects total). Each subject was orally administered 30 mg risedronate. Group 1 was fasted for 10 h prior to and 4 h after dosing (fasted group); Groups 2 and 3 were fasted for 10 h and were dosed 1 and 0.5 h, respectively, before a high-fat breakfast; and Group 4 was dosed 2 h after a standard dinner. Blood and urine samples were collected for 168 h after dosing. Pharmacokinetic parameters were estimated by simultaneous analysis of risedronate serum concentration and urinary excretion rate-time data. Results Extent of risedronate absorption (AUC and Ae) was comparable (P = 0.4) in subjects dosed 2 h after dinner and 0.5 h before breakfast; however, a significantly greater extent of absorption occurred when risedronate was given 1 or 4 h prior to a meal (1.4- to 2.3-fold greater). Administration 0.5, 1, or 4 h prior to a meal resulted in a significantly greater rate of absorption (Cmax 2.8-, 3.5-, and 4.1-fold greater, respectively) when compared with 2 h after dinner. Conclusions The comparable extent of risedronate absorption when administered either 0.5–1 h before breakfast or 2 h after an evening meal support previous clinical studies where risedronate was found to have similar effectiveness using these dosing regimens. This flexibility in the timing of risedronate administration may provide patients an alternative means to achieve the desired efficacy while maintaining their normal daily routine. PMID:10583024

Evening versus morning dosing regimen drug therapy for chronic kidney disease patients with hypertension in blood pressure patterns: a systematic review and meta-analysis.

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Wang, Caixia; Ye, Yuqiu; Liu, Chunyong; Zhou, Yongming; Lv, Linsheng; Cheng, Cailian; Li, Shaomin; Lou, Tanqi; Liu, Xun

2017-08-01

Evening dosing regimen drug therapy on blood pressure (BP) control is used widely, but its clinical benefits and preservation or re-establishment of the normal 24-h BP dipping pattern in chronic kidney disease (CKD) patients is not known. To investigate the effect of an evening dosing regimen of antihypertensive drugs on BP patterns of CKD patients with hypertension. A systematic review was conducted by searching PUBMED, EMBASE, ASN-ONLINE, the Cochrane Library and the reference lists of relevant articles of published papers. All trials designed to evaluate the effects of evening versus morning dosing regimen drug therapy for CKD patients with hypertension were included. Meta-analysis was performed using random or fixed effects models. Five randomised controlled trials and one comparative study, including 3732 patients, met the inclusion criteria. Compared with morning dosing regimen drug therapy, evening administration of antihypertensive medication was associated with a significant reduction of 40% in non-dipper BP patterns (risk ratio (RR), 95% CI, (0.43, 0.84)). We noted a significant decrease in nocturnal systolic blood pressure (SBP) (MD -3.17 mmHg, 95% CI (-5.41, -0.94)), a significant reduction in nocturnal diastolic blood pressure (DBP) (MD -1.37 mmHg, 95% CI (-2.05, -0.69)) and a significant increase in awake SBP (MD 1.15 mmHg, 95% CI (0.10, 2.19)) in patients assigned to the evening dosing regimen drug therapy group. Patients showed no significant differences for all-cause mortality and cardiovascular mortality. This review shows that evening dosing regimen drug therapy could reverse non-dipper BP patterns in hypertensive CKD patients. © 2017 Royal Australasian College of Physicians.

Comparison of a four-drug fixed-dose combination regimen with a single tablet regimen in smear-positive pulmonary tuberculosis.

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Bartacek, A; Schütt, D; Panosch, B; Borek, M

2009-06-01

To compare the efficacy, safety and acceptability of two short-course regimens of isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE) given either as fixed-dose combination (4-FDC) tablets or as single tablets (ST) in patients with newly diagnosed pulmonary tuberculosis (PTB). This randomised, open, multicentre, multinational study was conducted in 26 centres and included 1159 patients with smear-positive PTB. 4-FDC daily for 2 months then H+R for 4 months, or single preparations of H, R, Z and E for 2 months followed by H and R for 4 months were administered daily. Sputum smear conversion rates at 2, 4 and 6 months (end of treatment [EOT], primary endpoint) and at 9 and 12 months (follow-up) were measured, together with adverse events and the acceptability of the formulations. Smear conversion rates for 4-FDC and ST at EOT were 80.4% (468/582 patients) vs. 82.7% (477/577) in the intent-to-treat (ITT) population, and 98.1% (404/412) vs. 98.6% (416/422) in the per-protocol (PP) subgroup. Non-inferiority of 4-FDC was demonstrated at month 2, EOT and follow-up in both the ITT and the PP populations. Overall numbers of adverse events were not significantly different between the groups. The efficacy of the 4-FDC regimen was non-inferior to that of the ST regimens, but patient acceptability significantly improved with 4-FDC.

Terbinafine in combination with other antifungal agents for treatment of resistant or refractory mycoses: investigating optimal dosing regimens using a physiologically based pharmacokinetic model.

Science.gov (United States)

Dolton, Michael J; Perera, Vidya; Pont, Lisa G; McLachlan, Andrew J

2014-01-01

Terbinafine is increasingly used in combination with other antifungal agents to treat resistant or refractory mycoses due to synergistic in vitro antifungal activity; high doses are commonly used, but limited data are available on systemic exposure, and no assessment of pharmacodynamic target attainment has been made. Using a physiologically based pharmacokinetic (PBPK) model for terbinafine, this study aimed to predict total and unbound terbinafine concentrations in plasma with a range of high-dose regimens and also calculate predicted pharmacodynamic parameters for terbinafine. Predicted terbinafine concentrations accumulated significantly during the first 28 days of treatment; the area under the concentration-time curve (AUC)/MIC ratios and AUC for the free, unbound fraction (fAUC)/MIC ratios increased by 54 to 62% on day 7 of treatment and by 80 to 92% on day 28 compared to day 1, depending on the dose regimen. Of the high-dose regimens investigated, 500 mg of terbinafine taken every 12 h provided the highest systemic exposure; on day 7 of treatment, the predicted AUC, maximum concentration (Cmax), and minimum concentration (Cmin) were approximately 4-fold, 1.9-fold, and 4.4-fold higher than with a standard-dose regimen of 250 mg once daily. Close agreement was seen between the concentrations predicted by the PBPK model and the observed concentrations, indicating good predictive performance. This study provides the first report of predicted terbinafine exposure in plasma with a range of high-dose regimens.

Dose Response for Radiation Cataractogenesis: A Meta-Regression of Hematopoietic Stem Cell Transplantation Regimens

International Nuclear Information System (INIS)

Hall, Matthew D.; Schultheiss, Timothy E.; Smith, David D.; Nguyen, Khanh H.; Wong, Jeffrey Y.C.

2015-01-01

Purpose/Objective(s): To perform a meta-regression on published data and to model the 5-year probability of cataract development after hematopoietic stem cell transplantation (HSCT) with and without total body irradiation (TBI). Methods and Materials: Eligible studies reporting cataract incidence after HSCT with TBI were identified by a PubMed search. Seventeen publications provided complete information on radiation dose schedule, fractionation, dose rate, and actuarial cataract incidence. Chemotherapy-only regimens were included as zero radiation dose regimens. Multivariate meta-regression with a weighted generalized linear model was used to model the 5-year cataract incidence and contributory factors. Results: Data from 1386 patients in 21 series were included for analysis. TBI was administered to a total dose of 0 to 15.75 Gy with single or fractionated schedules with a dose rate of 0.04 to 0.16 Gy/min. Factors significantly associated with 5-year cataract incidence were dose, dose times dose per fraction (D•dpf), pediatric versus adult status, and the absence of an ophthalmologist as an author. Dose rate, graft versus host disease, steroid use, hyperfractionation, and number of fractions were not significant. Five-fold internal cross-validation showed a model validity of 83% ± 8%. Regression diagnostics showed no evidence of lack-of-fit and no patterns in the studentized residuals. The α/β ratio from the linear quadratic model, estimated as the ratio of the coefficients for dose and D•dpf, was 0.76 Gy (95% confidence interval [CI], 0.05-1.55). The odds ratio for pediatric patients was 2.8 (95% CI, 1.7-4.6) relative to adults. Conclusions: Dose, D•dpf, pediatric status, and regimented follow-up care by an ophthalmologist were predictive of 5-year cataract incidence after HSCT. The low α/β ratio indicates the importance of fractionation in reducing cataracts. Dose rate effects have been observed in single institution studies but not in the

Dose Response for Radiation Cataractogenesis: A Meta-Regression of Hematopoietic Stem Cell Transplantation Regimens

Energy Technology Data Exchange (ETDEWEB)

Hall, Matthew D. [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States); Schultheiss, Timothy E., E-mail: schultheiss@coh.org [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States); Smith, David D. [Division of Biostatistics, City of Hope National Medical Center, Duarte, California (United States); Nguyen, Khanh H. [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States); Department of Radiation Oncology, Bayhealth Cancer Center, Dover, Delaware (United States); Wong, Jeffrey Y.C. [Department of Radiation Oncology, City of Hope National Medical Center, Duarte, California (United States)

2015-01-01

Purpose/Objective(s): To perform a meta-regression on published data and to model the 5-year probability of cataract development after hematopoietic stem cell transplantation (HSCT) with and without total body irradiation (TBI). Methods and Materials: Eligible studies reporting cataract incidence after HSCT with TBI were identified by a PubMed search. Seventeen publications provided complete information on radiation dose schedule, fractionation, dose rate, and actuarial cataract incidence. Chemotherapy-only regimens were included as zero radiation dose regimens. Multivariate meta-regression with a weighted generalized linear model was used to model the 5-year cataract incidence and contributory factors. Results: Data from 1386 patients in 21 series were included for analysis. TBI was administered to a total dose of 0 to 15.75 Gy with single or fractionated schedules with a dose rate of 0.04 to 0.16 Gy/min. Factors significantly associated with 5-year cataract incidence were dose, dose times dose per fraction (D•dpf), pediatric versus adult status, and the absence of an ophthalmologist as an author. Dose rate, graft versus host disease, steroid use, hyperfractionation, and number of fractions were not significant. Five-fold internal cross-validation showed a model validity of 83% ± 8%. Regression diagnostics showed no evidence of lack-of-fit and no patterns in the studentized residuals. The α/β ratio from the linear quadratic model, estimated as the ratio of the coefficients for dose and D•dpf, was 0.76 Gy (95% confidence interval [CI], 0.05-1.55). The odds ratio for pediatric patients was 2.8 (95% CI, 1.7-4.6) relative to adults. Conclusions: Dose, D•dpf, pediatric status, and regimented follow-up care by an ophthalmologist were predictive of 5-year cataract incidence after HSCT. The low α/β ratio indicates the importance of fractionation in reducing cataracts. Dose rate effects have been observed in single institution studies but not in the

Assessment of serum magnesium levels and its outcome in neonates of eclamptic mothers treated with low-dose magnesium sulfate regimen

Science.gov (United States)

Das, Monalisa; Chaudhuri, Patralekha Ray; Mondal, Badal C.; Mitra, Sukumar; Bandyopadhyay, Debasmita; Pramanik, Sushobhan

2015-01-01

Objectives: Magnesium historically has been used for treatment and/or prevention of eclampsia. Considering the low body mass index of Indian women, a low-dose magnesium sulfate regime has been introduced by some authors. Increased blood levels of magnesium in neonates is associated with increased still birth, early neonatal death, birth asphyxia, bradycardia, hypotonia, gastrointestinal hypomotility. The objective of this study was to assess safety of low-dose magnesium sulfate regimen in neonates of eclamptic mothers treated with this regimen. Materials and Methods: This was a cross-sectional observational study of 100 eclampsia patients and their neonates. Loading dose and maintenance doses of magnesium sulfate were administered to patients by combination of intravenous and intramuscular routes. Maternal serum and cord blood magnesium levels were estimated. Neonatal outcome was assessed. Results: Bradycardia was observed in 18 (19.15%) of the neonates, 16 (17.02%) of the neonates were diagnosed with hypotonia. Pearson Correlation Coefficient showed Apgar scores decreased with increase in cord blood magnesium levels. Unpaired t-test showed lower Apgar scores with increasing dose of magnesium sulfate. The Chi-square/Fisher's exact test showed significant increase in hypotonia, birth asphyxia, intubation in delivery room, Neonatal Intensive Care Unit (NICU) care requirement, with increasing dose of magnesium sulfate. (P ≤ 0.05). Conclusion: Several neonatal complications are significantly related to increasing serum magnesium levels. Overall, the low-dose magnesium sulfate regimen was safe in the management of eclamptic mothers, without toxicity to their neonates. PMID:26600638

High exposure to nevirapine in plasma is associated with an improved virological response in HIV-1-infected individuals

NARCIS (Netherlands)

Veldkamp, A. I.; Weverling, G. J.; Lange, J. M.; Montaner, J. S.; Reiss, P.; Cooper, D. A.; Vella, S.; Hall, D.; Beijnen, J. H.; Hoetelmans, R. M.

2001-01-01

OBJECTIVE: To explore relationships between exposure to nevirapine and the virological response in HIV-1-infected individuals participating in the INCAS trial. METHODS: The elimination rate constant of plasma HIV-1 RNA (k) was calculated during the first 2 weeks of treatment with nevirapine,

Reuse of single-dose nevirapine in subsequent pregnancies for the prevention of mother-to-child HIV transmission in Lusaka, Zambia: A cohort study

Directory of Open Access Journals (Sweden)

Sinkala Moses

2008-12-01

Full Text Available Abstract Background Single-dose nevirapine (SDNVP for the prevention of mother-to-child HIV transmission (PMTCT results in the selection of resistance mutants among HIV-infected mothers. The effects of these mutations on the efficacy of SDNVP use in a subsequent pregnancy are not well understood. Methods We compared risks of perinatal HIV transmission between multiparous women who had previously received a dose of SDNVP (exposed and those that had not (unexposed and who were given SDNVP for the index pregnancy within a PMTCT clinical study. We also compared transmission risks among exposed and unexposed women who had two consecutive pregnancies within the trial. Logistic regression modeling was used to adjust for possible confounders. Results Transmission risks did not differ between 59 SDNVP-exposed and 782 unexposed women in unadjusted analysis or after adjustment for viral load and disease stage (adjusted odds ratio 0.6, 95% confidence interval [CI] 0.2 to 2.0. Among 43 women who had two consecutive pregnancies during the study, transmission risks were 7% (95% CI 1% to 19% at both the first (unexposed and second (exposed delivery. The results were unchanged, if infant death was included as an outcome. Conclusion These data suggest that the efficacy of SDNVP may not be diminished when reused in subsequent pregnancies.

Hypofractionation Regimens for Stereotactic Radiotherapy for Large Brain Tumors

International Nuclear Information System (INIS)

Yuan Jiankui; Wang, Jian Z.; Lo, Simon; Grecula, John C.; Ammirati, Mario; Montebello, Joseph F.; Zhang Hualin; Gupta, Nilendu; Yuh, William T.C.; Mayr, Nina A.

2008-01-01

Purpose: To investigate equivalent regimens for hypofractionated stereotactic radiotherapy (HSRT) for brain tumor treatment and to provide dose-escalation guidance to maximize the tumor control within the normal brain tolerance. Methods and Materials: The linear-quadratic model, including the effect of nonuniform dose distributions, was used to evaluate the HSRT regimens. The α/β ratio was estimated using the Gammaknife stereotactic radiosurgery (GKSRS) and whole-brain radiotherapy experience for large brain tumors. The HSRT regimens were derived using two methods: (1) an equivalent tumor control approach, which matches the whole-brain radiotherapy experience for many fractions and merges it with the GKSRS data for few fractions; and (2) a normal-tissue tolerance approach, which takes advantages of the dose conformity and fractionation of HSRT to approach the maximal dose tolerance of the normal brain. Results: A plausible α/β ratio of 12 Gy for brain tumor and a volume parameter n of 0.23 for normal brain were derived from the GKSRS and whole-brain radiotherapy data. The HSRT prescription regimens for the isoeffect of tumor irradiation were calculated. The normal-brain equivalent uniform dose decreased as the number of fractions increased, because of the advantage of fractionation. The regimens for potential dose escalation of HSRT within the limits of normal-brain tolerance were derived. Conclusions: The designed hypofractionated regimens could be used as a preliminary guide for HSRT dose prescription for large brain tumors to mimic the GKSRS experience and for dose escalation trials. Clinical studies are necessary to further tune the model parameters and validate these regimens

Effect of diurnal variation, CYP2B6 genotype and age on the pharmacokinetics of nevirapine in African children

NARCIS (Netherlands)

Bienczak, A.; Cook, A.; Wiesner, L.; Mulenga, V.; Kityo, C.; Kekitiinwa, A.; Walker, A.S.; Owen, A.; Gibb, D.M.; Burger, D.M.; McIlleron, H.; Denti, P.

2017-01-01

OBJECTIVES: To characterize the effects of CYP2B6 polymorphisms, diurnal variation and demographic factors on nevirapine pharmacokinetics in African children. METHODS: Non-linear mixed-effects modelling conducted in NONMEM 7.3 described nevirapine plasma concentration-time data from 414 children

Microbiological efficacy and tolerability of a single-dose regimen of 1 g of ceftriaxone in men with gonococcal urethritis.

Science.gov (United States)

Ito, Shin; Yasuda, Mitsuru; Hatazaki, Kyoko; Mizutani, Kosuke; Tsuchiya, Tomohiro; Yokoi, Shigeaki; Nakano, Masahiro; Deguchi, Takashi

2016-09-01

We treated men with gonococcal urethritis with a single-dose regimen of 1 g of ceftriaxone, which is recommended as the first-line treatment for gonorrhoea in Japan, to determine its microbiological outcomes and tolerability. We enrolled 255 men with gonococcal urethritis and treated them with a single-dose regimen of 1 g of ceftriaxone. We evaluated its microbiological outcomes and tolerability. We also determined ceftriaxone MICs for pretreatment isolates of Neisseria gonorrhoeae collected from the patients. The microbiological efficacy of the ceftriaxone regimen, which was determined between 5 and 9 days after treatment in 111 men based on the Japanese guideline for clinical research on antimicrobial agents in urogenital infections, was 100%. In the 194 men who returned to the clinic between 2 and 41 days after treatment, 191 (98.5%; 95% CI 96.8%-100%) were negative for N. gonorrhoeae after treatment. Ceftriaxone MICs determined for 136 pretreatment isolates obtained from these 194 men ranged from 0.001 to 0.25 mg/L. One isolate persisting after treatment exhibited a ceftriaxone MIC of 0.008 mg/L. For two isolates persisting after treatment, ceftriaxone MICs were not determined. Seven adverse events were observed in 7 (3.2%) of the 220 men treated with the ceftriaxone regimen. Four men had diarrhoea classified as grade 1. Three had urticaria during ceftriaxone administration, with one event classified as grade 1 and two events classified as grade 3. A single-dose regimen of 1 g of ceftriaxone was microbiologically effective against gonococcal urethritis and was safe and tolerable. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

A rational quantitative approach to determine the best dosing regimen for a target therapeutic effect: a unified formalism for antibiotic evaluation.

Science.gov (United States)

Li, Jun; Nekka, Fahima

2013-02-21

The determination of an optimal dosing regimen is a critical step to enhance the drug efficacy and avoid toxicity. Rational dosing recommendations based on mathematical considerations are increasingly being adopted in the process of drug development and use. In this paper, we propose a quantitative approach to evaluate the efficacy of antibiotic agents. By integrating both pharmacokinetic (PK) and pharmacodynamic (PD) information, this approach gives rise to a unified formalism able to measure the cause-effect of dosing regimens. This new pharmaco-metric allows to cover a whole range of antibiotics, including the two well known concentration and time dependent classes, through the introduction of the Hill-dependency concept. As a direct fallout, our formalism opens a new path toward the bioequivalence evaluation in terms of PK and PD, which associates the in vivo drug concentration and the in vitro drug effect. Using this new approach, we succeeded to reveal unexpected, but relevant behaviors of drug performance when different drug regimens and drug classes are considered. Of particular notice, we found that the doses required to reach the same therapeutic effect, when scheduled differently, exhibit completely different tendencies for concentration and time dependent drugs. Moreover, we theoretically confirmed the previous experimental results of the superiority of the once daily regimen of aminoglycosides. The proposed methodology is appealing for its computational features and can easily be applicable to design fair clinical protocols or rationalize prescription decisions. Copyright © 2012 Elsevier Ltd. All rights reserved.

Assessment of the efficacy of a novel tailored vitamin K dosing regimen in lowering the International Normalised Ratio in over-anticoagulated patients: a randomised clinical trial.

Science.gov (United States)

Kampouraki, Emmanouela; Avery, Peter J; Wynne, Hilary; Biss, Tina; Hanley, John; Talks, Kate; Kamali, Farhad

2017-09-01

Current guidelines advocate using fixed-doses of oral vitamin K to reverse excessive anticoagulation in warfarinised patients who are either asymptomatic or have minor bleeds. Over-anticoagulated patients present with a wide range of International Normalised Ratio (INR) values and response to fixed doses of vitamin K varies. Consequently a significant proportion of patients remain outside their target INR after vitamin K administration, making them prone to either haemorrhage or thromboembolism. We compared the performance of a novel tailored vitamin K dosing regimen to that of a fixed-dose regimen with the primary measure being the proportion of over-anticoagulated patients returning to their target INR within 24 h. One hundred and eighty-one patients with an index INR > 6·0 (asymptomatic or with minor bleeding) were randomly allocated to receive oral administration of either a tailored dose (based upon index INR and body surface area) or a fixed-dose (1 or 2 mg) of vitamin K. A greater proportion of patients treated with the tailored dose returned to within target INR range compared to the fixed-dose regimen (68·9% vs. 52·8%; P = 0·026), whilst a smaller proportion of patients remained above target INR range (12·2% vs. 34·0%; P vitamin K dosing is more accurate than fixed-dose regimen in lowering INR to within target range in excessively anticoagulated patients. © 2017 John Wiley & Sons Ltd.

Results of Hematopoietic Stem Cell Transplantation After Treatment With Different High-Dose Total-Body Irradiation Regimens in Five Dutch Centers

International Nuclear Information System (INIS)

Loes van Kempen-Harteveld, M.; Brand, Ronald; Kal, Henk B.; Verdonck, Leo F.; Hofman, Pieter; Schattenberg, Anton V.; Maazen, Richard W. van der; Cornelissen, Jan J.; Eijkenboom, Wil M.H.; Lelie, Johannes P. van der; Oldenburger, Foppe; Barge, Renee M.; Biezen, Anja van; Vossen, Jaak M.J.J.; Noordijk, Evert M.; Struikmans, Henk

2008-01-01

Purpose: To evaluate results of high-dose total-body irradiation (TBI) regimens for hematopoietic stem cell transplantation. Methods and Materials: A total of 1,032 patients underwent TBI in one or two fractions before autologous or allogeneic hematologic stem cell transplantation for acute leukemia and non-Hodgkin's lymphoma. The TBI regimens were normalized by using the biological effective dose (BED) concept. The BED values were divided into three dose groups. Study end points were relapse incidence (RI), non-relapse mortality (NRM), relapse-free survival (RFS), and overall survival (OS). Multivariate analysis was performed, stratified by disease. Results: In the highest TBI dose group, RI was significantly lower and NRM was higher vs. the lower dose groups. However, a significant influence on RFS and OS was not found. Relapses in the eye region were found only after shielding to very low doses. Age was of significant influence on OS, RFS, and NRM in favor of younger patients. The NRM of patients older than 40 years significantly increased, and OS decreased. There was no influence of age on RI. Men had better OS and RFS and lower NRM. Type of transplantation significantly influenced RI and NRM for patients with acute leukemia and non-Hodgkin's lymphoma. There was no influence on RFS and OS. Conclusions: Both RI and NRM were significantly influenced by the size of the BED of single-dose or two-fraction TBI regimens; OS and RFS were not. Age was of highly significant influence on NRM, but there was no influence of age on RI. Hyperfractionated TBI with a high BED might be useful, assuming NRM can be reduced

Lean body mass as an independent determinant of dose-limiting toxicity and neuropathy in patients with colon cancer treated with FOLFOX regimens

International Nuclear Information System (INIS)

Ali, Raafi; Sawyer, Michael B.; Bianchi, Laurent; Roberts, Sarah; Mollevi, Caroline; Senesse, Pierre; Baracos, Vickie E.; Assenat, Eric

2016-01-01

Evidence suggests that lean body mass (LBM) may be useful to normalize chemotherapy doses. Data from one prospective and one retrospective study were used to determine if the highest doses of oxaliplatin/kg LBM within FOLFOX regimens would be associated with dose-limiting toxicity (DLT) in colon cancer patients. Toxicity over four cycles was graded according to NCI Common Toxicity Criteria V2 or V3 (Common Terminology Criteria for Adverse Events, National Cancer Institute, Bethesda, MD). Muscle tissue was measured by computerized tomography (CT) and used to evaluate the LBM compartment of the whole body. In prospective randomized clinical trials conducted in France (n = 58), for patients given FOLFOX-based regimens according to body surface area, values of oxaliplatin/kg LBM were highly variable, ranging from 2.55 to 6.6 mg/kg LBM. A cut point of 3.09 mg oxaliplatin/kg LBM for developing toxicity was determined by Receiver Operating Characteristic (ROC) analysis, below this value 0/17 (0.0%) of patients experienced DLT; in contrast above this value 18/41 (44.0%) of patients were dose reduced or had treatment terminated owing to toxicity (≥Grade 3 or neuropathy ≥Grade 2); for 9/41 the DLT was sensory neuropathy. These findings were validated in an independent cohort of colon cancer patients (n = 80) receiving FOLFOX regimens as part of standard care, in Canada. Low LBM is a significant predictor of toxicity and neuropathy in patients administered FOLFOX-based regimens using conventional body surface area (BSA) dosing

RESULTS OF LONG-TERM THERAPY WITH GROWTH-HORMONE IN 2 DOSE REGIMENS IN TURNER SYNDROME

NARCIS (Netherlands)

NIENHUIS, HE; RONGENWESTERLAKEN, C; WIT, JM; OTTEN, BJ; KEIZERSCHRAMA, SMPFD; DRAYER, NM; DELEMARREVANDEWAAL, HA; VULSMA, T; OOSTDIJK, W; WAELKENS, JJJ

1993-01-01

Girls with Turner syndrome were divided according to age (group A 6-12 years, and group B 12-19 years) and human growth hormone (GH) dose regimen (A1 and B1, three injections/week; A2 and B2, six injections/week). All groups responded to GH, 24 IU/M2/week, with an increase in height velocity, though

Maternal deaths following nevirapine-based antiretroviral therapy

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E Bera

2012-10-01

Full Text Available We report 2 cases illustrating that it is too simplistic to link nevirapine (NVP toxicity exclusively to individuals with immune preservation. Not enough is known about the mechanism of hepatotoxicity or cutaneous eruption to predict these events. This type of hypersensitivity reaction occurs rarely among HIV-exposed infants taking NVP prophylaxis or antiretroviral therapy (ART-experienced adults with complete plasma viral load suppression. Conversely, HIV-uninfected adults and ART-naive pregnant women appear to be disproportionately affected by the adverse effects of NVP.

Switch from a ZDV/3TC-based regimen to a completely once daily (QD regimen of emtricitabine/tenofovir DF fixed dose combination plus a third QD agent (SONETT

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Arasteh K

2009-05-01

Full Text Available Abstract Objectives To assess the efficacy and safety of a treatment switch from a twice-daily (BID regimen containing zidovudine (ZDV and lamivudine (3TC plus a third agent to a once daily (QD regimen containing the fixed-dose combination of tenofovir DF/emtricitabine (TDF/FTC, Truvada® plus a divergent third QD agent in HIV-1 infected patients. Methods Prospective, 48-week, non-randomised, single-group, open-label, study. Fifty-one patients on stable ZDV/3TC-containing HAART, with HIV-1 RNA 50 cells/μl, were switched to TDF/FTC plus a third agent. Plasma HIV-1 RNA, CD4+ and CD8+ T-cell counts were assessed at baseline and weeks 4, 12, 24, 36 and 48 post-switch. Results During the 48-week study, 10 patients discontinued prematurely, including three due to adverse events (AEs. At week 48, plasma HIV-1 RNA was p Conclusions Results from this study support switching from a ZDV/3TC-containing HAART regimen to a completely QD regimen of TDF/FTC plus a third agent. Virologic and immunologic control are maintained, with apparent benefits in haemoglobin.

Off-label biologic regimens in psoriasis: a systematic review of efficacy and safety of dose escalation, reduction, and interrupted biologic therapy.

Directory of Open Access Journals (Sweden)

Elizabeth A Brezinski

Full Text Available OBJECTIVES: While off-label dosing of biologic treatments may be necessary in selected psoriasis patients, no systematic review exists to date that synthesizes the efficacy and safety of these off-label dosing regimens. The aim of this systematic review is to evaluate efficacy and safety of off-label dosing regimens (dose escalation, dose reduction, and interrupted treatment with etanercept, adalimumab, infliximab, ustekinumab, and alefacept for psoriasis treatment. DATA SOURCES AND STUDY SELECTION: We searched OVID Medline from January 1, 1990 through August 1, 2011 for prospective clinical trials that studied biologic therapy for psoriasis treatment in adults. Individual articles were screened for studies that examined escalated, reduced, or interrupted therapy with etanercept, adalimumab, infliximab, ustekinumab, or alefacept. DATA SYNTHESIS: A total of 23 articles with 12,617 patients matched the inclusion and exclusion criteria for the systematic review. Data were examined for primary and secondary efficacy outcomes and adverse events including infections, malignancies, cardiovascular events, and anti-drug antibodies. The preponderance of data suggests that continuous treatment with anti-TNF agents and anti-IL12/23 agent was necessary for maintenance of disease control. Among non-responders, dose escalation with etanercept, adalimumab, ustekinumab, and alefacept typically resulted in greater efficacy than standard dosing. Dose reduction with etanercept and alefacept resulted in reduced efficacy. Withdrawal of the examined biologics led to an increase in disease activity; efficacy from retreatment did not result in equivalent initial response rates for most biologics. Safety data on off-label dosing regimens are limited. CONCLUSION: Dose escalation in non-responders generally resulted in increased efficacy in the examined biologics used to treat moderate-to-severe psoriasis. Continuous treatment with anti-TNF agents and anti-IL12/23 agent

The impact on coagulation of an intravenous loading dose in addition to a subcutaneous regimen of low-molecular-weight heparin in the initial treatment of acute coronary syndromes

NARCIS (Netherlands)

Bijsterveld, Nick R.; Moons, Arno H.; Meijers, Joost C. M.; Levi, Marcel; Büller, Harry R.; Peters, Ron J. G.

2003-01-01

OBJECTIVES We sought to quantify the impact of adding an intravenous loading dose to a subcutaneous regimen of enoxaparin in patients with an acute coronary syndrome (ACS). BACKGROUND It is unclear whether an intravenous (M loading dose of enoxaparin should be added to a subcutaneous (SQ) regimen in

Population pharmacokinetics and pharmacodynamics of hydroxyurea in sickle cell anemia patients, a basis for optimizing the dosing regimen

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Galactéros Frédéric

2011-05-01

Full Text Available Abstract Background Hydroxyurea (HU is the first approved pharmacological treatment of sickle cell anemia (SCA. The objectives of this study were to develop population pharmacokinetic(PK-pharmacodynamic(PD models for HU in order to characterize the exposure-efficacy relationships and their variability, compare two dosing regimens by simulations and develop some recommendations for monitoring the treatment. Methods The models were built using population modelling software NONMEM VII based on data from two clinical studies of SCA adult patients receiving 500-2000 mg of HU once daily. Fetal hemoglobin percentage (HbF% and mean corpuscular volume (MCV were used as biomarkers for response. A sequential modelling approach was applied. Models were evaluated using simulation-based techniques. Comparisons of two dosing regimens were performed by simulating 10000 patients in each arm during 12 months. Results The PK profiles were described by a bicompartmental model. The median (and interindividual coefficient of variation (CV of clearance was 11.6 L/h (30%, the central volume was 45.3 L (35%. PK steady-state was reached in about 35 days. For a given dosing regimen, HU exposure varied approximately fivefold among patients. The dynamics of HbF% and MCV were described by turnover models with inhibition of elimination of response. In the studied range of drug exposures, the effect of HU on HbF% was at its maximum (median Imax was 0.57, CV was 27%; the effect on MCV was close to its maximum, with median value of 0.14 and CV of 49%. Simulations showed that 95% of the steady-state levels of HbF% and MCV need 26 months and 3 months to be reached, respectively. The CV of the steady-state value of HbF% was about 7 times larger than that of MCV. Simulations with two different dosing regimens showed that continuous dosing led to a stronger HbF% increase in some patients. Conclusions The high variability of response to HU was related in part to pharmacokinetics and

Therapeutic drug monitoring of nevirapine in saliva in Uganda using high performance liquid chromatography and a low cost thin-layer chromatography technique

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Lamorde, M.; Fillekes, Q.; Sigaloff, K.; Kityo, C.; Buzibye, A.; Kayiwa, J.; Merry, C.; Nakatudde-Katumba, L.; Burger, D.M.; Wit, T.F. de

2014-01-01

BACKGROUND: In resource limited settings access to laboratory monitoring of HIV treatment is limited and therapeutic drug monitoring is generally unavailable. This study aimed to evaluate nevirapine concentrations in saliva using low-cost thin-layer chromatography (TLC) and nevirapine concentrations

Therapeutic drug monitoring of nevirapine in saliva in Uganda using high performance liquid chromatography and a low cost thin-layer chromatography technique

NARCIS (Netherlands)

Lamorde, Mohammed; Fillekes, Quirine; Sigaloff, Kim; Kityo, Cissy; Buzibye, Allan; Kayiwa, Joshua; Merry, Concepta; Nakatudde-Katumba, Lillian; Burger, David; Rinke de Wit, Tobias F.

2014-01-01

In resource limited settings access to laboratory monitoring of HIV treatment is limited and therapeutic drug monitoring is generally unavailable. This study aimed to evaluate nevirapine concentrations in saliva using low-cost thin-layer chromatography (TLC) and nevirapine concentrations in plasma

A fixed-dose 24-hour regimen of artesunate plus sulfamethoxypyrazine-pyrimethamine for the treatment of uncomplicated Plasmodium falciparum malaria in eastern Sudan

DEFF Research Database (Denmark)

Adam, Ishag; Magzoub, Mamoun; Osman, Maha E

2006-01-01

-sulfamethoxypyrazine-pyrimethamine (AS+SMP f) administered at time intervals of 12 hours for a 24-hour therapy was compared with the efficacy of the same drug given as a loose combination (AS+SMP l) with a dose interval of 24 hours for 3 days for the treatment of uncomplicated Plasmodium falciparum malaria in eastern Sudan. RESULTS...... of the patients. CONCLUSION: both regimens of AS+SMP were effective and safe for the treatment of uncomplicated P. falciparum malaria in eastern Sudan. Due to its simplicity, the fixed dose one-day treatment regimen may improve compliance and therefore may be the preferred choice....

Rilpivirine exposure in plasma and sanctuary site compartments after switching from nevirapine-containing combined antiretroviral therapy.

Science.gov (United States)

Mora-Peris, Borja; Watson, Victoria; Vera, Jaime H; Weston, Rosy; Waldman, Adam D; Kaye, Steve; Khoo, Saye; Mackie, Nicola E; Back, David; Winston, Alan

2014-06-01

Pharmacokinetic parameters following modifications to antiretroviral therapy and sanctuary site exposure are often unknown for recently licensed antiretrovirals. We assessed plasma, CSF and seminal plasma (SP) exposure of rilpivirine after switching from nevirapine. HIV-infected male subjects receiving tenofovir/emtricitabine/nevirapine (245/200/400 mg) once daily switched to tenofovir/emtricitabine/rilpivirine (245/200/25 mg) once daily for 60 days when CSF and semen samples were collected. Mean and individual plasma concentrations of nevirapine and rilpivirine were compared with the proposed plasma target concentration for nevirapine (3000 ng/mL) and the protein binding-adjusted EC90 for rilpivirine (12.1 ng/mL). Mean rilpivirine CSF and SP concentrations were calculated and individual values compared with the EC50 and EC90 for wild-type virus (0.27 and 0.66 ng/mL, respectively). Of 13 subjects completing study procedures including CSF examination, 8 provided seminal samples. By day 3, the mean plasma rilpivirine trough concentration was 29.7 ng/mL (95% CI: 23.8-37). No patient presented rilpivirine plasma concentrations under the proposed threshold. The mean rilpivirine concentration in CSF was 0.8 ng/mL (95% CI: 0.7-1.0), representing a CSF : plasma ratio of 1.4%, with concentrations above the EC90 in 85% (11/13) of patients. In SP, the mean rilpivirine concentration was 4.9 ng/mL (95% CI: 3.3-7.2), representing an SP : plasma ratio of 9.5%, with all concentrations above the EC90. Switching from nevirapine- to rilpivirine-containing antiretroviral therapy was safe and well tolerated, with plasma rilpivirine concentrations above the protein binding-adjusted EC90 in all subjects. Rilpivirine concentrations were always above the EC50 in the CSF and the EC90 in SP. © The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Skin dose differences between intensity-modulated radiation therapy and volumetric-modulated arc therapy and between boost and integrated treatment regimens for treating head and neck and other cancer sites in patients

International Nuclear Information System (INIS)

Penoncello, Gregory P.; Ding, George X.

2016-01-01

The purpose of this study was (1) to evaluate dose to skin between volumetric-modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT) treatment techniques for target sites in the head and neck, pelvis, and brain and (2) to determine if the treatment dose and fractionation regimen affect the skin dose between traditional sequential boost and integrated boost regimens for patients with head and neck cancer. A total of 19 patients and 48 plans were evaluated. The Eclipse (v11) treatment planning system was used to plan therapy in 9 patients with head and neck cancer, 5 patients with prostate cancer, and 5 patients with brain cancer with VMAT and static-field IMRT. The mean skin dose and the maximum dose to a contiguous volume of 2 cm"3 for head and neck plans and brain plans and a contiguous volume of 5 cm"3 for pelvis plans were compared for each treatment technique. Of the 9 patients with head and neck cancer, 3 underwent an integrated boost regimen. One integrated boost plan was replanned with IMRT and VMAT using a traditional boost regimen. For target sites located in the head and neck, VMAT reduced the mean dose and contiguous hot spot most noticeably in the shoulder region by 5.6% and 5.4%, respectively. When using an integrated boost regimen, the contiguous hot spot skin dose in the shoulder was larger on average than a traditional boost pattern by 26.5% and the mean skin dose was larger by 1.7%. VMAT techniques largely decrease the contiguous hot spot in the skin in the pelvis by an average of 36% compared with IMRT. For the same target coverage, VMAT can reduce the skin dose in all the regions of the body, but more noticeably in the shoulders in patients with head and neck and pelvis cancer. We also found that using integrated boost regimens in patients with head and neck cancer leads to higher shoulder skin doses compared with traditional boost regimens.

Maternal anaemia and duration of zidovudine in antiretroviral regimens for preventing mother-to-child transmission: a randomized trial in three African countries.

Science.gov (United States)

Sartorius, Benn K D; Chersich, Matthew F; Mwaura, Mary; Meda, Nicolas; Temmerman, Marleen; Newell, Marie Louise; Farley, Timothy M M; Luchters, Stanley

2013-11-06

Although substantiated by little evidence, concerns about zidovudine-related anaemia in pregnancy have influenced antiretroviral (ARV) regimen choice for preventing mother-to-child transmission of HIV-1, especially in settings where anaemia is common. Eligible HIV-infected pregnant women in Burkina Faso, Kenya and South Africa were followed from 28 weeks of pregnancy until 12-24 months after delivery (n = 1070). Women with a CD4 count of 200-500 cells/mm(3) and gestational age 28-36 weeks were randomly assigned to zidovudine-containing triple-ARV prophylaxis continued during breastfeeding up to 6-months, or to zidovudine during pregnancy plus single-dose nevirapine (sd-NVP) at labour. Additionally, two cohorts were established, women with CD4 counts: 500 cells/mm(3) received zidovudine during pregnancy plus sd-NVP at labour. Mild (haemoglobin 8.0-10.9 g/dl) and severe anaemia (haemoglobin anaemia occurred subsequently in 194 (18.1%) women, mostly in those with low baseline haemoglobin, lowest socio-economic category, advanced HIV disease, prolonged breastfeeding (≥ 6 months) and shorter ARV exposure. Severe anaemia incidence was similar in the randomized arms (equivalence P-value = 0.32). After 1-2 months of ARV's, severe anaemia was significantly reduced in all groups, though remained highest in the low CD4 cohort. Severe anaemia occurs at a similar rate in women receiving longer triple zidovudine-containing regimens or shorter prophylaxis. Pregnant women with pre-existing anaemia and advanced HIV disease require close monitoring. ISRCTN71468401.

TH-302, a hypoxia-activated prodrug with broad in vivo preclinical combination therapy efficacy: optimization of dosing regimens and schedules.

Science.gov (United States)

Liu, Qian; Sun, Jessica D; Wang, Jingli; Ahluwalia, Dharmendra; Baker, Amanda F; Cranmer, Lee D; Ferraro, Damien; Wang, Yan; Duan, Jian-Xin; Ammons, W Steve; Curd, John G; Matteucci, Mark D; Hart, Charles P

2012-06-01

Subregional hypoxia is a common feature of tumors and is recognized as a limiting factor for the success of radiotherapy and chemotherapy. TH-302, a hypoxia-activated prodrug selectively targeting hypoxic regions of solid tumors, delivers a cytotoxic warhead to the tumor, while maintaining relatively low systemic toxicity. The antitumor activity, different dosing sequences, and dosing regimens of TH-302 in combination with commonly used conventional chemotherapeutics were investigated in human tumor xenograft models. Seven chemotherapeutic drugs (docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide) were tested in combination with TH-302 in eleven human xenograft models, including non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, fibrosarcoma, melanoma, and pancreatic cancer. The antitumor activity of docetaxel, cisplatin, pemetrexed, irinotecan, doxorubicin, gemcitabine, and temozolomide was increased when combined with TH-302 in nine out of eleven models tested. Administration of TH-302 2-8 h prior to the other chemotherapeutics yielded superior efficacy versus other sequences tested. Simultaneous administration of TH-302 and chemotherapeutics increased toxicity versus schedules with dosing separations. In a dosing optimization study, TH-302 administered daily at 50 mg/kg intraperitoneally for 5 days per week in the H460 NSCLC model showed the optimal response with minimal toxicity. TH-302 enhances the activity of a wide range of conventional anti-neoplastic agents in a broad panel of in vivo xenograft models. These data highlight in vivo effects of schedule and order of drug administration in regimen efficacy and toxicity and have relevance to the design of human regimens incorporating TH-302.

Characteristics of HIV antiretroviral regimen and treatment adherence

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Vera Lúcia da Silveira

Full Text Available The relationship between characteristics of HIV antiretroviral regimens and treatment adherence was studied in adolescent and adult patients who underwent antiretroviral therapy from January 1998 to September 2000, at the Service for Specialized Assistance in Pelotas. The patients were interviewed on two occasions, and the use of antiretrovirals during the previous 48 hours was investigated by a self-report. Adherence was defined as use of 95% or more of the prescribed medication. Social-demographic variables were collected through direct questionnaires. The antiretroviral regimen and clinical data were copied from the patients' records. Associations between the independent variables and adherence were analyzed by means of logistic regression. The multivariate analysis included characteristics of the antiretroviral regimens, social-demographic variables, as well as perception of negative effects, negative physiological states, and adverse effects of the treatment. Among the 224 selected patients, 194 participated in our study. Their ages varied from 17 to 67 years; most patients were men, with few years of schooling and a low family income. Only 49% adhered to the treatment. Adherence to treatment regimens was reduced when more daily doses were indicated: three to four doses (odds ratio of adherence to treatment (OR=0.47, 95% confidence interval (CI 0.22-1.01 and five to six (OR=0.24, 95% CI 0.09-0.62; two or more doses taken in a fasting state (OR=0.59, 95% CI 0.11-0.68, and for patients who reported adverse effects to the treatment (OR=0.39, 95% CI 0.19-0.77. Most of the regimens with more than two daily doses of medication included at least one dose apart from mealtimes. The results suggest that, if possible, regimens with a reduced number of doses should be chosen, with no compulsory fasting, and with few adverse effects. Strategies to minimize these effects should be discussed with the patients.

Skin dose differences between intensity-modulated radiation therapy and volumetric-modulated arc therapy and between boost and integrated treatment regimens for treating head and neck and other cancer sites in patients.

Science.gov (United States)

Penoncello, Gregory P; Ding, George X

2016-01-01

The purpose of this study was (1) to evaluate dose to skin between volumetric-modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT) treatment techniques for target sites in the head and neck, pelvis, and brain and (2) to determine if the treatment dose and fractionation regimen affect the skin dose between traditional sequential boost and integrated boost regimens for patients with head and neck cancer. A total of 19 patients and 48 plans were evaluated. The Eclipse (v11) treatment planning system was used to plan therapy in 9 patients with head and neck cancer, 5 patients with prostate cancer, and 5 patients with brain cancer with VMAT and static-field IMRT. The mean skin dose and the maximum dose to a contiguous volume of 2cm(3) for head and neck plans and brain plans and a contiguous volume of 5cm(3) for pelvis plans were compared for each treatment technique. Of the 9 patients with head and neck cancer, 3 underwent an integrated boost regimen. One integrated boost plan was replanned with IMRT and VMAT using a traditional boost regimen. For target sites located in the head and neck, VMAT reduced the mean dose and contiguous hot spot most noticeably in the shoulder region by 5.6% and 5.4%, respectively. When using an integrated boost regimen, the contiguous hot spot skin dose in the shoulder was larger on average than a traditional boost pattern by 26.5% and the mean skin dose was larger by 1.7%. VMAT techniques largely decrease the contiguous hot spot in the skin in the pelvis by an average of 36% compared with IMRT. For the same target coverage, VMAT can reduce the skin dose in all the regions of the body, but more noticeably in the shoulders in patients with head and neck and pelvis cancer. We also found that using integrated boost regimens in patients with head and neck cancer leads to higher shoulder skin doses compared with traditional boost regimens. Copyright © 2016 American Association of Medical Dosimetrists. Published by

The effect of the second dose 131I in patients with Grave's disease, treated with 185 MBq low-fixed dose regimen

International Nuclear Information System (INIS)

Bochev, P.; Klissarova, A.; Hristozov, H.; Chaushev, B.; Cvetanova, B.

2006-01-01

Full text: The aim of the study was to evaluate the success rate after application of a second dose 131 I in patients with Grave's disease, treated with a fixed dose 185 MBq 131 I and still hyperthyroid. 27 patients with Grave's disease, treated with 185 MBq 131 I. Each patient was followed up by physical exam, ultrasonography and hormone levels for a period of at least one year. On the sixth month after the initial treatment 14 patients (52%) were still hyperthyroid. Based on hormone levels and reduction of gland size a decision for applying a second dose 131 I was taken for 8 patients. The remaining six patients with persistent hyperthyroidism were treated with antithyroid drugs till the end of the first year. By the time of the study 12.5% of the patients being treated with a second dose are still hyperthyroid, 37.5% - euthyroid and 50% -hypothyroid with total success rate (hypo+euthyroid) of 87%. In comparison 16 % of the patients treated with antithyroid drugs are euthyroid. The use of a second dose 131 I in patients with Graves disease being treated with low-fixed dose regimen and still hyperthyroid by the sixth month after the initial treatment leads to a high overall success rate in one year

High rates of regimen change due to drug toxicity among a cohort of South Indian adults with HIV infection initiated on generic, first-line antiretroviral treatment.

Science.gov (United States)

Sivadasan, Ajith; Abraham, O C; Rupali, Priscilla; Pulimood, Susanne A; Rajan, Joyce; Rajkumar, S; Zachariah, Anand; Kannangai, Rajesh; Kandathil, Abraham Joseph; Sridharan, G; Mathai, Dilip

2009-05-01

To determine the rates, reasons and predictors of treatment change of the initial antiretroviral treatment (ART) regimen in HIV-infected south Indian adults. In this prospective cohort study, ART-naive adults initiated on generic, fixed dose combination ART as per the National AIDS Control Organization guidelines were followed up at an academic medical center. Treatment change was defined as any event which necessitated a change in or discontinuation of the initial ART regimen. Two hundred and thirty persons with HIV infection (males 74.8% and median age 37 years) were followed up for median duration of 48 weeks. The majority (98.7%) had acquired HIV infection through the heterosexual route. Most (70.4%) had advanced IV infection (WHO clinical stage 3 or 4) and 78% had CD4+ T-lymphocyte counts below 200 cells/microL. The initial ART regimens used were: Lamivudine (3TC) with Stavudine (d4T) (in 76%) or Azidothymidine (AZT) and Nevirapine (NVP) (in 86%) or Efavirenz (EFV). The cumulative incidence of treatment change was 39.6% (91 patients). Drug toxicity (WHO grade 3 or 4) was the reason for treatment change among 62 (27%) (incidence rate 35.9/100 person-years). The most common toxicities were attributable to the thymidine analogue nucleoside reverse transcriptase inhibitors (NRTIs), d4T and AZT [lactic acidosis (8.7%), anemia (7%) and peripheral neuropathy (5.2%)]. The other toxicities were rash (3.9%) and hepatitis (1.3%) due to NVP. The mortality (4.6/100 person-years) and disease progression rates (4.1/100 person-years) were low. The ART regimens used in this study were effective in decreasing disease progression and death. However, they were associated with high rates of drug toxicities, particularly those attributable to thymidine analogue NRTI. As efforts are made to improve access to ART, treatment regimens chosen should not only be potent, but also safe.

Cluster-randomized non-inferiority trial to compare supplement consumption and adherence to different dosing regimens for antenatal calcium and iron-folic acid supplementation to prevent preeclampsia and anaemia: rationale and design of the Micronutrient Initiative study

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Moshood O. Omotayo

2015-11-01

Full Text Available Background: To prevent pre-eclampsia in populations with insufficient dietary calcium (Ca intake, the World Health Organisation (WHO recommends routine Ca supplementation during antenatal care (ANC. WHO guidelines suggest a complex dosing regimen, requiring as many as 5 pill-taking events per day when combined with iron and folic acid (IFA supplements. Poor adherence may undermine public health effectiveness, so simpler regimens may be preferable. This trial will compare the effect of the WHO-recommended (higher-dose regimen vs. a simpler, lower-dose regimen on supplement consumption and pill-taking behaviours in Kenyan ANC clients. Design and methods: This is a parallel, non-inferiority, cluster-randomized trial; we examined 16 primary care health facilities in Kenya, 1047 pregnant women between 16-30 weeks gestational age. Higher-dose regimen: 1.5 g elemental calcium in 3 separate doses (500 mg Ca/pill and IFA (60 mg Fe + 400 μg folic acid taken with evening dose. Lower-dose regimen: 1.0 g calcium in 2 separate doses (500 mg Ca/pill with IFA taken as above. Measurements: Primary outcome is Ca pills consumed per day, measured by pill counts. Secondary outcomes include IFA pills consumed per day, client knowledge, motivation, social support, and satisfaction, measured at 4 to 10 weeks post-enrolment. Statistical analyses: Unit of randomization is the health-care facility; unit of analysis is individual client. Intent-to-treat analysis will be implemented with multi-level models to account for clustering. Expected public health impact: If pregnant women prescribed lower doses of Ca ingest as many pills as women prescribed the WHO-recommended regimen, developing a lower-dose recommendation for antenatal Ca and IFA supplementation programs could save resources.

Prophylactic antibiotic regimens in tumour surgery (PARITY)

DEFF Research Database (Denmark)

Petersen, Michael Mørk; Hettwer, Werner H; Grum-Schwensen, Tomas

2015-01-01

-day regimen of post-operative antibiotics, in comparison to a 24-hour regimen, decreases surgical site infections in patients undergoing endoprosthetic reconstruction for lower extremity primary bone tumours. METHODS: We performed a pilot international multi-centre RCT. We used central randomisation...... to conceal treatment allocation and sham antibiotics to blind participants, surgeons, and data collectors. We determined feasibility by measuring patient enrolment, completeness of follow-up, and protocol deviations for the antibiotic regimens. RESULTS: We screened 96 patients and enrolled 60 participants......% at one year (the remainder with partial data or pending queries). In total, 18 participants missed at least one dose of antibiotics or placebo post-operatively, but 93% of all post-operative doses were administered per protocol. CONCLUSIONS: It is feasible to conduct a definitive multi-centre RCT of post...

Influence of drug load and physical form of cinnarizine in new SNEDDS dosing regimens

DEFF Research Database (Denmark)

Siqueira, Scheyla D V S; Müllertz, Anette; Gräeser, Kirsten

2017-01-01

The aim of this work was to evaluate the influence of drug load and physical form of cinnarizine (CIN) in self-nanoemulsifying drug delivery systems (SNEDDS) on absorption in rats. Further, the predictivity of the dynamic in vitro lipolysis model was evaluated. The following dosing regimens were......, compared to the aqueous suspension. Since the drug level in the aqueous phase is traditionally considered as the fraction available for absorption, a lack of in vitro-in vivo relation was observed. This study revealed that the physical form of CIN in the current SNEDDS does not affect CIN absorption...

Development of drug resistance in patients receiving combinations of zidovudine, didanosine and nevirapine

NARCIS (Netherlands)

Conway, B.; Wainberg, M. A.; Hall, D.; Harris, M.; Reiss, P.; Cooper, D.; Vella, S.; Curry, R.; Robinson, P.; Lange, J. M.; Montaner, J. S.

2001-01-01

OBJECTIVE: To evaluate the development of phenotypic and genotypic resistance to zidovudine, didanosine and nevirapine as a function of the virologic response to therapy in a group of drug-naive individuals receiving various combinations of these agents. DESIGN: All patients were enrolled in a

A New Validated RP- HPLC Method for the Determination of Nevirapine in Human Plasma

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C. H. Venkata Kumar

2010-01-01

Full Text Available A rapid, selective and sensitive high performance liquid chromatographic method for the estimation of nevirapine in human plasma has been developed. Chromatography was carried out on a Hypersil BDS C18 column using a mixture of ammonium acetate buffer (pH 4.0 ± 0.05 and acetonitrile (85:15 v/v as the mobile phase. The eluents were monitored for the drug by UV detection at 254 nm. Oxcarbazepine was used as an internal standard for this study. The retention times for nevirapine and oxcarbazepine were found to be 7.2 and 14.7 min respectively. The method was found to be linear in the concentration range of 50 ng/mL to 5003.7 ng/mL. The method was validated as per FDA guidelines and was found to be suitable for bioequivalence and pharmacokinetic studies.

Comparison of different glucocorticoid regimens in the management of classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Science.gov (United States)

Ajish, T P; Praveen, V P; Nisha, B; Kumar, Harish

2014-11-01

There are recommendations regarding the total dose of hydrocortisone to be administered in the treatment of classical congenital adrenal hyperplasia (CAH) to achieve the twin objectives of glucocorticoid replacement and control of hyperandrogenism. However, there is evidence gap regarding the breakup, timing and type of the steroid regimen. Efficacy of three different glucocorticoid regimens having the same total dose of steroid, differing in either the timing or type of evening steroid administered, in achieving biochemical control of the disease was assessed. The study was done in 13 prepubertal children with classical CAH over a 6-month period with 2 months devoted to each regimen. We used a prospective cross-over design using 10-15 mg/m(2) total dose of hydrocortisone. Two-fifths of the total dose of hydrocortisone was administered in the morning and one-fifth of the total dose was administered at noon in all the regimens. The regimens differed in the timing of the evening dose of hydrocortisone, 06.00-07.00 pm in regimen 1 and 09.00-10.00 pm in regimen 2. The third regimen had the evening dose of hydrocortisone replaced by an equivalent dose of prednisolone suspension which was administered at 10.00 pm. Serum 17-hydroxyprogesterone and testosterone levels were compared to assess the efficacy of treatment regimens. The three different regimens were found to be similar in their ability to control 17-hydroxyprogesterone and testosterone levels. The percentage of patients with predefined criteria for biochemically controlled disease was similar in all the three regimens. However, there was a trend toward better control of 17-hydroxyprogesterone levels in patients receiving evening dose of prednisolone. There is no significant advantage in administering the hydrocortisone dose late at night in patients with classical CAH.

Severe Dopaminergic Neurotoxicity in Primates After a Common Recreational Dose Regimen of MDMA (``Ecstasy'')

Science.gov (United States)

Ricaurte, George A.; Yuan, Jie; Hatzidimitriou, George; Cord, Branden J.; McCann, Una D.

2002-09-01

The prevailing view is that the popular recreational drug (+/-)3,4-methylenedioxymethamphetamine (MDMA, or ``ecstasy'') is a selective serotonin neurotoxin in animals and possibly in humans. Nonhuman primates exposed to several sequential doses of MDMA, a regimen modeled after one used by humans, developed severe brain dopaminergic neurotoxicity, in addition to less pronounced serotonergic neurotoxicity. MDMA neurotoxicity was associated with increased vulnerability to motor dysfunction secondary to dopamine depletion. These results have implications for mechanisms of MDMA neurotoxicity and suggest that recreational MDMA users may unwittingly be putting themselves at risk, either as young adults or later in life, for developing neuropsychiatric disorders related to brain dopamine and/or serotonin deficiency.

Provider knowledge of treatment policy and dosing regimen with artemether-lumefantrine and quinine in malaria-endemic areas of western Kenya

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Watsierah Carren A

2012-12-01

Full Text Available Abstract Background Due to widespread anti-malarial drug resistance in many countries, Kenya included, artemisinin-based Combination Therapy (ACT has been adopted as the most effective treatment option against malaria. Artemether-lumefantrine (AL is the first-line ACT for treatment of uncomplicated malaria in Kenya, while quinine is preferred for complicated and severe malaria. Information on the providers’ knowledge and practices prior to or during AL and quinine implementation is scanty. The current study evaluated providers’ knowledge and practices of treatment policy and dosing regimens with AL and quinine in the public, private and not-for-profit drug outlets. Methods A cross-sectional survey using three-stage sampling of 288 (126 public, 96 private and 66 not-for-profits providers in drug outlets was conducted in western Kenya in two Plasmodium falciparum-endemic regions with varying malarial risk. Information on provider in-service training, knowledge (qualification, treatment policy, dosing regimen, recently banned anti-malarials and on practices (request for written prescription, prescription of AL, selling partial packs and advice given to patients after prescription, was collected. Results Only 15.6% of providers in private outlets had received any in-service training on AL use. All (100% in public and majority (98.4% in not-for-profit outlets mentioned AL as first line-treatment drug. Quinine was mentioned as second-line drug by 47.9% in private outlets. A total of 92.0% in public, 57.3% in private and 78.8% in not-for-profit outlets stated correct AL dose for adults. A total of 85.7% of providers in public, 30.2% in private and 41.0% in not-for-profit outlets were aware that SP recommendations changed from treatment for mild malaria to IPTp in high risk areas. In-service training influenced treatment regimen for uncomplicated malaria (P = 0.039 and P = 0.039 and severe malaria (P P = 0.002 in children and adults

Cluster Randomized Trail of the uptake of a take-home Infant dose ...

African Journals Online (AJOL)

Objective: To test whether a single take home dose of infant nevirapine increased infant uptake without decreasing institutional deliveries. Design: Cluster randomized post-test only study with control group. Setting: Ten hospitals in urban areas of Coast, Rift Valley, and Western provinces, Kenya. Participants: Pregnant ...

Survival of HIV/AIDS patients with antiretroviral therapy in association with first-line regimens from 2007 – 2010 in Haji AdamMalik general hospital Medan

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Kembaren, T.; Ginting, Y.; Saragih, R. H.

2018-03-01

The mortality related to AIDS have decreased dramatically among HIV infected patients taking HAART. HAART is the combination of at least 3 antiretroviral drugs based on the recommendation of WHO. The recent guideline for 1st line therapy recommended by the Indonesian Ministry of Health was Zidovudine/Lamivudine/Nevirapine (ZDV+3TC+NVP), Zidovudine/Lamivudine/Efavirenz (ZDV+3TC+EFV), Stavudine/Lamivudine/Nevirapine (d4T+3TC+NVP), Stavudine/Lamivudine/Efavirenz (d4T+3TC+EFV). Due to a side effect of Stavudine, Ministry of Health plan to pass out Stavudin from the regimens for 1stline therapy.We wanted to evaluate the survival of HIV/AIDS patients with first-line regimens in HAM general hospital Medan. A cohort retrospective study was conducted to evaluate the survival of HIV/AIDS patients taking a combination of 1st line antiretroviral therapy between January 2007 and December 2010. From 2007-2010, among 609 HIV/AIDS patients with first-line ARV medication, 77.5% were male, and 22.5% were female. The most common risk infection was heterosexual. The majority of the patients were in 25-34 years old group. Most of the patients with CD4 1-50 cell/mm3. 2 years survival rate in HIV/AIDS patients taking ZDV+3TC+NVP, ZDV+3TC+EFV, d4T+3TC+NVP, d4T+3TC+EFV were 61.5%, 61.2%, 57.5% and 59.3% respectively. There were no significant differences of 24 months survival in both regiment with or without d4T, 61.8% vs 63.6%.

Symptom-triggered benzodiazepine therapy for alcohol withdrawal syndrome in the emergency department: a comparison with the standard fixed dose benzodiazepine regimen.

LENUS (Irish Health Repository)

Cassidy, Eugene M

2012-10-01

The aim of the study was to compare symptom-triggered and standard benzodiazepine regimens for the treatment of alcohol withdrawal syndrome in an emergency department clinical decision unit. The authors found that the symptom-triggered approach reduced cumulative benzodiazepine dose and length of stay.

