pyrimidinones and probon

On the basis of the results of earlier published and recent examinations it could be concluded that among analgesics Probon is the first of choice especially in case of chronic pain accompanying chronic respiratory tract diseases. The value of the drug is also supported by the fact that the number of patients suffering from chronic obstructive respiratory failure increases continuously, since the equilibrium of these patients is very unstable; the smallest injury, such as an increase in secretion, a decrease in diaphragmatic movement, or chest expansion caused by pain, or even drug-induced respiration depression, may very easily upset this equilibrium.

Topics: Aged; Analgesics; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Male; Pain; Pyrimidinones; Respiration; Respiratory Tract Diseases

Topics: Analgesics; Arthritis; Arthritis, Rheumatoid; Chemical Phenomena; Chemistry; Drug Therapy, Combination; Drug Tolerance; Gastrointestinal Hemorrhage; Humans; Indomethacin; Pain; Pyrimidinones

On the basis of the results of earlier published and recent examinations it could be concluded that among analgesics Probon is the first of choice especially in case of chronic pain accompanying chronic respiratory tract diseases. The value of the drug is also supported by the fact that the number of patients suffering from chronic obstructive respiratory failure increases continuously, since the equilibrium of these patients is very unstable; the smallest injury, such as an increase in secretion, a decrease in diaphragmatic movement, or chest expansion caused by pain, or even drug-induced respiration depression, may very easily upset this equilibrium.

Topics: Aged; Analgesics; Clinical Trials as Topic; Drug Evaluation; Female; Humans; Male; Pain; Pyrimidinones; Respiration; Respiratory Tract Diseases

1,6-Dimethyl-3-carbethoxy-4-oxo-6,7,8,9-tetrahydro-homopyrimidazol (rimazolium, MZ-144) proved to be effective in all the analgesic assays used (independently of the nociceptive stimulus applied) (hot plate, tail flick, writhing tests, Randall-Selitto test, tail clip, surgical pain) differing in this respect from the nonsteroidal antiinflammatory analgetics. The analgesic, antiinflammatory and gastrointestinal effects of rimazolium, morphine and prostaglandin synthesis inhibitors were compared. The prostaglandin (PG) mediated pain (acetylcholine-, adenosine triphosphate- and acetic acid-induced writhing) was inhibited by all the three types of compounds, however, pain reaction where PGs are not involved (MgSO4-writhing) was inhibited only by rimazolium and morphine but not, or only slightly, by PG synthesis inhibitors. While the analgesic effect of rimazolium alone was not reversed by naloxone, the full analgesia evoked by the ineffective doses of morphine and rimazolium combinations was completely naloxone reversible (pA2 = 8.6). In addition, rimazolium produced weak analgesia by intrathecal administration, and its concomitant s.c. administration enhanced the analgesic effect of intrathecally administered morphine. Furthermore, chronic treatment with rimazolium failed to influence its analgesic activity, and no tolerance developed and no naloxone precipitated withdrawal syndrome could be seen. In addition, rimazolium did not substitute for morphine in morphine dependent rats, after morphine withdrawal, thus indicating that rimazolium lacks the capacity of producing opiate-like physiological dependence. Also rimazolium fails to show any indication of narcotic-like abuse liability by any of clinical assessments. Rimazolium, morphine and indometacin inhibited the carrageenin-induced edema formation. Gastrointestinal lesions produced by indometacin were depressed by rimazolium and enhanced by morphine.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Body Weight; Cats; Dogs; Drug Tolerance; Guinea Pigs; Indomethacin; Macaca mulatta; Male; Mice; Pyrimidinones; Rabbits; Rats; Reaction Time; Stomach Ulcer; Substance Withdrawal Syndrome; Substance-Related Disorders

The analgesic, anti-inflammatory and gastrointestinal effects of rimazolium, morphine and prostaglandin synthesis inhibitors were compared in a battery of tests. Rimazolium, morphine and indomethacin all inhibited carrageenin-induced inflammation; however, the onset of action was different. The first (histamine-serotonin) phase was inhibited by rimazolium, the second (kinin) phase by morphine and the third (prostaglandin) by indomethacin. The chemoluminescence of leucocytes was inhibited by morphine and indomethacin but was unaffected by rimazolium. Prostaglandin-mediated pain (ACh, ATP, acetic acid writhing) was inhibited by all three types of compound; however, pain reaction where prostaglandins (PGs) are not involved (MgSO4 writhing) was inhibited by rimazolium and morphine, but not (or only slightly) by PG synthesis inhibitors. Gastric lesions produced by indomethacin were depressed by rimazolium and aggravated by morphine. These results suggest different mechanisms of anti-inflammatory and analgesic action of rimazolium, morphine and PG synthesis inhibitors.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Female; Indomethacin; Leukocytes; Luminescent Measurements; Male; Morphine; Naloxone; Pyrimidinones; Rats; Rats, Inbred Strains; Stomach Ulcer

Topics: Adult; Aged; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Papaverine; Parasympatholytics; Pyrimidinones; Ureteral Calculi

