Synthesis and biological studies on analogs of cyclolinopeptide A with a shortened peptide chain

Continuing our work on the immunosuppressive activity of cyclolinopeptide A (CLA), a cyclic nonapeptide of the sequence: c-(-Leu-Ile-Ile-Leu-Val-Pro-Pro-Phe-Phe), we synthesized a series of 6 linear analogs of CLA, successively shortened at the N-terminus of the peptide chain. Immunosuppressive activity of acetates as well as trifluoroacetates of these peptides was investigated using PFC (humoral immunity) and DTH (cellular immunity) tests. It was found that the immunosuppressive potency of the peptides examined diminishes with shortening of the peptide chain. Octapeptide I with the sequence Ile-Ile-Leu-Val-Pro-Pro-Phe-Phe was found to be the most active of the whole series. The immunosuppressive activity increased again for a tripeptide fragment of CLA of the sequence Pro-Phe-Phe. The immunosuppressive activity of octapeptide probably depends on the suppression of IL-1, IL-6 and TNF production by the cells involved in immune and inflammatory response.     

Development of orally active oxytocin antagonists: studies on 1-(1-[4-[1-(2-methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy]-2- methoxybenzoyl]piperidin-4-yl)-1,4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and related pyridines

The previously reported oxytocin antagonist L-371,257 (2) has been modified at its acetylpiperidine terminus to incorporate various pyridine N-oxide groups. This modification has led to the identification of compounds with improved pharmacokinetics and excellent oral bioavailability. The pyridine N-oxide series is exemplified by L-372,662 (30), which possessed good potency in vitro (Ki = 4.1 nM, cloned human oxytocin receptor) and in vivo (intravenous AD50 = 0.71 mg/kg in the rat), excellent oral bioavailability (90% in the rat, 96% in the dog), good aqueous solubility (>8.5 mg/mL at pH 5.2) which should facilitate formulation for iv administration, and excellent selectivity against the human arginine vasopressin receptors. Incorporation of a 5-fluoro substituent on the central benzoyl ring of this class of oxytocin antagonists enhanced in vitro and in vivo potency but was detrimental to the pharmacokinetic profiles of these compounds. Although lipophilic substitution around the pyridine ring of compound 30 gave higher affinity in vitro, such substituents were a metabolic liability and caused shortfalls in vivo. Two approaches to prevent this metabolism, addition of a cyclic constraint and incorporation of trifluoromethyl groups, were examined. The former approach was ineffective because of metabolic hydroxylation on the constrained ring system, whereas the latter showed improvement in plasma pharmacokinetics in some cases.     

Rodent thyroid gland function under hot climatic conditions

Studies have been made on the effect of high temperature and intensive insolation upon the uptake of iodide and hormone formation in the thyroid of rodents (Rhombomys opimus, Spermophilopsis leptodactylus, Citellus fulvus) with different adaptation to the environment. It was shown that high temperature in combination with solar radiation significantly decreases functional activity of the thyroid and affects some of the physiological indices of the organism. Animals with different ecological specialization differ in their reaction to factors of the hot climate.     

Randomised trial of one versus two doses of prostaglandin E2 for induction of labour: 2. Analysis of cost

