Mid-trimester abortion with 15 (S) methyl prostaglandin F 2 alpha

The efficacy of intramuscular administration of 15 methyl (15S) prostaglandin F2alpha (PGF2a) in midtrimester pregnancy termination was evaluated in 16 healthy patients (mean age, 23.3; mean parity, 1.4; mean number of menstrual weeks, 16.1) by measuring dose response; oxytocin conversion; abortion time; side effects; intrauterine dynamics and progesterone withdrawal. Labor was monitored using extraovular balloon placed transvaginally; transcervically; and connected to a Physiograph machine. Patients not aborting within 48 hours after the first dose were considered failures. Blood samples were collected at 0, 3, and 6 hours and at abortion time for plasma progesterone measurement. Average dose given was 789 +or- 60 micrograms. Only 9 of 10 patients aborted within the prescribed 48 hours: 7 were complete abortions, and 2 were incomplete and required suction curettage. Mean induction to abortion time was 20.2 +or- 2.7 hours. Nausea, vomiting and diarrhea were the main side effects. The findings suggest that 15 methyl PGF2a in the dosages and routes prescribed is not as efficient as PGF2a. It is also suggested that prostaglandin affects the myometrium at 2 levels: 1) a membrane effect, and 2) a more fundamental intracellular regulatory effect which is necessary to initiate labor.     

O-Nitration of prostaglandins: synthesis of 15-O-nitrates of 11-deoxyprostaglandin E1 and its methyl ester

O-Nitration of the allylic hydroxyl group in prostaglandins and the synthesis of 15-O-nitrates of 11-deoxyprostaglandin E1 and its methyl ester are described for the first time.     

Preparation of prostaglandins A2, E2 and 11-epi-E2 from their 15 acetates methyl esters using an endogenous enzyme system present in plexaura Homomalla (Esper)

Enzymatic hydrolysis of prostaglandins A₂, E₂ and 11-epi E₂ methyl ester acetates has been accomplished using an endogenous enzyme system present in the cortex of Plexaura Homomalla (Esper).     

Effect of PGF2 alpha and 15(S)-15-methyl PGE2 methyl ester on feline generalized penicillin epilepsy.

The effect of PGF2alpha and 15(S)-15-methyl PGE2 methyl ester on transient generalized epilepsy in the cat induced by penicillin was examined. Epileptic activity before and after administration of the prostaglandins by several routes was determined from continuous EEG recordings and expressed in epileptic bursts per min. The PGE2 analogue given in single non-toxic doses (1.6-3 mug/kg) by intramuscular or intravenous routes at the peak of epileptic activity significantly reduced epileptic activity for up to four hours. Subcutaneous administration was less effective. PG2alpha given by the intramuscular route (0.3 mg/kg) also markedly reduced the number of epileptic bursts. Increasing the dosage 4-fold almost completely suppressed epileptic activity. Intracarotid infusion of PGF2alpha for one hour (10 mug/min) almost abolished all epileptic activity. Neither prostaglandin given in non-toxic doses induced EEG abnormalities in non-epileptic cats. Toxic doses of the E2 analogue (greater than 16 mug/kg) caused bilaterally synchronous high voltage slow wave activity. It is concluded that these prostaglandins reduce penicillin epilepsy in the cat. The findings are consistent with either a direct excitatory action on neurones of the medial reticular formation or anatagonism of the depressant action of norepinephrine on Purkinje cells.     

Gastric antisecretory effect of 15(R)-15-menthyl PGE2, methyl ester and of 15(S)-15-methyl ester.

Gastric juice was collected from gastric pouches in dogs stimulated with histamine. 15(R)-15-methyl PGE2, methyl ester inhibited gastric secretion in dogs when given orally, but was almost inactive when given intravenously, whereas 15(S)-15-methyl PGE2 methyl ester was active by both routes. When given directly into the small intestine (intrajejunally), the 15(S) was active and the 15(R) was inactive. The 15(R), diluted in acid and administered intrajejunally, became active in inhibiting gastric secretion. When the 15(S) was diluted in acid and administered intrajejunally, it lost half of its activity. When each analog was incubated in an acid medium, each was epimerized to give approximately a 1:1 mixture of both 15(R) and 15(S). Incubation of the 15(R) in pH 3 buffer resulted in only a trace of formation of 15(S). These results explain why the 15(R) is active orally but not intrajejunally. When given orally, the low pH of gastric secretion epimerizes much of the 15(R) into the 15(S),which is active by any route. The degree of acidity of gastric contents may determine whether the 15(R) will exert an antisecretory effect.     

A radioimmunoassay of 15 (S) 15 methyl prostaglandin F2α

A sensitive and relative specific radioimmunoassay for 15 (S) 15 methyl prostaglandin F_2α has been developed to enable the measurements of the concentrations of the drug in biological fluids after its administration for therapeutic abortion. The precision, accuracy and specificity of the assay are described.     

