Previous Monotherapy Research Articles

Candesartan plus hydrochlorothiazide fixed combination vs previous monotherapy plus diuretic in poorly controlled essential hypertensive patients

Objective: To assess efficacy and tolerability of candesartan cilexetil (CC) plus hydrochlorothiazide (HCTZ) fixed combination vs previous monotherapy (PM) plus HCTZ in hypertension. Design and Methods: After 2-4 weeks of run in, 409 outpatients (diastolic blood pressure, DBP >90 and ≤⃒110 mmHg; systolic blood pressure, SBP ≤⃒180 mmHg), aged 26-79 years, under monotherapy, were randomized in a PROBE multicenter trial to CC 16 mg plus HCTZ 12.5 mg or PM plus HCTZ 12.5 mg for 8 weeks. HCTZ was doubled after the first 4 weeks in non-responders (DBP ≥90 mmHg or SBP >180 mmHg). Results: Automatic oscillometric (Omron 705 CP) DBP and SBP were similarly reduced by CC + HCTZ and PM + HCTZ after 4 (12/15 and 10/13 mmHg) and 8 weeks (13/20 and 12/18 mmHg) in the intention-to-treat (ITT, n = 398) population. HCTZ dose was doubled in 18.1 and 31.2% of patients in the CC + HCTZ and PM + HCTZ group, respectively (p < 0.05). Rate of normalized patients (DBP <90 and/or SBP <140 mmHg) after 8 weeks of treatment was greater (p < 0.05) under CC + HCTZ (82.0 vs 72.6% vs PM + HCTZ). Pulse pressure was comparably reduced by CC + HCTZ and PM + HCTZ, at 4 (3 mmHg for both) and 8 weeks (7 and 6 mmHg, respectively). Heart rate was unchanged. Results of per-protocol analysis (n = 316) did not differ from those of ITT analysis. Rate of adverse events was low and comparable between groups. Conclusions: CC plus HCTZ fixed combination is an effective and safe alternative to other antihypertensive drugs, given either as monotherapy or in combination when they do not satisfactorily control patient's blood pressure.

Lamotrigine monotherapy compared with carbamazepine, phenytoin, or valproate monotherapy in patients with epilepsy*1

Objective. This open-label study evaluated the efficacy and tolerability of lamotrigine monotherapy compared with monotherapy with conventional antiepileptic drugs in patients converting from previous monotherapy because of inadequate seizure control or unacceptable side effects. Methods. This study was conducted in 26 neurology clinics and epilepsy centers throughout the United States. The study enrolled 115 patients with epilepsy converting from previous monotherapy because of inadequate seizure control or unacceptable side effects. Patients were randomized 1:1 to receive 24 weeks of lamotrigine monotherapy or monotherapy with a conventional antiepileptic drug (carbamazepine, phenytoin, or valproate based on physician’s choice). Patients were converted during an ⩽8-week Escalation/Taper Phase from their prestudy antiepileptic drug (carbamazepine, phenytoin, or valproate) to lamotrigine via a protocol-specified dosing algorithm or to conventional therapy via standard dosing guidelines. After monotherapy was achieved, patients continued in the study for a 24-week Maintenance Phase. Results. More lamotrigine patients (65%) than conventional therapy patients (57%) completed the 24-week Maintenance Phase (primary efficacy endpoint). The mean time to withdrawal from the study was 175 days (SD=83.1) for lamotrigine patients compared with 156 days (SD=80.7) for conventional therapy patients. Adverse events, the most common reason for discontinuing the Maintenance Phase, accounted for 16% of withdrawals among lamotrigine patients compared with 26% of withdrawals among conventional therapy patients. The mean reduction in seizure frequency was 53% (SD=55.1) for patients using lamotrigine compared with 32% (SD=149.9) for patients using conventional therapy. Humanistic measures including investigator global assessment, the patient self-assessment, and QOLIE-31 scores show that lamotrigine monotherapy was perceived by both physicians and patients to have benefits over monotherapy with conventional antiepileptic drugs. Conclusions. Converting from monotherapy with a less effective or poorly tolerated conventional antiepileptic drug to monotherapy with lamotrigine is associated with better clinical and humanistic outcomes than converting to an alternative conventional antiepileptic drug.

Lamotrigine monotherapy compared with carbamazepine, phenytoin, or valproate monotherapy in patients with epilepsy

Objective. This open-label study evaluated the efficacy and tolerability of lamotrigine monotherapy compared with monotherapy with conventional antiepileptic drugs in patients converting from previous monotherapy because of inadequate seizure control or unacceptable side effects. Methods. This study was conducted in 26 neurology clinics and epilepsy centers throughout the United States. The study enrolled 115 patients with epilepsy converting from previous monotherapy because of inadequate seizure control or unacceptable side effects. Patients were randomized 1:1 to receive 24 weeks of lamotrigine monotherapy or monotherapy with a conventional antiepileptic drug (carbamazepine, phenytoin, or valproate based on physician’s choice). Patients were converted during an ⩽8-week Escalation/Taper Phase from their prestudy antiepileptic drug (carbamazepine, phenytoin, or valproate) to lamotrigine via a protocol-specified dosing algorithm or to conventional therapy via standard dosing guidelines. After monotherapy was achieved, patients continued in the study for a 24-week Maintenance Phase. Results. More lamotrigine patients (65%) than conventional therapy patients (57%) completed the 24-week Maintenance Phase (primary efficacy endpoint). The mean time to withdrawal from the study was 175 days (SD=83.1) for lamotrigine patients compared with 156 days (SD=80.7) for conventional therapy patients. Adverse events, the most common reason for discontinuing the Maintenance Phase, accounted for 16% of withdrawals among lamotrigine patients compared with 26% of withdrawals among conventional therapy patients. The mean reduction in seizure frequency was 53% (SD=55.1) for patients using lamotrigine compared with 32% (SD=149.9) for patients using conventional therapy. Humanistic measures including investigator global assessment, the patient self-assessment, and QOLIE-31 scores show that lamotrigine monotherapy was perceived by both physicians and patients to have benefits over monotherapy with conventional antiepileptic drugs. Conclusions. Converting from monotherapy with a less effective or poorly tolerated conventional antiepileptic drug to monotherapy with lamotrigine is associated with better clinical and humanistic outcomes than converting to an alternative conventional antiepileptic drug.

Treatment of type 2 diabetes with a combination regimen of repaglinide plus pioglitazone

The efficacy and safety of combination therapy (repaglinide plus pioglitazone) was compared to repaglinide or pioglitazone in 24-week treatment of type 2 diabetes. This randomized, multicenter, open-label, parallel-group study enrolled 246 adults (age 24–85) who had shown inadequate response in previous sulfonylurea or metformin monotherapy (HbA 1c > 7%). Prior therapy was withdrawn for 2 weeks, followed by randomization to repaglinide, pioglitazone, or repaglinide/pioglitazone. In the first 12 weeks of treatment, repaglinide doses were optimized, followed by 12 weeks of maintenance therapy. Pioglitazone dosage was fixed at 30 mg per day. Baseline HbA 1c values were comparable (9.0% for repaglinide, 9.1% for pioglitazone, 9.3% for combination). Mean changes in HbA 1c values at the end of treatment were −1.76% for repaglinide/pioglitazone, −0.18% for repaglinide, +0.32% for pioglitazone. Fasting plasma glucose reductions were −82 mg/dl for combination therapy, −34 mg/dl for repaglinide, −18 mg/dl for pioglitazone. Minor hypoglycemia occurred in 5% of patients for the combination, 8% for repaglinide, and 3% for pioglitazone. Weight gains for combination therapy were correlated to individual HbA 1c reductions. In summary, for patients who had previously failed oral antidiabetic monotherapy, the combination repaglinide/pioglitazone had acceptable safety, with greater reductions of glycemic parameters than therapy using either agent alone.

Limitations of monotherapy trials in epilepsy.

Monotherapy is considered optimal management for most patients with epilepsy, but designing monotherapy trials in epilepsy has proved to be a complex endeavor. Consideration of the validity of evidence for efficacy, potential risks to patients, clinical applicability of results, and effects of dosing and titration rates on efficacy and tolerability creates unique challenges. This article reviews pertinent aspects of trials of conversion to monotherapy in refractory patients and equivalence trials in newly diagnosed patients to better understand their limitations. Despite the inherent difficulties in designing monotherapy trials in epilepsy, previous monotherapy studies have provided important information for clinical management with new treatments.

Experience with COSOPT, the fixed combination of timolol and dorzolamide, gained in Swiss ophthalmologists' offices

In managing glaucoma through the lowering of intraocular pressure (IOP), beta-blockers (e.g. timolol) are commonly the drug of first choice, with other drugs added to control IOP such as carbonic anhydrase inhibitors (e.g. dorzolamide). The present survey was instigated to assess the COSOPT (fixed combination of topical timolol and topical dorzolamide) prescription behaviour of Swiss office-based ophthalmologists and to evaluate the IOP-lowering efficacy of COSOPT under real-life private practice conditions. A survey was conducted in Swiss ophthalmologist practices. Ophthalmologists were asked to report their experience with COSOPT therapy prescribed to patients with glaucoma or ocular hypertension. Parameters recorded were: patient demographics, IOP, reason for choosing COSOPT, continuation of COSOPT therapy after completion of the survey and, if stopped, reason for discontinuation, and spontaneously occurring side-effects. All entries were optional. Since the purpose of this survey was to obtain a realistic picture of daily practice in Swiss ophthalmologists' offices, no guidelines with regard to measurement of IOP, time between visits and actual treatment were given. Data of 733 patients were included in this analysis. COSOPT as sole therapy was prescribed to 538 patients (74%), whereas 120 (16%) were put on a combination regimen of COSOPT + latanoprost. The remaining 75 patients (10%) received combinations of COSOPT with other ocular hypotensives. When assessing those patients put on COSOPT alone, IOP reduction in new, previously untreated patients was 10.8 mmHg (average), 5.4 mmHg (average) in upgrades from previous monotherapy and 2.7 mmHg after switch from free combination therapy. Patients treated with a combination of COSOPT + latanoprost showed an IOP reduction of 27 mmHg (new, previously untreated patients), 7.6 mmHg (upgrades from monotherapy) and 3.8 mmHg (switches from previous free combination regimen). Therapy was continued in 89% of all patients overall and in 91% of new patients treated with COSOPT alone (first line). 6.8% stopped therapy due to side-effects. COSOPT, the fixed combination of 0.5% timolol and 2% dorzolamide, is broadly prescribed to new, upgrade and switch patients in Switzerland. COSOPT therapy is well-tolerated and highly efficacious for patients requiring strong IOP lowering. Nine out ten patients stay on therapy after 1-2 months of treatment.

Experience with COSOPT, the fixed combination of timolol and dorzolamide, gained in Swiss ophthalmologists' offices

SUMMARYPurpose: In managing glaucoma through the lowering of intraocular pressure (IOP), beta-blockers (e.g. timolol) are commonly the drug of first choice, with other drugs added to control IOP such as carbonic anhydrase inhibitors (e.g. dorzolamide). The present survey was instigated to assess the COSOPT (fixed combination of topical timolol and topical dorzolamide) prescription behaviour of Swiss office-based ophthalmologists and to evaluate the IOP-lowering efficacy of COSOPT under real-life private practice conditions.Methods: A survey was conducted in Swiss ophthalmologist practices. Ophthalmologists were asked to report their experience with COSOPT therapy prescribed to patients with glaucoma or ocular hypertension. Parameters recorded were: patient demographics, IOP, reason for choosing COSOPT, continuation of COSOPT therapy after completion of the survey and, if stopped, reason for discontinuation, and spontaneously occurring side-effects. All entries were optional. Since the purpose of this survey was to obtain a realistic picture of daily practice in Swiss ophthalmologists' offices, no guidelines with regard to measurement of IOP, time between visits and actual treatment were given.Results: Data of 733 patients were included in this analysis. COSOPT as sole therapy was prescribed to 538 patients (74%), whereas 120 (16%) were put on a combination regimen of COSOPT + latanoprost. The remaining 75 patients (10%) received combinations of COSOPT with other ocular hypotensives. When assessing those patients put on COSOPT alone, IOP reduction in new, previously untreated patients was 10.8mmHg (average), 5.4mmHg (average) in upgrades from previous monotherapy and 2.7mmHg after switch from free combination therapy. Patients treated with a combination of COSOPT + latanoprost showed an IOP reduction of 27mmHg (new, previously untreated patients), 7.6mmHg (upgrades from monotherapy) and 3.8mmHg (switches from previous free combination regimen). Therapy was continued in 89% of all patients overall and in 91% of new patients treated with COSOPT alone (first line). 6.8% stopped therapy due to side-effects.Conclusions: COSOPT, the fixed combination of 0.5% timolol and 2% dorzolamide, is broadly prescribed to new, upgrade and switch patients in Switzerland. COSOPT therapy is well-tolerated and highly efficacious for patients requiring strong IOP lowering. Nine out ten patients stay on therapy after 1-2 months of treatment.

