Giora Davidai

Novel pharmacological targets for the treatment of Parkinson's disease

Dopamine deficiency, caused by the degeneration of nigrostriatal dopaminergic neurons, is the cause of the major clinical motor symptoms of Parkinsons disease. These symptoms can be treated successfully with a range of drugs that include levodopa, inhibitors of the enzymatic breakdown of levodopa and dopamine agonists delivered by oral, subcutaneous, transcutaneous, intravenous or intra-duodenal routes. However, Parkinsons disease involves degeneration of non-dopaminergic neurons and the treatment of the resulting predominantly non-motor features remains a challenge. This review describes the important recent advances that underlie the development of novel dopaminergic and non-dopaminergic drugs for Parkinsons disease, and also for the motor complications that arise from the use of existing therapies.

Telmisartan is more effective than losartan in reducing proteinuria in patients with diabetic nephropathy

In patients with diabetic nephropathy, lowering blood pressure and reducing proteinuria by over 30% correlates with a slower progression to kidney failure. We compared two different angiotensin receptor-blockers in a double blind, prospective trial of 860 patients with type 2 diabetes whose blood pressure levels was over 130/80 mmHg or who were receiving antihypertensive medication(s) and who had a morning spot urinary protein to creatinine ratio of 700 or more. Patients were randomized to telmisartan (a highly lipophilic agent with a long half-life) or losartan (with low lipophilicity and short half-life). The primary endpoint was the difference in the urinary albumin to creatinine ratio between the groups at 52 weeks. The geometric coefficient of variation and the mean of the urinary albumin to creatinine ratio fell in both groups at 52 weeks but both were significantly greater for the telmisartan compared to the losartan cohort. Mean systolic blood pressure reductions were not significantly different between groups at trial end. We conclude that telmisartan is superior to losartan in reducing proteinuria in hypertensive patients with diabetic nephropathy, despite a similar reduction in blood pressure.

Effects of the Angiotensin II Receptor Blockers Telmisartan vs Valsartan in Combination With Hydrochlorothiazide 25 mg Once Daily for the Treatment of Hypertension

To attain recent goals of blood pressure (BP) control, multiple drug therapy combinations are required, including higher doses of thiazide diuretics in combination with other classes of antihypertensive drug therapy. Thus, the authors evaluated the antihypertensive effects of telmisartan vs valsartan when combined with hydrochlorothiazide (HCTZ) 25 mg in a large (N=1066), placebo‐controlled trial in patients with stage 1 or 2 hypertension. The primary end points were the changes from baseline in seated diastolic and systolic BP at the end of the 8‐week treatment period. Safety end points included adverse events, changes in laboratory parameters, and pulse rate. Changes from baseline in BP following telmisartan‐HCTZ (−24.0/−17.6 mm Hg) were significantly greater than both placebo (−4.4/−6.8 mm Hg) and valsartan‐HCTZ (−21.2/−16.1 mm Hg) (vs placebo, P<.001 for systolic and diastolic BP; vs valsartan‐HCTZ, P=.004 for systolic BP and P=.019 for diastolic BP). The total number of patients with at least 1 adverse event reported were similar among the 3 treatment groups (placebo, 49%; telmisartan‐HCTZ, 43%; and valsartan‐HCTZ, 38%). In conclusion, telmisartan‐HCTZ at doses of 80/25 mg lowered both systolic and diastolic BP to a greater extent than valsartan‐HCTZ at doses of 160/25 mg. These data support using a higher dose of a thiazide diuretic (25 mg) with a long‐acting angiotensin receptor blocker as a useful strategy for improving hypertension control.

Ambulatory blood pressure monitoring in the primary care setting: assessment of therapy on the circadian variation of blood pressure from the MICCAT-2 Trial.

