Pharmacokinetics and safety of the anti-human cytomegalovirus drug letermovir in subjects with hepatic impairment.

AIMS: Human cytomegalovirus constitutes a prevalent and serious threat to immunocompromised individuals and requires new treatments. Letermovir is a novel viral-terminase inhibitor that has demonstrated prophylactic/pre-emptive activity against human cytomegalovirus in Phase 2 and 3 transplant trials. As unchanged letermovir is primarily excreted via the liver by bile, this trial aimed to assess the effect of hepatic impairment on letermovir pharmacokinetics. METHODS: Phase 1, open-label, parallel-group pharmacokinetic and safety comparison of multiple once-daily oral letermovir in female subjects with hepatic impairment and healthy matched controls. For 8 days, subjects with moderate hepatic impairment (n = 8) and their matched healthy controls (n = 9) received 60 mg letermovir/day and those with severe hepatic impairment (n = 8) and their matched healthy controls (n = 8) received 30 mg letermovir/day. Pharmacokinetic parameters were determined from blood samples. RESULTS: For subjects with moderate hepatic impairment, maximal observed concentration at steady state (Css,max ) and the area under the concentration vs. time curve over a dosing interval at steady state (AUCτ,ss ) for total letermovir were 1.37-fold (90% confidence interval: 0.87, 2.17) and 1.59-fold (0.98, 2.57) higher, respectively, than in healthy subjects. For subjects with severe hepatic impairment, Css,max and AUCτ,ss values of total letermovir were 2.34-fold (1.91, 2.88) and 3.82-fold (2.94, 4.97) higher, respectively, compared with healthy subjects. CONCLUSIONS: Moderate hepatic impairment increased exposure to letermovir <2-fold, while severe hepatic impairment increased letermovir exposure approximately 4-fold as compared with healthy subjects. Letermovir 60/30 mg/day was generally well-tolerated in subjects with hepatic impairment.

Efficacy and Acceptability of Indapamide Sustained Release in Elderly High-Risk Hypertensive Patients : the ARGUS Study.

OBJECTIVE: To assess the efficacy and acceptability of indapamide sustained-release (SR) monotherapy in elderly high-risk patients with moderate to severe hypertension. METHODS: 1277 hypertensive patients older than 55 years with moderate to severe hypertension, including 91% with systolic blood pressure (SBP) >160 mmHg and at least one cardiovascular risk factor (age >65 years, male, diabetes mellitus, coronary heart disease [CHD], cerebrovascular disease, dyslipidaemia, obesity, smoking) were enrolled in this observational study. They received indapamide SR 1.5 mg, one tablet daily, for 3 months. Blood pressure (BP) was assessed monthly by sphygmomanometer. Statistical analyses were performed using the χ(2) test, analysis of variance, and the Newman-Keuls test. RESULTS: After 3 months of treatment with indapamide SR, SBP had decreased by 34 ± 3 mmHg and diastolic BP (DBP) by 12 ± 6 mmHg (both p < 0.001). Ninety-two percent of patients responded to therapy (SBP/DBP reduction >20/10 mmHg) and 52% were normalized (SBP <140 mmHg and DBP <90 mmHg). BP targets were reached in 48% of patients older than 65 years, 31% of diabetic patients, and 33% of patients with CHD. There were no changes in serum creatinine, glucose or lipid parameters, and 3% of patients had hypokalaemia (<3.5 mmol/L). The patients self-assessment scores regarding general state of health improved and 34% of patients reported 'excellent' health after treatment. CONCLUSIONS: In the high-risk patients of the ARGUS study, monotherapy with indapamide SR showed antihypertensive efficacy with good acceptability and no changes in metabolic parameters over a 3-month period. Indapamide SR monotherapy normalized BP in half of the patients treated and proved an appropriate first-line treatment in hypertensive patients older than 55 years with added cardiovascular risk factors.

Validation of TM-2655 oscillometric device for blood pressure measurement.

