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Mutation Research. Genetic Toxicology... Mar 2015The repeated dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect genotoxic hepatocarcinogens that can be integrated into a general...
The repeated dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect genotoxic hepatocarcinogens that can be integrated into a general toxicity study. The assay methods were thoroughly validated by 19 Japanese facilities. Methapyrilene hydrochloride (MP), known to be a non-genotoxic hepatocarcinogen, was examined in the present study. MP was dosed orally at 10, 30 and 100mg/kg/day to 6-week-old male Crl:CD (SD) rats daily for 14 days. Treatment with MP resulted in an increase in micronucleated hepatocytes (MNHEPs) with a dosage of only 100mg/kg/day. At this dose level, cytotoxicity followed by regenerative cell growth was noted in the liver. These findings suggest that MP may induce clastogenic effects indirectly on the liver or hepatotoxicity of MP followed by regeneration may cause increase in spontaneous incidence of MNHEPs.
Topics: Administration, Oral; Age Factors; Animals; Body Weight; Bone Marrow; Carcinogens; Chromosome Aberrations; Cooperative Behavior; Dose-Response Relationship, Drug; Drug Administration Schedule; Hepatocytes; Humans; Japan; Liver; Male; Methaqualone; Micronucleus Tests; Organ Specificity; Rats; Rats, Sprague-Dawley; Reticulocytes; Societies, Pharmaceutical
PubMed: 24768639
DOI: 10.1016/j.mrgentox.2014.04.004 -
Archives of Pharmacal Research Jan 2015Amisulpride, a selective antagonist of D2 and D3 dopamine receptors, is used as an antipsychotic drug. In this study, we reported a sensitive LC-MS/MS method for...
Amisulpride, a selective antagonist of D2 and D3 dopamine receptors, is used as an antipsychotic drug. In this study, we reported a sensitive LC-MS/MS method for determining amisulpride concentrations in rat plasma, and a preclinical pharmacokinetic study in the rat. After a simple protein precipitation with acetonitrile containing methaqualone as an internal standard, the analytes were separated on a reversed-phase column with a mobile phase of 0.2 % aqueous formic acid and acetonitrile (3:7, v/v). The accuracy and precision of the assay were in accordance with FDA guidance for the validation of bioanalytical methods. This analytical method was used successfully to characterize the time course of the plasma concentration of amisulpride following oral administration of a single 10 mg/kg dose in rats.
Topics: Administration, Oral; Amisulpride; Animals; Chromatography, High Pressure Liquid; Drug Stability; Rats; Sulpiride; Tandem Mass Spectrometry
PubMed: 24619919
DOI: 10.1007/s12272-014-0361-1 -
Current Pharmaceutical Design 2013Current lipid-lowering drugs are often unable to achieve low density lipoprotein cholesterol (LDL-C) goals. Moreover, despite LDL-C lowering mostly by statins, a... (Review)
Review
Current lipid-lowering drugs are often unable to achieve low density lipoprotein cholesterol (LDL-C) goals. Moreover, despite LDL-C lowering mostly by statins, a considerable residual vascular risk remains. This is partly associated with atherogenic dyslipidemia where apolipoprotein (apo) B-containing lipoproteins predominate. Mitochondrial Triglyceride (TG) transfer protein (MTP) is a key enzyme for apoB-containing lipoprotein assembly and secretion. This is mostly attributed to its capacity to transfer lipid components (TGs, cholesterol esters and phospholipids) to the endoplasmic reticulum lumen, where these lipoproteins are assembled. Several agents were developed to inhibit MTP wherever it is expressed, namely the liver and/or the intestine. Liver-specific MTP inhibitors reduce secretion of very low density lipoproteins (VLDL) mostly containing apoB100, while the intestine-specific ones reduce secretion of chylomicrons containing apoB48. These drugs can significantly reduce total cholesterol, LDL-C, TGs, VLDL cholesterol, as well as apoB levels in vivo. They may also exert anti-atherosclerotic and insulin-sensitizing effects. Limited clinical data suggest that these compounds can also improve the serum lipid profile in patients with homozygous familial hypercholesterolemia (HoFH). The accumulation of unsecreted fat in the liver and intestinal lumen is associated with elevation of aminotransferases and steatorrhea. Liver steatosis can be avoided by the use of intestine-specific MTP inhibitors, while steatorrhea by low-fat diet. Future indications for these developing drugs may include dyslipidemia associated with insulin resistant states, familial combined hyperlipidemia and HoFH. Future clinical trials are warranted to assess the efficacy and safety of MTP inhibitors in various clinical states.
Topics: Animals; Apolipoproteins B; Benzamides; Benzimidazoles; Carrier Proteins; Dyslipidemias; Flavanones; Humans; Hypolipidemic Agents; Malonates; Methaqualone
PubMed: 23317403
DOI: 10.2174/1381612811319170023 -
Clinical Toxicology (Philadelphia, Pa.) Jan 2013Methylmethaqualone is a sedative designer drug created by adding a methyl group to the 3-phenyl ring of methaqualone, and is at present not subject to restrictive...