BackgroundWe conducted a large-scale, practice-based trial (MICCAT-2) to evaluate the effects of telmisartan alone and in combination with a diuretic on 24-h blood pressure (BP) profiles, including the early morning period, a time when cardiovascular risk is excessive. MethodsPatients with hypertension, either untreated or currently on treatment, were started on, or switched to, the angiotensin receptor blocker telmisartan 40 mg daily; after 2 weeks, if office blood pressure (BP) remained ≥140/85 mmHg, the dose was increased to 80 mg; and if necessary, hydrochlorothiazide 12.5 mg was added after a further 4 weeks and continued for a final 4-week period. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) was performed at baseline and at the end of the treatment period. Baseline and treatment ABPM measurements were completed in 1619 patients. ResultsThere were highly significant reductions in both the daytime (−11.8/−7.2 mmHg) and night-time (−9.6/−5.7 mmHg) mean BP following telmisartan alone or in combination with the diuretic. Evaluation of the 24-h profiles showed evidence for sustained pharmacodynamic effects of telmisartan over the entire dosing period. Ninety-five (6%) patients had a marked surge in early morning BP defined as >30 mmHg post-awakening change in systolic BP. The average reduction of in the early morning (post-awakening) BP in the entire cohort was −11.5/−7.0 mmHg (P<0.001; reductions were similar for monotherapy and combination therapy groups. The early morning post-awakening BPs fell by an average of −17.2/−10.1 mmHg in patients with large morning BP surges (P<0.05 versus non-surge patients). ConclusionsIn a community based study using ambulatory BP monitoring, telmisartan-based therapy induced highly significant reductions in systolic and diastolic BP over 24 h and was particularly effective in reducing BP during the early morning period.

The effect of telmisartan and ramipril on early morning blood pressure surge: a pooled analysis of two randomized clinical trials

ObjectivesThe period of early morning blood pressure surge is associated with a higher incidence of cardiovascular events than at other times of the day. Antihypertensive medication given once daily in the morning may not protect against this surge if its duration of action is too short. We compared telmisartan, an angiotensin II receptor blocker with a trough-to-peak ratio >90%, with ramipril, an angiotensin-converting enzyme inhibitor with a trough-to-peak ratio of around 50%. MethodsData from two prospective, randomized, open-label, blinded endpoint studies comparing telmisartan force titrated to 80 mg once daily and ramipril 10 mg once daily were pooled. Patients had mild-to-moderate hypertension and were assessed using 24-h ambulatory blood pressure monitoring at baseline and endpoint. Early morning blood pressure surge was defined as the difference between mean blood pressure within 2 h after arising and night-time low. Patients were grouped into quartiles according to their baseline systolic surge. ResultsData from 1279 patients were analyzed. Telmisartan changed the overall mean (SE) systolic surge by −1.5 (0.47) mmHg, and ramipril by +0.3 (0.47) mmHg (P=0.0049). The magnitude of surge reduction was greatest in the quartile with highest baseline systolic surge: telmisartan −12.7 (0.91), ramipril −7.8 (1.02) mmHg (P=0.0004). Telmisartan also reduced the surge compared with ramipril in dippers, but there were no differences between the two groups in nondippers. ConclusionsTelmisartan significantly reduced the early morning systolic blood pressure surge compared with ramipril. A reduction in this surge may help to reduce cardiovascular events in the morning period.

Effects of the angiotensin II receptor blockers telmisartan versus valsartan in combination with hydrochlorothiazide: a large, confirmatory trial