Synthesis of methyl 2-O-alpha-D-mannopyranosyl-alpha-D-talopyranoside and methyl 2-O-alpha-D-talopyranosyl-alpha-D-talopyranoside

Treatment of methyl 3-O-benzyl-2-O-(2,3,4,6-tetra-O-acetyl-alpha-D-mannopyranosyl)-alpha-D- mannopyranoside (1) with tert-butyldiphenylsilyl chloride in N,N-dimethylformamide afforded methyl 3-O-benzyl-6-O-tert-butyldiphenylsilyl-2-O-(2,3,4,6-tetra-O-acetyl -alpha-D- mannopyranosyl)-alpha-D-mannopyranoside (2). Oxidation of 2 with pyridinium chlorochromate, followed by reduction of the carbonyl group, and subsequent O-deacetylation afforded methyl 3-O-benzyl-6-O-tert-butyldiphenylsilyl-2-O-alpha-D-mannopyranosyl- alpha-D- talopyranoside (5). Cleavage of the tert-butyldiphenylsilyl group of 5 with tetrabutylammonium fluoride in oxolane, followed by hydrogenolysis, gave methyl 2-O-alpha-D-mannopyranosyl-alpha-D-talopyranoside (7). O-Deacetylation of 1 gave methyl 3-O-benzyl-2-O-alpha-D-mannopyranosyl-alpha-D-mannopyranoside (8). Treatment of 8 with tert-butyldiphenylsilyl chloride afforded a 6,6'-disilyl derivative, which was converted into a 2',3'-O-isopropylidene derivative, and then further oxidized with pyridinium chlorochromate. The resulting diketone was reduced and removal of the protecting groups gave methyl 2-O-alpha-D-talopyranosyl-alpha-D-talopyranoside (15). The structures of both 7 and 15 were established by 13C-n.m.r. spectroscopy.     

Mid-trimester abortion with 15 (S) methyl prostaglandin F2α

A Prostaglandin analog 15 Methyl PG F_2α administered intra-muscularly was used to induce mid-trimester abortion in 16 patients. The average dose given was 789 ± 60 ugm, and this resulted in only 9 successful abortions. The incidence of side effects was thought to be prohibitive. PG appears to produce two types of action on the myometrium, a membrane effect, and a more fundamental intracellular regulatory effect.     

Stereoselective synthesis of [13C]methyl 2-[15N]amino-2-deoxy-beta-D-glucopyranoside derivatives

The chemical structure of carrageenans produced by the gametophytic and tetrasporophytic life cycle phases of Gigartina pistillata has been determined by permethylation analysis, IR and 13C NMR spectroscopies. The chemistry of the galactans varies according to the biological phases of the plant, the gametophytic alga produces heterogeneous kappa-iota type carrageenan containing minor amounts of nu-carrabiose. The tetrasporophytic alga synthesizes a complex sulfated galactan composed of lambda-, xi-, pi-carrabioses and sulfated carrabioses containing 3-linked galactopyranose 2,6-disulfate.     

Acute toxicity of prostaglandins E2,F2α and 15 (s) 15 methyl prostaglandin E2 methyl ester in the baboon

The cardiovascular, uterine stimulant and gastrointestinal effects of prostaglandins E₂, F_2α and 15 (S) 15 methyl PGE₂ methyl ester in the East African Baboon (P. Anubis) have been studied. In these three parameters the baboon responds both qualitatively and quantitatively in a similar manner to man. The lethal doses of the prostaglandins given by bolus intravenous injelctions have been determined and the human lethal doses estimated.     

15-Keto-13,14-dihydroprostaglandin E2- and F2 alpha-metabolite levels in blood from men and women given prostaglandin E2 orally

Prostaglandin E2 (PGE2) was administered orally in a dose of 1 mg to healthy males (n = 20) and females (n = 10). Blood levels of 15-keto-13,14-dihydroprostaglandin F2 alpha (PGF2 alpha-M) and 15-keto-13,14-dihydroprostaglandin E2 (PGE2-M), determined as the rearrangement product 11-deoxy-15-keto-13,14-dihydro-11 beta, 16-cycloprostaglandin E2 (PGE2-cyclo-M), were measured. The levels of the two PG metabolites increased already 10 minutes after ingestion of the tablet and the mean peak value for PGE2-cyclo-M in the men was 4.64 nmol/l which was reached 50 minutes after PGE2 administration. The mean peak value in women was 4.99 nmol/l which was obtained after 30 minutes. The increase in PGE2-cyclo-M concentration was significantly faster (p less than 0.05) in women than in the men. The mean plasma concentration of PGF2 alpha in males were 0.20 nmol/l prior to treatment and rose after PGE2 ingestion to mean peak level of 0.84 nmol/l after 70 minutes. The corresponding values for the females were 0.18 nmol/l and 0.88 nmol/l 50 minutes into treatment. When the data from both sexes were amalgamated PGE2-cyclo-M peak levels were reached significantly (p = 0.004) sooner than the PGF2 alpha-M peak. The two PG metabolites returned to baseline levels in 70% of the individuals after 240 minutes. The increase in PGF2 alpha-M concentration following oral administration of PGE2 indicates that part of the PGE2 was reduced to PGF2 alpha.(ABSTRACT TRUNCATED AT 250 WORDS)