A randomized comparative trial of two low-dose oral isotretinoin regimens in moderate to severe acne vulgaris

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Dhaked, Daulat Ram; Meena, Ram Singh; Maheshwari, Anshul; Agarwal, Uma Shankar; Purohit, Saroj

2016-01-01

Background: Oral isotretinoin is highly effective in all forms and grades of acne, even in lower dosages (acne vulgaris. Materials and Methods: A total of 240 patients with moderate to severe acne vulgaris were selected and randomized into two groups and treated with a fixed dose of 20 mg of isotretinoin (Group A - daily and Group B - alternate days) for 24 weeks and followed up for 12 weeks post therapy. Results: A total of 234 patients completed the study. At the end of therapy, decrease in the total acne loads up to 98.99% (Group A) and 97.69% (Group B) was achieved from the baseline (P acne, Group A performed significantly better than Group B until the end of 36 weeks. While in the moderate acne, significant difference in the response between both groups was observed only up to 12 weeks. No serious side effect was observed. Conclusion: Both isotretinoin regimens were well tolerated and found to be an effective treatment for moderate to severe acne vulgaris. However, in moderate acne 20 mg alternate day regimen may be preferred. A 20 mg daily regimen is a better choice for severe acne in terms of response. Limitation: Small sample size and short follow-up period. PMID:27730033

Comparison of two dose regimens of ibuprofen for the closure of patent ductus arteriosus in preterm newborns,

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Laura Vargas Dornelles

2016-06-01

Full Text Available Abstract Objective: To compare the efficacy of intravenous ibuprofen at high (20-10-10 mg/kg/dose and low doses (10-5-5 mg/kg/dose the closure of patent ductus arteriosus in preterm newborns. Methods: A cohort study with historical control of newborns that received high- and low-dose intravenous ibuprofen, from 2010 to 2013 in a neonatal intensive care unit, for closure of the patent ductus arteriosus, documented by echocardiography. Secondary outcomes included the number of ibuprofen cycles, incidence of bronchopulmonary dysplasia, necrotizing enterocolitis, changes in renal function, and death. Results: Seventy-seven patients received three doses of ibuprofen for the treatment of patent ductus arteriosus, with 33 receiving high-dose and 44 low-dose therapy. The ductus closed after the first cycle in 25 (56.8% low-dose patients and in 17 (51.5% high-dose patients (p > 0.99. Sixteen patients received a second cycle of ibuprofen, and the ductus closed in 50% after low-dose and in 60% after high-dose therapy (p > 0.99. Seven patients required surgery for ductus closure, 13.6% in the low-dose group and 3% in the high-dose group (p = 0.22. Thirty-nine patients developed bronchopulmonary dysplasia, 50% in the low-dose group and 51.5% in the high-dose group (p > 0.99. Twenty-two (50% low-dose patients died vs. 15 (45.5% high-dose patients (p = 0.86. Conclusions: There was no difference in closure of the ductus arteriosus or occurrence of adverse effects between the two dose regimens.

Comparison of anti-retroviral therapy treatment strategies in prevention of mother-to-child transmission in a teaching hospital in Ethiopia.

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Kumela, Kabaye; Amenu, Demisew; Chelkeba, Legese

2015-01-01

More than 90% of Human immunodeficiency virus (HIV) infection in children is acquired due to mother-to-child transmission, which is spreading during pregnancy, delivery or breastfeeding. To determine the effectiveness of highly active antiretroviral and short course antiretroviral regimens in prevention of mother-to-child transmission of HIV and associated factors Jimma University Specialized Hospital (JUSH). A hospital based retrospective cohort study was conducted on HIV infected pregnant mothers who gave birth and had follow up at anti-retroviral therapy (ART) clinic for at least 6 months during a time period paired with their infants. The primary and secondary outcomes were rate of infant infection by HIV at 6 weeks and 6 months respectively. The Chi-square was used for the comparison of categorical data multivariate logistic regression model was used to identify the determinants of early mother-to-child transmission of HIV at 6 weeks. Cox proportional hazard model was used to analyze factors that affect the 6 month HIV free survival of infants born to HIV infected mothers. A total of 180 mother infant pairs were considered for the final analysis, 90(50%) mothers received single dose nevirapine (sdNVP) designated as regimen-3, 67 (37.2%) mothers were on different types of ARV regimens commonly AZT + 3TC + NVP (regimen-1), while the rest 23 (12.8%) mothers were on short course dual regimen AZT + 3TC + sdNVP (regimen-2). Early mother-to-child transmission rate at 6 weeks for regimens 1, 2 and 3 were 5.9% (4/67), 8.6% (2/23), and 15.5% (14/90) respectively. The late cumulative mother-to-child transmission rate of HIV at 6 months regardless of regimen type was 15.5% (28/180). Postnatal transmission at 6 months was 28.5% (8/28) of infected children. Factors that were found to be associated with high risk of early mother-to-child transmission of HIV include duration of ARV regimen shorter than 2 months during pregnancy (OR=4.3, 95%CI =1.38-13.46), base line CD4 less

Pharmacokinetics of Pyrazinamide and Optimal Dosing Regimens for Drug-Sensitive and -Resistant Tuberculosis.

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Chirehwa, Maxwell T; McIlleron, Helen; Rustomjee, Roxana; Mthiyane, Thuli; Onyebujoh, Philip; Smith, Peter; Denti, Paolo

2017-08-01

Pyrazinamide is used in the treatment of tuberculosis (TB) because its sterilizing effect against tubercle bacilli allows the shortening of treatment. It is part of standard treatment for drug-susceptible and drug-resistant TB, and it is being considered as a companion drug in novel regimens. The aim of this analysis was to characterize factors contributing to the variability in exposure and to evaluate drug exposures using alternative doses, thus providing evidence to support revised dosing recommendations for drug-susceptible and multidrug-resistant tuberculosis (MDR-TB). Pyrazinamide pharmacokinetic (PK) data from 61 HIV/TB-coinfected patients in South Africa were used in the analysis. The patients were administered weight-adjusted doses of pyrazinamide, rifampin, isoniazid, and ethambutol in fixed-dose combination tablets according to WHO guidelines and underwent intensive PK sampling on days 1, 8, 15, and 29. The data were interpreted using nonlinear mixed-effects modeling. PK profiles were best described using a one-compartment model with first-order elimination. Allometric scaling was applied to disposition parameters using fat-free mass. Clearance increased by 14% from the 1st day to the 29th day of treatment. More than 50% of patients with weight less than 55 kg achieved lower pyrazinamide exposures at steady state than the targeted area under the concentration-time curve from 0 to 24 h of 363 mg · h/liter. Among patients with drug-susceptible TB, adding 400 mg to the dose for those weighing 30 to 54 kg improved exposure. Average pyrazinamide exposure in different weight bands among patients with MDR-TB could be matched by administering 1,500 mg, 1,750 mg, and 2,000 mg to patients in the 33- to 50-kg, 51- to 70-kg, and greater than 70-kg weight bands, respectively. Copyright © 2017 American Society for Microbiology.

Comparison of two dose regimens of ibuprofen for the closure of patent ductus arteriosus in preterm newborns.

Science.gov (United States)

Dornelles, Laura Vargas; Corso, Andréa Lúcia; Silveira, Rita de Cássia; Procianoy, Renato Soibelmann

2016-01-01

To compare the efficacy of intravenous ibuprofen at high (20-10-10mg/kg/dose) and low doses (10-5-5mg/kg/dose) the closure of patent ductus arteriosus in preterm newborns. A cohort study with historical control of newborns that received high- and low-dose intravenous ibuprofen, from 2010 to 2013 in a neonatal intensive care unit, for closure of the patent ductus arteriosus, documented by echocardiography. Secondary outcomes included the number of ibuprofen cycles, incidence of bronchopulmonary dysplasia, necrotizing enterocolitis, changes in renal function, and death. Seventy-seven patients received three doses of ibuprofen for the treatment of patent ductus arteriosus, with 33 receiving high-dose and 44 low-dose therapy. The ductus closed after the first cycle in 25 (56.8%) low-dose patients and in 17 (51.5%) high-dose patients (p>0.99). Sixteen patients received a second cycle of ibuprofen, and the ductus closed in 50% after low-dose and in 60% after high-dose therapy (p>0.99). Seven patients required surgery for ductus closure, 13.6% in the low-dose group and 3% in the high-dose group (p=0.22). Thirty-nine patients developed bronchopulmonary dysplasia, 50% in the low-dose group and 51.5% in the high-dose group (p>0.99). Twenty-two (50%) low-dose patients died vs. 15 (45.5%) high-dose patients (p=0.86). There was no difference in closure of the ductus arteriosus or occurrence of adverse effects between the two dose regimens. Copyright © 2016 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

Efficacy and Safety of a Colistin Loading Dose, High-Dose Maintenance Regimen in Critically Ill Patients With Multidrug-Resistant Gram-Negative Pneumonia.

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Elefritz, Jessica L; Bauer, Karri A; Jones, Christian; Mangino, Julie E; Porter, Kyle; Murphy, Claire V

2017-09-01

Emergence of multidrug-resistant (MDR) gram-negative (GN) pathogens and lack of novel antibiotics have increased the use of colistin, despite unknown optimal dosing. This study aimed to evaluate the safety and efficacy of a colistin loading dose, high-dose (LDHD) maintenance regimen in patients with MDR-GN pneumonia. A retrospective cohort analysis was performed comparing critically ill patients with MDR-GN pneumonia pre- and postimplementation of a colistin LDHD guideline with a primary outcome of clinical cure. Safety was assessed using incidence of acute kidney injury (AKI) based on RIFLE (risk, injury, failure, loss, end-stage renal disease) criteria. Seventy-two patients met the inclusion criteria (42 preimplementation and 30 postimplementation). Clinical cure was achieved in 23 (55%) patients in the preimplementation group and 20 (67%) patients in the postimplementation group ( P = .31). AKI occurred in 50% of the patients during the preimplementation period and 58% during the postimplementation period ( P = .59) with no difference in initiation rates of renal replacement therapy. The increased clinical cure rate after implementation of the colistin LDHD guideline did not reach statistical significance. The LDHD guideline, however, was not associated with an increased incidence of AKI, despite higher intravenous colistin doses. Opportunity exists to optimize colistin dosage while balancing toxicity, but larger studies are warranted.

Sex differences in apolipoprotein A1 and nevirapine-induced toxicity

OpenAIRE

Aline Marinho; Clara Dias; Alexandra Antunes; Umbelina Caixas; Teresa Branco; Matilde Marques; Emília Monteiro; Sofia Pereira

2014-01-01

Nevirapine (NVP) is associated with severe liver and skin toxicity through sulfotransferase (SULT) bioactivation of the phase I metabolite 12-hydroxy-NVP [1–3]. The female sex, a well-known risk factor for NVP-induced toxicity, is associated with higher SULT expression [4] and lower plasma levels of 12-hydroxy-NVP [3]. Interestingly, apolipoprotein A1 (ApoA1) increases SULT2B1 activity and ApoA1 synthesis is increased by NVP [5, 6]. Herein, we explore the effect of ApoA1 levels on NVP metabol...

Leveraging protein binding and the EPR effect in legacy chemotherapy regimens

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Shireesh Apte

2016-12-01

Full Text Available Legacy chemotherapy regimens have the potential to be significantly more effective and less toxic if the dosage is titrated so that the mole ratio of drugs to circulating albumin is less than or equal to 1 and the order of administration of the drugs within each course of the regimen follows the sequence most hydrophobic (usually the least dose to least hydrophobic (usually the largest dose

A short 2 week dose titration regimen reduces the severity of flu-like symptoms with initial interferon gamma-1b treatment.

Science.gov (United States)

Devane, John G; Martin, Mary L; Matson, Mark A

2014-06-01

Flu-like symptoms (FLS) are commonly experienced by patients receiving interferon gamma-1b which may cause discontinuation or disruption of dosing during initial therapy or on re-initiation following a break in therapy. In contrast to Type I interferons, the impact of dose-titration on FLS has not been reported and is not a practice described or included in the approved prescribing information for interferon gamma-1b.The objective of this study was to assess the effect of a 2 week titration regimen on the severity of FLS during the initial 3 weeks of therapy with three times weekly subcutaneous injections of interferon gamma-1b. Healthy men and women were randomized into a double-blind, two-period, crossover study. Each study period was 3 weeks in duration and there was a minimum 15 day washout between treatment periods. Two treatment regimens were compared: No Titration dosing (full 50 mcg/m(2) subcutaneously [s.c.] three times weekly for 3 weeks) and Titration (15 mcg/m(2) s.c. three times weekly during week 1, 30 mcg/m(2) s.c. three times weekly during week 2 followed by the full dose of 50 mcg/m(2) s.c. three times weekly during week 3). Subjects remained in the clinic for at least 12 hours following each injection. FLS was based on a composite score for fever, chills, tiredness and muscle aches assessed at baseline and 4, 8 and 12 hours following each injection. Acetaminophen was allowed at the discretion of the PI. The primary endpoint was the change from baseline in FLS severity at 8 hours averaged over the 3 weeks of treatment. Additional endpoints included FLS at 4 and 12 hours, individual flu-like symptoms, rates of discontinuation, incidence of FLS and acetaminophen use. NCT 01929382. Of the 40 subjects randomized, there were 15 (37.5%) discontinuations. Titration resulted in a significant reduction in FLS severity at 8 hours (p = 0.023) averaged over the 3 week treatment period. The difference in 3 week FLS severity reflects differences

[Combination of busulfan with increased-dose of fludarabine as conditioning regimen for MDS and MDS-AML patients with allo-HSCT].

Science.gov (United States)

Yuan, Jing; Ren, Hanyun; Qiu, Zhixiang; Li, Yuan; Wang, Mangju; Liu, Wei; Xu, Weilin; Sun, Yuhua; Wang, Lihong; Liang, Zeyin; Dong, Yujun; Ou, Jinping; Wang, Wensheng; Yin, Yue; Cen, Xinan; Wang, Qian

2015-06-01

To investigate the safety and efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndrome (MDS) and secondary acute myelogenous leukemia (MDS-AML) using conditioning regimen with busulfan (Bu) and increased-dose of fludarabine (ID-Flu). A total of 49 patients with MDS or MDS-AML were treated by allo-HSCT, the clinical data was analyzed retrospectively. All patients achieved hematopoietic reconstitution. Neutrophil engraftment was at 10 - 22 days (median 13 days), and platelet engraftment was at 8 - 66 days (median 16 days). The cumulative incidences of Ⅱ-Ⅳ degree acute graft-versus-host disease (GVHD), hemorrhagic cystitis (HC), and hepatic venous occlusive disease (VOD) were 28.6%, 14.3% and 2.0%, respectively. The transplant-related mortality (TRM) was only 4.1% at 100d and 8.2% at 1-92 months of followed-up (median 14 months) period. Overall survival (OS) and disease free survival (DFS) was 75.5%, 73.5%, respectively. Kaplan-Meier curve showed that 3-year OS and 3-year DFS was (71.1 ± 7.8)%, (66.7 ± 8.3)%, respectively, with a relapse incidence (RI) 16.3%. OS for MDS and MDS-AML was 81.5% and 68.2%, and RI in two settings was 3.7%, 31.8%, respectively. OS for MDS-AML at complete remission (CR) and non-CR subgroup was 83.3% and 50.0%, respectively, while cumulative RR was 16.7% and 50.0%, respectively. OS and RI except for non-CR subgroup were 82.1% and 7.7%. Univariate analysis showed that pre-HSCT disease status had correlation with OS (P=0.031), but age, decitabine in conditioning regimen, stem cell source, HLA matching, patient-donor gender, dose of mononuclear cells and GVHD had no correlation with OS. Bu/ID-Flu conditioning regimen for MDS and MDS-AML has high efficiency, fewer complications, lower toxicity and TRM. The OS and DFS were higher and RI was lower except for refractory MDS-AML patients. The regimen is valuable for clinical application.

Etravirine and Rilpivirine Drug Resistance Among HIV-1 Subtype C Infected Children Failing Non-Nucleoside Reverse Transcriptase Inhibitor-Based Regimens in South India.

Science.gov (United States)

Saravanan, Shanmugam; Kausalya, Bagavathi; Gomathi, Selvamurthi; Sivamalar, Sathasivam; Pachamuthu, Balakrishnan; Selvamuthu, Poongulali; Pradeep, Amrose; Sunil, Solomon; Mothi, Sarvode N; Smith, Davey M; Kantor, Rami

2017-06-01

We have analyzed reverse transcriptase (RT) region of HIV-1 pol gene from 97 HIV-infected children who were identified as failing first-line therapy that included first-generation non-nucleoside RT inhibitors (Nevirapine and Efavirenz) for at least 6 months. We found that 54% and 65% of the children had genotypically predicted resistance to second-generation non-nucleoside RT inhibitors drugs Etravirine (ETR) and Rilpivirine, respectively. These cross-resistance mutations may compromise future NNRTI-based regimens, especially in resource-limited settings. To complement these investigations, we also analyzed the sequences in Stanford database, Monogram weighted score, and DUET weighted score algorithms for ETR susceptibility and found almost perfect agreement between the three algorithms in predicting ETR susceptibility from genotypic data.

Results of a Prospective Study of High-Dose or Conventional Anthracycline-Cyclophosphamide Regimen Plus Radiotherapy for Localized Adult Non-Hodgkin’s Primary Bone Lymphoma

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A. Schmidt-Tanguy

2014-01-01

Full Text Available Background. Primary bone lymphoma (PBL is a rare entity that has only been reviewed in one prospective and small retrospective studies, from which it is difficult to establish treatment guidelines. We prospectively evaluated high-dose or conventional anthracycline-cyclophosphamide dose and radiotherapy for PBL. Patients and Methods. The GOELAMS prospective multicenter study (1986–1998 enrolled adults with localized high-grade PBL according to age and performance status (PS. Patients <60 years received a high-dose CHOP regimen (VCAP and those ≥60 years a conventional anthracycline-cyclophosphamide regimen (VCEP-bleomycin; all received intrathecal chemotherapy and local radiotherapy. Results. Among the 26 patients included (VCAP: 19; VCEP-bleomycin: 7, 39% had poor PS ≥2. With a median follow-up of 8 years, overall survival, event-free survival, and relapse-free survival were 64%, 62%, and 65%, respectively, with no significant difference between treatment groups. Poor PS was significantly associated with shorter OS and EFS. Conclusions. Our results confirm the efficacy of our age-based therapeutic strategy. High-doses anthracycline-cyclophosphamide did not improve the outcome. VCEP-bleomycin is effective and well tolerated for old patients. The intensification must be considered for patients with PS ≥2, a poor prognostic factor.

Sex differences in hepatic and intestinal contributions to nevirapine biotransformation in rats.

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Pinheiro, P F; Marinho, A T; Antunes, A M M; Marques, M M; Pereira, S A; Miranda, J P

2015-05-25

The understanding of the intestine contribution to drug biotransformation improved significantly in recent years. However, the sources of inter-individual variability in intestinal drug biotransformation, namely sex-differences, are still elusive. Nevirapine (NVP) is an orally taken anti-HIV drug associated with severe idiosyncratic reactions elicited by toxic metabolites, with women at increased risk. As such, NVP is a good model to assess sex-dimorphic metabolism. The aim of this study was to perform a comparative profiling of NVP biotransformation in rat intestine and liver and evaluate whether or not it is organ- and sex-dependent. Therefore, nevirapine-containing solutions were perfused through the intestine, in a specially designed chamber, or incubated with liver slices, from male and female Wistar rats. The levels of NVP and its Phase I metabolites were quantified by HPLC-UV. Liver incubation experiments yielded the metabolites 2-, 3-, 8-, and 12-OH-NVP, being 12-OH-NVP and 2-OH-NVP the major metabolites in males and females, respectively. Inter-sex differences in the metabolic profile were also detected in the intestine perfusion experiments. Herein, the metabolites 3- and 12-OH-NVP were only found in male rats, whereas 2-OH-NVP levels were higher in females, both in extraluminal (pbiotransformation was observed, strengthening the relevance of the intestinal contribution in the biotransformation of orally taken-drugs. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Fracture during intravenous bisphosphonate treatment in a child with osteogenesis imperfecta: an argument for a more frequent, low-dose treatment regimen.

Science.gov (United States)

Biggin, Andrew; Briody, Julie N; Ormshaw, Elizabeth; Wong, Karen K Y; Bennetts, Bruce H; Munns, Craig F

2014-01-01

Intravenous bisphosphonate therapy is the mainstay of medical treatment in osteogenesis imperfecta (OI) and has been shown to increase bone mass, decrease bone pain, improve mobility, and reduce the incidence of fractures. Sclerotic metaphyseal lines parallel to the growth plate are seen on long bone radiographs following cyclical intravenous therapy. These areas create stress risers within the bone that may act as foci for subsequent fractures as exemplified in this clinical case. An 8-year-old girl with OI sustained a distal radial fracture following 3 years of treatment with 6-monthly intravenous zoledronate. Her diagnosis, response to treatment, and subsequent fracture at a sclerotic metaphyseal line is described. Peripheral quantitative computer tomography was used to characterise the presence of multiple stress risers at the distal forearm. Trabecular bone mineral density fluctuated from 34 to 126% compared to neighbouring 2-mm regions. There remain many unanswered questions about optimal bisphosphonate treatment regimens in children with OI. The formation of stress risers following intravenous bisphosphonate treatment raises the hypothesis that a more frequent and low-dose bisphosphonate regimen would provide more uniform dosing of bone in the growing child and reduce the likelihood of fractures compared to current treatment practices.

Dose escalation by image-guided intensity-modulated radiotherapy leads to an increase in pain relief for spinal metastases: a comparison study with a regimen of 30 Gy in 10 fractions.

Science.gov (United States)

He, Jinlan; Xiao, Jianghong; Peng, Xingchen; Duan, Baofeng; Li, Yan; Ai, Ping; Yao, Min; Chen, Nianyong

2017-12-22

Under the existing condition that the optimum radiotherapy regimen for spinal metastases is controversial, this study investigates the benefits of dose escalation by image-guided intensity-modulated radiotherapy (IG-IMRT) with 60-66 Gy in 20-30 fractions for spinal metastases. In the dose-escalation group, each D50 of planning gross tumor volume (PGTV) was above 60 Gy and each Dmax of spinal cord planning organ at risk volume (PRV) was below 48 Gy. The median biological effective dose (BED) of Dmax of spinal cord was lower in the dose-escalation group compared with that in the 30-Gy group (69.70 Gy vs. 83.16 Gy, p pain responses were better in the dose-escalation group than those in the 30-Gy group ( p = 0.005 and p = 0.024), and the complete pain relief rates were respectively 73.69% and 34.29% ( p = 0.006), 73.69% and 41.38% ( p = 0.028) in two compared groups. In the dose-escalation group, there is a trend of a longer duration of pain relief, a longer overall survival and a lower incidence of acute radiation toxicities. No late radiation toxicities were observed in both groups. Dosimetric parameters and clinical outcomes, including pain response, duration of pain relief, radiation toxicities and overall survival, were compared among twenty-five metastatic spinal lesions irradiated with the dose-escalation regimen and among forty-four lesions treated with the 30-Gy regimen. Conventionally-fractionated IG-IMRT for spinal metastases could escalate dose to the vertebral lesions while sparing the spinal cord, achieving a better pain relief without increasing radiation complications.

Comparison of current recommended regimens of atropinization in organophosphate poisoning.

Science.gov (United States)

Connors, Nicholas J; Harnett, Zachary H; Hoffman, Robert S

2014-06-01

Atropine is the mainstay of therapy in organophosphate (OP) toxicity, though research and consensus on dosing is lacking. In 2004, as reported by Eddleston et al. (J Toxicol Clin Toxicol 42(6):865-75, 2004), they noted variation in recommended regimens. We assessed revisions of original references, additional citations, and electronic sources to determine the current variability in atropine dosing recommendations. Updated editions of references from Eddleston et al.'s work, texts of Internal and Emergency Medicine, and electronic resources were reviewed for atropine dosing recommendations. For comparison, recommendations were assessed using the same mean dose (23.4 mg) and the highest dose (75 mg) of atropine as used in the original paper. Recommendations were also compared with the dosing regimen from the World Health Organization (WHO). Thirteen of the original recommendations were updated and 15 additional references were added giving a convenience sample of 28. Sufficient information to calculate time to targeted dose was provided by 24 of these samples. Compared to 2004, current recommendations have greatly increased the speed of atropinization with 13/24 able to reach the mean and high atropine dose within 30 min compared to 1/36 in 2004. In 2004, there were 13 regimens where the maximum time to reach 75 mg was over 18 h, whereas now, there are 2. While only one recommendation called for doubling the dose for faster escalation in 2004, 15 of the 24 current works include dose doubling. In 2004, Eddleston et al. called for an evidence-based guideline for the treatment of OP poisoning that could be disseminated worldwide. Many current recommendations can adequately treat patients within 1 h. While the WHO recommendations remain slow to treat patients with OP poisoning, other authorities are close to a consensus on rapid atropinization.

Comparison of Thromboemboli Prophylactic Effect of Aspirin and Low Dose Warfarin in Standard Risk Multiple Myeloma Patients that Treated with Regimens Containing Thalidomide

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Seyed Amir Dadkhahi

2017-05-01

Full Text Available Abstract Background: Most of the current regimens in the treatment of multiple myeloma include thalidomide. Thalidomide is a modulator of the immune system and according to several studies, its main complication is thromboembolism. The aim of this study is to compare the thromboemboli prophylactic effect of aspirin and low dose warfarin in standard risk multiple myeloma patients that treated with regimens containing thalidomide. Materials and Methods: In this double- blind clinical trial study, sixty-six patients with multiple myeloma under treatment with thalidomide-containing regimens with standard risk for thromboembolism who were admitted to Khansari hospital, entered the study according to inclusion and exclusion criteria. The incidence of thromboembolism in these patients was evaluated. Results: Five patients in the warfarin group and 2 patients in the aspirin group had thromboemboli. Chi square analyses showed no significant difference between groups (p=0.635. Conclusion: The results showed that both drugs are effective in preventing thromboembolism and can be used as a prophylactic treatment.

Treatment outcomes of fixed-dose combination versus separate tablet regimens in pulmonary tuberculosis patients with or without diabetes in Qatar.

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Al-Shaer, Mohammad H; Mansour, Hanine; Elewa, Hazem; Salameh, Pascale; Iqbal, Fatima

2017-02-02

Tuberculosis is considered the second most common cause of death due to infectious agent. The currently preferred regimen for treatment of pulmonary tuberculosis (PTB) is isoniazid, rifampin, pyrazinamide, and ethambutol, which has been used either as separate tablets (ST) or as fixed-dose combination (FDC). To date, no studies have compared both regimens in Qatar. We aim to evaluate the safety and effectiveness of FDC and ST regimen for treating PTB, in addition to comparing safety and efficacy of FDC and ST regimens in patients with diabetes treated for TB. A retrospective observational study was conducted in two general hospitals in Qatar. Patients diagnosed with PTB received anti-tuberculosis medications (either as FDC or ST) administered by the nurse. Sputum smears were tested weekly. We assessed the time to negative sputum smear and incidence of adverse events among FDC and ST groups. The study included 148 patients. FDC was used in 90 patients (61%). Effectiveness was not different between FDC and ST regimens as shown by mean time to sputum conversion (29.9 ± 18.3 vs. 35.6 ± 23 days, p = 0.12). Similarly, there was no difference in the incidence of adverse events, except for visual one that was higher in ST group. Among the 33 diabetic patients, 19 received the FDC and had faster sputum conversion compared to those who received ST (31 ± 12 vs. 49.4 ± 30.9 days, p = 0.05). Overall, diabetic patients needed longer time for sputum conversion and had more hepatotoxic and gastric adverse events compared to non-diabetics. ST group had higher visual side effects compared to FDC. FDC may be more effective in diabetic patients; however, further studies are required to confirm such finding.

Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria - a proposed model-derived age-based regimen for sub-Saharan Africa.

Science.gov (United States)

Taylor, W Robert; Naw, Htee Khu; Maitland, Kathryn; Williams, Thomas N; Kapulu, Melissa; D'Alessandro, Umberto; Berkley, James A; Bejon, Philip; Okebe, Joseph; Achan, Jane; Amambua, Alfred Ngwa; Affara, Muna; Nwakanma, Davis; van Geertruyden, Jean-Pierre; Mavoko, Muhindo; Lutumba, Pascal; Matangila, Junior; Brasseur, Philipe; Piola, Patrice; Randremanana, Rindra; Lasry, Estrella; Fanello, Caterina; Onyamboko, Marie; Schramm, Birgit; Yah, Zolia; Jones, Joel; Fairhurst, Rick M; Diakite, Mahamadou; Malenga, Grace; Molyneux, Malcolm; Rwagacondo, Claude; Obonyo, Charles; Gadisa, Endalamaw; Aseffa, Abraham; Loolpapit, Mores; Henry, Marie-Claire; Dorsey, Grant; John, Chandy; Sirima, Sodiomon B; Barnes, Karen I; Kremsner, Peter; Day, Nicholas P; White, Nicholas J; Mukaka, Mavuto

2018-01-18

In 2012, the World Health Organization recommended blocking the transmission of Plasmodium falciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), without testing for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicated falciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa. Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia, and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectively defined therapeutic-dose ranges of 0.15-0.4 mg PQ base/kg for children aged 1-5 years and 0.15-0.5 mg PQ base/kg for individuals aged ≥6 years (therapeutic indices 2.7 and 3.3, respectively). We chose 1.25 mg PQ base for infants aged 6-11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA. We modelled an anthropometric database of 661,979 African individuals aged ≥6 months (549,127 healthy individuals, 28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box-Cox transformation power exponential and tested PQ doses of 1-15 mg base, selecting dosing groups based on calculated mg/kg PQ doses. From the Box-Cox transformation power exponential model, five age categories were selected: (i) 6-11 months (n = 39,886, 6.03%), (ii) 1-5 years (n = 261,036, 45.46%), (iii) 6-9 years (n = 20,770, 3.14%), (iv) 10-14 years (n = 12,155, 1.84%) and (v) ≥15 years (n = 328,132, 49.57%) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and 99th centiles) mg/kg PQ base of: (i) 0.16 (0.12-0.25), (ii) 0.21 (0.13-0.37), (iii) 0.25 (0.16-0.38), (iv) 0.26 (0.15-0.38) and (v) 0.27 (0.17-0.40). The proportions of individuals predicted to receive optimal therapeutic PQ doses were: 73.2 (29,180/39,886), 93.7 (244

Suboptimal etravirine activity is common during failure of nevirapine-based combination antiretroviral therapy in a cohort infected with non-B subtype HIV-1.

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Taiwo, Babafemi; Chaplin, Beth; Penugonda, Sudhir; Meloni, Seema; Akanmu, Sulaimon; Gashau, Wadzani; Idoko, John; Adewole, Isaac; Murphy, Robert; Kanki, Phyllis

2010-04-01

The primary objective of this study was to estimate etravirine activity in a cohort of patients infected with non-B subtype HIV-1 and failing nevirapine-based therapy. Genotypic resistance testing was performed if viral load was >OR= 1,000 copies/ml after receiving at least six months of therapy. Suboptimal response to etravirine was predicted by a score >OR= 2.5 on the Tibotec weighting schema, >OR= 4 in the Monogram schema, or classification as high to low-level resistant by a modification of the Stanford HIVdb algorithm (Version 5.1.2). Bivariate and multivariate analyses were conducted to determine the risk factors for suboptimal etravirine activity. The patients (n=91) were receiving nevirapine and lamivudine plus stavudine (57.1%) or zidovudine (42.9%). Median duration of nevirapine exposure was 53 weeks (IQR 46-101 weeks). The most common etravirine resistance associated mutations were Y181C (42.9%), G190A (25.3%), H221Y (19.8%), A98G (18.7%), K101E (16.5%), and V90I (12.1%). Suboptimal etravirine activity was predicted in 47.3 to 56.0%. There were disparities in mutations listed in Tibotec versus Monogram Schemas. Predicted suboptimal activity was not associated with nucleoside reverse transcriptase inhibitor (NRTI) used, gender, pretreatment or current CD4 cell count or viral load, subtype or NRTI mutations. Etravirine has compromised activity in approximately half of the patients failing nevirapine-based first-line treatment in this cohort, which supports guidelines that caution against using it with NRTIs alone in such patients.

Three different up-titration regimens of ponesimod, an S1P1 receptor modulator, in healthy subjects.

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Scherz, Michael W; Brossard, Patrick; D'Ambrosio, Daniele; Ipek, Murat; Dingemanse, Jasper

2015-06-01

Ponesimod is a selective S1P1 receptor modulator, and induces dose-dependent reduction of circulating lymphocytes upon oral dosing. Previous studies showed that single doses up to 75 mg or multiple doses up to 40 mg once daily are well tolerated, and heart rate (HR) reduction and atrio-ventricular conduction delays upon treatment initiation are reduced by gradual up-titration to the maintenance dose. This single-center, open-label, randomized, multiple-dose, 3-treatment, 3-way crossover study compared the tolerability, safety, pharmacokinetics, cardiodynamics, and effects on lymphocytes of 3 different up-titration regimens of ponesimod in healthy male and female subjects. Up-titration regimens comprised escalating periods of b.i.d. dosing (2.5 or 5 mg) and q.d. dosing (10 or 20 mg or both). After the third up-titration period a variable-duration washout period of 1-3 days was followed by re-challenge with a single 20-mg dose of ponesimod. Adverse events were transient and mild to moderate in intensity, not different between regimens. HR decrease after the first dose was greater than after all subsequent doses, including up-titration doses. Little or no HR change was observed with morning doses of b.i.d. regimens, suggesting that 2.5 and 5 mg b.i.d. are sufficient to sustain cardiac desensitization for the 12-hours dosing interval. © 2015, The American College of Clinical Pharmacology.

Comparison of two dose regimens of growth hormone (GH) with different target IGF-1 levels on glucose metabolism, lipid profile, cardiovascular function and anthropometric parameters in gh-deficient adults.

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Cenci, Maria Claudia Peixoto; Soares, Débora Vieira; Spina, Luciana Diniz Carneiro; Brasil, Rosane Resende de Lima Oliveira; Lobo, Priscila Marise; Michmacher, Eduardo; Vaisman, Mario; Boguszewski, Cesar Luiz; Conceição, Flávia Lúcia

2012-01-01

To compare the effects of two regimens of GH therapy with different target IGF-1 levels on anthropometric parameters, glucose metabolism, lipid profile and cardiac function in adults with GH deficiency (GHD). Retrospective analysis of 14 GHD adults from Clementino Fraga Filho University Hospital, Rio de Janeiro, Brazil, who were treated with a GH regimen aimed at maintaining serum IGF-1 levels between the median and upper reference limit (high dose group - HDGH) and 18 GHD adults from Federal University Hospital, Curitiba, Brazil, who received a fixed GH dose of 0.2mg/day in the first year of treatment, followed by titration to maintain serum IGF-1 levels between the median and lower reference limit (low dose group - LDGH). All patients were followed for 2 years with analysis of anthropometric parameters, serum levels of IGF-1, glucose, insulin, HOMA-IR, lipid profile, and transthoracic echocardiography. Changes on weight, BMI and waist circumference were similar between the two groups. Insulin levels increased and HOMA-IR worsened in the LDGH group at 1year and improved thereafter. Total cholesterol and triglycerides did not change with therapy. LDL cholesterol reduced in both groups, while HDL-cholesterol significantly increased only in the HDGH group (p=0.007 vs LDGH). No significant variations on echocardiographic parameters were observed. The HDGH and LDGH regimens resulted in similar changes on anthropometric, echocardiographic, glucose and lipid parameters in GHD adults, except for increase in HDL cholesterol that was only observed in the HDGH regimen. Copyright © 2012 Elsevier Ltd. All rights reserved.

Minor drug-resistant HIV type-1 variants in breast milk and plasma of HIV type-1-infected Ugandan women after nevirapine single-dose prophylaxis.

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Pilger, Daniel; Hauser, Andrea; Kuecherer, Claudia; Mugenyi, Kizito; Kabasinguzi, Rose; Somogyi, Sybille; Harms, Gundel; Kunz, Andrea

2011-01-01

Nevirapine single-dose (NVP-SD) reduces mother-to-child transmission of HIV type-1 (HIV-1), but frequently induces resistance mutations in the HIV-1 genome. Little is known about drug-resistant HIV-1 variants in the breast milk of women who have taken NVP-SD. Blood and breast milk samples of 39 HIV-1-infected Ugandan women were taken 6-12 weeks after NVP-SD intake. Samples were analysed by population sequencing and allele-specific real-time PCR (AS-PCR) with detection limits for NVP-resistant HIV-1 variants (K103N and Y181C) of D n = 5, G n = 2 and C n = 1). A total of 7 (37%) and 10 (53%) women carried NVP-resistant virus in breast milk and plasma, respectively. Overall, 71% (5/7) women with NVP-resistant HIV-1 in breast milk displayed >1 drug-resistant variant. Resistance in breast milk was higher at week 6 (6/13 samples [46%]) compared with week 12 (1/6 samples [17%]). In total, 10 drug-resistant populations harbouring the K103N and/or Y181C mutation were detected in the 19 breast milk samples; 7 (70%) were caused by resistant minorities (< 5% of the total HIV-1 population). In the four women with drug-resistant virus in both plasma and breast milk, the mutation patterns differed between the two compartments. Minor populations of drug-resistant HIV-1 were frequently found in breast milk of Ugandan women after exposure to NVP-SD. Further studies need to explore the role of minor drug-resistant variants in the postnatal transmission of (resistant) HIV-1.

N348I in the connection domain of HIV-1 reverse transcriptase confers zidovudine and nevirapine resistance.

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Soo-Huey Yap

2007-12-01

Full Text Available The catalytically active 66-kDa subunit of the human immunodeficiency virus type 1 (HIV-1 reverse transcriptase (RT consists of DNA polymerase, connection, and ribonuclease H (RNase H domains. Almost all known RT inhibitor resistance mutations identified to date map to the polymerase domain of the enzyme. However, the connection and RNase H domains are not routinely analysed in clinical samples and none of the genotyping assays available for patient management sequence the entire RT coding region. The British Columbia Centre for Excellence in HIV/AIDS (the Centre genotypes clinical isolates up to codon 400 in RT, and our retrospective statistical analyses of the Centre's database have identified an N348I mutation in the RT connection domain in treatment-experienced individuals. The objective of this multidisciplinary study was to establish the in vivo relevance of this mutation and its role in drug resistance.The prevalence of N348I in clinical isolates, the time taken for it to emerge under selective drug pressure, and its association with changes in viral load, specific drug treatment, and known drug resistance mutations was analysed from genotypes, viral loads, and treatment histories from the Centre's database. N348I increased in prevalence from below 1% in 368 treatment-naïve individuals to 12.1% in 1,009 treatment-experienced patients (p = 7.7 x 10(-12. N348I appeared early in therapy and was highly associated with thymidine analogue mutations (TAMs M41L and T215Y/F (p < 0.001, the lamivudine resistance mutations M184V/I (p < 0.001, and non-nucleoside RTI (NNRTI resistance mutations K103N and Y181C/I (p < 0.001. The association with TAMs and NNRTI resistance mutations was consistent with the selection of N348I in patients treated with regimens that included both zidovudine and nevirapine (odds ratio 2.62, 95% confidence interval 1.43-4.81. The appearance of N348I was associated with a significant increase in viral load (p < 0.001, which

Resistance profiles and adherence at primary virological failure in three different highly active antiretroviral therapy regimens: analysis of failure rates in a randomized study

DEFF Research Database (Denmark)

Røge, B T; Barfod, T S; Kirk, O

2004-01-01

OBJECTIVES: To investigate the interplay between resistance and adherence in the virological failure of three fundamentally different highly active antiretroviral therapy (HAART) regimens. METHODS: We retrospectively identified 56 verified primary virological failures (viral load >400 HIV-1 RNA...... copies/mL) among 293 patients randomized to two nucleoside reverse transcriptase inhibitors (NRTIs)+ritonavir+saquinavir (RS-arm) (n=115), two NRTIs+nevirapine+nelfinavir (NN-arm) (n=118), or abacavir+stavudine+didanosine (ASD-arm) (n=60) followed up for a median of 90 weeks. Data on adherence were...... collected from patient files, and genotyping was performed on plasma samples collected at time of failure. RESULTS: Treatment interruption or poor adherence was mainly caused by side effects and accounted for 74% of failures, and was associated with absence of resistance mutations. In the 30 failing...

Reversal of atherogenic lipoprotein profile in HIV-1 infected patients with lipodystrophy after replacing protease inhibitors by nevirapine

NARCIS (Netherlands)

Negredo, Eugenia; Ribalta, Josep; Paredes, Roger; Ferré, Raimón; Sirera, Guillem; Ruiz, Lidia; Salazar, Juliana; Reiss, Peter; Masana, Lluís; Clotet, Bonaventura

2002-01-01

Background: The widespread use of protease inhibitors (PI) has been associated with abnormalities in the lipid profile of HIV-1-infected patients. Treatment simplification approaches in which PI are replaced by nevirapine (NVP) have been shown to improve PI-related toxicity. Objective: To assess the

The role of a low-dose ketamine-midazolam regimen in the management of severe painful crisis in patients with sickle cell disease.

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Tawfic, Qutaiba A; Faris, Ali S; Kausalya, Rajini

2014-02-01

Acute pain is one of the main causes of hospital admission in sickle cell disease, with variable intensity and unpredictable onset and duration. We studied the role of a low-dose intravenous (IV) ketamine-midazolam combination in the management of severe painful sickle cell crisis. A retrospective analysis was performed with data from nine adult patients who were admitted to the intensive care unit with severe painful sickle cell crises not responding to high doses of IV morphine and other adjuvant analgesics. A ketamine-midazolam regimen was added to the ongoing opioids as an initial bolus of ketamine 0.25mg/kg, followed by infusion of 0.2-0.25mg/kg/h. A midazolam bolus of 1mg followed by infusion of 0.5-1mg/h was added to reduce ketamine emergence reactions. Reduction in morphine daily requirements and improvement in pain scores were the determinants of ketamine-midazolam effect. The t-tests were used for statistical analysis. Nine patients were assessed, with mean age of 27±11 years. Morphine requirement was significantly lower after adding the IV ketamine-midazolam regimen. The mean±SD IV morphine requirement (milligram/day) in the pre-ketamine day (D0) was 145.6±16.5, and it was 112±12.2 on Day 1 (D1) of ketamine treatment (P=0.007). The Numeric Rating Scale scores on D0 ranged from eight to ten (mean 9.1), but improved to range from five to seven (mean 5.7) on D1. There was a significant improvement in pain scores after adding ketamine-midazolam regimen (P=0.01). Low-dose ketamine-midazolam IV infusion might be effective in reducing pain and opioid requirements in patients with sickle cell disease with severe painful crisis. Further controlled studies are required to prove this effect. Copyright © 2014 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Delayed rhabdomyolysis with paclitaxel, ifosfamide, carboplatin, and etoposide regimen: a case report.

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Sokolova, Alexandra; Chan, Onyee; Ullah, Waqas; Hamdani, Auon Abbas; Anwer, Faiz

2017-04-11

High-dose chemotherapy with autologous stem cell rescue is commonly used for the treatment of relapsed germ cell tumors. We report the first case of delayed rhabdomyolysis with paclitaxel, ifosfamide, carboplatin, and etoposide regimen. We report a case of a 21-year-old African-American man diagnosed with relapsed non-seminomatous germ cell tumor who received high-dose chemotherapy with carboplatin and etoposide following TIGER trial arm B off-protocol. His course was complicated by muscle pain and rhabdomyolysis after cycle 4 on day +12 after infusion of autologous stem cells. To the best of our knowledge, this complication has not been reported with this regimen. A differential diagnosis of sepsis and neutropenic fever along with side effects of high-dose chemotherapy were considered, but based on the timing of events, it was concluded that the etiology of rhabdomyolysis is high-dose chemotherapy. Rhabdomyolysis was successfully treated with hydration and did not recur during subsequent cycle 5. Delayed rhabdomyolysis after high-dose chemotherapy with paclitaxel, ifosfamide, carboplatin, and etoposide regimen has not been previously reported and needs to be considered for preventive strategy and prompt diagnosis and treatment to avoid renal complications. Physicians should have a low threshold to check creatine kinase enzymes in patients with unexplained muscle pain or renal insufficiency after high-dose chemotherapy.

Radiobiological effect of different irradiation fractionated regimens in human brain glioma

International Nuclear Information System (INIS)

Gai Xue; Yang Weizhi; Gao Li; Jiang Heng; Wang Mianrong; Shi Huizhen

2010-01-01

Objective: To evaluate the radiobiological effect of different irradiation fractionated regimens in human glioma cells (BT 325 cell line). Methods: The xenografts in Balb/c-nude mice were irradiated with different single and fractionated regimens. The single fraction dose was 10, 20, 30, 40 and 60 Gy, respectively. The fractionated regimens were 2 Gy x 5 fractions ( irradiated every day), and 3 Gy x 3 fractions (irradiated every other day), 3 Gy x 5 fractions (irradiated every day) and 4 Gy x 3 fractions (irradiated every other day), with total doses of 125 Gy, 114 Gy, 126 Gy and 112 Gy, respectively. The growth curve was used to evaluate the tumor doubling time. clonogenic assays was performed to draw the cell survival curve and analyze the radiobiological parameters with doses of 1, 2, 4, 6, 8 and 10 Gy. T 1/2 was measured by comet assay. Results: Tumor regression were not observed by single fraction irradiation, 2 Gy x 5 fractions and 3 Gy x 3 fractions irradiation regimens. The tumor regress was more significant with the increas of fraction dose. The 4 Gy x 3 fractions inhibited tumor more though not curing tumor. The cell doubling time of the BT 325 cell was 30. 16 h and the tumor doubling time of the xenograft was 43 days.When fitted with L-Q model, α was 0. 36 Gy -1 and β was 0. 057 Gy -2 . When fitted with the single-hit multi target model, D 0 was 1. 394 Gy, Dq was 2. 127 Gy and SF 2 was 0.714, respectively. The T 1/2 was 9.999 min. Conclusions: Glioma is a radioresistant tumor. Increase of the fraction dose improves recent effect.Further study is needed to control the tumor stem cells. (authors)

Immunogenicity and safety of purified chick-embryo cell rabies vaccine under Zagreb 2-1-1 or 5-dose Essen regimen in Chinese children 6 to 17 years old and adults over 50 years: a randomized open-label study.

Science.gov (United States)

Li, RongCheng; Li, YanPing; Wen, ShuQing; Wen, HuiChun; Nong, Yi; Mo, Zhaojun; Xie, Fang; Pellegrini, Michele

2015-01-01

The aim of this Phase IIIb, open-label, randomized study was to demonstrate the non-inferiority of immune responses and to assess the safety of a purified chick-embryo cell rabies vaccine (PCECV) in healthy Chinese children (6 to 17 years) and older adults (≥51 years) following 2 alternative intramuscular (IM) simulated post-exposure prophylaxis (PEP) regimens: 4-dose Zagreb or 5-dose Essen regimen. Serum samples were collected prior to vaccination on Days 1 and 15 and on day 43 to assess immune response by rabies virus neutralizing antibody (RVNA) concentrations. Solicited adverse events (AEs) were recorded for up to 7 days following each vaccine dose, and unsolicited AEs throughout the entire study period. PCECV vaccination induced a strong immune response at Day 15, and the non-inferiority in immune response of the Zagreb vs. the Essen regimen was demonstrated in children and older adults. At Day 15,100% of children (N = 224), and 99% of subjects ≥51 years of age (N = 376) developed adequate RVNA concentrations (≥0.5 IU/mL); at Day 43 all subjects achieved RVNA concentrations ≥0.5 IU/mL, for both PEP regimens. The well-known tolerability and safety profile of the PCECV was again observed in this study following either Zagreb or Essen regimens. Rabies PEP vaccination with PCECV following a Zagreb regimen induced immune responses non-inferior to those of the Essen regimen, and had a similar safety and tolerability profile to the Essen regimen in Chinese children, adolescents, and adults over 51 years. ClinicalTrials.gov identifier: NCT01680016.

Development of Nevirapine Resistance in Children Exposed to the Prevention of Mother-to-Child HIV-1 Transmission Programme in Maputo, Mozambique.

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Francisco Antunes

Full Text Available Single-dose nevirapine (sd-NVP has been the main option for prevention of mother-to-child transmission (PMTCT of HIV-1 in low-resource settings. However, sd-NVP can induce the selection of HIV-1 resistant mutations in mothers and infants. In Mozambique, there are limited data regarding the profile of NVP resistance associated mutations (RAM in the context of PMTCT.To assess the prevalence and the factors associated with NVP RAM among children born to HIV-1 infected mothers enrolled in the PMTCT programme adopted in Mozambique.One hundred and fifty seven children aged 6 to 48 weeks were sequentially included (July 2011 to March 2012 at four centres in Maputo. Genotyping of RAM was performed in samples with HIV-1 RNA≥ 100 copies/μL (Viroseq. Sequencing was performed with ABI 3100 (Applied Biosystems. Logistic regression modelling was undertaken to identify the factors associated with NVP RAM.Seventy-nine children had their samples genotyped. Their median age was 7.0 (3-12 months and 92.4% received prophylaxis with sd-NVP at birth plus daily NVP. 35.4% of mothers received antiretrovirals (ARVs for PMTCT. ARV RAM were detected in 43 (54.4% of the children. 45.6% of these children had at least one NVP RAM. The most common mutations associated with NVP resistance were K103N (n = 16 and Y181C (n = 15. NVP RAM was significantly associated with mother exposure to PMTCT (crude odds ratio [OR] 30.3, 95% CI 4.93-186.34 and with mother's CD4 count < 350 cells/mm3 (crude OR 3.08, 95% CI 1.02-9.32. In the multivariable analysis the mother's exposure to PMTCT was the only variable significantly associated with NVP RAM (adjusted OR 48.65, 95% CI 9.33-253.66.We found a high prevalence of NVP RAM among children who were exposed to the drug regimen for PMTCT in Mozambique. The mothers' exposure to PMTCT significantly increased the risk of NVP RAM.

A systematic review of effectiveness and safety of different regimens of levonorgestrel oral tablets for emergency contraception.

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Shohel, Mohammad; Rahman, Mohammad Mahfuzur; Zaman, Asif; Uddin, Mir Muhammad Nasir; Al-Amin, Md Mamun; Reza, Hasan Mahmud

2014-04-04

Unintended pregnancy is a complex phenomenon which raise to take an emergency decision. Low contraceptive prevalence and high user failure rates are the leading causes of this unexpected situation. High user failure rates suggest the vital role of emergency contraception to prevent unplanned pregnancy. Levonorgestrel - a commonly used progestin for emergency contraception. However, little is known about its pharmacokinetics and optimal dose for use. Hence, there is a need to conduct a systematic review of the available evidences. Randomized, double-blind trials were sought, evaluating healthy women with regular menstrual cycles, who requested emergency contraception within 72 h of unprotected coitus, to one of three regimens: 1.5 mg single dose levonorgestrel, two doses of 0.75 mg levonorgestrel given 12 h apart or two doses of 0.75 mg levonorgestrel given 24 h apart. The primary outcome was unintended pregnancy; other outcomes were side-effects and timing of next menstruation. Every trial under consideration successfully established the contraceptive effectiveness of levonorgestrel for preventing unintended pregnancy. Moreover, a single dose of levonorgestrel 1.5 mg for emergency contraception supports its safety and efficacy profile. If two doses of levonorgestrel 0.75 mg are intended for administration, the second dose can positively be taken 12-24 h after the first dose without compromising its contraceptive efficacy. The main side effect was frequent menstrual irregularities. No serious adverse events were reported. The review shows that, emergency contraceptive regimen of single-dose levonorgestrel is not inferior in efficacy to the two-dose regimen. All the regimens studied were very efficacious for emergency contraception and prevented a high proportion of pregnancies if taken within 72 h of unprotected coitus. Single levonorgestrel dose (1.5 mg) can substitute two 0.75 mg doses 12 or 24 h apart. With either regimen, the earlier the treatment is given

Gonadal status following bone marrow transplantation with low dose busulfan-cyclophosphamide regimen

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Mohsen Khosh niat Nikoo

2006-02-01

Full Text Available Background: Gonadal dysfunction is one of the short and long-term side effects following bone marrow transplantation (BMT. We assessed hypophyseal-gonadal axis after BMT by low dose busulfan-cyclophosphamide conditioning regimen (120 mg/kg. Methods: In this cohort study, we evaluated gonadal function in 48 patients (25 pubert males and 23 pubert females. Data were obtained by history, physical examination, LH, FSH, prolactin, estradiol (E2, progesterone, testosterone and semen analysis before BMT and in 6 and 12 months of post-BMT. Results: Gonadal axis in 16 male subjects (64% was normal before BMT and remained normal in 6 subjects (37% 12 months post BMT. In another 10 patients (63%, hypogonadism was started in 6 months post BMT. Spermatogenesis failure (31%, low level of testosterone (25% and spermatogenesis failure plus low level of testosterone in 12.5% were found. Gonadal axis in 20 female subjects (87% was normal before BMT, but remained normal only in 10% of subject until the end of the study. Other patients (90% had primary hypogonadism in 6 months of post BMT. Conclusion: There is a high prevalence of gonadal dysfunction following BMT in both adult sexes (especially in female patients. Therefore, regular gonadal assessment is recommended following BMT.

Immunogenicity and safety of purified chick-embryo cell rabies vaccine under Zagreb 2-1-1 or 5-dose Essen regimen in Chinese children 6 to 17 years old and adults over 50 years: A randomized open-label study

Science.gov (United States)

Li, RongCheng; Li, YanPing; Wen, ShuQing; Wen, HuiChun; Nong, Yi; Mo, Zhaojun; Xie, Fang; Pellegrini, Michele

2015-01-01

The aim of this Phase IIIb, open-label, randomized study was to demonstrate the non-inferiority of immune responses and to assess the safety of a purified chick-embryo cell rabies vaccine (PCECV) in healthy Chinese children (6 to 17 years) and older adults (≥51 years) following 2 alternative intramuscular (IM) simulated post-exposure prophylaxis (PEP) regimens: 4-dose Zagreb or 5-dose Essen regimen. Serum samples were collected prior to vaccination on Days 1 and 15 and on day 43 to assess immune response by rabies virus neutralizing antibody (RVNA) concentrations. Solicited adverse events (AEs) were recorded for up to 7 days following each vaccine dose, and unsolicited AEs throughout the entire study period. PCECV vaccination induced a strong immune response at Day 15, and the non-inferiority in immune response of the Zagreb vs. the Essen regimen was demonstrated in children and older adults. At Day 15,100% of children (N = 224), and 99% of subjects ≥51 years of age (N = 376) developed adequate RVNA concentrations (≥0.5 IU/mL); at Day 43 all subjects achieved RVNA concentrations ≥0.5 IU/mL, for both PEP regimens. The well-known tolerability and safety profile of the PCECV was again observed in this study following either Zagreb or Essen regimens. Rabies PEP vaccination with PCECV following a Zagreb regimen induced immune responses non-inferior to those of the Essen regimen, and had a similar safety and tolerability profile to the Essen regimen in Chinese children, adolescents, and adults over 51 years. ClinicalTrials.gov identifier: NCT01680016. PMID:25692350

Relative safety profiles of high dose statin regimens

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Carlos Escobar

2008-06-01

Full Text Available Carlos Escobar, Rocio Echarri, Vivencio BarriosDepartment of Cardiology, Hospital Ramón y Cajal, Madrid, SpainAbstract: Recent clinical trials recommend achieving a low-density lipoprotein cholesterol level of <100 mg/dl in high-risk and <70 mg/dl in very high risk patients. To attain these goals, however, many patients will need statins at high doses. The most frequent side effects related to the use of statins, myopathy, rhabdomyolysis, and increased levels of transaminases, are unusual. Although low and moderate doses show a favourable profile, there is concern about the tolerability of higher doses. During recent years, numerous trials to analyze the efficacy and tolerability of high doses of statins have been published. This paper updates the published data on the safety of statins at high doses.Keywords: statins, high doses, tolerability, liver, muscle

The efficacy, pharmacokinetics, safety and cardiovascular risks of switching nevirapine to rilpivirine in HIV-1 patients: the RPV switch study

NARCIS (Netherlands)

Rokx, C.; Blonk, M.; Verbon, A.; Burger, D.M.; Rijnders, B.J.

2014-01-01

INTRODUCTION: Nevirapine (NVP) induces cytochrome P450 3A4 by which rilpivirine (RPV) is metabolized. Switching NVP to RPV could result in decreased RPV exposure with subsequent virological failure and dyslipidemia because NVP is regarded as the least dyslipidemic, non-nucleoside, reverse

Abacavir-induced liver toxicity

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Maria Diletta Pezzani

2016-09-01

Full Text Available Abacavir-induced liver toxicity is a rare event almost exclusively occurring in HLA B*5701-positive patients. Herein, we report one case of abnormal liver function tests occurring in a young HLA B*5701-negative woman on a stable nevirapine-based regimen with no history of liver problems or alcohol abuse after switching to abacavir from tenofovir. We also investigated the reasons for abacavir discontinuation in a cohort of patients treated with abacavir-lamivudine-nevirapine.

Body friendly, safe and effective regimen of MgSO4 for eclampsia

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Gautam S. Aher, Urmila Gavali

2013-01-01

Full Text Available Pre-eclampsia and eclampsia are major health problems in developing countries. MgSO4 is the standard drug in the control of convulsions in eclampsia. Our study carried out at PDVVPF’s hospital is based on the low dose regimen than Pritchard, which is suitable for Indian women who are of smaller built thanwomen in western world. This prospective study included 50 eclampsia patients receiving low dose MgSO4 therapy. The loading dose of MgSO4 was 9gm. Following this 2.5 gm was given intramuscularly every 6 hourly for 24 hours after administration of the loading dose. Patients were monitored hourly by observing their respiratory rate, knee jerk and urine output. Out of 50, two patients required Pritchard regimen, rest completely recovered from eclampsia. The maternal and perinatal morbidity and mortality were comparable to those of the standard Pritchard regime. The study did not find a single case of magnesium related toxicity with low dose MgSO4 regime. Low dose magnesium sulphate regime was found to be safe and effective in eclampsia

A376S in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy

DEFF Research Database (Denmark)

Paredes, Roger; Puertas, Maria Carmen; Bannister, Wendy

2011-01-01

Background. The clinical relevance of mutations in the connection subdomain and the ribonuclease (RNase) H domain of HIV-1 reverse transcriptase (RT) is uncertain. Methods. The risk of virological failure to nonnucleoside RT inhibitor (NNRTI)-based antiretroviral therapy (ART) was evaluated...... in NNRTI-naive patients who started NNRTIs in the EuroSIDA study after July 1997 according to preexisting substitutions in the connection subdomain and the RNase H domain of HIV-1 RT. An observed association between A376S and virological failure was further investigated by testing in vitro NNRTI...... = .013). A376S conferred selective low-level nevirapine resistance in vitro, and led to greater affinity for double-stranded DNA. Conclusions. The A376S substitution in the connection subdomain of HIV-1 RT causes selective nevirapine resistance and confers an increased risk of virological failure...

Reduced-intensity conditioning regimen using low-dose total body irradiation before allogeneic transplant for hematologic malignancies: Experience from the European Group for Blood and Marrow Transplantation

International Nuclear Information System (INIS)

Belkacemi, Yazid; Labopin, Myriam; Hennequin, Christophe; Hoffstetter, Sylvette; Mungai, Raffaello; Wygoda, Marc; Lundell, Marie; Finke, Jurgen; Aktinson, Chris; Lorchel, Frederic; Durdux, Catherine; Basara, Nadezda

2007-01-01

Purpose: The high rate of toxicity is the limitation of myelobalative regimens before allogeneic transplantation. A reduced intensity regimen can allow engraftment of stem cells and subsequent transfer of immune cells for the induction of a graft-vs.-tumor reaction. Methods and Materials: The data from 130 patients (80 males and 50 females) treated between 1998 and 2003 for various hematologic malignancies were analyzed. The median patient age was 50 years (range, 3-72 years). Allogeneic transplantation using peripheral blood or bone marrow, or both, was performed in 104 (82%), 22 (17%), and 4 (3%) patients, respectively, from HLA identical sibling donors (n = 93, 72%), matched unrelated donors (n = 23, 18%), mismatched related donors (4%), or mismatched unrelated donors (6%). Total body irradiation (TBI) at a dose of 2 Gy delivered in one fraction was given to 101 patients (78%), and a total dose of 4-6 Gy was given in 29 (22%) patients. The median dose rate was 14.3 cGy/min (range, 6-16.4). Results: After a median follow-up period of 20 months (range, 1-62 months), engraftment was obtained in 122 patients (94%). Acute graft-vs.-host disease of Grade 2 or worse was observed in 37% of patients. Multivariate analysis showed three favorable independent factors for event-free survival: HLA identical sibling donor (p < 0.0001; relative risk [RR], 0.15), complete remission (p < 0.0001; RR, 3.08), and female donor to male patient (p = 0.006; RR 2.43). For relapse, the two favorable prognostic factors were complete remission (p < 0.0001, RR 0.11) and HLA identical sibling donor (p = 0.0007; RR 3.59). Conclusions: In this multicenter study, we confirmed high rates of engraftment and chimerism after the reduced intensity regimen. Our results are comparable to those previously reported. Radiation parameters seem to have no impact on outcome. However, the lack of a statistically significant difference in terms of dose rate may have been due, in part, to the small population

Performance of HIV Prevention of Mother-To-Child Transmission Programs in Sub-Saharan Africa: Longitudinal Assessment of 64 Nevirapine-Based Programs Implemented in 25 Countries, 2000-2011.