In 2004–2005, the antihypertensive effects of telmisartan 80 mg versus valsartan 160 mg combined with hydrochlorothiazide 25 mg were assessed in a large placebo-controlled trial in patients with stages 1 and 2 hypertension and demonstrated that both agents were highly effective in lowering blood pressure (BP) compared with placebo and that telmisartan lowered BP significantly greater than valsartan. To confirm this finding according to Food and Drug Administration guidelines, we performed a second large trial using the same design in an entirely separate patient population. The trial was double-blind with a 4 : 4 : 1 randomization scheme to compare once daily telmisartan 80 mg plus hydrochlorothiazide 25 mg versus once daily valsartan 160 mg plus hydrochlorothiazide 25 mg versus once daily placebo on reductions in seated clinic BP in patients with stages 1 and 2 hypertension. The primary endpoints were the changes from baseline in seated diastolic and systolic BP at the end of the 8-week treatment period. Safety endpoints included adverse events, changes in laboratory parameters and pulse rate. In total, 1185 patients were randomized (of which 1181 were treated and included in the primary analysis: 528 in the telmisartan-hydrochlorothiazide group, 523 in the valsartan-hydrochlorothiazide group, and 130 in the placebo group), changes from baseline in BP following telmisartan-hydrochlorothiazide (−24.6/−18.2 mmHg) were significantly greater than both placebo (−4.1/−6.1 mmHg) and valsartan-hydrochlorthiazide (−22.5/−17.0 mmHg) (versus placebo, P<0.0001 for systolic and diastolic BP; versus valsartan-hydrochlorothiazide, P=0.017 for systolic BP and P=0.025 for diastolic BP). The total number of patients with at least one adverse event reported was similar among the three treatment groups (placebo, 42%, telmisartan-hydrochlorothiazide, 36%, and valsartan-hydrochlorothiazide, 37%). Thus, this large, second trial confirms that telmisartan-hydrochlorothiazide at doses of 80/25 mg lowered both systolic and diastolic BP to a greater extent than valsartan-hydrochlorothiazide at doses of 160/25 mg in stages 1–2 hypertension. Although these are not the highest doses of these agents at present, at the time that the studies were conducted, they were the maximally approved dosages. Both studies support the strategy of using angiotensin receptor blockers with a higher dose of a thazide diuretic (25 mg) for enhancing the control of hypertension.

Quality of Life Measured in a Practice-Based Hypertension Trial of an Angiotensin Receptor Blocker

Effectiveness of antihypertensive treatment depends not only on drugs that avoid or minimize symptomatic side effects but also on therapy that has a positive effect on quality of life. This study assessed the effect on quality of life of a contemporary agent (an angiotensin receptor blocker) and evaluated the validity and practicality of using a quality‐of‐life instrument in the practice‐based setting. A total of 2716 hypertensive patients, either untreated or on single‐agent therapy, were started on or switched to 40 mg telmisartan for 6 weeks; in patients whose blood pressures remained above 130/85 mm Hg after 2 weeks, the dose was increased to 80 mg for the remaining 4 weeks of treatment. Quality of life was measured by patient self‐administration of the Psychological General Well‐Being Index (GWBI) at baseline and at the end of the study. Sixty‐eight percent (n=1858) of patients treated with telmisartan fully completed both GWBI tests; the test score increased by 5.2±0.3 (p<0.0001) from 77.7±0.4. This improvement was observed across all six emotional and health subscales of the GWBI. White and black patients, those aged <65 or >65 years, and men and women had similar increases, though the baseline value in women was sharply lower (p<0.001) than in men. The GWBI rose more in patients whose blood pressure was controlled by treatment (<140/90 mm Hg) than in noncontrolled patients (6.1 vs. 4.1, p<0.0001); for all patients the decreases in systolic and diastolic blood pressures produced by telmisartan correlated significantly (p<0.001 for each) with the increases in the GWBI scores. Controlling blood pressure appears to be an important element in improving subjective health perceptions of hypertensive patients.

Comparative antihypertensive efficacy of angiotensin receptor blocker-based treatment in African-American and white patients.