Mycophenolate mofetil in combination with recombinant interferon alfa-2a in interferon-nonresponder patients with chronic hepatitis C

Background/Aims: Since ribavirin was able to improve the antiviral efficacy of interferon alfa in patients with chronic hepatitis C, several other adjuncts have been studied. It has been shown that mycophenolate mofetil (MMF) is a more potent inhibitor of the inosine 5′-monophosphate-dehydrogenase (IMPDH) than ribavirin. The present study is a pilot study evaluating the efficacy and safety of combination therapy with interferon alfa-2a and MMF in interferon alfa nonresponder patients. Methods: Thirty-eight adult patients with chronic hepatitis C who did not respond to a previous interferon alfa monotherapy were enrolled to receive 6 million units of interferon alfa-2a tiw in combination with MMF (1 week 500 mg/day, 1 week 1000 mg/day, 22 weeks 2000 mg/day). Results: An interim analysis of 29 patients after 12 weeks of therapy showed that only one patient had negative hepatitis C virus-RNA at this time point. There was no significant reduction of the viral load during therapy. Due to inefficacy the study was discontinued. Conclusions: Combination therapy of interferon alfa-2a and MMF is ineffective in improving virological response rates in nonresponder patients with chronic hepatitis C. These data suggest that inhibition of the IMPDH seems not to be the major mechanism of ribavirin in enhancing the antiviral effect of interferon alfa in chronic hepatitis C.

A phase I and pharmacokinetic study of capecitabine in combination with epirubicin and cisplatin in patients with inoperable oesophago-gastric adenocarcinoma

BackgroundThe purpose of this study was to evaluate the dose-limiting toxicity (DLT) and maximum tolerated dose of capecitabine when used in combination with epirubicin and cisplatin (ECC) in patients with oesophageal or gastric adenocarcinoma. Response rate, progression-free survival (PFS) and overall survival were also determined, and the effect of previous oesophago-gastric surgery or concurrent oesophago-gastric cancer on the absorption and metabolism of capecitabine was evaluated. Patients and methodsPatients with inoperable oesophago-gastric adenocarcinoma received up to six cycles of epirubicin (50 mg/m2 i.v., 3-weekly), cisplatin (60 mg/m2 i.v., 3-weekly) and capecitabine, the latter administered orally in an intermittent schedule (14 days treatment; 7-day rest period) at 3-weekly intervals. Patients were recruited into one of four escalating dose cohorts (500, 825, 1000 and 1250 mg/m2 bd). Dose escalation occurred after six patients had completed at least one cycle of chemotherapy at the previous dose level, with DLT assessed on the toxicity of the first cycle only. Blood sampling for pharmacokinetic analyses was performed over the first 10 h of day 1 of cycle 1. ResultsThirty-two patients, median age 63 years (range 32–76 years), ECOG performance status ≤2 with locally advanced (10) or metastatic (22) disease were recruited and were evaluable for toxicity. Two of five patients experienced DLT at 1250 mg/m2 bd with grade II stomatitis (one patient) and grade III diarrhoea with febrile neutropenia (one patient). Cumulative toxicity for all cycles (n = 140) (worst grade per patient) includes grade IV oesophagitis (one patient), grade III diarrhoea (five), grade IV neutropenia with infection (seven), grade II stomatitis (four) and grade IV thrombocytopenia (one). Of 29 patients with evaluable disease, there was one complete response and six partial responses {24% response rate [95% confidence interval (CI) 10% to 44%]}, a median PFS of 22 weeks (95% CI 17–27 weeks) and median overall survival of 34 weeks (95% CI 19–49 weeks). Capecitabine was rapidly absorbed after oral administration, with a tmax of 1–2 h for capecitabine, DFCR (5′-deoxy-5-fluorocytidine) and DFUR (5′-deoxy-5-fluorouridine). The Cmax and AUC0–∞ for capecitabine, DFCR and DFUR were similar to those observed in previous monotherapy studies of capecitabine taken after food. ConclusionA dose of 1000 mg/m2 bd of capecitabine is recommended for use on an intermittent schedule in combination with these doses and schedule of epirubicin and cisplatin. This regimen is tolerable and active in oesophago-gastric adenocarcinoma. A randomised phase III comparison with ECF is justified.

