Long-term Combination Therapy Research Articles

Sa1012 Virological Response Does Not Lower Liver Disease Progression Among Chronic Hepatitis B Cirrhotic Patients Treated With Long-Term Nucleos(T)Ide-Analogue

Background: A large number of chronic hepatitis B patients with cirrhosis are on long-term nucleos(t)ide-analogue therapy. The impact of anti-viral treatment on liver disease progression among these cirrhotics remains to be characterized. Method: CHB cirrhotics treated with long-term LAM-ADV combination therapy or ETV monotherapy in our center were enrolled and followed for outcomes. Liver disease progression was defined as liver decompensation, development of hepatocellular carcinoma and death. Cumulative probability of virological and clinical outcomes was evaluated by Kaplan–Meier analysis, logrank test and Cox-regression analysis. Results: A total of 264 cirrhotics (compensated disease 87.5%) fulfilled enrollment criteria, of which 143 and 121 were treated with LAM-ADV and ETV respectively. In LAM-ADV group, 57 (39.9%) were HBeAg-positive, mean HBV-DNA was 5.8 (5.5–6.1) log IU/mL, mean LAM-ADV duration was 41.4 (14.5–68.3) months and mean follow-up was 72.8 (31.5–114.1) months. In ETV group, 48 (39.7%) were HBeAg-positive, mean HBV-DNA was 4.4 (4.1–4.7) log IU/mL, mean ETV duration was 33.3 (15.2–51.4) months and mean follow-up was 45.7 (16.8–74.6) months. Among LAM-ADV group, cumulative probability of (a) virological response were 59.9%, 92.2%, 95.6% and (b) liver disease progression was 4.5%, 17.6%, 32.9%, at year 1, 3 and 5 respectively. Among ETV group, cumulative probability of (a) virological response was 74.5%, 94.8%, 100% and (b) liver disease progression was 7.8%, 12.5%, 17.7% at year 1, 3 and 5 respectively. The probability of liver disease progression was not influenced by virological response (p = 0.174). When stratified by treatment group, virological response again did not impact on the cumulative probability of liver disease progression (LAM-ADV group: p =0.173 and ETV group: p =0.433). Among virological responders, there was also no difference between LAM-ADV combination and ETV monotherapy group (p =0.199). Cox-regression showed baseline decompensated disease status was a significant predictor of disease progression (HR 4.96; 95%CI 2.61–9.44; p < 0.01) whereas virological response had no impact (p = 0.196). Conclusion: Among cirrhotics treated with long-term LAM-ADV combination therapy or ETV monotherapy, despite the excellent anti-viral efficacy, there was still significant probability of liver disease progression. LAM-ADV combination or ETV-monotherapy induced virological response did not lower the probability of liver disease progression in these patients.

Long-term antiretroviral therapy initiated during primary HIV-1 infection is key to achieving both low HIV reservoirs and normal T cell counts

To characterize viro-immunological outcomes following long-term combined antiretroviral therapy (cART) initiated during primary HIV infection (PHI) or chronic HIV infection (CHI) and to identify factors predictive of optimal viro-immunological responder (OVIR) status. This was a prospective, single-centre cohort study of HIV-1-infected patients on effective cART. Total cell-associated HIV DNA levels and T cell counts before and during treatment were used to identify factors predictive of OVIR status {i.e. low HIV DNA level [<2.3 log10 copies/10(6) peripheral blood mononuclear cells (PBMCs)], together with normalization of the absolute/relative CD4+ T cell counts and CD4+/CD8+ ratio}. A total of 307 patients were enrolled, of whom 35 started cART during PHI (<4 months post-infection) and 272 during CHI. HIV DNA decay was modelled with a non-linear mixed-effects model that showed two phases of HIV DNA decay, both of which were significantly more pronounced in the PHI group. At the end of follow-up, after a median of 4 years of viral suppression (<50 copies/mL), HIV DNA levels were lower in the PHI group than in the CHI group (median = 2.15 versus 2.84 log10 copies/10(6) PBMCs; P< 0.0001). Immune reconstitution was more rapid and sustained in the PHI group (median = 883 versus 619 CD4+ cells/mm(3); 41% versus 31% CD4+; CD4+/CD8+ 1.31 versus 0.77; all P< 0.0001). Finally, OVIR status was obtained in 19/35 (54%) and 7/272 (3%) patients in the PHI and CHI groups (P< 0.0001), respectively. In a logistic regression analysis, cART initiation during PHI (OR = 16, 95% CI = 3.5-72.3) and HIV DNA level <3.3 log10 before treatment (OR = 4.8, 95% CI = 1.2-19.3) were independently predictive of OVIR status. Initiating cART during PHI represents a major opportunity to reduce HIV reservoirs and achieve optimal immune reconstitution.

