Structure-activity relationships (SAR) are studied in the series of 4,4-disubstituted piperidine morphinomimetics (42 compounds) by means of the Electronic-Topological Method (ETM). In the frameworks of this approach, its input data were taken as the results of conformational and quantum-mechanical calculations. These calculations had been carried out for all compounds from the series under study, taking into account their neutral and protonated by the nitrogen of piperidine cycle forms. The ETM application resulted in a set of pharmacophores and anti-pharmacophores, which formed a basis of a system used to predict analgesic activity. First of all, the system was tested on known analgesics. Testing has shown a good agreement with the experimental data. Then, the system was applied to a few compounds with similar structures but unknown activity. The results of the study could be used for computer screening and design of novel compounds with analgesics properties as new potential drugs.

Delirium is a common complication in hospitalized patients and is often associated with significant morbidity. It is important to recognize this syndrome early so that potential causes can be identified and properly managed. Although the etiology of delirium in critically or terminally ill patients is often multifactorial, opioid analgesics are often implicated as a potential underlying cause. Certain opioids, such as meperidine, have been identified as having a greater potential for causing delirium than others. There have been no published reports of anileridine-induced delirium and an illustrative case is presented.

This article describes our experience in the clinical use of nebulized opioids for the management of dyspnoea in patients with terminal cancer by reviewing three specific patient case studies in which this treatment was found to be both safe and effective in controlling breathlessness. The patients were treated with morphine, hydromorphone or anileridine in various doses according to their prior use of opioids. Additional formal studies are being initiated at this Centre.

The method for the analysis of anileridine, levorphanol, nalbuphine and ethamivan in urine by means of GC/NPD and GC/MSD is described. TFAA and MSTFA-MBTFA have been used in this procedure for TFA and TMS derivatization. The parent forms and the metabolites of the four drugs can be found by GC/NPD screening and GC/MSD confirmation. The method is reliable, fast and sensitive.

The analgesic effects of meperidine, anileridine, codeine and codeine + acetominophen on surgical and non-surgical pain in 101 patients were assessed using the McGill Pain Questionnaire. The quality of analgesia was determined by analyzing the changes in the pain descriptors chosen 1 hour after medication. Meperidine and anileridine differentially reduced pain qualities rated as "bright-phasic" by a student sample. Codeine and codeine + acetominophen produced similar patterns of analgesia that were homogeneous across "bright-phasic" and "dull-tonic" types of pain. The data suggest the possibility that opioids may differ in the quality of analgesia produced either as dose increases or different opioid receptor types are recruited.

Haemodynamic effects of equianalgesic doses of pethidine (1 mk kg -1) and anileridine (0.25 mg kg -1) were compared in patients with coronary artery disease, after induction of anaesthesia with flunitrazepam - N2O - pancuronium. Contrary to previous findings made in conscious patients, these analgesics produced a moderate circulatory depression. Heart rate, cardiac index and rate-pressure product were decreased by both drugs, and anileridine alone decreased mean arterial pressure. The only statistically significant differences in the haemodynamic changes between the two groups were those in pulmonary capillary wedge pressure and rate pressure product, which were slightly lower after anileridine than after pethidine.

Pigeons responded under a multiple fixed-ratio 30-response, fixed-interval 5-min schedule of food presentation. Daily administration of clorgyline (10 mg/kg, IM) tended to decrease rates of responding in both schedule components. Before daily clorgyline, tetrabenazine had no effect or decreased responding in the FI component at doses that markedly increased responding during chronic clorgyline. The clorgyline treatment resulted in a slight increase in sensitivity to the rate-decreasing effects of morphine, but no increased sensitivity to the rate-decreasing effects of meperidine, anileridine, alphaprodine, or fentanyl.

The haemodynamic effects of large bolus doses of metocurine 0.45 mg kg-1 and pancuronium 0.1 mg kg-1 were compared in patients with coronary artery disease anaesthetized with diazepam, anileridine and nitrous oxide. Hypotension occurred more frequently after metocurine and was a result of a decrease in systemic vascular resistance. After pancuronium there was no increase in arterial pressure or heart rate, but a small increase in cardiac index. The decrease in heart rate after metocurine was the principal cause of the statistically significant difference in cardiac index between the two groups. Contrary to previous findings, metocurine did not attenuate circulatory responses to tracheal intubation. During surgical stimulation, two of the 10 patients of the pancuronium group developed significant ST segment depression and three patients had a rate-pressure product greater than 12 000 mm Hg beat min-1. However, the difference in rate-pressure product between the groups was not statistically significant.

