Induction of parturition in bitches with minimal side effects by two injections of a low dose of fenprostalene, a prostaglandin F2alpha analogue, and pretreatment with prifinium bromide.
An experiment using 16 Beagle bitches (aged 11 months to 6 years and 2 months) in their 56th to 58th day of pregnancy was carried out to investigate the effects of two injections of a low dose of fenprostalene, a long-acting prostaglandin F2alpha analogue, and pretreatment with prifinium bromide, a parasympathetic nerve blocking agent, on the induction of parturition and severity of side effects. The bitches were divided into three treatment groups: one injection of 5 microg/kg of fenprostalene (group I, n=5); one injection of 7.5 mg/head of prifinium bromide followed by one injection of 5 microg/kg of fenprostalene at 5 min after prifinium bromide injection (group II, n=6); and one injection of 7.5 mg/head of prifinium bromide followed by two injections of 2.5 microg/kg of fenprostalene, one injection at 5 min after prifinium bromide injection and the next at 1 hr after the fenprostalene first injection (group III, n=5). Following the injection of fenprostalene, side effects such as salivation, vomiting, colic symptoms, and watery diarrhea occurred most frequently (80-100% of cases) in group I bitches. Apart from colic symptoms, no side effects were observed in group III bitches. Group III bitches also showed the smallest increase in plasma cortisol concentration. No significant difference in the time to initiation of parturition was found between the three groups. The one-week survival rate of newborn puppies was highest in group III. The results showed that pretreatment with prifinium bromide and two injections of 2.5 microg/kg of fenprostalene can alleviate side effects following fenprostalene administration and have no adverse effect on the survival of newborn puppies, indicating that this method is a reliable and safe way of inducing parturition in bitches. (+info)
Prostaglandin moieties that determine receptor binding specificity in the bovine corpus luteum.
This study provided a pharmacological evaluation of prostaglandin binding to bovine luteal plasma membrane. It was found that [3H]PGF2 alpha' [3H]PGE2' [3H]PGE1 and [3H]PGD2 all bound with high affinity to luteal plasma membrane but had different specificities. Binding of [3H]PGF2 alpha and [3H]PGD2 was inhibited by non-radioactive PGF2 alpha (IC50 values of 21 and 9 nmol l-1, respectively), PGD2 (35 and 21 nmol l-1), and PGE2 (223 and 81 nmol l-1), but not by PGE1 (> 10,000 and 5616 nmol l-1). In contrast, [3H]PGE1 was inhibited by non-radioactive PGE1 (14 nmol l-1) and PGE2 (7 nmol l-1), but minimally by PGD2 (2316 nmol l-1) and PGF2 alpha (595 nmol l-1). Binding of [3H]PGE2 was inhibited by all four prostaglandins, but slopes of the dissociation curves indicated two binding sites. Binding of [3H]PGE1 was inhibited, resulting in low IC50 values, by pharmacological agonists that are specific for EP3 receptor and possibly EP2 receptor. High affinity binding of [3H]PGF2 alpha required a C15 hydroxyl group and a C1 carboxylic acid that are present on all physiological prostaglandins. Specificity of binding for the FP receptor depended on the C9 hydroxyl group and the C5/C6 double bond. Alteration of the C11 position had little effect on affinity for the FP receptor. In conclusion, there is a luteal EP receptor with high affinity for PGE1' PGE2' agonists of EP3 receptors, and some agonists of EP2 receptors. The luteal FP receptor binds PGF2 alpha' PGD2 (high affinity), and PGE2 (moderate affinity) but not PGE1 due to affinity determination by the C9 and C5/C6 moieties, but not the C11 moiety. (+info)
Responses of intraocular pressure and the pupil of feline eyes to prostaglandin EP1 and FP receptor agonists.