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Joël Ladner

Full Text Available To evaluate the performance and to identify predictive factors of performance in prevention of mother-to-child HIV transmission programs (PMTCT in sub-Saharan African countries.From 2000 to 2011, PMTCT programs included in the Viramune Donation Programme (VDP were prospectively followed. Each institution included in the VDP provided data on program implementation, type of management institution, number of PMTCT sites, key programs outputs (HIV counseling and testing, NVP regimens received by mothers and newborns. Nevirapine Coverage Ratio (NCR, defined as the number of women who should have received nevirapine (observed HIV prevalence x number of women in antenatal care, was used to measure performance. Included programs were followed every six months through progress reports.A total of 64 programs in 25 sub-Saharan African countries were included. The mean program follow-up was 48.0 months (SD = 24.5; 20,084,490 women attended in antenatal clinics were included. The overall mean NCR was 0.52 (SD = 0.25, with an increase from 0.37 to 0.57 between the first and last progress reports (p<.0001; NCR increased by 3.26% per year-program. Between the first and the last report, the number of women counseled and tested increased from 64.3% to 86.0% (p<.0001, the number of women post-counseled from 87.5% to 91.3% (p = 0.08. After mixed linear regression analysis, type of responsible institution, number of women attended in ANC, and program initiation in 2005-2006 were significant predictive factors associated with the NCR. The effect of the time period increased from earlier to later periods.A longitudinal assessment of large PMTCT programs shows that scaling-up of programs was increased in sub-Saharan African countries. The PMTCT coverage increased throughout the study period, especially after 2006. Performance may be better for programs with a small or medium number of women attended in ANC. Identification of factors that predict PMTCT program

Shared peptide binding of HLA Class I and II alleles associate with cutaneous nevirapine hypersensitivity and identify novel risk alleles

DEFF Research Database (Denmark)

Pavlos, Rebecca; McKinnon, Elizabeth J.; Ostrov, David A.

2017-01-01

Genes of the human leukocyte antigen (HLA) system encode cell-surface proteins involved in regulation of immune responses, and the way drugs interact with the HLA peptide binding groove is important in the immunopathogenesis of T-cell mediated drug hypersensitivity syndromes. Nevirapine (NVP), is...

A study to determine the optimum romurtide regimen to prevent radiation-induced leukopenia

International Nuclear Information System (INIS)

Inoue, Toshihiko; Teshima, Teruki; Ohtani, Masatoshi

1994-01-01

To evaluate the best dose of romurtide to counter radiation-induced leukopenia, two romurtide regimens have been studied in 69 patients undergoing radiation therapy, said patients divided into two groups. Those assigned to Group A, consisting of 33 patients, received a daily subcutaneous injection of 200 μg of romurtide for 10 consecutive days, and those assigned to Group B, consisting of 36 patients, received the same injection dose of romurtide every other day. Three weeks after the start of this study, it was found that both the leukocyte count and neutrophil count were significantly higher in the Group B patients (p<0.05). These results suggest that leukopenia resulting from exposure to radiotherapy can be prevented from developing over a longer period by the every other day romurtide injection regimen, compared to the daily romurtide injection regimen. (author)

Efficacy and safety of various repeat treatment dosing regimens of rituximab in patients with active rheumatoid arthritis: results of a Phase III randomized study (MIRROR)

NARCIS (Netherlands)

Rubbert-Roth, Andrea; Tak, Paul P.; Zerbini, Cristiano; Tremblay, Jean-Luc; Carreño, Luis; Armstrong, Gillian; Collinson, Neil; Shaw, Tim M.

2010-01-01

Methods. Patients with active RA despite stable MTX (10-25 mg/week) were randomly assigned to one of the three treatment regimens comprising two courses of RTX given 24 weeks apart: 2 x 500 and 2 x 500 mg; 2 x 500 and 2 x 1000 mg (dose escalation); and 2 x 1000 and 2 x 1000 mg. The primary endpoint

Glucocorticoid regimens for prevention of Graves' ophthalmopathy progression following radioiodine treatment: systematic review and meta-analysis.

Science.gov (United States)

Shiber, Shachaf; Stiebel-Kalish, Hadas; Shimon, Ilan; Grossman, Alon; Robenshtok, Eyal

2014-10-01

Glucocorticoid (GC) therapy has been shown to prevent Graves' ophthalmopathy (GO) progression following radioactive iodine (RAI) treatment. However, the optimal regimen is controversial, with studies from recent years suggesting the use of lower doses and shorter GC treatment courses. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) and retrospective controlled trials comparing GC regimens versus placebo, no treatment, or other GC regimens. Eight trials evaluating 850 patients fulfilled inclusion criteria. In patients with preexisting GO, standard dose prednisone (0.4-0.5 mg/kg tapered over 3 months) was very effective for prevention of GO progression (OR 0.14 [CI 0.06-0.35], phyperthyroidism resolution (OR 1.05 [CI 0.69-1.58]), and GC side effects were common but mild. Current evidence supports a three-tier approach for prevention of GO progression following RAI. Standard dose prednisone is the best validated regimen and should be used in patients with mild to moderate GO who have high risk of progression, while low dose prednisone can be used in patients with mild GO, and in patients without preexisting GO who have risk factors and are selected for GC prophylaxis. Patients without preexisting GO and without risk factors should not be treated with GC prophylaxis.

Comparison of therapy augmentation and deviation rates from the recommended once-daily dosing regimen between LDX and commonly prescribed long-acting stimulants for the treatment of ADHD in youth and adults.

Science.gov (United States)

Setyawan, Juliana; Hodgkins, Paul; Guérin, Annie; Gauthier, Geneviève; Cloutier, Martin; Wu, Eric; Erder, M Haim

2013-10-01

To compare therapy augmentation and deviation rates from the recommended once-daily dosing regimen in Attention Deficit Hyperactivity Disorder (ADHD) patients initiated on lisdexamfetamine (LDX) vs other once-daily Food and Drug Administration (FDA) approved stimulants. ADHD patients initiated on a long-acting ADHD stimulant medication (index medication) in/after 2007 were selected from a large U.S. administrative claims database. Patients were required to be persistent for ≥90 days and continuously enrolled in their healthcare plan for ≥12 months following treatment initiation date. Based on age and previous treatment status, patients were classified into treatment-naïve children and adolescents (6-17 years old), previously treated children and adolescents, treatment-naïve adults (≥18 years old), and previously treated adults. Furthermore, patients were classified into four mutually exclusive treatment groups, based on index medication: lisdexamfetamine (LDX), osmotic release methylphenidate hydrochloride long-acting (OROS MPH), other methylphenidate/dexmethylphenidate long-acting (MPH LA), and amphetamine/dextroamphetamine long-acting (AMPH LA). The average daily consumption was measured as the quantity of index medication supplied in the 12-month study period divided by the total number of days of supply. Therapy augmentation was defined as the use of another ADHD medication concomitantly with the index medication for ≥28 consecutive days. Therapy augmentation and deviation rates from the recommended once-daily dosing regimen were compared between treatment groups using multivariate logistic regression models. Compared to the other treatment groups, LDX patients were less likely to augment with another ADHD medication (range odds ratios [OR]; 1.28-3.30) and to deviate from the recommended once-daily dosing regimen (range OR; 1.73-4.55), except for previously treated adult patients, where therapy augmentation differences were not statistically

Clinical treatment outcomes of tuberculosis treated with the basic regimen recommended by the Brazilian National Ministry of Health using fixed-dose combination tablets in the greater metropolitan area of Goiânia, Brazil.

Science.gov (United States)

Ferreira, Anna Carolina Galvão; Silva Júnior, José Laerte Rodrigues da; Conde, Marcus Barreto; Rabahi, Marcelo Fouad

2013-01-01

To describe the rates of cure, treatment failure, and treatment abandonment obtained with the basic regimen recommended by the Brazilian National Ministry of Health (rifampin, isoniazid, pyrazinamide, and ethambutol for two months, followed by isoniazid and rifampin for four months) involving the use of fixed-dose combination tablets (self-administered treatment), as well as to describe adverse events and their potential impact on treatment outcomes. This was a descriptive study based on prospective data obtained from the medical records of tuberculosis patients (> 18 years of age) treated with the basic regimen at either of two primary health care facilities in the greater metropolitan area of Goiânia, Brazil. The study sample comprised 40 tuberculosis patients. The rate of cure was 67.5%, the rate of treatment abandonment was 17.5%, and there were no cases of treatment failure. Of the 40 patients in the sample, 19 (47%) reported adverse reactions, which were mild and moderate, respectively, in 87% and 13% of the cases. It was not necessary to alter the regimen or discontinue the treatment in any of the cases evaluated. The rate of cure obtained with the self-administered, fixed-dose combination tablet form of the new basic regimen was similar to the historical rates of cure obtained with the previous regimen. The rate of treatment abandonment in our sample was much higher than that considered appropriate (up to 5%).

Clinical treatment outcomes of tuberculosis treated with the basic regimen recommended by the Brazilian National Ministry of Health using fixed-dose combination tablets in the greater metropolitan area of Goiânia, Brazil *

Science.gov (United States)

Ferreira, Anna Carolina Galvão; da Silva, José Laerte Rodrigues; Conde, Marcus Barreto; Rabahi, Marcelo Fouad

2013-01-01

OBJECTIVE: To describe the rates of cure, treatment failure, and treatment abandonment obtained with the basic regimen recommended by the Brazilian National Ministry of Health-rifampin, isoniazid, pyrazinamide, and ethambutol for two months, followed by isoniazid and rifampin for four months-involving the use of fixed-dose combination tablets (self-administered treatment), as well as to describe adverse events and their potential impact on treatment outcomes. METHODS: This was a descriptive study based on prospective data obtained from the medical records of tuberculosis patients (≥ 18 years of age) treated with the basic regimen at either of two primary health care facilities in the greater metropolitan area of Goiânia, Brazil. RESULTS: The study sample comprised 40 tuberculosis patients. The rate of cure was 67.5%, the rate of treatment abandonment was 17.5%, and there were no cases of treatment failure. Of the 40 patients in the sample, 19 (47%) reported adverse reactions, which were mild and moderate, respectively, in 87% and 13% of the cases. It was not necessary to alter the regimen or discontinue the treatment in any of the cases evaluated. CONCLUSIONS: The rate of cure obtained with the self-administered, fixed-dose combination tablet form of the new basic regimen was similar to the historical rates of cure obtained with the previous basic regimen. The rate of treatment abandonment in our sample was much higher than that considered appropriate (up to 5%). PMID:23503489

Single Dose Versus 3 Doses of Intramuscular Benzathine Penicillin for Early Syphilis in HIV: A Randomized Clinical Trial.

Science.gov (United States)

Andrade, Roberto; Rodriguez-Barradas, Maria C; Yasukawa, Kosuke; Villarreal, Erick; Ross, Michael; Serpa, Jose A

2017-03-15

Patients coinfected with syphilis and human immunodeficiency virus (HIV) may have a slower decrease in rapid plasma reagin (RPR) titers. Currently a single dose of 2.4 million units of intramuscular benzathine penicillin G (BPG) is recommended for the treatment of early syphilis. Some observational studies have suggested that this regimen may lead to high failure rates in coinfected patients. We conducted an open-label randomized clinical trial to compare the efficacy of single-dose and 3-dose regimens of BPG for the treatment of early syphilis in HIV-infected individuals. RPR titers were monitored every 3 months. Treatment success was defined as a decrease in RPR titers of ≥2 dilutions (4-fold) during a 12-month follow-up period. Sixty-four patients were included. In the intention-to-treat analysis, treatment success rates were 80% (28 of 35 subjects) and 93% (27 of 29 subjects) in the single-dose and 3-dose regimens, respectively (absolute difference, 13% [95% confidence interval {CI}, -5% to 30%; P = .17). In the per-protocol analysis, success rates were 93% (27 of 29) and 100% in the single-dose and 3-dose regimens, respectively (absolute difference, 7% [95% CI, -7% to 22%]; P = .49). CD4 T-cell count, RPR titer and syphilis stage did not affect treatment results. When compared with a single dose of BPG, a 3-dose regimen did not improve syphilis serological outcomes. Our results support the Centers for Disease Control and Prevention recommendation of a single dose of BPG in HIV-infected patients with early syphilis. NCT02611765. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.

Early diagnosis of HIV in children below 18 months using DNA PCR test--assessment of the effectiveness of PMTCT interventions and challenges in early initiation of ART in a resource-limited setting.

Science.gov (United States)

Gupta, Anil; Singh, Girraj; Kaushik, Pratap; Joshi, Bipin; Kalra, Kamlesh; Chakraborty, Sabyasachi

2013-04-01

This study was conducted to assess efficacy of the current Indian Prevention of Mother-to-Child Transmission (PMTCT) protocol in 217 HIV-exposed infants, and to assess challenges in the early initiation of antiretroviral treatment (ART) in 18 (8.3%) infants with HIV, as determined by the HIV-1 DNA polymerase chain reaction (PCR) test at ≥ 6 weeks to ART was initiated in 10 (55.6%) HIV-infected children at a mean ± standard deviation (SD) age of 10.45 ± 4.9 (range: 4-17.5) months; delay resulted in opportunistic infections in one-third of the children. A single-dose nevirapine PMTCT regimen should be replaced by a triple antiretroviral regimen; DBS DNA PCR-positive infants may be given ART, and simultaneously a whole blood specimen should be taken to determine whether ART should be continued.

Mitigation of Initial Cardiodynamic Effects of the S1P1 Receptor Modulator Ponesimod Using a Novel Up-Titration Regimen.

Science.gov (United States)

Juif, Pierre-Eric; Hoch, Matthias; Vaclavkova, Andrea; Krause, Andreas; Bush, Jim; Dingemanse, Jasper

2017-03-01

Ponesimod, a potent selective sphingosine-1-phosphate receptor 1 modulator, leads to a reduction in circulating total lymphocyte count and transient decreases in heart rate (HR). Based on a modeling and simulation approach, this study was conducted to investigate whether a gradual up-titration regimen may mitigate these cardiodynamic effects. In this double-blind, placebo-controlled, randomized, 2-way crossover study, 32 healthy participants (15 males) received placebo on day 1 followed by multiple-dose administration of either ponesimod or placebo (ratio 3:1). Ponesimod was administered alternately using regimen A (incremental dose increase from 2 to 20 mg in 9 steps) or B (10 mg for 7 days followed by a single-dose administration of 20 mg). Cardiodynamic (Holter and 12-lead ECG), pharmacokinetic, pharmacodynamic (total lymphocyte count), and safety variables were assessed. After first-dose ponesimod administration (day 2), a transient decrease in HR was observed (nadir 2-3 hours postdose, back to predose values within 4-5 hours) of approximately 6 and 12 beats/min (bpm) (mean) following regimens A and B, respectively. On day 2, occurrence of HR 20 ms, was lower following regimen A than B (14 vs 43 events). During the course of the study, incidence of HR <45 bpm was lower following regimen A than B (20 vs 58 events). Fewer participants reported adverse events following regimen A than B. Pharmacokinetics and pharmacodynamics were similar between the regimens. The novel gradual up-titration with ponesimod markedly mitigated initial cardiodynamic effects. © 2016, The American College of Clinical Pharmacology.

A comparison of twice-weekly MPD-PUVA and three times-weekly skin typing-PUVA regimens for the treatment of psoriasis

Energy Technology Data Exchange (ETDEWEB)

Buckley, D.A.; Rogers, S. [City of Dublin Skin and Cancer Hospital, Dublin (Ireland); Healy, E. [Royal Victoria Infirmary, Newcastle upon Tyne (United Kingdom)

1995-09-01

The most frequent PUVA treatment regimen in current use is three times weekly, using skin typing to estimate the starting dose. Recently, it was suggested that twice-weekly treatment, using the minimal phototoxic dose- (MPD) to calculate suberythmal starting doses of UVA, achieved similar clearance rates with fewer treatments and a lower cumulative UVA dose. We have carried out a trial on 83 patients, comparing twice-weekly MPD-PUVA with three times-weekly skin typing-PUVA, in order to test this hypothesis. Although clearance rates were comparable between the two regimens, there was no overall significant difference in the number of treatments or in the cumulative UVA doses at clearance. However, for patients with skin types I and II the cumulative UVA dose was significantly higher using the twice-weekly MPD regimen (70.OJ/cm{sup 2} vs. 55.8J/cm{sup 2}; P<0.05). Our results do not confirm that there is a reduction in cumulative UVA dosage with twice-weekly MPD-PUVA. (Author).

Pharmacogenetics and Pharmacokinetics in high-dose alkylating chemotherapy

NARCIS (Netherlands)

Ekhart, G.C. (Corine)

2008-01-01

High-dose chemotherapy in combination with peripheral blood progenitor cell transplantation has been developed as a possible curative treatment modality in several solid tumours. A frequently used high-dose regimen in the Netherlands is the CTC regimen, which is a 4-day course of cyclophosphamide,

Immunogenicity, safety and antibody persistence of a purified vero cell cultured rabies vaccine (Speeda) administered by the Zagreb regimen or Essen regimen in post-exposure subjects.

Science.gov (United States)

Shi, Nianmin; Zhang, Yibin; Zheng, Huizhen; Zhu, Zhenggang; Wang, Dingming; Li, Sihai; Li, Yuhua; Yang, Liqing; Zhang, Junnan; Bai, Yunhua; Lu, Qiang; Zhang, Zheng; Luo, Fengji; Yu, Chun; Li, Li

2017-06-03

To compare the safety, immunogenicity and long-term effect of a purified vero cell cultured rabies vaccine in post-exposure subjects following 2 intramuscular regimens, Zagreb or Essen regimen. Serum samples were collected before vaccination and on days 7, 14, 42, 180 and 365 post vaccination. Solicited adverse events were recorded for 7 d following each vaccine dose, and unsolicited adverse events throughout the entire study period. This study was registered with ClinicalTrials.gov (NCT01821911 and NCT01827917). No serious adverse events were reported. Although Zagreb regimen had a higher incidence of adverse reactions than Essen regimen at the first and second injection, the incidence was similar at the third and fourth injection between these 2 groups as well. At day 42, 100% subjects developed adequate rabies virus neutralizing antibody concentrations (≥ 0.5IU/ml) for both regimens. At days 180 and 365, the antibody level decreased dramatically, however, the percentage of subjects with adequate antibody concentrations still remained high (above 75% and 50% respectively). None of confirmed rabies virus exposured subjects had rabies one year later, and percentage of subjects with adequate antibody concentrations reached 100% at days 14 and 42. Rabies post-exposure prophylaxis vaccination with PVRV following a Zagreb regimen had a similar safety, immunogenicity and long-term effect to the Essen regimen in China.

Efficacy of Single-Dose and Triple-Dose Albendazole and Mebendazole against Soil-Transmitted Helminths and Taenia spp.: A Randomized Controlled Trial

Science.gov (United States)

Steinmann, Peter; Utzinger, Jürg; Du, Zun-Wei; Jiang, Jin-Yong; Chen, Jia-Xu; Hattendorf, Jan; Zhou, Hui; Zhou, Xiao-Nong

2011-01-01

Background The control of soil-transmitted helminth (STH) infections currently relies on the large-scale administration of single-dose oral albendazole or mebendazole. However, these treatment regimens have limited efficacy against hookworm and Trichuris trichiura in terms of cure rates (CR), whereas fecal egg reduction rates (ERR) are generally high for all common STH species. We compared the efficacy of single-dose versus triple-dose treatment against hookworm and other STHs in a community-based randomized controlled trial in the People's Republic of China. Methodology/Principal findings The hookworm CR and fecal ERR were assessed in 314 individuals aged ≥5 years who submitted two stool samples before and 3–4 weeks after administration of single-dose oral albendazole (400 mg) or mebendazole (500 mg) or triple-dose albendazole (3×400 mg over 3 consecutive days) or mebendazole (3×500 mg over 3 consecutive days). Efficacy against T. trichiura, Ascaris lumbricoides, and Taenia spp. was also assessed. Albendazole cured significantly more hookworm infections than mebendazole in both treatment regimens (single dose: respective CRs 69% (95% confidence interval [CI]: 55–81%) and 29% (95% CI: 20–45%); triple dose: respective CRs 92% (95% CI: 81–98%) and 54% (95% CI: 46–71%)). ERRs followed the same pattern (single dose: 97% versus 84%; triple dose: 99.7% versus 96%). Triple-dose regimens outperformed single doses against T. trichiura; three doses of mebendazole – the most efficacious treatment tested – cured 71% (95% CI: 57–82%). Both single and triple doses of either drug were highly efficacious against A. lumbricoides (CR: 93–97%; ERR: all >99.9%). Triple dose regimens cured all Taenia spp. infections, whereas single dose applications cured only half of them. Conclusions/Significance Single-dose oral albendazole is more efficacious against hookworm than mebendazole. To achieve high CRs against both hookworm and T. trichiura, triple-dose regimens are

Comparison of Current Recommended Regimens of Atropinization in Organophosphate Poisoning

OpenAIRE

Connors, Nicholas J.; Harnett, Zachary H.; Hoffman, Robert S.

2013-01-01

Atropine is the mainstay of therapy in organophosphate (OP) toxicity, though research and consensus on dosing is lacking. In 2004, as reported by Eddleston et al. (J Toxicol Clin Toxicol 42(6):865-75, 2004), they noted variation in recommended regimens. We assessed revisions of original references, additional citations, and electronic sources to determine the current variability in atropine dosing recommendations. Updated editions of references from Eddleston et al.’s work, texts of Internal ...

Comparison of two dose regimens of ibuprofen for the closure of patent ductus arteriosus in preterm newborns

Directory of Open Access Journals (Sweden)

Laura Vargas Dornelles

2016-05-01

Full Text Available Objective: To compare the efficacy of intravenous ibuprofen at high (20-10-10 mg/kg/dose and low doses (10-5-5 mg/kg/dose the closure of patent ductus arteriosus in preterm newborns. Methods: A cohort study with historical control of newborns that received high- and low-dose intravenous ibuprofen, from 2010 to 2013 in a neonatal intensive care unit, for closure of the patent ductus arteriosus, documented by echocardiography. Secondary outcomes included the number of ibuprofen cycles, incidence of bronchopulmonary dysplasia, necrotizing enterocolitis, changes in renal function, and death. Results: Seventy-seven patients received three doses of ibuprofen for the treatment of patent ductus arteriosus, with 33 receiving high-dose and 44 low-dose therapy. The ductus closed after the first cycle in 25 (56.8% low-dose patients and in 17 (51.5% high-dose patients (p > 0.99. Sixteen patients received a second cycle of ibuprofen, and the ductus closed in 50% after low-dose and in 60% after high-dose therapy (p > 0.99. Seven patients required surgery for ductus closure, 13.6% in the low-dose group and 3% in the high-dose group (p = 0.22. Thirty-nine patients developed bronchopulmonary dysplasia, 50% in the low-dose group and 51.5% in the high-dose group (p > 0.99. Twenty-two (50% low-dose patients died vs. 15 (45.5% high-dose patients (p = 0.86. Conclusions: There was no difference in closure of the ductus arteriosus or occurrence of adverse effects between the two dose regimens. Resumo: Objetivo: Comparar a eficácia do ibuprofeno endovenoso em doses altas (20, 10 e 10 mg/kg/dose e em doses baixas (10, 5 e 5 mg/kg/dose para o fechamento do canal arterial em recém-nascidos pré-termo. Métodos: Estudo de coorte com controle histórico pesquisando recém-nascidos que receberam ibuprofeno endovenoso, no período de 2010 à 2013 na unidade de internação neonatal, em doses altas e baixas para o fechamento do canal arterial, documentado por

Regimen durability in HIV-infected children and adolescents initiating first-line ART in a large public sector HIV cohort in South Africa.

Science.gov (United States)

Bonawitz, Rachael; Brennan, Alana T; Long, Lawrence; Heeren, Timothy; Maskew, Mhairi; Sanne, Ian; Fox, Matthew P

2018-04-15

In April 2010 tenofovir and abacavir replaced stavudine in public-sector first-line antiretroviral therapy (ART) for children under 20 years old in South Africa. The association of both abacavir and tenofovir with fewer side-effects and toxicities compared to stavudine could translate to increased durability of tenofovir or abacavir-based regimens. We evaluated changes over time in regimen durability for pediatric patients 3 to 19 years of age at 8 public sector clinics in Johannesburg, South Africa. Cohort analysis of treatment naïve, non-pregnant pediatric patients from 3 to 19 years old initiated on ART between April 2004-December 2013. First-line ART regimens before April 2010 consisted of stavudine or zidovudine with lamivudine and either efavirenz or nevirapine. Tenofovir and/or abacavir was substituted for stavudine after April 2010 in first-line ART. We evaluated the frequency and type of single-drug substitutions, treatment interruptions, and switches to second-line therapy. Fine and Gray competing risk regression models were used to evaluate the association of antiretroviral drug type with single-drug substitutions, treatment interruptions, and second-line switches in the first 24-months on treatment. 398 (15.3%) single-drug substitutions, 187 (7.2%) treatment interruptions and 86 (3.3%) switches to second-line therapy occurred among 2602 pediatric patients over 24-months on ART. Overall, the rate of single-drug substitutions started to increase in 2009, peaked in 2011 at 25%, then declined to 10% in 2013, well after the integration of tenofovir into pediatric regimens; no patients over the age of 3 were initiated on abacavir for first-line therapy. Competing risk regression models showed patients on zidovudine or stavudine had upwards of a 5-fold increase in single-drug substitution vs. patients initiated on tenofovir in the first 24-months on ART. Older adolescents also had a 2-3-fold increase in treatment interruptions and switches to second

The effect of malnutrition on the pharmacokinetics and virologic outcomes of lopinavir, efavirenz and nevirapine in food insecure HIV-infected children in Tororo, Uganda

NARCIS (Netherlands)

Bartelink, Imke H.; Savic, Rada M.; Dorsey, Grant; Ruel, Theodore; Gingrich, David; Scherpbier, Henriette J.; Capparelli, Edmund; Jullien, Vincent; Young, Sera L.; Achan, Jane; Plenty, Albert; Charlebois, Edwin; Kamya, Moses; Havlir, Diane; Aweeka, Francesca

2015-01-01

Malnutrition may impact the pharmacokinetics (PKs) of antiretroviral medications and virologic responses in HIV-infected children. The authors therefore evaluated the PK of nevirapine (NVP), efavirenz (EFV) and lopinavir (LPV) in associations with nutritional status in a cohort of HIV-infected

Impact of Drug Therapy, Radiation Dose, and Dose Rate on Renal Toxicity Following Bone Marrow Transplantation

International Nuclear Information System (INIS)

Cheng, Jonathan C.; Schultheiss, Timothy E.; Wong, Jeffrey Y.C.

2008-01-01

Purpose: To demonstrate a radiation dose response and to determine the dosimetric and chemotherapeutic factors that influence the incidence of late renal toxicity following total body irradiation (TBI). Methods and Materials: A comprehensive retrospective review was performed of articles reporting late renal toxicity, along with renal dose, fractionation, dose rate, chemotherapy regimens, and potential nephrotoxic agents. In the final analysis, 12 articles (n = 1,108 patients), consisting of 24 distinct TBI/chemotherapy conditioning regimens were included. Regimens were divided into three subgroups: adults (age ≥18 years), children (age <18 years), and mixed population (both adults and children). Multivariate logistic regression was performed to identify dosimetric and chemotherapeutic factors significantly associated with late renal complications. Results: Individual analysis was performed on each population subgroup. For the purely adult population, the only significant variable was total dose. For the mixed population, the significant variables included total dose, dose rate, and the use of fludarabine. For the pediatric population, only the use of cyclosporin or teniposide was significant; no dose response was noted. A logistic model was generated with the exclusion of the pediatric population because of its lack of dose response. This model yielded the following significant variables: total dose, dose rate, and number of fractions. Conclusion: A dose response for renal damage after TBI was identified. Fractionation and low dose rates are factors to consider when delivering TBI to patients undergoing bone marrow transplantation. Drug therapy also has a major impact on kidney function and can modify the dose-response function

Durability of Stavudine, Lamivudine and Nevirapine among Advanced HIV-1 Infected Patients with/without Prior Co-administration of Rifampicin: A 144-week Prospective Study

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Prasithisirikul Wisit

2008-10-01

Full Text Available Abstract Background To date, data on the durability of a regimen of stavudine, lamivudine and nevirapine are very limited, particularly from the resource-limited settings. Methods A prospective cohort study was conducted among 140 antiretroviral-naïve patients who were enrolled to initiate d4T, 3TC and NVP between November 2004 and March 2005. The objectives were to determine immunological and virological responses after 144 weeks of antiretroviral therapy. Seventy patients with tuberculosis also received rifampicin during the early period of antiviral treatment (TB group. Results Of all, median (IQR baseline CD4 cell count was 31 (14–79 cells/mm3; median (IQR baseline HIV-1 RNA was 433,500 (169,000–750,000 copies/mL. The average body weight was 55 kilograms. By intention-to-treat analysis at 144 weeks, the overall percentage of patients who achieved plasma HIV-1 RNA P = 0.731. Eight (5.8% patients discontinued d4T due to neuropathy and/or symptomatic lactic acidosis. Conclusion The overall durability and efficacy of antiviral response of d4T, 3TC and NVP are satisfied and they are not different between HIV-1 infected patients with and without co-administration of rifampicin due to tuberculosis. However, stavudine-related adverse effects are concerns. Trial registration ClinicalTrials.gov Identifier NCT00703898

Prevention of mother-to-child transmission of HIV infection: Views and perceptions about swallowing nevirapine in rural Lilongwe, Malawi

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Nyirenda Lot J

2010-06-01

Full Text Available Abstract Background In 2006 the World Health Organization described the status of prevention of mother to child transmission (PMTCT service implementation as unacceptable, with an urgent need for a renewed public health approach to improve access. For PMTCT to be effective it needs to be accessible, acceptable and affordable; however research in Africa into accessibility, uptake and acceptability of PMTCT services has been predominately urban based and usually focusing on women who deliver in hospitals. The importance of involving other community members to strengthen both PMTCT uptake and adherence, and to support women emotionally, has been advocated. Urban men's and rural traditional birth attendants' (TBAs involvement have improved uptake of HIV testing and of nevirapine. Methods A qualitative study was carried out in a rural district of Malawi's central region to explore the views about and perceptions of PMTCT antiretroviral treatment. Semi-structured interviews and focus group discussions were held with antenatal and postnatal women, fathers, grandmothers, TBAs, community leaders and PMTCT health workers. Results Two broad themes of findings emerged: those that relate to the hospital PMTCT service, and those that relate to the community. Trust in the hospital was strong, but distance, transport costs and perceived harsh, threatening health worker attitudes were barriers to access. Grandmothers were perceived to have influence on the management of labour, unlike fathers, but both were suggested as key people to ensure that babies are brought to the hospital for nevirapine syrup. TBAs were seen as powerful, local, and important community members, but some as uneducated. Conclusion PMTCT was seen as a community issue in which more than the mother alone can be involved. To support access to PMTCT, especially for rural women, there is need for further innovation and implementation research on involving TBAs in some aspects of PMTCT services

Tissue repair capacity and repair kinetics deduced from multifractionated or continuous irradiation regimens with incomplete repair

International Nuclear Information System (INIS)

Thames, H.D. Jr.; Peters, L.J.

1984-01-01

A model is proposed for cell survival after multiple doses, when the interfraction interval is insufficient for complete Elkind repair. In the limit of ever-increasing number of ever-smaller fractional doses, the model transforms into the accumulation model of survival after continuous irradiation. When adapted to describe tissue responses to isoeffective multifractionated regimens, wherein repair is incomplete, a generalization of the usually linear plot of reciprocal total dose versus dose per fraction is obtained, in which downward curvature is evident. There is an advantage in studying tissue responses to multifractionated regimens with incomplete repair in the interfraction intervals, or continuous exposures at various dose rates since, in addition to determination of repair capacity, there is an estimate of repair kinetics. Results of analyses of previously published data are presented as illustration. Estimated from the response of three acutely responding normal tissues in the mouse (jejunum, colon and bone marrow), repair halftimes ranged from 0.3-0.9 h and values of β/delta were approximately 0.1 Gy -1 . From the response of mouse lung (LD50 for pneumonitis) to multifractionated regimens with incomplete repair, the repair halftime was estimated at 1.5 h and β/delta was 0.27 Gy -1 . In the rat spinal cord β/delta was 0.7 Gy -1 and Tsub(1/2) was 1.5 h. (U.K.)

One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates.

Science.gov (United States)

Rao, Shripada C; Srinivasjois, Ravisha; Moon, Kwi

2016-12-06

Animal studies and trials in older children and adults suggest that a 'one dose per day' regimen of gentamicin is superior to a 'multiple doses per day' regimen. To compare the efficacy and safety of one dose per day compared to multiple doses per day of gentamicin in suspected or proven sepsis in neonates. Eligible studies were identified by searching the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 3) in the Cochrane Library (searched 8 April 2016), MEDLINE (1966 to 8 April 2016), Embase (1980 to 8 April 2016), and CINAHL (December 1982 to 8 April 2016). All randomised or quasi-randomised controlled trials comparing one dose per day ('once a day') compared to multiple doses per day ('multiple doses a day') of gentamicin to newborn infants. Data collection and analysis was performed according to the standards of the Cochrane Neonatal Review Group. Eleven RCTs were included (N = 574) and 28 excluded. All except one study enrolled infants of more than 32 weeks' gestation. Limited information suggested that infants in both 'once a day' as well as 'multiple doses a day' regimens showed adequate clearance of sepsis (typical RR 1.00, 95% CI 0.84 to 1.19; typical RD 0.00, 95% CI -0.19 to 0.19; 3 trials; N = 37). 'Once a day' gentamicin regimen was associated with fewer failures to attain peak level of at least 5 µg/ml (typical RR 0.22, 95% CI 0.11 to 0.47; typical RD -0.13, 95% CI -0.19 to -0.08; number needed to treat for an additional beneficial outcome (NNTB) = 8; 9 trials; N = 422); and fewer failures to achieve trough levels of 2 µg/ml or less (typical RR 0.38, 95% CI 0.27 to 0.55; typical RD -0.22, 95% CI -0.29 to -0.15; NNTB = 4; 11 trials; N = 503). 'Once a day' gentamicin achieved higher peak levels (MD 2.58, 95% CI 2.26 to 2.89; 10 trials; N = 440) and lower trough levels (MD -0.57, 95% CI -0.69 to -0.44; 10 trials; N = 440) than 'multiple doses a day' regimen. There was no significant difference in ototoxicity between two groups

The clinical pharmacology of alkylating agents in high-dose chemotherapy

NARCIS (Netherlands)

Huitema, A. D.; Smits, K. D.; Mathôt, R. A.; Schellens, J. H.; Rodenhuis, S.; Beijnen, J. H.

2000-01-01

Alkylating agents are widely used in high-dose chemotherapy regimens in combination with hematological support. Knowledge about the pharmacokinetics and pharmacodynamics of these agents administered in high doses is critical for the safe and efficient use of these regimens. The aim of this review is

A double-blind, randomized, multiple-dose, parallel-group study to characterize the occurrence of diarrhea following two different dosing regimens of neratinib, an irreversible pan-ErbB receptor tyrosine kinase inhibitor.

Science.gov (United States)

Abbas, Richat; Hug, Bruce A; Leister, Cathie; Sonnichsen, Daryl

2012-07-01

Neratinib, a potent, low-molecular-weight, orally administered, irreversible, pan-ErbB receptor tyrosine kinase inhibitor has antitumor activity in ErbB2 + breast cancer. The objective of this study was to characterize the onset, severity, and duration of diarrhea after administration of neratinib 240 mg once daily (QD) and 120 mg twice daily (BID) for ≤14 days in healthy subjects. A randomized, double-blind, parallel-group, inpatient study was conducted in 50 subjects given oral neratinib either 240 mg QD or 120 mg BID with food for ≤14 days. The primary endpoint was the proportion of subjects with diarrhea of at least moderate severity (grade 2; 5-7 loose stools/day). In subjects with grade 2 diarrhea, fecal analytes were determined. Pharmacokinetic profiles were characterized for neratinib on Days 1 and 7. No severe (grade 3) diarrhea was reported. By Day 4, all subjects had grade 1 diarrhea. Grade 2 diarrhea occurred in 11/22 evaluable subjects (50 % [90 % confidence interval (CI): 28-72 %]) in the QD group and 17/23 evaluable subjects (74 % [90 % CI: 52-90 %]) in the BID group (P = 0.130). In fecal analyses, 18 % tested positive for hemoglobin and 46 % revealed fecal lactoferrin. Specimen pH was neutral to slightly alkaline. In pharmacokinetic analyses, Day 1 peak plasma concentration and Day 7 steady-state exposure were higher with the QD regimen than the BID regimen. In an exploratory analysis, ABCG2 genotype showed no correlation with severity or onset of diarrhea. Incidences and onsets of at least grade 1 and at least grade 2 diarrhea were not improved on BID dosing compared with QD dosing.

Nevirapine and efavirenz elicit different changes in lipid profiles in antiretroviral-therapy-naive patients infected with HIV-1.

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Frank van Leth

2004-10-01

Full Text Available BACKGROUND: Patients infected with HIV-1 initiating antiretroviral therapy (ART containing a non-nucleoside reverse transcriptase inhibitor (NNRTI show presumably fewer atherogenic lipid changes than those initiating most ARTs containing a protease inhibitor. We analysed whether lipid changes differed between the two most commonly used NNRTIs, nevirapine (NVP and efavirenz (EFV. METHODS AND FINDINGS: Prospective analysis of lipids and lipoproteins was performed in patients enrolled in the NVP and EFV treatment groups of the 2NN study who remained on allocated treatment during 48 wk of follow-up. Patients were allocated to NVP (n = 417, or EFV (n = 289 in combination with stavudine and lamivudine. The primary endpoint was percentage change over 48 wk in high-density lipoprotein cholesterol (HDL-c, total cholesterol (TC, TC:HDL-c ratio, non-HDL-c, low-density lipoprotein cholesterol, and triglycerides. The increase of HDL-c was significantly larger for patients receiving NVP (42.5% than for patients receiving EFV (33.7%; p = 0.036, while the increase in TC was lower (26.9% and 31.1%, respectively; p = 0.073, resulting in a decrease of the TC:HDL-c ratio for patients receiving NVP (-4.1% and an increase for patients receiving EFV (+5.9%; p < 0.001. The increase of non-HDL-c was smaller for patients receiving NVP (24.7% than for patients receiving EFV (33.6%; p = 0.007, as were the increases of triglycerides (20.1% and 49.0%, respectively; p < 0.001 and low-density lipoprotein cholesterol (35.0% and 40.0%, respectively; p = 0.378. These differences remained, or even increased, after adjusting for changes in HIV-1 RNA and CD4+ cell levels, indicating an effect of the drugs on lipids over and above that which may be explained by suppression of HIV-1 infection. The increases in HDL-c were of the same order of magnitude as those seen with the use of the investigational HDL-c-increasing drugs. CONCLUSION: NVP-containing ART shows larger increases in HDL

High-dose metoclopramide + lorazepam versus low-dose metoclopramide + lorazepam + dehydrobenzperidol in the treatment of cisplatin-induced nausea and vomiting

DEFF Research Database (Denmark)

Herrstedt, Jørn; Hannibal, J; Hallas, Jesper

1991-01-01

In a randomized double-blind, cross-over trial of 34 patients receiving cisplatin-based chemotherapy (20-100 mg/m2), the antiemetic effect of high-dose metoclopramide (HDM) (10 mg/kg iv. loading dose + 7 hours continuous infusion) + lorazepam (L) (2.5 mg x 4 po) was compared with low......-dose metoclopramide (LDM) (70 mg) + L (2.5 mg x 2 po) + dehydrobenzperidol (5 mg x 2 im). Among the 29 patients who completed the cross-over, HDM significantly reduced the number of vomiting episodes (p = 0.002) and the degree of nausea (p = 0.004). Seventeen patients preferred the HDM and 4 the LDM regimen (p = 0.......01). Sedation was seen in all but 1 patient, and was graded as severe in 6 patients receiving the HDM and in 2 patients receiving the LDM regimen. No extrapyramidal adverse reactions were seen. We conclude that high-dose metoclopramide + lorazepam is a safe antiemetic regimen and significantly superior to low...

Preclinical Evaluations To Identify Optimal Linezolid Regimens for Tuberculosis Therapy

Science.gov (United States)

Drusano, George L.; Adams, Jonathan R.; Rodriquez, Jaime L.; Jambunathan, Kalyani; Baluya, Dodge L.; Brown, David L.; Kwara, Awewura; Mirsalis, Jon C.; Hafner, Richard; Louie, Arnold

2015-01-01

ABSTRACT Linezolid is an oxazolidinone with potent activity against Mycobacterium tuberculosis. Linezolid toxicity in patients correlates with the dose and duration of therapy. These toxicities are attributable to the inhibition of mitochondrial protein synthesis. Clinically relevant linezolid regimens were simulated in the in vitro hollow-fiber infection model (HFIM) system to identify the linezolid therapies that minimize toxicity, maximize antibacterial activity, and prevent drug resistance. Linezolid inhibited mitochondrial proteins in an exposure-dependent manner, with toxicity being driven by trough concentrations. Once-daily linezolid killed M. tuberculosis in an exposure-dependent manner. Further, 300 mg linezolid given every 12 hours generated more bacterial kill but more toxicity than 600 mg linezolid given once daily. None of the regimens prevented linezolid resistance. These findings show that with linezolid monotherapy, a clear tradeoff exists between antibacterial activity and toxicity. By identifying the pharmacokinetic parameters linked with toxicity and antibacterial activity, these data can provide guidance for clinical trials evaluating linezolid in multidrug antituberculosis regimens. PMID:26530386

Efficacy and tolerability of chemotherapy with modified dose-dense TCF regimen (TCF-dd) in locally advanced or metastatic gastric cancer: final results of a phase II trial.

Science.gov (United States)

Tomasello, Gianluca; Liguigli, Wanda; Poli, Rossana; Lazzarelli, Silvia; Brighenti, Matteo; Negri, Federica; Curti, Alessandra; Martinotti, Mario; Olivetti, Lucio; Rovatti, Massimo; Donati, Gianvito; Passalacqua, Rodolfo

2014-10-01

We previously studied a dose-dense TCF (TCF-dd) regimen demonstrating its feasibility and an activity comparable to epirubicin-based chemotherapy and TCF q3w in terms of overall survival and time to progression (TTP). We report here the final results of a phase II study of chemotherapy with a modified TCF-dd regimen in locally advanced or metastatic gastric cancer (MGC). Patients with histologically confirmed measurable MGC, not previously treated for advanced disease, received docetaxel 70 mg/m(2) day 1, cisplatin 60 mg/m(2) day 1, l-folinic acid 100 mg/m(2) days 1 and 2, followed by 5-fluorouracil (5-FU) 400 mg/m(2) bolus days 1 and 2, and then 600 mg/m(2) as a 22-h continuous infusion days 1 and 2, every 14 days, plus pegfilgrastim 6 mg on day 3. Patients aged ≥65 years received the same schedule with a dose reduction of 30 %. Study duration: December 2007-November 2010. Forty-six consecutive patients were enrolled (78 % male, 22 % female; median age, 66 years, range, 38-76 years; ECOG PS: 0, 48 %, 1, 46 %). Primary endpoint was overall response rate (ORR). A median of four cycles (range, one to six) was administered. Forty-three patients were evaluated for response (93.5 %) and all for toxicity: 3 complete response (CR), 25 partial response (PR), 10 stable disease (SD), and 5 progressive disease (PD) were observed, for an ORR by intention to treat (ITT) of 61 % (95 % CI 47-75). Median overall survival (OS) was 17.63 months (95 % CI, 13.67-20.67); median progression-free survival was 8.9 months (95 % CI, 6.5-13.4). Twenty-one patients (46.0 %) were treated at full doses without any delay, thus respecting the dose-dense criterion. Most frequent grade 3-4 toxicities were neutropenia (20 %), leukopenia (4 %), thrombocytopenia (2 %), anemia (2 %), febrile neutropenia (6 %), asthenia (22 %), diarrhea (4 %), nausea/vomiting (11 %), and hypokalemia (6 %). Overall, TCF-dd was shown to be safe. The TCF-dd regimen in locally advanced or MGC

Involved field radiation therapy for Hodgkin's disease autologous bone marrow transplantation regimens

International Nuclear Information System (INIS)

Pezner, Richard D.; Nademanee, Auayporn; Niland, Joyce C.; Vora, Nayana; Forman, Stephen J.

1995-01-01

From 1986 through 1992, involved-field radiation therapy (IF-RT) was administered to 29 of 86 patients with recurrent Hodgkin's disease (HD) who received a high-dose cyclophosphamide/etoposide regimen with autologous bone marrow transplantation (A-BMT). Patients without a significant history of prior RT received total body irradiation (TBI), initially as a single dose 5-7.5 Gy, and subsequently with fractionated TBI (F-TBI) delivering 12 Gy. Previously irradiated patients received a high-dose BCNU regimen instead of TBI. IF-RT was employed selectively, usually for sites of bulky disease (> 5 cm). IF-RT doses were typically 20 Gy at 2 Gy per fraction for TBI patients and 30-40 Gy at 1.8-2.0 Gy per fraction for non-TBI Patients. Fatal complications developed in four patients while second malignancies have developed in two. The region which received IF-RT was the site of first recurrence in only two cases (7%). With a median follow-up of 28 months, the two-year disease-free survival rate was 44%. For the 22 patients treated by either F-TBI or high-dose BCNU, the 2-year disease-free survival rate was 50% with a median follow up of 29 months. Selective use of IF-RT may increase the chances of complete remission and disease free survival in HD patients with a history of bulky disease

Human immunodeficiency virus type 1 mother-to-child transmission and prevention: successes and controversies.

Science.gov (United States)

Cavarelli, M; Scarlatti, G

2011-12-01

The World Health Organization (WHO) and United Nations Programme on HIV/AIDS (UNAIDS) estimated that an additional 370 000 new human immunodeficiency virus type 1 (HIV-1) infections occurred in children in 2009, mainly through mother-to-child transmission (MTCT). Intrapartum transmission contributes to approximately 20-25% of infections, in utero transmission to 5-10% and postnatal transmission to an additional 10-15% of cases. MTCT accounts for only a few hundred infected newborns in those countries in which services are established for voluntary counselling and testing of pregnant women, and a supply of antiretroviral drugs is available throughout pregnancy with recommendations for elective Caesarean section and avoidance of breastfeeding. The single-dose nevirapine regimen has provided the momentum to initiate MTCT programmes in many resource-limited countries; however, regimens using a combination of antiretroviral drugs are needed also to effectively reduce transmission via breastfeeding. 2011 The Association for the Publication of the Journal of Internal Medicine.

Dose response and factors related to interstitial pneumonitis after bone marrow transplant

International Nuclear Information System (INIS)

Sampath, Sagus; Schultheiss, Timothy E.; Wong, Jeffrey

2005-01-01

Purpose: Total body irradiation (TBI) and chemotherapy are common components of conditioning regimens for bone marrow transplantation. Interstitial pneumonitis (IP) is a known regimen-related complication. Using published data of IP in a multivariate logistic regression, this study sought to identify the parameters in the bone marrow transplantation conditioning regimen that were significantly associated with IP and to establish a radiation dose-response function. Methods and Materials: A retrospective review was conducted of articles that reported IP incidence along with lung dose, fractionation, dose rate, and chemotherapy regimen. In the final analysis, 20 articles (n = 1090 patients), consisting of 26 distinct TBI/chemotherapy regimens, were included in the analysis. Multivariate logistic regression was performed to determine dosimetric and chemotherapeutic factors that influenced the incidence of IP. Results: A logistic model was generated from patients receiving daily fractions of radiation. In this model, lung dose, cyclophosphamide dose, and the addition of busulfan were significantly associated with IP. An incidence of 3%-4% with chemotherapy-only conditioning regimens is estimated from the models. The α/β value of the linear-quadratic model was estimated to be 2.8 Gy. The dose eliciting a 50% incidence, D 50 , for IP after 120 mg/kg of cyclophosphamide was 8.8 Gy; in the absence of chemotherapy, the estimated D 50 is 10.6 Gy. No dose rate effect was observed. The use of busulfan as a substitute for radiation is equivalent to treating with 14.8 Gy in 4 fractions with 50% transmission blocks shielding the lung. The logistic regression failed to find a model that adequately fit the multiple-fraction-per-day data. Conclusions: Dose responses for both lung radiation dose and cyclophosphamide dose were identified. A conditioning regimen of 12 Gy TBI in 6 daily fractions induces an IP incidence of about 11% in the absence of lung shielding. Shielding the lung

Two low-dose bowel-cleansing regimens: efficacy and safety of senna and sodium phosphorus solution for colonoscopy

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Poyrazoglu OK

2015-09-01

Full Text Available Orhan Kursat Poyrazoglu, Mehmet Yalniz Department of Gastroenterology, School of Medicine, Firat University, Elazig, Turkey Background: The aim of the present study was to compare the efficacy, adequacy, side effects, and patient compliance of sodium phosphorus (NaP and senna solutions when preparing the colon before colonoscopy.Methods: A total of 137 consecutive patients who were considered for colonoscopy evaluation had randomly received one of two premeditated regimens: 90 mL of oral NaP (NaP group or 500 mL of 1,000 mg of sennosides A and B calcium +66.6 g of sorbitol (senna group. Patients’ compliance with the bowel-cleansing method was determined using a questionnaire prior to the colonoscopic examination. On the other hand, the adequacy of the bowel-cleansing method was evaluated by the colonoscopist who was blind to the bowel-cleansing regimen used prior to the examination of the colon from the rectum to the cecum.Results: Nausea and vomiting complaints were seen more frequently in the NaP group than in the senna group (47 vs 28 and 31 vs 10; P<0.05 and P<0.01, respectively. The response to the question of whether the patients would like to use the same regimen again or not was similar in both groups. The acceptable bowel-cleansing rate was also comparable across both groups. Nevertheless, the number of patients that experienced excellent bowel cleansing in terms of general appraisal of the colonoscopic evaluation was significantly greater in the NaP group than in the senna group (46 vs 25; P<0.001.Conclusion: Although bowel cleansing was better in the NaP group, both cleansing regimens were comparable regarding the admissibility of the preparations for the procedure. The senna regimen is, however, superior to the NaP regimen in terms of application compliance and its side effects, and it may be an effective alternative for cleansing the bowel prior to colonoscopic examination. Keywords: bowel preparation, colonoscopy, side effect

Efficacy of various single-dose regimens of ceftriaxone in ...

African Journals Online (AJOL)

The therapeutic efficacy of single intramuscular doses of ceftriaxone (Rocephin; Roche) (62,S, 125 and 250 mg), administered without probenecid, was evaluated in 167 adult males with uncomplicated acute gonococcal urethritis. Cure rates of 100% were achieved at 62,5 mg and 250 mg. In the 125 mg dose group, ...

Early intravenous immunoglobin (two-dose regimen) in the management of severe Rh hemolytic disease of newborn--a prospective randomized controlled trial.

Science.gov (United States)

Elalfy, Mohsen Saleh; Elbarbary, Nancy Samir; Abaza, Heba Wegdan

2011-04-01

Phototherapy is the standard treatment in moderately severe hemolytic disease of newborn (HDN), whereas exchange transfusion (ET) is the second line in progressive cases. Intravenous immunoglobin (IVIG) has been suggested to decrease the need for ET. We aimed at assessing the efficacy of early two-dose regimens of IVIG to avoid unnecessary ET in severe Rh HDN. The study included 90 full-term neonates with Rh incompatibility unmodified by antenatal treatment and not eligible for early ET and which were randomly assigned into one of three groups: group (I), treated by conventional method; groups IIa and IIb received IVIG once at 12 h postnatal age if PT was indicated, in a dose of 0.5 and 1 g/kg, respectively. Analysis revealed 11 neonates (22%) in the conventional group and 2 (5%) in the intervention group who administered low-dose IVIG at 12 h, while none in group IIb required exchange transfusion (p = 0.03). Mean bilirubin levels were significantly lower during the first 96 h in the intervention group compared to the conventional group (p < 0.0001). Shorter duration of phototherapy (52.8 ± 12.39 h) and hospital stay (3.25 ± 0.71 days) in the IVIG group compared to conventional group (84 ± 12.12 h and 4.72 ± 0.78 days, p < 0.0001, respectively) were observed. We conclude that IVIG administration at 12 h was effective in the treatment of severe Rh HDN; the low-dose IVIG (0.5 g/kg) was as effective as high dose (1 g/kg) in reducing the duration of phototherapy and hospital stay, but less effective in avoiding exchange transfusion.

Classifying insulin regimens

DEFF Research Database (Denmark)

Neu, A; Lange, K; Barrett, T

2015-01-01

Modern insulin regimens for the treatment of type 1 diabetes are highly individualized. The concept of an individually tailored medicine accounts for a broad variety of different insulin regimens applied. Despite clear recommendations for insulin management in children and adolescents with type 1...

Low-dose total skin electron beam therapy for cutaneous lymphoma : Minimal risk of acute toxicities.

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Kroeger, Kai; Elsayad, Khaled; Moustakis, Christos; Haverkamp, Uwe; Eich, Hans Theodor

2017-12-01

Low-dose total skin electron beam therapy (TSEBT) is attracting increased interest for the effective palliative treatment of primary cutaneous T‑cell lymphoma (pCTCL). In this study, we compared toxicity profiles following various radiation doses. We reviewed the records of 60 patients who underwent TSEBT for pCTCL between 2000 and 2016 at the University Hospital of Munster. The treatment characteristics of the radiotherapy (RT) regimens and adverse events (AEs) were then analyzed and compared. In total, 67 courses of TSEBT were administered to 60 patients. Of these patients, 34 (51%) received a standard dose with a median surface dose of 30 Gy and 33 patients (49%) received a low dose with the median surface dose of 12 Gy (7 salvage low-dose TSEBT courses were administered to 5 patients). After a median follow-up of 15 months, the overall AE rate was 100%, including 38 patients (57%) with grade 2 and 7 (10%) with grade 3 AEs. Patients treated with low-dose TSEBT had significantly fewer grade 2 AEs than those with conventional dose regimens (33 vs. 79%, P dose regimen compared to those with the conventional dose regimens (6 vs. 15%, P = 0.78). Multiple/salvage low-dose TSEBT courses were not associated with an increased risk of acute AEs. Low-dose TSEBT regimens are associated with significantly fewer grade 2 acute toxicities compared with conventional doses of TSEBT. Repeated/Salvage low-dose TSEBT, however, appears to be tolerable and can even be applied safely in patients with cutaneous relapses.

Once-daily dosing of saquinavir and low-dose ritonavir in HIV-1-infected individuals: a pharmacokinetic pilot study

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van Heeswijk, R. P.; Veldkamp, A. I.; Mulder, J. W.; Meenhorst, P. L.; Lange, J. M.; Beijnen, J. H.; Hoetelmans, R. M.

2000-01-01

To investigate the steady-state pharmacokinetics of a once-daily dosing regimen of saquinavir soft gelatin capsules in combination with a low dose of ritonavir in HIV-1-infected individuals. Open-label, multi-dose, pharmacokinetic pilot study. Seven HIV-1-infected individuals who were treated with

Efficacy of three-week oxytetracycline or rifampin monotherapy compared with a combination regimen against the filarial nematode Onchocerca ochengi.

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Bah, Germanus S; Ward, Emma L; Srivastava, Abhishek; Trees, Alexander J; Tanya, Vincent N; Makepeace, Benjamin L

2014-01-01

Onchocerciasis (river blindness), caused by the filarial nematode Onchocerca volvulus, is a major cause of visual impairment and dermatitis in sub-Saharan Africa. As O. volvulus contains an obligatory bacterial symbiont (Wolbachia), it is susceptible to antibiotic chemotherapy, although current regimens are considered too prolonged for community-level control programs. The aim of this study was to compare the efficacies of oxytetracycline and rifampin, administered separately or in combination, against a close relative of O. volvulus (Onchocerca ochengi) in cattle. Six animals per group were treated with continuous or intermittent oxytetracycline regimens, and effects on adult worm viability, dermal microfilarial loads, and Wolbachia density in worm tissues were assessed. Subsequently, the efficacies of 3-week regimens of oxytetracycline and rifampin alone and a combination regimen were compared, and rifampin levels in plasma and skin were quantified. A 6-month regimen of oxytetracycline with monthly dosing was strongly adulticidal, while 3-week and 6-week regimens exhibited weaker adulticidal effects. However, all three regimens achieved >2-log reductions in microfilarial load. In contrast, rifampin monotherapy and oxytetracycline-rifampin duotherapy failed to induce substantive reductions in either adult worm burden or microfilarial load, although a borderline effect on Wolbachia density was observed following duotherapy. Dermal rifampin levels were maintained above the MIC for >24 h after a single intravenous dose. We conclude that oxytetracycline-rifampin duotherapy is less efficacious against O. ochengi than oxytetracycline alone. Further studies will be required to determine whether rifampin reduces oxytetracycline bioavailability in this system, as suggested by human studies using other tetracycline-rifampin combinations.

Current regimen of pulse therapy for pemphigus: Minor modifications, improved results

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Pasricha J

2008-01-01

Full Text Available Background: If administered properly, dexamethasone cyclophosphamide pulse (DCP therapy has the potential to effect lifelong recovery from pemphigus. Aims: The objective of this paper is to highlight various parameters of DCP therapy and also, to report the effects of a few modifications in the regimen. Methods: An analysis of 123 patients treated with the DCP/DP regimen over a period of five years (1998 to 2002 is presented here. Seventeen patients who did not start/continue the treatment and three patients who died during the treatment have been excluded from the analysis. Twenty patients who had not yet started families were given only dexamethasone pulses (DPs while 103 patients received DCPs. Low dose (50 mg/day cyclophosphamide was used as in the standard regimen. The three modifications introduced into the regimen were: (1 an additional daily dose of oral betamethasone sufficient to control the disease activity during phase I, which was progressively tapered off completely as the patient recovered, (2 use of systemic antibiotics if the patient had skin lesions, and oral anti-candida drugs if the patient had oral ulcers until complete healing, and (3 insistence on thorough cleaning of the skin and scalp with a normal soap and shampoo, and proper maintenance of oral hygiene in spite of skin/mucosal lesions. The regimen consisted of DCP/DP repeated in exactly 28-day cycles, along with 50 mg cyclophosphamide per day, insistence on completing the treatment and avoiding irregular pulses in all patients. The number of DCPs/DPs during phase I varied in different patients depending upon the dose of betamethasone used and the rate of recovery, but phase II (nine DCPs/DPs in exactly 28-day cycles along with 50 mg cyclophosphamide per day and phase III (only 50 mg cyclophosphamide per day was fixed at nine months each. This was followed by posttreatment follow-up (phase IV. Results: At present, all the patients are in complete remission. The

Different Nebulized Budesonide Dosing Regimens in a Mouse Model of Chronic Asthma

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Pınar Uysal

2016-12-01

Full Text Available Objective: The aim of this study was to compare the effectiveness of different inhaled steroid regimens on the lungs and their potential side effects on the bone tissues in chronic asthma model. Materials and Methods: Thirty-five specific pathogen-free BALB/c mice were divided into five groups. The mice in all of the study groups except the control group were sensitized with chicken egg albumin. After sensitization, the mice in group 2 were treated with saline modeling twice daily, the mice in group 3 were treated with 250 mcg of nebulized budesonide twice daily, the mice in group 4 were treated with 500 mcg of budesonide once daily, and the mice in group 5 were treated with 1000 mcg of budesonide every other day for the last 14 days of the challenge period. After challenge, the mice were sacrificed and lung and tibia samples were histologically examined. Results: Pulmonary parameters, including subepithelial smooth muscle thickness, goblet cell count, mast cell count and epithelial thickness, were the lowest in group 5 compared to other groups (p0.01. Conclusion: The beneficial effect on lung tissue was highest in the treatment group receiving budesonide every other day (group 5 and no further measureable side effects on bone mineralization were observed in this group compared with the other treatment groups. Every-other-day treatment application seems to be the most effective regimen in chronic asthma model.

Novel agents and regimens for acute myeloid leukemia: 2009 ASH annual meeting highlights

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Zhu Xiongpeng

2010-04-01

Full Text Available Abstract Prognostic markers, such as NPM1, Flt3-ITD, and cytogenetic abnormalities have made it possible to formulate aggressive treatment plans for unfavorable acute myeloid leukemia (AML. However, the long-term survival of AML with unfavorable factors remains unsatisfactory. The latest data indicate that the standard dose of daunorubicin (DNR at 45 mg/m2 is inferior to high dose 90 mg/m2 for induction therapy. The rates of complete remission and overall survival are significantly better in the high dose induction regimen. New regimens exploring the new liposomal encapsulation of Ara-C and DNR as well as addition of gemtuzumab ozogamicin monoclonal antibody have been studied. New agents, including the nucleoside analogues (clofarabine, sapacitabine, elacytarabine, FLT3 inhibitor (sorafenib, farnesyl-transferase inhibitor (tipifarnib, histone deacetylase inhibitor (vorinostat, lenalidomide, as well as DNA methyltransferase inhibitors (decitabine, azacitidine, were recently reported for AML treatment in the 2009 ASH annual meeting. This review also summarizes the updates of the clinical trials on novel agents including voreloxin, AS1413, behenoylara-C, ARRY520, ribavirin, AZD1152, AZD6244, and terameprocol (EM-1421 from the 2009 ASH annual meeting.

Decrease of vitamin D concentration in patients with HIV infection on a non nucleoside reverse transcriptase inhibitor-containing regimen

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Colebunders Robert

2010-11-01

Full Text Available Abstract Background Vitamin D is an important determinant of bone health and also plays a major role in the regulation of the immune system. Interestingly, vitamin D status before the start of highly active antiretroviral therapy (HAART has been recently associated with HIV disease progression and overall mortality in HIV-positive pregnant women. We prospectively studied vitamin D status in HIV individuals on HAART in Belgium. We selected samples from HIV-positive adults starting HAART with a pre-HAART CD4 T-cell count >100 cells/mm3 followed up for at least 12 months without a treatment change. We compared 25-hydroxyvitamin D plasma [25-(OHD] concentration in paired samples before and after 12 months of HAART. 25-(OHD levels are presented using two different cut-offs: Results Vitamin D deficiency was common before HAART, the frequency of plasma 25-(OHD concentrations below 20 ng/ml and 30 below ng/ml was 43.7% and 70.1% respectively. After 12 months on HAART, the frequency increased to 47.1% and 81.6%. HAART for 12 months was associated with a significant decrease of plasma 25-(OHD concentration (p = 0.001. Decreasing plasma 25-(OHD concentration on HAART was associated in the multivariate model with NNRTI-based regimen (p = 0.001 and lower body weight (p = 0.008. Plasma 25-(OHD concentrations decreased significantly in both nevirapine and efavirenz-containing regimens but not in PI-treated patients. Conclusions Vitamin D deficiency is frequent in HIV-positive individuals and NNRTI therapy further decreases 25-(OHD concentrations. Consequently, vitamin D status need to be checked regularly in all HIV-infected patients and vitamin D supplementation should be given when needed.

