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Pharmacokinetics of the analgesic tilidine with special reference to the active metabolite
S461
PHARMACOKINETICS OF THE ANALGESIC TILIDINE WITH SPEC IAL REFERENCE TO THE ACTIVE METABOLITE K.-O. Vollmer, H. Hengy, P. Thomann (SPON: B. Bromm), Gijdecke Research Institute, Dept. of Pharmacokinetics and Metabolism, D-7800 Freiburg, FRG
I
Poster 92 BROWN Th-Fri ACC Hall E Abs No
896
I
AIM OF INVESTIGATION: This study was undertaken to compare pharmacokinetic parameters of tilidine and metabolites relevant for analgesia after peroral and intravenous administration. Tilidine is a prodrug from which the active metabolite nortilidine is formed by demethylation. METHODS: 50 mg tilidine-HCl were administered intravenously (10 min infusion) and orally in a crossover design to nine healthy male subjects. Tilidine, nortilidine and bisnortilidine were determined in plasma and urine at appropriate times by means of a specific GLC-method. Systemic availability of the parent substance was 6%. For the RESULTS: analgesically active metabolite nortilidine, the area ratio of the concentration time curves following intravenous versus peroral administration was found to be 0.99. The terminal half-life of nortilidine was 3.3 hours following oral and 4.9 hours following intravenous administration. Renal elimination of unchanged substance was 1.6% of the dose following intravenous administration and less than 0.1% of the dose following oral administration. Approximately 3% were recovered in urine as nortilidine following both routes of administration. Equivalent amounts of the analgesically active metabolite CONCLUSION: nortilidine are made available to the body following intravenous and oral administration of tilidine .
AUTOTOMY FOLLOWING PERIPHEARL DEAFFERENTATION IN THE,RAT DEPENDS ON THE AFFERENT INPUT FROM THE NEUROMA INCLUDING HISTAMINE-SENSITIVE C-FIBERS Y. Paran* , 2. Seltzer and A. Eisen* (SPON: S. Shapira) Physiology Branch, Faculty of Dental Medicine, Hebrew University of Jerusalem, POB 1172, 91010 Israel.
Poster 93 BROWN Th-Fri
-7 ACC
Hall
Abs No
E
897
AIM OF INVESTIGATION: This study evaluated the effects of neuroma resection on autotomy. In addinon, following reports that C-fibers in the neuroma develop histamine-sensitivity (Simmermann et al '871, we studied the effects on autotomy of Astemixol, a new Hl histamine receptor blocker with purely peripheral effects. METHODS: (A). The sciatic n. was cut in 2 groups of Sabra rats. At d22 the neuroma was resected [RESI in 15 rats and a sham resection [SHAM] was performed in 11 rats. The sciatic and saphenous were cut in additional 3 groups and the,neuromas resected on d33 (n=13), or d48 (n=12), or sham-resected at d38 (n=13). (B). In a second experiment, Astemizol LAST] was injected in 14 rats (0.33mg/Kg;0.lml;i.p.; l/day;for 40 days) after preparation of sciatic and saphenous neuromas. Vehicle [VHCLI was injected in 15 control rats. Autotomy was
followedfor 70 days, allowinga 30 days post-injectionperiod. RESULTS: (Al. RES at d22 caused a significant delay in the average autotomy onset day in rats who started to autotomize after d22 (63.9+-4.2SEM days, compared to 47.8+-9.6 days in SHAM-d22). A smaller number of rats autotomixed following RES at d22 (60% compared to 82% in SHAM-d22). Only 33% of the rats in RES-d22 autotomixed severely, compared to 60% of the SHAM-d22 rats. The average autotomy in the RES-d22 group during the period d23-d70 was 69.3+-2.9% of the SHAM-d22 group. The autotomy of RES-d33 group during the period d39-d70 was 40.8+-4.5% of the values of SHAM-d38, and that of RES-d48 in the period d49-d70 was 74.7%+-1.9 of the SHAM-d38 group. (B). AST injection suppressed autotomy compared to the The average value of the AST group at the end of the injections period was 1.4+-0.8, VHCL. 50% less than that of the VHCL group. After the injections stopped (d401, autotomy in the VHCL group increased until at d70 the average score was 6.8+-1.2. In the AST group, in contrast, the autotomy remained almost unchanged (only 2.1+-0.9 at d701. Resection of 'painful neuromas' temporarily relieves the pain in humans. CONCLUS~N& Similarly, resection of neuromas in this study suppressed the autotomy, indicating that autotomy depends on the input from the neuroma. Since only C-fibers in the neuroma are histamine-sensitive, suppression of autotomy by a peripheral anti-histamine indicates that histamine-sensitive C-fibers are part of the afferent drive of autotomy. Anti-histamines may suppress deafferentation pain in humans.
