The New Angiotensin II Receptor Antagonist, Irbesartan: Pharmacokinetic and Pharmacodynamic Considerations

This article reviews the pharmacokinetics and pharmacodynamics of angiotensin II (AII) receptor antagonists (AIIRA), with particular focus on the novel compound irbesartan. Irbesartan has the highest oral bioavailability in its class (60% to 80%) and, unlike valsartan, its absorption is not affected by food. Irbesartan displays linear, dose related pharmacokinetics and, with the exception of tasosartan's active metabolite, has the longest elimination half-life of the AIIRA (11 to 15 h). Irbesartan exhibits the lowest amount of protein binding, limiting its potential for drug interactions. No drug interactions with irbesartan have been identified. Unlike losartan, candesartan, and tasosartan, irbesartan does not require biotransformation for AII blockade. The pharmacokinetics of irbesartan are not altered in renally or hepatically impaired patients, probably owing to excretion characteristic by both biliary and renal routes, or by differences in gender or age. Within its therapeutic dose range (150 to 300 mg), irbesartan shows sustained, dose related blockade 24 h after dosing. Irbesartan lowers blood pressure in a dose related manner up to 300 mg daily. Some clear differences in pharmacokinetics and pharmacodynamics exist among the AIIRA, which may have clinical implications. Am J Hypertens 1997;10:311S-317S ©1997 American Journal of Hypertension, Lt

Endothelin Inhibition as a Biologic Target for Treating Hypertension

Endothelin, a 21-amino-acid peptide, binds to a specific receptor on vascular smooth muscle cells, thereby inducing vasoconstriction. Although plasma levels are not consistently elevated in hypertension, there is evidence that endothelin has an important role in its pathogenesis. Administration of endothelin antagonists has lowered blood pressure and reduced end-organ damage in some animal models. It has also reduced the cross-sectional area of neointima due both to hypertension and vascular injury. Coadministration of endothelin and angiotensin II to rats produced a synergistic hypertensive effect. Similarly, coadministration of an endothelin antagonist with an angiotensin converting enzyme inhibitor resulted in a synergistic lowering of blood pressure. Several preliminary clinical studies have been done. The endothelin antagonist bosentan has decreased vascular resistance and blood pressure and increased cardiac index in patients with congestive heart failure. Plasma endothelin levels are elevated in the acute phase of myocardial infarction and in chronic heart failure. The magnitude of this increase, measured 3 days after patients experienced myocardial infarction, had a significance at least equal to known risk factors in predicting 1 year survival. Thus, there are reasons to believe that endothelin antagonists may become a useful tool in the management of various cardiovascular disorder

Olmesartan medoxomil: current status of its use in monotherapy

Olmesartan medoxomil is an angiotensin II receptor antagonist. In pooled analyses of seven randomized, double-blind trials, 8 weeks’ treatment with olmesartan medoxomil was significantly more effective than placebo in terms of the response rate, proportion of patients achieving target blood pressure (BP) and mean change from baseline in diastolic (DBP) and systolic blood pressure (SBP). Olmesartan medoxomil had a fast onset of action, with significant between-group differences evident from 2 weeks onwards. The drug was well tolerated with a similar adverse event profile to placebo. In patients with type 2 diabetes, olmesartan medoxomil reduced renal vascular resistance, increased renal perfusion, and reduced oxidative stress. In several large, randomized, double-blind trials, olmesartan medoxomil 20 mg has been shown to be significantly more effective, in terms of primary endpoints, than recommended doses of losartan, valsartan, irbesartan, or candesartan cilexetil, and to provide better 24 h BP protection. Olmesartan medoxomil was at least as effective as amlodipine, felodipine and atenolol, and significantly more effective than captopril. The efficacy of olmesartan medoxomil in reducing cardiovascular risk beyond BP reduction is currently being investigated in trials involving patients at high risk due to atherosclerosis or type 2 diabetes

Measurement of Converting Enzyme Activity by Antibody-Trapping of Generated Angiotensin II: Comparison With Two Other Methods

