Efficacy and toxicity of aminoglycoside therapy in the elderly: combined effect of both once-daily regimen and therapeutic drug monitoring

This study was aimed to compare with previous results (Grillot et al., 1994), the efficacy of amikacin adaptive optimal control in a geriatric hospital. PATIENTS: During six months, 32 patients (aged of 82 +/- 8 years) were included versus 51 during two years (aged of 80 +/- 5). The mean age was not different between the two populations (NS, Student test). They received amikacin initial dosage of 17.7 +/- 5.1 mg/kg/d (vs 13.3 +/- 3.5 for the reference study) and maintenance dosage of 15.1 +/- 4.8 mg/kg/d (vs 11.8 +/- 5.1 for the reference study). METHOD: Two efficacy outcomes (E1 and E2) and 1 toxicity outcome (T) were taken into account: E1 estimated the effect of adaptive control on maximal drug level, E2: overall recovery. Toxicity outcome was used: T the nephrotoxicity (increasing creatininémia over 44 mumol/l). RESULTS: All the results are given versus the reference study. 57.6% versus 29.4% of adaptive strategy were once-a-day. E1: Chi square test show that initial dosage and maintenance dosage are greater our study than the previous one (p < 0.05: 78.8% versus 5.9% for initial dosage, 84.4% versus 13.8% for maintenance dosage). E2: 73.6% overall of recovery versus 77% (NS, Chi square test). T: 94% versus 85% (p < 0.05, Chi square test) of creatininemia variation are lower than 44 mumol/l. Duration of treatment is 9.8 +/- 4.8 versus 15 +/- 9 days (p < 0.5, Student test). CONCLUSIONS: Once-a-day strategy in amikacin therapeutic regimen is no more efficient but decreases toxicity and duration treatment.     

Approaches to the problem of individual doxorubicin dosing schedules

Doxorubicin is one of the most commonly used antineoplastic agents today. Dosing schedules are inexact and there remains a need to develop predictive models for its administration. Data from prior work in humans is difficult to interpret because of poor patient selection, poor drug assays, lack of knowledge of metabolite toxicity, concurrent treatment with other hepatically metabolized drugs, and individual pharmacogenetics which are poorly described. We have developed a rabbit model of in vivo drug pharmacokinetics in the setting of enzyme inhibition and sublethal hepatocellular necrosis. Our data suggest that the rabbit may be used as a model of hepatic drug metabolism and that changes in drug pharmacokinetics and pharmacodynamics in isolated hepatic disease may be simulated in the rabbit. The results obtained may be applied in more directed and controlled studies in humans.     

Making the most of once-daily anti-HIV therapy

More than two dozen anti-HIV drugs in development are given, or potentially can be given, only once a day. Sustiva (efavirenz) has taken the lead, gaining approval from the FDA. Several older anti-HIV drugs are also being researched in once-daily regimens. Once-daily dosing makes adhering to treatment regimens easier, and it is more conducive to directly observed therapy (DOT). DOT is a way of structuring and monitoring a patient's treatment in order to increase adherence to the treatment. Once-a-day dosing may also aid people in developing countries, home to 90 percent of the world's HIV-infected population.     

A pilot study of once-daily antiretroviral therapy integrated with tuberculosis directly observed therapy in a resource-limited setting

To determine the feasibility and effectiveness of integrating highly active antiretroviral therapy (HAART) into existing tuberculosis directly observed therapy (TB/DOT) programs, we performed a pilot study in an urban TB clinic in South Africa. Patients with smear-positive pulmonary TB were offered HIV counseling and testing. Twenty HIV-positive patients received once-daily didanosine (400 mg) plus lamivudine (300 mg) plus efavirenz (600 mg) administered concomitantly with standard TB therapy Monday to Friday and self-administered on weekends. After completing TB therapy, patients were referred to an HIV clinic for continued treatment. At baseline, patients had a mean CD4 count of 230 cells/mm(3) (range: 24-499 cells/mm(3)) and a mean viral load of 5.75 log(10) (range: 3.81-7.53 log(10)). Seventeen completed combined standard TB and HIV therapy; 16 of 20 (80%) patients enrolled and 15 of 17 (88%) patients completing standard TB therapy achieved a viral load <50 copies/mL and mean CD4 count increase of 148 cells/mm(3). TB was cured in 17 of 20 (85%) enrolled patients and 17 of 19 (89%) patients with drug-sensitive TB. Treatment was well tolerated, with minimal gastrointestinal, hepatic, skin, or neurologic toxicity. The project was well accepted and integrated into the daily TB clinic functions. This pilot study demonstrates that TB/DOT programs can be feasible and effective sites for HIV identification and the introduction and monitoring of a once-daily HAART regimen in resource-limited settings.     

