Purpose: To assess safety, pharmacokinetics, maximum tolerated dose, and preliminary efficacy of bivatuzumab mertansine. Bivatuzumab is a humanized monoclonal antibody directed against CD44v6, which previously seemed to be safe in phase I radioimmunotherapy trials, whereas the conjugated mertansine is a potent maytansine derivative. Experimental Design: Patients with incurable squamous cell carcinoma of the head and neck or esophagus were eligible. Bivatuzumab was given weekly for 3 consecutive weeks by i.v. infusion. One patient was planned to be treated at each dose tier as long as toxicity did not reach grade 2; otherwise, three patients had to be treated until dose-limiting toxicity occurred. Starting dose was 20 mg/m 2 and dose was subsequently escalated in steps of 20 mg/m 2 . Patients without diseaseprogression and not experiencing dose-limiting toxicity were eligible for repeated courses. Blood serum samples were taken throughout the treatment period to determine the pharmacokinetic properties of bivatuzumab mertansine and to assess the human anti^bivatuzumab mertansine antibody response. Results: Seven patients received a total of 23 weekly doses of bivatuzumab mertansine. One patient at the 100 mg/m 2 and one at the 120 mg/m 2 level experienced stable disease during treatment phase but also developed grade 1skin toxicity (desquamation). One of them received a second treatment course. At the highest dose level achieved in this study (140 mg/m 2 ), one patient developed toxic epidermal necrolysis after two infusions and died. Massive apoptosis of skin keratinocytes had occurred, whereas only symptomatic therapy for skin toxicity was available. The riskbenefit assessment of all patients treated in the total phase I program (4 clinical trials, 70 patients) turned out to be negative after consideration of this case of a toxic epidermal necrolysis and the skin-related adverse events observed in the other trials.Therefore, development of the conjugate was discontinued. Interindividual variability in pharmacokinetic variables was low and exposure to BIWI 1 increased proportionally with dose. No anti^bivatuzumab mertansine reactions were observed. Conclusion: The main toxicity of bivatuzumab mertansine was directed against the skin, most probably due to CD44v6 expression in this tissue. The majority of skin reactions was reversible; however, one fatal drug-related adverse event had occurred. Clinical development was discontinued before reaching maximum tolerated dose.

An 8-week, randomized, double-blind, controlled study with single-pill combinations of telmisartan 40 mg or 80 mg ⁄ amlodipine 5 mg (T40 ⁄ A5 or T80 ⁄ A5) vs monotherapy with amlodipine 5 mg or 10 mg (A10) in 1097 patients with uncontrolled hypertension (diastolic blood pressure [BP] !90 mm Hg). T40 ⁄ A5 and T80 ⁄ A5 resulted in significantly greater (P<.0001) reductions in seated trough systolic ⁄ diastolic BP vs A5 ()7.4 mm Hg ⁄ )3.6 mm Hg; )8.8 mm Hg ⁄ )4.9 mm Hg) and a significantly greater (P<.001) proportion of patients achieving systolic ⁄ diastolic BP goal rate (60.0% ⁄ 56.7%; 65.7% ⁄ 63.8%) vs A5 (39.2% ⁄ 42.0%). Superior BP reductions were also seen with T40-T80 ⁄ A5 vs A10, with BP goal rates at least as high as with A10; however, there was significantly more peripheral edema with A10 (27.2% vs 4.3% for pooled T40-T80 ⁄ A5; P<.0001). Switching patients with uncontrolled BP to a single-pill combination of T40 ⁄ A5 or T80 ⁄ A5 is a better treatment option than up-titration to full-dose monotherapy with A10. J Clin Hypertens (Greenwich). 2011;13:459-466. Ó2011 Wiley Periodicals, Inc.Current European and US guidelines emphasize the need for aggressive pharmacologic treatment of hypertension to reduce cardiovascular (CV) risk.1,2 Large clinical studies suggest that more than 50% of hypertensive patients receiving monotherapy with amlodipine 5 mg do not have their blood pressure (BP) controlled adequately, 3,4 and the 2007 guidelines from the European Society of Hypertension ⁄ European Society of Cardiology (ESH ⁄ ESC) emphasizes that the ability of any antihypertensive agent used alone to achieve target BP values (<140 ⁄ 90 mm Hg) does not exceed 20% to 30% of the overall hypertensive population except in patients with grade 1 hypertension.1 When initial monotherapy with an antihypertensive agent does not have the desired BP-lowering effect, the dose of the antihypertensive agent is often increased. Uptitrating amlodipine from 5 mg to 10 mg may improve BP response rates but typically also increases the incidence of side effects such as edema, which, in turn, may lead to reduced patient compliance and possibly to treatment discontinuation. To achieve the specified BP goals and to reduce the risk of CV morbidity and mortality, the majority of patients with hypertension will require !2 antihypertensive medications. 1,2Two drugs from different classes with complimentary mechanisms of action may result in additional BP decreases compared with either agent used alone.5 In a recent meta-analysis, Wald and colleagues 6 showed that the combination of drugs from two different antihypertensive drug classes was up to 5 times more effective in lowering BP than increasing the dose of one drug. Hypertensive patients whose BP is not controlled adequately by monotherapy amlodipine 5 mg may therefore benefit from combination therapy by adding an antihypertensive agent with a distinct and complementary mechanism of action. There are published data suggesting that the combination of a calcium channel blocker (CCB) with an ang...

Treatment with temozolomide was generally well tolerated, with occasionally moderate toxicity. As all patients developed progressive disease the results are rather discouraging. Temozolomide is ineffective for the treatment of patients with symptomatic progressive hormone-refractory prostate cancer.

In patients not achieving DBP goal with either A5 or A10 monotherapy, the vast majority achieved DBP goal with single-pill combinations of T40-T80/A5-A10. Long-term treatment was well tolerated with high compliance, promoting treatment adherence regardless of telmisartan/amlodipine dose. ClinicalTrials.gov identifiers: NCT00614380 (TEAMSTA-5 Follow-up) and NCT00624052 (TEAMSTA-10 Follow-up).