Topics: Aluminum Hydroxide; Aminopyrine; Anti-Inflammatory Agents; Biotransformation; Diclofenac; Drug Interactions; Humans; Indomethacin; Kinetics; Liver; Pyrimidinones; Rheumatic Diseases

The toxic side-effects and anti-inflammatory activity of combination treatment of Sprague-Dawley rats with indomethacin and Probon, a new type of analgesic, were investigated. Following four weeks of treatment with a combination of these two drugs, the characteristic gastrointestinal side-effect of indomethacin was markedly reduced. Mortality resulting from administration of the drug combination was significantly lower than that resulting from indomethacin treatment alone. The reduced toxicity of indomethacin in combination with Probon is probably due to a change in metabolism produced by the hepatic microsomal enzyme inducer, Probon. The anti-inflammatory effect was also investigated using a contact thermographic method following one, three or seven days pretreatment. The advantage of this combination is that, using a higher dose of indomethacin in combination with the minor analgesic, we could achieve a more reliable anti-inflammatory effect together with a pain-killing action.

Topics: Animals; Antipyrine; Drug Interactions; Drug Therapy, Combination; Female; Indomethacin; Male; Peptic Ulcer; Pyrimidinones; Rats; Rats, Inbred Strains

Rimazolium inhibits ethylmorphine-N-demethylation and ethoxycoumarin-O-deethylation by rat liver homogenate when added in vitro in dependence on reaction differently, but marked effects are observed with high concentrations only (10(-3) mol). Both reactions are inhibited after administration of a high sedative dose (180 mg/kg) by 30-40%, after a non-sedative dose no inhibition could be observed. After a 4 d treatment both reactions were not influenced when investigated 24 h after the last administration, the induction by phenobarbital is inhibited in case of ethylmorphine-N-demethylation by rimazolium, but increased in case of ethoxycoumarin-O-deethylation.

Topics: 7-Alkoxycoumarin O-Dealkylase; Animals; Biotransformation; Ethylmorphine-N-Demethylase; Hexobarbital; Kinetics; Oxygenases; Protein Binding; Pyrimidinones; Rats; Rats, Inbred Strains

Topics: Chromatography, Thin Layer; Pyrimidinones

Topics: Adult; Aged; Coronary Disease; Drug Evaluation; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Myocardial Infarction; Pyrimidinones

Topics: Angina Pectoris; Humans; Myocardial Infarction; Pyrimidinones

Topics: Adult; Aged; Analgesics; Angina Pectoris; Female; Humans; Male; Middle Aged; Pyrimidinones; Surgical Procedures, Operative

Topics: Acute Disease; Adolescent; Adult; Aged; Analgesics; Chronic Disease; Drug Evaluation; Humans; Joint Diseases; Middle Aged; Pyrimidinones

Both the analgesic and the antitussive effects of morphine, codeine and azidomorphine, azidocodeine and azidoethylmorphine are potentiated in rats and cats by Probon, a minor analgesic, with a homopyrimidazole structure. The analgesic effect of opiates and their toxicity are more strongly influenced by the N-methylhomopyrimidazoles than their antitussive effect. In the potentiation between Probon and morphine derivatives metabolic interference may play a role at the N-demethylation level, occuring in the liver microsomes.

Topics: Analgesics; Animals; Antitussive Agents; Central Nervous System; Cough; Drug Interactions; In Vitro Techniques; Microsomes, Liver; Morphine; Narcotics; Pyrimidinones; Rats

1. Structure-activity relationship studies with new semi-synthetic isomorphine derivatives revealed that substitution of an azido group in position 6 (azidomorphines) greatly increases the analgesic potency whereas tolerance and dependence liability tend to decrease. 2. Azidomorphine (6-deoxy-6-azidodihydroisomorphine) and 14-hydroxyazidomorphine (6-deoxy-6-azidodihydro-14-hydroxyisomorphine) being in animal tests 40-300 times more potent than morphine, are the most effective analgesics among the semi-synthetic morphine alkaloids. 3. As demonstrated on mice, rats and rhesus monkeys, a remarkable dissociation between the analgesic potency and physical dependence capacity was the result of the introduction of the 6-azido group into dihydroisomorphine. 4. A dichotomy between analgesic effect and tolerance and addiction liability was demonstrated with azidomorphine also in man and the new substance proved to exert significantly less untoward effects than either morphine or pentazocine. 5. Rymazolium (Probon) a new non-narcotic analgesic which strongly potentiates the analgesic and antagonizes the respiratory depressant effect of morphine alkaloids in animals proved to hinder the development of tolerance to morphine in animals and man. 6. The azidomorphine-rymazolium association was found to be less respiratory depressant than azidomorphine administered alone. In patients with chronic intractable pain, an association of azidomorphine (0.5 mg) and rymazolium (150 mg) achieved total pain relief without noticeable euphoria and none of the twelve patients showed, according to the Himmelsbach scoring system, acute abstinence syndromes after nalorphine administration.

Topics: Analgesics; Analgesics, Opioid; Animals; Drug Synergism; Drug Tolerance; Humans; Macaca mulatta; Mice; Morphine Dependence; Morphine Derivatives; Pyrimidinones; Rats