Two Families with Normosmic Congenital Hypogonadotropic Hypogonadism and Biallelic Mutations in KISS1R (KISS1 Receptor): Clinical Evaluation and Molecular Characterization of a Novel Mutation

Context KISS1R mutations have been reported in few patients with normosmic congenital hypogonadotropic hypogonadism (nCHH) (OMIM #146110).ObjectiveTo describe in detail nCHH patients with biallelic KISS1R mutations belonging to 2 unrelated families, and to functionally characterize a novel KISS1R mutation.ResultsAn original mutant, p.Tyr313His, was found in the homozygous state in 3 affected kindred (2 females and 1 male) from a consanguineous Portuguese family. This mutation, located in the seventh transmembrane domain, affects a highly conserved amino acid, perturbs the conformation of the transmembrane segment, and impairs MAP kinase signaling and intracellular calcium release. In the second family, a French Caucasian male patient with nCHH was found to carry two recurrent mutations in the compound heterozygous state (p.Leu102Pro/Stop399Arg). In this man, pulsatile GnRH (Gonadotropin Releasing Hormone) administration restored pulsatile LH (Luteinizing Hormone) secretion and testicular hormone secretion. Later, long-term combined gonadotropin therapy induced spermatogenesis, enabling 3 successive pregnancies that resulted in 2 miscarriages and the birth of a healthy boy.ConclusionWe show that a novel loss-of-function mutation (p.Tyr313His) in the KISS1R gene can cause familial nCHH, revealing the crucial role of this amino acid in KISS1R function. The observed restoration of gonadotropin secretion by exogenous GnRH administration further supports, in humans, the hypothalamic origin of the gonadotropin deficiency in this genetic form of nCHH.

Long-term Combined Therapy with Very-low-dose Peginterferon and Ursodeoxycholic Acid Decreased the Spleen Size in a Patient with Hepatitis C Virus-related Cirrhosis

A 42-year-old woman with hepatitis C virus-related cirrhosis underwent peginterferon alpha-2b therapy combined with ribavirin but could not achieve a sustained viral response. Following discontinuation of this combined therapy, the patient's serum transaminase levels suddenly became elevated. Therefore, the administration of very-low-dose peginterferon alpha-2a with ursodeoxycholic acid was introduced. Thereafter, the patient's serum transaminase levels gradually improved. Four years later, enhanced computed tomography showed shrinkage of the spleen and enlargement of the liver. Long-term combined therapy with very-low-dose peginterferon and ursodeoxycholic acid may be effective not only in preventing disease progression, but also in improving portal hypertension in patients hepatitis C virus-related cirrhosis.

Safety and efficacy of long-term combination therapy with bezafibrate and ezetimibe in patients with dyslipidemia in the prospective, observational J-COMPATIBLE study

