The pharmacology of 1841 CERM, a new analgesic.

A new non-narcotic analgesic, 2(3-trifluormethyl)-phenyl-tetrahydro-1,4-oxazine (1841 CERM) was compared with morphine, codeine and acetylsalicylic acid (ASA) in various pharmacological tests for analgesic activity. Studies for possible tolerance and physical dependence liability were also carried out. In these tests, 1841 CERM was a more powerful analgesic than morphine, and particularly codeine when given orally. It did not lead to tolerance or physical dependence.     

新型镇痛药氟吡啶的镇痛作用研究进展

新型中枢性镇痛药氟吡啶对于手术、创伤等引起的中等程度的急性疼痛有良好疗效，对慢性疼痛以及癌痛等也有效。其作用机制与阿片类药物不同，可能与去甲肾上腺素系统有关，拮抗N－甲基－D－天门冬氨酸（NMDA）受体可能是其发挥镇痛作用的受体机制之一，但其更深入的镇痛作用机制还有待进一步阐明，以利于设计创新的镇痛药物。     

The animal pharmacology of buprenorphine, an oripavine analgesic agent.

1. The general pharmacology of buprenorphine, a potent analgesic agent derived from oripavine, is described. 2. After cute administration of buprenorphine, the spontaneous locomotor activity of mice was increased; rats displayed stereotyped licking and biting movements; behavioural depression was marked in guinea-pigs but mild in rhesus monkeys. The behaviour of cats was unchanged. 3. In general, buprenorphine reduced heart rate but had no significant effect on arterial blood pressure in conscious rats and dogs. 4. In anaesthetized, open-chest cats buprenorphine (0.10 and 1.0 mg/kg, i.v.) caused no major haemodynamic changes. 5. Buprenorphine (0.01-10 mg/kg i.a.) and morphine (0.30-30 mg/kg, i.a.) increased arterial PCO2 values and reduced PO2 values in conscious rats. With doses of buprenorphine greater than 0.10 mg/kg (a) the duration of respiratory depression became less, (b) ceiling effects occurred such that the maximum effects produced were less than those obtained with morphine. 6. Buprenorphine was a potent and long-lasting antagonist of citric acid-induced coughing in guinea-pigs. 7. At a dose level 20 times greater than the ED50 for antinociception (tail pressure), morphine suppressed urine output to a greater extent than the corresponding dose of buprenorphine in rats. 8. Over the range 0.01-1.0 mg/kg (s.c.), buprenorphine slowed the passage of a charcoal meal along the gastrointestinal tract in rats. After doses in excess of 1 mg/kg, the meal travelled increasingly further such that the distances measured at 10 and 30 mg/kg did not differ significantly from control values. In contrast, the morphine dose-response relationship was linear.     

Fenbufen, a new anti-inflammatory analgesic: synthesis and structure-activity relationships of analogs.

One hundred analogs of fenbufen were prepared and tested using the carrageenan, polyarthritis, and UV erythema anti-inflammatory tests and the 2-phenyl-1,4-benzoquinone writhing and inflamed paw pressure analgesic tests. Only three retained the same full spectrum of activity as fenbufen: dl-4-(4-biphenylyl)-4-hydroxybutyric acid, dl-4-(4-biphenylyl)-1,4-butanediol, and 4-biphenylacetic acid. Fenbufen had the same spectrum of activity as aspirin, phenylbutazone, and indomethacin in the five tests. In addition, dose-response derived potencies show fenbufen more potent than aspirin and at least as potent as phenylbutazone in all five tests. Two related compounds were generally similar.     

The pharmacology of iprindole,a new antidepressant

Summary Iprindole, a tricyclic indole antidepressant shares in common with imipramine-type antidepressants the ability to potentiate the central effects of amphetamine, and potentiate the peripheral effects of direct acting catecholamines. In contrast to imipramine-type compounds iprindole does not inhibit H³NE uptake centrally or peripherally, does not block the peripheral actions of indirect acting sympathomimetic amines nor block the inhibiting effects of guanethidine on the vas deferens preparation. These findings suggest that iprindole enhances activity of adrenergic receptors through a mechanism unrelated to inhibition of reuptake of norepinephrine.The minimal anticholinergic and antihistaminic activity of iprindole supports the contention that these effects are unnecessary for antidepressant activity.Tests involving potentiation of amphetamine proved to be more predictive of the antidepressant activity of iprindole than tests involving reserpine antagonism.     

