Designation of oripavine as a basic class of controlled substance. Final rule.

This is a final rule issued by the Drug Enforcement Administration (DEA) designating oripavine (3-O-demethylthebaine or 6,7,8,14-tetradehydro-4,5-alpha-epoxy-6-methoxy-17-methylmorphinan-3-ol) as a basic class in schedule II of the Controlled Substances Act (CSA). Although oripavine was not previously listed in schedule II of the CSA, it has been controlled in the United States as a derivative of thebaine and, as such, is controlled as a schedule II controlled substance which includes "Opium and opiate, and any salt, compound, derivative, or preparation of opium or opiate." Oripavine is a derivative of thebaine, a natural constituent of opium, hence oripavine has been and continues to be, by virtue of the definition of "narcotic drug", a schedule II controlled substance. International control of oripavine in schedule I of the 1961 Single Convention on Narcotic Drugs (1961 Convention) during the 50th session of the Commission on Narcotic Drugs (CND) in 2007 prompted the DEA to specifically designate oripavine as a basic class of controlled substance in schedule II of the CSA.

Stimulation of lipid peroxidation and impairment of glutathione-dependent defense system in Wistar rats treated with cryptopine, a rare non-narcotic opium alkaloid.

The present study was designed to evaluate the effect of repeated oral administration of cryptopine at differential dosing regimens (50, 100, 150, 200 mg/kg bwt) in vivo on lipid peroxide measures, glutathione levels (GSH) and activity of glutathione S-transferase (GST) and glutathione reductase (GR) in the liver, spleen, kidney and lung of Male Wistar rats after a 5 day treatment period. In all the tissues examined, we observed an increase in lipid peroxidation and a decline in glutathione content and activity of glutathione S-transferase and glutathione reductase in a dose-dependent manner. The decrease in GSH content did not definitively correlate with a concomitant increase of lipid peroxidation in all the tissues. Our results ensemble that the enhancement of lipid peroxidation in the tissues investigated is a consequence of depletion of glutathione to certain critical levels and impairment of the glutathione-dependent enzyme systems viz. GST and GR. Our study potentiates that decreased levels of GSH may lead to lipid peroxidation, one of the key events in cellular damage. The inhibition of GST also suggests that the detoxification of the alkaloid could be suppressed following acute exposures. Conclusively, it appears that cryptopine in vivo disturbs the cellular defense system, so that it tips in the direction of autoxidative lipid peroxidation, producing cytotoxicity.

Onset and pattern of substance use in intravenous drug users of an opiate maintenance program.

OBJECTIVES: To assess the initiation of substance use of participants in an opiate maintenance program by a cross-sectional survey. METHOD: Participants (n=184) filled out a questionnaire assessing age at initial substance use and age at onset of regular drug use. RESULTS: Of 15 substances investigated, alcohol, nicotine, analgesics and marijuana were initiated and consumed regularly before the age of 18 years. Barbiturates, benzodiazepines, cocaine, and opiates were begun later. The time gap between initial and regular use varied depending on the substance. Regular use exceeded 50% for alcohol, benzodiazepines, cocaine, heroin, marijuana and nicotine. CONCLUSIONS: Specific knowledge about the age of onset and sequence of substances used by drug addicts may help to prevent substance use more age specifically.

Characterization and identification of 6 mutagens in opium pyrolysates implicated in oesophageal cancer in Iran.

Previous epidemiological studies have indicated an association between the ingestion of opium pyrolysates, dietary deficiencies, and a high incidence of oesophageal cancer in subjects in north-east Iran. Laboratory studies have shown that pyrolysates of opium and particularly of morphine, a major opium alkaloid, are highly mutagenic in bacteria and induce sister-chromatid exchanges in mammalian cells after metabolic activation. We now report the ability of these pyrolysates to transform Syrian hamster embryo cells in culture and present some evidence for their carcinogenicity in mice and hamsters following topical, subcutaneous, intratracheal and intragastric administration. 6 of the most abundant mutagenic compounds present in morphine pyrolysate were isolated and purified by high-performance liquid chromatography and characterized by gas chromatography/mass spectrometry and 1H-Fourier transform nuclear magnetic resonance spectroscopy. These hitherto unknown compounds, all containing a hydroxy-phenanthrene moiety, were identified as: 3-methyl-3H-naphth[1,2-e]indol-10-ol; 1,2-dihydro-3-methyl-3H-naphth[1,2-e]indol-10-ol; 6-methylaminophenanthren-3-ol; 2-methylphenanthro[3,4-d] [1,3]oxazol-10-ol; 2,3-dimethyl-3H-phenanthro[3,4-d]imidazol-10-ol and 2-methyl-3H-phenanthro[3,4-d]imidazol-10-ol. Mutagenicity in Salmonella typhimurium TA98 of these compounds increased in the order listed, the last compound being 35 times more active than benzo[a]pyrene. The mechanisms, by which these mutagens are formed and metabolically activated are discussed.