Alternative temozolomide dosing regimens and novel combinations for the treatment of advanced metastatic melanoma

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Wen-Jen Hwu

2011-12-01

Full Text Available Over the past 30 years, there has been no significant improvement in treatment outcomes for patients with advanced stage IV metastatic melanoma, and prognosis remains poor. Melanoma is known to be responsive to immunomodulatory agents, to be a highly vascular tumor, and to be fairly resistant to standard cytotoxic chemotherapy. Ongoing research is attempting to find novel combinations that may have therapeutic synergy. Alternative dosedense schedules of temozolomide appear promising and are being actively investigated, based on their potential to overcome chemoresistance to alkylating agents and the proven activity of temozolomide in the brain. Outcomes of studies investigating single-agent temozolomide suggest that it has activity similar to single-agent dacarbazine. Other studies combining temozolomide with either interferon- alfa or thalidomide suggest that the addition of these immunomodulatory agents to temozolomide improves response rates and may improve overall survival. The best results have been achieved with the extended, daily, dosedense temozolomide regimen. Further research is needed to determine the optimal temozolomide regimen and best combination approach

Toxicity assessment of molecularly targeted drugs incorporated into multiagent chemotherapy regimens for pediatric Acute Lymphocytic Leukemia (ALL): Review from an International Consensus Conference

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T.M. Horton (Terzah); R. Sposto (Richard); P. Brown (Patrick); C.P. Reynolds (Patrick); S.P. Hunger (Stephen); N.J. Winick (Naomi); E.A. Raetz (Elizabeth); W.L. Carroll (William); R.J. Arceci (Robert); M.J. Borowitz (Michael); P.S. Gaynon (Paul); L. Gore (Lia); S. Jeha (Sima); B.J. Maurer (Barry); S.E. Siegel (Stuart); A. Biondi (Andrea); P. Kearns (Pamela); A. Narendran (Aru); L.B. Silverman (Lewis); M.A. Smith (Malcolm); C.M. Zwaan (Christian Michel); J.A. Whitlock (James)

2010-01-01

textabstractOne of the challenges of incorporating molecularly targeted drugs into multi-agent chemotherapy (backbone) regimens is defining dose-limiting toxicities (DLTs) of the targeted agent against the background of toxicities of the backbone regimen. An international panel of 22 pediatric acute

Tradução e validação para o português do Medication Regimen Complexity Index Translation and validation into portuguese Language of the Medication Regimen Complexity Index

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Ana Carolina Melchiors

2007-10-01

Full Text Available FUNDAMENTO: A complexidade da farmacoterapia consiste de múltiplas características do regime prescrito, incluindo o número de diferentes medicações no esquema, o número de unidades de dosagem por dose, o número total de doses por dia e os cuidados na administração dos medicamentos. O Medication Regimen Complexity Index (MRCI é um instrumento específico, validado e utilizado para medir a complexidade da farmacoterapia, desenvolvido originalmente em língua inglesa. OBJETIVO: Tradução transcultural e validação desse instrumento para o português do Brasil. MÉTODOS: Foi desenvolvido um estudo transversal envolvendo 95 pacientes com diabete do tipo 2 utilizando múltiplas medicações. O processo de validação teve início pela tradução, retrotradução e pré-teste do instrumento, gerando uma versão adaptada chamada Índice de Complexidade da Farmacoterapia (ICFT. Em seguida foram analisados parâmetros psicométricos, incluindo validade convergente, validade divergente, confiabilidade entre avaliadores e teste-reteste. RESULTADOS: A complexidade da farmacoterapia medida pelo ICFT obteve média de 15,7 pontos (desvio padrão = 8,36. O ICFT mostrou correlação significativa com o número de medicamentos em uso (r = 0,86; p BACKGROUND: The complexity of pharmacotherapy is a result of a multiplicity of prescribed regimen factors, including the number of different drugs in the regimen, the number of dosage units per dose, the total number of prescribed doses per day and administration instructions. The Medication Regimen Complexity Index (MRCI is a specific, reliable and valid tool used to measure the complexity of pharmacotherapy, originally developed in English language. OBJECTIVE: Transcultural translation and validation of this tool into Brazilian Portuguese. METHODS: A cross-sectional study was developed with 95 type-2 diabetes patients, receiving multiple medications. The validation process included translation into

A randomized controlled trial of increased dose and frequency of albendazole with standard dose DEC for treatment of Wuchereria bancrofti microfilaremics in Odisha, India.

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Kar, Shantanu Kumar; Dwibedi, Bhagirathi; Kerketa, Anna Salomi; Maharana, Antaryami; Panda, Sudanshu S; Mohanty, Prafulla Chandra; Horton, John; Ramachandran, Cherubala P

2015-03-01

Although current programmes to eliminate lymphatic filariasis have made significant progress it may be necessary to use different approaches to achieve the global goal, especially where compliance has been poor and 'hot spots' of continued infection exist. In the absence of alternative drugs, the use of higher or more frequent dosing with the existing drugs needs to be explored. We examined the effect of higher and/or more frequent dosing with albendazole with a fixed 300 mg dose of diethylcarbamazine in a Wuchereria bancrofti endemic area in Odisha, India. Following screening, 104 consenting adults were randomly assigned to treatment with the standard regimen annually for 24 months (S1), or annually with increased dose (800 mg albendazole)(H1) or with increased frequency (6 monthly) with either standard (S2) or increased (H2) dose. Pre-treatment microfilaria counts (GM) ranged from 348 to 459 mf/ml. Subjects were followed using microfilaria counts, OG4C3 antigen levels and ultrasound scanning for adult worm nests. Microfilarial counts tended to decrease more rapidly with higher or more frequent dosing at all time points. At 12 months, Mf clearance was marginally greater with the high dose regimens, while by 24 months, there was a trend to higher Mf clearance in the arm with increased frequency and 800 mg of albendazole (76.9%) compared to other arms, (S1:64%, S2:69.2% & H1:73.1%). Although higher and/or more frequent dosing showed a trend towards a greater decline in antigenemia and clearance of "nests", all regimens demonstrated the potential macrofilaricidal effect of the combination. The higher doses of albendazole did not result in a greater number or more severe side effects. The alternative regimens could be useful in the later stages of existing elimination programmes or achieving elimination more rapidly in areas where programmes have yet to start.

Camptothecin-Based Regimens for Treatment of Ewing Sarcoma: sPast Studies and Future Directions

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Lars Wagner

2011-01-01

Full Text Available New therapies are needed to improve survival for patients with Ewing sarcoma. Over the past decade, camptothecin agents such as topotecan and irinotecan have demonstrated activity against Ewing sarcoma, especially in combination with alkylating agents. Previous studies have shown camptothecin-based combinations to be tolerable outpatient strategies that are attractive for salvage therapy. This paper highlights important issues related to drug dosing, schedule of administration, pharmacokinetics, toxicity, and activity of commonly used camptothecin-based regimens. Also discussed are strategies for incorporating these regimens into therapy for newly diagnosed patients, including several potential possibilities for combination with targeted agents.

EXPERIMENTAL CONFIRMATION FOR SELECTION OF IRRADIATION REGIMENS FOR INTRAPERITONEAL PHOTODYNAMIC THERAPY WITH PORPHYRIN AND PHTHALOCYANINE PHOTOSENSITIZERS

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A. A. Pankratov

2017-01-01

Full Text Available Optimized irradiation regimens for intraperitoneal photodynamic therapy with porphyrin and phthalocyanine photosensitizers are determined in in vitro and in vivo studies.The experimental  study on НЕр2 cell line showed that reduce of power density for constant  light dose increased significantly the efficacy of photodynamic therapy (the reduce of power density from 20-80 mW/cm2 to 10 mW/cm2 had the same results (90% cell death for half as much concentration of the photosensitizer.The obtained results were confirmed in vivo in mice with grafted tumor S-37. For light dose of 90 J/cm2  and power density of 25 mW/cm2 none of animals in the experimental  group had total resorption of the tumor. For the same light dose and decrease  of power density to 12 mW/cm2  total tumor resorption was achieved in 34% of animals, 66% of animals died from phototoxic  shock. For twofold decrease  of light dose – to 45 J/cm2  with the same low-intensity power density (12 mW/cm2 we managed total tumor resorption in 100% of animals.In the following studies of optimized irradiation regimen for intrapleural photodynamic therapy the reaction of intact peritoneum of rats on photodynamic exposure was assessed and optimized parameters of laser irradiation, which did not cause necrosis and intense inflammatory reaction of peritoneum, were determined – light dose of 10 J/cm2  with power density of mW/cm2.Thus, the reasonability for use of low-intensity regimens of irradiation for intraperitoneal photodynamic therapy was confirmed experimentally with possibility of high efficacy of treatment without inflammatory reactions of peritoneum.

Drug-Drug Interactions Between the Anti-Hepatitis C Virus 3D Regimen of Ombitasvir, Paritaprevir/Ritonavir, and Dasabuvir and Eight Commonly Used Medications in Healthy Volunteers.

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Polepally, Akshanth R; King, Jennifer R; Ding, Bifeng; Shuster, Diana L; Dumas, Emily O; Khatri, Amit; Chiu, Yi-Lin; Podsadecki, Thomas J; Menon, Rajeev M

2016-08-01

The three direct-acting antiviral regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir (3D regimen) is approved for treatment of hepatitis C virus (HCV) genotype 1 infection. Drug-drug interaction (DDI) studies of the 3D regimen and commonly used medications were conducted in healthy volunteers to provide information on coadministering these medications with or without dose adjustments. Three phase I studies evaluated DDIs between the 3D regimen (ombitasvir/paritaprevir/ritonavir 25/150/100 mg once daily + dasabuvir 250 mg twice daily) and hydrocodone bitartrate/acetaminophen (5/300 mg), metformin hydrochloride (500 mg), diazepam (2 mg), cyclobenzaprine hydrochloride (5 mg), carisoprodol (250 mg), or sulfamethoxazole/trimethoprim (SMZ/TMP) (800/160 mg twice daily), all administered orally. DDI magnitude was determined using geometric mean ratios and 90 % confidence intervals for the maximum plasma concentration (C max) and area under the plasma concentration-time curve (AUC). Changes in exposures (C max and AUC geometric mean ratios) of acetaminophen, metformin, sulfamethoxazole, trimethoprim, and diazepam were ≤25 % upon coadministration with the 3D regimen. The C max and AUC of nordiazepam, an active metabolite of diazepam, increased by 10 % and decreased by 44 %, respectively. Exposures of cyclobenzaprine and carisoprodol decreased by ≤40 and ≤46 %, respectively, whereas exposures of hydrocodone increased up to 90 %. Ombitasvir, paritaprevir, ritonavir, and dasabuvir exposures changed by ≤25 %, except for a 37 % decrease in paritaprevir C max with metformin and a 33 % increase in dasabuvir AUC with SMZ/TMP. Acetaminophen, metformin, sulfamethoxazole, and trimethoprim can be coadministered with the 3D regimen without dose adjustment. Higher doses may be needed for diazepam, cyclobenzaprine, and carisoprodol based on clinical monitoring. A 50 % lower dose and/or clinical monitoring should be considered for hydrocodone. No dose

Analysis of nevirapine (NVP) resistance in Ugandan infants who were HIV infected despite receiving single-Dose (SD) NVP versus SD NVP plus daily NVP up to 6 weeks of age to prevent HIV vertical transmission.

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Church, Jessica D; Omer, Saad B; Guay, Laura A; Huang, Wei; Lidstrom, Jessica; Musoke, Philippa; Mmiro, Francis; Jackson, J Brooks; Eshleman, Susan H

2008-10-01

Single-dose nevirapine (SD NVP) at birth plus NVP prophylaxis for the infant up to 6 weeks of age is superior to SD NVP alone for prevention of vertical transmission of human immunodeficiency virus (HIV) through breastfeeding. We analyzed NVP resistance in HIV-infected Ugandan infants who received either SD NVP or extended NVP prophylaxis. We tested plasma HIV by using a genotyping assay (ViroSeq; Celera Diagnostics), a phenotypic resistance assay (PhenoSense; Monogram Biosciences), and sensitive point mutation assay (LigAmp, for K103N, Y181C, and G190A). When infants were 6 weeks old, ViroSeq detected NVP resistance in a higher proportion of infants in the extended NVP arm than in the SD NVP arm (21 of 25 [84%] vs. 12 of 24 [50%]; P = .01). Similar results were obtained with LigAmp and PhenoSense. In both study arms, infants who were HIV infected at birth frequently had NVP resistance detected. In contrast, infants in the extended NVP arm who were HIV infected after birth were more likely to have resistance detected at 6 weeks, compared with infants in the SD NVP arm. The use of extended NVP prophylaxis was also associated with detection of NVP resistance by ViroSeq at 6 months (7 of 7 [100%] infants in the extended NVP arm had resistance detected, compared with 1 of 6 [16.7%] infants in the SD NVP arm; P = .005). The use of extended NVP prophylaxis was associated with increased selection for and persistence of NVP resistance in HIV-infected Ugandan infants.

A randomized open-labeled study to demonstrate the non-inferiority of purified chick-embryo cell rabies vaccine administered in the Zagreb regimen (2-1-1) compared with the Essen regimen in Chinese adults.

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Ma, Jingchen; Wang, Hongchang; Li, Jun; Chang, Likuan; Xie, Yun; Liu, Zhonglin; Zhao, Yuliang; Malerczyk, Claudius; Claudius, Malerczyk

2014-01-01

The Zagreb regimen has been used for 20 years in various countries. In China, until 2010, the Zagreb schedule was only approved for purified chick embryo cell vaccine (PCECV) and purified Vero cell rabies vaccines (PVRV). In this phase III clinical trial, we aimed to demonstrate the safety and immunogenic non-inferiority of the Zagreb regimen compared with the Essen regimen in healthy adult Chinese immunized with PCECV (Rabipur®). The study enrolled 825 subjects aged 18 to 50 years; serum samples were collected on Days 0, 7, 14, 42, and at 13 months to assess rabies virus neutralizing antibody (RVNA) concentrations. Solicited and unsolicited local and systemic reactions were recorded for 6 days following the day of vaccination, and collected throughout the entire study period (Day 1 until Month 13). The Zagreb regimen was non-inferior to the Essen regimen with regard to RVNA concentrations after 7, 14, and 42 days, and 13 months of immunization. The non-inferiority of seroconversion was established at Days 14 and 42. The incidence of local and systemic reactions was similar between groups, and mostly of mild or moderate severity. Vaccine-related adverse events occurred more frequently in the Essen group than in the Zagreb group. Vaccination with PCECV under a 2-1-1 regimen is as safe and immunogenic as under the traditional 5-dose Essen regimen for rabies post-exposure prophylaxis, and is a more cost-effective option, has a more practical vaccination schedule, and can potentially increase compliance.

[Nevirapine related hepatotoxicity: the prevalence and risk factors in a cohort of ART naive Han Chinese with AIDS].

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Gao, Shi-cheng; Gui, Xi-en; Deng, Li-ping; Zhang, Yong-xi; Yan, Ya-jun; Rong, Yu-ping; Liang, Ke; Yang, Rong-rong

2010-09-01

To investigate the incidence of hepatotoxicity in acquired immunodeficiency syndrome (AIDS) patients on combined anti-retroviral therapy (cART) containing nevirapine (NVP) and to assess the risk factors and its impact on cART. 330 AIDS patients from March 2003 to June 2008 at local county were enrolled and a retrospective study using Kaplan-meier survival and Multivariate logistic regression modeling was conducted. 267 out of 330 patients received NVP based cART and 63 cases received EFV-based cART. The deference of prevalences of hepatotoxicity between the two groups is statistically significant (Chi2 = 6.691, P = 0.01). 133 out of 267 (49.8%) patients on NVP based cART had at least one episode of ALT elevation during a median 21 months (interquartile ranges, IQR 6, 37) follow-up time, amounts for 28.5 cases per 100 person-years. Baseline ALT elevation (OR = 14.368, P = 0.017)and HCV co-infection (OR = 3.009, P = 0.000) were risk factors for cART related hepatotoxicity, while greatly increased CD4+ T(CD4) cell count was protective against hepatotoxicity development (OR = 0.996, P = 0.000). Patients co-infected with HCV received NVP-based cART had the higher probability of hepatotoxicity than those without HCV co-infection (Log rank: Chi2 = 16.764, P = 0.000). 23 out of the 133 subjects (17.3%) with NVP related hepatotoxicity discontinued cART temporarily or shifted NVP to efavirenz. NVP related hepatotoxicity was common among ARV naive HIV infected subjects in our cohort. Baseline ALT elevation and HCV co-infection were associated statistically with the development of hepatotoxicity. Hepatotoxicity led to discontinuing cART temporarily or switching to other regimens in some subjects. It suggested that NVP should be used with caution in patients co-infected with HCV among whom anti-HCV therapy before cART initiation may contribute to minimizing the probability of NVP associated hepatotoxicity.

Characteristics and risk factors of oral mucositis after allogeneic stem cell transplantation with FLU/MEL conditioning regimen in context with BU/CY2.

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Vokurka, S; Steinerova, K; Karas, M; Koza, V

2009-11-01

The fludarabine (FLU)/melphalan (MEL) conditioning regimen containing FLU and high-dose MEL was analyzed in comparison with the BU/CY2 regimen to characterize oral mucositis (OM) and risk factors. OM incidence significantly varied between BU/CY2 and FLU/MEL (100 vs 78%, P=0.004), but the incidence of severe OM grades 3-4 WHO and kinetics of OM were fully comparable. Patients with OM persisting on day +21 had more acute GVHD (68 vs 32%, P=0.005), which tended to occur earlier than among those without such prolonged OM. Multivariate analysis showed significant dependency of acute GVHD on severity and prolonged duration of OM and significant correlation between OM severity and its prolonged duration. Body surface area-based dosing in the FLU/MEL regimen led to a wide range of MEL doses administered per kilogram body weight (2.5-5.2 mg/kg, median 3.5). In multivariate analysis, MEL dose per kilogram of body weight was found to be a significant predictor of OM incidence and severity. Female gender and lower body mass index were less important variables than the fact that the actual dose of MEL administered per kilogram of body weight was relatively high when the dosage was calculated on the basis of body surface area.

Targeted ultraviolet B phototherapy in vitiligo: A comparison between once-weekly and twice-weekly treatment regimens

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Imran Majid

2015-01-01

Full Text Available Background: Targeted ultraviolet B (T-UVB phototherapy in vitiligo is usually administered twice or thrice a week on non-consecutive days. It is difficult for many patients to adhere to this regimen, forcing them to discontinue treatment. Aim: The study aimed to compare the efficacy of twice-weekly and once-weekly targeted ultraviolet B phototherapy regimens in vitiligo. Methods: Sixty patients with non-segmental vitiligo on the face, neck or trunk were divided into two groups of 30 patients each. The patients in group A received targeted ultraviolet B twice weekly, while those in group B received targeted ultraviolet B once weekly. Repigmentation was monitored and graded as excellent (≥75% repigmentation, good (50−74% repigmentation and poor (<50% repigmentation. The extent of repigmentation at each body site (primary outcome measure, the number of doses required for initiation of pigmentation, and the cumulative dose of targeted ultraviolet B administered was calculated and compared between both groups. Results: A total of 90 lesions (48 in the twice weeklygroup and 42 in the once weekly group were treated on the face, neck and trunk. Excellent results were obtained in 62.5% (30/48 of lesions treated twice weekly, and 64.3% (27/42 in lesions treated once weekly. The mean number of doses required for initiation of pigmentation was 4.69 in the twice weekly group, and 4.35 in the once weekly group. The patients in the twice weekly group received a mean cumulative dose of 8.26 J/cm 2, while the once weekly group received 7.69 J/cm 2. No statistically significant differences were observed between the two groups with respect to the outcome, with respect to the total repigmentation, the number of doses till onset of pigmentation, as well as the cumulative dose of targeted UVB. Conclusion: Once-weekly targeted ultraviolet B phototherapy appears to be as efficacious as the twice-weekly regimen in vitiligo.

Inactivated H9N2 avian influenza virus vaccine with gel-primed and mineral oil-boosted regimen could produce improved immune response in broiler breeders.

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Lee, D-H; Kwon, J-S; Lee, H-J; Lee, Y-N; Hur, W; Hong, Y-H; Lee, J-B; Park, S-Y; Choi, I-S; Song, C-S

2011-05-01

The frequent economic losses incurred with H9N2 low pathogenic avian influenza viruses (LPAI) infection have raised serious concerns for the poultry industry. A 1-dose regimen with inactivated H9N2 LPAI vaccine could not prevent vaccinated poultry from becoming infected and from shedding wild viruses. A study was conducted to determine whether a 2-dose regimen of inactivated H9N2 LPAI vaccine could enhance the immunologic response in chickens. Such gel-primed and mineral oil-boosted regimen has produced encouraging results associated with improved immune responses to an H9N2 LPAI. This strategy could be cost effective and helpful for preventing avian influenza virus in the poultry industry.

Short-Term Dosage Regimen for Stimulation-Induced Long-Lasting Desynchronization

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Thanos Manos

2018-04-01

Full Text Available In this paper, we computationally generate hypotheses for dose-finding studies in the context of desynchronizing neuromodulation techniques. Abnormally strong neuronal synchronization is a hallmark of several brain disorders. Coordinated Reset (CR stimulation is a spatio-temporally patterned stimulation technique that specifically aims at disrupting abnormal neuronal synchrony. In networks with spike-timing-dependent plasticity CR stimulation may ultimately cause an anti-kindling, i.e., an unlearning of abnormal synaptic connectivity and neuronal synchrony. This long-lasting desynchronization was theoretically predicted and verified in several pre-clinical and clinical studies. We have shown that CR stimulation with rapidly varying sequences (RVS robustly induces an anti-kindling at low intensities e.g., if the CR stimulation frequency (i.e., stimulus pattern repetition rate is in the range of the frequency of the neuronal oscillation. In contrast, CR stimulation with slowly varying sequences (SVS turned out to induce an anti-kindling more strongly, but less robustly with respect to variations of the CR stimulation frequency. Motivated by clinical constraints and inspired by the spacing principle of learning theory, in this computational study we propose a short-term dosage regimen that enables a robust anti-kindling effect of both RVS and SVS CR stimulation, also for those parameter values where RVS and SVS CR stimulation previously turned out to be ineffective. Intriguingly, for the vast majority of parameter values tested, spaced multishot CR stimulation with demand-controlled variation of stimulation frequency and intensity caused a robust and pronounced anti-kindling. In contrast, spaced CR stimulation with fixed stimulation parameters as well as singleshot CR stimulation of equal integral duration failed to improve the stimulation outcome. In the model network under consideration, our short-term dosage regimen enables to robustly induce

Short-Term Dosage Regimen for Stimulation-Induced Long-Lasting Desynchronization.

Science.gov (United States)

Manos, Thanos; Zeitler, Magteld; Tass, Peter A

2018-01-01

In this paper, we computationally generate hypotheses for dose-finding studies in the context of desynchronizing neuromodulation techniques. Abnormally strong neuronal synchronization is a hallmark of several brain disorders. Coordinated Reset (CR) stimulation is a spatio-temporally patterned stimulation technique that specifically aims at disrupting abnormal neuronal synchrony. In networks with spike-timing-dependent plasticity CR stimulation may ultimately cause an anti-kindling, i.e., an unlearning of abnormal synaptic connectivity and neuronal synchrony. This long-lasting desynchronization was theoretically predicted and verified in several pre-clinical and clinical studies. We have shown that CR stimulation with rapidly varying sequences (RVS) robustly induces an anti-kindling at low intensities e.g., if the CR stimulation frequency (i.e., stimulus pattern repetition rate) is in the range of the frequency of the neuronal oscillation. In contrast, CR stimulation with slowly varying sequences (SVS) turned out to induce an anti-kindling more strongly, but less robustly with respect to variations of the CR stimulation frequency. Motivated by clinical constraints and inspired by the spacing principle of learning theory, in this computational study we propose a short-term dosage regimen that enables a robust anti-kindling effect of both RVS and SVS CR stimulation, also for those parameter values where RVS and SVS CR stimulation previously turned out to be ineffective. Intriguingly, for the vast majority of parameter values tested, spaced multishot CR stimulation with demand-controlled variation of stimulation frequency and intensity caused a robust and pronounced anti-kindling. In contrast, spaced CR stimulation with fixed stimulation parameters as well as singleshot CR stimulation of equal integral duration failed to improve the stimulation outcome. In the model network under consideration, our short-term dosage regimen enables to robustly induce long

A Faropenem, Linezolid, and Moxifloxacin Regimen for Both Drug-Susceptible and Multidrug-Resistant Tuberculosis in Children: FLAME Path on the Milky Way.

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Deshpande, Devyani; Srivastava, Shashikant; Nuermberger, Eric; Pasipanodya, Jotam G; Swaminathan, Soumya; Gumbo, Tawanda

2016-11-01

 The regimen of linezolid and moxifloxacin was found to be efficacious in the hollow fiber system model of pediatric intracellular tuberculosis. However, its kill rate was slower than the standard 3-drug regimen of isoniazid, rifampin, and pyrazinamide. We wanted to examine the effect of adding a third oral agent, faropenem, to this dual combination.  We performed a series of studies in the hollow fiber system model of intracellular Mycobacterium tuberculosis, by mimicking pediatric pharmacokinetics of each antibiotic. First, we varied the percentage of time that faropenem persisted above minimum inhibitory concentration (T MIC ) on the moxifloxacin-linezolid regimen. After choosing the best faropenem exposure, we performed experiments in which we varied the moxifloxacin and linezolid doses in the triple regimen. Finally, we performed longer-duration therapy validation experiments. Bacterial burden was quantified using both colony-forming units per milliliter (CFU/mL) and time to positivity (TTP). Kill slopes were modeled using exponential regression.  TTP was a more sensitive measure of bacterial burden than CFU/mL. A faropenem T MIC > 62% was associated with steepest microbial kill slope. Regimens of standard linezolid and moxifloxacin plus faropenem T MIC > 60%, as well as higher-dose moxifloxacin, achieved slopes equivalent to those of the standard regimen based by both TTP and CFU/mL over 28 days of treatment.  We have developed an oral faropenem-linezolid-moxifloxacin (FLAME) regimen that is free of first-line drugs. The regimen could be effective against both multidrug-resistant and drug-susceptible tuberculosis in children. © The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America.

Front-Loaded Linezolid Regimens Result in Increased Killing and Suppression of the Accessory Gene Regulator System of Staphylococcus aureus

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Brown, Tanya; Parasrampuria, Ridhi; Brazeau, Daniel A.; Forrest, Alan; Kelchlin, Pamela A.; Holden, Patricia N.; Peloquin, Charles A.; Hanna, Debra; Bulitta, Jurgen B.

2012-01-01

Front loading is a strategy used to optimize the pharmacodynamic profile of an antibiotic through the administration of high doses early in therapy for a short duration. Our aims were to evaluate the impact of front loading of linezolid regimens on bacterial killing and suppression of resistance and on RNAIII, the effector molecule of the accessory gene regulator system (encoded by agr) in methicillin-resistant Staphylococcus aureus (MRSA). Time-killing experiments over 48 h were utilized for linezolid against four strains of MRSA: USA100, USA300, USA400, and ATCC 29213. A hollow-fiber infection model simulated traditional and front-loaded human therapeutic regimens of linezolid versus USA300 at 106 CFU/ml over 240 h. Over 48 h in time-kill experiments, linezolid displayed bacteriostatic activity, with reductions of >1 log10 CFU/ml for all strains. Front-loaded regimens that were administered over 5 days, 1,200 mg every 12 h (q12h) (total, 10 doses) and 2,400 mg q12h (total, 10 doses) followed by 300 mg q12h thereafter, resulted in sustained bactericidal activity, with reductions of the area under the CFU curve of −6.15 and −6.03, respectively, reaching undetectable limits at the 10-day study endpoint. All regimens displayed a reduction in RNAIII relative expression at 24 h and 240 h compared with that of the growth control. Monte Carlo simulations predicted a linezolid are promising and may be of utility in severe MRSA infections, where early aggressive therapy is necessary. PMID:22526313

Optimization of inactivated H5N9 highly pathogenic avian influenza vaccine and inactivated Salmonella enterica serovar Typhimurium vaccine with antigen dose and prime-boost regimen in domestic ducks.

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Yuk, Seong-Su; To, Eredene-Ochir; Kwon, Jung-Hoon; Noh, Jin-Yong; Hong, Woo-Tack; Jeong, Jei-Hyun; Gwon, Gyeong-Bin; Song, Chang-Seon

2017-09-01

Owing to the increase in the number of diseases affecting ducks and the demand for food safety by consumers, vaccination has become one of the factors that influence duck meat productivity. The highly pathogenic avian influenza (HPAI) virus is one of the most prevalent and causes one of the most lethal diseases in domestic ducks, and Salmonella enterica serovar Typhimurium is a food-borne pathogen persistent in the domestic duck population. To better understand the optimal usage of HPAI and S. enterica serovar Typhimurium vaccines, we aimed to determine antigen dose, oil and gel adjuvant usage with prime-boost regimen, and vaccination age, inducing the best immune response in ducks, without an effect on body weight gain. In the case of the inactivated H5N9 vaccine, a single dose of vaccine was inadequate to induce proper antibody titer when administered to day-old ducks, which necessitates boost vaccination. Administration of the oil-adjuvanted H5N9 vaccine administration in day-old and 2-week-old ducks resulted in a lower body weight at the time of slaughtering, compared to that of gel-adjuvanted H5N9 vaccine. However, gel-adjuvanted H5N9 vaccine failed to induce proper immune response to an extent recommend by OIE-World Organization for Animal Health. In the case of the Salmonella enterica serovar Typhimurium vaccine, a moderate or low dose of vaccine was appropriate for day-old ducks receiving the gel prime-oil boost vaccination. Single vaccination with oil adjuvants affects the mean body weight of 7-week-old ducks, suggesting that the gel adjuvant is more suitable for meat production. We expect that the use of adjuvants in a prime-boost regimen and at antigen doses set in this study will be helpful to maximize body weight in the case of domestic duck production at the actual farm site. © 2017 Poultry Science Association Inc.

Effectiveness of a triple-drug regimen for global elimination of lymphatic filariasis: A modelling study

NARCIS (Netherlands)

M.A. Irvine (Michael A.); W.A. Stolk (Wilma); Smith, M.E. (Morgan E); S.V. Subramanian; B.K. Singh (Brajendra K.); G.J. Weil (Gary); E. Michael (Edwin); T.D. Hollingsworth (T. Déirdre)

2017-01-01

textabstractBackground: Lymphatic filariasis is targeted for elimination as a public health problem by 2020. The principal approach used by current programmes is annual mass drug administration with two pairs of drugs with a good safety profile. However, one dose of a triple-drug regimen

Low-dose hydrocortisone (HC) replacement therapy is associated with improved bone remodeling balance in hypopituitary subjects

LENUS (Irish Health Repository)

Behan, L A

2011-06-01

The effect of commonly used glucocorticoid replacement regimens on bone health in hypopituitary subjects is not well known. We aimed to assess the effect of 3 hydrocortisone (HC) replacement dose regimens on bone turnover in this group.10 hypopituitary men with severe ACTH deficiency were randomised in a crossover design to 3 HC dose regimens, Dose A (20mg mane, 10mg tarde), Dose B (10mg twice daily) and Dose C (10mg mane, 5mg tarde). Following 6 weeks of each regimen participants underwent fasting sampling of bone turnover markers.Data from matched controls were used to produce a Z score for subject bone formation and resorption markers and to calculate the bone remodeling balance (formation Z score-resorption Z score) and turnover index ((formation Z + resorption Z)\\/2). A positive bone remodeling balance with increased turnover is consistent with a favourable bone cycle. Data are expressed as median (range).The Pro Collagen Type 1 Peptide (PINP) bone formation Z-score was significantly increased in Dose C, (1.805 (-0.6-10.24)) compared to Dose A (0.035 (-1.0-8.1)) p<0.05 while there was no difference in the C-terminal crosslinking telopeptide (CTx) resorption Z score. The bone remodeling balance was significantly lower for dose A -0.02 (-1.05-4.12) compared to dose C 1.13 (0.13-6.4) (p<0.05). Although there was a trend to an increased bone turnover index with the lower dose regimen, this was not statistically significant.Low dose HC replacement (10mg mane\\/5 mg tarde) was associated with increased bone formation and improved bone remodeling balance which is associated with a more favourable bone cycle. This may have a long term beneficial effect on bone health.

Maternal methadone dosing schedule and fetal neurobehavior

Science.gov (United States)

Jansson, Lauren M.; DiPietro, Janet A.; Velez, Martha; Elko, Andrea; Knauer, Heather; Kivlighan, Katie T.

2008-01-01

Objective Daily methadone maintenance is the standard of care for opiate dependency during pregnancy. Previous research has indicated that single-dose maternal methadone administration significantly suppresses fetal neurobehaviors. The purpose of this study was to determine if split-dosing would have less impact on fetal neurobehavior than single-dose administration. Methods Forty methadone-maintained women were evaluated at peak and trough maternal methadone levels on single- and split-dosing schedules. Monitoring sessions occurred at 36 and 37 weeks gestation in a counterbalanced study design. Fetal measures included heart rate, variability, accelerations, motor activity and fetal movement-heart rate coupling (FM-FHR). Maternal measures included heart period, variability, skin conductance, respiration and vagal tone. Repeated measure analysis of variance was used to evaluate within-subject changes between split- and single-dosing regimens. Results All fetal neurobehavioral parameters were suppressed by maternal methadone administration, regardless of dosing regimen. Fetal parameters at peak were significantly lower during single vs. split methadone administration. FM-FHR coupling was less suppressed from trough to peak during split-dosing vs. single-dosing. Maternal physiologic parameters were generally unaffected by dosing condition. Conclusion Split- dosed fetuses displayed less neurobehavioral suppression from trough to peak maternal methadone levels as compared to single-dosed fetuses. Split-dosing may be beneficial for methadone-maintained pregnant women. PMID:19085624

Evaluation of the Efficacy and Safety of High Dose Short Duration Enrofloxacin Treatment Regimen for Uncomplicated Urinary Tract Infections in Dogs

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Westropp, JL; Sykes, JE; Irom, S; Daniels, JB; Smith, A; Keil, D; Settje, T; Wang, Y; Chew, DJ

2012-01-01

Background Uncomplicated urinary tract infections (UTI) in dogs usually are treated with antimicrobial drugs for 10–14 days. Shorter duration antimicrobial regimens have been evaluated in human patients. Hypothesis A high dose short duration (HDSD) enrofloxacin protocol administered to dogs with uncomplicated UTI will not be inferior to a 14-day treatment regimen with amoxicillin-clavulanic acid. Animals Client-owned adult, otherwise healthy dogs with aerobic bacterial urine culture yielding ≥103 CFU/mL of bacteria after cystocentesis. Methods Prospective, multicenter, controlled, randomized blinded clinical trial. Enrolled dogs were randomized to group 1 (enrofloxacin 18–20 mg/kg PO q24h for 3 days) or group 2 (amoxicillin-clavulanic acid 13.75–25 mg/kg PO q12h for 14 days). Urine cultures were obtained at days 0, 10, and 21. Microbiologic and clinical cure rates were evaluated 7 days after antimicrobial treatment was discontinued. Lower urinary tract signs and adverse events also were recorded. Results There were 35 dogs in group 1 and 33 in group 2. The microbiologic cure rate was 77.1 and 81.2% for groups 1 and 2, respectively. The clinical cure rate was 88.6 and 87.9% for groups 1 and 2, respectively. Cure rates between groups did not differ according to the selected margin of noninferiority. Conclusions and Clinical Importance HDSD enrofloxacin treatment was not inferior to a conventional amoxicillin-clavulanic acid protocol for the treatment of uncomplicated bacterial UTI in dogs. Further research is warranted to determine if this protocol will positively impact owner compliance and decrease the emergence of antimicrobial resistance. PMID:22486931

Clinical and microbiological outcomes in treatment of men with non-gonococcal urethritis with a 100-mg twice-daily dose regimen of sitafloxacin.

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Ito, Shin; Yasuda, Mitsuru; Seike, Kensaku; Sugawara, Takashi; Tsuchiya, Tomohiro; Yokoi, Shigeaki; Nakano, Masahiro; Deguchi, Takashi

2012-06-01

Several microorganisms cause non-gonococcal urethritis (NGU). Failure to eradicate Mycoplasma genitalium from the urethra could be associated with persistent or recurrent urethritis; thus, the choice of antibiotics with activities potent enough to eradicate M. genitalium is crucial in the treatment of NGU. In in vitro studies, sitafloxacin has been shown to be highly active against Chlamydia trachomatis and M. genitalium. We treated 89 males with NGU, including 15 patients with persistent or recurrent NGU and 1 patient with post-gonococcal urethritis, with a 100-mg twice-daily dose regimen of sitafloxacin to assess its efficacy against NGU. We examined first-void urine samples for the presence of C. trachomatis, M. genitalium, Ureaplasma parvum, and Ureaplasma urealyticum. After treatment, we evaluated 73 patients for clinical outcomes and 44 for microbiological outcomes. Symptoms were alleviated in 62 (84.9%) patients, who were judged clinically cured. Microorganisms detected before treatment were eradicated in 42 (95.5%) patients, who were judged microbiologically cured. Regarding microbiological outcomes of specific microorganisms, eradication rates of C. trachomatis (n = 33), M. genitalium (n = 11), and U. urealyticum (n = 10) were 100%, 100%, and 80.0%, respectively. In all 5 patients with M. genitalium-positive persistent or recurrent NGU who had experienced treatment failures with antibiotics, the mycoplasma was eradicated. These results suggested that the sitafloxacin regimen used, which was effective on both M. genitalium and C. trachomatis infections, could be useful as an appropriate option as first- and second-line treatment of NGU.

Modification of Enrofloxacin Treatment Regimens for Poultry Experimentally Infected with Salmonella enterica Serovar Typhimurium DT104 To Minimize Selection of Resistance▿

Science.gov (United States)

Randall, Luke P.; Cooles, Sue W.; Coldham, Nick C.; Stapleton, Ken S.; Piddock, Laura J. V.; Woodward, Martin J.

2006-01-01

We hypothesized that higher doses of fluoroquinolones for a shorter duration could maintain efficacy (as measured by reduction in bacterial count) while reducing selection in chickens of bacteria with reduced susceptibility. Chicks were infected with Salmonella enterica serovar Typhimurium DT104 and treated 1 week later with enrofloxacin at the recommended dose for 5 days (water dose adjusted to give 10 mg/kg of body weight of birds or equivalence, i.e., water at 50 ppm) or at 2.5 or 5 times the recommended dose for 2 days or 1 day, respectively. The dose was delivered continuously (ppm) or pulsed in the water (mg/kg) or by gavage (mg/kg). In vitro in sera, increasing concentrations of 0.5 to 8 μg/ml enrofloxacin correlated with increased activity. In vivo, the efficacy of the 1-day treatment was significantly less than that of the 2- and 5-day treatments. The 2-day treatments showed efficacy similar to that of the 5-day treatment in all but one repeat treatment group and significantly (P < 0.01) reduced the Salmonella counts. Dosing at 2.5× the recommended dose and pulsed dosing both increased the peak antibiotic concentrations in cecal contents, liver, lung, and sera as determined by high-pressure liquid chromatography. There was limited evidence that shorter treatment regimens (in particular the 1-day regimen) selected for fewer strains with reduced susceptibility. In conclusion, the 2-day treatment would overall require a shorter withholding time than the 5-day treatment and, in view of the increased peak antibiotic concentrations, may give rise to improved efficacy, in particular for treating respiratory and systemic infections. However, it would be necessary to validate the 2-day regimen in a field situation and in particular against respiratory and systemic infections to validate or refute this hypothesis. PMID:17030564

An integrated disease/pharmacokinetic/pharmacodynamic model suggests improved interleukin-21 regimens validated prospectively for mouse solid cancers.

Directory of Open Access Journals (Sweden)

Moran Elishmereni

2011-09-01

Full Text Available Interleukin (IL-21 is an attractive antitumor agent with potent immunomodulatory functions. Yet thus far, the cytokine has yielded only partial responses in solid cancer patients, and conditions for beneficial IL-21 immunotherapy remain elusive. The current work aims to identify clinically-relevant IL-21 regimens with enhanced efficacy, based on mathematical modeling of long-term antitumor responses. For this purpose, pharmacokinetic (PK and pharmacodynamic (PD data were acquired from a preclinical study applying systemic IL-21 therapy in murine solid cancers. We developed an integrated disease/PK/PD model for the IL-21 anticancer response, and calibrated it using selected "training" data. The accuracy of the model was verified retrospectively under diverse IL-21 treatment settings, by comparing its predictions to independent "validation" data in melanoma and renal cell carcinoma-challenged mice (R(2>0.90. Simulations of the verified model surfaced important therapeutic insights: (1 Fractionating the standard daily regimen (50 µg/dose into a twice daily schedule (25 µg/dose is advantageous, yielding a significantly lower tumor mass (45% decrease; (2 A low-dose (12 µg/day regimen exerts a response similar to that obtained under the 50 µg/day treatment, suggestive of an equally efficacious dose with potentially reduced toxicity. Subsequent experiments in melanoma-bearing mice corroborated both of these predictions with high precision (R(2>0.89, thus validating the model also prospectively in vivo. Thus, the confirmed PK/PD model rationalizes IL-21 therapy, and pinpoints improved clinically-feasible treatment schedules. Our analysis demonstrates the value of employing mathematical modeling and in silico-guided design of solid tumor immunotherapy in the clinic.

Pharmacokinetic/pharmacodynamic based dosing of ciprofloxacin in complicated urinary tract infections

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Ana Sabo

2015-08-01

Full Text Available Ciprofloxacin is often used in treatment of complicated urinary tract infections in areas with high rates of resistance to first line agents. The aim of this study was to evaluate efficacy of ciprofloxacin in standard dosing regimens in treatment of complicated urinary tract infections. Plasma concentration curves were simulated and minimum inhibitory concentration (MIC and post-antibiotic effect were determined. Ciprofloxacin MIC ranged from 0.0156 for Gram-negative and to 0.125-0.5 µg/mL for Gram-positive bacteria. Both dosing regimens were suitable for eradication of Gram-negative bacteria, with slight supremacy of 750 mg/12 hours over 500 mg/12 hours dosing regimen. Even though all strains were fully susceptible to ciprofloxacin, pharmaco-kinetic/pharmacodynamic parameters did not meet target thresholds for pathogens with MIC over 0.1-0.2 µg/mL regardless of the administered dose. Ciprofloxacin remains an excellent choice for treatment of complicated urinary tract infections caused by Gram-negative bacteria, but in infection caused by Gram-positive strains, deeper analysis is necessary in order to achieve optimal results.

Cost-effectiveness of a 12-dose regimen for treating latent tuberculous infection in the United States

Science.gov (United States)

Shepardson, D.; Marks, S. M.; Chesson, H.; Kerrigan, A.; Holland, D. P.; Scott, N.; Tian, X.; Borisov, A. S.; Shang, N.; Heilig, C. M.; Sterling, T. R.; Villarino, M. E.; Mac Kenzie, W. R.

2017-01-01

SUMMARY SETTING A large randomized controlled trial recently showed that for treating latent tuberculous infection (LTBI) in persons at high risk of progression to tuberculosis (TB) disease, a 12-dose regimen of weekly rifapentine plus isoniazid (3HP) administered as directly observed treatment (DOT) can be as effective as 9 months of daily self-administered isoniazid (9H). OBJECTIVES To assess the cost-effectiveness of 3HP compared to 9H. DESIGN A computational model was designed to simulate individuals with LTBI treated with 9H or 3HP. Costs and health outcomes were estimated to determine the incremental costs per active TB case prevented and per quality-adjusted life year (QALY) gained by 3HP compared to 9H. RESULTS Over a 20-year period, treatment of LTBI with 3HP rather than 9H resulted in 5.2 fewer cases of TB and 25 fewer lost QALYs per 1000 individuals treated. From the health system and societal perspectives, 3HP would cost respectively US$21 525 and $4294 more per TB case prevented, and respectively $4565 and $911 more per QALY gained. CONCLUSIONS 3HP may be a cost-effective alternative to 9H, particularly if the cost of rifapentine decreases, the effectiveness of 3HP can be maintained without DOT, and 3HP treatment is limited to those with a high risk of progression to TB disease. PMID:24200264

The Effect of a New Sodium Bicarbonate Loading Regimen on Anaerobic Capacity and Wrestling Performance

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Krzysztof Durkalec-Michalski

2018-05-01

Full Text Available Gastrointestinal side effects are the main problem with sodium bicarbonate (SB use in sports. Therefore, our study assessed the effect of a new SB loading regimen on anaerobic capacity and wrestling performance. Fifty-eight wrestlers were randomized to either a progressive-dose regimen of up to 100 mg∙kg−1 of SB or a placebo for 10 days. Before and after treatment, athletes completed an exercise protocol that comprised, in sequence, the first Wingate, dummy throw, and second Wingate tests. Blood samples were taken pre- and post-exercise. No gastrointestinal side effects were reported during the study. After SB treatment, there were no significant improvements in the outcomes of the Wingate and dummy throw tests. The only index that significantly improved with SB, compared to the placebo (p = 0.0142, was the time-to-peak power in the second Wingate test, which decreased from 3.44 ± 1.98 to 2.35 ± 1.17 s. There were also no differences in blood lactate or glucose concentrations. In conclusion, although the new loading regimen eliminated gastrointestinal symptoms, the doses could have been too small to elicit additional improvements in anaerobic power and wrestling performance. However, shortening the time-to-peak power during fatigue may be particularly valuable and is one of the variables contributing to the final success of a combat sports athlete.

The Effect of a New Sodium Bicarbonate Loading Regimen on Anaerobic Capacity and Wrestling Performance.

Science.gov (United States)

Durkalec-Michalski, Krzysztof; Zawieja, Emilia Ewa; Podgórski, Tomasz; Zawieja, Bogna Ewa; Michałowska, Patrycja; Łoniewski, Igor; Jeszka, Jan

2018-05-30

Gastrointestinal side effects are the main problem with sodium bicarbonate (SB) use in sports. Therefore, our study assessed the effect of a new SB loading regimen on anaerobic capacity and wrestling performance. Fifty-eight wrestlers were randomized to either a progressive-dose regimen of up to 100 mg∙kg -1 of SB or a placebo for 10 days. Before and after treatment, athletes completed an exercise protocol that comprised, in sequence, the first Wingate, dummy throw, and second Wingate tests. Blood samples were taken pre- and post-exercise. No gastrointestinal side effects were reported during the study. After SB treatment, there were no significant improvements in the outcomes of the Wingate and dummy throw tests. The only index that significantly improved with SB, compared to the placebo ( p = 0.0142), was the time-to-peak power in the second Wingate test, which decreased from 3.44 ± 1.98 to 2.35 ± 1.17 s. There were also no differences in blood lactate or glucose concentrations. In conclusion, although the new loading regimen eliminated gastrointestinal symptoms, the doses could have been too small to elicit additional improvements in anaerobic power and wrestling performance. However, shortening the time-to-peak power during fatigue may be particularly valuable and is one of the variables contributing to the final success of a combat sports athlete.

A simplified 4-site economical intradermal post-exposure rabies vaccine regimen: a randomised controlled comparison with standard methods.

Directory of Open Access Journals (Sweden)

Mary J Warrell

2008-04-01

Full Text Available The need for economical rabies post-exposure prophylaxis (PEP is increasing in developing countries. Implementation of the two currently approved economical intradermal (ID vaccine regimens is restricted due to confusion over different vaccines, regimens and dosages, lack of confidence in intradermal technique, and pharmaceutical regulations. We therefore compared a simplified 4-site economical PEP regimen with standard methods.Two hundred and fifty-four volunteers were randomly allocated to a single blind controlled trial. Each received purified vero cell rabies vaccine by one of four PEP regimens: the currently accepted 2-site ID; the 8-site regimen using 0.05 ml per ID site; a new 4-site ID regimen (on day 0, approximately 0.1 ml at 4 ID sites, using the whole 0.5 ml ampoule of vaccine; on day 7, 0.1 ml ID at 2 sites and at one site on days 28 and 90; or the standard 5-dose intramuscular regimen. All ID regimens required the same total amount of vaccine, 60% less than the intramuscular method. Neutralising antibody responses were measured five times over a year in 229 people, for whom complete data were available.All ID regimens showed similar immunogenicity. The intramuscular regimen gave the lowest geometric mean antibody titres. Using the rapid fluorescent focus inhibition test, some sera had unexpectedly high antibody levels that were not attributable to previous vaccination. The results were confirmed using the fluorescent antibody virus neutralisation method.This 4-site PEP regimen proved as immunogenic as current regimens, and has the advantages of requiring fewer clinic visits, being more practicable, and having a wider margin of safety, especially in inexperienced hands, than the 2-site regimen. It is more convenient than the 8-site method, and can be used economically with vaccines formulated in 1.0 or 0.5 ml ampoules. The 4-site regimen now meets all requirements of immunogenicity for PEP and can be introduced without further

A simplified 4-site economical intradermal post-exposure rabies vaccine regimen: a randomised controlled comparison with standard methods.

Science.gov (United States)

Warrell, Mary J; Riddell, Anna; Yu, Ly-Mee; Phipps, Judith; Diggle, Linda; Bourhy, Hervé; Deeks, Jonathan J; Fooks, Anthony R; Audry, Laurent; Brookes, Sharon M; Meslin, François-Xavier; Moxon, Richard; Pollard, Andrew J; Warrell, David A

2008-04-23

The need for economical rabies post-exposure prophylaxis (PEP) is increasing in developing countries. Implementation of the two currently approved economical intradermal (ID) vaccine regimens is restricted due to confusion over different vaccines, regimens and dosages, lack of confidence in intradermal technique, and pharmaceutical regulations. We therefore compared a simplified 4-site economical PEP regimen with standard methods. Two hundred and fifty-four volunteers were randomly allocated to a single blind controlled trial. Each received purified vero cell rabies vaccine by one of four PEP regimens: the currently accepted 2-site ID; the 8-site regimen using 0.05 ml per ID site; a new 4-site ID regimen (on day 0, approximately 0.1 ml at 4 ID sites, using the whole 0.5 ml ampoule of vaccine; on day 7, 0.1 ml ID at 2 sites and at one site on days 28 and 90); or the standard 5-dose intramuscular regimen. All ID regimens required the same total amount of vaccine, 60% less than the intramuscular method. Neutralising antibody responses were measured five times over a year in 229 people, for whom complete data were available. All ID regimens showed similar immunogenicity. The intramuscular regimen gave the lowest geometric mean antibody titres. Using the rapid fluorescent focus inhibition test, some sera had unexpectedly high antibody levels that were not attributable to previous vaccination. The results were confirmed using the fluorescent antibody virus neutralisation method. This 4-site PEP regimen proved as immunogenic as current regimens, and has the advantages of requiring fewer clinic visits, being more practicable, and having a wider margin of safety, especially in inexperienced hands, than the 2-site regimen. It is more convenient than the 8-site method, and can be used economically with vaccines formulated in 1.0 or 0.5 ml ampoules. The 4-site regimen now meets all requirements of immunogenicity for PEP and can be introduced without further studies. Controlled

A phase II study of V-BEAM as conditioning regimen before second auto-SCT for multiple myeloma.

Science.gov (United States)

Wang, T-F; Fiala, M A; Cashen, A F; Uy, G L; Abboud, C N; Fletcher, T; Wu, N; Westervelt, P; DiPersio, J F; Stockerl-Goldstein, K E; Vij, R

2014-11-01

High-dose melphalan has been the standard conditioning regimen for auto-SCT in multiple myeloma (MM) for decades. A more effective conditioning regimen may induce deeper responses and longer remission duration. It is especially needed in the setting of second auto-SCT, which rarely achieves comparable results with the first auto-SCT using the same conditioning regimen. Here we conducted a phase II study to investigate the efficacy and safety of a conditioning regimen V-BEAM (bortezomib-BEAM) before second auto-SCT for multiple myeloma. Ten patients were enrolled from September 2012 to May 2013. The CR rate at day +100 after auto-SCT was 75%; all except for one patient remained in remission after a median follow-up of 6 months. Three patients developed Clostridium difficile infection. Two patients died within the first 30 days of auto-SCT from neutropenic colitis and overwhelming sepsis, respectively. Due to the high rate of morbidity and mortality, the study was terminated after 10 patients. In summary, although the conditioning regimen V-BEAM before second auto-SCT for MM provided promising responses, it was associated with unexpected treatment-related toxicity and should not be investigated further without modifications.

Febrile Neutropenia Risk Assessment and Granulocyte-Colony Stimulating Factor Support in Patients with Diffuse Large B Cell Lymphoma Receiving R-CHOP Regimens

DEFF Research Database (Denmark)

Salar, Antonio; Haioun, Corinne; Rossi, Francesca Gaia

2009-01-01

BACKGROUND: ASCO and EORTC guidelines recommend granulocyte colony-stimulating factor (G-CSF) primary prophylaxis for cancer patients with a ≥20% overall risk of febrile neutropenia (FN), and to support delivery of dose-dense regimens. CHOP-like regimens (with rituximab [R]) are the current...... standard of care for the management of aggressive non-Hodgkin lymphoma (NHL), but they are often associated with significant myelosuppression. Neutropenic events, particularly febrile neutropenia (FN), can be life-threatening and may lead to dose delays or reductions that compromise the efficacy......-CSF primary prophylaxis. Across all cycles, 29% of R-CHOP-21 patients had an unplanned hospitalization, with neutropenia/FN being the main reason. Subsequently, 67% of patients achieved a relative dose intensity (RDI) of ≥90% of their planned treatment (with respect to cyclophosphamide, doxorubicin...

Maximally effective dosing regimens of meropenem in patients with septic shock

DEFF Research Database (Denmark)

Sjövall, Fredrik; Alobaid, Abdulaziz S; Wallis, Steven C

2018-01-01

was required for both empirical and targeted treatment. In patients with a CL CR of ≤ 100 mL/min, successful concentration targets could be reached with intermittent dosing of 1000 mg/8 h. Conclusions: In patients with septic shock and possible augmented renal clearance, doses should be increased and...

Toxicity Profile and Pharmacokinetic Study of A Phase I Low-Dose Schedule-Dependent Radiosensitizing Paclitaxel Chemoradiation Regimen for Inoperable Non-Small-Cell Lung Cancer

International Nuclear Information System (INIS)

Chen, Yuhchyau; Pandya, Kishan J.; Feins, Richard; Johnstone, David W.; Watson, Thomas; Smudzin, Therese; Keng, Peter C.

2008-01-01

Purpose: We report the toxicity profile and pharmacokinetic data of a schedule-dependent chemoradiation regimen using pulsed low-dose paclitaxel for radiosensitization in a Phase I study for inoperable non-small-cell lung cancer. Methods and Materials: Paclitaxel at escalating doses of 15 mg/m 2 , 20 mg/m 2 , and 25 mg/m 2 were infused on Monday, Wednesday, and Friday with daily chest radiation in cohorts of 6 patients. Daily radiation was delayed for maximal G2/M arrest and apoptotic effect, an observation from preclinical investigations. Plasma paclitaxel concentration was determined by high-performance liquid chromatography. Results: Dose-limiting toxicities included 3 of 18 patients with Grade 3 pneumonitis and 3 of 18 patients with Grade 3 esophagitis. There was no Grade 4 or 5 pneumonitis or esophagitis. There was also no Grade 3 or 4 neutropenia, thrombocytopenia, anemia or neuropathy. For Dose Levels I (15 mg/m 2 ), II (20 mg/m 2 ), and III (25 mg/m 2 ), the mean peak plasma level was 0.23 ± 0.06 μmol/l, 0.32 ± 0.05 μmol/l, and 0.52 ± 0.14 μmol/l, respectively; AUC was 0.44 ± 0.09 μmol/l, 0.61 ± 0.1 μmol/l, and 0.96 ± 0.23 μmol/l, respectively; and duration of drug concentration >0.05 μmol/l (t > 0.05 μmol/l) was 1.6 ± 0.3 h, 1.9 ± 0.2 h, and 3.0 ± 0.9 h, respectively. Conclusion: Pulsed low-dose paclitaxel chemoradiation is associated with low toxicity. Pharmacokinetic data showed that plasma paclitaxel concentration >0.05 μmol/l for a minimum of 1.6 h was sufficient for effective radiosensitization

Radiosensitivity in Fanconi anaemia: application to the conditioning regimen for bone marrow transplantation

Energy Technology Data Exchange (ETDEWEB)

Gluckman, E.; Devergie, A. (Hopital Saint-Louis, 75 - Paris (France)); Dutreix, J. (Institut Gustave Roussy, 94 - Villejuif (France))

1983-07-01

Fanconi anaemia, an autosomal recessive constitutional aplastic anaemia, seems to be related to a DNA repair mechanism defect. Bone marrow transplantation is the only treatment which can cure these patients. Previous attempts at BMT have shown an increased sensitivity to Cyclophosphamide used for the conditioning. Such a sensitivity has also been observed in vitro when Fanconi anaemia cells were incubated with alkylating agents. We have tested the in vivo radiosensitivity and cell repair after skin contact radiotherapy to calculate the irradiation dose which could be tolerated by FA patients. Eight patients have been tested and the results confirmed the suspected increased radiosensitivity in the majority of patients. Following these results, four patients were conditioned with low dose Cyclophosphamide (20 mg/kg) associated with 5 Grays thoraco-abdominal irradiation. All had a take and no major complication of the conditioning regimen. All are alive in good condition from day 51 to day 330 after transplant. Oesophagitis was one major unexpected complication. This study confirms the possibility of curing FA patients with BMT when the conditioning regimen is modified according to the pathophysiology of the disease.

Radiosensitivity in Fanconi anaemia: application to the conditioning regimen for bone marrow transplantation

International Nuclear Information System (INIS)

Gluckman, E.; Devergie, A.; Dutreix, J.

1983-01-01

Fanconi anaemia, an autosomal recessive constitutional aplastic anaemia, seems to be related to a DNA repair mechanism defect. Bone marrow transplantation is the only treatment which can cure these patients. Previous attempts at BMT have shown an increased sensitivity to Cyclophosphamide used for the conditioning. Such a sensitivity has also been observed in vitro when Fanconi anaemia cells were incubated with alkylating agents. We have tested the in vivo radiosensitivity and cell repair after skin contact radiotherapy to calculate the irradiation dose which could be tolerated by FA patients. Eight patients have been tested and the results confirmed the suspected increased radiosensitivity in the majority of patients. Following these results, four patients were conditioned with low dose Cyclophosphamide (20 mg/kg) associated with 5 Grays thoraco-abdominal irradiation. all had a take and no major complication of the conditioning regimen. All are alive in good condition from day 51 to day 330 after transplant. Oesophagitis was one major unexpected complication. This study confirms the possibility of curing FA patients with BMT when the conditioning regimen is modified according to the pathophysiology of the disease. (author)

The Impact of a One-Dose versus Two-Dose Oral Cholera Vaccine Regimen in Outbreak Settings: A Modeling Study

Science.gov (United States)

Azman, Andrew S.; Luquero, Francisco J.; Ciglenecki, Iza; Grais, Rebecca F.; Sack, David A.; Lessler, Justin

2015-01-01

Background In 2013, a stockpile of oral cholera vaccine (OCV) was created for use in outbreak response, but vaccine availability remains severely limited. Innovative strategies are needed to maximize the health impact and minimize the logistical barriers to using available vaccine. Here we ask under what conditions the use of one dose rather than the internationally licensed two-dose protocol may do both. Methods and Findings Using mathematical models we determined the minimum relative single-dose efficacy (MRSE) at which single-dose reactive campaigns are expected to be as or more effective than two-dose campaigns with the same amount of vaccine. Average one- and two-dose OCV effectiveness was estimated from published literature and compared to the MRSE. Results were applied to recent outbreaks in Haiti, Zimbabwe, and Guinea using stochastic simulations to illustrate the potential impact of one- and two-dose campaigns. At the start of an epidemic, a single dose must be 35%–56% as efficacious as two doses to avert the same number of cases with a fixed amount of vaccine (i.e., MRSE between 35% and 56%). This threshold decreases as vaccination is delayed. Short-term OCV effectiveness is estimated to be 77% (95% CI 57%–88%) for two doses and 44% (95% CI −27% to 76%) for one dose. This results in a one-dose relative efficacy estimate of 57% (interquartile range 13%–88%), which is above conservative MRSE estimates. Using our best estimates of one- and two-dose efficacy, we projected that a single-dose reactive campaign could have prevented 70,584 (95% prediction interval [PI] 55,943–86,205) cases in Zimbabwe, 78,317 (95% PI 57,435–100,150) in Port-au-Prince, Haiti, and 2,826 (95% PI 2,490–3,170) cases in Conakry, Guinea: 1.1 to 1.2 times as many as a two-dose campaign. While extensive sensitivity analyses were performed, our projections of cases averted in past epidemics are based on severely limited single-dose efficacy data and may not fully capture

The Impact of a One-Dose versus Two-Dose Oral Cholera Vaccine Regimen in Outbreak Settings: A Modeling Study.

