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Analgesic dipeptides. VI.: Synthesis and structure-activity relationships of N-terminal modified analogues of the analgesic compounds H-Xaa-Trp(Nps)-OMe (Xaa=Lys, Orn, Arg).

In order to determine the influence of the N-terminal amino group of the dipeptide derivatives H-Xaa-Trp(Nps)-OMe[Xaa = Lys (2a), Orn (2b), Arg (2c)] on their antinociceptive effects, the syntheses of their corresponding deaminated, acetylated and dimethylated analogues have been achieved. Deamino and dimethyl analogues of 2a,b,6a,b, and 18a,b were prepared by coupling the corresponding N omega-Z- and N omega-Z-N alpha-Me2 amino acids with H-Trp-OMe, using the DCC/HOSu method, followed by sulfenylation of the resulting compounds and removal of the Z groups. Guanidylation of 6b and 18b provided the arginine analogues 6c and 18c, respectively. Ac-Xaa-Trp(Nps)-OMe [Xaa = Lys (11a), Orn (11b) were synthesized by acetylation of H-Xaa(Z)-Trp(Nps)-OMe with acetic anhydride, in the presence of 4-dimethylaminopyridine, and subsequent removal of the Z groups. Coupling of Ac-Arg-OH.HC1 with H-Trp-OMe, using the DCC/HOSu procedure, followed by sulfenylation of the resulting 8:3 diastereomeric mixture of L,L and L,D dipeptides afforded Ac-ambo-Arg-Trp(Nps)-OMe 11c+11d. The antinociceptive effects of 6a-c, 11a-d, and 18 a-c were evaluated after i.c.v. administration in mice. The N alpha-acetyl dipeptides 11 were found to exhibit a naloxone-reversible antinociceptive effects comparable with those of 2, while N-deaminated and N,N-dimethylated analogues were inactive.

Analgesics↗

The analgesic efficacy and neuroendocrine response in paediatric patients treated with two analgesic techniques: using morphine-epidural and patient-controlled analgesia.

BACKGROUND: Pain treatment is one of the main concerns of paediatric anaesthesiologists. The purpose of this study was to assess and compare the quality of analgesia and stress suppression by morphine when used [epidural (single shot) (EP) or with intravenous (i.v.) for patient-controlled analgesia (PCA) in children]. METHODS: Forty-four children, aged 5-15 years, and who were undergoing major genitourinary or lower abdominal surgery with a standardized general anaesthesia technique, were included in this study. In the EP group (n=24) 0.1 mg x kg(-1) morphine in 0.2 ml x kg(-1) saline were given epidurally at the L3-4 level and in the PCA group (n=20) 0.1 mg x kg-1 morphine was given i.v. immediately after intubation. Postoperative PCA bolus doses were 0.5 mg for patients weighing less than 20 kg, 1 mg for children weighing 20-30 kg and 1.5 mg for children weighing 30-40 kg. Blood samples were withdrawn following induction and at 1, 8, 12 and 24 h after morphine administration for measurement of blood glucose, insulin, cortisol and morphine levels. Patients were observed for 24 h postoperatively; heart rate, systolic blood pressure, respiratory rate, FACES pain scores, sedation scores and complications were recorded. RESULTS: The PCA group received 0.56 +/- 0.33 mg x kg(-1) x day(-1) morphine. The FACES pain scores, sedation scores, cortisol, blood glucose and insulin levels were similar in both groups. Haemodynamic and respiratory evaluations and cortisol levels were stable but blood glucose and insulin changes at certain time periods were significant (P < 0.05). Serum morphine levels and incidence of vomiting were different between groups (P < 0.05). Serum morphine levels were similar at the first hour. CONCLUSIONS: Both techniques provided sufficient pain relief and attenuated the hormonal response without life-threatening complications.

Adolescent↗