Induction of SCE by opium pyrolysates in CHO cells and human peripheral blood lymphocytes.

The induction of sister chromatid exchange (SCE) by opium pipe scrapings (sukhteh, Su) and the pyrolysis products of opium (Op) and of its major alkaloids, morphine (Mo), have been compared with that of cigarette smoke condensate (CSC). All pyrolysates induced SCE and the frequency was further increased by the inclusion of S9-mix in the protocol. The pyrolysates of Op induced considerably more SCE than CSC when the same concentrations were compared on a weight basis, and the rank in order of potency in CHO cells was MO greater than Op greater than CSC greater than Su. The Op pyrolysates may therefore contribute a significant risk factor to the observed high incidence of oesophageal cancer in areas of Iran where heavy Op usage occurs.

Drug therapy reviews: pharmacotherapy of diarrhea.

Gastrointestinal physiology, and the pathophysiology, diagnosis, symptoms and treatment of acute and chronic diarrhea are reviewed. Drugs used in the treatment of diarrhea include opiates (morphine, codeine), synthetic anti-diarrheals (diphenoxylate, loperamide), anticholinergics (atropine, propantheline), adsorbents (kaolin, pectin, cholestyramine resin) and Lactobacillus acidophilus. Chronic diarrhea and acute diarrhea caused by microorgansims, drugs and viruses are described. The management of diarrhea can be divided into three categories: (1) supportive therapy (fluid and electrolyte replacement); (2) symptomatic therapy which improves the consistency of the stool and reduces the frequency of bowel movements; and (3) specific therapy aimed at treating the cause (e.g., antibiotics for bacteria-induced diarrhea) or blocking the cellular mechanisms of fluid and electrolyte loss. Most acute diarrheal conditions can be managed successfully by avoiding oral solids and ingesting carbohydrate-electrolyte solutions. Synthetic antidiarrheals may increase the toxicity associated with bacterial diahhrea.

[Naloxone--a clinical study on dosage (author's transl)]. / Naloxon. (Eine klinische Untersuchung zur Frage der Dosierung).

In 50 Patients (group I) anaesthetized with neuroleptanalgesia and in 20 patients (group II) anaesthetized with moderate doses of fentanyl given to supplement nitrous oxide - halothane anaesthesia the postoperative respiratory depression was antagonized with naloxone. Each patient was carefully titrated with small increments of naloxone (40 microgram) given in 1-2 minute intervals. A reversal of the narcotic induced respiratory depression was taken for granted, when respiratory rate exceeded 12/min, tidal volume and blood gas analysis showed normal values. The results demonstrated a correlation between the need for naloxone and the time interval from the last administration of fentanyl to the completion of the operation and the fentanyl consumption per hour. When the interval was less than 1 hour more than 90% of the patients required postsurgical naloxone for respiratory inadequacy. The mean naloxone dose was 20 to 30% of the fentanyl dose given per hour: 1,2 microgram/kg naloxone reversed 4,9 microgram/kg.h fentanyl (group I) and 0,6 microgram/kg naloxone reversed 2,9 microgram/kg.h fentanyl (group II) respectively. To prevent renarcotization it is recommended to administer naloxone i.m. 30 to 45 min after the last naloxone-injection using the total i.v. dose.

Oral premedication with oxypertine.