Methylmethaqualone is a sedative designer drug created by adding a methyl group to the 3-phenyl ring of methaqualone, and is at present not subject to restrictive regulation in many countries. To our knowledge, no case of methylmethaqualone abuse has been published to date in the scientific literature, and the only sources of information are users' reports on Web discussion forums and data from preclinical animal studies. We report a case of oral methylmethaqualone abuse confirmed by liquid chromatography tandem mass spectrometry in a 24-year-old previously healthy Caucasian male. Observed symptoms and signs such as central nervous system depression alternating with excitation, psychomotor agitation, muscle hyperactivity, and tachycardia were compatible with methaqualone-induced adverse effects. Except for the mild tachycardia (115 beats/min), other vital signs were normal: blood pressure 134/89 mmHg, body temperature 36.2°C (97.16°F), and peripheral oxygen saturation 99% while breathing room air. The ECG showed no prolongation of the QT interval and the QRS duration was normal. Laboratory analysis revealed a slight increase in creatine kinase (368 U/L) and alanine aminotransferase (90 U/L) serum concentrations. Blood alcohol concentration was 0.32 g/L. Methylmethaqualone was identified in a serum sample collected on admission which was analyzed by a liquid chromatography tandem mass spectrometry toxicological screening method using turbulent flow online extraction. After a few days the patient ingested the same amount of substance with identical symptoms. Based on the chemical structure and animal data, and according to this case report and users' Web reports, methylmethaqualone appears to have a similar acute toxicity profile to methaqualone, with marked psychomotor stimulation. Symptoms of acute toxicity can be expected to resolve with supportive care.
Topics: Adult; Chromatography, High Pressure Liquid; Designer Drugs; Humans; Hypnotics and Sedatives; Male; Methaqualone; Methylation; Neurotoxicity Syndromes; Severity of Illness Index; Tandem Mass Spectrometry; Treatment Outcome; Young Adult
PubMed: 23298217
DOI: 10.3109/15563650.2012.758855 -
African Journal of Psychiatry Sep 2012There is growing concern about the effect of substance use on HIV treatment outcomes. The study objectives included: (i) evaluating whether the use of validated... (Comparative Study)
Comparative Study
OBJECTIVE
There is growing concern about the effect of substance use on HIV treatment outcomes. The study objectives included: (i) evaluating whether the use of validated questionnaires (AUDIT and DUDIT) provide useful and consistent information of alcohol and drug consumption when compared with the use of biomarkers of alcohol in (urine and hair) and drugs in (urine) and (ii) assessing the feasibility of using self-report measures compared with urine and hair tests.
METHOD
Participants were HIV positive patients attending an HIV community health clinic in Kraaifontein, Cape Town. Hair and urine samples were collected and analysed for alcohol, in Fatty Acid Ethyl Esters (FAEE) and in Ethyl Glucuronide and (EtG), and drugs. Biological markers were compared with self-report measures of alcohol and drug consumption in terms of sensitivity, specificity. Forty-three participants completed the self-report measures, while 30 provided hair and urine samples.
RESULTS
On the AUDIT, 18 (41.9%) participants screened positive for harmful and hazardous drinking and 13 (30.2%) participants on the DUDIT screened positive for having a drug-related problem. Two of 30 participants (7%) tested positive for alcohol abuse on FAEE analysis. For EtG, 6 of 24 (25%) participants tested positive for alcohol abuse. On hair drug analysis, all 30 participants tested negative for cannabis, amphetamines, opiates, cocaine, PCP and methaqualone. On the urinalysis, 1 of 30 participants tested positive for cannabis and everyone tested negative for all other drugs included in the screening.
CONCLUSION
Substance use among patients attending HIV clinics appears to be a problem, especially alcohol. Self-report measures seem to be a more cost effective option for screening of alcohol and drug abuse in resource poor settings.
Topics: Alcoholism; Ambulatory Care Facilities; Biomarkers; Cross-Sectional Studies; Feasibility Studies; Female; HIV Infections; Hair; Humans; Male; Pilot Projects; Reproducibility of Results; Self Report; Sensitivity and Specificity; South Africa; Substance-Related Disorders; Surveys and Questionnaires
PubMed: 23044889
DOI: 10.4314/ajpsy.v15i5.43 -
Acta Crystallographica. Section E,... Mar 2012In the title methaqua-lone analogue, C(23)H(20)N(2)O(2), the planes of the terminal aromatic rings [dihedral angle between them = 64.52 (7)°] approximately face the...
In the title methaqua-lone analogue, C(23)H(20)N(2)O(2), the planes of the terminal aromatic rings [dihedral angle between them = 64.52 (7)°] approximately face the fused-ring methyl group and both are twisted with respect to the pyrimidine plane (r.m.s. deviation = 0.028 Å), forming dihedral angles of 86.9 (3) (with the 2-tolyl ring) and 65.57 (7)°. The 2-tolyl residue is disordered over two almost coplanar but opposite orientations with the major component having a site-occupancy factor of 0.893 (3). The three-dimensional crystal packing is consolidated by C-H⋯O, C-H⋯π and π-π [2-tol-yl-2-tolyl centroid-centroid distance = 3.8099 (6) Å] inter-actions.
