M. J. Jamieson

Effect of food on oral availability of apresoline and controlled release hydralazine in hypertensive patients

Summary Hydralazine is a vasodilator antihypertensive drug that has been in use for many years. Efficacy after oral administration correlates well with the levels of the drug in blood. Factors such as food ingestion that affect blood levels of hydralazine may therefore be of importance. There is dispute regarding the effect of food intake on blood levels of hydralazine and on the antihypertensive response. This randomized cross-over study examined the effect of food (642 K calories, 25 g protein, 43 g fat, 40 g carbohydrates, 32 mEq sodium, 17 mEq potassium) ingested immediately before hydralazine (taken as Apresoline, Ciba Geigy, or as slow-release hydralazine, SRH, Pennwalt Corporation) on the blood levels of hydralazine in 16 essential hypertensive patients who were slow acetylators currently taking at least 100 mg Apresoline daily. Peak blood hydralazine levels were reduced by food after both Apresoline and SRH, by 69 and 66%, respectively. Time to peak blood hydralazine concentration was delayed significantly with SRH. We could detect a statistically significant food-related reduction of area under blood hydralazine concentration versus time curves (AUC) only with Apresoline (by 44%). The AUC for SRH was decreased only 29% by food. Hydralazine should be taken at a consistent time with respect to meals.

The assessment of the beta-blocking activity of urapidil: a new method.

SummaryUrapidil is an antihypertensive vasodilator agent whose pharmacological action in man has not yet been fully defined. We have assessed the beta blocking activity of urapidil 15 mg and 30 mg i.v. in a single blind study of 10 healthy male volunteers. Urapidil at plasma concentrations in the same range as those shown to have antihypertensive affect did not significantly attenuate the chronotropic effect of isoproterenol. Propranolol 5 mg iv, the positive control, significantly shifted the isoproterenol dose-response curve to the right. We describe a new method of analyzing incomplete dose response curves whereby a linear terminal segment can be reproducibly defined.

The local effects of systemic digoxin on the cutaneous microcirculation.

AbstractObjective: The present study was designed to explore whether digoxin modifies cutaneous vascular responses to an endothelium-dependent vasodilator (acetylcholine) or to the vasoconstrictor norepinephrine. Methods: In a double-blind cross-over study 12 healthy subjects received digoxin 0.25 mg twice daily (after adequate loading doses) or placebo for a total of 11 days. Dose-response curves to iontophoresis of acetylcholine or norepinephrine were constructed at day 11. Laser Doppler flux (LDF) was measured at the same sites. Mean arterial pressure (MAP) was measured non-invasively and cutaneous vascular conductance (CVC) was calculated (CVC=LDF/MAP). Results: Serum concentrations of digoxin were within the therapeutic range [1.3 (0.5) ng · ml−1; mean with (SD)]. Blood pressure and heart rate were significantly lower during supine rest under digoxin treatment [mean with (SD); minute 10 to 70 of supine rest; systolic blood pressure: 121 (11) mmHg (placebo) vs 116 (11) mmHg (digoxin); P = 0.001; diastolic blood pressure: 63 (6) mmHg vs 58 (8) mmHg; P = 0.007; heart rate: 60 (10) beats · min−1 vs 54 (8) beats · min−1; P = 0.001]. Digoxin also caused significantly higher baseline CVC [169 (25) Perfusion Units (PU) · mmHg−1 (digoxin) vs 109 (14) PU · mmHg−1 (placebo); P = 0.013] and significantly increased the vasoconstriction to norepinephrine iontophoresis. Acetylcholine iontophoresis was unaltered by digoxin treatment. Conclusions: Digoxin does not modify the cutaneous vascular response to an administered endothelium-dependent vasodilator. It reduces resting heart rate, blood pressure and baseline cutaneous blood flow and augments the vasoconstrictive effect of exogenous norepinephrine. The findings do not support the hypothesis that digoxin lowers diastolic blood pressure through a direct action on blood vessels.

Determination of α-adrenergic blocking potency

Determination of the α‐adrenergic blocking potency of drugs in humans is usually done by measuring the shift in the blood pressure versus logarithm of intravenous phenylephrine dose‐response relationship. Change in blood pressure activates homeostatic reflexes that may change this relationship. This study examines the effect of autonomie (β1‐ and β2‐adrenergic, parasympathetic, and α‐adrenergic) blockade on the dose versus blood pressure response relationship to sequential doses of phenylephrine in humans. Phenylephrine dose responses were conducted under controlled conditions, during propranolol and atropine infusion, during prazosin‐induced a‐adrenergic blockade, and during prazosin, propranolol, and atropine administration. Propranolol‐atropine infusion decreased the threshold dose of phenylephrine required to increase mean blood pressure (p < 0.00001), increased the slope of the phenylephrine dose versus increase in mean blood pressure relationship (p = 0.019), and decreased the dose of phenylephrine required to increase mean blood pressure by 20 mm Hg (p < 0.00001). Determination of the α‐adrenergic blocking potency of prazosin was not affected by autonomie blockade with propranolol and atropine (dose ratio 5.2 before and 5.0 after autonomie blockade; p = 0.465). We conclude that β1‐and β2‐adrenergic and muscarinic blockade increase sensitivity to phenylephrine by increasing the slope and decreasing the threshold dose of the phenylephrine dose‐response curve, and that α‐adrenergic‐blocking potency of prazosin may be determined with or without blocking homeostatic blood pressure regulatory mechanisms in humans.

Histamine response and local cooling in the human skin

Clinical Pharmacology & Therapeutics (1999) 65, 147–147; doi:

Miscompliance by proxy

Clinical Pharmacology & Therapeutics (1995) 58, 594–594; doi: