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A D Forbes
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Serum FSH, LH and testosterone in the male rhesus following prostaglandin injection.
Adult male rhesus were treated with PGE2, PGF2 alpha or the 13,14-dihydro-15-keto metabolite of PGE2 in a randomized crossover design. Serum concentrations of FSH, LH and testosterone were determined and compared to the respective values in the same uninjected animals. No significant changes were noted in controls or following the metabolite injection. FSH increased gradually for 4 hours after metabolite treatment. In contrast, injection of PGF2 alpha was followed by an abrupt (within 15 minutes) increase in LH and testosterone. FSH increased gradually in 2 of 3 treated animals. Injection of PGE2 was followed by a similar abrupt increase in LH concentration. This was not always associated with a significant increase in testosterone or FSH. These results demonstrate that injections of PGE2 or PGF2 alpha can change serum gonadotropin and testosterone concentrations in male rhesus monkeys, and that the effects of these two prostaglandins are qualitatively different.
Characterization of the exfoliative antispermatogenic agent 1-(2,4-dichlorobenzyl)-H-indazole-3-carboxylic acid in the rhesus monkey.
The effects of oral doses of 1-(2,4-dichlorobenzyl)-1H-indazole-3-carboxylic acid (DICA) on spermatogenesis in the rhesus monkey (Macaca mulatta) was studied. Four animals given five daily 50 mg/kg doses or three or five daily 500 mg/kg doses showed that DICA was an exfoliating antispermatogenic compound. The inhibition of spermatogenesis was only partially reversible following 500 mg/kg doses of DICA. Weekly and monthly 50 mg/kg doses of DICA only partially inhibiting spermatogenesis as measured by electro-ejaculated sperm counts. Response in individual monkeys ranged from azoospermia to no effect. Testicular biopsies confirmed this finding. DICA did not affect serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), or testosterone concentrations. The blood absorption or urinary excretion rates of uniformly tritiated DICA in the animals that responded well did not differ from those monkeys that responded poorly. DICA metabolites were not detected in monkey urine. Serum testosterone concentrations appeared to vary with the season of the year, but FSH concentrations and ejaculated sperm count did not.
Effects of 19-hydroxy-prostaglandins on oviductal and uterine motility.
The effects of 19-hydroxyprostaglandins (19-OH-PGs) were tested in vivo on the rabbit oviduct and uterus and on the rhesus monkey (Macaca mulatta) uterus. The 19-OH-PGEs suppressed spontaneous oviductal and uterine activity in the rabbit. The qualitative effect on the rabbit oviduct of 19-OH-PGEs was similar to that of PGE2. However, the typical response of the rabbit uterus to PGE2 was an increase in muscle activity. With regard to the rabbit oviduct, 19(R)-OH-PGE2 was as potent as PGE2, but 19(S)-OH-PGE2 was approximately 1/2 as potent as PGE2. Based on the dose of 19-OH-PGEs usually required to cause a minimal suppression and the dose of PGE2 required to cause a minimal stimulation of rabbit uterine activity, 19(R)-OH-PGE2 was twice as potent as PGE2 while 19(S)-OH-PGE2 was 1/2 as potent as PGE2. Stimulatory effects on the rabbit oviduct and uterus were observed following administration of 19-OH-PGFs and PGF2alpha. The potency on the rabbit oviduct of 19(S)-OH-PGF2alpha was about 1/5 to 1/10 that of PGF2alpha; the potency of 19(R)-OH-PGF2alpha was about 1/10 to 1/20 that of PGF2alpha. Both 19-OH-PGFs were approximately 1/5 to 1/10 as potent as PGF2alpha on the rabbit uterus. At the doses tested 19-OH-PGFs were inactive on the monkey uterus. Thus, these compounds are at least 1/5 as active as PGF2alpha. In contrast, 19(R)-OH-PGE2 had approximately the same potency as PGE2 in stimulating monkey uterine activity; but 19(S)-OH-PGE2 was approximately 1/3 as potent as PGE2.
Effects of PGF2alpha and PGF2alpha, 1-15 lactone on the corpus luteum and on early pregnancy in the rhesus monkey.