Blood pressure (BP) reuctions with agents that block the renin‐angiotensin system are regarded as less effective as monotherapy in African Americans than other ethnic groups. This practice‐based study compares the efficacy of an angiotensin receptor blocker‐based regimen in African‐American and Caucasian patients. Included in the 10‐week study were 173 African‐American and 1296 Caucasian patients. Efficacy was based on differences in 24‐hour ambulatory BP. After baseline ambulatory BP monitoring and office BPs were obtained, all patients were started or switched to the angiotensin receptor blocker telmisartan, 40–80 mg daily, plus hydro‐chlorothiazide 12.5 mg daily (if needed for office BP control: <140/90 mm Hg). More African Americans required the addition of a low‐dose thiazide diuretic than Caucasians (47.3% vs. 34.9%; p=0.021). Once patients with white coat hypertension were excluded (i.e., those with baseline ambulatory BP monitoring <130/80 mm Hg), ambulatory BP monitoring changes were similar between groups. A greater proportion of African Americans than Caucasians without white coat hypertension also needed combination therapy (52.1% vs. 39.5%; p=0.04). While achievement of BP goal was similar between groups by office criterion (<140/90 mm Hg), differences were noted by ambulatory BP monitoring (<130/80 mm Hg) (48.0% in African American vs. 63.2% in Caucasians; p=0.01) despite the same BP reductions, reflecting higher baseline values in African Americans. We conclude that an angiotensin receptor blocker as part of a BP‐lower‐ing strategy is effective in previously untreated African‐American patients, although a higher proportion will require the use of a diuretic compared with Caucasians.

Safety, Efficacy, and Pharmacokinetics of Telmisartan in Pediatric Patients With Hypertension

Objective. To assess the safety, pharmacokinetics (PKs), and blood pressure (BP)-lowering efficacy of telmisartan in pediatric (6 to <18 years) patients with hypertension. Study design. Patients with diagnosed hypertension were randomized to 4 weeks of treatment with placebo, or with 1 of 2 nominal telmisartan dose levels (1 mg/kg/d or 2 mg/kg/d). The primary end point was change in seated systolic BP (SBP) from baseline to study end. Results. A total of 77 patients were randomized and received at least 1 dose of study medication (placebo, n = 16; low-dose telmisartan, n = 30; high-dose telmisartan, n = 31). Adjusted mean changes (standard errors) in SBP from baseline to study end were −6 (2.4), −14 (1.7), and −9.7 (1.7) mm Hg, respectively, in the placebo, high-dose telmisartan, and low-dose telmisartan groups. Conclusions. Telmisartan may be an appropriate therapy for treatment of pediatric hypertension, although more extensive studies are required in patients younger than age 12.

Impact of angiotensin receptor blockade in combination with hydrochlorothiazide 25 mg in 2121 patients with stage 1–2 hypertension

The antihypertensive effects of telmisartan 80 mg versus valsartan 160 mg, both combined with hydrochlorothiazide (HCTZ) 25 mg, were assessed in a pooled analysis from two large trials with identical study designs in patients with stage 1–2 hypertension. The trials were double-blind with a 4:4:1 randomization scheme to compare once-daily telmisartan 80 mg and HCTZ 25 mg versus once-daily valsartan 160 mg and HCTZ 25 mg versus once-daily placebo on reductions in clinic blood pressure (BP). The primary end point was changes from baseline in BP at the end of 8 weeks. In total, 2121 patients were randomized (telmisartan–HCTZ, 942, valsartan–HCTZ, 952, and placebo, 227) and had baseline seated BPs of 154/102 and 155/102 mm Hg in the two studies, respectively. Changes from baseline in BP after administration of telmisartan–HCTZ (−24.5/−18.0 mm Hg) were significantly greater than for both placebo (−4.1/−6.5 mm Hg) and valsartan–HCTZ (−22.3/−16.8 mm Hg) (versus placebo, P<0.0001 for systolic and diastolic BP; versus valsartan–HCTZ, P=0.0004 for systolic BP and P=0.0019 for diastolic BP). Adverse event rates were higher in the placebo group than in the active treatment groups (placebo, 41%, telmisartan–HCTZ, 30%, and valsartan–HCTZ, 30%, P<0.05). These data confirm that telmisartan–HCTZ at doses of 80/25 mg lowered systolic and diastolic BP to a greater extent than valsartan–HCTZ at doses of 160/25 mg in stage 1–2 hypertension. The magnitude of the BP-lowering effect provides support for the use of angiotensin receptor blockers with higher doses of a thiazide diuretic (25 mg) to improve hypertension control.