The preoperative effects of oral oxypertine have been compared with those of papaveretum and atropine in 185 patients in a double-blind between-patient study. Oxypertine 20 mg given orally as a nocturnal sedative and again on the morning of operation produced relief of anxiety comparable to that of papaveretum 10 mg and atropine 0.6 mg. It is concluded that oxypertine may be of value in medication before anaesthesia.

Recent developments in opiate research and their implications for psychiatry.

Considerable progress in opiate research has been made during the last few years regarding the identification and localization of opiate receptors in vitro and in vivo, the analysis of drug-receptor interactions and the characterization of an endogenous ligand of the opiate receptor. There is little evidence that effects induced by chronic exposure to opiates - development of tolerance and dependence -are due to changes in opiate receptor mechanisms; it is supposed that the adaptive changes occur mainly in the chain of events triggered by the drug-receptor interaction. Such changes may be directly or indirectly related to the metabolism of neurotransmitters and/or cyclic nucleotides. The obvious links between physical and psychic equivalents of opiate dependence are discussed. Present data points to the significance of brain stem and limbic structures in both these processes, monoamines probably playing an important role. Relations between psychic manifestations of opiate addiction and mental disorders are pointed out.

Patterns of illicit drug use in the Army.

The authors collected detailed histories of illicit drug use in the Army in individual interviews with a stratified random sample of 262 enlisted men at six military posts across the United States. Approximately half of the sample (N equals 128) were classified as drug users; 90 of these individuals were identified as career multiple-drug users. Most of these subjects used a variety of drugs in frequently changing patterns. The authors emphasize the individualistic nature of drug use and question the appropriateness of an addiction model for most users of illicit drugs.

Application of radioimmunoassay techniques in support of toxicologic investigations of aircraft accidents.

With the increased emphasis on establishing the presence or absence of drugs associated with aircraft accidents and the fact that fragmentation of tissue may be a problem in investigating these accidents, the need arises for a rapid, sensitive, and specific toxicologic means for detecting drugs that may be present in nanogram concentrations and when only extremely limited quantities of specimens are avialable for study. The use of radioimmunoassay (RIA) for the detection of drugs (e.g., amphetamines, barbiturates, opiates, and methaqualone) in selected aircraft accident cases is presented.

Simultaneous detection of a wide variety of commonly abused drugs in a urine screening program using thin-layer identification techniques.

A single-step extraction method and thin-layer identification techniques capable of testing a wide variety of drugs of abuse are presented. These techniques are well suited for large and/or small drug programs involved in urine testing because they provide substantial economic benefits and improve clinical functioning. The drugs are absorbed on a 6 X 6 cm piece of paper loaded with cation-exchange resin and then eluted from the paper at pH 10.1 using ammonium chloride-ammonia buffer. The simultaneous thin-layer detection of sedatives, hypnotics, narcotic analgesics, central nervous system stimulants and miscellaneous drugs is accomplished by spotting the solution of extracted residue on a 20 X 20 cm Gelman pre-coated silica gel glass microfiber sheet (ITLC Type SA). A two-stage solvent system is used in order to obtain a chromatogram with optimum separation of a wide range of drugs. This system can separate methadone and/or cocaine from propoxyphene, methaqualone, methylphenidate, pentazocine, pipradrol, Doxepin, chlorpromazine, phenazocine, naloxone, naltrexone, imipramine and trimeprazine; amphetamine from phenylpropanolamine and dimethyltryptamine; codeine from dextromethorphan; methamphetamine from dimethyltryptamine, etc. Different detection reagents are then applied in succession to different marked areas of the developed chromatogram. This elegant method of extraction and spraying has enabled us to detect morphine base at a sensitivity level of 0.15 mug/ml, amphetamine sulfate at 1.0 mug/ml, methamphetamine hydrochloride at 0.5 mug/ml, phenmetrazine hydrochloride at 0.5 mug/ml, codeine phosphate at 0.5 mug/ml, methadone hydrochloride at 1.0 mug/ml, secobarbital at 0.36 mug/ml and phenobarbital at 0.5 mug/ml in urine. The minimum volume of urine needed to achieve these sensitivities is 20 ml. The cost of analysis per urine specimen using these techniques for concomitant screening of these drugs is less than US$ 1.