The effects of prostaglandin (PG)F2alpha and PGF2alpha, 1-15 lactone were compared in luteal phase, non-pregnant and in early pregnant rhesus monkeys. Animals treated with either PG after pretreatment with human chorionic gonadotropin (hCG) had peripheral plasma progesterone concentrations that were not statistically different from those in animals treated with hCG and vehicle. However, menstrual cycle lengths in monkeys treated with PGF2alpha, 1-15 lactone were significantly (P less than 0.02) shorter than those in vehicle treated animals. In the absence of hCG pretreatment, plasma progesterone concentrations were significantly (P less than 0.008) lower by the second day after the initial treatment with either PGF2alpha or PGF2alpha, 1-15 lactone than in vehicle treated monkeys. Menstrual cycle lengths in monkeys treated with either PG were significantly (P less than 0.04) shorter than those in animals treated with vehicle. There were no changes in plasma progesterone concentrations in early pregnant monkeys treated with PGF2alpha, and pregnancy was not interrupted. In contrast, plasma progesterone declined and pregnancy was terminated in 5 of 6 early pregnant monkeys treated with PGF2alpha, 1-15 lactone. These data indicate that PGF2alpha, 1-15 lactone decreases menstrual cycle lengths in non-pregnant rhesus monkeys. More importantly, PGF2alpha, 1-15 lactone terminates early pregnancy in the monkey at a dose which is less than an ineffective dose of PGF2alpha.
Evaluation of vaginal delivery systems containing 15[s]15-methyl PGF2alpha methyl ester.
Silicone vaginal delivery systems containing 15[S]15-methyl-PGF2alpha methyl ester have been evaluated in vitro, and in vivo in the rhesus monkey. Three types of vaginal devices have been formulated to contain different concentrations of drug. The cumulative amount of 15[s]15-methyl-PGF2alpha methyl ester released in vitro from a planar silicone rubber matrix was dependent upon the initial loading dose of the prostaglandin. Drug-containing vaginal rings were evaluated in early pregnant and mid-trimester pregnant monkeys. Within 10 min after ring administration there was an increase in the amplitude and frequency of contractions. In mid-trimester pregnant animals there was an initial increase in plasma progesterone and then a decrease following treatment, while there was a progressive decrease in plasma progesterone in early pregnant animals. All 6 mid-trimester pregnant monkeys treated with vaginal rings aborted. Pregnancy was terminated in 4 of 5 early pregnant monkeys treated with vaginal rings. Blood levels of 15-methyl-PGF2alpha rose rapidly to attain a peak 1 hr after treatment with vaginal rings. After the peak, plasma levels of 15-methul-PGF2alpha declined to a plateau which was fairly constant between 2 and 8 hr. Vaginal silicone-gelatin laminates containing 15[s]15-methyl-PGF2alpha methyl ester were also effective in causing an increase in uterine muscle activity and terminating pregnancy in mid-trimester in pregnant monkeys. Plasma progesterone also increased shortly after treatment in these animals, and then declined after the peak at 8 hr. The plasma profile of 15-methyl-PGF2alpha when animals were treated with these vaginal laminates was different from that observed following ring treatment. In pregnant animals the concentration of 15-methyl-PGF2alpha rose more slowly following laminate insertion, and the peak values were considerably less than those following ring treatment. Vaginal devices used in monkeys and humans caused plasma concentrations of 15-methyl-PGF2alpha that were generally lower than those observed in monkeys treated with either vaginal rings or laminates. These studies have demonstrated that silicone vaginal delivery systems containing 15[S]15-methyl-PGF2alpha methyl ester result in sustained and fairly constant plasma levels of 15-methyl-PGF2alpha, and terminate both 1st- and 2nd-trimester pregnancies in the monkey. The vaginal device offers the possibility for self-administration of PGs for early pregnancy termination and menstrual cycle regulation.
Sound envelope averaging and the differential diagnosis of systolic murmurs.
Phonocardiography previously has been limited in scope because the attained suboptimal signal-to-noise ratio has interfered with the sensitivity and clarity of recordings. A new system is described that reduces this problem by utilizing demodulation and synchronous averaging of the "envelop" of cardiac sounds. A limited survey of the differential diagnostic capabilities of this technique is presented for 80 patients having one of six common forms of pathological systolic murmurs and an 89 per cent diagnostic accuracy is demonstrated. This system promises to be a valuable noninvasive adjunct in cardiologic diagnosis research and education.