EXPLORATORY EVALUATION OF NOVEL, NON-HORMONAL MALE CONTRACEPTIVE DRUG PROTOTYPES ACTING IN VAS DEFERENS Nnaemeka I.B. Amobiab and I. Christopher H. Smith; King's Collegea, London SE1 1UL. Joanna Cocker, Melanie Wood and Ruth Turl; Royal Veterinary College, Hatfield Campus, AL9 7TA John Guillebaud; Elliot-Smith Clinic b, Churchill Hospital, Headington, Oxford, OX3 7L J
1 BACKGROUND The development i s based on our discovery of the mode of drug action for a side-effect shared by two therapeutic drugs, thioridazine and phenoxybe nzamine (PBZ) INHIBITION OF SEMEN EMISSION, WHICH OCCURS WITHOUT AFFECTING PENILE ERECTION, ORGASM OR LIBIDO
1.Greenberg H R & Carrillo C (1968). Thioridazine-induced inhibition of masturbatory ejaculation in an adolescent. The American journal of
2.Singh H (1963). Therapeutic use of thioridazine in premature ejaculation. The American journal of psychiatry, 119, 891.
3.Kedia K R & Persky L (1981). Effect of phenoxybenzamine (dibenzyline) on sexual function in man. Urology, 18(6), 620-1.
4.Homonnai Z T, Shilon M & Paz G F (1984). Phenoxybenzamine--an effective male contraceptive pill. Contraception, 29(5), 479-91.
• The potential of PBZ as a male contraceptive was tested by Homonnai et al.(1984) – Reported total inhibition of semen emission
within 3-4 days with little probability of female impregnation thereafter. Ejaculate recovery occurred within 5 days after cessation of dosing. However, for medical reasons PBZ and thioridazine are unsuitable for routin e male contraceptive purposes. PROPULSIVE MECHANISM AND MODE OF DRUG ACTION UNDERLYING THE SIDE EFFECT Dual effect of longitudinal muscle inactivation (persistent tissue slack) and unabated circular muscle contractility (lumen closure) disrupts the coordinated activity that sustains efficient propulsive function in semen emission. CURRENT STUDY - NOVEL PROTOTYPES [diphenyl- aryloxy- alkylamine derivatives] replicating this action in human and ram vasa were evaluated in vivo in order to identify prototypes producing ≥ 50% reduction in ram ejaculate within 4-16 hr. PROTOTYPE XN73 – DIFFERENT DOSES REDUCED IN VIVO EJACULATE SPERM CONTENT & VOLUME IN TWO RAMS BY 67- 83%
3 RESULTS BLOOD SAMPLE ANALYSIS - XN73 plasma levels
were 16.7 ng/ml (IV - 0.67 mg/kg) and 66.2 ng/ml (IV - 1.4 mg/kg) after 4 hr of administration but declined rapidly to undetectable levels (animal 1) & 10 ng/ml (animal 2) within 16 hr.
IN SILICO ANALYSIS of microspecies revealed a predominance of ionized microspecies with zero un- ionized microspecies at pH 1.5, 5.0, 6.5 & 7.4. The decline in plasma drug levels and inadequate microspecies distribution underlie the less than
100% efficacy in the ram experiments and corrected
[TM; time-matched controls (saline), Interval between tests with saline (controls) and drug prototypes – 12 days]
for in the latest chemically modified prototypes. PROTOTYPE XN6 – REDUCED IN VIVO SPERM CONTENT & VOLUME BY 64 – 66% CONCLUSION The prototypes, though unoptimized, have BLOOD SAMPLE ANALYSIS demonstrable potential in terms of
¾ Short-term inhibition of semen emission for male contraception &
(1.4 mg/kg IV) after 4 hr and within 16 hr were 94 ng/ml (animal 3; IV
¾ Drug-like properties
1.34 mg/kg) and 0-0.6 ng/ml Collaborative milestone-based funding is required to (animal 4; IV 0.7 & 1.4 mg/kg) . start work on evaluating the modified prototypes select drugs with the best contraceptive efficacy We gratefully acknowledge the support of CONRAD (USA) for this profile, oral bioavailability, metabolic stability and pivotal in-vivo prototype study. safety attributes.
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