Pharmacokinetics of once-daily IV busulfan as part of pretransplantation preparative regimens: a comparison with an every 6-hour dosing schedule.

In pretransplantation therapy busulfan is typically given every 6 hours. We infused busulfan once daily at 130 mg/m2 for 4 days, performing pharmacokinetic analyses on plasma concentration-time data (n = 60 patients) on days 1, 3, and/or 4. Mean (percent coefficient of variation) maximum concentration, volume of distribution, half-life, and clearance were 3.6 microg/mL (13.8%), 22.6 L/m2 (20.2%), 2.73 hours (27.5%), and 109 mL/min/m2 (26%), respectively. The mean (percent coefficient of variation) and median daily areas under the curve were 4873 (21.8%) and 4871 microM x minute. Intrapatient variability in day-to-day estimated clearance was <20%, without day-to-day drug accumulation. The pharmokinetic parameters were compared with those from 47 patients given intravenous busulfan at approximately 0.8 mg/kg (approximately 32 mg/m2) every 6 hours. We conclude that there is (1) a dose proportionality based on mean and median areas under the curve, (2) unchanged estimated clearance with a 4-fold increase in dose and a 2.5-fold difference in dosing rate, (3) negligible variability in dose-to-dose pharmacokinetics and negligible interdose accumulation with once-daily administration, and (4) no change in pharmokinetic parameter(s) with concomitant use of imidazole antifungals, oral contraceptives, or phenytoin. In summary, intravenous busulfan has highly predictable, linear pharmacokinetics from 32 mg/m2 (approximately 0.8 mg/kg) to 130 mg/m2 (approximately 3.2 mg/kg). Further, once-daily intravenous busulfan dosing is convenient, favoring its more widespread application.     

Indacaterol provides sustained 24 h bronchodilation on once-daily dosing in asthma: a 7-day dose-ranging study

Background:  Indacaterol is a novel, once-daily β₂-agonist in development for the treatment of asthma and chronic obstructive pulmonary disease. Studies were required to determine optimal dose(s) for continuing investigation.
Objective:  A dose-ranging study was undertaken to evaluate efficacy and safety of indacaterol.
Methods:  A total of 436 patients with persistent asthma receiving inhaled corticosteroids were randomized to 7 days treatment with once-daily indacaterol 50, 100, 200, or 400 μg via multi-dose dry-powder inhaler (MDDPI; Certihaler^™), indacaterol 400 μg via single-dose dry-powder inhaler (SDDPI), or placebo. Serial 24-h spirometry was performed on days 1 and 7. Vital signs, laboratory evaluations, and adverse events were monitored.
Results:  All doses of indacaterol increased the mean time-standardized area under the curve of forced expiratory volume in 1 s (FEV₁) from 22 to 24 h postdose ( P  ≤ 0.001 vs placebo) on days 1 and 7, with clinically relevant treatment-placebo differences of 240, 260, 350, 300, and 380 ml on day 1 and 230, 220, 320, 250, and 270 ml on day 7 for indacaterol 50, 100, 200, and 400 μg via MDDPI and 400 μg via SDDPI, respectively. All doses increased mean FEV₁ ( P  < 0.05 vs placebo) from 5 min to 24 h postdose on days 1 and 7. All doses were well tolerated. Most adverse events were mild-to-moderate in severity: most frequently reported were respiratory, thoracic, and mediastinal disorders.
Conclusion:  Once-daily dosing with indacaterol provided sustained 24-h bronchodilation in patients with moderate-to-severe asthma, with a satisfactory overall safety profile. Indacaterol 200 μg appears the optimum dose, offering the best efficacy/safety balance.     

Adherence to isoniazid prophylaxis among HIV-infected children: a randomized controlled trial comparing two dosing schedules

Background  

Tuberculosis contributes significantly to morbidity and mortality among HIV-infected children in sub-Saharan Africa. Isoniazid prophylaxis can reduce tuberculosis incidence in this population. However, for the treatment to be effective, adherence to the medication must be optimized. We investigated adherence to isoniazid prophylaxis administered daily, compared to three times a week, and predictors of adherence amongst HIV-infected children.     

Adherence to isoniazid prophylaxis among HIV-infected children: a randomized controlled trial comparing two dosing schedules

Background

An understanding of how public health research output from India is changing in relation to the disease burden and public health priorities is required in order to inform relevant research development. We therefore studied the trends in the public health research output from India during 2001-2008 that was readily available in the public domain.

Methods

The scope and type of the published research from India in 2007 that was included in the PubMed database was assessed and compared with a previous similar assessment for 2002. Papers were classified based on the review of abstracts and original public health research papers were assessed in detail. Impact factors for the journals were used to compute quality-adjusted research output. The websites of governmental organizations, academic and research institutions and international organizations were searched in order to identify and review reports on original public health research produced in India from 2001 to 2008. The reports were classified based on the topics covered and quality and their trends over time were assessed.

Results

The number of original health research papers from India in PubMed doubled from 4494 in 2002 to 9066 in 2007. This included a 3.1-fold increase in public health research papers, but these comprised only 5% of the total papers in 2007. Within public health, the increase was lowest for the health system and policy category. Several major causes of disease burden in India continued to be underrepresented in the quality-adjusted public health research output in 2007. The number of papers evaluating population health interventions increased from 2002 to 2007, but there were none on the leading non-communicable causes of disease burden or on road traffic injuries. The number of identified original public health research reports increased by 64.7% from 204 in 2001-2004 to 336 in 2005-2008. The proportion of reports on reproductive and child health was very high but decreased slightly from 38.7% of the total in 2001-2004 to 31.5% in 2005-2008 (P = 0.09); those on the leading chronic non-communicable conditions and injuries increased from 6.4% to 13.4% (P = 0.01) but this was still much lower than their contribution to the disease burden. Health system/policy issues were the topic in 27.4% reports but health information issues were covered in a miniscule 0.6% reports. The proportion of reports that were evaluations increased slightly from 26% in 2001-2004 to 31.5% in 2005-2008, with this proportion being higher among the reports commissioned by international organizations (P < 0.001). The proportion of reports commissioned by Indian governmental organizations alone, or in collaboration with international organizations, doubled from 2001-2004 to 2005-2008 (P < 0.001). Only 25% of the total 540 reports had a quality score of adequate or better. The quality of reports produced by collaborations between Indian and international organizations was higher than those produced by Indian or international organizations alone (P < 0.001).

Conclusion

This is the first analysis from India that includes research reports in addition to published papers. It provides the most up-to-date understanding of public health research output from India. The increase in available public health research output and the increase in commissioning of this research by Indian governmental organizations are encouraging. However, the distribution of research topics and the quality of research reports continue to be unsatisfactory. It is necessary for health policy to address these continuing deficits in public health research in order to reduce the very large disease burden in India.     

Low frequency of elevated prothrombin times in patients with lupus anticoagulants when using a recombinant thromboplastin reagent: implications for dosing and monitoring of oral anticoagulant therapy

Many patients with lupus anticoagulants (LA) are treated with oral anticoagulation and monitored using the international normalised ratio (INR) derived from the prothrombin time (PT). Recent reports have produced conflicting conclusions about the extent to which LA interferes with PT determination. The degree of anticoagulation may be overestimated in a patient whose LA affects the PT. A number of reports conclude that specific thromboplastin reagents containing recombinant tissue factor are sensitive to the presence of LAs and should not be used to monitor oral anticoagulant therapy in these patients. These studies were performed on orally anticoagulated patients. The present retrospective study on 400 patients with LAs who were not receiving therapeutic anticoagulation was performed to ascertain the frequency of prolonged PT in these patients when using Innovin recombinant thromboplastin. Only 17 (4.3%) out of 400 had prolonged PT in the presence of LA. As this is a low prevalence, and not all patients with LAs will require anticoagulant therapy, it is concluded that baseline INR determination should be used to highlight the need to monitor individual patients with LA-insensitive reagents. As the use of moderate-intensity oral anticoagulation for patients with LAs and previous thrombosis is receiving wider acceptance, an informed approach to anticoagulant monitoring will reduce the possibility of under-anticoagulating patients receiving this therapy.