BackgroundThere are numerous reports describing the efficacy of fenofibrate in combination with ezetimibe for treating dyslipidemia. In contrast, a study combining bezafibrate and ezetimibe has not yet been conducted. In this study, we examined the safety, including the risk of gallstone formation, and the efficacy of long-term combination therapy with bezafibrate and ezetimibe for treating dyslipidemia.MethodsDyslipidemic patients treated with 400 mg/day bezafibrate in combination with 10 mg/day ezetimibe for the first time were eligible. We selected 157 institutions in Japan and conducted a 12-month prospective observational study, with patients enrolled on the day they started combination therapy. Safety of the combination was examined in terms of the type, onset, and severity of adverse drug reactions (ADRs). Efficacy was evaluated in terms of the changes in low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), triglyceride (TG), and non-HDL cholesterol (non-HDL-C) levels from the start of combination therapy (baseline) to the last observation carried forward (LOCF). Lipid levels were assessed at 1, 3, 6, and 12 months after starting combination therapy.ResultsWe enrolled 665 patients in this observational study. Safety was evaluated in 659, and ADRs occurred in 42 patients (6.4%). The most frequent ADRs were blood creatine phosphokinase increase (1.5%) and myalgia (0.8%). Asymptomatic gallstones were observed in four patients (0.6%). Effectiveness was evaluated in 622 patients. LDL-C, HDL-C, TG, and non-HDL-C levels improved significantly from baseline to LOCF by −17.4%, 8.8%, –40.5%, and −21.6%, respectively (all, p < 0.001). Lipid levels also improved from baseline to each evaluation time-point.ConclusionsBezafibrate in combination with ezetimibe is safe and effective, and is potentially useful for comprehensive management of dyslipidemia.

Combination of Amlodipine plus Angiotensin Receptor Blocker or Diuretics in High-Risk Hypertensive Patients

Antihypertensive therapy is effective in reducing the risk of major adverse cardiovascular events. However, blood pressure (BP) control rate remains poor and the optimal combination therapy against hypertension is not established in China. The objective of this study was to evaluate the long-term efficacy and safety of two antihypertensive regimens, amlodipine plus telmisartan and amlodipine plus amiloride/hydrochlorothiazide, in patients with essential hypertension and at least one cardiovascular risk factor. In a multicenter open-label clinical trial, eligible patients were randomized to receive treatment with amlodipine 2.5-5 mg plus amiloride/hydrochlorothiazide 1.25-2.5 mg/12.5-25 mg (Group A) or amlodipine 2.5-5 mg plus telmisartan 40-80 mg (Group T). If a target BP was not reached, other antihypertensive agents would be added. The target BP was <130/80 mmHg for patients with diabetes mellitus or chronic kidney disease and <140/90 mmHg for others. Efficacy variables were changes from baseline in systolic BP and diastolic BP at the endpoint of 96 weeks. Safety evaluations included monitoring of any adverse events (AEs). Of 13,542 patients randomized, 13,080 (96.6%) completed the study: 6529 in Group A and 6551 in Group T. At endpoint, the BP levels were reduced by 27.4/14.3 mmHg in Group A and 27.1/14.5 mmHg in Group T. The BP control rates were similar for the two therapeutic regimens (87.5% vs 86.1%). Less than 4% of patients in each group discontinued their drugs during follow-up. Peripheral edema was one of the most common AEs, and occurred in only 24 patients in Group A and 19 in Group T. Long-term combination therapy with amlodipine plus telmisartan or amlodipine plus amiloride/hydrochlorothiazide was not only well tolerated but also efficacious in reducing BP levels with acceptable control rates in the majority of hypertensive patients. ClinicalTrials.gov number NCT01011660.

Hepatitis B Immune Globulin in Liver Transplantation Prophylaxis: An Update

Liver transplantation is the best treatment option for end-stage liver disease following hepatitis B (HBV) infection. However, the high rate of recurrence of HBV infection following transplantation is a disadvantage of this option. Over the past 2 decades, the gold standard of prophylactic treatment for the prevention of HBV re-infection following liver transplantation has been the administration of low- to high-dose hepatitis B immune globulin (HBIg) along with an antiviral agent to induce passive immunity. The effectiveness of HBIg in preventing the recurrence of HBV depends on the dosage, route of administration, and duration of HBIg treatment, and the viremic status at the time of transplantation. There is currently no consensus on a standardized recommendation for therapeutic options that include HBIg administration. This review attempts to summarize the available data on the feasibility of such options. Most recent studies support the use of long-term combination therapy of HBIg and antiviral NAs (especially new agents).