PHARMACOKINETICS OF THE ANALGESIC TILIDINE WITH SPEC IAL REFERENCE TO THE ACTIVE METABOLITE K.-O. Vollmer, H. Hengy, P. Thomann (SPON: B. Bromm), Gijdecke Research Institute, Dept. of Pharmacokinetics and Metabolism, D-7800 Freiburg, FRG
I
Poster 92 BROWN Th-Fri ACC Hall E Abs No
896
I
AIM OF INVESTIGATION: This study was undertaken to compare pharmacokinetic parameters of tilidine and metabolites relevant for analgesia after peroral and intravenous administration. Tilidine is a prodrug from which the active metabolite nortilidine is formed by demethylation. METHODS: 50 mg tilidine-HCl were administered intravenously (10 min infusion) and orally in a crossover design to nine healthy male subjects. Tilidine, nortilidine and bisnortilidine were determined in plasma and urine at appropriate times by means of a specific GLC-method. Systemic availability of the parent substance was 6%. For the RESULTS: analgesically active metabolite nortilidine, the area ratio of the concentration time curves following intravenous versus peroral administration was found to be 0.99. The terminal half-life of nortilidine was 3.3 hours following oral and 4.9 hours following intravenous administration. Renal elimination of unchanged substance was 1.6% of the dose following intravenous administration and less than 0.1% of the dose following oral administration. Approximately 3% were recovered in urine as nortilidine following both routes of administration. Equivalent amounts of the analgesically active metabolite CONCLUSION: nortilidine are made available to the body following intravenous and oral administration of tilidine .
AUTOTOMY FOLLOWING PERIPHEARL DEAFFERENTATION IN THE,RAT DEPENDS ON THE AFFERENT INPUT FROM THE NEUROMA INCLUDING HISTAMINE-SENSITIVE C-FIBERS Y. Paran* , 2. Seltzer and A. Eisen* (SPON: S. Shapira) Physiology Branch, Faculty of Dental Medicine, Hebrew University of Jerusalem, POB 1172, 91010 Israel.
Poster 93 BROWN Th-Fri
-7 ACC
Hall
Abs No
E
897
AIM OF INVESTIGATION: This study evaluated the effects of neuroma resection on autotomy. In addinon, following reports that C-fibers in the neuroma develop histamine-sensitivity (Simmermann et al '871, we studied the effects on autotomy of Astemixol, a new Hl histamine receptor blocker with purely peripheral effects. METHODS: (A). The sciatic n. was cut in 2 groups of Sabra rats. At d22 the neuroma was resected [RESI in 15 rats and a sham resection [SHAM] was performed in 11 rats. The sciatic and saphenous were cut in additional 3 groups and the,neuromas resected on d33 (n=13), or d48 (n=12), or sham-resected at d38 (n=13). (B). In a second experiment, Astemizol LAST] was injected in 14 rats (0.33mg/Kg;0.lml;i.p.; l/day;for 40 days) after preparation of sciatic and saphenous neuromas. Vehicle [VHCLI was injected in 15 control rats. Autotomy was
followedfor 70 days, allowinga 30 days post-injectionperiod. RESULTS: (Al. RES at d22 caused a significant delay in the average autotomy onset day in rats who started to autotomize after d22 (63.9+-4.2SEM days, compared to 47.8+-9.6 days in SHAM-d22). A smaller number of rats autotomixed following RES at d22 (60% compared to 82% in SHAM-d22). Only 33% of the rats in RES-d22 autotomixed severely, compared to 60% of the SHAM-d22 rats. The average autotomy in the RES-d22 group during the period d23-d70 was 69.3+-2.9% of the SHAM-d22 group. The autotomy of RES-d33 group during the period d39-d70 was 40.8+-4.5% of the values of SHAM-d38, and that of RES-d48 in the period d49-d70 was 74.7%+-1.9 of the SHAM-d38 group. (B). AST injection suppressed autotomy compared to the The average value of the AST group at the end of the injections period was 1.4+-0.8, VHCL. 50% less than that of the VHCL group. After the injections stopped (d401, autotomy in the VHCL group increased until at d70 the average score was 6.8+-1.2. In the AST group, in contrast, the autotomy remained almost unchanged (only 2.1+-0.9 at d701. Resection of 'painful neuromas' temporarily relieves the pain in humans. CONCLUS~N& Similarly, resection of neuromas in this study suppressed the autotomy, indicating that autotomy depends on the input from the neuroma. Since only C-fibers in the neuroma are histamine-sensitive, suppression of autotomy by a peripheral anti-histamine indicates that histamine-sensitive C-fibers are part of the afferent drive of autotomy. Anti-histamines may suppress deafferentation pain in humans.