Therapeutic and economic controversies in antihypertensive therapy.

Diuretics are recommended for initial antihypertensive therapy because of their low cost and lack of subjective side effects. Unlike alpha- and beta-adrenergic agents, however, diuretics frequently induce metabolic abnormalities that necessitate supplemental therapy and increased monitoring of clinical laboratory tests. These factors increase the total cost of diuretic therapy, making it comparable to that of the alpha- or beta-adrenergic drugs. We show that the total yearly costs of therapy, exclusive of office visits, for patients treated with any of these three classes of agents is approximately $175 to $250, regardless of the drug used. Diuretics are cost effective only in patients who do not require laboratory follow-up or supplemental therapy. Thus, the choice of a drug for initial therapy of hypertension may be based more appropriately on medical (particularly side effects and metabolic abnormalities) rather than financial considerations.

Comparative antihypertensive effects of guanabenz and clonidine.

The safety and efficacy of guanabenz and clonidine were compared in 188 hypertensive patients during a 6-month double-blind trial. Mean supine diastolic blood pressure (SDBP) decreased from 103 to 88 mm Hg (p less than 0.01) among guanabenz patients and from 101 to 88 mm Hg (p less than 0.01) among clonidine patients who completed 6 months of b.i.d. therapy. Clinically significant individual SDBP decreases occurred in 85% of the guanabenz patients and 83% of the clonidine patients after 6 months. Adverse effects, consisting primarily of drowsiness, dry mouth, dizziness, and weakness, were similar in the two therapy groups. The responses obtained with guanabenz (b.i.d.) were maintained, along with a decrease in adverse effects, by an equivalent single daily dose of guanabenz during a second 6 months of therapy. Seventy-six per cent (13/17) of the patients whose blood pressure was not adequately controlled by guanabenz alone after 8 weeks of therapy subsequently responded to a combination of guanabenz and hydrochlorothiazide. Similarly, 85% (17/20) of the patients who failed to respond to clonidine alone subsequently responded to guanabenz either alone or in combination with hydrochlorothiazide. These results suggest that guanabenz or the combination of guanabenz and hydrochlorothiazide is effective therapy for the majority of hypertensive patients.

Long-term therapy of hypertension with guanabenz.

Guanabenz, a centrally acting antihypertensive (alpha-agonist) that does not induce secondary sodium retention or other metabolic disturbances, was evaluated for up to two years at 19 investigational sites. In 329 patients completing six months of therapy, the mean supine diastolic blood pressure (SDBP) fell from 101 to 90 mmHg (P less than 0.01). Clinically significant individual SDBP decreases occurred in 74% of the patients by week 2, and these reductions were maintained in 72% at six months. Mean weight was reduced 1.4 lb (P less than 0.01), and mean supine pulse rate was decreased 5 beats/min (P less than 0.01). The most frequent effective doses were 8 and 16 mg BID (range, 2 to 32 mg BID). Principal side effects, usually mild, were sedation (31%), dry mouth (24%), dizziness (6%), and weakness (6%). Postural hypotension, impotence, and abrupt discontinuation symptoms were rare or absent. There were no clinically significant drug-related laboratory changes other than a 10 mg/100 ml mean serum cholesterol decrease. Two hundred twenty-two patients completed one year of therapy, and 80 completed two years, with little change in any parameters other than improvement in mean SDBP to 85 mmHg and in individual response rate to 84%. These results suggest that guanabenz is safe and effective for initial and sole therapy of hypertension.

Comparative antihypertensive effects of guanabenz and methyldopa.

The effects of guanabenz acetate, a centrally acting alpha-adrenergic, non-sodium-retaining antihypertensive agent, were compared with those of methyldopa in 248 hypertensive outpatients during a one-year, double-blind, multi-center study. Mean supine diastolic blood pressure (SDBP) decreased from 102 to 91 mmHg (P less than 0.01) among 78 guanabenz-treated patients and from 101 to 92 mmHg (P less than 0.01) among 89 methyldopa-treated patients who completed six months of treatment. Clinically significant individual SDBP decreases occurred in 76% of the guanabenz-treated patients and in 63% of the methyldopa-treated patients (P less thn 0.05). Blood pressure remained unchanged during the second six months, with response of 82% and 60%, respectively, for guanabenz and methyldopa (P less than 0.05). Although drowsiness and dry mouth occurred more frequently with guanabenz, evidence of fluid retention, such as weight gain, edema, and congestive heart failure, was significantly more frequent with methyldopa than with guanabenz. Because it does not induce volume expansion, guanabenz, unlike methyldopa, may be useful as sole initial antihypertensive therapy.

Radioimmunoassay of indomethacin in biological fluids.