PURPOSE: Previous studies suggested that FP receptors do not mediate the relaxation of the ciliary muscle and reduction of intraocular pressure in cats by prostaglandin (PG) F2alpha. The present study was undertaken to determine whether the reduction of intraocular pressure in cats induced by PGF2alpha is mediated by FP or other prostaglandin receptors. METHODS: One eye of each cat was treated topically with prostaglandin F2alpha, fluprostenol (FP receptor agonist), or 17-phenyl trinor PGE2 (EP1 receptor agonist) in a dose range of 12.5 to 50 microg. The effects of SC19220 and SC51089 (EP1 receptor antagonists), BWA868c, and SQ29548 (DP and TP receptor antagonists, respectively) on the intraocular response to PGF2alpha were also examined. At intervals up to 6 hours after treatment, intraocular pressure was measured with a pneumotonometer, and pupil diameters were measured with a millimeter ruler. RESULTS: In the dose ranges used, PGF2alpha and 17-phenyl trinor PGE2 decreased intraocular pressure and pupil diameter. The greatest reduction of intraocular pressure by 50.0 microg PGF2alpha was 5.0+/-1.4 mm Hg, whereas that by 50 microg 17-phenyl trinor PGE2 was 6.2+/-1.5 mm Hg. The isopropyl ester of PGF 2alpha at a dose of 1.25 microg reduced intraocular pressure by 3.75+/-0.25 mm Hg at 2 hours. At doses up to 100 microg, fluprostenol did not decrease intraocular pressure but did reduce pupil diameter. SC19220, a weak but selective EP1 receptor antagonist, inhibited the intraocular pressure response to both PGF2alpha and 17-phenyl trinor PGE2. The more potent EP1 receptor antagonist SC51089 had a greater inhibitory effect than SC19220 on the intraocular pressure response to PGF2alpha. Both of these antagonists had a small but non-dose dependent and statistically insignificant effect on the pupil response to PGF2alpha. These observations suggest that in cats, intraocular pressure and pupil responses to PGF2alpha, are mediated by EP1 and FP receptors, respectively. However, SC19220 significantly and dose-dependently inhibited the pupil response to 17-phenyl trinor PGE2alpha suggesting that EP1 receptors mediate pupil response to this agonist. DP and TP receptor antagonists at doses 5- to 20-fold greater than the IC50 values had no effect on the ocular hypotensive response to PGF2alpha. The concurrent administration of 12.5 microg of each of PGF2alpha and 17-phenyl trinor PGE2 did not produce an additive effect on intraocular pressure, indicating that in cats PGF2alpha and 17-phenyl trinor PGE2 act on the same receptor type. CONCLUSIONS: These results suggest that a significant proportion of the ocular hypotensive action of PGF2alpha in cats is mediated by EP1 but not by FP receptor. Evidence was also provided to show that 17-phenyl trinor PGE2 is an ocular hypotensive agent in cats. (+info)
Source and site of action of anti-luteolytic interferon in red deer (Cervus elaphus): possible involvement of extra-ovarian oxytocin secretion in maternal recognition of pregnancy.
Six conceptuses were collected from red deer hinds on day 22 after synchronization of oestrus with intravaginal progesterone-releasing devices (removal of device = day 0). Within 24 h of culture in vitro, the supernatant from five of six conceptuses showed detectable antiviral activity. Interferon alpha (IFN-alpha) receptors were identified by immunohistochemistry on the luminal surface of the endometrium, in the neurohypophysis and paraventricular hypothalamus, but not in the ovaries of the hinds from which the conceptuses were collected. Another 16 intact hinds were synchronized as above. Injection of 4 mg IFN i.m. twice a day on days 13-15 had no effect on cloprostenol-induced oxytocin secretion on day 15 and did not prevent cloprostenol-induced luteal regression. Sixteen ovariectomized hinds received a protocol of steroid treatment to mimic ovarian hormone secretion during the normal oestrous cycle. On day 16, hinds showed undulant oxytocin secretion that showed a degree of temporal association with uterine PGF2 alpha release. Treatment with 4 mg IFN-alpha I 1 twice a day on days 13-16 had no effect on this spontaneous oxytocin secretion, but reduced the magnitude of cloprostenol-induced oxytocin secretion on day 17 (P < 0.05). These results indicate that red deer conceptuses secrete an anti-luteolytic IFN to which the endometrium expresses a receptor during early pregnancy. The presence of IFN receptors in the hypothalamus and posterior pituitary and the IFN-induced suppression of extra-ovarian oxytocin secretion provides tentative evidence of an involvement of the central nervous system in maternal recognition of pregnancy in deer. (+info)
Comparison of the intraocular pressure lowering effect of latanoprost and a fixed combination of timolol-pilocarpine eye drops in patients insufficiently controlled with beta adrenergic antagonists. French Latanoprost Study Group, and the Swedish Latanoprost Study Group.