PubMed: 22412719
DOI: 10.1107/S1600536812007362 -
Acta Crystallographica. Section E,... Mar 2012In the title methaqua-lone analogue, C(16)H(13)N(3)O(3), the 2-tolyl group is almost orthogonal [dihedral angle = 85.20 (5)°] to the fused ring system (r.m.s....
In the title methaqua-lone analogue, C(16)H(13)N(3)O(3), the 2-tolyl group is almost orthogonal [dihedral angle = 85.20 (5)°] to the fused ring system (r.m.s. deviation of fitted non-H atoms = 0.029 Å). In the crystal, twofold symmetry generates two-mol-ecule aggregates linked by C-H⋯O and π-π inter-actions [ring centroid-centroid distance = 3.4967 (6) Å].
PubMed: 22412718
DOI: 10.1107/S1600536812007350 -
Biomedical Chromatography : BMC Apr 2012Recently a pyrimidine nucleoside, uridine, has been show to have a protective effect on cultured human corneal epithelial cells, and on dry eye animal model and...
Recently a pyrimidine nucleoside, uridine, has been show to have a protective effect on cultured human corneal epithelial cells, and on dry eye animal model and patients. In this study, we introduce a sensitive liquid chromatography/tandem mass spectrometry method for the determination of uridine in rabbit plasma and urine. After protein precipitation with methanol including methaqualone (internal standard), the analyte was chromatographed on a reversed-phase column with a mobile phase of 0.1% formic acid aqueous solution and methanol (1:4, v/v). The accuracy and precision of the assay were in accordance with Food and Drug Administration regulations for the validation of bioanalytical methods. This method was used to measure the concentrations of uridine in plasma and urine after a single oral administration of 450 mg/kg uridine in rabbits.
Topics: Animals; Chromatography, Liquid; Rabbits; Sensitivity and Specificity; Tandem Mass Spectrometry; Uridine
PubMed: 22392515
DOI: 10.1002/bmc.1698 -
Bioorganic & Medicinal Chemistry Letters Jan 2012A new series of 2,3,8-trisubstituted-4(3H)-quinazoline derivatives were synthesized, evaluated for their anticonvulsant activity against electrically (MES) and...
A new series of 2,3,8-trisubstituted-4(3H)-quinazoline derivatives were synthesized, evaluated for their anticonvulsant activity against electrically (MES) and chemically (PTZ, picrotoxin and Strychnine) induced seizures and compared with the standard drugs methaqualone and sodium valproate. Compounds 3, 17 and 22 proved to be the most potent compounds of this series with relatively low neurotoxicity and low toxicity in the median lethal dose test as compared with the reference drugs. The obtained results showed that the most active compounds could be useful as a template for future design, modification and investigation to produce more active analogs.
Topics: Animals; Anticonvulsants; Chemistry, Pharmaceutical; Drug Design; Humans; Male; Methaqualone; Mice; Models, Chemical; Nervous System; Quinazolines; Seizures; Valproic Acid
PubMed: 22137344
DOI: 10.1016/j.bmcl.2011.11.007 -
Studies in History and Philosophy of... Dec 2011In 1955 Carter Products launched its new tranquilizer Miltown with a huge marketing blitz; Miltown soon became one of America's earliest "blockbuster" celebrity drugs....
In 1955 Carter Products launched its new tranquilizer Miltown with a huge marketing blitz; Miltown soon became one of America's earliest "blockbuster" celebrity drugs. In 1981, federal agents shut down a network of "stress clinics" and arrested the owners, medical staff, and other personnel for illegally trafficking in the sedative Quaalude; Quaalude soon became a "Schedule I Controlled Substance." Both of these stories are familiar, indeed archetypal, moments from America's postwar medical system. As the Miltown example reminds us, this fundamentally commercial system was built on the creation and courting of consumer demand for medical products and services, particularly drugs. As the Quaalude example shows, however, this system also incorporated tools for reining in excessive consumer demand. Together the two episodes affirm an enduring irony of the American medical system: the need for regulatory campaigns to tame lively markets for drugs that had become popular, in part, because of advertising campaigns. This article uses the Miltown and Quaalude sagas to explore the issue of consumer demand for prescription medicines, arguing that efforts to stoke or quash that demand have shaped (and linked) America's medical system and its drug control regimes.
Topics: Ambulatory Care Facilities; Drug Industry; Health Services Needs and Demand; History, 20th Century; Humans; Hypnotics and Sedatives; Legislation, Drug; Marketing; Meprobamate; Methaqualone; Prescription Drugs; Stress, Psychological; United States
PubMed: 22035715
DOI: 10.1016/j.shpsc.2011.05.005