These studies were undertaken to determine the effects of morphine and other opiate and opioid agonists on body temperature in the mouse. Mice were lightly restrained, and rectal temperatures were monitored after injection of opiate analgesics at each of three ambient temperatures. The drugs tested were pure agonists representing eight different chemical classes. At 20 degrees C, morphine, hydromorphone, levorphanol, oxymorphone, methadone, etonitazene, fentanyl, etorphine and meperidine produced hyperthermia in low doses and hypothermia as the doses were raised. Codeine produced only hypothermia at 20 degrees C in the doses studied. At 25 degrees C, the hypothermic responses were greatly reduced in magnitude, and most drugs produced biphasic or only hyperthermic responses. At 30 degrees C, dose-related hyperthermia was the usual response with the exception of meperidine which produced only hypothermia, although a temperature increase was observed after anileridine, a closely related phenylpiperidine. There is good correlation between the relative potencies of the agonists with respect to their hypothermic effects in mice and their relative potencies as analgesics in mice. The temperature effects of morphine are complex but appear to be characteristic of opiate agonists as a class. The magnitude and the direction of the temperature responses to opiates are dose-dependent and profoundly influenced by the environmental temperature.

The effects of morphine, meperidine, alphaprodine, and anileridine were studied alone and in the presence of 1 mg/kg of naloxone in rats on level pressing under a fixed-ratio 20-response schedule of food presentation and on tail-withdrawal latency from warm water (55 degrees C) as a measure of analgesia. All four narcotics decreased rates of lever pressing and increased tail-withdrawal latencies. Naloxone antagonized the effects of all four narcotics on tail-withdrawal, but did not antagonize the rate-decreasing effect of meperidine on lever pressing. Naloxone shifted the morphine dose-effect for lever-pressing by a factor of 4-8; the alphaprodine dose-effect curve by a factor of 4-8; and the anileridine dose-effect curve by a factor of 2. These results strengthen the interpretation that meperidine's effect on schedule-controlled responding is not mediated by a narcotic action whereas the analgesic effect is. The results also suggest that anileridine has significant non-narcotic actions like meperidine.

The ability of pentobarbital, diazepam, and chlorpromazine to attenuate the rate-decreasing effects of a high dose (10 or 30 mg/kg) of meperidine was tested in pigeons responding under a multiple fixed-ratio, fixed-interval schedule of food presentation. Pentobarbital (10 mg/kg) attenuated the meperidine-induced rate decreases, whereas diazepam (0.3--3 mg/kg) or chlorpromazine (3--30 mg/kg) did not reliably attenuate the response rate decreases. The combination of 10 mg/kg of pentobarbital and meperidine resulted in a marked disruption of the pattern of responding in the fixed-interval component of the multiple schedule. Pentobarbital (1, 3, 10, and 17.5 mg/kg) was also tested in combination with rate-decreasing doses of normeperidine (17.5 mg/kg), anileridine (10 mg/kg), alphaprodine (10 mg/kg), and fentanyl (0.3 mg/kg). Pentobarbital reliably attenuated the rate-decreasing effects of normeperidine, anileridine, and alphaprodine, but not the rate decreases induced by fentanyl.

The separate and combined analgesic effects of 10 mg of oral amphetamine sulfate and 25 mg of oral anileridine dihydrochloride were studied in 24 healthy, adult, male volunteers. Tolerance of progressively increasing pain produced by the Submaximum Effort Tourniquet Technique was tested four times in each subject: after amphetamine, after anileridine, after the combination, and after a matching placebo. Treatments were administered double blind and in counterbalanced order. Elapsed time to report of slight, moderately distressing, very distressing, and unbearable pain was recorded on each trial. The four oral treatments differed significantly for very distressing and for unbearable pain. At each of the three upper pain levels, the mean tolerance times for anileridine and amphetamine were similar; each was longer than placebo but shorter than the combination; and the effect of the combination was approximately the sum of the effects of the two components.

The acute administration of levorphanol, morphine, anileridine, methadone, cyclazocine and pentazocine was found to increase brain levels of 3-methoxy-4-hydroxyphenylethylene glycol sulfate (MOPEG-SO4) in rats. Drug-induced increases in brain levels of this norepinephrine metabolite were dose-dependent and peak drug effects generally occurred 1 hr after intraperitoneal injection. Six to 8 hr after opiate agonist or partial agonist administration, MOEG-SO4 levels returned to control values or below. The narcotic effect appeared to be stereospecific, since high doses of d-methadone and dextrorphan produced either no change or only minimal increases in brain MOPEG-SO4 levels when compared with saline-treated controls. The relative potency of the analgesics tested in producing increases in brain MOPEG-SO4 levels appeared to correlate reasonably well with the ability of these drugs to produce other characteristic pharmacological effects. The drug-induced increases in brain MOPEG-SO4 levels were antagonized by naloxone. The rate of disappearance of MOPEG-SO4 from the brains of animals treated with pargyline was not decreased by the opiate agonists or partial agonists tested indicating that these drugs did not inhibit the acid transport process. These results indicate that the production of an increase in brain norepinephrine turnover is a specific component of the pharmacological actions of narcotic analgesics.