Dr Wyllie made the following two points: (i) the blood pressure was relatively low in the hypertensive group; and (ii) the absence of a decrease in blood pressure under alfuzosin in the hypertensive group may be explained by the relatively low baseline blood pressure in this group, because alfuzosin has previously been shown to have a significant effect on blood pressure in other studies of hypertensive patients.

The responses, provided in the same order as the comments, are:

(i) Patients included in the analysis of hypertensive patients in Table 3 of the paper were those reporting a history of hypertension at baseline and also include those with controlled hypertension (i.e. normal blood pressure) on antihypertensive medications. This would explain the mean values in the Table, which are lower than expected for the definition of hypertension.

(ii) Dr Wyllie also mentions that alfuzosin had been shown to lower blood pressure in two early studies of hypertension [1,2]; in these studies, older formulations (not once daily) were used, at relatively higher doses (5 mg twice daily to 20 mg four times daily [1]; 2.5 mg up to 10 mg twice daily [2]); moreover, the results showed a significant difference in favour of propranolol at 4 weeks and there was no equivalence of alfuzosin vs propranolol [2], as mentioned.

The clinical uroselectivity of an α-blocker (clearly shown with alfuzosin) is related to many factors that contribute at different levels to the final benefit/risk ratio, e.g. pharmacological selectivity, absence of passage through the blood–brain barrier, preferential distribution in prostatic tissue, dose, and formulation (Cmax, Tmax). Affinity studies on human-cloned α1-receptor subtypes showed that alfuzosin, like terazosin and doxazosin, is devoid of significant receptor subtype selectivity [3,4], but in isolated human tissues, alfuzosin had the highest selectivity ratio for the prostate over vascular tissue (ratio 144) compared with tamsulosin (90), doxazosin (51) and terazosin (19) [5]. In addition, in a conscious-rat model, it was shown that the primary effect of alfuzosin is as a urethral relaxant and not an antihypertensive effect [6]. Alfuzosin also penetrates the brain poorly, which may contribute to a lower incidence of CNS-related adverse events, e.g. dizziness and somnolence [7]. A preferential distribution in prostatic tissue has also been reported [8]. While it is possible that high doses of other than once-daily formulations of alfuzosin may produce some lowering effect on blood pressure, there have been no significant changes in blood pressure reported with alfuzosin 10 mg once-daily compared with placebo, even in hypertensive patients [9–11]. The cardiovascular safety of this formulation was similar to placebo even in hypertensive patients [10].

The importance of the formulation and dosage is also evident; e.g. tamsulosin clearly has a very different cardiovascular profile using a conventional formulation than with a controlled-released formulation (conventional formulation 0.2 mg produced orthostatic hypotension in half the subjects; in contrast the controlled-release formulation 0.2 mg produced no hypotension) [12]. The immediate-release formulation of tamsulosin has never been launched in USA or in Europe. Similarly, the cardiovascular safety of alfuzosin was improved when comparing the once-daily with the three times daily formulation [9].

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