OBJECTIVE: To compare the impact upon maternity unit resources and finances of two protocols for induction of labour using prostaglandins. DESIGN: A prospective randomised trial comparing a single dose of prostaglandin E2 (2 mg) in the evening with two doses of prostaglandin E2 (2 mg), the second being given after six hours if labour had not started or the cervix was still unripe, followed if necessary by formal induction of labour by amniotomy and oxytocin infusion 14 to 20 hours after the initial prostaglandin E2 dose. Outcome for nulliparae and multiparae were analysed separately, by treatment intention. SETTING: A maternity unit in a district general hospital delivering > 6000 women annually. PARTICIPANTS: Nine hundred and fifty-five women with viable singleton pregnancies and cephalic presentation at term without previous history of caesarean section who were advised to have labour induced with prostaglandins. MAIN OUTCOME MEASURES: Costs incurred in managing all aspects of labour, including time spent on the antenatal ward and, in the delivery unit; costs associated with formal induction, augmentation of labour and epidural analgesia; costs of intrapartum maternal morbidity, mode of delivery and immediate neonatal care. Costs of postpartum hospital stay were estimated from unit statistics. RESULTS: The overall mean cost of induction of labour was Pounds 5.00 and Pounds 7.22 less per woman for nulliparae and multiparae, respectively, if the two dose regimen was used. The main reason for the differences was due to delivery suite costs from the slightly greater rate of assisted deliveries in the single treatment groups. In contrast, costs for neonatal care were marginally lower if only one prostaglandin dose was used. CONCLUSIONS: The increased drug costs providing two prostaglandin E2 doses when required were off-set by reductions in the costs of other intrapartum interventions for both nulliparae and multiparae. The advantages of less time spent on the antenatal ward for multiparae when two prostaglandin E2 doses were used may be eliminated if amniotomy and oxytocin infusion was commenced six hours after the initial prostaglandin dose had been given if labour had not started.     

Acute effects of estradiol infusion and naloxone on luteinizing hormone secretion in pubertal boys

We have shown previously in pubertal boys that testosterone (T) suppresses the nocturnal augmentation of luteinizing hormone (LH) secretion principally by decreasing LH pulse frequency. As T can be aromatised to estradiol (E2), and E2 effects on LH secretory dynamics may be separate from those of T, we examined the effects of acute E2 infusion on LH secretion in pubertal boys. Opioid receptor blockade has been reported to increase LH secretion after estradiol suppression in adult men, so we also examined whether naloxone might augment LH secretion during E2 treatment in pubertal boys. Starting at 1000 h, eight pubertal boys were given a 33 h saline infusion, followed 1 week later by an E2 infusion at 4.6 nmol/m2/h. During both infusions, four iv boluses of saline were given hourly beginning at 1200 h on the first day, and four naloxone iv boluses, 0.1 mg/kg each, were given hourly beginning at 1200 h on the second day. Blood was obtained every 15 min for LH, and every 60 min for T and E2, from 1200 h until the end of the infusion. Pituitary responsiveness to gonadotropin-releasing hormone (GnRH) was assessed after both infusions by iv administration of 250 ng/kg synthetic GnRH. Estradiol infusion increased the mean plasma E2 concentration from 23 +/- 4 to 46 +/- 6 pmol/L (P < 0.01) and suppressed mean plasma T from 4.9 +/- 1.4 to 3.0 +/- 3.5 nmol/L (saline vs. E2 infusion, P < 0.05). The overall mean LH was suppressed by E2 infusion from 3.7 +/- 0.5 to 2.2 +/- 0.4 IU/L (saline vs. E2 infusion, P < 0.01). LH pulse frequency was suppressed by 50%, whereas mean LH pulse amplitude was not different between saline and E2 infusions. Administration of naloxone did not alter the mean LH, LH pulse frequency, or amplitude during either saline or E2 infusions. Pituitary responsiveness to exogenous GnRH was similar during both infusions. These studies indicate that E2 produces its negative feedback in pubertal boys principally by suppression of LH pulse frequency, and naloxone does not reverse these suppressive effects. Thus E2 suppression of LH secretion is mediated by a decrease of hypothalamic GnRH secretion that is independent of endogenous opioid pathways.     

Changes in resistance and capacitance functions of skeletal muscle vessels during the amplitude-frequency modulation of the perfusion blood flow

Changes of venous outflow, pre- and postcapillary resistance of the skeletal muscle vessels were found to depend on values of amplitude and frequency of the perfusion blood flow in cats. Three types of the responses were distinguished: either increase, or decrease, or absence of them. The findings suggest a possibility to affect haemodynamic parameters with the aid of amplitude-frequency deviations in the organ blood flow.