OBJECTIVE: To perform validation for an arm-type oscillometric TM-2655 device (A&D Company Ltd, Tokyo, Japan) for blood pressure measurement according to the British Hypertension Society protocol. METHODS: Eighty-five study participants (33 men and 52 women) were included in the study. Mean age was 52.9+/-15.0 years, systolic blood pressure range was 84-208 mmHg and diastolic blood pressure range was 48-120 mmHg. For each participant, three readings of TM-2655 were compared with sequential auscultatory measurements by two trained independent observers. The observers used a calibrated mercury sphygmomanometer and dual stethoscope. The results were graded according to the British Hypertension Society protocol 1993. RESULTS: The average difference between mercury sphygmomanometer and TM-2655 readings for systolic blood pressure was -1.0+5.2 mmHg (mean+/-SD) and for diastolic blood pressure -0.9+/-4.7 mmHg. The proportions of values agreeing to within 5, 10 and 15 mmHg were 72.5, 93.7 and 99.6% for systolic blood pressure and 78.8, 96.9 and 100% for diastolic blood pressure between the observers and the device (A/A British Hypertension Society grade). CONCLUSIONS: The TM-2655 device achieved British Hypertension Society grade A/A and therefore can be recommended for blood pressure measurement in an adult population.

Validation of the TM-2564G device for in-hospital blood pressure measurement.

OBJECTIVE: To perform clinical validation of the TM-2564G device for in-hospital blood pressure measurement according to the British Hypertension Society protocol. METHODS: The tests were carried out on 85 patients aged 19-82 years (41 male patients, mean age 50+/-19 years) with systolic blood pressure 75-219 mmHg and diastolic blood pressure 43-117 mmHg (mean 142+/-33/85+/-20 mmHg). For each patient, three readings of the TM-2564G device were compared with simultaneous auscultatory measurements by two trained independent observers. The observers used a mercury-calibrated sphygmomanometer and dual stethoscope. The results were graded according to the British Hypertension Society protocol 1993. RESULTS: The average difference was -1.85 mmHg for systolic blood pressure and -1.20 mmHg for diastolic blood pressure. The standard deviation of the difference between TM-2564G and the observers' results was 4.85 and 4.16 mmHg for systolic and diastolic blood pressures, respectively. Systolic blood pressure percentage of readings agreeing to within 5 mmHg was 75.7%, 10 mmHg 95.36% and 15 mmHg 99.6%, and for DBP 82.7, 97.6 and 99.8%, respectively. CONCLUSIONS: The TM-2564G device achieved A/A British Hypertension Society grade and can be recommended for in-hospital measurement of blood pressure.

Alcohol dehydrogenase ADH2-1 and ADH2-2 allelic isoforms in the Russian population correlate with type of alcoholic disease.

The frequency ADH2-2 allele in the Moscow urban population and a correlation between the ADH2-2 allele, alcoholic dependence without cirrhosis, symptomatic alcoholic cirrhosis and status on hepatitis B and C infection have been studied. One hundred and twenty-three inhabitants of Moscow (50 healthy donors, 36 patients with alcoholic cirrhosis (subdivided into infected and uninfected by HBV and/or HCV) and 37 patients with alcoholic dependence) of a similar age/sex and drinking pattern have been analysed. The frequency of 41% for ADH2-2 allele is characteristic for an urban Moscow population. This value is intermediate between that found for Asian peoples and for Central and Western Europe. There is a negative correlation between the ADH2-2 allele and alcohol misuse (both alcoholic dependence and alcoholic cirrhosis). This correlation is expressed more in alcoholic dependence. In spite of the possession of the ADH2-2 allele (or genotype ADH2-1/2), alcohol misuse increases the risk of cirrhosis. At the same time, positive status for active hepatitis B, C or combined infection B + C (replication markers HBV-DNA or HCV-RNA) increases the risk for symptomatic alcoholic cirrhosis in alcohol abusing patients, independently of ADH2 genotype.