Potential therapeutic agents derived from the cannabinoid nucleus.

PIP: Drugs derived from Cannabis sativa (Cannabinceae) were used until the 1940's for their stimulant and depressant effects for treating somatic and psychiatric illnesses. Renewed interest in marihuana research began in the 1970's and again pointed to the therapeutic potential of cannabinoids. Safer and more useful therapeutic agents may be generated from cannabinoids similarly to morphine, lysergic acid diethylamide, and cocaine which have structurally related analgesics, oxytoxics, and local anesthetics respectively. It has been shown that the C-ring in cannabinoids can be substituted with a variety of nitrogen and sulfur-containing rings without loss of CNS (central nervous system) activity. Cannabinoids have been shown to inhibit prostaglandin synthesis, intensify pressor effects of endogenous amines like norepinephrine, and enhance the stimulant effects of amphetamine. Cannabinoids' therapeutic potential lies in the areas of analgesics and anticonvulsants, and for use as a sedative-hypnotic, an antiglaucoma agent, an antiasthmatic agent, an antidiarrheal agent, and possibly as an anticancer and immunosuppressant agent.^ieng

Trial of prostaglandin-synthetase inhibitors in primary dysmenorrhoea.

The prostaglandin-synthetase inhibitors, mefenamic acid and flufenamic acid, were compared with the analgesic, dextropropoxyphene/paracetamol, in the treatment of primary dysmenorrhoea in a double-blind crossover trial. Results were assessed in 30 patients who took each drug during menstruation for three consecutive cycles. The patients' assessment of each drug suggests that both mefenamic acid and flufenamic acid are more effective than the other analgesic for general relief of symptoms and for most of nine individual symptoms subjectively assessed by the patient. There was less absenteeism from work or school during mefenamic-acid treatment and fewer capsules of mefenamic acid were taken compared with the other two drugs. Patients took significantly fewer additional analgesics during mefenamic-acid therapy than during treatment with the other two drugs. 5 patients had possible side-effects--3 patients on mefenamic acid and 2 on dextropropoxyphene/paracetamol.

PIP: In a double-blind corss-over trial, 30 patients experiencing primary dysmenorrhea were treated with 2 prostaglandin inhibitors, mefenamic acid (250mg) and flufenamic acid (100 mg), and an analgesia, dexhropropoxyphene (32.5 mg)/paracetamol (325 mg) (D.H. and P.). The patients took each drug for 3 consecutive cycles and were subjectively assessed. Results indicate that there was no significant difference between mefenamic acid and flufenamic acid nor flufenamic acid and D.H. and P.; however, mefenamic acid was significantly better than D.H. and P. The total number of mefenamic acid capsules taken was significantly less than either flufenamic acid or D.H. and P. In rating side effects, mefenamic acid was significantly better in reducing the effects of faintness, nausea, and constipation and flufenamic acid was statistically significant in reducing nausea. There were possible side effects in 3 women taking mefenamic acid and in 2 women taking D.H. and P.

Letter: Prostaglandins and induction of labour.

PIP: In response to a recent editorial advocating use of prostaglandins (PGs) for preterm labor induction in women with essential and renal hypertension, preeclampsia, growth-retarded fetuses, diabetes, and rhesus incompatibility, this letter questions the logic of such a recommendation. Given that PGF2 alpha has been shown to have a vasconstrictive effect on placental veins and on umbilical arteries; that hypertensive states in pregnancy may cause pathological lesions in uteroplacental arteries; and that preeclampsia involves an inadequate response of the uteroplacental arteries to placentation; PG induction of labor may exacerbate the conditions of complicated pregnancy which necessitated labor induction in the first place. Use of PGs for premature induction of labor in pregnancies by hypertensive states, and perhaps in other conditions associated with intrauterine hypoxia, may aggravate fetal distresses. The letter suggests that in vitro biopsy studies of human pregnanted uterus need to be perform to investigate the action, if any, of PGs on myometrial blood vessels before PGs can be recommended for premature labor induction in cases of hypoxia and fetal distress.^ieng

Anaprox in dysmenorrhea: reduction of pain and intrauterine pressure.