Trends in treatment of newly treated schizophrenia‐spectrum disorder patients in Taiwan from 1999 to 2006

This study aimed to examine trends in the first-year pharmacological treatment of newly treated schizophrenia patients in Taiwan between 1999 and 2006. We collected data from the National Health Insurance Research Database of all newly treated patients with a diagnosis of schizophrenia-spectrum disorder (ICD-9 295.x). We analyzed all prescription records after diagnosis of schizophrenia and described the patterns of antipsychotics use, other concomitant psychotropic agents use, and mental health system utilization. We tested for trend using multivariate logistic regression and Spearman's partial correlation rank test. A total of 2895 newly treated patients with schizophrenia were enrolled. The percentage of prescriptions of second-generation antipsychotics (SGAs) was found to have increased significantly, from 27.5% in 1999 to 76.9% in 2006. The ratio of good antipsychotics adherence (medication possession ratio >0.8) also increased, from 23.2% in 1998 to 38.9% in 2006. Corresponding to this, the percentage of usage of first-generation antipsychotic drugs, anticholinergic agents, and long-term combination therapy declined. However, the prescription of antidepressants and mood stabilizers and the hospitalization rate increased. No change was noted in the number of psychiatric visits. In the first-year treatment of newly treated schizophrenic patients between 1999 and 2006, we found pharmacological treatment had changed in terms of types of antipsychotics, adherence, and the use of other concomitant psychotropic agents, with the introduction of SGAs. The benefits and costs of the changes with a trend toward an increasing prescription of SGAs warrant further investigation.

Hepatitis B Immune Globulin in Liver Transplantation Prophylaxis: An Update

: Context: Liver transplantation is the best treatment option for end-stage liver disease following hepatitis B (HBV) infection. However, the high rate of recurrence of HBV infection following transplantation is a disadvantage of this option.Evidence Acquisition: Over the past 2 decades, the gold standard of prophylactic treatment for the prevention of HBV re-infection following liver transplantation has been the administration of low- to high-dose hepatitis B immune globulin (HBIg) along with an antiviral agent to induce passive immunity.Results: The effectiveness of HBIg in preventing the recurrence of HBV depends on the dosage, route of administration, and duration of HBIg treatment, and the viremic status at the time of transplantation. There is currently no consensus on a standardized recommendation for therapeutic options that include HBIg administration.Conclusion: This review attempts to summarize the available data on the feasibility of such options. Most recent studies support the use of long-term combination therapy of HBIg and antiviral NAs (especially new agents). Implication for health policy/practice/research/medical education:The article is suitable for hepatologist, internists, infectious specialists and liver transplantation departments. Please cite this paper as:Dindoost P, Jazayeri SM, Alavian SM. Hepatitis B Immune Globulin and Liver Transplantation Prophylaxis: An UpDate. Hepat Mon.2012;12(3):168-76. DOI: 10.5812/hepatmon.832 Copyright © 2012 Kowsar Corp. All rights reserved.

Clinical Outcomes Using Long-Term Combination Therapy with Insulin Glargine and Exenatide in Patients with Type 2 Diabetes Mellitus

To examine the long-term effects of combination insulin glargine/exenatide treatment on glycemic control. We conducted a 24-month retrospective US chart review of patients with inadequately controlled type 2 diabetes (T2DM) and hemoglobin A1c (A1C) levels >7.0% for whom glargine and exenatide were coprescribed in differing order (glargine added after exenatide [exenatide/glargine]; exenatide added after glargine [glargine/exenatide]). Treatment order groups were combined to form a pooled treatment group. Changes from baseline in A1C, patients with A1C ≤7.0%, body weight, glargine/exenatide daily dose, oral antidiabetic drug (OAD) use, and hypoglycemia were evaluated. Treatment groups were similar at baseline; however, patients in the glargine/exenatide group (n = 121) (vs exenatide/glargine group [n = 44]) had longer disease duration (11.8 vs 8.0 years) and took fewer OADs (1.7 vs 2.3). Overall, baseline A1C was 8.8 ± 1.3% and weight was 109.5 ± 25.3 kg. Significant A1C reductions emerged at month 6 and persisted throughout 24 months (vs baseline) in both treatment groups (pooled: -0.7 ± 1.6; P<.001), and 33.0% of patients achieved an A1C level ≤7.0%. After 24 months of exenatide/glargine, body weight remained unchanged (0.7 ± 8.3 kg; P = .640). With glargine/exenatide, body weight decreased (-2.5 ± 6.7 kg; P = .001). At month 24, daily glargine dose was 0.40 ± 0.23 units/kg for the exenatide/glargine group and 0.47 ± 0.30 units/kg for the glargine/exenatide group. Hypoglycemia frequency was similar in both treatment groups. Regardless of treatment order, long-term combined therapy with glargine and exenatide for up to 24 months in patients with inadequately controlled T2DM suggests reduction of A1C without significant weight gain or increased hypoglycemia risk.