Response of Severe HIV-Associated Thrombocytopenia to Highly Active Antiretroviral Therapy Including Protease Inhibitors

Objective: To investigate the response of HIV-associated severe thrombocytopenia (STP) to highly active antiretroviral therapy (HAART) including protease-inhibitors.Methods: In this retrospective study, 15 patients with HIV-associated STP (platelet count < 50×109/l), mostly antiretroviral experienced (13/15), underwent HAART for at least 6 months (median 21; range 6–41 months) during which the platelet (PLT) count and plasmatic HIV-RNA were monitored. The PLT response was compared to that observed in 19 patients previously treated with zidovudine (AZT) monotherapy.Results: HAART induced a significant increase in the PLT count (χ2=10.53,P =0.01) within the third month which was sustained up to the sixth month of therapy. No STP relapse was observed among eight PLT responders followed for longer than 6 months (median 27; range 7–41 months). The PLT increase after HAART was similar to that observed with AZT monotherapy, but a greater number of HAART patients were antiretroviral-experienced. HAART determined a PLT response in 10/13 subjects whose thrombocytopenia had not improved after previous AZT monotherapy. After 6 months of HAART, a complete platelet response occurred more frequently in patients with undetectable plasma HIV-RNA levels (P=0.01).Conclusions: HAART induces a sustained PLT response in HIV-associated STP, even in antiretroviral-experiencedsubjects and in those with AZT-resistant thrombocytopenia. An undetectable plasma HIV viraemia induced by HAART is necessary for STP recovery.

High dose interferon induction therapy does not improve response to combination therapy in relapsers and nonresponders to previous interferon monotherapy

High dose interferon induction therapy does not improve response to combination therapy in relapsers and nonresponders to previous interferon monotherapy

High dose interferon induction therapy does not improve response to combination therapy in relapsers and nonresponders to previous interferon monotherapy

High dose interferon induction therapy does not improve response to combination therapy in relapsers and nonresponders to previous interferon monotherapy

Pilot study of interferon-alpha high-dose induction therapy in combination with ribavirin plus amantadine for nonresponder patients with chronic hepatitis C.

Ribavirin plus interferon-alpha (IFN alpha) combination has led to a marked advance in the treatment of IFN alpha-naive or relapser patients with chronic hepatitis C but was shown to be only marginally effective in IFN alpha-nonresponders. We therefore conducted a pilot study to see whether an intensified treatment protocol might be more effective in inducing a virological response in patients who had not responded virologically to previous IFN alpha monotherapy. 14 nonresponder patients with histologically proven chronic hepatitis C were included in the study. Patients received 9 MU IFN alpha-2a daily for one week followed by 9 MU IFN alpha every second day for further 5 weeks. With the beginning of the seventh week, patients were treated with 6 MU IFN alpha thrice in week (tiw) for a period of 6 weeks (until week 12). IFN alpha was continued up to 48 weeks at a dose of 3 MU IFN alpha tiw. Ribavirin (1000-1200 mg/day) and amantadine sulphate (200 mg/day) was given orally for 48 weeks. One patient discontinued therapy after first IFN alpha injection and one other patient after 12 weeks of therapy because of side effects. The remaining 12 patients completed treatment according to the protocol. An initial virological response at week 24 was achieved in 2 of the 14 patients (14%) and both patients remained HCV RNA negative at the end of treatment. However, both patients relapsed 4 weeks after completion of therapy, and therefore none of the patients achieved a virological sustained response. Viral dynamics studies showed a marked decline in hepatitis C viremia during the first 6 weeks of high-dose IFN alpha. After IFN alpha dose reduction, however, viremia stabilized or increased in most patients. These data indicate, that even triple therapy with high-dose IFN alpha plus ribavirin and amantadine fails to improve significantly the response rates in IFN alpha-nonresponders.