Directory of Open Access Journals (Sweden)

Andrew S Azman

2015-08-01

Full Text Available In 2013, a stockpile of oral cholera vaccine (OCV was created for use in outbreak response, but vaccine availability remains severely limited. Innovative strategies are needed to maximize the health impact and minimize the logistical barriers to using available vaccine. Here we ask under what conditions the use of one dose rather than the internationally licensed two-dose protocol may do both.Using mathematical models we determined the minimum relative single-dose efficacy (MRSE at which single-dose reactive campaigns are expected to be as or more effective than two-dose campaigns with the same amount of vaccine. Average one- and two-dose OCV effectiveness was estimated from published literature and compared to the MRSE. Results were applied to recent outbreaks in Haiti, Zimbabwe, and Guinea using stochastic simulations to illustrate the potential impact of one- and two-dose campaigns. At the start of an epidemic, a single dose must be 35%-56% as efficacious as two doses to avert the same number of cases with a fixed amount of vaccine (i.e., MRSE between 35% and 56%. This threshold decreases as vaccination is delayed. Short-term OCV effectiveness is estimated to be 77% (95% CI 57%-88% for two doses and 44% (95% CI -27% to 76% for one dose. This results in a one-dose relative efficacy estimate of 57% (interquartile range 13%-88%, which is above conservative MRSE estimates. Using our best estimates of one- and two-dose efficacy, we projected that a single-dose reactive campaign could have prevented 70,584 (95% prediction interval [PI] 55,943-86,205 cases in Zimbabwe, 78,317 (95% PI 57,435-100,150 in Port-au-Prince, Haiti, and 2,826 (95% PI 2,490-3,170 cases in Conakry, Guinea: 1.1 to 1.2 times as many as a two-dose campaign. While extensive sensitivity analyses were performed, our projections of cases averted in past epidemics are based on severely limited single-dose efficacy data and may not fully capture uncertainty due to imperfect

Comparison of safety and immunogenicity of purified chick embryo cell vaccine using Zagreb and Essen regimens in patients with category II exposure in China.

Science.gov (United States)

Hu, Quan; Liu, Man-Qing; Zhu, Zheng-Gang; Zhu, Ze-Rong; Lu, Sha

2014-01-01

The aim was to compare the safety and immunogenicity of purified chick embryo cell vaccine (PCECV) with Zagreb 2-1-1 and Essen 1-1-1-1-1 regimens in patients with WHO category II exposure in China. Side effects including systemic and local symptoms were recorded for all patients during vaccination with purified chick embryo cell vaccine (PCECV) under Zagreb 2-1-1 or Essen 1-1-1-1-1 regimens, and the rabies neutralization antibody titers in patients' serum at days 0, 7, 14, 45, 365 post-immunization were measured to determine the immunogenicity. Fever and pain were the most common events for systemic and local symptoms respectively, and most side effects (86.78%, 105/121) occurred after the first dose of vaccination. Safety analysis showed differences in side effects inZagreb and Essen regimens, especially after the first dose of vaccination (P = 0.043). Immunogenicity analysis indicated that Zagreb can achieve higher neutralization antibody titers and a greater seroconversion rate in a shorter time but had less persistence than Essen. When compared with the Essen regimen, the Zagreb regimen had a different immunogenicity in all study subjects, and different safety profile in young children, and a further study with a larger population and longer surveillance is warranted.

Oral antidiabetic therapy in a large Italian sample: drug supply and compliance for different therapeutic regimens

CERN Document Server

Vittorino Gaddi, A; Capello, F; Di Pietro, C; Cinconze, E; Rossi, E; De Sando, V; Cevenini, M; D'Alò, G

2014-01-01

Objectives: To define the main features of patients treated with oral antidiabetics, evaluating monotherapy (MT), loose-dose combination therapy (LDCT) and fixed-dose combination therapy (FDCT); to describe medication adherence to the different therapies; and to evaluate the differences in compliance with the prescribed therapy regimen among prevalent and incident patient cohorts. Study design: This study was a retrospective cohort analysis based on the ARNO database, a national record that tracks reimbursable prescription claims submitted from selected pharmacies to the Italian national health system. In total, 169,375 subjects, from an overall population of 4,040,624 were included in this study. The patients represented 12 different local health units. Each patient had at least one oral antidiabetic prescription claim (A10B ATC code). Methods: Patients were divided into four groups according to their treatment regimen during the recruitment period (1 January 2008-31 December 2008): MT, FDCT, LDCT and swi...

Efficacy of various single-dose regimens of ceftriaxone in ...

African Journals Online (AJOL)

1990-08-18

Aug 18, 1990 ... The therapeutic efficacy of single intramuscular doses of ceftriaxone (Rocephin; Roche) (62,S, 125 and 250 mg), admini- stered without probenecid, was evaluated in 167 adult males with uncomplicated acute gonococcal urethritis. Cure rates of 100% were achieved at 62,5 mg and 250 mg. In the 125 mg.

CMV and BKPyV Infections in Renal Transplant Recipients Receiving an mTOR Inhibitor-Based Regimen Versus a CNI-Based Regimen: A Systematic Review and Meta-Analysis of Randomized, Controlled Trials.

Science.gov (United States)

Mallat, Samir G; Tanios, Bassem Y; Itani, Houssam S; Lotfi, Tamara; McMullan, Ciaran; Gabardi, Steven; Akl, Elie A; Azzi, Jamil R

2017-08-07

The objective of this meta-analysis is to compare the incidences of cytomegalovirus and BK polyoma virus infections in renal transplant recipients receiving a mammalian target of rapamycin inhibitor (mTOR)-based regimen compared with a calcineurin inhibitor-based regimen. We conducted a comprehensive search for randomized, controlled trials up to January of 2016 addressing our objective. Other outcomes included acute rejection, graft loss, serious adverse events, proteinuria, wound-healing complications, and eGFR. Two review authors selected eligible studies, abstracted data, and assessed risk of bias. We assessed quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation methodology. We included 28 randomized, controlled trials with 6211 participants classified into comparison 1: mTOR inhibitor versus calcineurin inhibitor and comparison 2: mTOR inhibitor plus reduced dose of calcineurin inhibitor versus regular dose of calcineurin inhibitor. Results showed decreased incidence of cytomegalovirus infection in mTOR inhibitor-based group in both comparison 1 (risk ratio, 0.54; 95% confidence interval, 0.41 to 0.72), with high quality of evidence, and comparison 2 (risk ratio, 0.43; 95% confidence interval, 0.24 to 0.80), with moderate quality of evidence. The available evidence neither confirmed nor ruled out a reduction of BK polyoma virus infection in mTOR inhibitor-based group in both comparisons. Secondary outcomes revealed more serious adverse events and acute rejections in mTOR inhibitor-based group in comparison 1 and no difference in comparison 2. There was no difference in graft loss in both comparisons. eGFR was higher in the mTOR inhibitor-based group in comparison 1 (mean difference =4.07 ml/min per 1.73 m 2 ; 95% confidence interval, 1.34 to 6.80) and similar to the calcineurin inhibitor-based group in comparison 2. More proteinuria and wound-healing complications occurred in the mTOR inhibitor-based groups. We found

Reversible reduction of nevirapine plasma concentrations during rifampicin treatment in patients coinfected with HIV-1 and tuberculosis.

Science.gov (United States)

Matteelli, Alberto; Saleri, Nuccia; Villani, Paola; Bonkoungou, Victor; Carvalho, Anna Cristina C; Kouanda, Seni; Sanou, Marie J; Simporé, Jacques; Monno, Laura; Carosi, Giampiero; Regazzi, Mario; Dembele, Mathurin

2009-09-01

Nevirapine (NVP) plasma levels are reduced in patients receiving rifampicin (RFM) for tuberculosis (TB) treatment. We determined variations over time of the pharmacokinetic parameters of NVP in patients who receive RFM. HIV-1-infected patients with CD4+ T-lymphocyte count dose combination of stavudine, lamivudine, and NVP. Full NVP pharmacokinetic curves were calculated at 4 (T1) and 10 weeks (T2) of combined therapy and at 4 (T3) and 26 weeks after termination of anti-TB therapy. In 16 enrolled subjects, the median value of the area under the curve of NVP was reduced by 25.6% at T1 compared with NVP alone (43.7 vs. 58.7 microg x mL(-1) x h(-1); P = 0.02). The reduction was only 7.5% at T2 (54.3 vs. 58.7 microg x mL(-1) x h(-1); P = 0.17). The median C trough was reduced of 19.5% at T1 compared with T3 (3.3 vs. 4.2 microg/mL; P = 0.02) and of 7.1% at T2 compared with T3 (3.9 vs. 4.2 microg/mL; P = 0.17). The proportion of subjects with C trough values

Therapeutical evaluation of different dose regimens of praziquantel in schistosomiasis mansoni, based on the quantitative oogram technique

Directory of Open Access Journals (Sweden)

Aloísio Sales da Cunha

1987-10-01

Full Text Available A clinical trial involving 80 patients of both sexes, from ages 15 to 55, with chronic intestinal or hepatointestinal schistosomiasis mansoni, was carried out to evaluate the therapeutical efficacy of different dose regimens of praziquantel. The patients were randomly allocated into four groups with an equal number of cases and were then treated with one of the following dosages: 60 mg/kg for 1 day; 60 mg/kg daily for 2 days; 60 mg/kg daily for 3 days; and 30 mg/kg daily for 6 days. The assessment of parasitological cure was based on the quantitative oogram technique through rectal mucosa biopsies which were undertaken prior to, as well as, 1,2,4 and 6 months post-treatment. Concurrently, stool examinations according to the qualitative Hoffman, Pons & Janer (HPJ and the quantitative Kato-Katz (K-K methods were also performed. The best tolerability was observed with 30 mg/kg daily for 6 days whereas the highest incidence of side-effects (mainly dizziness and nausea was found with 60 mg/kg daily for 3 days. No serious adverse drug reaction has occurred. The achieved cure rates were: 25% with 60 mg/kg for 1 day; 60% with 60 mg/kg daily for 2 days; 89.5% with 60 mg/kg daily for 3 days; and 90% with 30 mg/kg daily for 6 days. At the same time there has been a downfall of 64%, 73%, 87% and 84% respectively, in the median number of viable S. mansoni ova per gram of tissue. Thus, a very clear direct correlation between dose and effect could be seen. The corresponding cure rates according to stool examinations by HPJ were 39%, 80%, 100% and 95%; by K-K 89%, 100%, 100% and 100%. This discrepancy in results amongst the three parasitological methods is certainly due to their unequal accuracy. In fact, when the number of viable eggs per gram of tissue fell below 5,000 the difference in the percentage of false negative findings between HPJ (28% and K-K (80% became significative. When this number dropped to less than 2,000 the percentage of false negative

Primary radiotherapy of stage IIA/B-IIIB cervical carcinoma. A comparison of continuous versus sequential regimens

International Nuclear Information System (INIS)

Mayer, A.; Nemeskeri, C.; Petnehazi, C.; Varga, S.; Naszaly, A.; Borgulya, G.

2004-01-01

Background: comprehensive literature on cervical cancer demonstrates, even today, the need for optimization of the timing of external-beam radiotherapy (EBRT) and high-dose-rate brachytherapy (HDR-BT) in the treatment of stage IIA/B-IIIB cervical carcinoma. Patients and methods: 210 patients with carcinoma of the cervix were treated in the Municipal Center of Oncoradiology between January 1991 and December 1996 (FIGO IIA: n = 10, FIGO IIB: n = 113, and FIGO IIIB: n = 87). Two regimens were compared: sequential radiation therapy (SRT) with 4 x 8 Gy HDR-BT to point A followed by EBRT, and continuous radiation therapy (CRT) in which 5 x 6 Gy HDR-BT to point A, one session per week, was integrated into the EBRT. A total dose of 68-70 Gy to point A and 52-54 Gy to point B was given in EBRT with SRT, five fractions per week were applied. Four fractions per week were applied in CRT, i.e., no EBRT was performed on the day of HDR-BT. Total doses to points A and B were identical in both regimens. Overall treatment time (OTT) amounted to 56 days for SRT and 35 days for CRT. Median follow-up time was 3.4 (2.5-4.2) years. Results: progression-free 5-year-survival (PFS) was 71% in the CRT and 56% in the SRT group. Nevertheless, this difference was not statistically significant (p = 1.00), and the same was found in a subgroup analysis of the different tumor stages, showing, however, an unequivocal trend. Late bladder and rectal injuries occurred in 13% and 25%, respectively. Late rectal injuries were significantly more frequent with SRT than CRT (35 patients in the SRT and 18 patients in the CRT group; p = 0.037). This was due to the higher doses per fraction of HDR-BT in the SRT group. No difference was found regarding late bladder injuries (p = 0.837). Conclusion: for the patients included in this study, no advantage has been found so far in using CRT, i.e., shortening the OTT by weekly integration of HDR-BT into EBRT. Nevertheless, an obvious trend exists. The dose of 8 Gy per

Single-dose ceftriaxone for chancroid.

Science.gov (United States)

Bowmer, M I; Nsanze, H; D'Costa, L J; Dylewski, J; Fransen, L; Piot, P; Ronald, A R

1987-01-01

Men with genital ulcers that were culture positive for Haemophilus ducreyi were treated with intramuscular ceftriaxone and randomized to three different dose regimens. All but 1 of 50 men treated with 1 g of intramuscular ceftriaxone were cured. Similarly, 0.5 and 0.25 g cured 43 of 44 men and 37 of 38 men, respectively. A single dose of 250 mg of intramuscular ceftriaxone is an effective treatment for chancroid. PMID:3566241

Predictive tools for designing new insulins and treatment regimens

DEFF Research Database (Denmark)

Klim, Søren

The thesis deals with the development of "Predictive tools for designing new insulins and treatments regimens" and consists of two parts: A model based approach for bridging properties of new insulin analogues from glucose clamp experiments to meal tolerance tests (MTT) and a second part that des......The thesis deals with the development of "Predictive tools for designing new insulins and treatments regimens" and consists of two parts: A model based approach for bridging properties of new insulin analogues from glucose clamp experiments to meal tolerance tests (MTT) and a second part...... that describes an implemented software program able to handle stochastic differential equations (SDEs) with mixed effects. The thesis is supplemented with scientific papers published during the PhD. Developing an insulin analogue from candidate molecule to a clinical drug consists of a development programme...... and efficacy are investigated. Numerous methods are used to quantify dose and efficacy in Phase II - especially of interest is the 24-hour meal tolerance test as it tries to portray near normal living conditions. Part I describes an integrated model for insulin and glucose which is aimed at simulating 24-hour...

Optimizing dosing frequencies for bisphosphonates in the management of postmenopausal osteoporosis: patient considerations

Directory of Open Access Journals (Sweden)

John Sunyecz

2008-12-01

Full Text Available John SunyeczMenopauseRx, Inc., Hopwood, PA, USAAbstract: Postmenopausal osteoporosis is common and underrecognized among elderly women. Osteoporotic fractures cause disability and disfigurement and threaten patients’ mobility, independence, and survival. Care for incident fractures in this age group must go beyond orthopedic repair, to assessment and treatment of the underlying bone fragility. Fracture risk can be reduced by vitamin D and calcium supplementation along with antiresorptive drug treatment. First-line osteoporosis pharmacotherapy employs nitrogen-containing bisphosphonates. The inconvenience of daily oral treatment has motivated development of weekly, monthly, and intermittent oral regimens, as well as quarterly and yearly intravenous (iv regimens. Ibandronate is the first bisphosphonate to have shown direct anti-fracture efficacy with a non-daily regimen; it was approved for once-monthly oral dosing in 2005 and for quarterly iv dosing in 2006. Intermittent oral risedronate and yearly iv zoledronic acid were approved in 2007. Newly available regimens with extended dosing intervals reduce the inconvenience of bisphosphonate therapy and provide patients with a range of options from which to select a maximally sustainable course of treatment. This review discusses the development, efficacy, safety, and tolerability of extended-interval bisphosphonate regimens and examines their potential to improve patient acceptance and long-term success of osteoporosis treatment.Keywords: ibandronate, alendronate, risedronate, zoledronic acid, adherence, persistence

Comparison between chloral hydrate and propofol-ketamine as sedation regimens for pediatric auditory brainstem response testing.

Science.gov (United States)

Abulebda, Kamal; Patel, Vinit J; Ahmed, Sheikh S; Tori, Alvaro J; Lutfi, Riad; Abu-Sultaneh, Samer

2017-10-28

The use of diagnostic auditory brainstem response testing under sedation is currently the "gold standard" in infants and young children who are not developmentally capable of completing the test. The aim of the study is to compare a propofol-ketamine regimen to an oral chloral hydrate regimen for sedating children undergoing auditory brainstem response testing. Patients between 4 months and 6 years who required sedation for auditory brainstem response testing were included in this retrospective study. Drugs doses, adverse effects, sedation times, and the effectiveness of the sedative regimens were reviewed. 73 patients underwent oral chloral hydrate sedation, while 117 received propofol-ketamine sedation. 12% of the patients in the chloral hydrate group failed to achieve desired sedation level. The average procedure, recovery and total nursing times were significantly lower in the propofol-ketamine group. Propofol-ketamine group experienced higher incidence of transient hypoxemia. Both sedation regimens can be successfully used for sedating children undergoing auditory brainstem response testing. While deep sedation using propofol-ketamine regimen offers more efficiency than moderate sedation using chloral hydrate, it does carry a higher incidence of transient hypoxemia, which warrants the use of a highly skilled team trained in pediatric cardio-respiratory monitoring and airway management. Copyright © 2017 Associação Brasileira de Otorrinolaringologia e Cirurgia Cérvico-Facial. Published by Elsevier Editora Ltda. All rights reserved.

Optimizing lithium dosing in hemodialysis

DEFF Research Database (Denmark)

Bjarnason, N H; Munkner, R; Kampmann, J P

2006-01-01

We studied a 62-year-old female hemodialysis patient during initiation and maintenance of lithium carbonate therapy. Three different methods were applied to estimate the regimen: a scenario based on volume of distribution (V(d)), a scenario based on glomerular filtration rate (GFR), and a scenario...... estimates. Furthermore, the maintenance dose estimated from the central compartment (V1) led to plasma concentrations within the therapeutic range. Thus, a regimen where 12.2 mmol lithium was given after each hemodialysis session resulted in stable between-dialysis plasma lithium concentrations...... in this patient with no residual kidney function. We did not observe adverse effects related to this regimen, which was monitored from 18 days to 8 months of therapy, and the patient experienced relief from her severe depressive disorder. In conclusion, dialysis patients may be treated with lithium administrated...

Comparative study on the immunogenicity and safety of a purified chick embryo cell rabies vaccine (PCECV) administered according to two different simulated post exposure intramuscular regimens (Zagreb versus Essen).

Science.gov (United States)

Mahendra, B J; Narayana, Dh Ashwath; Agarkhedkar, Sharad; Ravish, H S; Harish, B R; Agarkhedkar, Shalaka; Madhusudana, S N; Belludi, Ashwin; Ahmed, Khaleel; Jonnalagedda, Rekha; Vakil, Hoshang; Bhusal, Chiranjiwi; Arora, Ashwani Kumar

2015-01-01

Despite availability of effective rabies vaccines, India has the highest global mortality rate for rabies. Low socio-economic communities are most affected due to lack of awareness of the disease and poor compliance to post-exposure prophylactic regimens. Currently, the only approved intramuscular regimen for post-exposure prophylaxis (PEP) against rabies in India is the Essen regimen, which consists of 5 injections administered over 5 separate days in a period of one month. The high number of doses and clinical visits, however, are major reasons for non-compliance, and thus a shorter regimen would be beneficial. In a simulated PEP trial in healthy, adult subjects, this study evaluated whether purified chick embryo cell vaccine (PCECV), administered according to the WHO-recommended 4-dose/3 visit Zagreb vaccination regimen is of equal immunogenicity and safety as the standard Essen regimen in Indian subjects. Two hundred and 50 healthy adults were enrolled and randomized into a Zagreb or Essen group, each receiving PCECV according to their respective regimen. Blood samples were collected on Days 0, 7, 14 and 42 and analyzed using the rapid fluorescent focus inhibition test (RFFIT). By Day 14, all subjects across both groups attained rabies virus neutralizing antibody (RVNA) concentrations of ≥ 0.5IU/ml. The Zagreb regimen was then demonstrated to be immunologically non-inferior to the Essen regimen by Day 14, which was the primary endpoint of the study. No safety issues were noted and the occurrence of adverse events was similar in both groups (17% and 15%, respectively). NCT01365494. CTRI No.: CTRI/2011/07/001857.

Low rate of mother-to-child transmission of HIV-1 after nevirapine intervention in a pilot public health program in Yaoundé, Cameroon.

Science.gov (United States)

Ayouba, Ahidjo; Tene, Gilbert; Cunin, Patrick; Foupouapouognigni, Yacouba; Menu, Elisabeth; Kfutwah, Anfumbom; Thonnon, Jocelyn; Scarlatti, Gabriella; Monny-Lobé, Marcel; Eteki, Nicole; Kouanfack, Charles; Tardy, Michèle; Leke, Robert; Nkam, Maurice; Nlend, Anne E; Barré-Sinoussi, Françoise; Martin, Paul M V; Nerrienet, Eric

2003-11-01

To determine the percentage of infected children for whom nevirapine (NVP) was used to prevent peripartum mother-to-child transmission (MTCT) of HIV in Yaoundé, Cameroon. The study was a prospective Public Health Pilot Program covering a 3-year period (January 2000-December 2002). Counseled and consenting HIV-1-positive pregnant women were given a single dose of NVP at the onset of labor. Babies were given 2 mg/kg NVP syrup within the first 72 hours of life. NVP-treated children were regularly followed up and examined for HIV-1 infection at 6-8 weeks and 5-6 months through plasma viral load (VL) quantification with the bDNA system. One hundred twenty-three children were diagnosed with perinatal HIV-1 infection at 6-8 weeks and 5-6 months. Thirteen children (10.6% [13/123]; 95% confidence interval, 5.1-16) were infected and presented with high VLs, in general >500,000 copies/mL. Two children had intermediate VLs (between 50 and 3500 copies/mL) at both time points. One hundred seven children (87%) were considered not infected at 6-8 weeks of age. Our results indicate that the HIV-1 MTCT rate 6-8 weeks after NVP administration was not >13% (16/123), thus demonstrating the effectiveness of NVP for lowering the risk of HIV-1 MTCT in real-life settings.

Tumor Volume-Adapted Dosing in Stereotactic Ablative Radiotherapy of Lung Tumors

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Trakul, Nicholas; Chang, Christine N.; Harris, Jeremy [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); Chapman, Christopher [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); University of Michigan School of Medicine, Ann Arbor, MI (United States); Rao, Aarti [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); University of California, Davis, School of Medicine, Davis, CA (United States); Shen, John [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); University of California, Irvine, School of Medicine, Irvine, CA (United States); Quinlan-Davidson, Sean [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); Department of Radiation Oncology, McMaster University, Juravinski Cancer Centre, Hamilton, Ontario (Canada); Filion, Edith J. [Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA (United States); Departement de Medecine, Service de Radio-Oncologie, Centre Hospitalier de l' Universite de Montreal, Montreal, Quebec (Canada); Wakelee, Heather A.; Colevas, A. Dimitrios [Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, CA (United States); Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA (United States); Whyte, Richard I. [Department of Cardiothoracic Surgery, Division of General Thoracic Surgery, Stanford University School of Medicine, Stanford, CA (United States); Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA (United States); and others

2012-09-01

Purpose: Current stereotactic ablative radiotherapy (SABR) protocols for lung tumors prescribe a uniform dose regimen irrespective of tumor size. We report the outcomes of a lung tumor volume-adapted SABR dosing strategy. Methods and Materials: We retrospectively reviewed the outcomes in 111 patients with a total of 138 primary or metastatic lung tumors treated by SABR, including local control, regional control, distant metastasis, overall survival, and treatment toxicity. We also performed subset analysis on 83 patients with 97 tumors treated with a volume-adapted dosing strategy in which small tumors (gross tumor volume <12 mL) received single-fraction regimens with biologically effective doses (BED) <100 Gy (total dose, 18-25 Gy) (Group 1), and larger tumors (gross tumor volume {>=}12 mL) received multifraction regimens with BED {>=}100 Gy (total dose, 50-60 Gy in three to four fractions) (Group 2). Results: The median follow-up time was 13.5 months. Local control for Groups 1 and 2 was 91.4% and 92.5%, respectively (p = 0.24) at 12 months. For primary lung tumors only (excluding metastases), local control was 92.6% and 91.7%, respectively (p = 0.58). Regional control, freedom from distant metastasis, and overall survival did not differ significantly between Groups 1 and 2. Rates of radiation pneumonitis, chest wall toxicity, and esophagitis were low in both groups, but all Grade 3 toxicities developed in Group 2 (p = 0.02). Conclusion: A volume-adapted dosing approach for SABR of lung tumors seems to provide excellent local control for both small- and large-volume tumors and may reduce toxicity.

Once-daily use of inhaled corticosteroids: A new regimen in the treatment of persistent asthma

Directory of Open Access Journals (Sweden)

Jeffrey Leflein

2000-01-01

Strict patient adherence with prescribed anti-inflammatory medication is crucial for obtaining optimal therapeutic benefit for patients with asthma. Despite the proven effectiveness of inhaled corticosteroids, patient adherence to prescribed therapy is often low, resulting in increased patient morbidity. Complex dosing regimens contribute greatly to patient non-adherence. Thus, new once-daily regimens of inhaled corticosteroid treatment have been introduced as means to improve patient adherence and provide optimal therapeutic benefit. In the present review, the complex inflammatory and remodeling processes in asthma and their contributions to the clinical manifestations of the disease will be discussed. Currently available, once-daily inhaled corticosteroid treatment options and the advantages of these therapeutic options in the treatment of persistent asthma also will be discussed.

Bimonthly 24 h infusion of high-dose 5-fluorouracil vs EAP regimen in patients with advanced gastric cancer. A randomized phase II study.

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Popov, I P; Jelić, S B; Krivokapić, Z V; Jezdić, S D; Pesko, P M; Micev, M T; Babić, D R

2008-01-01

To investigate the activity and toxicity of high dose (HD) infusional 5-FU in comparison to EAP regimen as first-line chemotherapy in patients with advanced gastric cancer. Histologically confirmed measurable advanced gastric cancer, age EAP arm: doxorubicin (40 mg/m(2)), etoposide (360 mg/m(2)), and cisplatin (80 mg/m(2)) every 28 d; HD 5-FU arm: 5-FU 2.6 g/m(2) 24 h infusion, biweekly. Sixty patients were randomized. Patient characteristics (arms EAP/HD 5-FU): Median age 57/55 yr, median PS 1/1, LAD (patients) 3/8, M1 (patients) 27/22. Median number of cycles (range): EAP arm 4 (2-8), HD 5-FU arm 2 (1-8). Worst toxicity per cycle (grade 3 and 4 in%): Neutropenia 20/3, thrombocytopenia 9/0, anemia 9/13, diarrhea 3/10, nausea 17/7, vomiting 10/0 for EAP and HD 5-FU arms, respectively. All patients were eligible for response in both arms. Confirmed response rate (95%CI): EAP arm 34% [16-50%]/HD 5-FU arm 10% (0-21%), no change: 46/40%, progression of disease: 20/50, respectively. Overall survival (range): EAP arm A 7 mo [3-27], HD 5-FU arm 6 mo (4-25). Infusional HD 5-FU showed a low incidence of severe toxicity. But given the low efficacy of 5-FU in the dosage we applied in the study, it cannot be recommended as a single treatment for further studies. Assessment of higher dose intensity and/or dose density of 5-FU, with introduction of other active drugs in combination, could be an option for further studies.

Effectiveness of modified hyper-CVAD chemotherapy regimen in the treatment of adult acute lymphoblastic leukemia: a retrospective experience.

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Jalaeikhoo, Hasan; Rajaeinejad, Mohsen; Keyhani, Manoutchehr; Zokaasadi, Mohammad; Dehghani Firoozabadi, Mohammad Mehdi

2018-03-01

Several chemotherapy regimens have been developed for the treatment of acute lymphoblastic leukemia (ALL), but relapse still presents the most common obstacles to attaining long-term survival. The hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and prednisolone)/HD MTX and Ara-C (high-dose methotrexate and cytarabine) chemotherapy regimen was first started in the MD Anderson Cancer Center as an intensive regimen for adult patients with ALL. The purpose of this study was to evaluate the effectiveness of a modified hyper-CVAD protocol. We used hyper-CVAD as consolidation/maintenance after remission induction with daunorubicin, vincristine, and prednisolone (and cyclophosphamide for T-cell ALL only) rather than standard hyper-CVAD in order to reduce treatment complications. This study was conducted as a retrospective review of medical records of ALL patients at 501 army hospital, Tehran, Iran, from 2005 to 2015. Three hundred and one patients underwent modified hyper-CVAD chemotherapy regimen. Complete remission and overall survival (OS) rates were measured as primary endpoints. Two hundred and forty-six (81.7%) reached complete remission (CR) during the first 6 months of treatment, and 55 patients (18.3%) did not reach CR. The 5-year OS rate was 51.8% (95% CI (confidence interval): 45.1-57.8%). Modified hyper-CVAD regimen is an efficient intensive chemotherapy regimen for consolidation/maintenance of adults with newly diagnosed ALL and has an acceptable 5-year overall that is comparable to standard hyper-CVAD regimen. © 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

Albumin treatment regimen for type 1 hepatorenal syndrome: a dose-response meta-analysis.

Science.gov (United States)

Salerno, Francesco; Navickis, Roberta J; Wilkes, Mahlon M

2015-11-25

Recommended treatment for type 1 hepatorenal syndrome consists of albumin and vasoconstrictor. The optimal albumin dose remains poorly characterized. This meta-analysis aimed to determine the impact of albumin dose on treatment outcomes. Clinical studies of type 1 hepatorenal syndrome treatment with albumin and vasoconstrictor were sought. Search terms included: hepatorenal syndrome; albumin; vasoconstrictor; terlipressin; midodrine; octreotide; noradrenaline; and norepinephrine. A meta-analysis was performed of hepatorenal syndrome reversal and survival in relation to albumin dose. Nineteen clinical studies with 574 total patients were included, comprising 8 randomized controlled trials, 8 prospective studies and 3 retrospective studies. The pooled percentage of patients achieving hepatorenal syndrome reversal was 49.5% (95% confidence interval, 40.0-59.1%). Increments of 100 g in cumulative albumin dose were accompanied by significantly increased survival (hazard ratio, 1.15; 95% confidence interval, 1.02-1.31; p = 0.023). A non-significant increase of similar magnitude in hepatorenal syndrome reversal was also observed (odds ratio, 1.15; 95% confidence interval, 0.97-1.37; p = 0.10). Expected survival rates at 30 days among patients receiving cumulative albumin doses of 200, 400 and 600 g were 43.2% (95% confidence interval, 36.4-51.3%), 51.4% (95% confidence interval, 46.3-57.1%) and 59.0% (95% confidence interval, 51.9-67.2), respectively. Neither survival nor hepatorenal syndrome reversal was significantly affected by vasoconstrictor dose or type, treatment duration, age, baseline serum creatinine, bilirubin or albumin, baseline mean arterial pressure, or study design, size or time period. This meta-analysis suggests a dose-response relationship between infused albumin and survival in patients with type 1 hepatorenal syndrome. The meta-analysis provides the best current evidence on the potential role of albumin dose selection in improving outcomes of

Escalating dose, multiple binge methamphetamine regimen does not impair recognition memory in rats.

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Clark, Robert E; Kuczenski, Ronald; Segal, David S

2007-07-01

Rats exposed to methamphetamine (METH) in an acute high dose "binge" pattern have been reported to exhibit a persistent deficit in a novel object recognition (NOR) task, which may suggest a potential risk for human METH abusers. However, most high dose METH abusers initially use lower doses before progressively increasing the dose, only eventually engaging in multiple daily administrations. To simulate this pattern of METH exposure, we administered progressively increasing doses of METH to rats over a 14 day interval, then treated them with daily METH binges for 11 days. This treatment resulted in a persistent deficit in striatal dopamine (DA) levels of approximately 20%. We then tested them in a NOR task under a variety of conditions. We could not detect a deficit in their performance in the NOR task under any of the testing conditions. These results suggest that mechanisms other than or additional to the decrement in striatal DA associated with an acute METH binge are responsible for the deficit in the NOR task, and that neuroadaptations consequential to prolonged escalating dose METH pretreatment mitigate against these mechanisms.

Nevirapine Concentration in Hair Samples Is a Strong Predictor of Virologic Suppression in a Prospective Cohort of HIV-Infected Patients.

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Sanjiv M Baxi

Full Text Available Effective antiretroviral (ARV therapy depends on adequate drug exposure, yet methods to assess ARV exposure are limited. Concentrations of ARV in hair are the product of steady-state pharmacokinetics factors and longitudinal adherence. We investigated nevirapine (NVP concentrations in hair as a predictor of treatment response in women receiving ARVs. In participants of the Women's Interagency HIV Study, who reported NVP use for >1 month from 2003-2008, NVP concentrations in hair were measured via liquid-chromatography-tandem mass-spectrometry. The outcome was virologic suppression (plasma HIV RNA below assay threshold at the time of hair sampling and the primary predictor was nevirapine concentration categorized into quartiles. We controlled for age, race/ethnicity, pre-treatment HIV RNA, CD4 cell count, and self-reported adherence over the 6-month visit interval (categorized ≤ 74%, 75%-94% or ≥ 95%. We also assessed the relation of NVP concentration with changes in hepatic transaminase levels via multivariate random intercept logistic regression and linear regression analyses. 271 women contributed 1089 person-visits to the analysis (median 3 of semi-annual visits. Viral suppression was least frequent in concentration quartile 1 (86/178 (48.3% and increased in higher quartiles (to 158/204 (77.5% for quartile 4. The odds of viral suppression in the highest concentration quartile were 9.17 times (95% CI 3.2-26, P < 0.0001 those in the lowest. African-American race was associated with lower rates of virologic suppression independent of NVP hair concentration. NVP concentration was not significantly associated with patterns of serum transaminases. Concentration of NVP in hair was a strong independent predictor of virologic suppression in women taking NVP, stronger than self-reported adherence, but did not appear to be strongly predictive of hepatotoxicity.

Efficacy of two regimens of dexamethasone for management of preterm labour: pilot study

International Nuclear Information System (INIS)

Rasool, A.; Farooq, U.

2017-01-01

Background: Dexamethasone is widely used for prevention of respiratory distress syndrome (RDS), necrotising enterocolitis (NEC) and intra-ventricular haemorrhage (IVH) in preterm babies; decreasing the neonatal mortality rate. There is no consensus on the dose of corticosteroid administered to the mother expected to have a preterm baby. This study is conducted to compare the effectiveness of two popular regimens of dexamethasone administration in decreasing incidence of RDS, necrotizing enterocolitis, IVH and neonatal mortality rate. Methods: Randomized control trial was conducted at Ayub Teaching Hospital, Abbottabad from 1st to 31st August, 2014. Sample size was set at 50. Block randomization was employed in the trial to allocate the patients into corresponding groups 'A' and 'B'. Group A was administered 6mg dexamethasone in 4 doses 12 hours apart and group B was administered 2 doses 12 hours apart. Results: Forty-eight patients participated in the study with 24 patients in each group. Mean age and period gestation of participants were 28.4 years±4.3 SD and 34 weeks±1.9 SD respectively. Four patients in group A gave birth to neonate with RDS compared to two cases in group B. Group B had higher incidence of necrotizing enterocolitis and neonatal mortalities. However, none of these differences observed were statistically significant. No case of IVH was reported in either of the groups. Conclusion: Both the popular regimens of dexamethasone administration are equally effective in decreasing the incidence of neonatal diseases. (author)

Efficacy and safety of a modified intravenous recombinant tissue plasminogen activator regimen in Chinese patients with acute ischemic stroke.

Science.gov (United States)

Pan, Shu-Ming; Liu, Jia-Fu; Liu, Ming; Shen, Sa; Li, Hao-Jun; Dai, Li-Hua; Chen, Xiang-Jun

2013-07-01

Thrombolytic treatment with intravenous (IV) recombinant tissue plasminogen activator (rtPA; 0.90 mg/kg, with a maximum dose of 90 mg) has been recommended as the standard management for acute ischemic stroke (AIS) thrombolysis. However, the dose of IV rtPA in Asia remains controversial. This study was designed to verify the safety and efficacy of IV rtPA treatment for AIS with a lower dosage (0.90 mg/kg, with a maximum dose of 50 mg). Patients were divided into 3 dosage groups according to body weight (BW): group 1, 67 kg for descent were included in the study. The baseline characteristics of the 3 dosage groups were well matched. In group 1 (BW 67 kg for <0.75 mg/kg; n = 31; P = .362). There were no significantly statistical differences in the incidence of symptomatic intracerebral hemorrhage and mortality rate. This IV rtPA regimen (0.90 mg/kg, with a maximum dose of 50 mg) not only shows sufficient favorable outcome in clinical practice in Chinese patients with AIS but also good health economic savings. This regimen could be suitable for many developing countries. Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Standard effective doses for proliferative tumours

International Nuclear Information System (INIS)

Jones, L.C.; Hoban, P.

1999-01-01

This study was undertaken to investigate the treatment schedules used clinically for highly proliferative tumours, particularly with reference to the effects of fraction size, fraction number and treatment duration. The linear quadratic model (with time component) is used here to compare non-standard treatment regimens (e.g. accelerated and hyperfractionated schedules), currently the focus of randomized trials, with each other and some common 'standard regimens'. To ensure easy interpretation of results, two parameters known as proliferative standard effective dose one (PSED 1 ) and proliferative standard effective dose two (PSED 2 ) have been calculated for each regimen. Graphs of PSED 1 and PSED 2 versus potential doubling time (T p ) have been generated for a range of fractionation regimens which are currently under trial in various randomized studies. From these graphs it can be seen that the highly accelerated schedules (such as CHART) only show advantages for tumours with very short potential doubling times. Calculations for most of the schedules considered showed at least equivalent tumour control expected for the trial schedule compared with the control arm used and these values agree quite well with clinical results. These calculations are in good agreement with clinical results available at present. The greater the PSED 1 or PSED 2 for the schedule considered the greater the tumour control, which can be expected. However, as has been seen with clinical trials, this higher cell kill also results in higher acute effects which have proved too great for some accelerated schedules to continue. (author)

Exposure of the Heart in Breast Cancer Radiation Therapy: A Systematic Review of Heart Doses Published During 2003 to 2013

International Nuclear Information System (INIS)

Taylor, Carolyn W.; Wang, Zhe; Macaulay, Elizabeth; Jagsi, Reshma; Duane, Frances; Darby, Sarah C.

2015-01-01

Purpose: Breast cancer radiation therapy cures many women, but where the heart is exposed, it can cause heart disease. We report a systematic review of heart doses from breast cancer radiation therapy that were published during 2003 to 2013. Methods and Materials: Eligible studies were those reporting whole-heart dose (ie, dose averaged over the whole heart). Analyses considered the arithmetic mean of the whole-heart doses for the CT plans for each regimen in each study. We termed this “mean heart dose.” Results: In left-sided breast cancer, mean heart dose averaged over all 398 regimens reported in 149 studies from 28 countries was 5.4 Gy (range, <0.1-28.6 Gy). In regimens that did not include the internal mammary chain (IMC), average mean heart dose was 4.2 Gy and varied with the target tissues irradiated. The lowest average mean heart doses were from tangential radiation therapy with either breathing control (1.3 Gy; range, 0.4-2.5 Gy) or treatment in the lateral decubitus position (1.2 Gy; range, 0.8-1.7 Gy), or from proton radiation therapy (0.5 Gy; range, 0.1-0.8 Gy). For intensity modulated radiation therapy mean heart dose was 5.6 Gy (range, <0.1-23.0 Gy). Where the IMC was irradiated, average mean heart dose was around 8 Gy and varied little according to which other targets were irradiated. Proton radiation therapy delivered the lowest average mean heart dose (2.6 Gy, range, 1.0-6.0 Gy), and tangential radiation therapy with a separate IMC field the highest (9.2 Gy, range, 1.9-21.0 Gy). In right-sided breast cancer, the average mean heart dose was 3.3 Gy based on 45 regimens in 23 studies. Conclusions: Recent estimates of typical heart doses from left breast cancer radiation therapy vary widely between studies, even for apparently similar regimens. Maneuvers to reduce heart dose in left tangential radiation therapy were successful. Proton radiation therapy delivered the lowest doses. Inclusion of the IMC doubled typical heart dose.

A retrospective evaluation of activity of gemcitabine/platinum regimens in the treatment of recurrent ovarian cancer

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Tran N. Le

2017-11-01

Full Text Available Abstract Background While many of these agents have been compared in prospective clinical trials, the gemcitabine/platinumbased regimens have not been compared in a prospective, randomized clinical trial. While bothgemcitabine/carboplatin and gemcitabine/cisplatin have a similar ORR in separate clinical trials, the tworegimens have never been directly been compared. With overlapping dose-limiting toxicity of thrombocytopenia, the gemcitabine/carboplatin regimen has been challenging to employ in the clinical setting in previously treated ovarian cancer patients and is often associated with treatment delays and/or dose reductions. Gemcitabine/cisplatin can also be a challenge due to its dose limiting neuropathy and renal toxicity, especially in previously treated patients. In the absence of any prospective, head to head comparison this retrospective study was embarked upon to compare the response rate and toxicity profiles of gemcitabine/cisplatin verses gemcitabine/carboplatin for the treatment of platinum-sensitive verses platinum-resistant recurrent ovarian cancer. Methods This was a retrospective chart review study that identified patients that had received either gemcitabine/cisplatin or gemcitabine/carboplatin for treatment of recurrent ovarian cancer and compared documented hematological and non-hematological toxicity and response based on RECIST (v1.1. Data was evaluated based upon platinum sensitivity/resistance as well. Results A total of 93 patients were identified that had received a gemcitabine/platinum regimen with 48 with recurrent ovarian cancer that were included in the study. There were 21 patients in the gemcitabine/cisplatin arm and 27 patients identified in the gemcitabine/carboplatin arm. Objective response rate (ORR was greater in platinum-sensitive patients that received gemcitabine/carboplatin compared to gemcitabine/cisplatin (8 (67% vs 2 (25%, p < 0.05. Conversely, ORR was greater in platinum-resistant patients treated

Predicting Optimal Dihydroartemisinin-Piperaquine Regimens to Prevent Malaria During Pregnancy for Human Immunodeficiency Virus-Infected Women Receiving Efavirenz.

Science.gov (United States)

Wallender, Erika; Vucicevic, Katarina; Jagannathan, Prasanna; Huang, Liusheng; Natureeba, Paul; Kakuru, Abel; Muhindo, Mary; Nakalembe, Mirium; Havlir, Diane; Kamya, Moses; Aweeka, Francesca; Dorsey, Grant; Rosenthal, Philip J; Savic, Radojka M

2018-03-05

A monthly treatment course of dihydroartemisinin-piperaquine (DHA-PQ) effectively prevents malaria during pregnancy. However, a drug-drug interaction pharmacokinetic (PK) study found that pregnant human immunodeficiency virus (HIV)-infected women receiving efavirenz-based antiretroviral therapy (ART) had markedly reduced piperaquine (PQ) exposure. This suggests the need for alternative DHA-PQ chemoprevention regimens in this population. Eighty-three HIV-infected pregnant women who received monthly DHA-PQ and efavirenz contributed longitudinal PK and corrected QT interval (QTc) (n = 25) data. Population PK and PK-QTc models for PQ were developed to consider the benefits (protective PQ coverage) and risks (QTc prolongation) of alternative DHA-PQ chemoprevention regimens. Protective PQ coverage was defined as maintaining a concentration >10 ng/mL for >95% of the chemoprevention period. PQ clearance was 4540 L/day. With monthly DHA-PQ (2880 mg PQ), 96% of women, respectively. All regimens were safe, with ≤2% of women predicted to have ≥30 msec QTc increase. For HIV-infected pregnant women receiving efavirenz, low daily DHA-PQ dosing was predicted to improve protection against parasitemia and reduce risk of toxicity compared to monthly dosing. NCT02282293. © The Author(s) 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.

Does short-term virologic failure translate to clinical events in antiretroviral-naïve patients initiating antiretroviral therapy in clinical practice?

DEFF Research Database (Denmark)

NN, NN; Mugavero, Michael J; May, Margaret

2008-01-01

, nevirapine, lopinavir/ritonavir, nelfinavir, or abacavir as third drugs in combination with a zidovudine and lamivudine nucleoside reverse transcriptase inhibitor backbone. MAIN OUTCOME MEASURES: Short-term (24-week) virologic failure (>500 copies/ml) and clinical events within 2 years of ART initiation.......58-2.22), lopinavir/ritonavir (1.32, 95% CI = 1.12-1.57), nelfinavir (3.20, 95% CI = 2.74-3.74), and abacavir (2.13, 95% CI = 1.82-2.50). However, the rate of clinical events within 2 years of ART initiation appeared higher only with nevirapine (adjusted hazard ratio for composite outcome measure 1.27, 95% CI = 1......OBJECTIVE: To determine whether differences in short-term virologic failure among commonly used antiretroviral therapy (ART) regimens translate to differences in clinical events in antiretroviral-naïve patients initiating ART. DESIGN: Observational cohort study of patients initiating ART between...

Tumor Volume-Adapted Dosing in Stereotactic Ablative Radiotherapy of Lung Tumors

International Nuclear Information System (INIS)

Trakul, Nicholas; Chang, Christine N.; Harris, Jeremy; Chapman, Christopher; Rao, Aarti; Shen, John; Quinlan-Davidson, Sean; Filion, Edith J.; Wakelee, Heather A.; Colevas, A. Dimitrios; Whyte, Richard I.

2012-01-01

Purpose: Current stereotactic ablative radiotherapy (SABR) protocols for lung tumors prescribe a uniform dose regimen irrespective of tumor size. We report the outcomes of a lung tumor volume-adapted SABR dosing strategy. Methods and Materials: We retrospectively reviewed the outcomes in 111 patients with a total of 138 primary or metastatic lung tumors treated by SABR, including local control, regional control, distant metastasis, overall survival, and treatment toxicity. We also performed subset analysis on 83 patients with 97 tumors treated with a volume-adapted dosing strategy in which small tumors (gross tumor volume <12 mL) received single-fraction regimens with biologically effective doses (BED) <100 Gy (total dose, 18–25 Gy) (Group 1), and larger tumors (gross tumor volume ≥12 mL) received multifraction regimens with BED ≥100 Gy (total dose, 50–60 Gy in three to four fractions) (Group 2). Results: The median follow-up time was 13.5 months. Local control for Groups 1 and 2 was 91.4% and 92.5%, respectively (p = 0.24) at 12 months. For primary lung tumors only (excluding metastases), local control was 92.6% and 91.7%, respectively (p = 0.58). Regional control, freedom from distant metastasis, and overall survival did not differ significantly between Groups 1 and 2. Rates of radiation pneumonitis, chest wall toxicity, and esophagitis were low in both groups, but all Grade 3 toxicities developed in Group 2 (p = 0.02). Conclusion: A volume-adapted dosing approach for SABR of lung tumors seems to provide excellent local control for both small- and large-volume tumors and may reduce toxicity.

The history of antiretrovirals: key discoveries over the past 25 years.

Science.gov (United States)

De Clercq, Erik

2009-09-01

Within 25 years after zidovudine (3'-azido-2',3'-dideoxythymidine, AZT) was first described as an inhibitor of HIV replication, 25 anti-HIV drugs have been formally approved for clinical use in the treatment of HIV infections: seven nucleoside reverse transcriptase inhibitors (NRTIs): zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir and emtricitabine; one nucleotide reverse transcriptase inhibitor (NtRTI): tenofovir [in its oral prodrug form: tenofovir disoproxil fumarate (TDF)]; four non-nucleoside reverse transcriptase inhibitors (NNRTIs): nevirapine, delavirdine, efavirenz and etravirine; ten protease inhibitors (PIs): saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir, atazanavir, fosamprenavir, tipranavir and darunavir; one fusion inhibitor (FI): enfuvirtide; one co-receptor inhibitor (CRI): maraviroc and one integrase inhibitor (INI): raltegravir. These compounds are used in various drug combination (some at fixed dose) regimens so as to achieve the highest possible benefit and tolerability, and to diminish the risk of virus-drug resistance development. (c) 2009 John Wiley & Sons, Ltd.

Phase I dose-finding study of cabazitaxel administered weekly in patients with advanced solid tumours

International Nuclear Information System (INIS)

Fumoleau, Pierre; Trigo, Jose Manuel; Isambert, Nicolas; Sémiond, Dorothée; Gupta, Sunil; Campone, Mario

2013-01-01

Cabazitaxel is approved in patients with metastatic hormone-refractory prostate cancer previously treated with a docetaxel-containing regimen. This study evaluated a weekly cabazitaxel dosing regimen. Primary objectives were to report dose-limiting toxicities (DLTs) and to determine the maximum tolerated dose (MTD). Efficacy, safety and pharmacokinetics were secondary objectives. Cabazitaxel was administered weekly (1-hour intravenous infusion at 1.5–12 mg/m2 doses) for the first 4 weeks of a 5-week cycle in patients with solid tumours. Monitoring of DLTs was used to determine the MTD and the recommended weekly dose. Thirty-one patients were enrolled. Two of six patients experienced DLTs at 12 mg/m 2 , which was declared the MTD. Gastrointestinal disorders were the most common adverse event. Eight patients developed neutropenia (three ≥ Grade 3); one occurrence of febrile neutropenia was reported. There were two partial responses (in breast cancer) and 13 patients had stable disease (median duration of 3.3 months). Increases in C max and AUC 0–t were dose proportional for the 6–12 mg/m 2 doses. The MTD of weekly cabazitaxel was 12 mg/m 2 and the recommended weekly dose was 10 mg/m 2 . The observed safety profile and antitumour activity of cabazitaxel were consistent with those observed with other taxanes in similar dosing regimens. The study was registered with ClinicalTrials.gov as http://www.clinicaltrials.gov/ct2/show/NCT01755390

Responses of rat R-1 cells to low dose rate gamma radiation and multiple daily dose fractions

International Nuclear Information System (INIS)

Kal, H.B.; Bijman, J.Th.

1981-01-01

Multifraction irradiation may offer the same therapeutic gain as continuous irradiation. Therefore, a comparison of the efficacy of low dose rate irradiation and multifraction irradiation was the main objective of the experiments to be described. Both regimens were tested on rat rhabdomyosarcoma (R-1) cells in vitro and in vivo. Exponentially growing R-1 cells were treated in vitro by a multifraction irradiation procedure with dose fractions of 2 Gy gamma radiation and time intervals of 1 to 3 h. The dose rate was 1.3 Gy.min -1 . The results indicate that multifractionation of the total dose is more effective with respect to cell inactivation than continuous irradiation. (Auth.)

Influence of the number of daily pills and doses on adherence to antiretroviral treatment: a 7-year study.

Science.gov (United States)

Hernández Arroyo, M J; Cabrera Figueroa, S E; Sepúlveda Correa, R; Valverde Merino, M P; Luna Rodrigo, G; Domínguez-Gil Hurlé, A

2016-02-01

Antiretroviral treatment (ART) is hampered by complicated regimens, high pill burden, drug-drug interactions, and frequent short- and long-term adverse effects, leading to decreased adherence. Over recent years, considerable effort has been directed at developing regimens that are less burdening. We undertook a 7-year retrospective study of the records of 264 HIV-infected subjects enrolled in a pharmaceutical care programme to document the progress made and to study the influence of the number of ART pills and doses on the level of treatment adherence. Antiretroviral dispensing records were analysed for the number of pills and doses administered and the ART adherence rate estimated. In 2005, the patients took a mean of 6·2 pills daily (CI 95%: 5·9-6·6), and 92·9% of them were on a twice-a-day (BID) dosage regimen. By 2012, the mean number of pills was reduced to 4·1 (CI 95%: 3·8-4·4), and only 50·9% were on a BID regimen. No statistically significant relation was observed between number of daily pills and doses and ART adherence reached by the patients in any of the analyses performed. There has been a continuous reduction in the number of pills and doses of antiretrovirals taken by individual patients over the last 7 years due largely to the introduction of improved treatments and regimens. More daily pills or doses was not associated with worse ART adherence in our pharmaceutical care programme. © 2015 John Wiley & Sons Ltd.

Intermittent preventive treatment of malaria with sulphadoxine-pyrimethamine during pregnancy in Burkina Faso: effect of adding a third dose to the standard two-dose regimen on low birth weight, anaemia and pregnancy outcomes

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Roberfroid Dominique

2010-11-01

Full Text Available Abstract Background Intermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP is being implemented in most malaria endemic countries as a standard two-doses regimen as it reduces the risk of low birth weight (LBW and the prevalence of maternal anaemia. Nevertheless, where the risk of infection close to delivery is high because of intense transmission, a third IPTp-SP dose may further reduce the negative effects of malaria on pregnancy outcome. Methods Pregnant women in the 2nd or 3rd trimester were randomized to receive either 2 (SP2 or 3 doses (SP3 of SP. Trained field workers paid home visits to the women for drug administration according to a predefined drug delivery schedule. Women were encouraged to attend their scheduled ANC visits and to deliver at the health facilities where the new-born was weighed. The prevalence of LBW ( Results Data from 1274 singleton pregnancies were analysed (641 in the SP3 and 633 in the SP2 group. The uptake of the intervention appeared to be low. Though the prevalence of LBW in both intervention groups was similar (adjusted Incident Rate Ratio, AIRR = 0.92, 95%CI: 0.69-1.24 in the ITT analysis, the risk of severe anaemia was significantly lower in the SP3 group compared to the SP2 group (AIRR = 0.38, 95%CI: 0.16 - 0.90. The PP analysis showed a trend of reduced risk of LBW, severe anaemia and premature delivery in the SP3 group, albeit the difference between two and three IPTp-SP did not reach statistical significance. Conclusion The risk of LBW and severe anaemia tended to be lower in the SP3 group, though this was not statistically significant, probably due to the low uptake of the intervention which reduced the power of the study. Further studies are needed for establishing whether a third SP dose has a real benefit in preventing the negative effects of malaria in pregnancy in settings where transmission is markedly seasonal.

Intermittent preventive treatment of malaria with sulphadoxine-pyrimethamine during pregnancy in Burkina Faso: effect of adding a third dose to the standard two-dose regimen on low birth weight, anaemia and pregnancy outcomes.

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Valea, Innocent; Tinto, Halidou; Drabo, Maxime K; Huybregts, Lieven; Henry, Marie-Claire; Roberfroid, Dominique; Guiguemde, Robert T; Kolsteren, Patrick; D'Alessandro, Umberto

2010-11-12

Intermittent preventive treatment with sulphadoxine-pyrimethamine (IPTp-SP) is being implemented in most malaria endemic countries as a standard two-doses regimen as it reduces the risk of low birth weight (LBW) and the prevalence of maternal anaemia. Nevertheless, where the risk of infection close to delivery is high because of intense transmission, a third IPTp-SP dose may further reduce the negative effects of malaria on pregnancy outcome. Pregnant women in the 2nd or 3rd trimester were randomized to receive either 2 (SP2) or 3 doses (SP3) of SP. Trained field workers paid home visits to the women for drug administration according to a predefined drug delivery schedule. Women were encouraged to attend their scheduled ANC visits and to deliver at the health facilities where the new-born was weighed. The prevalence of LBW (anaemia (Hb pregnancies were analysed (641 in the SP3 and 633 in the SP2 group). The uptake of the intervention appeared to be low. Though the prevalence of LBW in both intervention groups was similar (adjusted Incident Rate Ratio, AIRR = 0.92, 95%CI: 0.69-1.24) in the ITT analysis, the risk of severe anaemia was significantly lower in the SP3 group compared to the SP2 group (AIRR = 0.38, 95%CI: 0.16 - 0.90). The PP analysis showed a trend of reduced risk of LBW, severe anaemia and premature delivery in the SP3 group, albeit the difference between two and three IPTp-SP did not reach statistical significance. The risk of LBW and severe anaemia tended to be lower in the SP3 group, though this was not statistically significant, probably due to the low uptake of the intervention which reduced the power of the study. Further studies are needed for establishing whether a third SP dose has a real benefit in preventing the negative effects of malaria in pregnancy in settings where transmission is markedly seasonal.

An increase in rates of obstetric haemorrhage in a setting of high HIV seroprevalence

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E Shabalala

2017-07-01

Full Text Available Background. Obstetric haemorrhage (OH is the leading cause of maternal mortality worldwide, although, indirectly, HIV is also a leading cause of maternal mortality in some settings with a high HIV seroprevalence. Objective. To determine the possible association between increasing rates of OH and HIV or its treatment. Methods. We conducted a retrospective chart review of women with OH at King Edward VIII Hospital, Durban, South Africa, over a 3-year period (2009 - 2011, during which the drug regimen for the prevention of mother-to-child transmission was evolving from single-dose nevirapine to antenatal zidovudine combined with intrapartum nevirapine (also referred to as dual therapy, and finally to a combination or highly active antiretroviral therapy (cART or HAART. Cases of OH (including abruptio placentae, placenta praevia, unspecified antepartum haemorrhage (APH, and postpartum haemorrhage (PPH were identified from maternity delivery records, and the relevant data extracted. Results. We analysed the records of 448 women diagnosed with OH. Even though the incidence of OH was low, the study found an increasing number of cases during the 3-year period. PPH – not APH – was associated with HIV seropositivity (odds ratio 1.84, 95% confi­dence interval 1.14 - 2.95. cART was not associated with an increased risk of haemorrhage. Conclusion. HIV was associated with a high risk of PPH, and its possible association with HIV treatment needs further research.

Association between number of doses per day, number of medications and patient's non-compliance, and frequency of readmissions in a multi-ethnic Asian population

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Ming Ren Toh

2014-01-01

Conclusion: Complex medication regimen (i.e. multiple medications and multiple doses per day is a statistically significant predictor of number of readmissions. Simplifying therapeutic regimens with alternatives such as longer-acting or fixed-dose combination drugs may facilitate better patient adherence and reduce costly readmissions.

Advancing tuberculosis drug regimen development through innovative quantitative translational pharmacology methods and approaches.

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Hanna, Debra; Romero, Klaus; Schito, Marco

2017-03-01

The development of novel tuberculosis (TB) multi-drug regimens that are more efficacious and of shorter duration requires a robust drug development pipeline. Advances in quantitative modeling and simulation can be used to maximize the utility of patient-level data from prior and contemporary clinical trials, thus optimizing study design for anti-TB regimens. This perspective article highlights the work of seven project teams developing first-in-class translational and quantitative methodologies that aim to inform drug development decision-making, dose selection, trial design, and safety assessments, in order to achieve shorter and safer therapies for patients in need. These tools offer the opportunity to evaluate multiple hypotheses and provide a means to identify, quantify, and understand relevant sources of variability, to optimize translation and clinical trial design. When incorporated into the broader regulatory sciences framework, these efforts have the potential to transform the development paradigm for TB combination development, as well as other areas of global health. Copyright © 2016. Published by Elsevier Ltd.

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.

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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.).

Formulation, optimization, and evaluation of self-emulsifying drug delivery systems of nevirapine.

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Chintalapudi, Ramprasad; Murthy, T E G K; Lakshmi, K Rajya; Manohar, G Ganesh

2015-01-01

The aim of the present study was to formulate and optimize the self-emulsifying drug delivery systems (SEDDS) of nevirapine (NVP) by use of 2(2) factorial designs to enhance the oral absorption of NVP by improving its solubility, dissolution rate, and diffusion profile. SEDDS are the isotropic mixtures of oil, surfactant, co-surfactant and drug that form oil in water microemulsion when introduced into the aqueous phase under gentle agitation. Solubility of NVP in different oils, surfactants, and co-surfactants was determined for the screening of excipients. Pseudo-ternary phase diagrams were constructed by the aqueous titration method, and formulations were developed based on the optimum excipient combinations with the help of data obtained through the maximum micro emulsion region containing combinations of oil, surfactant, and co-surfactant. The formulations of SEDDS were optimized by 2(2) factorial designs. The optimum formulation of SEDDS contains 32.5% oleic acid, 44.16% tween 20, and 11.9% polyethylene glycol 600 as oil, surfactant, and co-surfactant respectively. The SEDDS was evaluated for the following drug content, self-emulsification time, rheological properties, zeta potential, in vitro diffusion studies, thermodynamic stability studies, and in vitro dissolution studies. An increase in dissolution was achieved by SEDDS compared to pure form of NVP. Overall, this study suggests that the dissolution and oral bioavailability of NVP could be improved by SEDDS technology.

Comparison of Effectiveness between Rifampicin Ofloxin-Minocycline Regimen and Multidrug Therapy-World Health Organization in Multibacillary Leprosy Patients

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Octawyana Moestopo

2016-12-01

Full Text Available Background: Multidrug therapy (MDT which is recommended by the World Health Organization (WHO for multibacillary (MB leprosy patients has some side effects; it is given in 12 doses over 12-18 months. Patients who refuse or are contraindicated in undertaking MDT-WHO can be given alternative rifampicin-ofloxacin-minocycline (ROM regimen for 24 months, whose side effects are less but more expensive. This study was conducted to compare the effectiveness between ROM and MDT-WHO regimen in the first 12 months based on the derivation in morphological index (MI of acid-fast bacilli (AFB in MB leprosy patient. Methods: This was an observational analytical study with retrospective cohort method. Data was collected from medical records of MB leprosy patients in the Medical Record Installation and Morbus Hansen Clinic, Dr. Hasan Sadikin General Hospital Bandung. The overall derivation in MI in 12 months was assessed according to the type of therapy undertaken by the patient. Data was analyzed by Mann-Whitney U Test. Results: A total of 59 data were selected out of 800 data of new leprosy patients based on the inclusion and exclusion criteria. Among those, 20 patients were treated by ROM and 39 by MDT-WHO. Derivation of MI occurred among both groups, but ROM regimen had higher percentage (94.83% compared with MDT-WHO regimen (79.57% with p value=0.003 (p <0.05. Conclusions: ROM regimen has better effectiveness than MDT-WHO regimen in the first 12 months in MB leprosy patients.