α-Blocker Monotherapy and α-Blocker Plus 5-Alpha-Reductase Inhibitor Combination Treatment in Benign Prostatic Hyperplasia; 10 Years' Long-Term Results

PurposeWe compared the effects of alpha-adrenergic receptor blocker (α-blocker) monotherapy with those of combination therapy with α-blocker and 5-alpha-reductase inhibitor (5-ARI) on benign prostatic hyperplasia (BPH) progression for over 10 years.Materials and MethodsA total of 620 patients with BPH who received α-blocker monotherapy (α-blocker group, n=368) or combination therapy (combination group, n=252) as their initial treatment were enrolled from January 1989 to June 2000. The incidences of acute urinary retention (AUR) and BPH-related surgery were compared between the two groups. Incidences stratified by follow-up period, prostate-specific antigen (PSA), and prostate volume (PV) were compared between the two groups.ResultsThe incidence of AUR was 13.6% (50/368) in the α-blocker group and 2.8% (7/252) in the combination group (p<0.001). A total of 8.4% (31/368) and 3.2% (8/252) of patients underwent BPH-related surgery in the α-blocker and combination groups, respectively (p=0.008). According to the follow-up period, the incidence of AUR was significantly decreased in combination group. However, the incidence of BPH-related surgery was significantly reduced after 7 years of combination therapy. Cutoff levels of PSA and PV for reducing the incidences of AUR and BPH-related surgery were 2.0 ng/ml and 35 g, respectively (p<0.001).ConclusionsLong-term combination therapy with α-blocker and 5-ARI can suppress the progression of BPH more efficiently than α-blocker monotherapy. For patients with BPH with PSA >2.0 ng/ml or PV >35 ml, combination therapy promises a better effect for reducing the risk of BPH progression.

EFFICACY OF COMBINED ANTIHYPERTENSIVE THERAPY IN ACHIEVEMENT OF TARGET BLOOD PRESSURE IN DIABETIC PATIENTS

Aim. To evaluate the efficacy of long-term combined antihypertensive therapy (AHT) based on renin-angiotensin-aldosterone system (RAAS) blockers, indapamide and calcium channel blocker (CCB) in hypertensive patients with diabetes mellitus (DM) in accordance with target blood pressure (BP) &lt;130/80 mm Hg achievement rate, dynamics of 24-hour BP profile, metabolic indices, and local stiffness of the main arteries. Besides, to study the effects of the CCB addition to dual therapy on these parameters. Material and methods. Patients (16 men, 31 women, 57.2±6.6 years old) with arterial hypertension degrees 1–3 and mild to moderate DM type 2 were included into the study. The patients were treated with perindopril (5–10 mg/day) or valsartan (80–160 mg/day) in combination with indapamide SR (1.5 mg/day) and amlodipine (5–10 mg/day). Examination included office BP measurement and ambulatory BP monitoring (ABPM), common carotid arteries sonarography , evaluation of serum levels of potassium, creatinine, uric acid, glucose metabolism and lipid profile parameters, calculation of insulin resistance index (HOMA) at baseline and after 30–32 weeks of treatment. Results. Target BP was achieved in 86.7% of patients. Evenly reduction of day and night BP without reflex tachycardia and hypotension episodes was observed. Office BP decreased from 149.5±12.0/90.0±8.3 to 125.0±7.6/76.8±4.9 mm Hg (p&lt;0.05) and average daily BP (ABPM) decreased to 120.1±10.0/71.7±6.9 mmHg. Three drugs were needed to achieve target BP in baseline systolic BP &gt;150 mm Hg (office) or &gt;134 mmHg (ABPM). Marked beneficial effect on the morphological and functional characteristics of the vascular wall and its elastic properties, improvement of glycemic control, tissue insulin sensitivity and lipids profile were found. These effects were associated mainly with amlodipine inclusion into the therapy. Conclusion. The combined AHT based on RAAS blockers, indapamide SR and CCB provides achievement of target BP in the most of hypertensive patients with DM and accompanied by positive changes in vascular remodeling and metabolism.