A randomized, double-blind controlled trial of interferon alpha-2b and ribavirin vs. interferon alpha-2b and amantadine for treatment of chronic hepatitis C non-responder to interferon monotherapy

Background/Aims : Interferon-based regimens (alone or with ribavairin) are standard therapies for chronic hepatitis C. The aim of this study was to compare a 24-week regimen of interferon alpha-2b+ribavirin (IFN+RIBA) to interferon alpha-2b+amantadine (IFN+AMANT) in non-responders to previous interferon monotherapy. Methods : In a multi-center, double-blind clinical trial, 118 patients (non-responders to previous interferon monotherapy) were equally randomized into the two arms: interferon alpha-2b (3 MU thrice weekly) and ribavirin (800 mg daily) vs. interferon alpha-2b (3 MU thrice weekly) and amantadine (200 mg daily). Results : After 24 weeks of therapy, HCV RNA became undetectable in 34.8% (95% CI: 23.7–49.2) of IFN+RIBA and 19.6% (95% CI: 10.6–34.7) of IFN+AMANT ( P =0.10). This response was sustained in 3.9% (95% CI: 1.0–14.9) of IFN+RIBA and 0% of IFN+AMANT ( P =0.16). Ten patients from IFN+AMANT (17%) and 12 patients (20%) from IFN+RIBA were discontinued before completion of therapy. Of these, 7% in IFN+AMANT and 12% in IFN+RIBA were discontinued due to adverse effects. Conclusions : Re-treatment of interferon non-responders with a 24-week course of IFN+AMANT was not associated with any sustained viral eradication. Although IFN+RIBA in this group was associated with a reasonable end of treatment response, relapses were common and sustained responses were low.

Interferon Alfacon-1 for the treatment of HCV genotype 1 non responder to previous monotherapy in which ribavirin is contraindicated

Interferon Alfacon-1 for the treatment of HCV genotype 1 non responder to previous monotherapy in which ribavirin is contraindicated

Efficacy and Tolerability of a Combination Tablet of Candesartan Cilexetil and Hydrochlorothiazide in Insufficiently Controlled Primary Hypertension - Comparison with a Combination of Losartan and Hydrochlorothiazide