Analysis of factors affecting the outcome of Graves disease patients treated with two regimens of fixed Iodine-131 doses (10 mCi and 15 mCi)

International Nuclear Information System (INIS)

Machado, Ana C.B.; Santos, Roberto B.; Chaves, Fatima R.; Romaldini, Joao H.; Ward, Laura S.

2005-01-01

Full text: The use of fixed doses of radioiodine ( 131 I) simplifies the approach to treatment for Graves' disease (GD) patients with potential cost savings. In order to evaluate factors that may affect the outcome of 2 different regimens of 131 I, we prospectively examined 128 patients with overt thyrotoxicosis from GD, as confirmed by suppressed serum TSH, presence of TRAb, increased serum T 3 and FT 4 values. Group 1 comprised 76 patients who received a fixed dose of 10 mCi and Group 2=52 patients who received a fixed dose of 15 mCi. 36 patients did not use any antithyroid drugs and 92 patients used methimazole that was withdrawn at least 5 days before radioiodine administration. Antithyroid drugs treatment was restarted at least 7 days following 131 I therapy when needed. Baseline serum TSH and FT 4 levels were measured at 3, 6, 9 and 12 months after treatment. The groups were similar concerning age, gender, smoke, eye disease, goiter size, serum T 3 , FT 4 , TRAb, anti-Tg and anti-TPO levels as well as 24-hour 131 I or Tec-uptake values and thyroid scan. Clinical outcome was evaluated at the end of 1-year follow-up and cure of hyperthyroidism was defined as clinical and laboratory evidence of either euthyroidism or hypothyroidism in the absence of antithyroid drugs. The cure rate obtained was similar in groups 1 and 2: 73.7% and 80.8%, respectively (p=0.35). Hypothyroidism was diagnosed in 56.5% and 71.15% of the patients from groups 1 and 2, respectively (p=0.13). There was no correlation between clinical features, thyroid uptake, antibodies, serum hormones and outcome. However, logistic regression analysis demonstrated that patients with larger thyroids (weight >60 g) that, consequently, received a lower dose of radioiodine in MBq/g, had 2.4 times less chance to cure (95% Cl=1.18-4.96). The use of fixed doses of radioiodine ( 131 I) simplifies the approach to treatment for Graves' disease (GD) patients with potential cost savings. In order to evaluate

Dose titration of BAF312 attenuates the initial heart rate reducing effect in healthy subjects.

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Legangneux, Eric; Gardin, Anne; Johns, Donald

2013-03-01

Previous studies have shown transient decreases in heart rate (HR) following administration of sphingosine 1-phosphate (S1P) receptor modulators including BAF312. This study was conducted to determine whether dose titration of BAF312 reduces or eliminates these effects. Fifty-six healthy subjects were randomized 1:1:1:1 to receive BAF312 in one of two dose titration (DT) regimens (DT1 and DT2: 0.25-10 mg over 9-10 days), no titration (10 mg starting dose) or placebo. Pharmacodynamic and pharmacokinetic parameters were assessed. Neither DT1 nor DT2 resulted in clinically significant bradycardia or atrioventricular conduction effects. Both titration regimens showed a favourable difference on each of days 1-12 vs. the non-titration regimen on day 1 for HR effects (P titration was 1.18 (95% confidence interval [CI] 1.13, 1.23) and 1.14 (95% CI 1.09, 1.18) for DT2 (both P titration HRs showed considerable separation from placebo throughout the study. There was no statistically significant reduction in HR vs. placebo on day 1 in either titration regimen. On days 3-7 subjects in DT1 and DT2 experienced minor reductions in HR vs. placebo (approximately 5 beats min⁻¹; P ≤ 0.0001). From days 9-12, HRs in both titration regimens were comparable with placebo. Both titration regimens effectively attenuated the initial bradyarrhythmia observed on day 1 of treatment with BAF312 10 mg. © 2012 Novartis Institutes for BioMedical Research (NIBIR). British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Transversus Abdominis Plane Blocks with Single-Dose Liposomal Bupivacaine in Conjunction with a Nonnarcotic Pain Regimen Help Reduce Length of Stay following Abdominally Based Microsurgical Breast Reconstruction.

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Jablonka, Eric M; Lamelas, Andreas M; Kim, Julie N; Molina, Bianca; Molina, Nathan; Okwali, Michelle; Samson, William; Sultan, Mark R; Dayan, Joseph H; Smith, Mark L

2017-08-01

Side effects associated with use of postoperative narcotics for pain control can delay recovery after abdominally based microsurgical breast reconstruction. The authors evaluated a nonnarcotic pain control regimen in conjunction with bilateral transversus abdominis plane blocks on facilitating early hospital discharge. A retrospective analysis was performed of consecutive patients who underwent breast reconstruction using abdominally based free flaps, with or without being included in a nonnarcotic protocol using intraoperative transversus abdominis plane blockade. During this period, the use of locoregional analgesia evolved from none (control), to continuous bupivacaine infusion transversus abdominis plane and catheters, to single-dose transversus abdominis plane blockade with liposomal bupivacaine solution. Demographic factors, length of stay, inpatient opioid consumption, and complications were reported for all three groups. One hundred twenty-eight consecutive patients (182 flaps) were identified. Forty patients (62 flaps) were in the infusion-liposomal bupivacaine group, 48 (66 flaps) were in the single-dose blockade-catheter group, and 40 (54 flaps) were in the control group. The infusion-liposomal bupivacaine patients had a significantly shorter hospital stay compared with the single-dose blockade-catheter group (2.65 ± 0.66 versus 3.52 ± 0.92 days; p plane blocks performed with single injections of liposomal bupivacaine help facilitate early hospital discharge after abdominally based microsurgical breast reconstruction. A trend toward consistent discharge by postoperative day 2 was seen. This could result in significant cost savings for health care systems. Therapeutic, III.

Target-mediated pharmacokinetic/pharmacodynamic model based meta-analysis and dosing regimen optimization of a long-acting release formulation of exenatide in patients with type 2 diabetes mellitus

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Hanqing Li

2015-02-01

Full Text Available A hybrid pharmacokinetic/pharmacodynamic (PK/PD model with extended-release (ER process and target mediated drug disposition (TMDD was developed for exenatide ER to account for its complex absorption process and glucagon-like peptide 1 receptor (GLP-1R-mediated non-linear PK behaviors along with its influences to fasting plasma glucose (FPG and hemoglobin A1c (HbA1c. Using hybrid PK/PD model, simulations were done to explore the potential dosing regimens which could achieve likelihood of more pharmacodynamic exposure with respect to FPG and HbA1c over a much shorter period compared with the currently used treatment protocol. The mean PK/PD data about exenatide ER for type 2 diabetes mellitus (T2DM were digitized from the publications, and the hybrid PK/PD model was performed using the Monolix 4.3 program. The plasma concentration-time and FPG/HbA1c-time profiles for exenatide ER subcutaneously administrated to patients with T2DM were well described by this hybrid model. Monte Carlo simulation was applied to mimic the PK profiles when higher loading dose 7.5 and 5.0 mg exenatide ER were subcutaneously administrated with different dosing intervals at the first 3 weeks of 30-week treatment. Two potentially optimizing schedules could improve the likelihood of achieving much more FPG and HbA1c exposures than currently used clinical treatment protocol.

Biologically effective dose in total-body irradiation and hematopoietic stem cell transplantation

International Nuclear Information System (INIS)

Kal, H.B.; Kempen-Harteveld, M.L. van; Heijenbrok-Kal, M.H.; Struikmans, H.

2006-01-01

Background and Purpose: Total-body irradiation (TBI) is an important part of the conditioning regimen for hematopoietic stem cell transplantation (HSCT) in patients with hematologic malignancies. The results after treatment with various TBI regimes were compared, and dose-effect relationships for the endpoints relapse incidence, disease-free survival, treatment-related mortality, and overall survival were derived. The aim was to define requirements for an optimal treatment schedule with respect to leukemic cell kill and late normal-tissue morbidity. Material and Methods: A literature search was performed. Three randomized studies, four studies comparing results of two or three TBI regimens, and nine reports with results of one specific TBI regimen were identified. Biologically effective doses (BEDs) were calculated. The results of the randomized studies and the studies comparing results of two or three TBI regimens were pooled, and the pooled relative risk (RR) was calculated for the treatments with high BED values versus treatments with a low BED. BED-effect relationships were obtained. Results: RRs for the high BED treatments were significantly lower for relapse incidence, not significantly different for disease-free survival and treatment-related mortality, and significantly higher for overall survival. BED-effect relationships indicate a decrease in relapse incidence and treatment-related mortality and an increase in disease-free and overall survival with higher BED values. Conclusion: 'More dose is better', provided that a TBI setting is used limiting the BEDs of lungs, kidneys, and eye lenses. (orig.)

Four-year evolution of insulin regimens, glycaemic control, hypoglycaemia and body weight after starting insulin therapy in type 2 diabetes across three continents.

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Home, Philip D; Dain, Marie-Paule; Freemantle, Nick; Kawamori, Ryuzo; Pfohl, Martin; Brette, Sandrine; Pilorget, Valérie; Scherbaum, Werner A; Vespasiani, Giacomo; Vincent, Maya; Balkau, Beverley

2015-05-01

It is of interest to understand how insulin therapy currently evolves in clinical practice, in the years after starting insulin in people with type 2 diabetes. We aimed to describe this evolution prospectively over 4 years, to assist health care planning. People who had started any insulin were identified from 12 countries on three continents. Baseline, then yearly follow-up, data were extracted from clinical records over 4 years. Of the 2999 eligible people, 2272 were followed over 4 years. When starting insulin, mean (SD) duration of diabetes was 10.6 (7.8) years, HbA1c 9.5 (2.0)% (80 [22]mmol/mol) and BMI 29.3 (6.3)kg/m(2). Initial insulin therapy was basal 52%, premix 23%, mealtime+basal 14%, mealtime 8% and other 3%; at 4 years, 30%, 25%, 33%, 2% and 5%, respectively, with 5% not on insulin. Insulin dose was 20.2U/day at the start and 45.8U/day at year 4. There were 1258 people (55%) on their original regimen at 4 years, and this percentage differed according to baseline insulin regimen. HbA1c change was -2.0 (2.2)% (-22 [24]mmol/mol) and was similar by final insulin regimen. Hypoglycaemia prevalence was <20% in years 1-4. Body weight change was mostly in year 1, and was very variable, mean +2.7 (7.5)kg at year 4. Different insulin regimens were started in people with differing characteristics, and they evolved differently; insulin dose, hypoglycaemia and body weight change were diverse and largely independent of regimen. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Efficacy, safety and proper dose analysis of PEGylated granulocyte colony-stimulating factor as support for dose-dense adjuvant chemotherapy in node positive Chinese breast cancer patients.

Science.gov (United States)

Zhang, Fan; LingHu, RuiXia; Zhan, XingYang; Li, Ruisheng; Feng, Fan; Gao, Xudong; Zhao, Lei; Yang, Junlan

2017-10-03

For high-risk breast cancer patients with positive axillary lymph nodes, dose-dense every-two-week epirubicin/cyclophosphamide-paclitaxel (ddEC-P) regimen is the optimal postoperative adjuvant therapy. However, this regimen is limited by the grade 3/4 neutropenia and febrile neutropenia (FN). There is an urgent need to explore the efficacy, safety and proper dosage of PEGylated granulocyte colony-stimulating factor (PEG-G-CSF) as support for ddEC-P in Chinese breast cancer patients with positive axillary lymph nodes. Prospectively, 40 women with stage IIIA to IIIC breast cancer received ddEC-P ± trastuzumab as adjuvant treatment. PEG-G-CSF was injected subcutaneously in a dose of 6 mg or 3 mg on the 2 th day of each treatment cycle. With administration of PEG-G-CSF, all of the 40 patients completed 8 cycles of ddEC-P ± trastuzumab regimen without dose reductions or treatment delays. Moreover, no FN cases were observed. Further analysis showed that the proper dosage of PEG-G-CSF was 6 mg for ddEC treatment, and 3 mg for ddP treatment. PEG-G-CSF exhibits advantages compared with G-CSF in convenient of administration and tolerance for high risk Chinese breast cancer patients. More importantly, the proper dose of PEG-G-CSF for high risk Chinese breast cancer patients during ddEC-P chemotherapy may be 6 mg for ddEC treatment and 3 mg for ddP treatment.

A physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model of the histone deacetylase (HDAC) inhibitor vorinostat for pediatric and adult patients and its application for dose specification.

Science.gov (United States)

Moj, Daniel; Britz, Hannah; Burhenne, Jürgen; Stewart, Clinton F; Egerer, Gerlinde; Haefeli, Walter E; Lehr, Thorsten

2017-11-01

This study aimed at recommending pediatric dosages of the histone deacetylase (HDAC) inhibitor vorinostat and potentially more effective adult dosing regimens than the approved standard dosing regimen of 400 mg/day, using a comprehensive physiologically based pharmacokinetic/pharmacodynamic (PBPK/PD) modeling approach. A PBPK/PD model for vorinostat was developed for predictions in adults and children. It includes the maturation of relevant metabolizing enzymes. The PBPK model was expanded by (1) effect compartments to describe vorinostat concentration-time profiles in peripheral blood mononuclear cells (PBMCs), (2) an indirect response model to predict the HDAC inhibition, and (3) a thrombocyte model to predict the dose-limiting thrombocytopenia. Parameterization of drug and system-specific processes was based on published and unpublished in silico, in vivo, and in vitro data. The PBPK modeling software used was PK-Sim and MoBi. The PBPK/PD model suggests dosages of 80 and 230 mg/m 2 for children of 0-1 and 1-17 years of age, respectively. In comparison with the approved standard treatment, in silico trials reveal 11 dosing regimens (9 oral, and 2 intravenous infusion rates) increasing the HDAC inhibition by an average of 31%, prolonging the HDAC inhibition by 181%, while only decreasing the circulating thrombocytes to a tolerable 53%. The most promising dosing regimen prolongs the HDAC inhibition by 509%. Thoroughly developed PBPK models enable dosage recommendations in pediatric patients and integrated PBPK/PD models, considering PD biomarkers (e.g., HDAC activity and platelet count), are well suited to guide future efficacy trials by identifying dosing regimens potentially superior to standard dosing regimens.

SINGLE-DOSE VERSUS 3-DAY PROPHYLAXIS WITH CIPROFLOXACIN IN TRANSURETHRAL SURGERY - A CLINICAL-TRIAL

NARCIS (Netherlands)

BIJL, W; JANKNEGT, RA

1993-01-01

in 235 patients who underwent transurethral surgery, perioperative oral ciprofloxacin prophylaxis was given as a single dose 500 mg versus a 3-day regimen. Out of 180 evaluable patients, 84 received a single dose and 96 received a 3-day course. In the single dose prophylaxis group there were 5

Aggressive regimens for multidrug-resistant tuberculosis decrease all-cause mortality.

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Carole D Mitnick

Full Text Available A better understanding of the composition of optimal treatment regimens for multidrug-resistant tuberculosis (MDR-TB is essential for expanding universal access to effective treatment and for developing new therapies for MDR-TB. Analysis of observational data may inform the definition of an optimized regimen.This study assessed the impact of an aggressive regimen-one containing at least five likely effective drugs, including a fluoroquinolone and injectable-on treatment outcomes in a large MDR-TB patient cohort.This was a retrospective cohort study of patients treated in a national outpatient program in Peru between 1999 and 2002. We examined the association between receiving an aggressive regimen and the rate of death.In total, 669 patients were treated with individualized regimens for laboratory-confirmed MDR-TB. Isolates were resistant to a mean of 5.4 (SD 1.7 drugs. Cure or completion was achieved in 66.1% (442 of patients; death occurred in 20.8% (139. Patients who received an aggressive regimen were less likely to die (crude hazard ratio [HR]: 0.62; 95% CI: 0.44,0.89, compared to those who did not receive such a regimen. This association held in analyses adjusted for comorbidities and indicators of severity (adjusted HR: 0.63; 95% CI: 0.43,0.93.The aggressive regimen is a robust predictor of MDR-TB treatment outcome. TB policy makers and program directors should consider this standard as they design and implement regimens for patients with drug-resistant disease. Furthermore, the aggressive regimen should be considered the standard background regimen when designing randomized trials of treatment for drug-resistant TB.

Low-dose total skin electron beam therapy for cutaneous lymphoma. Minimal risk of acute toxicities

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Kroeger, Kai; Elsayad, Khaled; Moustakis, Christos; Haverkamp, Uwe; Eich, Hans Theodor [University Hospital of Muenster, Department of Radiation Oncology, Muenster (Germany)

2017-12-15

Low-dose total skin electron beam therapy (TSEBT) is attracting increased interest for the effective palliative treatment of primary cutaneous T-cell lymphoma (pCTCL). In this study, we compared toxicity profiles following various radiation doses. We reviewed the records of 60 patients who underwent TSEBT for pCTCL between 2000 and 2016 at the University Hospital of Munster. The treatment characteristics of the radiotherapy (RT) regimens and adverse events (AEs) were then analyzed and compared. In total, 67 courses of TSEBT were administered to 60 patients. Of these patients, 34 (51%) received a standard dose with a median surface dose of 30 Gy and 33 patients (49%) received a low dose with the median surface dose of 12 Gy (7 salvage low-dose TSEBT courses were administered to 5 patients). After a median follow-up of 15 months, the overall AE rate was 100%, including 38 patients (57%) with grade 2 and 7 (10%) with grade 3 AEs. Patients treated with low-dose TSEBT had significantly fewer grade 2 AEs than those with conventional dose regimens (33 vs. 79%, P < 0.001). A lower grade 3 AE rate was also observed in patients who had received the low-dose regimen compared to those with the conventional dose regimens (6 vs. 15%, P = 0.78). Multiple/salvage low-dose TSEBT courses were not associated with an increased risk of acute AEs. Low-dose TSEBT regimens are associated with significantly fewer grade 2 acute toxicities compared with conventional doses of TSEBT. Repeated/Salvage low-dose TSEBT, however, appears to be tolerable and can even be applied safely in patients with cutaneous relapses. (orig.) [German] Eine niedrigdosierte Ganzhautelektronenbestrahlung (TSEBT) wird vermehrt zur effektiven palliativen Behandlung von Patienten mit primaer kutanen T-Zell-Lymphomen (pCTCL) eingesetzt. In dieser Studie vergleichen wir die Toxizitaetsprofile verschiedener Dosiskonzepte. Untersucht wurden 60 zwischen 2000 und 2016 am Universitaetsklinikum Muenster mittels TSEBT

Thai national guidelines for the prevention of mother-to-child transmission of human immunodeficiency virus 2017

Science.gov (United States)

Lolekha, Rangsima; Chokephaibulkit, Kulkanya; Phanuphak, Nittaya; Chaithongwongwatthana, Surasith; Kiertiburanakul, Sasisopin; Chetchotisakd, Pleonchan; Boonsuk, Sarawut

2018-01-01

Background Thailand has made progress in reducing perinatal HIV transmission rates to levels that meet the World Health Organization targets for so-called “elimination” (HIV/AIDS Treatment Prevention Working Group issued a new version of its National Prevention of MTCT guidelines in March 2017 aimed to reduce MTCT rate to HIV is diagnosed for ART naïve HIV-infected pregnant women. An alternative regimen is TDF or zidovudine (AZT) plus 3TC/FTC plus lopinavir/ritonavir (LPV/r) for HIV-infected pregnant women suspected resistant to non-nucleoside reverse transcriptase inhibitors. Treatment should be started immediately irrespective of gestational age and continued after delivery for life. Raltegravir is recommended in addition to the ART regimen for HIV-infected pregnant women who present late (gestational age (GA) ≥32 weeks) or those who have a viral load (VL) >1000 copies/mL at GA ≥32 weeks. HIV-infected pregnant women who conceive while receiving ART should continue their treatment regimen during pregnancy. HIV-infected pregnant women who present in labor and are not receiving ART should receive single-dose nevirapine immediately along with oral AZT, and continue ART for life. Infants born to HIV-infected mothers are categorized as high or standard risk for MTCT. High MTCT risk is defined as an infant whose mother has a viral load (VL) > 50 copies/mL at GA > 36 weeks or has received ART HIV-exposed infants. PMID:29861798

Renexin as a rescue regimen for noise-induced hearing loss

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So Young Park

2014-01-01

Full Text Available Renexin, a compound of cilostazol and ginkgo biloba extract, has been reported to produce neuroprotective effects through antioxidant, antiplatelet, and vasodilatory mechanisms. This study was designed to investigate the protective effects of renexin on hearing, the organ of Corti (OC, and medial olivocochlear efferents against noise-induced damage. C57BL/6 mice were exposed to 110 dB SPL white noise for 60 min and then randomly divided into three groups: high- and low-dose renexin-treated groups and noise only group. Renexin were administered for 7 days: 90 mg/kg to the low-dose, and 180 mg/kg to the high-dose groups. All mice, including the controls underwent hearing tests on postnoise day 8 and were killed for cochlear harvest. We compared the hearing thresholds and morphology of the OC and cochlear efferents across the groups. The renexin-treated groups recovered from the immediate threshold shifts in a dose-dependent manner, while the noise group showed a permanent hearing loss. The renexin-treated ears demonstrated less degeneration of the OC. The diameters of the efferent terminals labeled with α-synuclein were preserved in the high-dose renexin-treated group. In the western blot assay of the cochlear homogenates, the treated groups displayed stronger expressions of α-synuclein than the noise and control groups, which may indicate that noise-induced enhanced activity of the cochlear efferent system was protected by renexin. Our results suggest that pharmacologic treatment with renexin is hopeful to reduce or prevent noise-induced hearing loss as a rescue regimen after noise exposure.

Toxicity assessment of molecularly targeted drugs incorporated into multiagent chemotherapy regimens for pediatric acute lymphocytic leukemia (ALL): review from an international consensus conference.

Science.gov (United States)

Horton, Terzah M; Sposto, Richard; Brown, Patrick; Reynolds, C Patrick; Hunger, Stephen P; Winick, Naomi J; Raetz, Elizabeth A; Carroll, William L; Arceci, Robert J; Borowitz, Michael J; Gaynon, Paul S; Gore, Lia; Jeha, Sima; Maurer, Barry J; Siegel, Stuart E; Biondi, Andrea; Kearns, Pamela R; Narendran, Aru; Silverman, Lewis B; Smith, Malcolm A; Zwaan, C Michel; Whitlock, James A

2010-07-01

One of the challenges of incorporating molecularly targeted drugs into multi-agent chemotherapy (backbone) regimens is defining dose-limiting toxicities (DLTs) of the targeted agent against the background of toxicities of the backbone regimen. An international panel of 22 pediatric acute lymphocytic leukemia (ALL) experts addressed this issue (www.ALLNA.org). Two major questions surrounding DLT assessment were explored: (1) how toxicities can be best defined, assessed, and attributed; and (2) how effective dosing of new agents incorporated into multi-agent ALL clinical trials can be safely established in the face of disease- and therapy-related systemic toxicities. The consensus DLT definition incorporates tolerance of resolving Grade 3 and some resolving Grade 4 toxicities with stringent safety monitoring. This functional DLT definition is being tested in two Children's Oncology Group (COG) ALL clinical trials. Copyright 2010 Wiley-Liss, Inc.

Efficacy, safety and proper dose analysis of PEGylated granulocyte colony-stimulating factor as support for dose-dense adjuvant chemotherapy in node positive Chinese breast cancer patients

OpenAIRE

Zhang, Fan; LingHu, RuiXia; Zhan, XingYang; Li, Ruisheng; Feng, Fan; Gao, Xudong; Zhao, Lei; Yang, Junlan

2017-01-01

For high-risk breast cancer patients with positive axillary lymph nodes, dose-dense every-two-week epirubicin/cyclophosphamide-paclitaxel (ddEC-P) regimen is the optimal postoperative adjuvant therapy. However, this regimen is limited by the grade 3/4 neutropenia and febrile neutropenia (FN). There is an urgent need to explore the efficacy, safety and proper dosage of PEGylated granulocyte colony-stimulating factor (PEG-G-CSF) as support for ddEC-P in Chinese breast cancer patients with posit...

Prophylactic low-dose aspirin is effective antithrombotic therapy for combination treatments of thalidomide or lenalidomide in myeloma.

Science.gov (United States)

Niesvizky, Ruben; Martínez-Baños, Déborah; Jalbrzikowski, Jessica; Christos, Paul; Furst, Jessica; De Sancho, Maria; Mark, Tomer; Pearse, Roger; Mazumdar, Madhu; Zafar, Faiza; Pekle, Karen; Leonard, John; Jayabalan, David; Coleman, Morton

2007-12-01

Multiple myeloma (MM) patients have a propensity for thromboembolic events (TE), and treatment with thalidomide/dexamethasone or lenalidomide/dexamethasone increases this risk. This report describes the use of low-dose aspirin (81 mg) as primary thromboprophylaxis in three series of MM patients receiving thalidomide or lenalidomide with other drugs. In the first regimen (clarithromycin, thalidomide, dexamethasone), initiation of low-dose aspirin negated the occurrence of any further TE. In a second study, prophylactic aspirin given with thalidomide/dexamethasone resulted in a rate of TE similar to that seen with dexamethasone alone (without aspirin). A third study (n = 72) evaluated thrombosis rates with aspirin and a lenalidomide-containing regimen (clarithromycin, lenalidomide, dexamethasone). Of nine occurrences of thromboembolism, five were associated with aspirin interruption or poor compliance. Low-dose aspirin appears to reduce the incidence of thrombosis with these regimens. Routine use of aspirin as antithrombotic prophylaxis in MM patients receiving immunomodulatory drugs with corticosteroids is warranted.

Treating tuberculosis with high doses of anti-TB drugs: mechanisms and outcomes.

Science.gov (United States)

Xu, Yuhui; Wu, Jianan; Liao, Sha; Sun, Zhaogang

2017-10-03

Tuberculosis (TB) is considered as one of the most serious threats to public health in many parts of the world. The threat is even more severe in the developing countries where there is a lack of advanced medical amenities and contemporary anti-TB drugs. In such situations, dosage optimization of existing medication regimens seems to be the only viable option. Therapeutic drug monitoring study results suggest that high-dose treatment regimens can compensate the low serum concentration of anti-TB drugs and shorten the therapy duration. The article presents a critical review on the possible changes that occur in the host and the pathogen upon the administration of standard and high-dose regimens. Some of the most common factors that are responsible for low anti-TB drug concentrations in the serum are differences in hosts' body weight, metabolic processing of the drug, malabsorption and/or drug-drug interaction. Furthermore, failure to reach the cavitary pulmonary and extrapulmonary tissues also contributes to the therapeutic inefficiency of the drugs. In such conditions, administration of higher doses can help in compensating the pathogenic outcomes of enhancement of the pathogen's physical barriers, efflux pumps and genetic mutations. The present article also presents a summary of the recorded treatment outcomes of clinical trials that were conducted to test the efficacy of administration of high dose of anti-tuberculosis drugs. This review will help physicians across the globe to understand the underlying pathophysiological changes (including side effects) that dictate the clinical outcomes in patients administered with standard and/or high dose anti-TB drugs.

Dose-response relationship in the treatment of gastrointestinal disorders.

Science.gov (United States)

Weihrauch, T R; Demol, P

1989-08-01

Numerous clinical studies have been performed to establish efficacy and safety of drugs in gastroenterological disorders. Only in a few if any of these studies, however, the rationale for the optimal dose and the dose regimens, respectively, have been addressed. Adequate and well-controlled dose finding studies play a key role in the clinical assessment of new drugs and in the evaluation of new indications. Hereby the range from the minimal effective dose to the maximal effective and well tolerated dose can be assessed and thus the optimal dose-range and dosage regimen be determined. Meaningful pharmacodynamic studies can be performed in the gastrointestinal tract also in healthy volunteers provided that a method with a high predictability for the desired therapeutic effect is available such as measurement of gastric acid secretion and its inhibition by a drug. Dose finding studies in gastroenterology can be carried out under two main aspects: First, to assess the pharmacodynamic and therapeutic effect of a compound on the gastrointestinal tract (e.g. anti-ulcer drug). Second, to evaluate the side effects of a drug on the gastrointestinal tract (e.g. gastric mucosal damage by non-steroidal anti-inflammatory drugs). For the evaluation of new drugs in gastrointestinal therapy a number of methods are available which yield accurate and reproducible data. While careful clinical-pharmacological dose-response studies using these methods have been carried out already more than a decade ago, it is surprising that therapeutic dose finding studies have become available only during the past few years. For scientific as well as for ethical reasons more trials which determine the optimal therapeutic dose are warranted.

Optimal Hemodialysis Prescription: Do Children Need More Than a Urea Dialysis Dose?

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Fischbach Michel

2011-01-01

Full Text Available When prescribing hemodialysis in children, the clinician should first establish an adequate regimen, before seeking to optimize the treatment (Fischbach et al. 2005. A complete dialysis dose should consist of a urea dialysis dose and a determined convective volume. Intensified and more frequent dialysis regimens should not be considered exclusively as rescue therapy. Interestingly, a recent single-center study demonstrated that frequent on-line HDF provides an optimal dialysis prescription, both in terms of blood pressure control (and therefore avoidance of left ventricular hypertrophy, and catch-up growth, that is, no malnutrition or cachexia and less resistance to growth hormone. Nevertheless, this one-center experience would benefit from a prospective randomized study.

Optimization of the fractionated irradiation scheme considering physical doses to tumor and organ at risk based on dose–volume histograms

Energy Technology Data Exchange (ETDEWEB)

Sugano, Yasutaka [Graduate School of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo, Hokkaido 060-0812 (Japan); Mizuta, Masahiro [Laboratory of Advanced Data Science, Information Initiative Center, Hokkaido University, Kita-11, Nishi-5, Kita-ku, Sapporo, Hokkaido 060-0811 (Japan); Takao, Seishin; Shirato, Hiroki; Sutherland, Kenneth L. [Department of Radiation Medicine, Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-5, Kita-ku, Sapporo, Hokkaido 060-8638 (Japan); Date, Hiroyuki, E-mail: date@hs.hokudai.ac.jp [Faculty of Health Sciences, Hokkaido University, Kita-12, Nishi-5, Kita-ku, Sapporo, Hokkaido 060-0812 (Japan)

2015-11-15

Purpose: Radiotherapy of solid tumors has been performed with various fractionation regimens such as multi- and hypofractionations. However, the ability to optimize the fractionation regimen considering the physical dose distribution remains insufficient. This study aims to optimize the fractionation regimen, in which the authors propose a graphical method for selecting the optimal number of fractions (n) and dose per fraction (d) based on dose–volume histograms for tumor and normal tissues of organs around the tumor. Methods: Modified linear-quadratic models were employed to estimate the radiation effects on the tumor and an organ at risk (OAR), where the repopulation of the tumor cells and the linearity of the dose-response curve in the high dose range of the surviving fraction were considered. The minimization problem for the damage effect on the OAR was solved under the constraint that the radiation effect on the tumor is fixed by a graphical method. Here, the damage effect on the OAR was estimated based on the dose–volume histogram. Results: It was found that the optimization of fractionation scheme incorporating the dose–volume histogram is possible by employing appropriate cell surviving models. The graphical method considering the repopulation of tumor cells and a rectilinear response in the high dose range enables them to derive the optimal number of fractions and dose per fraction. For example, in the treatment of prostate cancer, the optimal fractionation was suggested to lie in the range of 8–32 fractions with a daily dose of 2.2–6.3 Gy. Conclusions: It is possible to optimize the number of fractions and dose per fraction based on the physical dose distribution (i.e., dose–volume histogram) by the graphical method considering the effects on tumor and OARs around the tumor. This method may stipulate a new guideline to optimize the fractionation regimen for physics-guided fractionation.

AUC versus peak-trough dosing of vancomycin: applying new pharmacokinetic paradigms to an old drug.

Science.gov (United States)

Brown, Daniel L; Lalla, Christina D; Masselink, Andrew J

2013-08-01

To compare and contrast the pharmacokinetic/pharmacodynamic foundations of traditional "peak-trough" vancomycin dosing methods versus newer "area under the curve" (AUC) strategies. To propose a new AUC-based dosing chart for empirically determining an initial vancomycin dosing regimen designed to achieve a desired AUC24 using the minimum inhibitory concentration (MIC), creatinine clearance (CrCl), and vancomycin clearance (ClVanco). Peak-trough vancomycin dosing is designed to achieve a Cpeak of 20-40 mg/L and a Ctrough of 10-15 or 15-20 mg/L, depending on the severity of the infection and the nature of the pathogen. New treatment guidelines for vancomycin suggest that therapy should achieve an AUC24/MIC of ≥400. AUC-based vancomycin dosing derives the daily dose from ClVanco, MIC, and the desired AUC24/MIC, without consideration of the patient's weight. A vancomycin dosing chart is proposed that estimates ClVanco using the following formula developed by Matzke et al: ClVanco in L/h = [(CrClmL/min × 0.689) + 3.66] × 0.06, which simplifies to (CrClmL/min × 0.41) + 0.22. Two levels of dosing are included-high dose (Ctrough: 15-20 mg/L) and moderate dose (Ctrough: 10-15 mg/L). Although the chart has not been validated clinically, it represents the product of standard dosing equations that are used to determine a starting dosing regimen based on well-established vancomycin pharmacokinetic parameters. An understanding of pharmacokinetic and pharmacodynamic principles, including the relevance of AUC in relation to MIC, enables clinicians to make the best use of vancomycin dosing options. The proposed dosing chart is pharmacokinetically valid but has yet to be applied clinically. It provides a foundation for further study of how clinicians can determine an optimal AUC-based starting vancomycin dosing regimen without having to derive ClVanco or AUC24.

Dose rate and dose fractionation studies in total body irradiation of dogs

International Nuclear Information System (INIS)

Kolb, H.J.; Netzel, B.; Schaffer, E.; Kolb, H.

1979-01-01

Total body irradiation (TBI) with 800-900 rads and allogeneic bone marrow transplantation according to the regimen designated by the Seattle group has induced remissions in patients with otherwise refractory acute leukemias. Relapse of leukemia after bone marrow transplantation remains the major problem, when the Seattle set up of two opposing 60 Co-sources and a low dose rate is used in TBI. Studies in dogs with TBI at various dose rates confirmed observations in mice that gastrointestinal toxicity is unlike toxicity against hemopoietic stem cells and possibly also leukemic stem cells depending on the dose rate. However, following very high single doses (2400 R) and marrow infusion acute gastrointestinal toxicity was not prevented by the lowest dose rate studied (0.5 R/min). Fractionated TBI with fractions of 600 R in addition to 1200 R (1000 rads) permitted the application of total doses up to 300 R followed by marrow infusion without irreversible toxicity. 26 dogs given 2400-3000 R have been observed for presently up to 2 years with regard to delayed radiation toxicity. This toxicity was mild in dogs given single doses at a low dose rate or fractionated TBI. Fractionated TBI is presently evaluated with allogeneic transplants in the dog before being applied to leukemic patients

Lipid-based nutrient supplements do not affect efavirenz but lower plasma nevirapine concentrations in Ethiopian adult HIV patients

DEFF Research Database (Denmark)

Abdissa, A; Olsen, Mette Frahm; Yilma, D

2015-01-01

OBJECTIVES: Lipid-based nutrient supplements (LNSs) are increasingly used in HIV programmes in resource-limited settings. However, the possible effects of LNSs on the plasma concentrations of antiretroviral drugs have not been assessed. Here, we aimed to assess the effects of LNSs on plasma...... efavirenz and nevirapine trough concentrations in Ethiopian adult HIV-infected patients. METHODS: The effects of LNSs were studied in adults initiating antiretroviral therapy (ART) in a randomized trial. Patients with body mass index (BMI) > 17 kg/m(2) (n = 282) received daily supplementation of an LNS.......9; -0.9 μg/mL; P = 0.01), respectively, compared with the group not receiving supplements. There were no differences between groups with respect to efavirenz plasma concentrations. The CYP2B6 516 G>T polymorphism was associated with a 5 μg/mL higher plasma efavirenz concentration compared with the wild...

18-month effectiveness of short-course antiretroviral regimens combined with alternatives to breastfeeding to prevent HIV mother-to-child transmission.

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Valériane Leroy

Full Text Available OBJECTIVE: We assessed the 18-month effectiveness of short-course (sc antiretroviral peripartum regimens combined with alternatives to prolonged breastfeeding to prevent mother-to-child transmission (MTCT of HIV-1 in Abidjan, Côte d'Ivoire. METHODOLOGY: HIV-1 infected pregnant women received from >/=32-36 weeks of gestation scZidovudine (ZDV+/-Lamivudine (3TC+single-dose Nevirapine (sdNVP at delivery within the ANRS 1201/1202 DITRAME-Plus cohort (2001-2003. Neonates received a sdNVP+7-day ZDV prophylaxis. Two infant-feeding interventions were systematically offered free of charge: formula-feeding or exclusive shortened breastfeeding with early cessation from four months. The reference group was the ANRS 049a DITRAME cohort (1994-2000 exposed to scZDV from 36 weeks, then to prolonged breastfeeding. Pediatric HIV infection was defined by a positive plasma HIV-1 RNA at any age, or if aged >/=18 months, a positive HIV-1 serology. Turnbull estimates of cumulative transmission risks (CTR and effectiveness (HIV-free survival were compared by exposure group using a Cox model. FINDINGS: Among 926 live-born children enrolled, 107 (11.6% were HIV-infected at 18 months. CTRs were 22.3% (95% confidence interval[CI]:16-30% in the 238 ZDV long-term breastfed reference group, 15.9% (CI:10-27% in the 169 ZDV+sdNVP shortened breastfed group; 9.4% (CI:6-14% in the 195 ZDV+sdNVP formula-fed group; 6.8% (CI:4-11% in the 198 ZDV+3TC+sdNVP shortened breastfed group, and 5.6% (CI:2-10% in the 126 ZDV+3TC+sdNVP formula-fed group. Each combination had a significantly higher effectiveness than the ZDV long-term breastfed group except for ZDV+sdNVP shortened breastfed children, ranging from 51% (CI:20-70% for ZDV+sdNVP formula fed children to 63% (CI:40-80% for ZDV+3TC+NVPsd shortened breastfed children, after adjustment for maternal eligibility for antiretroviral therapy (ART, home delivery and low birth-weight. Substantial MTCT risk reductions are reachable in Africa

Accelerated split course regimen in the treatment of brain metastases

International Nuclear Information System (INIS)

Franchin, G.; Minatel, E.; Roncadin, M.; Trovo, M.G.; De Paoli, A.; Bortolus, R.; Arcicasa, M.; Boz, G.; Gobitti, C.; Grigoletto, E.; Bassignano, G.

1988-01-01

63 patients, with brain metastases were treated with an accelerated split course regimen; irradiation was given to the whole brain in 3 daily fractions of 160 cGy each for 5 days a week. The cycle was repeated after 2 weeks to a total dose of 4800 cGy. Male-female ratio was 3:1. Median age was 58 years. The most frequent site of primary tumor was lung (41 patients), breast in 6 patients, melanoma in 3 patients, other sites in 8 patients and unknown cancer in 5 patients. Thirty-five patients had multiple brain metastases localizations. Two patients failed to complete the scheduled treatment: one because of early death and the other by refusal of therapy during treatment. Complete remission was obtained in 4 patients and partial remission in 24 patients. The median survival time was 21 weeks. The overall response rate was 42.5%. Toxicity was not considerable. The treatment results were not influenced by the site of primary tumor or by disease spreading; only the neurologic status before radiotherapy and the response to treatment influenced survival. The results obtained are similar to those reported by others; however, with the accelerated split course regimen the treatment time was reduced and a shorter period of hospitalization was required. 36 refs.; 2 figs.; 3 tabs

SU-D-204-02: BED Consistent Extrapolation of Mean Dose Tolerances

Energy Technology Data Exchange (ETDEWEB)

Perko, Z; Bortfeld, T; Hong, T; Wolfgang, J; Unkelbach, J [Massachusetts General Hospital, Boston, MA (United States)

2016-06-15

Purpose: The safe use of radiotherapy requires the knowledge of tolerable organ doses. For experimental fractionation schemes (e.g. hypofractionation) these are typically extrapolated from traditional fractionation schedules using the Biologically Effective Dose (BED) model. This work demonstrates that using the mean dose in the standard BED equation may overestimate tolerances, potentially leading to unsafe treatments. Instead, extrapolation of mean dose tolerances should take the spatial dose distribution into account. Methods: A formula has been derived to extrapolate mean physical dose constraints such that they are mean BED equivalent. This formula constitutes a modified BED equation where the influence of the spatial dose distribution is summarized in a single parameter, the dose shape factor. To quantify effects we analyzed 14 liver cancer patients previously treated with proton therapy in 5 or 15 fractions, for whom also photon IMRT plans were available. Results: Our work has two main implications. First, in typical clinical plans the dose distribution can have significant effects. When mean dose tolerances are extrapolated from standard fractionation towards hypofractionation they can be overestimated by 10–15%. Second, the shape difference between photon and proton dose distributions can cause 30–40% differences in mean physical dose for plans having the same mean BED. The combined effect when extrapolating proton doses to mean BED equivalent photon doses in traditional 35 fraction regimens resulted in up to 7–8 Gy higher doses than when applying the standard BED formula. This can potentially lead to unsafe treatments (in 1 of the 14 analyzed plans the liver mean dose was above its 32 Gy tolerance). Conclusion: The shape effect should be accounted for to avoid unsafe overestimation of mean dose tolerances, particularly when estimating constraints for hypofractionated regimens. In addition, tolerances established for a given treatment modality cannot

Characterization of HIV-1 from patients with virological failure to a boosted protease inhibitor regimen

DEFF Research Database (Denmark)

Lillemark, Marie Rathcke; Gerstoft, Jan; Obel, Niels

2011-01-01

The use of highly active antiretroviral treatment (HAART) regimens with unboosted protease inhibitors (PIs) has resulted in a high level of virological failure primarily due to the development of resistant virus. Current boosted PI regimens combine successfully low-dose ritonavir (r) with a second.......3%) experienced virological failure, of whom 19 (83%) started PI/r treatment before 2001. Patients from Copenhagen (n=19) were selected to study the development of protease (PR) and gag cleavage site (CS) mutations during PI/r treatment and PI plasma levels at the time of virological failure. Three patients (16......%) developed major PI resistance mutations. Mutations in the p7/p1 and p1/p6 gag CS only developed in patients with major or minor mutations in PR. Drug concentrations were low or undetectable in 10 out of the 19 patients. In total PR resistance mutations and low drug levels could account for 12 (63...

Variation in training regimens in professional showjumping yards

NARCIS (Netherlands)

Lönnell, A C; Bröjer, J; Nostell, K; Hernlund, E; Roepstorff, L; Tranquille, C A; Murray, R C; Oomen, A; van Weeren, René; Bitschnau, C; Montavon, S; Weishaupt, M A; Egenvall, A

2014-01-01

REASONS FOR PERFORMING STUDY: Training regimens of showjumping horses under field conditions are largely undocumented. OBJECTIVES: The aims of this study were to quantify and compare training regimens used in professional-level showjumping yards, with respect to time exercised and type of activity.

Randomized controlled study of a novel triple nitazoxanide (NTZ)-containing therapeutic regimen versus the traditional regimen for eradication of Helicobacter pylori infection.

Science.gov (United States)

Shehata, Mona Ah; Talaat, Raghda; Soliman, Samah; Elmesseri, Huda; Soliman, Shaimaa; Abd-Elsalam, Sherief

2017-10-01

Helicobacter pylori infection has become more and more resistant to conventional first-line treatment regimens. So, there is a considerable interest in evaluating new antibiotic combinations and regimens. Nitazoxanide is an anti-infective drug with demonstrated activity against protozoa and anaerobic bacteria including H. pylori. This work is designed to evaluate the efficacy and safety of a unique triple nitazoxanide-containing regimen as a treatment regimen in Egyptian patients with H. pylori infection. Two hundred and 24 patients with upper gastrointestinal tract (GIT) dyspeptic symptoms in whom H. pylori -induced GIT disease was confirmed were included in the study. They have been randomized to receive either nitazoxanide 500 mg b.i.d., clarithromycin 500 mg b.i.d., and omeprazole 40 mg twice daily for 14 days or metronidazole 500 mg b.i.d., clarithromycin 500 mg b.i.d., and omeprazole 40  mg twice daily for 14 days. Laboratory evaluation for H. pylori antigen within the stool was performed 6 weeks after cessation of H. pylori treatment regimens to assess the response. The response to treatment was significantly higher in group 1 of nitazoxanide treatment regimen than group 2 of traditional treatment regimen. One hundred and six cases (94.6%) of 112 patients who completed the study in group 1 showed complete cure, while only 63 cases (60.6%) of 104 patients who completed the study in group 2 showed the same response according to per-protocol (PP) analysis (Ppylori. (ClinicalTrials.gov Identifier: NCT02422706). © 2017 John Wiley & Sons Ltd.

Modeling of Body Weight Metrics for Effective and Cost-Efficient Conventional Factor VIII Dosing in Hemophilia A Prophylaxis

Directory of Open Access Journals (Sweden)

Alanna McEneny-King

2017-10-01

Full Text Available The total body weight-based dosing strategy currently used in the prophylactic treatment of hemophilia A may not be appropriate for all populations. The assumptions that guide weight-based dosing are not valid in overweight and obese populations, resulting in overdosing and ineffective resource utilization. We explored different weight metrics including lean body weight, ideal body weight, and adjusted body weight to determine an alternative dosing strategy that is both safe and resource-efficient in normal and overweight/obese adult patients. Using a validated population pharmacokinetic model, we simulated a variety of dosing regimens using different doses, weight metrics, and frequencies; we also investigated the implications of assuming various levels of endogenous factor production. Ideal body weight performed the best across all of the regimens explored, maintaining safety while moderating resource consumption for overweight and obese patients.

Basal Insulin Regimens for Adults with Type 1 Diabetes Mellitus: A Cost-Utility Analysis.

Science.gov (United States)

Dawoud, Dalia; Fenu, Elisabetta; Higgins, Bernard; Wonderling, David; Amiel, Stephanie A

2017-12-01

To assess the cost-effectiveness of basal insulin regimens for adults with type 1 diabetes mellitus in England. A cost-utility analysis was conducted in accordance with the National Institute for Health and Care Excellence reference case. The UK National Health Service and personal and social services perspective was used and a 3.5% discount rate was applied for both costs and outcomes. Relative effectiveness estimates were based on a systematic review of published trials and a Bayesian network meta-analysis. The IMS CORE Diabetes Model was used, in which net monetary benefit (NMB) was calculated using a threshold of £20,000 per quality-adjusted life-year (QALY) gained. A wide range of sensitivity analyses were conducted. Insulin detemir (twice daily) [iDet (bid)] had the highest mean QALY gain (11.09 QALYs) and NMB (£181,456) per patient over the model time horizon. Compared with the lowest cost strategy (insulin neutral protamine Hagedorn once daily), it had an incremental cost-effectiveness ratio of £7844/QALY gained. Insulin glargine (od) [iGlarg (od)] and iDet (od) were ranked as second and third, with NMBs of £180,893 and £180,423, respectively. iDet (bid) remained the most cost-effective treatment in all the sensitivity analyses performed except when high doses were assumed (>30% increment compared with other regimens), where iGlarg (od) ranked first. iDet (bid) is the most cost-effective regimen, providing the highest QALY gain and NMB. iGlarg (od) and iDet (od) are possible options for those for whom the iDet (bid) regimen is not acceptable or does not achieve required glycemic control. Copyright © 2017 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Ovulation induction using clomiphene citrate using stair – Step regimen versus traditional regimen in polycystic ovary syndrome women – A randomized control trial

Directory of Open Access Journals (Sweden)

K Agrawal

2017-01-01

Full Text Available Objective: To determine the efficacy of the stair-step protocol (SSP using clomiphene citrate (CC in patients with polycystic ovary syndrome (PCOS and compare it with traditional regimen. Design: This was randomized control trial. Setting: Infertility Clinic. Patient(s: Sixty infertile PCOS women. Intervention(s: Patients were randomized into the study (SSP – 30 patients and control group (traditional protocol – 30 patients. In the SSP, patients were treated with CC 50 mg/day for 5 days and in nonresponsive patients, the dosage was increased to 100 mg/day for 5 days in the same cycle. Maximum dose of 150 mg was given until the dominant follicle was generated. In control group, the dose increment in nonovulatory cases was done in subsequent cycle. Ultrasonography follow-up was done to detect ovulation. Main Outcome Measure(s: Ovulation rate and duration of treatment. Results: Ovulation (66.7% vs. 50% respectively and pregnancy rates (26.7% vs. 15.7% were similar between the stair step and the control group. The duration of treatment was significantly shorter in stair step compared to traditional protocol (17.23 vs. 53 days. CC 100 mg was the most effective dose for ovulation in either group. There were no significant differences in the systemic side effect. Conclusions: By using SSP, effective treatment is provided in significantly shorter time period without any detrimental effect on the ovulation and pregnancy rates.

Single-dose fluconazole versus standard 2-week therapy for oropharyngeal candidiasis in HIV-infected patients: a randomized, double-blind, double-dummy trial.

NARCIS (Netherlands)

Hamza, O.J.M.; Matee, M.I.N.; Bruggemann, R.J.M.; Moshi, M.J.; Simon, E.N.; Mugusi, F.; Mikx, F.H.M.; Lee, H.A.L. van der; Verweij, P.E.; Ven, A.J.A.M. van der

2008-01-01

BACKGROUND: Oropharyngeal candidiasis is the most common opportunistic infection affecting patients with human immunodeficiency virus (HIV) infection. Because of convenience, cost, and reluctance to complicate antiretroviral treatment regimens, single-dose fluconazole may be a favorable regimen for

Inappropriate Tuberculosis Treatment Regimens in Chinese Tuberculosis Hospitals

NARCIS (Netherlands)

Xue He, Guang; van den Hof, Susan; van der Werf, Marieke J.; Guo, Hui; Hu, Yuan Lian; Fan, Ji Huan; Zhang, Wei Min; Tostado, Christopher P.; Borgdorff, Martien W.

2011-01-01

This investigation of tuberculosis (TB) treatment regimens in 6 TB hospitals in China showed that only 18% of patients with new cases and 9% of patients with retreatment cases were prescribed standard TB treatment regimens. Adherence to treatment guidelines needs to be improved in TB hospitals to

Effectiveness of two different doses of rituximab for the treatment of rheumatoid arthritis in an international cohort

DEFF Research Database (Denmark)

Chatzidionysiou, Katerina; Lie, Elisabeth; Nasonov, Evgeny

2016-01-01

months. DAS28 reductions at 6 months were comparable in the 2 dose regimens [mean DeltaDAS28 ± SD -2.0 ± 1.3 (high dose) vs. -1.7 ± 1.4 (low dose), p = 0.23 adjusted for baseline differences]. Similar percentages of patients achieved EULAR good response in the two dose groups, 18.4 % vs. 17...

Right dose, right now: using big data to optimize antibiotic dosing in the critically ill.

Science.gov (United States)

Elbers, Paul W G; Girbes, Armand; Malbrain, Manu L N G; Bosman, Rob

2015-01-01

Antibiotics save lives and are essential for the practice of intensive care medicine. Adequate antibiotic treatment is closely related to outcome. However this is challenging in the critically ill, as their pharmacokinetic profile is markedly altered. Therefore, it is surprising that critical care physicians continue to rely on standard dosing regimens for every patient, regardless of the actual clinical situation. This review outlines the pharmacokinetic and pharmacodynamic principles that underlie the need for individualized and personalized drug dosing. At present, therapeutic drug monitoring may be of help, but has major disadvantages, remains unavailable for most antibiotics and has produced mixed results. We therefore propose the AutoKinetics concept, taking decision support for antibiotic dosing back to the bedside. By direct interaction with electronic patient records, this opens the way for the use of big data for providing the right dose at the right time in each patient.

Rapid accumulation of HIV-1 thymidine analogue mutations and phenotypic impact following prolonged viral failure on zidovudine-based first-line ART in sub-Saharan Africa.

Science.gov (United States)

Goodall, Ruth L; Dunn, David T; Nkurunziza, Peter; Mugarura, Lincoln; Pattery, Theresa; Munderi, Paula; Kityo, Cissy; Gilks, Charles; Kaleebu, Pontiano; Pillay, Deenan; Gupta, Ravindra K

2017-05-01

Lack of viral load monitoring of ART is known to be associated with slower switch from a failing regimen and thereby higher prevalence of MDR HIV-1. Many countries have continued to use thymidine analogue drugs despite recommendations to use tenofovir in combination with a cytosine analogue and NNRTI as first-line ART. The effect of accumulated thymidine analogue mutations (TAMs) on phenotypic resistance over time has been poorly characterized in the African setting. A retrospective analysis of individuals with ongoing viral failure between weeks 48 and 96 in the NORA (Nevirapine OR Abacavir) study was conducted. We analysed 36 genotype pairs from weeks 48 and 96 of first-line ART (14 treated with zidovudine/lamivudine/nevirapine and 22 treated with zidovudine/lamivudine/abacavir). Phenotypic drug resistance was assessed using the Antivirogram assay (v. 2.5.01, Janssen Diagnostics). At 96 weeks, extensive TAMs (≥3 mutations) were present in 50% and 73% of nevirapine- and abacavir-treated patients, respectively. The mean (SE) number of TAMs accumulating between week 48 and week 96 was 1.50 (0.37) in nevirapine-treated participants and 1.82 (0.26) in abacavir-treated participants. Overall, zidovudine susceptibility of viruses was reduced between week 48 [geometric mean fold change (FC) 1.3] and week 96 (3.4, P  =   0.01). There was a small reduction in tenofovir susceptibility (FC 0.7 and 1.0, respectively, P  =   0.18). Ongoing viral failure with zidovudine-containing first-line ART is associated with rapidly increasing drug resistance that could be mitigated with effective viral load monitoring. © The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.

Immunological Effect of aGV Rabies Vaccine Administered Using the Essen and Zagreb Regimens: A Double-Blind, Randomized Clinical Trial.

Science.gov (United States)

Miao, Li; Shi, Liwei; Yang, Yi; Yan, Kunming; Sun, Hongliang; Mo, Zhaojun; Li, Li

2018-04-01

This study evaluated the immunological effect of an aGV rabies virus strain using the Essen and Zagreb immunization programs. A total of 1,944 subjects were enrolled and divided into three groups: the Essen test group, Essen control group, and Zagreb test group. Neutralizing antibody levels and antibody seroconversion rates were determined at 7 and 14 days after the initial inoculations and then 14 days after the final inoculation in all of the subjects. The seroconversion rates for the Essen test group, Essen control group, and Zagreb test group, which were assessed 7 days after the first dosing in a susceptible population, were 35.74%, 26.92%, and 45.49%, respectively, and at 14 days, the seroconversion rates in this population were 100%, 100%, and 99.63%, respectively. At 14 days after the final dosing, the seroconversion rates were 100% in all three of the groups. The neutralizing serum antibody levels of the Essen test group, Essen control group, and Zagreb test group at 7 days after the first dosing in the susceptible population were 0.37, 0.26, and 0.56 IU/mL, respectively, and at 14 days after the initial dosing, these levels were 16.71, 13.85, and 16.80 IU/mL. At 14 days after the final dosing, the neutralizing antibody levels were 22.9, 16.3, and 18.62 IU/mL, respectively. The results of this study suggested that the aGV rabies vaccine using the Essen program resulted in a good serum immune response, and the seroconversion rates and the neutralizing antibody levels generated with the Zagreb regimen were higher than those with the Essen regimen when measured 7 days after the first dose.

Selections of appropriate regimen of high-dose chemotherapy combined with adoptive cellular therapy with dendritic and cytokine-induced killer cells improved progression-free and overall survival in patients with metastatic breast cancer: reargument of such contentious therapeutic preferences.

Science.gov (United States)

Ren, Jun; Di, Lijun; Song, Guohong; Yu, Jing; Jia, Jun; Zhu, Yuling; Yan, Ying; Jiang, Hanfang; Liang, Xu; Che, Li; Zhang, Jie; Wan, Fengling; Wang, Xiaoli; Zhou, Xinna; Lyerly, Herbert Kim

2013-10-01

We hypothesized that combination of dendritic cell (DC) with autologous cytokine-induced killer (CIK) immunotherapy in setting of high-dose chemotherapy (HDC) would be effective for selected metastatic breast cancer (MBC) patients. Our previous work showed thiotepa could eradicate breast cancer stem cells. From 2004 to 2009, 79 patients received standard dose chemotherapy (SDC) of 75 mg/m(2) docetaxel and 75 mg/m(2) thiotepa versus 87 patients of HDC + DC/CIK: 120 mg/m(2) docetaxel to mobilize peripheral CD34(+) progenitor cells, a sequence of HDC (120 mg/m(2) docetaxel, plus 175 mg/m(2) thiotepa) + DC/CIK, with or without 400 mg/m(2) carboplatin depending upon bone marrow function. The endpoints were response rates (RR), progression-free survival (PFS), and overall survival (OS). Compared with SDC, PFS and OS were improved in HDC + DC/CIK (median PFS 10.2 vs. 3.7 months, P < 0.001; median OS 33.1 vs. 15.2 months, P < 0.001). Patients of pre-menopausal, HDC as first-line treatment after metastasis, or with visceral metastasis showed prolonged PFS and OS. SDC group also achieved the similar response as previous reports. Our study demonstrated the novel combination of HDC with DC/CIK to be an effective choice for the selected MBC population, in which choosing appropriate chemo regimens played important roles, and also specific HDC regimen plus DC/CIK immunotherapy showed the clinical benefits compared with chemotherapy alone.

Etanercept provides an effective, safe and flexible short- and long-term treatment regimen for moderate-to-severe psoriasis: a systematic review of current evidence.

Science.gov (United States)

Strohal, Robert; Chimenti, Sergio; Vena, Gino Antonio; Girolomoni, Giampiero

2013-06-01

The treatment of psoriasis requires long-lasting intervention. Conventional treatments for psoriasis comprise topical, phototherapeutic and systemic modalities, such as methotrexate or cyclosporine. Biological therapies are advocated by treatment guidelines for the use in moderate-to-severe psoriasis, when conventional treatments have failed, are contraindicated or are associated with severe adverse events. Etanercept is an anti-TNF recombinant fusion protein that has emerged as a standard biologic treatment option for moderate-to-severe psoriasis. The present review summarizes data from pivotal and post-marketing randomized controlled etanercept trials to treat moderate-to-severe psoriasis for 24 weeks and longer. During the first 12 weeks, etanercept can be administered in different dosing regimens: 50 mg twice weekly (BIW) and 50 mg once weekly. Although both regimens are effective, it has been shown that the 50 mg BIW dosage leads to higher response rates at week 24. In addition, after 24 weeks' treatment etanercept provides the unique possibility of continuous or intermittent long-term treatment programmes. The medium- to long-term efficacy of etanercept was consistent, regardless of whether etanercept therapy was interrupted or continuous. Taking the chronic nature of psoriasis into account, this flexibility in dosing regimen bestows a key advantage in facilitating individualisation of long-term treatment according to patient needs.

Paying to waste lives: the affordability of reducing mother-to-child transmission of HIV in South Africa.

Science.gov (United States)

Skordis, Jolene; Nattrass, Nicoli

2002-05-01

It is estimated that each HIV-positive child in South Africa costs the government more in terms of health and welfare expenses than it does to reduce mother-to-child transmission (MTCT) of HIV through the use of antiretroviral regimens (where the mother continues to breast-feed). Programmes to reduce MTCT of HIV/AIDS are, thus, clearly affordable. Using Nevirapine (according to the HIVNET 012 Protocol) saves more lives and [corrected] is more cost-effective than using Zidovudine (CDC 2 weeks regime).

Initiating sacubitril/valsartan (LCZ696) in heart failure: results of TITRATION, a double-blind, randomized comparison of two uptitration regimens.

Science.gov (United States)

Senni, Michele; McMurray, John J V; Wachter, Rolf; McIntyre, Hugh F; Reyes, Antonio; Majercak, Ivan; Andreka, Peter; Shehova-Yankova, Nina; Anand, Inder; Yilmaz, Mehmet B; Gogia, Harinder; Martinez-Selles, Manuel; Fischer, Steffen; Zilahi, Zsolt; Cosmi, Franco; Gelev, Valeri; Galve, Enrique; Gómez-Doblas, Juanjo J; Nociar, Jan; Radomska, Maria; Sokolova, Beata; Volterrani, Maurizio; Sarkar, Arnab; Reimund, Bernard; Chen, Fabian; Charney, Alan

2016-09-01

To assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction ≤35%). A 5-day open-label run-in (sacubitril/valsartan 50 mg twice daily) preceded an 11-week, double-blind, randomization period [100 mg twice daily for 2 weeks followed by 200 mg twice daily ('condensed' regimen) vs. 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily ('conservative' regimen)]. Patients were stratified by pre-study dose of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB; low-dose stratum included ACEI/ARB-naïve patients). Of 540 patients entering run-in, 498 (92%) were randomized and 429 (86.1% of randomized) completed the study. Pre-defined tolerability criteria were hypotension, renal dysfunction and hyperkalaemia; and adjudicated angioedema, which occurred in ('condensed' vs. 'conservative') 9.7% vs. 8.4% (P = 0.570), 7.3% vs. 7.6% (P = 0.990), 7.7% vs. 4.4% (P = 0.114), and 0.0% vs. 0.8% of patients, respectively. Corresponding proportions for pre-defined systolic blood pressure 5.5 mmol/L, and serum creatinine >3.0 mg/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks (77.8% vs. 84.3% for 'condensed' vs. 'conservative'; P = 0.078). Rates by ACEI/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose/'condensed' vs. high-dose/'conservative' and 84.9% vs. 73.6% (P = 0.030) for low-dose/'conservative' vs. low-dose/'condensed'. Initiation/uptitration of sacubitril/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation/uptitration maximized attainment of target dose in the low-dose

Comparison of evening and morning dosing of travoprost 0.004%/timolol 0.5% fixed combination in 6 month period.

