A Dose-Finding Study to Guide Use of Verapamil as an Adjunctive Therapy in Tuberculosis.

Induction of mycobacterial efflux pumps is a cause of Mycobacterium tuberculosis (Mtb) drug tolerance, a barrier to shortening antitubercular treatment. Verapamil inhibits Mtb efflux pumps that mediate tolerance to rifampin, a cornerstone of tuberculosis (TB) treatment. Verapamil's mycobacterial efflux pump inhibition also limits Mtb growth in macrophages in the absence of antibiotic treatment. These findings suggest that verapamil could be used as an adjunctive therapy for TB treatment shortening. However, verapamil is rapidly and substantially metabolized when co-administered with rifampin. We determined in a dose-escalation clinical trial of persons with pulmonary TB that rifampin-induced clearance of verapamil can be countered without toxicity by the administration of larger than usual doses of verapamil. An oral dosage of 360 mg sustained-release (SR) verapamil given every 12 hours concomitantly with rifampin achieved median verapamil exposures of 903.1 ng.h/mL (area under the curve (AUC)0-12 h ) in the 18 participants receiving this highest studied verapamil dose; these AUC findings are similar to those in persons receiving daily doses of 240 mg verapamil SR but not rifampin. Moreover, norverapamil:verapamil, R:S verapamil, and R:S norverapamil AUC ratios were all significantly greater than those of historical controls receiving SR verapamil in the absence of rifampin. Thus, rifampin administration favors the less-cardioactive verapamil metabolites and enantiomers that retain similar Mtb efflux inhibitory activity to verapamil, increasing overall benefit. Finally, rifampin exposures were 50% greater after verapamil administration, which may also be advantageous. Our findings suggest that a higher dosage of verapamil can be safely used as adjunctive treatment in rifampin-containing treatment regimens.

A dose-finding study to guide use of verapamil as an adjunctive therapy in tuberculosis.

Induction of mycobacterial efflux pumps is a cause of Mycobacterium tuberculosis (Mtb) drug tolerance, a barrier to shortening antitubercular treatment. Verapamil inhibits Mtb efflux pumps that mediate tolerance to rifampin, a cornerstone of tuberculosis treatment. Verapamil's mycobacterial efflux pump inhibition also limits Mtb growth in macrophages in the absence of antibiotic treatment. These findings suggest that verapamil could be used as an adjunctive therapy for TB treatment shortening. However, verapamil is rapidly and substantially metabolized when co-administered with rifampin. We determined in a dose-escalation clinical trial that rifampin-induced clearance of verapamil can be countered without toxicity by the administration of larger than usual doses of verapamil. An oral dosage of 360 mg sustained-release (SR) verapamil given every 12 hours concomitantly with rifampin achieved median verapamil exposures of 903.1 ng.h/ml (AUC 0-12h), similar to those in persons receiving daily doses of 240 mg verapamil SR but not rifampin. Norverapamil:verapamil, R:S verapamil and R:S norverapamil AUC ratios were all significantly greater than those of historical controls receiving SR verapamil in the absence of rifampin, suggesting that rifampin administration favors the less-cardioactive verapamil metabolites and enantiomers. Finally, rifampin exposures were significantly greater after verapamil administration. Our findings suggest that a higher dosage of verapamil can be safely used as adjunctive treatment in rifampin-containing treatment regimens.

Stability indicating RP-HPLC method for simultaneous determination of amlodipine and benazepril hydrochloride from their combination drug product.

A stability indicating reversed-phase HPLC method has been developed and subsequently validated for simultaneous estimation of amlodipine (AM) present as amlodipine besylate (AB), and benazepril hydrochloride (BH) from their combination product. The proposed RP-HPLC method utilizes a Zorbax SB C18, 5 microm, 250 mm x 4.6 mm i.d. column, mobile phase consisting of phosphate buffer and acetonitrile in the proportion of 65:35 (v/v) with apparent pH adjusted to 7.0, and UV detection at 240 nm using a photodiode array detector. AB, BH, and their combination drug product were exposed to thermal, photolytic, hydrolytic, and oxidative stress conditions, and the stressed samples were analysed by the proposed method. Peak homogeneity data of AM and BH peaks obtained using photodiode array detector, in the stressed sample chromatograms, demonstrated the specificity of the method for their estimation in presence of degradants. The described method was linear over a range of 6-14 microg/ml for AM and 12-28 microg/ml for BH. The mean recoveries were 99.91 and 100.53% for AM and BH, respectively. F-test and t-test at 95% confidence level were used to check the intermediate precision data obtained under different experimental setups; the calculated value was found to be less than critical value.

Comparative bioavailability of two hydrofluoroalkane formulations of formoterol fumarate both delivered by pressurised metered dose inhaler.

A randomised, open-label, single dose, four-period crossover study was performed in healthy male human subjects to compare the pharmacokinetics of formoterol fumarate (CAS 43229-80-7) after inhalation from two different hydrofluoroalkane (HFA) pressurised metered dose inhaler (pMDI) formulations at two dose levels, 12 and 24 microg. This is the first study which has evaluated two HFA formulations of formoterol. Fourteen subjects were randomised, of which 13 completed the study. Each subject received in separate periods a single dose of 12 microg or 24 microg of each formulation. Blood samples for determination of formoterol plasma concentrations were taken pre-administration of study treatments and subsequently at 2, 5, 10, 20, 30, 45, 60, 90 min and 2, 3, 4, 6, 8, 12, 24 and 36 h post-administration of the study treatments. The pharmacokinetic profiles of both the formulations were similar in shape and a dose-related increase in formoterol plasma concentration was seen at all time points for both the test and reference formoterol HFA formulations between the dose levels 12 microg and 24 microg. Overall, the findings indicate that treatment with the test formoterol HFA preparation has a lung absorption pattern and systemic exposure comparable to the already licensed reference formoterol HFA preparation.