pyrimidinones and Substance-Withdrawal-Syndrome

A study was designed to determine the interactions, both clinical and pharmacokinetic, between methadone and lopinavir-ritonavir. Results demonstrated a 36% reduction in the methadone area under the plasma concentration-time curve after the introduction of lopinavir-ritonavir, with no coincident symptoms of opioid withdrawal and no requirement for methadone dose adjustment.

Topics: Adult; Analgesics, Opioid; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Male; Methadone; Opioid-Related Disorders; Pyrimidinones; Ritonavir; RNA, Viral; Substance Withdrawal Syndrome

This study examines the pharmacokinetic/pharmacodynamic interactions between (1) lopinavir-ritonavir (L/R), a fixed combination of protease inhibitors used for the treatment of HIV disease, and (2) ritonavir alone at the same dosage as that in the L/R formulation, with methadone, an opiate frequently used in substance abuse pharmacotherapy for opioid (heroin)-dependent injection drug users, many of whom are infected with HIV. L/R was associated with significant reductions in the methadone area under the concentration-time curve (P<.001), maximum concentration (P<.001), and minimum concentration (P<.001), as well as increased methadone oral clearance (P<.001) and increased opiate withdrawal symptoms (P=.013), whereas ritonavir use alone modestly and nonsignificantly increased methadone concentrations. Lopinavir is a potent inducer of methadone metabolism, and treatment with L/R requires clinical monitoring and increased methadone doses in some patients, whereas ritonavir has no significant effect on methadone metabolism.

Topics: HIV Infections; HIV Protease Inhibitors; Humans; Lopinavir; Methadone; Narcotics; Opioid-Related Disorders; Pyrimidinones; Ritonavir; Substance Withdrawal Syndrome

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

In virtually all fur-coated and feathered animals, shaking movements of the body, similar to that made by a dog when wet, occur in response to irritation of the skin or in response to sensations of intense cold. Vigorous shaking movements occur in rats undergoing opiate withdrawal. I was led by this observation to investigations on the pharmacology of agents that stimulate or inhibit shaking. Thyrotropin-releasing hormone, injected centrally at submicrogram doses, produced in nondependent, barbiturate-anesthetized animals, shaking behavior identical in its general features to that of morphine withdrawal. AG-3-5 (1-[2-hydroxyphenyl]-4[3-nitrophenyl]-1,2,3,6-tetrahydropyrimidine-2-one), another chemical stimulant of shaking, produced specific sensations of cold in man by a peripheral site of action. In this context, it should be noted that sensations of cold, and the associated emotional discomfort, are conspicuous symptoms of opiate withdrawal in man. Shaking movements elicited by a variety of stimuli were inhibited by central administration of nanomolar doses of drugs that act as agonists on opiate, muscarinic, and alpha-adrenergic receptors. These observations may provide information on a) the identity of substances in brain that, when released, provoke opiate withdrawal signs and symptoms; b) the chemical nature of substances that stimulate peripheral cold receptors; and c) the pharmacologic classification of centrally acting agents that attenuate withdrawal and produce antinociception.

Topics: Animals; Cold Temperature; Escape Reaction; Humans; Morphine Dependence; Naloxone; Pentobarbital; Pyrimidinones; Rats; Receptors, Adrenergic, alpha; Receptors, Muscarinic; Receptors, Opioid; Sensation; Shivering; Structure-Activity Relationship; Substance Withdrawal Syndrome; Thyrotropin-Releasing Hormone

RX 336-M (7,8-dihydro-5',6'-dimethylcyclohex-5'-eno-1',2',8',14 codeinone) and four other chemically-diverse agents--AG-3-5 (1-[2-hydroxyphenyl]-4-[3-nitrophenyl]-1,2,3,6-tetrahydropyrimidine-2-one), Sgd 8473 (alpha-[4-chlorobenzylideneamino)-oxy]-isobutyric acid), thyrotropin releasing hormone (TRH), and sodium valproate--each induce signs of withdrawal, most notably 'wet-dog' shaking, after acute i.p. administration in drug-naive rats. They are therefore additions to a recently recognized and, as yet, ill-defined class of behaviorally active compounds. The pharmacological baselines that link these disparate agents together have been studied in the present work, using 'wet-dog' shaking as the behavioral measure and RX 336-M as the reference shake-inducing compound. Peripheral administration of clonidine, haloperidol, d-lysergic acid diethylamide, or morphine suppressed chemically induced shaking: naloxone had no marked effect. Reverse tolerance was associated with TRH-induced shaking whereas tolerance occurred with the other four compounds. Cross-tolerance interactions were asymmetrical. Thus, rats rendered tolerant to RX 336-M were cross-tolerant to AG-3-5, TRH, and sodium valproate but not to Sgd 8473; in contrast, RX 336-M-induced shaking was only significantly reduced in rats made tolerant to Sgd 8473. In view of the unidirectional nature of the cross-tolerance relationships studied, it is concluded that AG-3-5, Sgd 8473, sodium valproate, and TRH initiate 'wet-dog' shaking through neural substrates that differ from the one(s) associated with RX 336-M. Nevertheless, all five compounds may eventually trigger a common shake-inducing mechanism.

Topics: Animals; Codeine; Drug Tolerance; Humans; Hydroxamic Acids; Male; Morphine Dependence; Pyrimidinones; Rats; Shivering; Structure-Activity Relationship; Substance Withdrawal Syndrome; Thyrotropin-Releasing Hormone; Valproic Acid