In a double-blind parallel trial, 24 dysmenorrheic women received a single dose of Anaprox (1,100 mg) or placebo. Over the next 2 hours, pain intensity was scored and intrauterine pressure was measured using an immobilized microballoon. At the end of 2 hours, all 11 patients given Anaprox (but only three of the 13 given placebo) experienced complete pain relief (p = 0.0004). The resting intrauterine pressure (IUP) decreased from a mean of 51.4 to 26.8 mm Hg in the Anaprox-treated group, while in the placebo group the mean resting IUP values remained essentially unchanged ( drop from 55.4 to 51.9 mm Hg was observed). This difference between the two treatment groups was statistically significant in favor of Anaprox (p = 0.03). Several patients from each group were given 0.2 mg of ergonovine by intramuscular injection following the 2 hour trial. In both groups, the resting IUP increased within 30 minutes; the corresponding increase in pain intensity was more pronounced, however, in the placebo group. These results support the premise that a decrease in resting IUP is directly linked to the pain-relieving effects of Anaprox.

PIP: 24 women with regular menstrual cycles but suffering from dysmenorrhea were studied in a double-blind parallel trial to determine the effects of anaprox on pain reduction. 11 patients received anaprox (1100 mg) and 13 received placebos while a microballoon-tipped catheter was inserted into the uterine cavity to measure intrauterine pressure. After 2 hours, all patients experienced complete pain relief and their IUP (intrauterine pressure) decreased from a mean 51.4 to 26.8 mm Hg, while only 3 of the 13 patients experienced relief having a mean IUP decrease from 55.4 to 51.9 mm Hg. Patients who showed the greatest reduction in IUP also showed the most pain relief. 6 of the 11 women were given ergonovine by injection and although their IUP increased their dysmenorrhea was minimal; whereas, in 7 of the 13 women given ergonovine injection, 4 had an increase in dysmenorrhea within 30 minutes.

Clinical application of prostaglandins in human reproduction.

PIP: In this discussion of the clinical application of prostaglandins (PGs) in human reproduction, attention is directed to indications for PG administration, potential therapeutic applications, PG drugs, routes and schedules of PG administration, contraindications to PG administration, and side effects and complications. Termination of pregnancy is the most common reason for using PGs. Induction of early abortion by PGs up to 8 weeks following the 1st day of the last menstrual period offers many advantages that make this approach competitive with vacuum aspiration. Being a nonsurgical method that can be self-administered, it presents an attractive clinical potential. The preferred routes of administration are the vaginal route and to a lesser extent the intramuscular injection route. From the 8th week of gestation up to the 12th week, vacuum aspiration and conventional curettage are the most efficient abortion methods. PGs, hypertonic saline, and vaginal surgical evacuation are the most popular methods for performing 2nd trimester abortions. In abnormal pregnancies with fetal death or molar changes, PGs appear to be most valuable and to be a logical primary choice, particularly in uterine sizes exceeding 12 weeks. Induction of labor by PGs continues to be a controversial issue, but the consensus is that although these compounds may be more efficient than oxytocin, they probably are more risky at labor inducing doses from the danger of uterine hyperstimulation. Intramyometrial injection of PGF2alpha has been shown to be a valuable method for treatment of atonic postpartum hemorrhage. More recently, intramuscular administration of 15-methyl-PGF2alpha has been reported to be highly effective and life saving in severe uncontrollable atonic postpartum hemorrhage when all other nonsurgical lines of treatment already have failed. Toxemia of pregnancy is 1 area in which PGs may prove to be of clinical value in management, especially because recent reports implicate these compounds in the pathogenesis of this serious disorder. At least 3 generations of PGs have thus far developed: the classic PGE2 and PGF2alpha represent the 1st generation, and only PGE2 still is used clinically; 15-methyl-PGF2alpha, representing the 2nd generation; and the 3rd generation of PGs, the one with the greatest clinical potential for induction of abortion, made up totally of E analogues. PGs have been used by every possible route of administration, including systemic routes and locally. Recently, PGE2 was administered intranasally. The contraindications to PG administration differ according to the type of PG, the indication for use, and the mode of administration. In general terms, the absolute contraindications include glaucoma and cardiac disease. Side effects include gastrointestinal side effects.^ieng