EFFECT OF THE COMBINED ANTIHYPERTENSIVE THERAPY WITH TARGET BLOOD PRESSURE ACHIEVEMENT ON INTRARENAL BLOOD FLOW IN PATIENTS WITH TYPE 2 DIABETES

Aim. To compare the dynamics of intrarenal vascular resistance (IRVR), circadian blood pressure (BP) profile and glomerular filtration rate (GFR) in patients with arterial hypertension (HT) and type 2 diabetes mellitus (DM) who achieved the target BP levels (&lt;130/80 mmHg) due to long-term combined antihypertensive therapy with or without renin-angiotensin-aldosterone system (RAAS) inhibitors. Material and methods. Patients (n=61) with HT and DM without clinical symptoms of nephroangiopathy were included into the open randomized study , 59 of these patients completed study. Patients of Group 1 (n=41) received therapy with valsartan (n=20), 80–160 mg/day , or perindopril (n=21), 5–10 mg/day , in combination with indapamide retard, 1.5 mg/day , and amlodipine, 5–10 mg/day. Patients of Group 2 (n=18) received amlodipine (5–10 mg/day) in combination with indapamide retard (1.5 mg/day) and metoprolol succinate (50–100 mg/day). Initially and after 30–32 weeks of therapy the following examinations were performed: duplex ultrasound scanning of the main renal (MRA) and intrarenal arteries (IRA) with resistive index (RI) calculation, ambulatory BP monitoring (ABPM), GFR calculation (by Cockcroft-Gault formula). Results. The target BP levels were achieved in all patients of both groups. Patient’s baseline characteristics including age, sex, duration of disease, office BP , GFR, RI in MRA and IRA did not differ in the groups as well as decrease in office BP due to treatment. However patients of Group 2 had higher levels of systolic BP and systolic BP load at night time than these in patients of Group 1 during all period of the treatment. In patients of Group 2 RI in MRA and arcuate IRA were increased from 0.67±0.06 to 0.69±0.06 (p=0.02) and from 0.62±0.07 to 0.64±0.06 (p=0.02), respectively. The increase in IRA was positively associated with systolic BP at night time in these patients (r=0.6; p=0.01). There were no significant changes of IRA in Group 1 totally. At the same time, initially high IRVR decreased in 61% of patients. GFR increased in patients of Group 2 (p=0.01), while dynamics of GFR was not found in patients of Group 1. Conclusion. Achievement of target BP levels due to antihypertensive therapy not including RAAS inhibitors resulted in increase in IRVR that associated with the lack of systolic BP reduction at night time.

分子標的薬治療中に消化管穿孔を合併した進行性腎細胞癌の2例

(Case 1) An 82-year-old man started immunotherapy with interferon because of lung metastasis 5 years after he had undergone radical nephrectomy. Three years later, he developed multiple metastases, and was started on sorafenib (400 mg/day) and nonsteroidal anti-inflammatory drug (NSAID) orally. As his cancer-related pain worsened with time, he was administered 30 Gy radiation therapy for bone metastasis of L4. He was then admitted to our hospital for pain control because of ineffective radiation therapy. One day, he suddenly had abdominal pain and vomiting, and was diagnosed as bowel perforation based on computed tomography. He was managed conservatively by nasogastric suction and antibiotic course. (Case 2) A 62-year-old man diagnosed as metastatic renal cell cancer began immunotherapy soon after undergoing radical nephrectomy in Dec., 2006. Although he was started on oral sorafenib (800 mg/day) in July, 2008, metastatic foci enlarged after 18 months. He was then changed to sunitinib (50 mg/day). Sunitinib had immediate and long-lasting effect on the cancer for about 10 months, but he was then admitted to our hospital for pleural effusion. While under treatment for thoracic cavity drainage, he experienced upper abdominal pain and was diagnosis as bowel perforation based on computed tomography. He underwent emergency laparotomy. Molecular target drugs such as sorafenib and sunitinib have serious adverse effects. Bowel perforation is rare, but among those adverse effects. It should be remembered that caution is required for long-term use or combined radiation therapy and NSAIDs with molecular target drug.