Science.gov (United States)

Suić, Smiljka Popović; Laus, Katia Novak; Dosen, Vukosava Maricic; Ekert, Miroslav; Mandić, Zdravko; Bojić, Lovro

2010-09-01

An open label, multi-center, 6 months observational study of new fixed combination (travoprost 0.004%/timolol 0.5%), in order to evaluate both efficacy (intraocular pressure lowering) and tolerability (patient and investigator satisfaction) of two dosing regimens--evening (PM) and morning (AM). After screening for enrollment, to 40 patients (79 eyes with primary open angle glaucoma or ocular hypertension), new fixed combination travoprost 0.004%/timolol 0.5% was prescribed once a day in the evening (PM). Patients were enrolled according to each investigator decision on indication for travoprost 0.004%/timolol 0.5% fixed combination once a day, without washout period after previous medication. Intraocular pressure was measured at 9 AM at all time control points: at baseline, after 1 month, after 3 months and after 6 month. After 1 month, screening for nonresponders (criteria: 20% intraocular pressure lowering) and subjects with major side effects was performed. At second control visit, after 3 months PM dosing, intraocular pressure was measured and patients were instructed to continue once a day the same medication, but in the morning (AM) for consequent 3 months. After 1 month, reduction in mean intraocular pressure value was 21.66%. At the visit after 3 month, the mean intraocular pressure was 15.67 +/- 2.17 mm Hg (reduction 21.14%). 3 month after dosing regimen changed to AM (6 month after beginning of travoprost 0.004%/timolol 0.5% combination therapy), reduction in intraocular pressure value was 19.86%. The differences (mean +/- standard deviation) in intraocular pressure values after 1, 3 and 6 month were all highly statistically significant compared to baseline values. The tolerability was evaluated in five steps (Likert scale) ranging from unsatisfactory to excellent by both patient and investigator--taken at 3 and 6 month control visit. 95% of patients and 100% of investigators were satisfied with the possibility of choosing dosing regimen for travoprost 0

Assessment of non-standard HIV antiretroviral therapy regimens at ...

African Journals Online (AJOL)

2016-03-06

Mar 6, 2016 ... Most patients were transitioned to standard regimens, ... In cases of first-line regimen treatment failure, ..... tute; National Heart, Lung, and Blood Institute; National. Institute of Dental & Craniofacial Research; National Insti-.

The 'Harmonizing Optimal Strategy for Treatment of coronary artery stenosis - sAfety & effectiveneSS of drug-elUting stents & antiplatelet REgimen' (HOST-ASSURE trial: study protocol for a randomized controlled trial

Directory of Open Access Journals (Sweden)

Park Kyung

2012-03-01

Full Text Available Abstract Background Second-generation drug-eluting stents (DES have raised the bar of clinical performance. These stents are mostly made from cobalt chromium alloy. A newer generation DES has been developed from platinum chromium alloy, but clinical data regarding the efficacy and safety of the platinum chromium-based everolimus-eluting stent (PtCr-EES is limited, with no comparison data against the cobalt chromium-based zotarolimus-eluting stent (CoCr-ZES. In addition, an antiplatelet regimen is an integral component of medical therapy after percutaneous coronary intervention (PCI. A 1-week duration of doubling the dose of clopidogrel (double-dose antiplatelet therapy (DDAT was shown to improve outcome at 1 month compared with conventional dose in acute coronary syndrome (ACS patients undergoing PCI. However in Asia, including Korea, the addition of cilostazol (triplet antiplatelet therapy (TAT is used more commonly than doubling the dose of clopidogrel in high-risk patients. Methods In the 'Harmonizing Optimal Strategy for Treatment of coronary artery stenosis - sAfety & effectiveneSS of drug-elUting stents & antiplatelet REgimen' (HOST-ASSURE trial, approximately 3,750 patients are being prospectively and randomly assigned in a 2 × 2 factorial design according to the type of stent (PtCr-EES vs CoCr-ZES and antiplatelet regimen (TAT vs DDAT. The first primary endpoint is target lesion failure at 1 year for the stent comparison, and the second primary endpoint is net clinical outcome at 1 month for comparison of antiplatelet therapy regimen. Discussion The HOST-ASSURE trial is the largest study yet performed to directly compare the efficacy and safety of the PtCr-EES versus CoCr-ZES in an 'all-comers' population. In addition, this study will also compare the clinical outcome of TAT versus DDAT for 1-month post PCI. Trial registration ClincalTrials.gov number NCT01267734.

Modelling normal tissue isoeffect distribution in conformal radiotherapy of glioblastoma provides an alternative dose escalation pattern through hypofractionation without reducing the total dose

International Nuclear Information System (INIS)

Mangel, L.; Skriba, Z.; Major, T.; Polgar, C.; Fodor, J.; Somogyi, A.; Nemeth, G.

2002-01-01

The purpose of this study was to prove that by using conformal external beam radiotherapy (RT) normal brain structures can be protected even when applying an alternative approach of biological dose escalation: hypofractionation (HOF) without total dose reduction (TDR). Traditional 2-dimensional (2D) and conformal 3-dimensional (3D) treatment plans were prepared for 10 gliomas representing the subanatomical sites of the supratentorial brain. Isoeffect distributions were generated by the biologically effective dose (BED) formula to analyse the effect of conventionally fractionated (CF) and HOF schedules on both the spatial biological dose distribution and biological dose-volume histograms. A comparison was made between 2D-CF (2.0 Gy/day) and 3D-HOF (2.5 Gy/day) regimens, applying the same 60 Gy total doses. Integral biologically effective dose (IBED) and volumes received biologically equivalent to a dose of 54 Gy or more (V-BED54) were calculated for the lower and upper brain stem as organs of risk. The IBED values were lower with the 3D-HOF than with the 2D-CF schedule in each tumour location, means 22.7±17.1 and 40.4±16.9 in Gy, respectively (p<0.0001). The V-BED54 values were also smaller or equal in 90% of the cases favouring the 3D-HOF scheme. The means were 2.7±4.8 ccm for 3D-HOF and 10.7±12.7 ccm for 2D-CF (p=0.0006). Our results suggest that with conformal RT, fraction size can gradually be increased. HOF radiotherapy regimens without TDR shorten the treatment time and seem to be an alternative way of dose escalation in the treatment of glioblastoma

Modelling normal tissue isoeffect distribution in conformal radiotherapy of glioblastoma provides an alternative dose escalation pattern through hypofractionation without reducing the total dose

Energy Technology Data Exchange (ETDEWEB)

Mangel, L.; Skriba, Z.; Major, T.; Polgar, C.; Fodor, J.; Somogyi, A.; Nemeth, G. [National Research Inst. for Radiobiology and Radiohygiene, Budapest (Hungary)

2002-04-01

The purpose of this study was to prove that by using conformal external beam radiotherapy (RT) normal brain structures can be protected even when applying an alternative approach of biological dose escalation: hypofractionation (HOF) without total dose reduction (TDR). Traditional 2-dimensional (2D) and conformal 3-dimensional (3D) treatment plans were prepared for 10 gliomas representing the subanatomical sites of the supratentorial brain. Isoeffect distributions were generated by the biologically effective dose (BED) formula to analyse the effect of conventionally fractionated (CF) and HOF schedules on both the spatial biological dose distribution and biological dose-volume histograms. A comparison was made between 2D-CF (2.0 Gy/day) and 3D-HOF (2.5 Gy/day) regimens, applying the same 60 Gy total doses. Integral biologically effective dose (IBED) and volumes received biologically equivalent to a dose of 54 Gy or more (V-BED54) were calculated for the lower and upper brain stem as organs of risk. The IBED values were lower with the 3D-HOF than with the 2D-CF schedule in each tumour location, means 22.7{+-}17.1 and 40.4{+-}16.9 in Gy, respectively (p<0.0001). The V-BED54 values were also smaller or equal in 90% of the cases favouring the 3D-HOF scheme. The means were 2.7{+-}4.8 ccm for 3D-HOF and 10.7{+-}12.7 ccm for 2D-CF (p=0.0006). Our results suggest that with conformal RT, fraction size can gradually be increased. HOF radiotherapy regimens without TDR shorten the treatment time and seem to be an alternative way of dose escalation in the treatment of glioblastoma.

Successful Outcome of Low-Dose S-1 Used to Treat Buccal Squamous Cell Carcinoma

Directory of Open Access Journals (Sweden)

Kazuyuki Yusa

2017-01-01

Full Text Available This case report describes an 86-year-old woman with dormant right buccal squamous cell carcinoma who was able to maintain a reasonable quality of life after being treated with oral low-dose S-1 (80 mg/day. The treatment regimen started in April 2014 and consisted of two weeks of S-1 followed by a one-week interval. The patient remains on this regimen while maintaining her quality of life and she has been under follow-up as an outpatient for 36 months. The outcomes for this patient indicated that low-dose S-1 is a valid anticancer therapy that may help maintain quality of life for some patients with incurable or dormant cancers.

HIV testing during the neonatal period

African Journals Online (AJOL)

2015-04-24

Apr 24, 2015 ... transmission interventions on 6-week HIV polymerase ... and daily dose nevirapine (NVP) infant prophylaxis (Option B or B+) ... out other antiretrovirals, 32% of intrapartum-infected infants tested HIV DNA PCR negative.

Relieving Pain using Dose-Extending Placebos: A Scoping Review

Science.gov (United States)

Colloca, Luana; Enck, Paul; DeGrazia, David

2017-01-01

Placebos are often used by clinicians, usually deceptively and with little rationale or evidence of benefit, making their use ethically problematic. In contrast with their typical current use, a provocative line of research suggests that placebos can be intentionally exploited to extend analgesic therapeutic effects. Is it possible to extend the effects of drug treatments by interspersing placebos? We reviewed a database of placebo studies, searching for studies that indicate that placebos given after repeated administration of active treatments acquire medication-like effects. We found a total of 22studies in both animals and humans hinting of evidence that placebos may work as a sort of dose extender of active painkillers. Wherever effective in relieving clinical pain, such placebo use would offer several advantages. First, extending the effects of a painkiller through the use of placebos may reduce total drug intake and side effects. Second, dose-extending placebos may decrease patient dependence. Third, using placebos along with active medication, for part of the course of treatment, should limit dose escalation and lower costs. Importantly, provided that nondisclosure is pre-authorized in the informed consent process and that robust evidence indicates therapeutic benefit comparable to that of standard full-dose therapeutic regimens, introducing dose-extending placebos into the clinical arsenal should be considered. This novel prospect of placebo use has the potential to change our general thinking about painkiller treatments, the typical regimens of painkiller applications, and the ways in which treatments are evaluated. PMID:27023425

Combination chemotherapy concurrent with small dose radiation therapy for small cell carcinoma of the lung

International Nuclear Information System (INIS)

Tada, Toshihiko; Fujita, Hiroji; Shintomi, Takenori

1987-01-01

Forty consecutive patients with small cell carcinoma of the lung were treated with chemotherapy, radiotherapy or both. Of 34 patients treated with chemotherapy, 24 were treated with combination chemotherapy, containing cyclophosphamide vincristine methotrexate and procarbazine, concurrent with small dose radiation therapy (500 cGy/5 fraction) as a chemosensitizer (COMPrt). The response rate to this regimen was 81 % (29 % complete) and the 2 year survival rate was 28.6 %. These results have been superior to other regimens and the toxicity was not see to be any higher. After completion of COMPrt regimen, 10 patients were treated with intrathoracic radiation therapy (average dose 3000 cGy) and 3 recieved surgical treatment. Radiation therapy improved the 2-year survival rate (42.2 %) when compared with those patients who received no radiation therapy (18.2 %). Three patients received surgical treatment were considered to be disease-free for 23, 17, and 9 months respectively, after induction of chemotherapy. (author)

Management of factor VII-deficient patients undergoing joint surgeries--preliminary results of locally developed treatment regimen.

Science.gov (United States)

Windyga, J; Zbikowski, P; Ambroziak, P; Baran, B; Kotela, I; Stefanska-Windyga, E

2013-01-01

Inherited factor VII (FVII) deficiency is a rare coagulation disorder with variable haemorrhagic manifestations. In severely affected cases spontaneous haemarthroses leading to advanced arthropathy have been observed. Such cases may require surgery. Therapeutic options for bleeding prevention in FVII deficient patients undergoing surgery comprise various FVII preparations but the use of recombinant activated factor VII (rFVIIa) seems to be the treatment of choice. To present the outcome of orthopaedic surgery under haemostatic coverage of rFVIIa administered according to the locally established treatment regimen in five adult patients with FVII baseline plasma levels below 10 IU dL(-1). Two patients required total hip replacement (THR); three had various arthroscopic procedures. Recombinant activated factor VII was administered every 8 h on day of surgery (D0) followed by every 12-24 h for the subsequent 9-14 days, depending on the type of surgery. Factor VII plasma coagulation activity (FVII:C) was determined daily with no predefined therapeutic target levels. Doses of rFVIIa on D0 ranged from 18 to 37 μg kg(-1) b.w. and on the subsequent days--from 13 to 30 μg kg(-1) b.w. Total rFVIIa dose per procedure ranged from 16 to 37.5 mg, and the total number of doses per procedure was 16-31. None of our patients developed excessive bleeding including those in whom FVII:C trough levels returned nearly to the baseline level on the first post-op day. Preliminary results demonstrate that rFVIIa administered according to our treatment regimen is an effective and safe haemostatic agent for hypoproconvertinaemia patients undergoing orthopaedic surgery. © 2012 Blackwell Publishing Ltd.

Efficacy and Safety of Three Antiretroviral Regimens for Initial Treatment of HIV-1: A Randomized Clinical Trial in Diverse Multinational Settings

Science.gov (United States)

Campbell, Thomas B.; Smeaton, Laura M.; Kumarasamy, N.; Flanigan, Timothy; Klingman, Karin L.; Firnhaber, Cynthia; Grinsztejn, Beatriz; Hosseinipour, Mina C.; Kumwenda, Johnstone; Lalloo, Umesh; Riviere, Cynthia; Sanchez, Jorge; Melo, Marineide; Supparatpinyo, Khuanchai; Tripathy, Srikanth; Martinez, Ana I.; Nair, Apsara; Walawander, Ann; Moran, Laura; Chen, Yun; Snowden, Wendy; Rooney, James F.; Uy, Jonathan; Schooley, Robert T.; De Gruttola, Victor; Hakim, James Gita; Swann, Edith; Barnett, Ronald L.; Brizz, Barbara; Delph, Yvette; Gettinger, Nikki; Mitsuyasu, Ronald T.; Eshleman, Susan; Safren, Steven; Fiscus, Susan A.; Andrade, Adriana; Haas, David W.; Amod, Farida; Berthaud, Vladimir; Bollinger, Robert C.; Bryson, Yvonne; Celentano, David; Chilongozi, David; Cohen, Myron; Collier, Ann C.; Currier, Judith Silverstein; Cu-Uvin, Susan; Eron, Joseph; Flexner, Charles; Gallant, Joel E.; Gulick, Roy M.; Hammer, Scott M.; Hoffman, Irving; Kazembe, Peter; Kumwenda, Newton; Lama, Javier R.; Lawrence, Jody; Maponga, Chiedza; Martinson, Francis; Mayer, Kenneth; Nielsen, Karin; Pendame, Richard B.; Ramratnam, Bharat; Sanne, Ian; Severe, Patrice; Sirisanthana, Thira; Solomon, Suniti; Tabet, Steve; Taha, Taha; van der Horst, Charles; Wanke, Christine; Gormley, Joan; Marcus, Cheryl J.; Putnam, Beverly; Loeliger, Edde; Pappa, Keith A.; Webb, Nancy; Shugarts, David L.; Winters, Mark A.; Descallar, Renard S.; Steele, Joseph; Wulfsohn, Michael; Said, Farideh; Chen, Yue; Martin, John C; Bischofberger, Norbert; Cheng, Andrew; Jaffe, Howard; Sharma, Jabin; Poongulali, S.; Cardoso, Sandra Wagner; Faria, Deise Lucia; Berendes, Sima; Burke, Kelly; Mngqibisa, Rosie; Kanyama, Cecelia; Kayoyo, Virginia; Samaneka, Wadzanai P.; Chisada, Anthony; Faesen, Sharla; Chariyalertsak, Suwat; Santos, Breno; Lira, Rita Alves; Joglekar, Anjali A.; Rosa, Alberto La; Infante, Rosa; Jain, Mamta; Petersen, Tianna; Godbole, Sheela; Dhayarkar, Sampada; Feinberg, Judith; Baer, Jenifer; Pollard, Richard B.; Asmuth, David; Gangakhedkar, Raman R; Gaikwad, Asmita; Ray, M. Graham; Basler, Cathi; Para, Michael F.; Watson, Kathy J.; Taiwo, Babafemi; McGregor, Donna; Balfour, Henry H.; Mullan, Beth; Kim, Ge-Youl; Klebert, Michael K.; Cox, Gary Matthew; Silberman, Martha; Mildvan, Donna; Revuelta, Manuel; Tashima, Karen T.; Patterson, Helen; Geiseler, P. Jan; Santos, Bartolo; Daar, Eric S; Lopez, Ruben; Frarey, Laurie; Currin, David; Haas, David H.; Bailey, Vicki L.; Tebas, Pablo; Zifchak, Larisa; Noel-Connor, Jolene; Torres, Madeline; Sha, Beverly E.; Fritsche, Janice M.; Cespedes, Michelle; Forcht, Janet; O'Brien, William A.; Mogridge, Cheryl; Hurley, Christine; Corales, Roberto; Palmer, Maria; Adams, Mary; Luque, Amneris; Lopez-Detres, Luis; Stroberg, Todd

2012-01-01

Background Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world. Methods and Findings 1,571 HIV-1-infected persons (47% women) from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV), atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC), or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF) (EFV+FTC-TDF). ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR) was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18%) among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72–1.27; p = 0.74). Safety endpoints occurred in 243 (46%) participants assigned to EFV+FTC-TDF versus 313 (60%) assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54–0.76; p<0.001) and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39–0.64 for women; HR 0.79, CI 0.62–1.00 for men; p = 0.01). Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21%) among 526 participants assigned to ATV+DDI+FTC and 76 (15%) among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12–2.04; p = 0.007). Conclusion EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected

Efficacy and safety of three antiretroviral regimens for initial treatment of HIV-1: a randomized clinical trial in diverse multinational settings.

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Thomas B Campbell

Full Text Available Antiretroviral regimens with simplified dosing and better safety are needed to maximize the efficiency of antiretroviral delivery in resource-limited settings. We investigated the efficacy and safety of antiretroviral regimens with once-daily compared to twice-daily dosing in diverse areas of the world.1,571 HIV-1-infected persons (47% women from nine countries in four continents were assigned with equal probability to open-label antiretroviral therapy with efavirenz plus lamivudine-zidovudine (EFV+3TC-ZDV, atazanavir plus didanosine-EC plus emtricitabine (ATV+DDI+FTC, or efavirenz plus emtricitabine-tenofovir-disoproxil fumarate (DF (EFV+FTC-TDF. ATV+DDI+FTC and EFV+FTC-TDF were hypothesized to be non-inferior to EFV+3TC-ZDV if the upper one-sided 95% confidence bound for the hazard ratio (HR was ≤1.35 when 30% of participants had treatment failure. An independent monitoring board recommended stopping study follow-up prior to accumulation of 472 treatment failures. Comparing EFV+FTC-TDF to EFV+3TC-ZDV, during a median 184 wk of follow-up there were 95 treatment failures (18% among 526 participants versus 98 failures among 519 participants (19%; HR 0.95, 95% CI 0.72-1.27; p = 0.74. Safety endpoints occurred in 243 (46% participants assigned to EFV+FTC-TDF versus 313 (60% assigned to EFV+3TC-ZDV (HR 0.64, CI 0.54-0.76; p<0.001 and there was a significant interaction between sex and regimen safety (HR 0.50, CI 0.39-0.64 for women; HR 0.79, CI 0.62-1.00 for men; p = 0.01. Comparing ATV+DDI+FTC to EFV+3TC-ZDV, during a median follow-up of 81 wk there were 108 failures (21% among 526 participants assigned to ATV+DDI+FTC and 76 (15% among 519 participants assigned to EFV+3TC-ZDV (HR 1.51, CI 1.12-2.04; p = 0.007.EFV+FTC-TDF had similar high efficacy compared to EFV+3TC-ZDV in this trial population, recruited in diverse multinational settings. Superior safety, especially in HIV-1-infected women, and once-daily dosing of EFV+FTC-TDF are

Efficacy and safety of a flexible extended regimen of ethinylestradiol/drospirenone for the treatment of dysmenorrhea: a multicenter, randomized, open-label, active-controlled study

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Momoeda M

2017-05-01

Full Text Available Mikio Momoeda,1 Masami Kondo,2 Joerg Elliesen,3 Masanobu Yasuda,2 Shigetomo Yamamoto,4 Tasuku Harada5 1Department of Integrated Women’s Health, St Luke’s International Hospital, Tokyo, 2Product Development, Bayer Yakuhin Ltd, Osaka, Japan; 3Global Clinical Development, Bayer AG, Berlin, Germany; 4Medical Affairs, Bayer Yakuhin Ltd, Osaka, 5Department of Obstetrics and Gynecology, Tottori University Faculty of Medicine, Tottori, Japan Background: Dysmenorrhea is a common condition in women, which is characterized by menstrual pain. Low-dose estrogen/progestin combined oral contraceptives have been shown to reduce the severity of dysmenorrhea symptoms, and a 28-day cyclic regimen of ethinylestradiol/drospirenone (28d regimen is approved for this indication in Japan. Aim: The aim of this study was to assess the safety and efficacy of a flexible extended regimen of ethinylestradiol/drospirenone (flexible regimen in Japanese women with dysmenorrhea. Methods: This multicenter, open-label study was performed in Japanese women with dysmenorrhea who, after a baseline observational phase, were randomized to receive ethinylestradiol 20 µg/drospirenone 3 mg in a flexible regimen (one tablet each day for 24–120 days followed by a 4-day tablet-free interval or in the standard 28d regimen (one tablet each day for 24 days, followed by 4 days of placebo tablets for six cycles. The primary endpoint was the number of days with dysmenorrhea of at least mild intensity over a 140-day evaluation period. Dysmenorrhea scores, bleeding patterns, and other pain-related parameters were also assessed. Results: A total of 216 women (mean age 29.7 years were randomized to the flexible regimen (n=108 or 28d regimen (n=108 and 212 were included in the full analysis sets (flexible regimen, n=105; 28d regimen, n=107. Women in the flexible-regimen group reported a mean of 3.4 fewer days with dysmenorrheic pain than women in the 28d-regimen group, with similar decreases in

A randomized trial of three single - dose radiation therapy regimens in the treatment of metastatic bone pain

International Nuclear Information System (INIS)

Jeremic, Branislav; Shibamoto, Yuta; Acimovic, Ljubisa; Milicic, Biljana; Milisavljevic, Slobodan; Nikolic, Nebojsa; Aleksandrovic, Jasna; Igrutinovic, Ivan

1998-01-01

Purpose: To investigate efficacy of three single dose radiation therapy (RT) regimens in the treatment of painful bone metastasis. Material and Methods: Patient self-assessment by using pain chart enabled evaluation of response to treatment that consisted of either one of the three single fractions of 4 Gy (group I; n = 109), 6 Gy (group II; n = 108), or 8 Gy (group III; n = 110). Results: Patients in groups II and III had higher complete response rate than those in group I, but not significantly, and with no difference between group II and III. However, both patients in group II (73%) and group III (78%) had significantly higher overall response rates when compared to those observed in group I (59%) (I vs II, p = 0.025; I vs III, p = 0.0019), and with no difference between groups II and III (p 0.39). Patients in group III had shortest time to the occurrence of any pain relief which was significantly better than those observed in group I (Welch's t-test, p = 0.012), with no difference between group I and II and group II and III, respectively. There was no difference between the three treatment groups in duration of response and retreatment rate. No effect of histology or metastatic site treated was found. No pathological fractures or spinal cord compressions were observed during the 8 weeks post-RT. Conclusion: Results of this study seem to confirm that 8 Gy could be considered as probably 'lowest' optimal single fraction RT in the treatment of painful bone metastasis, although single fraction RT of 4 Gy should not be easily discarded due to its applicability in specific cases. Since single fraction RT of 6 Gy achieved results not different from that obtained with 8 Gy, further studies are warranted in order to get more informations about 'lowest' optimal single fraction RT in the treatment of painful bone metastasis

A Phase 2 Randomized Trial of a Rifapentine plus Moxifloxacin-Based Regimen for Treatment of Pulmonary Tuberculosis.

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Marcus B Conde

Full Text Available The combination of rifapentine and moxifloxacin administered daily with other anti-tuberculosis drugs is highly active in mouse models of tuberculosis chemotherapy. The objective of this phase 2 clinical trial was to determine the bactericidal activity, safety, and tolerability of a regimen comprised of rifapentine, moxifloxacin, isoniazid, and pyrazinamide administered daily during the first 8 weeks of pulmonary tuberculosis treatment.Adults with sputum smear-positive pulmonary tuberculosis were randomized to receive either rifapentine (approximately 7.5 mg/kg plus moxifloxacin (investigational arm, or rifampin (approximately 10 mg/kg plus ethambutol (control daily for 8 weeks, along with isoniazid and pyrazinamide. The primary endpoint was sputum culture status at completion of 8 weeks of treatment.121 participants (56% of accrual target were enrolled. At completion of 8 weeks of treatment, negative cultures using Löwenstein-Jensen (LJ medium occurred in 47/60 (78% participants in the investigational arm vs. 43/51 (84%, p = 0.47 in the control arm; negative cultures using liquid medium occurred in 37/47 (79% in the investigational arm vs. 27/41 (66%, p = 0.23 in the control arm. Time to stable culture conversion was shorter for the investigational arm vs. the control arm using liquid culture medium (p = 0.03, but there was no difference using LJ medium. Median rifapentine area under the concentration-time curve (AUC0-24 was 313 mcg*h/mL, similar to recent studies of rifapentine dosed at 450-600 mg daily. Median moxifloxacin AUC0-24 was 28.0 mcg*h/mL, much lower than in trials where rifapentine was given only intermittently with moxifloxacin. The proportion of participants discontinuing assigned treatment for reasons other than microbiological ineligibility was higher in the investigational arm vs. the control arm (11/62 [18%] vs. 3/59 [5%], p = 0.04 although the proportions of grade 3 or higher adverse events were similar (5/62 [8%] in the

Pharmacodynamic evaluation of intragastric pH and implications for famotidine dosing in the prophylaxis of non-steroidal anti-inflammatory drug induced gastropathy-a proof of concept analysis.

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Kent, Jeffery D; Holt, Robert J; Jung, Donald; Tidmarsh, George F; Grahn, Amy Y; Ball, Julie; Peura, David A

2014-01-01

Famotidine given at a dose of 80 mg/day is effective in preventing NSAID-induced gastropathy. The aim of this proof of concept study was to compare twice a day (BID) vs 3-times a day (TID) administration of this total dose of famotidine on intragastric pH in healthy volunteers. Two analyses were undertaken: (1) a 13 subject controlled cross-over 24-h intragastric pH evaluation of the BID and TID administration of 80 mg/day of famotidine, as well as measures for drug accumulation over 5 days (EudraCT, number 2006-002930-39); and (2) a pharmacokinetic (PK)/pharmacodynamic (PD) model which predicted steady-state famotidine plasma concentrations and pH of the two regimens. For the cross-over study, gastric pH was above 3.5 for a mean of 20 min longer for TID dosing compared to BID dosing on Day 1. On Day 5, the mean time above this threshold was higher with the BID regimen by ∼25 min. For pH 4, subjects' gastric pH was above this pH value for a mean of 25 min longer for TID dosing compared to BID dosing on Day 1. For Day 5, the pH was above 4 for ∼45 min longer with the TID regimen as compared with the BID regimen. The mean 24-h gastric pH values when taken in the upright position trended higher for the TID dosing period compared to the BID regimen on Day 1. The steady-state simulation model indicated that, following TID dosing, intragastric pH will be above 3 for 24 h vs 16 h for the BID regimen. There was no evidence for plasma accumulation of famotidine with TID dosing as compared to BID dosing from either analysis. The data indicate that overall more time is spent above the acidic threshold pH values when 80 mg/day of famotidine is administered TID vs BID. Key limitations included small study size with a short duration and lack of a baseline examination, but was compensated for by the cross-over and PK/PD modeling design. Although most of the comparisons in this proof of concept study were not statistically significant these results have

The effectiveness of low-dose and high-dose tranexamic acid in posterior lumbar interbody fusion: a double-blinded, placebo-controlled randomized study.

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Kim, Ki-Tack; Kim, Cheung-Kue; Kim, Yong-Chan; Juh, Hyung-Suk; Kim, Hyo-Jong; Kim, Hyeon-Soo; Hong, Se Jung; Hey, Hwee Weng Dennis

2017-11-01

Tranexamic acid is a proven drug used for reduction of intraoperative blood loss in spinal surgery. However, optimal dosing considering risk/benefits is not well established owing to the heterogeneity in patient selection and surgical procedures of previous studies. This study aimed to evaluate the effectiveness and safety of various tranexamic acid regimens in reducing perioperative blood loss in single-level posterior lumbar interbody fusion (PLIF). Patients were randomly grouped into three different interventions: low-dose tranexamic acid (LD), high-dose tranexamic acid (HD), and placebo-controlled (PC) groups. The HD and LD groups received 10 and 5 mg/kg of bolus loading dose and 2 and 1 mg/kg of continuous infusion until 5 h after surgery, respectively. Data on patient demographics and preoperative and 24-h postoperative laboratory values were collected. Outcome parameters include intraoperative blood loss, 24-h postoperative blood loss, and blood loss during removal of the last drain. Seventy-two patients (mean age 63.3 ± 7.6 years) showed similar baseline characteristics. Intraoperatively, blood loss was reduced by the administration of tranexamic acid (P = 0.04), contributed predominantly by a difference between the LD and HD groups (123 mL; P tranexamic acid use were noted. Tranexamic acid administration for single-level PLIF was effective and safe in reducing perioperative blood loss in a dose-dependent manner. An HD regimen comprising 10 mg/kg of bolus loading dose and 2 mg/kg/h of continuous infusion is recommended. Level 1 study according to Oxford Centre for Evidence-Based Medicine 2011 Levels of Evidence.

Biocatalytic preparation of 5-methyluridine (5-MU)

CSIR Research Space (South Africa)

Gordon, GER

2008-11-01

Full Text Available the biocatalytic reaction to produce 5-MU at bench-scale (10 L) while meeting the required reaction performance with respect to guanosine conversion, 5-MU yield, reactor productivity and fi nal product concentration. INTRODUCTION Sub-Saharan Africa remains.... Stavudine (d4T), zidovudine (AZT), lamivudine (3TC), nevirapine (NVP) and efavirenz (EFV) are widely used in the fi rst line regimen treatment of HIV/ Aids. The drugs are generally in combination therapy and represent 96% of the ARVʼs procured to date...

Dose evaluation of narrow-beam

International Nuclear Information System (INIS)

Goto, Shinichi

1999-01-01

Reliability of the dose from the narrow photon beam becomes more important since the single high-dose rate radiosurgery becoming popular. The dose evaluation for the optimal dose is difficult due to absence of lateral electronic equilibrium. Data necessary for treatment regimen are TMR (tissue maximum ratio), OCR (off center ratio) and S c,p (total scatter factor). The narrow-beam was 10 MV X-ray from Varian Clinac 2100C equipped with cylindrical Fischer collimator CBI system. Detection was performed by Kodak XV-2 film, a PTW natural diamond detector M60003, Scanditronics silicon detector EDD-5 or Fujitec micro-chamber FDC-9.4C. Phantoms were the water equivalent one (PTW, RW3), water one (PTW, MP3 system) and Wellhofer WP600 system. Factors above were actually measured to reveal that in the dose evaluation of narrow photon beam, TMR should be measured by micro-chamber, OCR, by film, and S c,p , by the two. The use of diamond detector was recommended for more precise measurement and evaluation of the dose. The importance of water phantom in the radiosurgery system was also shown. (K.H.)

Outcomes of autologous transplantation for multiple myeloma according to different induction regimens

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Edvan de Queiroz Crusoe

2014-01-01

Full Text Available Background: Induction therapy followed by high-dose chemotherapy and autologous transplantation is the standard treatment for suitable patients with multiple myeloma. Objective: The aim of this study was to assess whether induction therapy with thalidomidecontaining regimens was associated with improved results compared to vincristine, doxorubicin, and dexamethasone, and whether cyclophosphamide, thalidomide, and dexamethasone were associated with better results than thalidomide and dexamethasone. Methods: The records of 152 patients who underwent autologous transplantation at this institution from August of 2004 to January of 2012 were reviewed, selecting those with at least partial response to a maximum of eight cycles of induction therapy and sufficient follow-up information for analysis. Results: This study included 89 patients; 44 were female, with a mean age of 55 years (there was a significant trend for increasing age over the years of the study.The median number of induction therapy cycles was four, again with a trend of increase over the years.At least a very good partial response to induction therapy was achieved more often in the cyclophosphamide, thalidomide, and dexamethasone group (61.1% and in the thalidomide and dexamethasone group (59.2% than in the vincristine, doxorubicin, and dexamethasone group (16.2%. The overall median progression-free survival was 34 months, with no statistically significant difference between the three groups. The overall median survival was not reached, and there was no significant difference between the three groups; the estimated five-year overall survival was 55%. Conclusion: Although the quality of responses appeared to be better with thalidomidecontaining regimens, these improvements did not translate into improved long-term outcomes. Given its track record, cyclophosphamide, thalidomide, and dexamethasone is currently considered the preferred regimen for first-line induction therapy in the

The lowest-dose, extended-cycle combined oral contraceptive pill with continuous ethinyl estradiol in the United States: a review of the literature on ethinyl estradiol 20 µg/levonorgestrel 100 µg + ethinyl estradiol 10 µg

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Sheila Krishnan

2010-08-01

Full Text Available Sheila Krishnan, Jessica KileyDepartment of Obstetrics and Gynecology, Northwestern University, Chicago, Illinois, USAAbstract: Extended-cycle oral contraceptives (OCs are increasing in popularity in the United States. A new extended-cycle OC that contains the lowest doses of ethinyl estradiol (EE and levonorgestrel (LNG + continuous EE throughout the cycle is now available. It provides 84 days of a low-dose, combined active pill containing levonorgestrel 100 µg and ethinyl estradiol 20 µg. Instead of 7 days of placebo following the active pills, the regimen delivers 7 days of ethinyl estradiol 10 µg. Existing studies reveal a similar efficacy and adverse effect profile compared with other extended-regimen OCs. Specifically, the unscheduled bleeding profile is similar to other extended-cycle OCs and improves with the increase in the duration of use. Although lower daily doses of hormonal exposure have potential benefit, to our knowledge, there are no published studies indicating that this specific regimen offers a lower incidence of hormone-related side effects or adverse events. In summary, this new extended-cycle OC provides patients a low-dose, extended-regimen OC option without sacrificing efficacy or tolerability.Keywords: continuous regimen, ethinyl estradiol, extended cycle, oral contraceptive

Development of antibiotic regimens using graph based evolutionary algorithms.

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Corns, Steven M; Ashlock, Daniel A; Bryden, Kenneth M

2013-12-01

This paper examines the use of evolutionary algorithms in the development of antibiotic regimens given to production animals. A model is constructed that combines the lifespan of the animal and the bacteria living in the animal's gastro-intestinal tract from the early finishing stage until the animal reaches market weight. This model is used as the fitness evaluation for a set of graph based evolutionary algorithms to assess the impact of diversity control on the evolving antibiotic regimens. The graph based evolutionary algorithms have two objectives: to find an antibiotic treatment regimen that maintains the weight gain and health benefits of antibiotic use and to reduce the risk of spreading antibiotic resistant bacteria. This study examines different regimens of tylosin phosphate use on bacteria populations divided into Gram positive and Gram negative types, with a focus on Campylobacter spp. Treatment regimens were found that provided decreased antibiotic resistance relative to conventional methods while providing nearly the same benefits as conventional antibiotic regimes. By using a graph to control the information flow in the evolutionary algorithm, a variety of solutions along the Pareto front can be found automatically for this and other multi-objective problems. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Modeling Outcomes of First-Line Antiretroviral Therapy and Rate of CD4 Counts Change among a Cohort of HIV/AIDS Patients in Ethiopia: A Retrospective Cohort Study.

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Tadesse Awoke

Full Text Available Antiretroviral therapy has shown to be effective in reducing morbidity and mortality in patients infected with HIV for the past couples of decades. However, there remains a need to better understand the characteristics of long-term treatment outcomes in resource poor settings. The main aim of this study was to determine and compare the long-term response of patients on nevirapine and efavirenz based first line antiretroviral therapy regimen in Ethiopia.Hospital based retrospective cohort study was conducted from January 2009 to December 2013 at University hospital located in Northwest Ethiopia. Human subject research approval for this study was received from University of Gondar Research Ethics Committee and the medical director of the hospital. Cox-proportional hazards model was used to assess the effect of baseline covariates on composite outcome and a semi-parametric mixed effect model was used to investigate CD4 counts response to treatments.A total of 2386 HIV/AIDS naive patients were included in this study. Nearly one-in-four patients experienced the events, of which death, lost to follow up, treatment substitution and discontinuation of Non-Nucleoside Reverse Transcriptase Inhibitors(NNRTI accounted: 99 (26.8%, 122 (33.0%, 137 (37.0% and 12 (3.2%, respectively. The hazard of composite outcome on nevirapine compared with efavirenz was 1.02(95%CI: 0.52-1.99 with p-value = 0.96. Similarly, the hazard of composite outcome on tenofovir and stavudine compared with zidovudine were 1.87 (95%CI: 1.52-2.32, p-value < 0.0001 and 1.72(95% CI: 1.22-2.32, p-value = 0.002, respectively. The rate of CD4 increase in response to treatment was high during the first 10 months and stabilized later.This study revealed that treatment responses were comparable whether nevirapine or efavirenz was chosen to initiate antiretroviral therapy for HIV/AIDS patients in Ethiopia. There was significant difference on risk of composite outcome between patients who were

A heterologous prime-boost Ebola virus vaccine regimen induces durable neutralizing antibody response and prevents Ebola virus-like particle entry in mice.

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Chen, Tan; Li, Dapeng; Song, Yufeng; Yang, Xi; Liu, Qingwei; Jin, Xia; Zhou, Dongming; Huang, Zhong

2017-09-01

Ebola virus (EBOV) is one of the most virulent pathogens known to humans. Neutralizing antibodies play a major role in the protection against EBOV infections. Thus, an EBOV vaccine capable of inducing a long-lasting neutralizing antibody response is highly desirable. We report here that a heterologous prime-boost vaccine regimen can elicit durable EBOV-neutralizing antibody response in mice. A chimpanzee serotype 7 adenovirus expressing EBOV GP (denoted AdC7-GP) was generated and used for priming. A truncated version of EBOV GP1 protein (denoted GP1t) was produced at high levels in Drosophila S2 cells and used for boosting. Mouse immunization studies showed that the AdC7-GP prime/GP1t boost vaccine regimen was more potent in eliciting neutralizing antibodies than either the AdC7-GP or GP1t alone. Neutralizing antibodies induced by the heterologous prime-boost regimen sustained at high titers for at least 18 weeks after immunization. Significantly, in vivo challenge studies revealed that the entry of reporter EBOV-like particles was efficiently blocked in mice receiving the heterologous prime-boost regimen even at 18 weeks after the final dose of immunization. These results suggest that this novel AdC7-GP prime/GP1t boost regimen represents an EBOV vaccine approach capable of establishing long-term protection, and therefore warrants further development. Copyright © 2017 Elsevier B.V. All rights reserved.

Impact of cyclophosphamide dose of conditioning on the outcome of allogeneic hematopoietic stem cell transplantation for aplastic anemia from human leukocyte antigen-identical sibling.

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Mori, Takehiko; Koh, Hideo; Onishi, Yasushi; Kako, Shinichi; Onizuka, Makoto; Kanamori, Heiwa; Ozawa, Yukiyasu; Kato, Chiaki; Iida, Hiroatsu; Suzuki, Ritsuro; Ichinohe, Tatsuo; Kanda, Yoshinobu; Maeda, Tetsuo; Nakao, Shinji; Yamazaki, Hirohito

2016-04-01

The standard conditioning regimen in allogeneic hematopoietic stem cell transplantation (HSCT) for aplastic anemia from a human leukocyte antigen (HLA)-identical sibling has been high-dose cyclophosphamide (CY 200 mg/kg). In the present study, results for 203 patients with aplastic anemia aged 16 years or older who underwent allogeneic HSCT from HLA-identical siblings were retrospectively analyzed using the registry database of Japan Society for Hematopoietic Cell Transplantation. Conditioning regimens were defined as a (1) high-dose CY (200 mg/kg or greater)-based (n = 117); (2) reduced-dose CY (100 mg/kg or greater, but less than 200 mg/kg)-based (n = 38); and (3) low-dose CY (less than 100 mg/kg)-based (n = 48) regimen. Patient age and the proportion of patients receiving fludarabine were significantly higher in the reduced- and low-dose CY groups than the high-dose CY group. Engraftment was comparable among the groups. Five-year overall survival (OS) tended to be higher in the low-dose CY group [93.0 % (95 % CI 85.1-100.0 %)] than the high-dose CY [84.2 % (95 % CI 77.1-91.3 %)] or reduced-dose CY groups [83.8 % (95 % CI 71.8-95.8 %); P = 0.214]. Age-adjusted OS was higher in the low-dose CY group than the high- and reduced-dose CY groups with borderline significance (P = 0.067). These results suggest that CY dose can safely be reduced without increasing graft rejection by adding fludarabine in allogeneic HSCT for aplastic anemia from an HLA-identical sibling.

Single Tablet Regimen Usage and Efficacy in the Treatment of HIV Infection in Australia

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B. Armstrong

2015-01-01

Full Text Available Single tablet regimens (STRs for HIV infection improve patient satisfaction, quality of life, medication adherence, and virological suppression compared to multitablet regimens (MTRs. This is the first study assessing STR uptake and durability in Australia. This retrospective audit of all patients receiving an STR (n=299 at a large Sydney HIV clinic (January 2012–December 2013 assessed patient demographics, treatment prior to STR, HIV RNA load and CD4 during MTR and STR dosing, and reasons for STR switch. 206 patients switched from previous antiretroviral treatment to an STR, of which 88% switched from an MTR. Reasons for switching included desire to simplify treatment (57%, reduced side effects or toxicity (18%, and cost-saving for the patient. There was no switching for virological failure. Compared to when on an MTR, patients switching to an STR had significantly lower HIV RNA counts (p<0.001 and significantly higher CD4 counts (p<0.001. The discontinuation rate from STR was very low and all patients who switched to an STR maintained virological suppression throughout the study duration, although the study is limited by the absence of a control group.

Efficacy of Antimicrobial Treatments and Vaccination Regimens for Control of Porcine Reproductive and Respiratory Syndrome Virus and Streptococcus suis Coinfection of Nursery Pigs

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Halbur, P.; Thanawongnuwech, R.; Brown, G.; Kinyon, J.; Roth, J.; Thacker, E.; Thacker, B.

2000-01-01

Seventy-six, crossbred, porcine reproductive and respiratory syndrome virus (PRRSV)-free pigs were weaned at 12 days of age and randomly assigned to seven groups of 10 to 11 pigs each. Pigs in group 1 served as unchallenged controls. Pigs in groups 2 to 7 were challenged intranasally with 2 ml of high-virulence PRRSV isolate VR-2385 (104.47 50% tissue culture infective doses per 2 ml) on day 0 of the study (30 days of age). Seven days after PRRSV challenge, pigs in groups 2 to 7 were challenged intranasally with 2 ml of Streptococcus suis serotype 2 (108.30 CFU/2 ml). Group 2 pigs served as untreated positive controls. Antimicrobial treatments included daily intramuscular injection with 66,000 IU of procaine penicillin G per kg of body weight on days 8 to 10 (group 3), drinking water medication with 23.1 mg of tiamulin per kg during days 8 to 10 (group 4), and daily intramuscular injection of 5.0 mg of ceftiofur hydrochloride per kg on days 8 to 10 (group 5). Vaccination regimens included two intramuscular doses of an autogenous killed S. suis vaccine (group 6) prior to S. suis challenge or a single 2-ml intramuscular dose of an attenuated live PRRSV vaccine (group 7) 2 weeks prior to PRRSV challenge. Mortality was 0, 63, 45, 54, 9, 40, and 81% in groups 1 to 7, respectively. Ceftiofur treatment was the only regimen that significantly (P < 0.05) reduced mortality associated with PRRSV and S. suis coinfection. The other treatments and vaccinations were less effective. We conclude that ceftiofur administered by injection for three consecutive days following S. suis challenge was the most effective regimen for minimizing disease associated with PRRSV and S. suis coinfection. PMID:10699012

Priority-Setting for Novel Drug Regimens to Treat Tuberculosis: An Epidemiologic Model.

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Emily A Kendall

2017-01-01

Full Text Available Novel drug regimens are needed for tuberculosis (TB treatment. New regimens aim to improve on characteristics such as duration, efficacy, and safety profile, but no single regimen is likely to be ideal in all respects. By linking these regimen characteristics to a novel regimen's ability to reduce TB incidence and mortality, we sought to prioritize regimen characteristics from a population-level perspective.We developed a dynamic transmission model of multi-strain TB epidemics in hypothetical populations reflective of the epidemiological situations in India (primary analysis, South Africa, the Philippines, and Brazil. We modeled the introduction of various novel rifampicin-susceptible (RS or rifampicin-resistant (RR TB regimens that differed on six characteristics, identified in consultation with a team of global experts: (1 efficacy, (2 duration, (3 ease of adherence, (4 medical contraindications, (5 barrier to resistance, and (6 baseline prevalence of resistance to the novel regimen. We compared scale-up of these regimens to a baseline reflective of continued standard of care. For our primary analysis situated in India, our model generated baseline TB incidence and mortality of 157 (95% uncertainty range [UR]: 113-187 and 16 (95% UR: 9-23 per 100,000 per year at the time of novel regimen introduction and RR TB incidence and mortality of 6 (95% UR: 4-10 and 0.6 (95% UR: 0.3-1.1 per 100,000 per year. An optimal RS TB regimen was projected to reduce 10-y TB incidence and mortality in the India-like scenario by 12% (95% UR: 6%-20% and 11% (95% UR: 6%-20%, respectively, compared to current-care projections. An optimal RR TB regimen reduced RR TB incidence by an estimated 32% (95% UR: 18%-46% and RR TB mortality by 30% (95% UR: 18%-44%. Efficacy was the greatest determinant of impact; compared to a novel regimen meeting all minimal targets only, increasing RS TB treatment efficacy from 94% to 99% reduced TB mortality by 6% (95% UR: 1%-13%, half the

A comparison of traditional vs. Canadian tailored prophylaxis dosing of prophylactic factor infusions in children with haemophilia A and B in a single hemophilia treatment center.

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Dodd, C; Watts, R G

2012-07-01

Prophylactic infusion of clotting factor concentrates is a developing standard of care for individuals with haemophilia. The ideal schedule and techniques of prophylactic infusions remain incompletely defined. Our aim was to determine the optimal techniques and schedules for factor prophylaxis in paediatric patients. A retrospective electronic medical record review of all children treated with prophylactic factor infusions in a single Haemophilia Treatment Center was conducted. Comparison of traditional vs. Canadian dosing regimens and primary vs. secondary prophylaxis was made. Failure of prophylaxis was defined as the first serious bleed. A total of 58 children were identified for review. Five cases were excluded (four due to high titre inhibitors and one due to repeated non-compliance), thus there were 53 total cases: 46 with severe haemophilia, 2 with moderate haemophilia, 5 with mild haemophilia, 44 with haemophilia A and 9 with haemophilia B; 32 Traditional dosing and 21 Canadian dosing regimens. Patients on primary prophylaxis had a decreased failure rate (25%) compared to children treated with secondary prophylaxis (67%) regardless of technique of prophylaxis. When compared to a 'Traditional' factor prophylaxis schedule, the 'Canadian' tailored prophylaxis protocol was comparable with the exception of a decreased use of implanted venous devices in the 'Canadian' group. Ongoing bleeding (primarily joint bleeds) occurs with all prophylactic regimens. The lowest incidence of treatment failure was noted in children who began primary prophylaxis at a young age and before initial joint bleeds. Primary prophylaxis is superior to secondary prophylaxis regardless of dosing regimen. Traditional and Canadian dosing regimens were equivalent in outcome when measured over several years of follow-up. © 2012 Blackwell Publishing Ltd.

Classifying insulin regimens--difficulties and proposal for comprehensive new definitions.

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Neu, A; Lange, K; Barrett, T; Cameron, F; Dorchy, H; Hoey, H; Jarosz-Chobot, P; Mortensen, H B; Robert, J-J; Robertson, K; de Beaufort, C

2015-09-01

Modern insulin regimens for the treatment of type 1 diabetes are highly individualized. The concept of an individually tailored medicine accounts for a broad variety of different insulin regimens applied. Despite clear recommendations for insulin management in children and adolescents with type 1 diabetes there is little distinctiveness about concepts and the nomenclature is confusing. Even among experts similar terms are used for different strategies. The aim of our review--based on the experiences of the Hvidoere Study Group (HSG)--is to propose comprehensive definitions for current insulin regimens reflecting current diabetes management in childhood and adolescence. The HSG--founded in 1994--is an international group representing 24 highly experienced pediatric diabetes centers, from Europe, Japan, North America and Australia. Different benchmarking studies of the HSG revealed a broad variety of insulin regimens applied in each center, respectively. Furthermore, the understanding of insulin regimens has been persistently different between the centers since more than 20 yr. Not even the terms 'conventional' and 'intensified therapy' were used consistently among all members. Besides the concepts 'conventional' and 'intensified', several other terms for the characterization of insulin regimens are in use: Basal Bolus Concept (BBC), multiple daily injections (MDI), and flexible insulin therapy (FIT) are most frequently used, although none of these expressions is clearly or consistently defined. The proposed new classification for insulin management will be comprehensive, simple, and catchy. Currently available terms were included. This classification may offer the opportunity to compare therapeutic strategies without the currently existing confusion on the insulin regimen. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

A two-dose heterologous prime-boost vaccine regimen eliciting sustained immune responses to Ebola Zaire could support a preventive strategy for future outbreaks.

Science.gov (United States)

Shukarev, Georgi; Callendret, Benoit; Luhn, Kerstin; Douoguih, Macaya

2017-02-01

The consequences of the 2013-16 Ebola Zaire virus disease epidemic in West Africa were grave. The economies, healthcare systems and communities of Guinea, Sierra Leone and Liberia were devastated by over 18 months of active Ebola virus transmission, followed by sporadic resurgences potentially related to sexual transmission by survivors with viral persistence in body fluids following recovery. The need to develop and implement strategies to prevent and mitigate future outbreaks is now beyond dispute. The potential for unpredictable outbreaks of indeterminate duration, and control challenges posed by the possibility of sporadic re-emergence, mean that implementation of an effective vaccination program for outbreak containment necessitates a vaccine providing durable immunity. Heterologous prime-boost vaccine regimens deliver the same or similar antigens through different vaccine types, the first to prime and the second to boost the immune system. Ad26.ZEBOV/MVA-BN-Filo is an investigational Ebola Zaire vaccine regimen that uses this heterologous prime-boost approach. Preliminary Phase 1 data suggest that Ad26.ZEBOV/MVA-BN-Filo confers durable immunity for at least 240 d and is well-tolerated with a good safety profile. This regimen may therefore be suitable for prophylactic use in a regional or targeted population vaccination strategy, and could potentially aid prevention and control of future Ebola outbreaks.

Personalized versus standardized dosing strategies for the treatment of childhood amblyopia: study protocol for a randomized controlled trial.

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Moseley, Merrick J; Wallace, Michael P; Stephens, David A; Fielder, Alistair R; Smith, Laura C; Stewart, Catherine E

2015-04-25

Amblyopia is the commonest visual disorder of childhood in Western societies, affecting, predominantly, spatial visual function. Treatment typically requires a period of refractive correction ('optical treatment') followed by occlusion: covering the nonamblyopic eye with a fabric patch for varying daily durations. Recent studies have provided insight into the optimal amount of patching ('dose'), leading to the adoption of standardized dosing strategies, which, though an advance on previous ad-hoc regimens, take little account of individual patient characteristics. This trial compares the effectiveness of a standardized dosing strategy (that is, a fixed daily occlusion dose based on disease severity) with a personalized dosing strategy (derived from known treatment dose-response functions), in which an initially prescribed occlusion dose is modulated, in a systematic manner, dependent on treatment compliance. A total of 120 children aged between 3 and 8 years of age diagnosed with amblyopia in association with either anisometropia or strabismus, or both, will be randomized to receive either a standardized or a personalized occlusion dose regimen. To avoid confounding by the known benefits of refractive correction, participants will not be randomized until they have completed an optical treatment phase. The primary study objective is to determine whether, at trial endpoint, participants receiving a personalized dosing strategy require fewer hours of occlusion than those in receipt of a standardized dosing strategy. Secondary objectives are to quantify the relationship between observed changes in visual acuity (logMAR, logarithm of the Minimum Angle of Resolution) with age, amblyopia type, and severity of amblyopic visual acuity deficit. This is the first randomized controlled trial of occlusion therapy for amblyopia to compare a treatment arm representative of current best practice with an arm representative of an entirely novel treatment regimen based on statistical

Design and statistical considerations for studies evaluating the efficacy of a single dose of the human papillomavirus (HPV) vaccine.

Science.gov (United States)

Sampson, Joshua N; Hildesheim, Allan; Herrero, Rolando; Gonzalez, Paula; Kreimer, Aimee R; Gail, Mitchell H

2018-05-01

Cervical cancer is a leading cause of cancer mortality in women worldwide. Human papillomavirus (HPV) types 16 and 18 cause about 70% of all cervical cancers. Clinical trials have demonstrated that three doses of either commercially available HPV vaccine, Cervarix ® or Gardasil ®, prevent most new HPV 16/18 infections and associated precancerous lesions. Based on evidence of immunological non-inferiority, 2-dose regimens have been licensed for adolescents in the United States, European Union, and elsewhere. However, if a single dose were effective, vaccine costs would be reduced substantially and the logistics of vaccination would be greatly simplified, enabling vaccination programs in developing countries. The National Cancer Institute (NCI) and the Agencia Costarricense de Investigaciones Biomédicas (ACIB) are conducting, with support from the Bill & Melinda Gates Foundation and the International Agency for Research on Cancer (IARC), a large 24,000 girl study to evaluate the efficacy of a 1-dose regimen. The first component of the study is a four-year non-inferiority trial comparing 1- to 2-dose regimens of the two licensed vaccines. The second component is an observational study that estimates the vaccine efficacy (VE) of each regimen by comparing the HPV infection rates in the trial arms to those in a contemporaneous survey group of unvaccinated girls. In this paper, we describe the design and statistical analysis for this study. We explain the advantage of defining non-inferiority on the absolute risk scale when the expected event rate is near 0 and, given this definition, suggest an approach to account for missing clinic visits. We then describe the problem of estimating VE in the absence of a randomized placebo arm and offer our solution. Copyright © 2018. Published by Elsevier Inc.

Genital lesions: An indication for changing ART regimen.

Science.gov (United States)

Kumar, S Arun; Kumar, N; Kumarasamy, N

2011-01-01

Genital lesions are common in HIV positive patients and aetiology for these are mainly due to HSV, HPV or bacterial. They usually respond to HAART, antiviral or antimicrobials. We are presenting a young patient on HAART with non-healing genital ulcer lesions for sixteen months. He responded well to a change in ART regimen within a period of 15 days. This happened after a change to a more potent ART regimen.

Desfechos clínicos do tratamento de tuberculose utilizando o esquema básico recomendado pelo Ministério da Saúde do Brasil com comprimidos em dose fixa combinada na região metropolitana de Goiânia Clinical treatment outcomes of tuberculosis treated with the basic regimen recommended by the Brazilian National Ministry of Health using fixed-dose combination tablets in the greater metropolitan area of Goiânia, Brazil

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Anna Carolina Galvão Ferreira

2013-02-01

Full Text Available OBJETIVO: Descrever as taxas de cura, falência e abandono do tratamento da tuberculose com o esquema básico preconizado pelo Ministério da Saúde (tratamento com rifampicina, isoniazida, pirazinamida e etambutol por dois meses seguido de isoniazida e rifampicina por quatro meses utilizando comprimidos em dose fixa combinada em regime autoadministrado e descrever os eventos adversos e seus possíveis impactos nos desfechos do tratamento. MÉTODOS: Estudo descritivo utilizando dados coletados prospectivamente dos prontuários médicos de pacientes com tuberculose (idade > 18 anos tratados com o esquema básico em duas unidades básicas de saúde da região metropolitana de Goiânia, GO. RESULTADOS: A amostra foi composta por 40 pacientes com tuberculose. A taxa de cura foi de 67,5%, a taxa de abandono foi de 17,5%, e não ocorreram casos de falência. Nessa amostra, 19 pacientes (47% relataram reações adversas aos medicamentos. Essas foram leves e moderadas, respectivamente, em 87% e 13% dos casos. Em nenhum caso houve necessidade de mudança do esquema ou suspensão do tratamento. CONCLUSÕES: A taxa de cura do esquema básico com o uso de comprimidos em dose fixa combinada sob regime autoadministrado foi semelhante às taxas históricas do esquema anterior. A taxa de abandono, na amostra estudada, foi muito acima da taxa preconizada como adequada (até 5%.OBJECTIVE: To describe the rates of cure, treatment failure, and treatment abandonment obtained with the basic regimen recommended by the Brazilian National Ministry of Health (rifampin, isoniazid, pyrazinamide, and ethambutol for two months, followed by isoniazid and rifampin for four months involving the use of fixed-dose combination tablets (self-administered treatment, as well as to describe adverse events and their potential impact on treatment outcomes. METHODS: This was a descriptive study based on prospective data obtained from the medical records of tuberculosis patients (> 18

ACCELERATED REGIMENS OF ADJUVANT RADIOTHERAPY IN THE TREATMENT OF BREAST CANCER

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G. V. Afonin

2017-01-01

Full Text Available Treatment of breast cancer (BC is a complex multidisciplinary problem. Often, radiation therapy is an obligatory component of treatment of breast cancer patients. Numerous large randomized trials have proved the efficacy of adjuvant radiotherapy in both the standard fractionation regimen in a single focal dose of 2 Gy to a total focal dose of 50 Gy for 25 fractions and in modes of hypofractionation using radiation exposure at a larger daily dose with a reduction in the total treatment time. The presented review summarizes the data of the largest studies on the modes of hypofractionation of postoperative radiotherapy for breast cancer. Most of the studies comparing the standard mode of fractionation of postoperative radiotherapy with the modes of hypofractionation showed comparable results for the main oncological parameters with similar tolerability, frequency of complications and good cosmetic results. It also shows the economic feasibility of applying accelerated regimes in everyday practice. Despite the fact that radiotherapy in the mode of hypofractionation has already become the standard of treatment and is recommended for use by the largest European and American cancer associations, indications for its conduct, the criteria for selection in the studies and the range of recommended single focal doses differ. The obtained results do not give an opportunity to confidently judge the advantage of one or another regime. It is necessary to determine the factors of a favorable and unfavorable prognosis, to clarify the indications for the use of various radiotherapy techniques. Therefore, questions about the optimal mode of hypo-fractionation of adjuvant radiotherapy, the timing of its initiation and the criteria for selecting patients for this type of therapy as part of the comprehensive treatment of breast cancer have not yet been fully resolved. Also open is the choice of optimal single and total doses of radiation, its combination with drug

Growth hormone therapy for children born small for gestational age: height gain is less dose dependent over the long term than over the short term.

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de Zegher, Francis; Hokken-Koelega, Anita

2005-04-01

Approximately 3% of children are born small for gestational age (SGA), and approximately 10% of SGA children maintain a small body size throughout childhood and often into adult life. Among short SGA children, growth hormone (GH) therapy increases short-term growth in a dose-dependent manner; experience with long-term therapy is limited. To delineate the dose dependency of long-term height gain among short SGA children receiving GH therapy. We performed an epianalysis of the first adult height data for SGA children (n = 28) enrolled in 3 randomized trials comparing the growth-promoting efficacy of 2 continuous GH regimens (33 or 67 microg/kg per day for approximately 10 years, starting at approximately 5 years of age); in addition, we performed a meta-analysis of the adult height results published previously and those presented here. Epianalysis outcomes (n = 28) suggested that adult height increased more with a higher-dose regimen than with a lower-dose regimen. In the meta-analysis (n = 82), the higher-dose regimen was found to elicit a long-term height gain superior to that achieved with the lower-dose regimen by a mean of 0.4 SD (approximately 1 inch). Children who were shorter at the start of therapy experienced more long-term height gain. These findings confirm GH therapy as an effective and safe approach to reduce the adult height deficit that short SGA children otherwise face. In addition, the first meta-analysis indicated that height gain is less dose dependent over the long term than over the short term, at least within the dose range explored to date. For SGA children whose stature is not extremely short, current data support the use of a GH dose of approximately 33 microg/kg per day from start to adult height, particularly if treatment starts at a young age; shorter children (for example, height below -3 SD) might benefit from an approach in which short-term catch-up growth is achieved with a higher dose (> or =50 microg/kg per day) and long-term growth

Differences in pharmacokinetics and pharmacodynamics of colistimethate sodium (CMS) and colistin between three different CMS dosage regimens in a critically ill patient infected by a multidrug-resistant Acinetobacter baumannii.