This randomized, double-blind study compared the antihypertensive effect, safety and tolerability of a candesartan cilexetil/hydrochlorothiazide (candesartan/HCT; 16/12.5 mg) combination tablet with that of a losartan/HCT (50/12.5 mg) combination tablet in patients with mild-to-moderate primary hypertension insufficiently controlled on previous monotherapy. Men and women, aged 20-80 years, with a sitting diastolic blood pressure (DBP) > or = 90 and < or = 110 mmHg and sitting systolic blood pressure (SBP) < or = 200 mmHg during treatment with any kind of antihypertensive monotherapy for at least 4 weeks were randomized to candesartan/HCT or losartan/HCT once daily for 12 weeks. All BP measurements were performed 24 h after previous dose. Mean values and standard deviations (SD) or confidence intervals (CI) are given. A total of 340 patients were enrolled, of whom 299 (144 women and 155 men, mean age 59.5 [10.5] years) were randomized to candesartan/HCT (n = 151) or losartan/HCT (n = 148). BPs at randomization were 159.5 (15.4)/98.4 (5.8)mmHg and 160.5 (16.1)/98.5 (5.4)mmHg, respectively. There was a greater reduction in BP with candesartan/HCT than with losartan/HCT: DBP -10.4 (-11.8; -8.9) vs -7.8 (-9.3; -6.3) mmHg, difference between treatments -2.6 (-4.7; -0.5) mmHg (p = 0.016); SBP -19.4 (-22.1; -16.7) vs - 13.7 (-16.5; - 10.9) mmHg, difference between treatments -5.7 (-9.6; -1.8) mmHg (p = 0.004). The proportion of patients achieving a DBP < or = 90 mmHg was greater in the candesartan/HCT group: 60.9 (53.1; 68.7) vs 49.3 (41.3; 57.4)% (p = 0.044). There were 12 withdrawals in the candesartan/HCT group, of which 8 were due to adverse events, and 17 and 12, respectively in the losartan/HCT group. We conclude that the combination of candesartan and HCT reduces BP effectively and is well tolerated. BP was normalized in 61% of these patients who had insufficient response to previous monotherapy. The reduction in BP and the proportion of patients with normalized BP were greater with the candesartan/HCT 16/12.5 mg combination than with the losartan/ HCT 50/12.5 mg combination.

Long-term celiprolol therapy lowers fasting plasma leptin levels. Celiprolol Multicenter Study Group.

The effects of celiprolol on fasting plasma leptin levels, glucose tolerance, and insulin sensitivity were studied in a randomized, investigator-masked, and parallel clinical trial. Modified oral glucose tolerance tests (OGTT) were performed during the previous antihypertensive monotherapy (beta- or Ca-blocker, or ACE inhibitor), and 6 and 12 months after randomization to celiprolol (200-400 mg daily) or to control group, where the therapy was kept unchanged. One hundred sixty-nine dyslipidemic and hypertensive nondiabetics with an age range of 42-65 years and an average body mass index of 28.4 kg/m2 completed the study according to the protocol. The mean circulating leptin level decreased from 7.5 to 6.6 ng/mL in men (p < 0.05) and from 23.0 to 19.7 ng/mL in women during the 12-month celiprolol treatment. The incremental glucose area under the curve (AUC) in the 2-hour OGTT decreased from 3.8 to 3.0 h* mmol/L (p < 0.01), and insulin AUC decreased from 134 to 99 h* mU/L (p < 0.01). The insulin sensitivity index increased by 22% (p < 0.01) and the serum triglyceride level decreased by 15% in the celiprolol group. Changes in serum cholesterol were clinically insignificant. In the control group, no significant change was seen in any measured variable. A decrease in leptin levels in the celiprolol group was associated with improved insulin sensitivity, while the weight of the moderately obese patients did not change. The clinical significance of a 14% decrease in fasting plasma leptin level remains to be elucidated. The results suggest amelioration of leptin resistance during long-term celiprolol therapy.

Open-label dosage and tolerability study of tiagabine monotherapy in patients with refractory complex partial seizures

This study was designed to determine the highest tiagabine dosage that could be administered as monotherapy to patients with complex partial seizures refractory to treatment with other antiepileptic drugs (AEDs) without unacceptable adverse events. Thirty-one patients, 18–47 years of age, participated at three sites. During a 3-week initiation phase, tiagabine was started and the dosage increased while concomitant AED dosage was reduced. During a 7-week dose-evaluation phase, dosage was adjusted until the maximum tolerated dosage was reached. During the dose termination phase, patients tolerating the drug entered a long-term open-label study of tiagabine monotherapy. Of 31 patients, 19 converted to monotherapy; in 12 cases, monotherapy was tolerated well enough to be continued for 7 weeks. Of the 12 nonconverters, seven left during the initiation phase due to adverse events and five due to inadequate seizure control. Most events were mildly or moderately severe and were associated with the central nervous system. Plasma tiagabine concentrations were similar in both converters and nonconverters. Conversion to tiagabine monotherapy was accomplished in most patients with difficult-to-control seizures when previous AED monotherapy was replaced in under 4 weeks. The ideal dosage appeared to be approximately 38 mg/day given in three divided doses.