AIMS: To compare the effect on intraocular pressure (IOP) of latanoprost monotherapy and timolol-pilocarpine in patients with glaucoma or ocular hypertension with inadequately controlled IOP on topical beta adrenergic antagonists. METHODS: This was a multicentre, randomised, observer masked, 6 week study performed in France and Sweden. 23 centres enrolled 237 patients with glaucoma or ocular hypertension and an IOP of at least 22 mm Hg on treatment with topical beta adrenergic antagonists, alone or in combination. After a 21 day run in period on timolol 0.5% twice daily, patients were randomised either to latanoprost 0.005% once daily or to a fixed combination of timolol-pilocarpine twice daily. Changes in mean diurnal IOP from the baseline to the 6 week visit were determined with an analysis of covariance. RESULTS: Mean diurnal IOP was statistically significantly decreased from baseline in both groups (p<0.001). Switching to latanoprost treatment reduced mean diurnal IOP by 5.4 (SEM 0.3) mm Hg (ANCOVA -22%) and switching to timolol-pilocarpine treatment reduced mean diurnal IOP by 4.9 (0.4) mm Hg (-20%). Blurred vision, decreased visual acuity, decreased twilight vision, and headache were statistically significantly more frequent in the timolol-pilocarpine group. CONCLUSIONS: Latanoprost monotherapy was at least as effective as fixed combination timolol-pilocarpine twice daily treatment in reducing mean diurnal IOP in patients not adequately controlled on topical beta adrenergic antagonists. Latanoprost was better tolerated than timolol-pilocarpine regarding side effects. These results indicate that a switch to latanoprost monotherapy can be attempted before combination therapy is initiated. (+info)
A comparison of latanoprost and dorzolamide in patients with glaucoma and ocular hypertension: a 3 month, randomised study. Ireland Latanoprost Study Group.
AIMS: To compare the effects on intraocular pressure (IOP) and side effects of monotherapy with either latanoprost or dorzolamide in patients with glaucoma or ocular hypertension. METHODS: 224 patients with open angle glaucoma or ocular hypertension were recruited to a 3 month open labelled study. Previous glaucoma medications were washed out and the patients were randomised to receive either latanoprost 0.005% once daily or dorzolamide 2% three times daily. RESULTS: Of 224 patients 213 were included in the analysis of efficacy. After 3 months, latanoprost reduced mean baseline diurnal IOP from 27.2 (SD 3.0) mm Hg by 8.5 (3.3) mm Hg. The corresponding figures for dorzolamide were 27.2 (3.4) and 5.6 (2.6) mm Hg. The difference of 2.9 mm Hg (95% CI: 2.3-3.6) was highly significant (p<0.001, ANCOVA). Latanoprost reduced IOP at peak by 8.6 mm Hg (32%) compared with 6.2 mm Hg (23%) for dorzolamide, and the difference of 2.4 mm Hg was significant (p<0.001, ANCOVA). The corresponding figures at trough were 8.1 mm Hg (31%) for latanoprost and 4.7 mm Hg (17%) for dorzolamide, a significant difference of 3.4 mm Hg (p<0.001, ANCOVA). Both drugs were well tolerated systemically and locally. CONCLUSION: Latanoprost was superior to dorzolamide in reducing the IOP, judged both from the effect on IOP at peak and trough and by the effect on diurnal IOP. (+info)
Effect of timolol, latanoprost, and dorzolamide on circadian IOP in glaucoma or ocular hypertension.