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Luque, Sònia; Grau, Santiago; Valle, Marta; Sorlí, Luisa; Horcajada, Juan Pablo; Segura, Concha; Alvarez-Lerma, Francisco

2013-08-01

Use of colistin has re-emerged for the treatment of infections caused by multidrug-resistant (MDR) Gram-negative bacteria, but information on its pharmacokinetics and pharmacodynamics is limited, especially in critically ill patients. Recent data from pharmacokinetic/pharmacodynamic (PK/PD) population studies have suggested that this population could benefit from administration of higher than standard doses of colistimethate sodium (CMS), but the relationship between administration of incremental doses of CMS and corresponding PK/PD parameters as well as its efficacy and toxicity have not yet been investigated in a clinical setting. The objective was to study the PK/PD differences of CMS and colistin between three different CMS dosage regimens in the same critically ill patient. A critically ill patient with nosocomial pneumonia caused by a MDR Acinetobacter baumannii received incremental doses of CMS. During administration of the different CMS dosage regimens, CMS and colistin plasma concentrations were determined and PK/PD indexes were calculated. With administration of the highest CMS dose once daily (720 mg every 24h), the peak plasma concentration of CMS and colistin increased to 40.51 mg/L and 1.81 mg/L, respectively, and the AUC0-24/MIC of colistin was 184.41. This dosage regimen was efficacious, and no nephrotoxicity or neurotoxicity was observed. In conclusion, a higher and extended-interval CMS dosage made it possible to increase the exposure of CMS and colistin in a critically ill patient infected by a MDR A. baumannii and allowed a clinical and microbiological optimal response to be achieved without evidence of toxicity. Copyright © 2013 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

[Pretreatment doses of antithymocyte globubin-fresenius for allogeneic hematopoietic stem cell transplantation for beta-thalassemia major].

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Li, Chunfu; Wang, Yanhua; Wu, Xuedong; Pei, Fuyu; He, Yuelin; Feng, Xiaoqin; Liu, Huaying

2012-05-01

To investigate the effects of different doses of antithymocyte globubin-fresenius (ATG-F) for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with beta-thalassemia Major. Sixty-four children with beta-thalassemia major undergoing allo-HSCT were divided into two equal groups to receive ATG-F pretreatments at high (30 mg/kg) or low (15 mg/kg) doses as part of the conditioning regimen including mainly cyclophosphamide, busulfan, fludarabine, and thiotepa. The outcomes of the patients were compared between the two groups. No obvious difference were noted in the time to leukocyte and platelet engraftment between the two groups. The incidence of grade II-IV acute graft-versus-host disease (aGVHD) appeared to be higher in the low-dose group than in the high-dose group (12.5% vs 9.4%). The incidence of grade III-IV aGVHD was also higher in the low dose group (12.5% vs 6.3%), but the difference was not statistically significant. Application of high-dose ATG-F was associated with a higher rate of probable and possible fungal infection (P<0.05). The two doses of ATG-F is feasible as a part of the conditioning regimen for allo-HSCT in children with beta-thalassemia major.

Aggressive Regimens for Multidrug-Resistant Tuberculosis Reduce Recurrence

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Franke, Molly F.; Appleton, Sasha C.; Mitnick, Carole D.; Furin, Jennifer J.; Bayona, Jaime; Chalco, Katiuska; Shin, Sonya; Murray, Megan; Becerra, Mercedes C.

2013-01-01

Background. Recurrent tuberculosis disease occurs within 2 years in as few as 1% and as many as 29% of individuals successfully treated for multidrug-resistant (MDR) tuberculosis. A better understanding of treatment-related factors associated with an elevated risk of recurrent tuberculosis after cure is urgently needed to optimize MDR tuberculosis therapy. Methods. We conducted a retrospective cohort study among adults successfully treated for MDR tuberculosis in Peru. We used multivariable Cox proportional hazards regression analysis to examine whether receipt of an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion from positive to negative was associated with a reduced rate of recurrent tuberculosis. Results. Among 402 patients, the median duration of follow-up was 40.5 months (interquartile range, 21.2–53.4). Receipt of an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion was associated with a lower risk of recurrent tuberculosis (hazard ratio, 0.40 [95% confidence interval, 0.17–0.96]; P = .04). A baseline diagnosis of diabetes mellitus also predicted recurrent tuberculosis (hazard ratio, 10.47 [95% confidence interval, 2.17–50.60]; P = .004). Conclusions. Individuals who received an aggressive MDR tuberculosis regimen for ≥18 months following sputum conversion experienced a lower rate of recurrence after cure. Efforts to ensure that an aggressive regimen is accessible to all patients with MDR tuberculosis, such as minimization of sequential ineffective regimens, expanded drug access, and development of new MDR tuberculosis compounds, are critical to reducing tuberculosis recurrence in this population. Patients with diabetes mellitus should be carefully managed during initial treatment and followed closely for recurrent disease. PMID:23223591

Fluid regimens for colostomy irrigation: a systematic review.

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Lizarondo, Lucylynn; Aye Gyi, Aye; Schultz, Tim

2008-09-01

Background  Various techniques for managing faecal evacuation have been proposed; however, colostomy irrigation is favoured as it leads to better patient outcomes. Alternative fluid regimens for colostomy irrigation have been suggested to achieve effective evacuation. Aim  The objective of this review was to summarise the best available evidence on the most effective fluid regimen for colostomy irrigation. Search strategy  Trials were identified by electronic searches of CINAHL, PubMed, MEDLINE, Current Contents, the Cochrane Library and EMBASE. Unpublished articles and references lists from included studies were also searched. Selection criteria  Randomised controlled trials and before-and-after studies investigating any fluid regimen for colostomy irrigation were eligible for inclusion. Outcomes measured included fluid inflow time, total wash-out time, haemodynamic changes during irrigation, cramps, leakage episodes, quality of life and level of satisfaction. Data collection and analysis  Trial selection, quality appraisal and data extraction were carried out independently by two reviewers. Differences in opinion were resolved by discussion. Main results  The systematic literature search strategy identified two cross-over trials that compared water with another fluid regimen. Owing to the differences in irrigating solutions used, the results were not pooled for analysis. Both the polyethylene glycol electrolyte solution and glyceryl trinitrate performed significantly better than water. Conclusion  There is some evidence to support the effectiveness of fluid regimens other than water, such as polyethylene glycol electrolyte and glyceryl trinitrate, for colostomy irrigation. Further well-designed clinical trials are required to establish solid evidence on the effectiveness of other irrigating solutions that might enhance colonic irrigation. © 2008 The Authors. Journal Compilation © Blackwell Publishing Asia Pty Ltd.

Loading regimen required to rapidly achieve therapeutic trough plasma concentration of teicoplanin and evaluation of clinical features

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Seki M

2012-11-01

Full Text Available Masafumi Seki,1,* Kaori Yabuno,1,2,* Koji Miyawaki,1,2 Yoshihiro Miwa,2 Kazunori Tomono11Division of Infection Control and Prevention, 2Department of Pharmacy, Osaka University Hospital, Suita, Osaka, Japan*These authors contributed equally to this workBackground: A trough concentration of >20 mg/L is considered the optimal dosage of teicoplanin required to ensure early therapeutic effects against methicillin-resistant Staphylococcus aureus (MRSA infections including those in patients who develop febrile neutropenia after chemotherapy. This study determines appropriate initial doses during the first 2 days of administration and evaluates the therapeutic target teicoplanin trough concentration.Method: A 2-day regimen was evaluated in patients treated with 600 mg and 1200 mg or 1200 mg and 600 mg (total 1800 mg, Group 1, 800 mg and 800 mg (total 1600 mg, Group 2, and 800 mg and 400 mg (total 1200 mg, Group 3 of teicoplanin on Days 1 and 2, respectively. We also compared the efficiency and adverse effects at trough concentrations of 15–20 mg/L (Group A, n = 28 with >20 mg/L (Group B, n = 27 of teicoplanin, and also compared them with those on the similar concentrations of vancomycin (Groups C and D, n = 50 and 34, respectively.Results: The mean trough concentrations of teicoplanin on Days 4 or 5 were 22.2, 17.5, and 16.2 mg/L in Groups 1, 2, and 3, respectively. The clinical efficiency was 85.7%, 81.5%, 92.0%, and 91.5%, in Groups A, B, C, and D, respectively. The rates of adverse effects were not high in teicoplanin (nephrotoxicity, 7.1% and 3.7%, and hepatotoxicity, 14.3% and 11.1% in Groups A and B, respectively. However, more adverse effects tended to arise in patients who received vancomycin in nephrotoxicity (14.0% and 11.8%, in Groups C and D, respectively.Conclusion: These results suggest that the 2-day regimens with total 1800 mg achieved the most effective therapeutic trough plasma concentration of teicoplanin (20 mg/L. However, 15–20

The effects of low-dose radiotherapy on fresh osteochondral allografts: An experimental study in rabbits

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Uğur Gönç

2016-10-01

Conclusion: In osteochondral massive allograft transplantations, the immune reaction of the host could be precluded with radiotherapy, and the side-effects can be prevented by low-dose fractionated regimen. The total dose of fractionated radiotherapy for an immune suppression should be adjusted not to damage the cartilage tissue, but to avoid articular degeneration in the long term.

Radioimmunotherapy (RIT) Dose-Escalation Studies in Prostate Cancer Using Anti-PSMA Antibody 177Lu-J591: RIT Alone and RIT in Combination with Docetaxel

National Research Council Canada - National Science Library

Vallabhajosula, Shankar

2007-01-01

Phase I dose escalation studies with 177Lu-DOTA-huJ591 using dose fractionation regimen will be performed in patients with PCa and who have recurrent and/or metastatic disease. The 177Lu dose (20-45 mCi/m2...

Radioimmunotherapy (RIT) Dose-Escalation Studies in Prostate Cancer Using Anti-PSMA Antibody 177Lu-J591: RIT Alone and RIT in Combination With Docetaxel

National Research Council Canada - National Science Library

Vallabhajosula, Shankar

2006-01-01

Phase I dose escalation studies with 177Lu-DOTA-huJ591 using dose fractionation regimen will be performed in patients with PCa and who have recurrent and/or metastatic disease. The 177Lu dose (20-45 mCi/m2...

make up JUNE issue nicky

African Journals Online (AJOL)

Nicky

2005-06-01

Jun 1, 2005 ... positive, a single dose of nevirapine syrup was offered to their infants as PEP ... After delivery 5 751 (76.7%) women were offered VCT, and of these 3 794 (66%) ... services were only offered during routine working hours.

Successful hematopoietic stem cell transplantation following a cyclophosphamide-containing preparative regimen with concomitant phenobarbital administration.

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Weber, Catherine; Kasberg, Heather; Copelan, Edward

2012-01-01

Cyclophosphamide is an immunosuppressive agent and an anticancer prodrug which requires bioactivation catalyzed primarily by cytochrome P450 enzymes in order to be transformed into its active alkylating compounds. Concomitant administration of drugs known to inhibit or induce this enzyme system is a clinical concern. Herein, we present the case of a chronically ill 21-year-old patient who received high-dose cyclophosphamide, equine antithymocyte globulin (eATG), and total body irradiation (TBI) followed by an allogeneic hematopoietic stem cell transplant (HSCT) for severe aplastic anemia. Throughout her hospitalization, she continued to receive quadruple anticonvulsant therapy including phenobarbital for her long-standing seizure history. The preparative regimen was tolerated well aside from a hypersensitivity reaction to eATG, and minimal cyclophosphamide-related toxicities. Safe and effective administration of high-dose cyclophosphamide was possible with multidisciplinary care consisting of physician, nursing, pharmacy, neurology consultation, as well as social work and case management.

Population-based evaluation of the effectiveness of two regimens for emergency contraception.

Science.gov (United States)

Leung, Vivian W Y; Soon, Judith A; Lynd, Larry D; Marra, Carlo A; Levine, Marc

2016-06-01

To estimate and compare the effectiveness of the levonorgestrel and Yuzpe regimens for hormonal emergency contraception in routine clinical practice. A retrospective population-based study included women who accessed emergency contraceptives for immediate use prescribed by community pharmacists in British Columbia, Canada, between December 2000 and December 2002. Linked administrative healthcare data were used to discern the timings of menses, unprotected intercourse, and any pregnancy-related health services. A panel of experts evaluated the compatibility of observed pregnancies with the timing of events. The two regimens were compared with statistical adjustments for potential confounding. Among 7493 women in the cohort, 4470 (59.7%) received levonorgestrel and 3023 (40.3%) the Yuzpe regimen. There were 99 (2.2%) compatible pregnancies in the levonorgestrel group and 94 (3.1%) in the Yuzpe group (P=0.017). The estimated odds ratio for levonorgestrel compared with the Yuzpe regimen after adjusting for potential confounders was 0.64 (95% confidence interval 0.47-0.87). Against an expected pregnancy rate of approximately 5%, the relative and absolute risk reductions were 56.0% and 2.8%, respectively, for levonorgestrel and 36.7% and 1.8% for the Yuzpe regimen. The levonorgestrel regimen is more effective than the Yuzpe regimen in routine use. The data suggest that both regimens are less effective than has been observed in randomized trials. Copyright © 2016 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

Caffeine Citrate Dosing Adjustments to Assure Stable Caffeine Concentrations in Preterm Neonates.

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Koch, Gilbert; Datta, Alexandre N; Jost, Kerstin; Schulzke, Sven M; van den Anker, John; Pfister, Marc

2017-12-01

To identify dosing strategies that will assure stable caffeine concentrations in preterm neonates despite changing caffeine clearance during the first 8 weeks of life. A 3-step simulation approach was used to compute caffeine doses that would achieve stable caffeine concentrations in the first 8 weeks after birth: (1) a mathematical weight change model was developed based on published weight distribution data; (2) a pharmacokinetic model was developed based on published models that accounts for individual body weight, postnatal, and gestational age on caffeine clearance and volume of distribution; and (3) caffeine concentrations were simulated for different dosing regimens. A standard dosing regimen of caffeine citrate (using a 20 mg/kg loading dose and 5 mg/kg/day maintenance dose) is associated with a maximal trough caffeine concentration of 15 mg/L after 1 week of treatment. However, trough concentrations subsequently exhibit a clinically relevant decrease because of increasing clearance. Model-based simulations indicate that an adjusted maintenance dose of 6 mg/kg/day in the second week, 7 mg/kg/day in the third to fourth week and 8 mg/kg/day in the fifth to eighth week assures stable caffeine concentrations with a target trough concentration of 15 mg/L. To assure stable caffeine concentrations during the first 8 weeks of life, the caffeine citrate maintenance dose needs to be increased by 1 mg/kg every 1-2 weeks. These simple adjustments are expected to maintain exposure to stable caffeine concentrations throughout this important developmental period and might enhance both the short- and long-term beneficial effects of caffeine treatment. Copyright © 2017 Elsevier Inc. All rights reserved.

Addition of Ceftriaxone and Amikacin to a Ciprofloxacin plus Metronidazole Regimen for Preventing Infectious Complications of Transrectal Ultrasound-Guided Prostate Biopsy: A Randomized Controlled Trial

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Mohammad-Hossein Izadpanahi

2017-01-01

Full Text Available Background. The objective of this study was to evaluate the efficacy of adding single doses of ceftriaxone and amikacin to a ciprofloxacin plus metronidazole regimen on the reduction of infectious complications following transrectal ultrasound-guided prostate biopsy (TRUS Bx. Materials and Methods. Four hundred and fifty patients who were candidates for TRUS Bx were divided into two groups of 225 each. The control group received ciprofloxacin 500 mg orally every 12 hours together with metronidazole 500 mg orally every 8 hours from the day prior to the procedure until the fifth postoperative day. In the second group, single doses of ceftriaxone 1 g by intravenous infusion and amikacin 5 mg/kg intramuscularly were administered 30–60 minutes before TRUS Bx in addition to the oral antimicrobials described for group 1. The incidence of infection was compared between the groups. Results. The incidence of infectious complications in the intervention group was significantly lower than that in the control group (4.6% versus 0.9%, p=0.017. Conclusion. The addition of single doses of intramuscular amikacin and intravenously infused ceftriaxone to our prophylactic regimen of ciprofloxacin plus metronidazole resulted in a statistically significant reduction of infectious complications following TRUS Bx.

Low dosing of gonadotropins in in vitro fertilization cycles for women with poor ovarian reserve: systematic review and meta-analysis

NARCIS (Netherlands)

Youssef, Mohamed Abdel-Fattah; van Wely, Madelon; Mochtar, Monique; Fouda, Usama Mohamed; Eldaly, Ashraf; El Abidin, Eman Zein; Elhalwagy, Ahmed; Mageed Abdallah, Ahmed Abdel; Zaki, Sherif Sameh; Abdel Ghafar, Mohamed Sayed; Mohesen, Mohamed Nagi; van der Veen, Fulco

2018-01-01

Objective: To evaluate the effectiveness of low doses of gonadotropins and gonadotropins combined with oral compounds compared with high doses of gonadotropins in ovarian stimulation regimens in terms of ongoing pregnancy per fresh IVF attempt in women with poor ovarian reserve undergoing

High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: a randomised trial.

Science.gov (United States)

Pearson, Andrew D J; Pinkerton, C Ross; Lewis, Ian J; Imeson, John; Ellershaw, Caroline; Machin, David

2008-03-01

The current standard treatment for patients with high-risk neuroblastoma includes initial induction chemotherapy with a 21-day interval between induction treatments. We aimed to assess whether an intensive chemotherapy protocol that had a 10-day interval between treatments would improve event-free survival (EFS) in patients aged 1 year or over with high-risk neuroblastoma. Between Oct 30, 1990, and March 18, 1999, patients with stage 4 neuroblastoma who had not received previous chemotherapy were enrolled from 29 centres in Europe. Patients were randomly assigned to rapid treatment (cisplatin [C], vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C], known as COJEC) or standard treatment (vincristine [O], cisplatin [P], etoposide [E], and cyclophosphamide [C], ie, OPEC, alternated with vincristine [O], carboplatin [J], etoposide [E], and cyclophosphamide [C], ie, OJEC). Both regimens used the same total cumulative doses of each drug (except vincristine), but the dose intensity of the rapid regimen was 1.8-times higher than that of the standard regimen. The standard regimen was given every 21 days if patients showed haematological recovery, whereas the rapid regimen was given every 10 days irrespective of haematological recovery. Response to chemotherapy was assessed according to the conventional International Neuroblastoma Response Criteria (INRC). In responders, surgical excision of the primary tumour was attempted, followed by myeloablation (with 200 mg/m2 of melphalan) and haemopoietic stem-cell rescue. Primary endpoints were 3-year, 5-year, and 10-year EFS. Data were analysed by intention to treat. This trial is registered on the clinical trials site of the US National Cancer Institute website, number NCT00365755, and also as EU-20592 and CCLG-NB-1990-11. 262 patients, of median age 2.95 years (range 1.03-20.97), were randomly assigned-132 patients to standard and 130 patients to rapid treatment. 111 patients in the standard group and 109

Dietary regimens of athletes competing at the Delhi 2010 Commonwealth Games.

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Pelly, Fiona E; Burkhart, Sarah J

2014-02-01

The aim of this study was to investigate the dietary regimens reported by athletes competing at a major international competition and report whether these were based on nutrient composition, religious beliefs, cultural eating style, food intolerance or avoidance of certain ingredients. A questionnaire was randomly distributed to 351 athletes in the main dining hall of the athletes' village over the three main meal periods during the Delhi 2010 Commonwealth Games (23rd Sept-14th Oct, 2010). The majority (n = 218, 62%) of athletes reported following one or more dietary regimens, with 50% (n = 174) following a diet based on the nutrient composition of the food. Significantly more athletes from weight category and aesthetic sports (28%, p = .005) and from power/sprint sports (41%, p = .004) followed low fat and high protein regimens respectively. Other specialized dietary regimens were followed by 33% of participants, with avoidance of red meat (13%), vegetarian (7%), Halal (6%), and low lactose regimens (5%) reported most frequently. Significantly more athletes from non-Western regions followed a vegetarian diet (p food items are available at similar events.

Patient and regimen characteristics associated with self-reported nonadherence to antiretroviral therapy.

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Patrick S Sullivan

Full Text Available BACKGROUND: Nonadherence to antiretroviral therapy (ARVT is an important behavioral determinant of the success of ARVT. Nonadherence may lead to virological failure, and increases the risk of development of drug resistance. Understanding the prevalence of nonadherence and associated factors is important to inform secondary HIV prevention efforts. METHODOLOGY/PRINCIPAL FINDINGS: We used data from a cross-sectional interview study of persons with HIV conducted in 18 U.S. states from 2000-2004. We calculated the proportion of nonadherent respondents (took or=4 medications; living in a shelter or on the street; and feeling "blue" >or=14 of the past 30 days. We found weaker associations with having both male-male sex and injection drug use risks for HIV acquisition; being prescribed ARVT for >or=21 months; and being prescribed a protease inhibitor (PI-based regimen not boosted with ritonavir. The median proportion of doses missed was 50%. The most common reasons for missing doses were forgetting and side effects. CONCLUSIONS/SIGNIFICANCE: Self-reported recent nonadherence was high in our study. Our data support increased emphasis on adherence in clinical settings, and additional research on how providers and patients can overcome barriers to adherence.

IIVP salvage regimen induces high response rates in patients with relapsed lymphoma before autologous stem cell transplantation.

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Abali, Huseyin; Oyan, Basak; Koc, Yener; Kars, Ayse; Barista, Ibrahim; Uner, Aysegul; Turker, Alev; Demirkazik, Figen; Tekin, Fatma; Tekuzman, Gulten; Kansu, Emin

2005-06-01

Patients with relapsed lymphoma can be cured with high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT). New therapeutic approaches with better cytoreductive capacity are needed for relapsed patients to keep their chance for cure with transplantation. We report 30 patients with relapsed lymphoma, median age 43 years, treated with IIVP salvage regimen consisting of ifosfamide, mesna, idarubicin, and etoposide for 2 or 3 cycles. Seventeen patients had non-Hodgkin lymphoma (NHL) and 13 patients had Hodgkin disease (HD). Fourteen (47%) patients were at their first relapse. Overall response rate was 86.6% (n = 26) with 19 patients (63.3%) achieving complete response. Overall response rate was 92% in patients with HD and 82% in NHL. The most frequent side effects observed were grade III-IV neutropenia (87%) and thrombocytopenia (73%). IIVP regimen is a highly effective salvage therapy for patients with relapsed HD or NHL who are candidates for autologous HSCT. Close follow up is necessary because of the high incidence of grade III-IV hematologic toxicity.

The Sex Res Non Naturales and the Regimen of Health

DEFF Research Database (Denmark)

Agerholm, Frank Juul

The paper discusses the ethical and social soundness of the classical idea of diaita/regimen vis-à-vis the contemporary focus on healthy lifestyle......The paper discusses the ethical and social soundness of the classical idea of diaita/regimen vis-à-vis the contemporary focus on healthy lifestyle...

Relationship between person's health beliefs and diabetes self-care management regimen.

Science.gov (United States)

Albargawi, Moudi; Snethen, Julia; Al Gannass, Abdulaziz; Kelber, Sheryl

2017-12-01

To examine the relationship between the health beliefs of Saudi adults with type 2 diabetes mellitus (T2DM) and their adherence to daily diabetes self-care management regimen. A secondary aim was to examine the health beliefs of adults with a diabetic foot ulcer (DFU) and participants without a DFU. Descriptive correlational design with a convenience sample of 30 participants. Participants were recruited for this pilot study from an outpatient clinic at King Abdulaziz Medical City in Riyadh. The participants completed self-reported questionnaires about their health beliefs, daily diabetes self-care management regimen, and demographic characteristics. Hierarchical multiple regression analysis was used to test the interaction effects. Participants who reported having a high internal health locus of control (IHLoC) and a high level of self-efficacy (SE) adhered well to their foot care regimen (P = .038). The more the participants believed that God controls their health, and the higher their SE, the greater the participant's adherence to their medication regimen (P = .035). The stronger the participant's belief that following their diabetes treatment regimen will lead to good outcomes, the greater the participant's adherence to their dietary regimen for those with a low IHLoC (P = .015). Participants with a high SE and reported that their doctor is able to help them control their diabetes were more likely to follow their dietary regimen (P = .048). Participants with a DFU reported having additional health conditions besides T2DM (P = .018) and had less than a college education (P = .015). Although participants with a DFU reported that they were responsible for their diabetes (P = .21), they stated that God manages their diabetes (P = .29), and the disease can be controlled based on luck (P = .10). Participants' beliefs were found to influence their daily self-care management regimen. Further studies are needed using a larger sample. Copyright © 2017

Clinical and virological efficacy of etravirine plus two active Nucleos(tide analogs in an heterogeneous HIV-infected population.

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Luis F López-Cortés

Full Text Available Etravirine (ETV is recommended in combination with a boosted protease inhibitor plus an optimized background regimen for salvage therapy, but there is limited experience with its use in combination with two nucleos(tide reverse-transcriptase inhibitors (NRTIs. This multicenter study aimed to assess the efficacy of this combination in two scenarios: group A subjects without virologic failure on or no experience with non-nucleoside reverse-transcriptase inhibitors (NNRTIs switched due to adverse events and group B subjects switched after a virologic failure on an efavirenz- or nevirapine-based regimen. The primary endpoint was efficacy at 52 weeks analysed by intention-to-treat. Virologic failure was defined as the inability to suppress plasma HIV-RNA to 200 copies/mL in patients who had previously achieved a viral suppression or had an undetectable viral load at inclusion. Two hundred eighty seven patients were included. Treatment efficacy rates in group A and B were 88.0% (CI95, 83.9-92.1% and 77.4% (CI95, 65.0-89.7%, respectively; the rates reached 97.2% (CI95, 95.1-99.3% and 90.5% (CI95, 81.7-99.3, by on-treatment analysis. The once-a-day ETV treatment was as effective as the twice daily dosing regimen. Grade 1-2 adverse events were observed motivating a treatment switch in 4.2% of the subjects. In conclusion, ETV (once- or twice daily plus two analogs is a suitable, well-tolerated combination both as a switching strategy and after failure with first generation NNRTIs, ensuring full drug activity.ClinicalTrials.gov NCT01437241.

Successful Hematopoietic Stem Cell Transplantation Following a Cyclophosphamide-Containing Preparative Regimen with Concomitant Phenobarbital Administration

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Catherine Weber

2012-01-01

Full Text Available Cyclophosphamide is an immunosuppressive agent and an anticancer prodrug which requires bioactivation catalyzed primarily by cytochrome P450 enzymes in order to be transformed into its active alkylating compounds. Concomitant administration of drugs known to inhibit or induce this enzyme system is a clinical concern. Herein, we present the case of a chronically ill 21-year-old patient who received high-dose cyclophosphamide, equine antithymocyte globulin (eATG, and total body irradiation (TBI followed by an allogeneic hematopoietic stem cell transplant (HSCT for severe aplastic anemia. Throughout her hospitalization, she continued to receive quadruple anticonvulsant therapy including phenobarbital for her long-standing seizure history. The preparative regimen was tolerated well aside from a hypersensitivity reaction to eATG, and minimal cyclophosphamide-related toxicities. Safe and effective administration of high-dose cyclophosphamide was possible with multidisciplinary care consisting of physician, nursing, pharmacy, neurology consultation, as well as social work and case management.

The mean lung dose (MLD). Predictive criterion for lung damage

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Geyer, Peter; Appold, Steffen [Dresden University of Technology (TU Dresden), Clinic and Polyclinic for Radiotherapy and Radiation Oncology, Carl Gustav Carus Medical Faculty, Dresden (Germany); Herrmann, Thomas

2015-07-15

The purpose of this work was to prove the validity of the mean lung dose (MLD), widely used in clinical practice to estimate the lung toxicity of a treatment plan, by reevaluating experimental data from mini pigs. A total of 43 mini pigs were irradiated in one of four dose groups (25, 29, 33, and 37 Gy). Two regimens were applied: homogeneous irradiation of the right lung or partial irradiation of both lungs - including parts with lower dose - but with similar mean lung doses. The animals were treated with five fractions with a linear accelerator applying a CT-based treatment plan. The clinical lung reaction (breathing frequency) and morphological changes in CT scans were examined frequently during the 48 weeks after irradiation. A clear dose-effect relationship was found for both regimens of the trial. However, a straightforward relationship between the MLD and the relative number of responders with respect to different grades of increased breathing frequency for both regimens was not found. A morphologically based parameter NTCP{sub lung} was found to be more suitable for this purpose. The dependence of this parameter on the MLD is markedly different for the two regimens. In clinical practice, the MLD can be used to predict lung toxicity of a treatment plan, except for dose values that could lead to severe side effects. In the latter mentioned case, limitations to the predictive value of the MLD are possible. Such severe developments of a radiation-induced pneumopathy are better predicted by the NTCP{sub lung} formalism. The predictive advantage of this parameter compared to the MLD seems to remain in the evaluation and comparison of widely differing dose distributions, like in the investigated trial. (orig.) [German] Es soll unter Reevaluation von Tierversuchsdaten am Minischwein geprueft werden, ob die in der klinischen Praxis zur Beurteilung der Lungentoxizitaet eines Bestrahlungsregims regelhaft verwendete mittlere Lungendosis (MLD) eine zuverlaessige

Every-other-day Dosing of Oral Viscous Budesonide Is not Effective in the Management of Eosinophlic Esophagitis.

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Rubinstein, Eitan; Hait, Elizabeth E; Mitchell, Paul D; Lee, John J

2018-03-01

Eosinophilic esophagitis (EoE) is a clinicopathologic disorder characterized histologically by esophageal eosinophilia. Oral viscous budesonide (OVB) is an effective treatment with remission rates reported between 55% and 87%; however, topical corticosteroids are associated with increased risk of candidal esophagitis and adrenal suppression. Attempts to decrease the daily dose of topical steroids have resulted in disease relapse. The objective of this study was to determine whether or not reducing the frequency of OVB administration would be effective in controlling esophageal eosinophilia in children and adolescents. Data were obtained by retrospective chart review of patients at Boston Children's Hospital diagnosed with EoE, based on endoscopic findings of >15 eosinophils per high power field (eos/HPF) on esophageal biopsies while on acid blockade. Patients with histologic evidence of response (<15 eos/HPF) while on daily OVB had been offered the option of maintenance therapy based on a Monday-Wednesday-Friday (MWF) dosing regimen. Changes in peak esophageal eosinophil counts over time were examined. Eight male patients ages 5 to 18 years attained clinical response while receiving daily OVB and were subsequently maintained on a MWF OVB dosing regimen for 3 to 7 months. All 8 patients showed an increase in peak esophageal eosinophils, with 7 of 8 (88%) experiencing disease relapse. In fact, the distribution of peak esophageal eosinophils after MWF dosing was not statistically different from peak levels at diagnosis (P = 0.95). An MWF dosing regimen of OVB was not effective at maintaining histologic response in children and adolescents with EoE. Larger prospective studies are warranted to confirm these results.

Hand hygiene regimens for the reduction of risk in food service environments.

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Edmonds, Sarah L; McCormack, Robert R; Zhou, Sifang Steve; Macinga, David R; Fricker, Christopher M

2012-07-01

Pathogenic strains of Escherichia coli and human norovirus are the main etiologic agents of foodborne illness resulting from inadequate hand hygiene practices by food service workers. This study was conducted to evaluate the antibacterial and antiviral efficacy of various hand hygiene product regimens under different soil conditions representative of those in food service settings and assess the impact of product formulation on this efficacy. On hands contaminated with chicken broth containing E. coli, representing a moderate soil load, a regimen combining an antimicrobial hand washing product with a 70% ethanol advanced formula (EtOH AF) gel achieved a 5.22-log reduction, whereas a nonantimicrobial hand washing product alone achieved a 3.10log reduction. When hands were heavily soiled from handling ground beef containing E. coli, a wash-sanitize regimen with a 0.5% chloroxylenol antimicrobial hand washing product and the 70% EtOH AF gel achieved a 4.60-log reduction, whereas a wash-sanitize regimen with a 62% EtOH foam achieved a 4.11-log reduction. Sanitizing with the 70% EtOH AF gel alone was more effective than hand washing with a nonantimicrobial product for reducing murine norovirus (MNV), a surrogate for human norovirus, with 2.60- and 1.79-log reductions, respectively. When combined with hand washing, the 70% EtOH AF gel produced a 3.19-log reduction against MNV. A regimen using the SaniTwice protocol with the 70% EtOH AF gel produced a 4.04-log reduction against MNV. These data suggest that although the process of hand washing helped to remove pathogens from the hands, use of a wash-sanitize regimen was even more effective for reducing organisms. Use of a high-efficacy sanitizer as part of a wash-sanitize regimen further increased the efficacy of the regimen. The use of a well-formulated alcohol-based hand rub as part of a wash-sanitize regimen should be considered as a means to reduce risk of infection transmission in food service facilities.

Use of an in vitro pharmacodynamic model to derive a moxifloxacin regimen that optimizes kill of Yersinia pestis and prevents emergence of resistance.

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Louie, A; Heine, H S; VanScoy, B; Eichas, A; Files, K; Fikes, S; Brown, D L; Liu, W; Kinzig-Schippers, M; Sörgel, F; Drusano, G L

2011-02-01

Yersinia pestis, the causative agent of bubonic, septicemic, and pneumonic plague, is classified as a CDC category A bioterrorism pathogen. Streptomycin and doxycycline are the "gold standards" for the treatment of plague. However, streptomycin is not available in many countries, and Y. pestis isolates resistant to streptomycin and doxycycline occur naturally and have been generated in laboratories. Moxifloxacin is a fluoroquinolone antibiotic that demonstrates potent activity against Y. pestis in in vitro and animal infection models. However, the dose and frequency of administration of moxifloxacin that would be predicted to optimize treatment efficacy in humans while preventing the emergence of resistance are unknown. Therefore, dose range and dose fractionation studies for moxifloxacin were conducted for Y. pestis in an in vitro pharmacodynamic model in which the half-lives of moxifloxacin in human serum were simulated so as to identify the lowest drug exposure and the schedule of administration that are linked with killing of Y. pestis and with the suppression of resistance. In the dose range studies, simulated moxifloxacin regimens of ≥175 mg/day killed drug-susceptible bacteria without resistance amplification. Dose fractionation studies demonstrated that the AUC (area under the concentration-time curve)/MIC ratio predicted kill of drug-susceptible Y. pestis, while the C(max) (maximum concentration of the drug in serum)/MIC ratio was linked to resistance prevention. Monte Carlo simulations predicted that moxifloxacin at 400 mg/day would successfully treat human infection due to Y. pestis in 99.8% of subjects and would prevent resistance amplification. We conclude that in an in vitro pharmacodynamic model, the clinically prescribed moxifloxacin regimen of 400 mg/day is predicted to be highly effective for the treatment of Y. pestis infections in humans. Studies of moxifloxacin in animal models of plague are warranted.

A single daily dose enhances the adherence to immunosuppressive treatment in kidney transplant recipients: a cross-sectional study.

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Obi, Yoshitsugu; Ichimaru, Naotsugu; Kato, Taigo; Kaimori, Jun-Ya; Okumi, Masayoshi; Yazawa, Koji; Rakugi, Hiromi; Nonomura, Norio; Isaka, Yoshitaka; Takahara, Shiro

2013-04-01

Nonadherence to treatment regimens for immunosuppressive agents is one of the major risk factors for allograft failure in kidney transplant recipients. The aim of this study was to estimate the relative effect of daily dosing on treatment adherence, not to identify how patients are non-adherent, in long-term kidney transplant recipients. In January 2009, a cross-sectional, anonymous, and voluntary questionnaire survey was given to kidney transplant recipients who regularly visited Inoue Hospital. A self-reporting questionnaire underestimates nonadherence, but we reasoned that the effect of the dosing regimen should be estimated with relative accuracy by using the generalized ordered logit/partial proportional hazard odds model given that the distribution patterns in the degree of nonadherence have been shown to be similar with other measures. Of 336 eligible patients, 312 (92.9 %) participated in this study. Two hundred seventy-four patients (87.8 %) were more than 3 years post-transplant. Univariate analysis revealed that a single daily dose was significantly associated with better adherence. After controlling for age, sex, time since transplantation, and the number of prescribed drugs, the effect of a single daily dose still remained significant [odds ratio, 0.40 (95 % confidence interval, 0.19-0.81); p = 0.011]. Several sensitivity analyses yielded similar results. To our knowledge, this is the first report that, in long-term kidney transplant recipients, a single daily regimen-one of few modifiable factors-might improve treatment adherence and allograft survival.

Zidovudine-induced nail pigmentation in a 12-year-old boy

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Chawre, Sanjeevani M.; Pore, Shraddha M.; Nandeshwar, Manish B.; Masood, Nausheen M.

2012-01-01

Zidovudine is an important component of first-line antiretroviral treatment (ART) regimens used to manage pediatric HIV. Nail pigmentation with zidovudine is a well-documented occurrence in adults, especially dark-skinned individuals. But it has so far not been reported in children. Here, we report a pediatric case of zidovudine-induced nail pigmentation. A 12-year-old boy receiving ART with zidovudine, lamivudine, and nevirapine presented to dermatology OPD with complaint of diffuse bluish-brown discoloration of all fingernails. The pigmentation was noticed by the patient after 3 months of initiating zidovudine-based regimen. It first appeared in thumb nails, gradually involved all fingernails, and increased in intensity over time. Though harmless and reversible, psychological aspects of this noticeable side effect may hamper adherence to therapy and may lead to unnecessary investigations and treatment for misdiagnosis such as cyanosis or melanoma. PMID:23248416

Eruptive furunculosis following the soak and smear regimen.

Science.gov (United States)

Martires, Kathryn; Sukhdeo, Kumar; Meinhardt, Eric

2015-02-18

The 'soak and smear' regimen is a highly effective method for localised topical therapy employed by dermatologists for widespread inflammatory skin conditions. The regimen involves application of topical medication under occlusion after soaking in water. Complications from this treatment method are rare. We present a case of multiple, generalised methicillin-resistant Staphylococcus aureus (MRSA)-positive furuncles arising in a patient as an unexpected consequence of therapy. The case highlights an unanticipated risk of a commonly employed treatment amid an epidemic of MRSA in the community. 2015 BMJ Publishing Group Ltd.

Simultaneous quantitation of lamivudine, zidovudine and nevirapine in human plasma by liquid chromatography–tandem mass spectrometry and application to a pharmacokinetic study

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Murali Krishna Matta

2012-10-01

Full Text Available A rapid and sensitive LC–MS/MS method for the simultaneous quantitation of lamivudine, zidovudine and nevirapine in human plasma using abacavir as internal standard has been developed and validated. The analytes and IS were extracted from plasma by solid phase extraction using Oasis HLB cartridges and separated on a Hypurity Advance C18 column using a mixture of acetonitrile:0.1% formic acid (76:24, v/v at a flow rate of 0.8 mL/min. Detection involved an API-4000 LC–MS/MS with electrospray ionization in the positive ion mode and multiple-reaction monitoring for analysis. The method was validated according to FDA guidelines and shown to provide intra- and inter-day precision and accuracy within acceptable limits in a run time of only 3.5 min. The method was successfully applied to a pharmacokinetic study involving a single oral administration of a combination tablet to human male volunteers.

Dose rate and fractionation: Relative importance in radiation for bone marrow transplantation

International Nuclear Information System (INIS)

Tarbell, N.J.; Rosenblatt, M.; Mauch, P.; Hellman, S.

1987-01-01

The optimal dose rate and fractionation schedules for total body irradiation (TBI) in bone marrow transplantation (BMT) are presently unknown. This study compares several fractionation and dose rate schedules that are currently in clinical use. C/sub 3/H/HeJ were given TBI and the bone marrow survival fraction was calculated using the CFU's assay. Irradiation was given as low dose rate (LDR) at 5 cGy/min or high dose rate (HDR) at 80 cGy/min, in single fraction (SF) and fractionated (FX) regimens. These results indicate no increase in survival for the normal bone marrow stem cells with fractionation either at high or low dose-rates. In fact, fractionation seemed to decrease the bone marrow survival over single fraction radiation

DHAP plus filgrastim as an effective peripheral stem cell mobilization regimen for autologous stem-cell transplantation in patients with relapsed/refractory lymphoma: A single center experience.

Science.gov (United States)

Berber, Ilhami; Erkurt, Mehmet Ali; Kuku, Irfan; Kaya, Emin; Bag, Harika Gozukara; Nizam, Ilknur; Koroglu, Mustafa; Ozgul, Mustafa

2016-02-01

This study aimed to evaluate the efficiency of DHAP regimen plus filgrastim for mobilization of stem cells in patients with recurrent and/or refractory lymphoma. Thirty-four patients who took DHAP as salvage therapy prior to autologous stem cell transplantation were included. After chemotherapies, 2 cycles of DHAP plus filgrastim were administered to the patients. Stem cells from 32 patients (94%) were collected on median 11th day (8-12), and the median collected CD34(+) cell dose was 9.7 × 10(6)/kg (range 3.8-41.6). DHAP plus filgrastim was found to be an effective chemotherapy regimen in mobilizing CD34(+) stem cells into the peripheral. Copyright © 2016 Elsevier Ltd. All rights reserved.

Control of hypertension with single daily doses of sotalol hydrochloride.

Science.gov (United States)

Gabriel, R

A study was carried out in 12 previously untreated hypertensive patients to assess the efficacy of sotalol given in a once-daily dosage regimen. After an initial dosage titration period (mean 3 weeks) during which diastolic pressure was stabilized at less than 100 mmHg, all patients were satisfactorily maintained on a constant once-daily dose of sotalol for 3 months. Eight of the 12 patients required 320 mg or less daily (mean dose 190 mg). Whilst blood pressure remained controlled for at least 26 hours after daily doses the pulse rate, counted at the same time, showed escape from beta-blockade. Side-effects (vivid dreams) were reported in only 1 patient.

Selective Changes in the Immune Profile of Tumor-Draining Lymph Nodes After Different Neoadjuvant Chemoradiation Regimens for Locally Advanced Cervical Cancer

International Nuclear Information System (INIS)

Battaglia, Alessandra; Buzzonetti, Alexia; Martinelli, Enrica; Fanelli, Mara; Petrillo, Marco; Ferrandina, Gabriella; Scambia, Giovanni; Fattorossi, Andrea

2010-01-01

Purpose: To assess how neoadjuvant chemoradiation regimens modulate the immune system state in tumor-draining lymph nodes (TDLN), in the setting of advanced cervical cancer. Methods and Materials: Tumor-draining lymph nodes of patients undergoing chemotherapy only (nonirradiated, NI-TDLN) and chemoradiation with lower-dose (39.6 Gy, LD-TDLN) and higher-dose radiation (50 Gy, HD-TDLN) were analyzed by multicolor flow cytometry. Results: Enlarging our previous data, LD-TDLN showed features overall indicative of an enhanced antitumor response as compared with NI-TDLN, namely a significant Th1 and Tc1 polarization and a lower amount of the potent CD4 + Foxp3 + CD25 high regulatory T cell (Treg) subset identified by neuropilin-1 expression. Conversely, compared with NI-TDLN, HD-TDLN showed features overall indicative of an impaired antitumor response, namely a significantly inverted CD4/CD8 cell ratio, a higher Nrp1 + Treg frequency, and a higher frequency of CCR4 + Treg, a Treg subset facilitated in migrating out from TDLN to suppress the immune response against distant cancer cells. Moreover, the Th1 and Tc1 polarization induced by LD radiation was lost, and there was an unfavorable tolerogenic/immunogenic dendritic cell ratio compared with LD-TDLN. Conclusions: Even minor differences in radiation dose in neoadjuvant regimens for locally advanced cervical cancer are crucial for determining the balance between a tolerogenic and an efficacious antitumor immune response in TDLN. Because most of the anticancer immune response takes place in TDLN, the present findings also emphasize the importance of chemoradiation protocols in the context of immunotherapeutic trials.

Radiobiological responses for two cell lines following continuous low dose-rate (CLDR) and pulsed dose rate (PDR) brachytherapy

International Nuclear Information System (INIS)

Hanisch, Per Henrik; Furre, Torbjoern; Olsen, Dag Rune; Pettersen, Erik O.

2007-01-01

The iso-effective irradiation of continuous low-dose-rate (CLDR) irradiation was compared with that of various schedules of pulsed dose rate (PDR) irradiation for cells of two established human lines, T-47D and NHIK 3025. Complete single-dose response curves were obtained for determination of parameters α and β by fitting of the linear quadratic formula. Sublethal damage repair constants μ and T 1/2 were determined by split-dose recovery experiments. On basis of the acquired parameters of each cell type the relative effectiveness of the two regimens of irradiation (CLDR and PDR) was calculated by use of Fowler's radiobiological model for iso-effect irradiation for repeated fractions of dose delivered at medium dose rates. For both cell types the predicted and observed relative effectiveness was compared at low and high iso-effect levels. The results indicate that the effect of PDR irradiation predicted by Fowler's model is equal to that of CLDR irradiation for both small and large doses with T-47D cells. With NHIK 3025 cells PDR irradiation induces a larger effect than predicted by the model for small doses, while it induces the predicted effect for high doses. The underlying cause of this difference is unclear, but cell-cycle parameters, like G2-accumulation is tested and found to be the same for the two cell lines

A simple high-dose gentamicin regimen showed no side effects among neonates

DEFF Research Database (Denmark)

Blaabjerg, Anne Sofie; Kofoed, Poul-Erik; Dalegaard, Mette Correll

2017-01-01

INTRODUCTION: Treatment of infections in neonates with gentamicin is a balance between optimising bactericidal effect and minimising adverse effects. Previously, at the Neonatal Intensive Care Unit (NICU) at Kolding Hospital, Denmark, neonates suspected of having infections were treated daily...... and 2012 and treated with gentamicin were included retrospectively in the study. Neonates with trough serum (S)-gentamicin level ≥ 2.0 mg/l before the third dose were reviewed in detail. RESULTS: In total, S-gentamicin level was measured in 253 treated neonates of whom 7% displayed elevated trough values....... Neonates elevated S...

Challenges in the concurrent management of malaria and HIV in pregnancy in sub-Saharan Africa.

Science.gov (United States)

Brentlinger, Paula E; Behrens, Christopher B; Micek, Mark A

2006-02-01

Approximately one million pregnancies are complicated by both malaria and HIV infection in sub-Saharan Africa annually. Both infections have been associated with maternal and infant morbidity and mortality. Intermittent preventive treatment, usually with sulfadoxine-pyrimethamine, has been shown to prevent pregnancy-related malaria and its complications. Several different regimens of antiretroviral therapy are now available to prevent mother-to-child transmission of HIV and/or progression of maternal HIV infection during pregnancy. However, no published studies have yet shown whether standard intermittent preventive treatment and antiretroviral regimens are medically and operationally compatible in pregnancy. We reviewed existing policies regarding prevention and treatment of HIV and malaria in pregnancy, as well as published literature on adverse effects of antiretrovirals and antimalarials commonly used in pregnancy in developing countries, and found that concurrent prescription of sulfadoxine-pyrimethamine, co-trimoxazole (trimethoprim-sulfamethoxazole), and antiretroviral agents including nevirapine and zidovudine per existing protocols for prevention of malaria and vertical HIV transmission may result in adverse drug interactions or overlapping, diagnostically challenging drug toxicities. Insecticide-treated bednets should be provided for HIV-infected pregnant women at risk for malaria. Sulfadoxine-pyrimethamine should be prescribed cautiously in women concurrently receiving daily nevirapine and/or zidovudine, and should be avoided in women on daily co-trimoxazole. Further research is urgently needed to define safe and effective protocols for concurrent management of HIV and malaria in pregnancy, and to define appropriate interventions for different populations subject to differing levels of malaria transmission and antimalarial drug resistance.

German Adjuvant Intergroup Node-positive Study (GAIN): a phase III trial comparing two dose-dense regimens (iddEPC versus ddEC-PwX) in high-risk early breast cancer patients.

Science.gov (United States)

Möbus, V; von Minckwitz, G; Jackisch, C; Lück, H-J; Schneeweiss, A; Tesch, H; Elling, D; Harbeck, N; Conrad, B; Fehm, T; Huober, J; Müller, V; Bauerfeind, I; du Bois, A; Loibl, S; Nekljudova, V; Untch, M; Thomssen, C

2017-08-01

Dose-dense (dd) regimens are one of the preferred options for the adjuvant treatment of breast cancer patients with intermediate to high risk. The German Adjuvant Intergroup Node-positive trial aimed at optimizing intense dd (idd) strategies by evaluating drug combinations and the addition of capecitabine. Women (aged 18 years and biologically <65 years) with histologically involved axillary lymph nodes were randomly assigned to receive three courses each of epirubicin (E) 150 mg/m2, paclitaxel (P) 225 mg/m2 and cyclophosphamide (C) 2500 mg/m2 (reduced to 2000 mg/m2 after recruitment of 1200 patients) q2w intravenously (i.v.) (iddEPC-regimen) or ddEC (E 112.5 mg/m2 + C 600 mg/m2, i.v. q2w for 4 cycles) followed by paclitaxel weekly (Pw 67.5 mg/m2 i.v. q8d for 10 weeks) plus capecitabine (X 2000 mg/m2 p.o. days 1-14, q22 for 4 cycles) (ddEC-PwX-regimen). Further randomization assigned patients to ibandronate for 2 years versus observation and to pegfilgrastim day 2 versus 4. From June 2004 to August 2008, 2994 patients were randomized to either iddEPC (N = 1498), or ddEC-PwX (N = 1496) and started treatment. Median age was 50 years; pN1 (37.8%), pN2 (35.3%); pN3 (26.9%); 46.4% were G3 tumors; 76.9% hormone receptor-positive and 22% HER2-positive. After a median follow-up of 74 months, 645 events and 383 deaths were recorded. Hematological adverse events grades 3-4 were more common with iddEPC (P < 0.001), nonhematological with ddEC-PwX (P = 0.04), even if the toxicity profile of the two regimens was different. At 5 years, estimated disease-free survival rates for ddEC-PwX and iddEPC were 81.7% [95% confidence interval (CI) 79.5-83.6] versus 80.2% (95% CI 78.0-82.2). Hazard ratio (HR)=0.95 (95% CI 0.81-1.11, log-rank P = 0.49). Five-year overall survival rates were 89.4% for ddEC-PwX (95% CI 87.7-91.0) and 89.0% for iddEPC (95% CI 87.2-90.6), HR = 0.85 (95% CI 0.69-1.04, log-rank P = 0.10). Adding

A comparison of different antibiotic regimens for the treatment of infective endocarditis.

Science.gov (United States)

Martí-Carvajal, Arturo J; Dayer, Mark; Conterno, Lucieni O; Gonzalez Garay, Alejandro G; Martí-Amarista, Cristina Elena; Simancas-Racines, Daniel

2016-04-19

alone reporting uncertain effects on all-cause mortality (8/31 (26%) with levofloxacin plus standard treatment versus 9/39 (23%) with standard treatment alone; RR 1.12, 95% CI 0.49 to 2.56, very low quality evidence). The second trial compared daptomycin versus low-dose gentamicin plus an anti-staphylococcal penicillin (nafcillin, oxacillin or flucloxacillin) or vancomycin. This showed uncertain effects in terms of cure rates (9/28 (32.1%) with daptomycin versus 9/25 (36%) with low-dose gentamicin plus anti-staphylococcal penicillin or vancomycin, RR 0.89 95% CI 0.42 to 1.89; very low quality evidence). The third trial compared cloxacillin plus gentamicin with a glycopeptide (vancomycin or teicoplanin) plus gentamicin. In participants receiving gentamycin plus glycopeptide only 13/23 (56%) were cured versus 11/11 (100%) receiving cloxacillin plus gentamicin (RR 0.59, 95% CI 0.40 to 0.85; very low quality evidence). The fourth trial compared ceftriaxone plus gentamicin versus ceftriaxone alone and found no conclusive differences in terms of cure (15/34 (44%) with ceftriaxone plus gentamicin versus 21/33 (64%) with ceftriaxone alone, RR 0.69, 95% CI 0.44 to 1.10; very low quality evidence).The trials reported adverse events, need for cardiac surgical interventions, uncontrolled infection and relapse of endocarditis and found no conclusive differences between comparison groups (very low quality evidence). No trials assessed septic emboli or quality of life. Limited and very low quality evidence suggested that there were no conclusive differences between antibiotic regimens in terms of cure rates or other relevant clinical outcomes. However, because of the very low quality evidence, this needs confirmation. The conclusion of this Cochrane review was based on randomised controlled trials with high risk of bias. Accordingly, current evidence does not support or reject any regimen of antibiotic therapy for treatment of infective endocarditis.

Patient Characteristics, Health Care Resource Utilization, and Costs Associated with Treatment-Regimen Failure with Biologics in the Treatment of Psoriasis.

Science.gov (United States)

Foster, Shonda A; Zhu, Baojin; Guo, Jiaying; Nikai, Enkeleida; Ojeh, Clement; Malatestinic, William; Goldblum, Orin; Kornberg, Lori J; Wu, Jashin J

2016-04-01

Psoriasis is a chronic, incurable, and immune-mediated skin disorder that is characterized by erythematous scaly papules and plaques. Understanding of psoriasis at the molecular level has led to the development of biologic agents that target disease-specific inflammatory mediators in psoriatic lesions. Biologic agents have become important components of the psoriasis armamentarium, but some patients become refractory to these agents over time or fail to respond to subsequent biologics. To (a) evaluate demographic and clinical characteristics of psoriasis patients who have treatment patterns suggestive of failure to a newly initiated biologic agent (treatment-regimen failures) compared with those who do not (non-treatment-regimen failures) and (b) to assess health care-related resource utilization and costs in non-treatment-regimen failures and treatment-regimen failures. In this retrospective observational cohort study, patients were selected from the MarketScan claims database of commercially insured individuals and individuals with Medicare supplemental insurance. The index event was a newly initiated biologic agent for the treatment of psoriasis (etanercept, adalimumab, ustekinumab, or infliximab) between January 2010 and December 2011. The analysis included psoriasis patients aged ≥ 18 years with ≥ 1 prescription claim for a biologic and continuous enrollment 12 months pre- and post-index date. Patients with claims for a biologic in the pre-index period were excluded. Patients were divided into treatment-regimen-failure and non-treatment-regimen-failure groups based on their treatment patterns post-index date. The treatment-regimen-failure group included patients who switched to another biologic, discontinued the biologic without restarting, increased the dose of the biologic, or augmented treatment with a nontopical psoriasis medication during the post-index period. Between-group patient characteristics and medication use were compared using analysis of

Dealing with large-scale supply lines when introducing new regimens.

Science.gov (United States)

Malati, Christine; Rosenfeld, Joshua; Mowafy, Sherif; Rittmiller, Trevor; Kuritsky, Joel; Crowley, John

2017-07-01

As programs plan the introduction of a new antiretroviral as part of a regimen for HIV treatment, supply chain considerations need to be taken into account. The key to success is balancing the introduction of a new regimen with the phasing out of an old regimen in a manner that does not result in either a shortage or an excess supply of either product while ensuring that patients continue receiving their medications. This necessitates that country programs, donors, and procurement entities possess an appreciation of the global antiretroviral market and understand the dynamics that the manufacturing of new antiretrovirals will have on the transition. Supply, demand, and financial considerations affect the capacity of the supply chain to facilitate a successful antiretroviral transition. Although this commentary draws on United States Agency for International Development experiences under the President's Emergency Plan for AIDS Relief from earlier antiretroviral treatment shifts, the approaches are applicable to other institutions and to future transitions. Three approaches were employed: ensuring the engagement of all key stakeholders in transition planning and execution, including clinicians, advocacy groups, supply chain professionals, ministry, and donors; conducting and updating regularly the national quantification and supply plans for all regimens; and introducing antiretroviral products into programs from regional warehouses based on firm orders. Extensive planning and accounting for supply chain factors is essential to ensuring a smooth transition to a new regimen and to enable the global antiretroviral market to respond adequately.

Relation between treatment efficacy and cumulative dose of alpha interferon in chronic hepatitis B. European Concerted Action on Viral Hepatitis (Eurohep)

DEFF Research Database (Denmark)

Krogsgaard, K; Christensen, E; Bindslev, N

1996-01-01

Alpha interferon (IFN) is an established treatment of chronic hepatitis B. The effect has been shown to be dose related, recommended dose regimens being associated with a doubling of the spontaneous, baseline HBeAg to anti-HBe seroconversion rate. However, the efficacy of IFN treatment in relation...

Individualized Ranibizumab Regimen Driven by Stabilization Criteria for Central Retinal Vein Occlusion

DEFF Research Database (Denmark)

Larsen, Michael; Waldstein, Sebastian M; Boscia, Francesco

2016-01-01

ischemia (exploratory analysis). RESULTS: At baseline, the mean BCVA was 53.0 letters and mean CRVO duration was 8.9 months (median, 2.4 months). Ranibizumab 0.5-mg treatment resulted in a statistically significant mean gain in BCVA from baseline at month 12 of 12.3 letters (standard deviation [SD], 16......PURPOSE: To assess the 12-month efficacy and safety profile of an individualized regimen of ranibizumab 0.5 mg driven by stabilization criteria in patients with macular edema secondary to central retinal vein occlusion (CRVO). DESIGN: A 24-month, prospective, open-label, single-arm, multicenter...... study. PARTICIPANTS: Three hundred fifty-seven patients. METHODS: Patients were treated with monthly ranibizumab 0.5-mg injections (minimum of 3 injections) until stable visual acuity (VA) was maintained for 3 consecutive months. Thereafter, ranibizumab 0.5 mg was dosed as needed if monthly monitoring...

Different antibiotic regimens for treating asymptomatic bacteriuria in pregnancy.

Science.gov (United States)

Guinto, Valerie T; De Guia, Blanca; Festin, Mario R; Dowswell, Therese

2010-09-08

Asymptomatic bacteriuria occurs in 5% to 10% of pregnancies and, if left untreated, can lead to serious complications. To assess which antibiotic is most effective and least harmful as initial treatment for asymptomatic bacteriuria in pregnancy. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (March 2010) and reference lists of retrieved studies. Randomized controlled trials comparing two antibiotic regimens for treating asymptomatic bacteriuria. Review authors independently screened the studies for inclusion and extracted data. We included five studies involving 1140 women with asymptomatic bacteriuria. We did not perform meta-analysis; each trial examined different antibiotic regimens and so we were not able to pool results. In a study comparing a single dose of fosfomycin trometamol 3 g with a five-day course of cefuroxime, there was no significant difference in persistent infection (risk ratio (RR) 1.36, 95% confidence interval (CI) 0.24 to 7.75), shift to other antibiotics (RR 0.08, 95% CI 0.00 to 1.45), or in allergy or pruritus (RR 2.73, 95% CI 0.11 to 65.24). A comparison of seven-day courses of 400 mg pivmecillinam versus 500 mg ampicillin, both given four times daily, showed no significant difference in persistent infection at two weeks or recurrent infection, but there was an increase in vomiting (RR 4.57, 95% CI 1.40 to 14.90) and women were more likely to stop treatment early with pivmecillinam (RR 8.82, 95% CI 1.16 to 66.95). When cephalexin 1 g versus Miraxid(R) (pivmecillinam 200 mg and pivampicillin 250 mg) were given twice-daily for three days, there was no significant difference in persistent or recurrent infection. A one- versus seven-day course of nitrofurantoin resulted in more persistent infection with the shorter course (RR 1.76, 95% CI 1.29 to 2.40), but no significant difference in symptomatic infection at two weeks, nausea, or preterm birth. Comparing cycloserine with sulphadimidine, no significant differences in

A better cure rate with 800 mg than with 400 mg clarithromycin regimens in one-week triple therapy for Helicobacter pylori infection in cigarette-smoking peptic ulcer patients.

Science.gov (United States)

Ishioka, Hidehiko; Mizuno, Motowo; Take, Susumu; Ishiki, Kuniharu; Nagahara, Yasuhiro; Yoshida, Tomowo; Okada, Hiroyuki; Yokota, Kenji; Oguma, Keiji

2007-01-01

In Helicobacter pylori eradication therapy, using a proton pump inhibitor plus amoxicillin and clarithromycin (PPI/AC regimen), the impact of the clarithromycin dose and smoking on efficacy is conflicting. Here, we compared the efficacy of 400 and 800 mg of clarithromycin in the regimen in relation to smoking in patients with peptic ulcer disease. We studied 601 H. pylori-positive patients with peptic ulcer disease who had received amoxicillin 750 mg and clarithromycin 200 or 400 mg together with lansoprazole 30 mg b.i.d. 305 patients were treated with a regimen containing 400 mg of clarithromycin (C400 group), and 296 patients with a regimen containing 800 mg (C800 group). Overall cure rates between the two groups were not significantly different, but the cure rate in the C800 group was significantly better than that in the C400 group among patients infected with clarithromycin-sensitive strains (p = 0.03). This difference could be attributed to differences among smokers versus non-smokers: the cure rate among smokers in the C800 group (91.0%) was better than that in the C400 group (80.0%, p = 0.003). 800 mg of clarithromycin is recommended in the PPI/AC regimen for patients who smoke and are infected with clarithromycin-sensitive H. pylori. 2007 S. Karger AG, Basel

Methamphetamine treatment during development attenuates the dopaminergic deficits caused by subsequent high-dose methamphetamine administration

OpenAIRE

McFadden, Lisa M; Hoonakker, Amanda J; Vieira-Brock, Paula L; Stout, Kristen A; Sawada, Nicole M; Ellis, Jonathan D; Allen, Scott C; Walters, Elliot T; Nielsen, Shannon M; Gibb, James W; Alburges, Mario E; Wilkins, Diana G; Hanson, Glen R; Fleckenstein, Annette E

2011-01-01

Administration of high doses of methamphetamine (METH) causes persistent dopaminergic deficits in both nonhuman preclinical models and METH-dependent persons. Noteworthy, adolescent (i.e., postnatal day (PND) 40) rats are less susceptible to this damage than young adult (PND90) rats. In addition, biweekly treatment with METH, beginning at PND40 and continuing throughout development, prevents the persistent dopaminergic deficits caused by a “challenge” high-dose METH regimen when administered ...