The pharmacologic effect of flupirtine, a structurally new analgesic

The analgesic potency of ethyl-N-[2-amino-6-(4-fluorophenylmethylamino)pyridin-3-yl]carb ama te (flupirtine, D 9998) in mice and rats in Haffner's test, electro-pain test and Randall-Selitto test (inflammation induced pain) lies between the more potent dextromoramide and methadone and the more weakly active pethidine, dextropropoxyphene, codeine, phenacetin and paracetamol. In comparison to codeine flupirtine is up to 4 times more potent, up to 2 times more active than pethidine and 4 times more potent than dextropropoxyphene in the above-mentioned methods. With one exception of inflammation induced pain, where flupirtine shows an activity of about 1 1/2 times that of phenacetin and paracetamol, both analgesics are about 10 to nearly 30 times less active than flupirtine in other above-mentioned tests. In the hot plate test flupirtine is twice as active as codeine and approximately 10 times more active than phenacetin and paracetamol. The weakest analgesic activity of flupirtine is seen in acetic acid test where it is about half as active as codein and approximately as active as dextropropoxyphene. Nevertheless, flupirtine is up to 10 times more potent than phenacetin and paracetamol. The acetic acid test is claimed to be non-specific according to our own experience and to other authors. Flupirtine is enterally absorbed at a higher degree than the other tested centrally acting analgesics. In regard to the results of various analgesic investigations in mice and rats flupirtine can be classified as a medium to strong acting analgesic. The duration of action of flupirtine is comparable to that of codeine. Experiments with flupirtine suggest that there are some convincing criteria for a pronounced central acting component of its analgesic activity. These criteria are the strong efficacy in the hot-plate and Haffner's test, in which only centrally acting analgesics show distinct effects, and the finding that flupirtine increases the pain threshold for vocalisation in rats and mice excluding a pure reflex of the spinal cord. In current experiments concerning the mode of action flupirtine exhibits a distinct central analgesic component of action. In spite of its relatively high analgesic potency which corresponds to that of opiates flupirtine does not show any other signs of opiate properties and other potent analgesics. Thus, flupirtine does not develop tolerance in mice and rats after 19 or 17 days of daily administration.(ABSTRACT TRUNCATED AT 400 WORDS)     

Nicafenine, a new analgesic. I. Synthesis and physicochemical properties.

The synthesis of 2-[(7-chloro-4-quinolyl)-amino] benzoic acid 3-pyridine carboxamide-N-ethyl ester (nicafenine) was carried out by a new method using isatoic anhydride. The IR, NMR, MS and UV spectrophotometric studies are described, together with the characteristics of this compound.     

The effects of a new benzodiazepine derivative,ID-540, on the averaged photopalpebral reflex in man

The effects of 7-chloro-5-(2-fluorophenyl)-1-methyl-1 H, 1·4-benzodiazepin-2(3 H)-one (ID-540), a recently introduced benzodiazepine derivative, on the averaged photopalpebral reflex (PPR), subjective symptoms, and serum levels of ID-540 and its principal metabolite, N-desmethyl-ID-540, following an oral dose of 0.5 mg or placebo were investigated in six male Japanese students in a double-blind, crossover design. The peak latencies of PPR showed a statistically significant prolongation, with maximum level at 3h after administration, which recovered to the initial level within 4h. The amplitude of PPR failed to show a definite response to the drug. The serum concentration of ID-540 reached a peak level 2–3h after administration, and then decreased at 4h. N-Desmethyl-ID-540 exhibited a slow, gradual rise in serum. The latencies of PPR were positively correlated with the serum level of ID-540 but not with the N-desmethyl-ID-540. It is concluded that the PPR test may be a useful method for predicting the clinical effects of psychotropic drugs.To whom requests for offprints should be sent     

Dihydroetorphine: a potent analgesic: pharmacology,toxicology, pharmacokinetics,and clinical effects