PURPOSE: To compare the around-the-clock intraocular pressure (IOP) reduction induced by timolol 0.5%, latanoprost 0.005%, and dorzolamide in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT). METHODS: In this crossover trial, 20 patients with POAG (n = 10) or OHT (n = 10) were treated with timolol, latanoprost, and dorzolamide for 1 month. The treatment sequence was randomized. All patients underwent measurements for four 24-hour tonometric curves: at baseline and after each 1-month period of treatment. The patients were admitted to the hospital, and IOP was measured by two well-trained evaluators masked to treatment assignment. Measurements were taken at 3, 6, and 9 AM and noon and at 3, 6, and 9 PM and midnight by handheld electronic tonometer (TonoPen XL; Bio-Rad, Glendale, CA) with the patient supine and sitting, and a Goldmann applanation tonometer (Haag-Streit, Bern, Switzerland) with the patient sitting at the slit lamp. Systemic blood pressure was recorded at the same times. The between-group differences were tested for significance by means of parametric analysis of variance. The circadian IOP curve of a small group of untreated healthy young subjects was also recorded using the same procedures. To compare the circadian IOP rhythms in the POAG-OHT and control groups, the acrophases for each subject were calculated. RESULTS: When Goldmann sitting values were considered, all the drugs significantly reduced IOP in comparison with baseline at all times, except for timolol at 3 AM. Latanoprost was more effective in lowering IOP than timolol at 3, 6, and 9 AM (P = 0.03), noon (P = 0.01), 9 PM, and midnight (P = 0.05) and was more effective than dorzolamide at 9 AM, noon (P = 0.03), and 3 and 6 PM (P = 0.04). Timolol was more effective than dorzolamide at 3 PM (P = 0.05), whereas dorzolamide performed better than timolol at midnight and 3 AM (P = 0.05). An ancillary finding of this study was that in the group of healthy subjects, the pattern of IOP curve was different that in patients with eye disease. CONCLUSIONS: Latanoprost seemed to lead to a fairly uniform circadian reduction in IOP, whereas timolol seemed to be less effective during the nighttime hours. Dorzolamide was less effective than latanoprost but led to a significant reduction in nocturnal IOP. The reason for the difference in the pattern of the IOP curve of healthy subjects is currently unknown and deserves further investigation. (+info)
Replacement of the carboxylic acid group of prostaglandin f(2alpha) with a hydroxyl or methoxy substituent provides biologically unique compounds.
Replacement of the carboxylic acid group of PGF(2alpha) with the non-acidic substituents hydroxyl (-OH) or methoxy (-OCH(3)) resulted in an unexpected activity profile. Although PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) exhibited potent contractile effects similar to 17-phenyl PGF(2alpha) in the cat lung parenchymal preparation, they were approximately 1000 times less potent than 17-phenyl PGF(2alpha) in stimulating recombinant feline and human FP receptors. In human dermal fibroblasts and Swiss 3T3 cells PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) produced no Ca(2+) signal until a 1 microM concentration was exceeded. Pretreatment of Swiss 3T3 cells with either 1 microM PGF(2alpha) 1-OH or PGF(2alpha) 1-OCH(3) did not attenuate Ca(2+) signal responses produced by PGF(2alpha) or fluprostenol. In the rat uterus, PGF(2alpha) 1-OH was about two orders of magnitude less potent than 17-phenyl PGF(2alpha) whereas PGF(2alpha) 1-OCH(3) produced only a minimal effect. Radioligand binding studies on cat lung parenchymal plasma membrane preparations suggested that the cat lung parenchyma does not contain a homogeneous population of receptors that equally respond to PGF(2alpha)1-OH, PGF(2alpha)1-OCH(3), and classical FP receptor agonists. Studies on smooth muscle preparations and cells containing DP, EP(1), EP(2), EP(3), EP(4), IP, and TP receptors indicated that the activity of PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) could not be ascribed to interaction with these receptors. The potent effects of PGF(2alpha) 1-OH and PGF(2alpha) 1-OCH(3) on the cat lung parenchyma are difficult to describe in terms of interaction with the FP or any other known prostanoid receptor. (+info)