Activity of the angiotensin converting enzyme (ACE) is usually measured in vitro by estimation of products cleaved by the enzyme from synthetic substrates. These substrates have affinities for ACE different from the natural substrate angiotensin I, and insensitive detection systems necessitate milli-molar substrate concentrations while physiological angiotensin I concentrations are in the picomolar range. A new assay for ACE activity measurement was developed which reliably quantitates femtomoles of generated angiotensin II in plasma from angiotensin I added at a 17 pmol/mL concentration. The production of high affinity monoclonal antibodies against angiotensin II (Kd = 7 × 10-11 mol/L) allowed a quantitative trapping (and thus protection from degrading enzymes) of angiotensin II generated during the incubation step and subsequent ra-dioimmunoassay by simple dilution with labelled angiotensin II. Using 40 µL plasma, the detection limit was 20 fmol/mL/min. Normal human plasma has an ACE activity of 335 ± 83 fmol/mL/min (mean ± SD). Precision was characterized by coefficients of variation of ^ 11% both within-assay and between-assays. Accuracy of the new method was established by comparing ACE activity with the ratio of plasma angiotensin II/angiotensin I in plasma obtained from normal volunteers 0.5 to 24 h after oral administration of 20 mg enalapril. The percentage of ACE inhibition indicated by both methods was almost identical (r = 0.93, n = 60, P < .001). Since the latter ratio appears to reflect in vivo ACE activity, these results indicate that accurate measurement in vitro of ACE activity in vivo has been achieved. Am J Hypertens 1992;5:393-39

Dynamics of Manufacturing Competitiveness in South Asia: Analysis through Export Data

The outstanding export performance of South Asian countries (India in particular) over the 1990s has prompted some observers to see in it the roots of an export-led growth similar to that of its Southeast Asian neighbors. We employ export unit values (UVs) cum real competitiveness analysis to the manufacturing sector of four South Asian countries (with particular focus on India), in order to investigate the determinants of this apparent success. Shifts toward higher UVs relative to technology leaders serve as the most appropriate indication of underlying structural changes, and such change is manifested in technology closing-up processes among countries. According to our indices, the export competitiveness of South Asian countries (except Pakistan) seems to have slightly improved relative to its Southeast Asian comparators, but not relative to the Organisation for Economic Co-operation and Development. South Asian export growth has been mainly driven by relative quantity expansion through a reduction in relative costs rather than relative quality improvement. Such expansion has been concentrated in naturalresource-intensive, standard technology-intensive (in India), and labor-intensive sectors (in Bangladesh). On the other hand, the more technology-intensive sectors in India still suffer from a significant gap relative to Thailand that has not been closing up in the last decade. These findings suggest some notes of caution in interpreting the recent good export performance of South Asian economies

Combination Antihypertensive Therapy: Does It Have a Role in Rational Therapy?

The pharmacological treatment of hypertension allows one to reduce substantially the risk of developing a cardiovascular complication. It appears more and more important to bring blood pressure to normal values in order to get the maximal benefit from antihypertensive therapy. Blood pressure lowering drugs make it possible to control blood pressure in about half of the patients when administered as monotherapy. The fraction of patients with a normal blood pressure can be markedly increased by combining drugs acting by different mechanisms. Low doses of antihypertensive agents are generally enough when coadministered. This helps to keep the incidence of side effects minimal and facilitates the patient's compliance with long-term treatment. Low-dose, fixed-dose combination therapy may therefore represent a valuable option not only to treat hypertensive patients unresponsive to drugs given as monotherapy, but also to initiate the treatment. Am J Hypertens 1997;10:131S-137S ©1997 American Journal of Hypertension, Lt

Defects and D-Brane Monodromies

In this paper D-brane monodromies are studied from a world-sheet point of view. More precisely, defect lines are used to describe the parallel transport of D-branes along deformations of the underlying bulk conformal field theories. This method is used to derive B-brane monodromies in Kahler moduli spaces of non-linear sigma models on projective hypersurfaces. The corresponding defects are constructed at Landau-Ginzburg points in these moduli spaces where matrix factorisation techniques can be used. Transporting them to the large volume phase by means of the gauged linear sigma model we find that their action on B-branes at large volume can be described by certain Fourier-Mukai transformations which are known from target space geometric considerations to represent the corresponding monodromies.Comment: 49 pages, 5 figure