Dihydroetorphine (DHE) is one of the strongest analgesic opioid alkaloids known; it is 1000 to 12000 times more potent than morphine. Several in vitro and in vivo studies have shown that DHE is a selective mu-opioid receptor (OP(3)) agonist that also binds and activates all human recombinant mu-, delta-, and kappa-opioid receptors (OP(3), OP(1), and OP(2)). The onset of the analgesic effect of DHE in rodents is rapid, 5 to 15 min after parenteral administration; the duration of action is short, the analgesic effect disappears within 120 min after administration. By oral administration much higher doses of DHE are required to produce analgesic effects. These characteristics are accounted for by the pharmacokinetic properties of DHE in the rat, namely, by rapid distribution of DHE from the injection site to the brain and rapid metabolism by glucuronidation in the gut and liver followed by elimination into the bile. Continuous infusion and repeated administration of DHE lead to the development of tolerance to analgesia, physical dependence, and a rewarding effect in normal rats but not in animals with formalin-induced inflammation. Although formalin-induced inflammation is only one type of pain stimulus, these findings suggest that DHE addiction would be observed only in the case of pain-free conditions. Clinical reports in China show that sublingual doses of DHE, 20 to 180 microg, produce a potent analgesic effect with only mild side effects, including dizziness, somnolence, nausea, vomiting, constipation, and shortness of breath. To improve the short-lasting effect following sublingual administration, transdermal delivery of DHE via a patch has been investigated. The patch formulation of DHE produces continuous analgesic effect with minimal physical dependence and rewarding effect in rats suffering from chronic pain. This patch formulation, which is very suitable for DHE, may be viable for the treatment of severe pain and is likely to improve patients' quality of life.     

The rise of a new GABA pharmacology

Key developments in GABA pharmacology over the last 30 years are reviewed with special reference to the advances pioneered by Erminio Costa. His passion for innovative science, and his quest for novel therapies for psychiatric disorders are particularly apparent in his fundamental contributions to the field of GABA research, with a focus on anxiety disorders and schizophrenia. He was a cofounder of the GABAergic mechanism of action of benzodiazepines. He envisaged partial agonists as novel anxiolytics. He identified DBI (diazepam binding inhibitor) as endogenous agonist of neurosteroidogenesis with multiple CNS effects and he pointed to the developmental origin of GABAergic dysfunctions in schizophrenia through his discovery of a reelin deficit, all this in collaboration with Sandro Guidotti. Today, the GABA pharmacology comprises selective hypnotics, non-sedative anxiolytics, memory enhancers and powerful analgesics. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.     

Pharmacokinetics and bioavailability of ciramadol,a new analgesic

Healthy male volunteers participated in two studies of the pharmacokinetics of ciramadol, an investigational analgesic. For the dose-proportionality study, subjects received single i.v. doses of 15, 30, or 60 mg of ciramadol on three separate occasions. Serum samples and urine were collected 48 hr after each dose. Overall mean kinetic values for ciramadol were: volume of distribution, 1.5 liters/kg; elimination half-life, 3.7 hr; total clearance, 4.9 ml/min/kg. Clearance did not change systematically with dose. Mean 48-hr urinary excretion was 40% of the dose as the intact drug, with another 24% excreted as ciramadol conjugates; these were dose-independent. For the bioavailability study, subjects received a 30-mg dose of ciramadol i.v., i.m., or orally on three separate occasions. The mean absolute systemic availability of the i.m. dose was 98%; the absolute availability of the oral dose was 82%. Peak serum concentration of 235 and 155 ng/ml were attained at 0.27 and 1.5 hr after the i.m. and oral doses, respectively.     

The chemistry, pharmacology and clinical pharmacology of diflunisal.

Studies are reviewed on diflunisal, a new analgesic agent with an improved therapeutic index, compared with acetylsalicylic acid, in animals and humans. Pharmacokinetic data indicate that a twice-daily dosage regimen of diflunisal is adequate for therapeutic purposes. Diflunisal inhibits prostaglandin E synthesis, but in humans at clinically effective doses it does not alter bleeding time or platelet aggregation. Diflunisal is uricosuric at clinically effective doses. No clinically important drug interactions with diflunisal have been found to date, although some slight alterations in blood and urine drug levels have been noted. The slight increase in prothrombin time seen when diflunisal and acenocoumarol were co-administered is not considered to be of major clinical importance.