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Relation between biological activities and blood levels of LHRH or its analogues by different routes of administration in rats
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A7
A PHARMACEUTICAL APPROACH TO LONG-TERM THERAPY WITH PEPTIDES. W. Petri*, R. Seidel and J. Sandow, Depts. of Galenlcs and Pharmacology, Hoechst AG, D-6230 Frankfurt/Main 80, Germany F.R. Metered-dose nebullzers (dosage pumps) represent a reliable form for long-term nasal application of peptldes. The dosage pump is both the device that dispenses the Individual sprays and an application aid. The meterlng accurancy of the dosage pump represents a very important and characteristic value: intraindlvldually there must be a good reproducibillty and lnterindividually all pumps of a batch must have a very small frequency dlstrlbution. The nebulizer must not lose its original meterlng accuracy during sterilization and storage. Conditions for sterilezing or disinfecting the device may critically affect compositlon of the polymer constituents. Aqueous solutions are preferable, whereas absorption for oily solutions 01‘ ointments 1s inferior. The cllnical effect of such a nasal spray 1s reproducible. Its use in contraceptive studies, endometriosls and prostate carcinoma has been monltored by clinical parameters (inltlal LH release, consistent suppresslon of gonadal steroid secretion). The absorption can be measured by pharmacokinetics of buserelin or‘ pharmacodynamics of LH release. Buccal absorption of LHRH agonists 1s unsatisfactory for therapy, absorption is lower than for oral administration. The blological effect of buserelin implants can be tested by using osmotic minlpumps as a model system, comparing their release characteristics with the effect of biodegradable implant materials. Results ~111 be presented for In vitro and in vlvo test systems to assess the release rate and the pharmacodynamlc effect..
RELATION BETWEEN BIOLOGICAL ACTIVITIES AND BLOOD LEVELS OF LHRH OR ITS ANALOGUES BY DIFFERENT ROUTES OF ADMINISTRATION IN RATS. I. Yamazaki* Biology Laboratories, Central Research Division, Takeda Chemical Industries, Ltd., 17-85, Jusohonmachi 2-Chome, Yodogawaku, Osaka 532, Japan. The dual biological activities of LHRH, its intermediately potent agonist, LHRH-A (des-Gly"-LHRH-ethylamide), and highly potent agonist, LHRH-B (des-Gly'"-[D-Leu61-LHRH-ethylamide), administered by different routes were compared. As for the profertility phenomenon of ovulation induction in diestrous rats, parenteral routes were markedly more effective than the other routes. The effectiveness of LHRH and its analogues by the vaginal, rectal and nasal routes was less than 15% of that by the subcutaneous route. As for the paradoxical antireproductive phenomenon of luteolysis in pregnant rats, the vaginal dose of LHRH-B was 752 times more effective than the subcutaneous route. By the rectal and nasal routes, the effectiveness was, respectively, 62% and less than 5% than that of the subcutaneous route. The serum level of LHRH-B after a subcutaneous dose reached a peak at 40 min and decreased sharply thereafter; the half-life was 32 min. By the vaginal route, the peak level was lower but the half-life was 3 times that of the subcutaneous route. By the rectal route, the half-life was between those of the subcutaneous and vaginal routes. By the nasal route, the level attained a peak within 5 min and decreased; the half-life was comparable to that of the subcutaneous route. These data indicate that, by these routes, the ovulation-inducing effectiveness of the peptides was proportional to the their peak concentration but not to their half-life. On the other hand, the pregnancy-terminating effectiveness was not proportional to the peak concentration but did parallel the half-life.
A7
A PHARMACEUTICAL APPROACH TO LONG-TERM THERAPY WITH PEPTIDES. W. Petri*, R. Seidel and J. Sandow, Depts. of Galenlcs and Pharmacology, Hoechst AG, D-6230 Frankfurt/Main 80, Germany F.R. Metered-dose nebullzers (dosage pumps) represent a reliable form for long-term nasal application of peptldes. The dosage pump is both the device that dispenses the Individual sprays and an application aid. The meterlng accurancy of the dosage pump represents a very important and characteristic value: intraindlvldually there must be a good reproducibillty and lnterindividually all pumps of a batch must have a very small frequency dlstrlbution. The nebulizer must not lose its original meterlng accuracy during sterilization and storage. Conditions for sterilezing or disinfecting the device may critically affect compositlon of the polymer constituents. Aqueous solutions are preferable, whereas absorption for oily solutions 01‘ ointments 1s inferior. The cllnical effect of such a nasal spray 1s reproducible. Its use in contraceptive studies, endometriosls and prostate carcinoma has been monltored by clinical parameters (inltlal LH release, consistent suppresslon of gonadal steroid secretion). The absorption can be measured by pharmacokinetics of buserelin or‘ pharmacodynamics of LH release. Buccal absorption of LHRH agonists 1s unsatisfactory for therapy, absorption is lower than for oral administration. The blological effect of buserelin implants can be tested by using osmotic minlpumps as a model system, comparing their release characteristics with the effect of biodegradable implant materials. Results ~111 be presented for In vitro and in vlvo test systems to assess the release rate and the pharmacodynamlc effect..
RELATION BETWEEN BIOLOGICAL ACTIVITIES AND BLOOD LEVELS OF LHRH OR ITS ANALOGUES BY DIFFERENT ROUTES OF ADMINISTRATION IN RATS. I. Yamazaki* Biology Laboratories, Central Research Division, Takeda Chemical Industries, Ltd., 17-85, Jusohonmachi 2-Chome, Yodogawaku, Osaka 532, Japan. The dual biological activities of LHRH, its intermediately potent agonist, LHRH-A (des-Gly"-LHRH-ethylamide), and highly potent agonist, LHRH-B (des-Gly'"-[D-Leu61-LHRH-ethylamide), administered by different routes were compared. As for the profertility phenomenon of ovulation induction in diestrous rats, parenteral routes were markedly more effective than the other routes. The effectiveness of LHRH and its analogues by the vaginal, rectal and nasal routes was less than 15% of that by the subcutaneous route. As for the paradoxical antireproductive phenomenon of luteolysis in pregnant rats, the vaginal dose of LHRH-B was 752 times more effective than the subcutaneous route. By the rectal and nasal routes, the effectiveness was, respectively, 62% and less than 5% than that of the subcutaneous route. The serum level of LHRH-B after a subcutaneous dose reached a peak at 40 min and decreased sharply thereafter; the half-life was 32 min. By the vaginal route, the peak level was lower but the half-life was 3 times that of the subcutaneous route. By the rectal route, the half-life was between those of the subcutaneous and vaginal routes. By the nasal route, the level attained a peak within 5 min and decreased; the half-life was comparable to that of the subcutaneous route. These data indicate that, by these routes, the ovulation-inducing effectiveness of the peptides was proportional to the their peak concentration but not to their half-life. On the other hand, the pregnancy-terminating effectiveness was not proportional to the peak concentration but did parallel the half-life.