P67 Switch to other nucleos(t)ide analogues therapy in chronic hepatitis B cohort on long-term de-novo combination therapy with lamivudine plus adefovir: efficacy and safety

IntroductionLong-term de-novo combination therapy with lamivudine (LAM) 100 mg/d + adefovir (ADV) 10 mg/d is highly efficient, with no/minimal drug resistance and good safety profile. Tenofovir (TDF) 245 mg/d or...

Long‐term adefovir plus lamivudine therapy does not decrease creatinine clearance in HBeAg‐negative chronic hepatitis B patients

As there are concerns about potential nephrotoxicity of nucleotide analogues, we evaluated renal function parameters during long-term adefovir and lamivudine combination therapy. Forty-six HBeAg-negative patients with lamivudine-resistance treated with adefovir and lamivudine for up to 90 months were included. Renal function was assessed by estimated creatinine clearance (eC(CR) ) and compared with a matched control group of untreated inactive hepatitis B virus carriers. Serum HBV DNA became undetectable in 39 (85%) patients after a mean of 37 ± 21 months. Three (6.5%) patients developed virological breakthrough. Adefovir resistance was detected in two patients. At the end of follow up, there was a significant decrease in mean eC(CR) (95 ± 31-83 ± 30 ml/min, P = 0.003) in the treated patients with 16% presenting aeC(CR) decrease >30%. Similar changes in eC(CR) were observed in the control group (108 ± 28-96 ± 26 ml/min, P = 0.003). In multiple regression analysis, age and baseline eC(CR) were independent predictors of eC(CR) reduction. Adefovir and lamivudine combination therapy is not an independent factor for significant renal dysfunction in HBeAg-negative patients with lamivudine-resistance. Baseline age and creatinine clearance are the only independent predictors of worsening renal function.

Efficacy of combined treatment with S-carboxymethylcysteine (carbocisteine) and clarithromycin in chronic rhinosinusitis patients without nasal polyp or with small nasal polyp

In Japan, fourteen-membered ring macrolides, antibacterial agents, and S-carboxymethylcysteine (SCMC; carbocisteine), a mucolytic, are commonly used to treat chronic rhinosinusitis (CRS), and they are also used in combination. However, no large-scale randomized study has examined the effects of these pharmacotherapies. The aim of this study is to evaluate the effect of combined administration of clarithromycin (CAM), a fourteen-membered ring macrolide, and SCMC, compared with CAM single therapy. Patients with CRS were centrally registered and randomly assigned to treatment with CAM (200mg/day) alone (monotherapy group) or CAM (200mg/day) in combination with SCMC (1500mg/day; combination group) for 12 weeks. We assessed the clinical efficacy of the treatments using measures of subjective symptoms and objective findings, health-related quality of life (HRQOL) determined by the 20-Item Sino-Nasal Outcome Test (SNOT-20) score and computed tomography (CT) score. Four hundred twenty-five subjects were enrolled (combination group, 213; monotherapy group, 212). At week 12 of treatment, the rate of effectiveness was significantly higher in the combination group (64.2%) compared with the monotherapy group (45.6%; P=0.001). In addition, objective findings, including characteristics of nasal discharge (P=0.008) and post-nasal discharge (P=0.002) were significantly improved in the combination group. In both groups, SNOT-20 and CT scores were significantly improved from week 0 (P<0.001), and were not significantly different between groups. The results indicated that long-term combination therapy with SCMC at a dose of 1500mg/day and CAM at a dose of 200mg/day is effective for improving subjective symptoms and objective findings in adult patients with CRS.