A radioimmunoassay was developed for the determination of indomethacin in biological fluids at concentrations as low as 50 ng/ml. Antibodies were produced in rabbits immunized with a conjugate of bovine serum albumin and indomethacin. This conjugate was prepared by an N-hydroxysuccinimide active ester procedure. Antiserums exhibited minimal cross-reactivity with the O-desmethyl and deschlorobenzoyl metabolites. However, the glucuronide conjugate was about three times as reactive as indomethacin, thus invalidating direct determinations of indomethacin in urine. This difficulty was circumvented by analyzing urine aliquots before and after conjugate hydrolysis. Concentrations of free and conjugated indomethacin were calculated by difference.

Analysis of sulindac and metabolites by combined isotope dilution-radioimmunoassay.

Sulindac, a new anti-inflammatory agent, and its sulfone and sulfide metabolites were conjugated to bovine serum albumin by the N-hydroxysuccinimide active ester procedure. Antiserum from rabbits immunized with each of these haptens exhibited extensive cross-reactivity, precluding differential analyses of the three species by displacement assay without prior separation. Therefore, an analytical method based on a combination of isotope dilution and radioimmunoassay was devised. A known mixture of the three chemical species, each labeled with tritium, was equilibrated with plasma or urine samples, reisolated chromatographically, and quantitated by binding to an appropriate immunoglobulin. The radiolabeled materials thus served as recovery standards as well as labeled antigens for each displacement assay. Sulindac and each of its metabolites in plasma or urine at concentrations as low as 500 ng/sample were differentially determined by this procedure. However, since an extraction is required, several milliliters of plasma can be used for each sample, thus increasing the actual sensitivity of the assay.

The disposition of sulindac.

The disposition of sulindac, a new nonsteroid anti-inflammatory drug, has been studied in normal volunteers in five separate clinical studies. Based upon material balance considerations, a minimum of approximately 88% of an oral dose is absorbed. The major biotransformations involve irreversible oxidation of the sulfinyl group of sulindac to sulfone and reduction to the corresponding sulfide. The latter, which all available evidence indicates to be the pharmacologically active form of sulindac, is not excreted in urine, and has an apparent terminal half-life of 18.2 hr, well suited to twice daily dosage of its pro-drug. Following twice daily dosage of sulindac for 5 days, plasma levels of sulfide approach an apparent steady state with concentrations varying only within a twofold range over each dosage interval. The reversible biotransformation between sulindac and its active sulfide metabolite provides the basis for two therapeutic advantages relating to the gastrointestinal intolerance usually associated with anti-inflammatory drugs: (1) circumvention of initial exposure of gastric and small intestinal mucosa to the active form of the drug and (2) maintenance of systemic levels of active drug by means of enterohepatic recycling, principally of inactive pro-drug.

Bioavailability of dexamethasone. II. Dexamethasone phosphate.

Plasma levels of dexamethasone phosphate (DP) and dexamethasone free alcohol (DA) were determined by a modification of existing radioimmunoassay methodology following intravenous administration of DP in man. Areas under DA plasma profiles were a linear function of DP dosage over the 40-fold range 0.05 to 2.0 mg/kg, and, by comparison with values obtained after DA was intravenously administered, indicated an overall conversion of DP to DA of 90%. The first-order rate constant for the conversion, 4.03 hr-1, was approximately 25 times that for hydrolysis in whole blood incubated in vitro. This relationship as well as disposition kinetics suggested that the major component of DP hydrolysis occurs within highly perfused organ(s) comprising the central kinetic compartment. Eighteen subjects were studied in a crossover experiment, and no significant differences were observed in best-fit parameters for the 4 mg/ml parenteral solution of DP in current use and an experimental high potency preparation of 24 mg/ml.

Aromatic amino acid hydroxylase inhibitors. 4. 3-Substituted alpha-methyltyrosines.

In the present study a series of 3-alkenyl-alpha-methyltyrosines and their corresponding 3-alkyl-and dihydrobenzofuran analogs was synthesized for potential tyrosine hydroxylase (TH) inhibitory activity. The appropriately substituted hydantoins IIIa and IIIb, which were prepared from the corresponding allyloxybenzylhydantoins IIa and IIb through Claisen rearrangement, served as intermediates for the synthesis of these amino acids. TH inhibition was reduced upon either saturation of the double bond in the side chain or cyclization to form the dihydrobenzofuran analogs. Formation of the epoxide had a similar effect. The inhibitory activity of these compounds against aromatic amino acid decarboxylase (AADC) and dopamine beta-hydroxylase (DBH) was also investigated. Unsaturation, in both cases, decreases the inhibitory activity; however, the presence of a free phenolic group appears to be essential for AACD inhibitory activity.