Evaluation of efficacy and safety of thymus humoral factor-gamma 2 in the management of chronic hepatitis B

Background/Aims: We investigated the antiviral and immunomodulatory effects of a combination of treatment using thymus humoral factor-gamma 2 and alpha-interferon in patients with chronic hepatitis B in whom previous monotherapy with interferon had failed. Methods: Nine HBeAg and HBV-DNA seropositive patients removed thymus humoral factor-gamma 2 alone for 2 months, thymus humoral factor-gamma 2 plus alpha-interferon for 2 months and finally alpha-interferon alone for 2 months. Results: Treatment with thymus humoral factor-gamma 2 alone was not associated with any side effects. The interferon-induced lymphopenia was significantly less marked during the combined therapy in comparison to the previous course with interferon alone (mean reduction of lymphocyte counts 33.5±11.6% versus 56.3±16.7%, respectively, p<0.05). The combination of thymus humoral factor-gamma 2 plus interferon showed a significantly more profound inhibition of serum HBV-DNA (mean reduction from the pretreatment level 90.6±13.3%) compared to the earlier monotherapy with interferon in the same patients (mean reduction 55.5±34.7%, p<0.01). As a result of the combined thymus humoral factor-gamma 2 plus alpha-interferon regimen three out of nine patients became HBV-DNA negative and seroconverted to anti-HBe. Thymus humoral factor-gamma 2 appears to exert mainly a functional effect on T lymphocytes, as interleukin-2 production was increased in the majority of treated patients, whilst the expression of lymphocyte activation markers remained unchanged. Conclusions: These data suggest that thymus humoral factor-gamma 2 may be useful in a combined therapeutic approach in chronic HBV carriers.

Fluvastatin in severe hypercholesterolemia:Analysis of a clinical trial database

Many patients with severe primary hypercholesterolemia—lowdensity lipoprotein cholesterol (LDL-C) >240 mg/dL—have heterozygous familial hypercholesterolemia. In such familial hypercholesterolemic patients, the lipid-lowering efficacy of fluvastatin is related to genetic factors, and it is of interest whether the response to treatment differs from that in patients with more moderate hypercholesterolemia. Thus an exploratory analysis of randomized, controlled clinical trials and their open-label extensions (12–78 weeks), conducted worldwide with fluvastatin ≥20 mg/day (n = 1810) and placebo (n = 783), assessed whether, apart from the potential differences between familial hypercholesterolemic and nonfamilial hypercholesterolemic patients, the response to 40 mg of fluvastatin is influenced by baseline plasma lipid levels in relation to disease severity. Entry criteria included LDL-C ≥190 mg/dL with ≤1 risk factor and no coronary artery disease, or ≥160 mg/dL with >1 risk factor or definite coronary artery disease. Of these patients, 591 (33%) given fluvastatin (20–40 mg/day) and 187 (24%) given placebo had severe hypercholesterolemia with baseline LDL-C >240 mg/dL. In controlled studies, the mean ± SD duration of exposure was 21.1 ± 16.1 and 19.4 ± 15.5 weeks for fluvastatin and placebo, respectively, whereas longterm efficacy was assessed after 55.3 ± 21.7 weeks (fluvastatin) and 21.1 ± 12.3 weeks (fluvastatin + cholestyramine, after previous monotherapy). In summary, fluvastatin at 40 mg/day lowered LDL-C by 25–26% from baseline in controlled studies (n = 622), and by 27% in long-term studies (32–33% with fluvastatin + cholestyromine; n = 386), irrespective of severity of cholesterolemia. High density lipoprotein cholesterol (HDL-C) and triglyceride responses were enhanced, when at baseline HDL-C levels were low and triglycerides raised, irrespective of baseline cholesterolemia, whereas the LDL-C response was unrelated to baseline in patients with LDL-C levels >240 mg/dL. In patients in the highest triglyceride tertile, fluvastatin plus cholestyramine apparently abolished the triglyceride increase expected with cholestyromine. This influence of baseline levels on fluvastatin response can be considered beneficial, as hypercholesterolemic patients with low HDL-C and high triglyceride levels are at particularly high cardiovascular risk.