The effects of combination therapy with dutasteride plus tamsulosin on clinical outcomes in men with symptomatic BPH: 4-year post hoc analysis of European men in the CombAT study

CombAT (Combination of Avodart and Tamsulosin) was a randomised, double-blind study in men (n=4844) aged ≥ 50 years with a clinical diagnosis of BPH. Patients were randomised to daily tamsulosin 0.4 mg, dutasteride 0.5 mg or both for 4 years. The primary endpoint was time to acute urinary retention (AUR) or BPH-related surgery. Secondary endpoints included BPH clinical progression, symptoms and maximum urinary flow rate. A post hoc analysis of data from the European subgroup was conducted. A total of 2925 men were randomised to treatment in Europe as part of CombAT (tamsulosin, n=972; dutasteride, n=970; combination, n=983). Combination therapy significantly reduced the relative risk of AUR or BPH-related surgery compared with either monotherapy at 4 years, and also significantly reduced the risk of BPH clinical progression. Combination therapy also provided significantly greater symptom improvement than either monotherapy at 4 years. Safety and tolerability of dutasteride plus tamsulosin was consistent with previous experience of this combination and with the monotherapies. These data provide further evidence to support the use of long-term combination therapy (dutasteride plus tamsulosin) in men with moderate-to-severe lower urinary tract symptoms because of BPH and prostatic enlargement. The results in the European subgroup are generally consistent with those in the overall study population.

Actinomycetoma: dramatic response to modified two‐step regimen

Mycetoma is a chronic granulomatous infection of the subcutaneous tissue caused by fungi or fungus-like bacteria. The infection eventually spreads to bone resulting in significant morbidity. Rarely, viscera may be involved through contiguous spread. It is common in tropical countries like India, though disease is worldwide in distribution. A 22-year-old male patient, a farmer by occupation, presented with multiple discharging sinuses over the left chest wall, shoulder, upper arm, and adjacent neck of eight months duration. A diagnosis of actinomycetoma was made based on clinical and histopathological features as culture was negative for both fungus and bacteria. The patient was treated with a modified two-step regimen. It consisted of an intensive phase with intravenous gentamicin 80 mg 12th hourly and cotrimoxazole 320/1600 mg twice daily orally for four weeks. This was followed by a maintenance phase with oral cotrimoxazole and doxycycline 100 mg twice daily. Patient showed excellent response with healing of all sinuses after two months of therapy. Involvement of covered parts of the body such as chest wall and shoulders is common in actinomycetoma compared to eumycetoma. Early institution of long-term combination therapy with antimicrobials results in excellent outcome.

Drug treatment for lower urinary tract symptoms

Lower urinary tract symptoms (LUTS) are classified into three groups: storage, voiding, and post-micturition symptoms. The most popular causes of LUTS are benign prostatic hyperplasia (BPH) and overactive bladder (OAB). Although BPH is a pathologic term, clinically, we use this when patients have LUTS due to benign prostatic enlargement and obstruction. OAB is defined as urgency, with or without urge incontinence, usually with frequency and nocturia. Currently α1-adrenoceptor antagonists are the most common drug treatment for BPH, and are thought to act by relaxing the prostatic smooth muscle. They are all effective for the treatment of LUTS/BPH. 5α-reductase inhibitors, such as fiansteride and dutasteride, are another treatment option for BPH symptoms, which reduce the prostatic volume by inducing epithelial atrophy. Long-term combination therapy with alpha-1-blockers and 5α-reductase inhibitors reduces the risk of the overall clinical progression of BPH significantly more than does treatment with either drug alone. Antimuscarinics are the mainstay for the treatment of OAB. Antimuscarinics competitively block muscarinic receptors of all subtypes but with variations in selectivity for the different subtypes. When they are used for the treatment of OAB, they are active during the storage phase of the bladder, with little or no effect on voiding contractions. Desmopressin acetate is a synthetic analogue of Arginin vasopressin, which has been proven effective for the treatment of nocturnal polyuria in LUTS.