Acute reactions to drugs of abuse.
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Effects of repeated in vivo inhalant nitrite exposure on gene expression in mouse liver and lungs.
Exposure to inhalant organic nitrites (drugs of abuse commonly known as "poppers") has been reported to enhance tumor growth in mice, but the mechanism is not fully defined. This study examined the effect of repeated in vivo nitrite exposures on gene expression in the mouse liver and lungs using a gene array panel of 94 cancer- and angiogenesis-related genes. Using 2-fold change as a threshold criterion, repeated nitrite exposure was found to alter the expression of 65 and 23 genes in the liver and lungs, respectively. Six genes were significantly upregulated (p<or=0.05), viz., those encoding VEGF, VEGFD (vascular endothelial growth factor A and D, respectively) in the lungs and FGF1, FGF4 (fibroblast growth factor 1 and 4, respectively), Hsp70 (heat shock 70kDa protein 4), and PF4 (platelet factor 4) in the liver. mRNA encoding HO-1 (heme oxygenase-1) and Smad7 were marginally (p=0.057) stimulated in the liver. Follow-up studies in the liver revealed significant nitrite-induced expression of VEGF protein and mRNA. Immuno-staining of liver slices revealed that the increased hepatic VEGF expression resided mainly in hepatocytes. Stimulation of hepatic VEGF expression by ISBN was not different in endothelial nitric oxide synthase (eNOS) knockout vs. wild-type mice. In conclusion, multiple exposures to inhalant nitrite appeared to cause alteration in the expression of a number of genes relating to cancer and angiogenesis, including VEGF. eNOS presence did not appear to be essential for nitrite-induced VEGF expression. These studies demonstrate that in vivo exposure to inhalant nitrites results in changes in the angiogenesis cascade.
Administration, Inhalation↗
Effects of cigarette smoke and 3-methylcholanthrene on the disposition of phencyclidine and its N-ethylamine analogue in the isolated perfused lung of rats.
The isolated perfused lung (IPL) of rats were used to examine the pulmonary disposition and metabolism of radiolabeled phencyclidine (PCP) and N-ethyl-1-phenylcyclohexylamine (PCE). The IPL removed PCP and PCE from the perfusate and converted them to free and conjugated metabolites. At the conclusion of a 1-h perfusion, the lung accumulated at least 20% of the administered radioactivity and metabolized more than 30% of the added drug. Pretreatment of rats with 3-MC or cigarette smoke enhanced significantly PCP and PCE metabolism by the IPL. The concentration of conjugated PCE metabolite in the perfusate of the IPL was increased significantly by both 3-MC and cigarette smoke pretreatments whereas the concentration of conjugated PCP metabolite was not affected by cigarette smoke exposure and increased only slightly after 3-MC pretreatment. Pretreatment of rats with 3-MC or cigarette smoke also altered the amount of radioactivity accumulated by the lung tissue at the conclusion of a 1-h perfusion. Inasmuch as PCP and PCE are often abused by humans via smoke inhalation, a significant amount of these drugs may be stored or metabolized by the lung.
Animals↗
Demonstration of in vivo formation of the nitrosamine N-nitroso-N-methylaniline from amyl nitrite.
Kaposi's sarcoma is associated with Acquired Immune Deficiency Syndrome (AIDS) in U.S. homosexuals. A possible explanation is that butyl nitrite, inhaled as a drug of abuse, initiates the tumor via the in vivo formation of N-nitroso compounds. To demonstrate that such a process can occur, we injected mice i.p. with the amine N-methylaniline (250 mg/kg), gavaged them 30 min later with amyl nitrite (AmNO2, 40 mg/kg), killed the mice after another 30 or 60 min, and analyzed the carcasses for N-nitroso-N-methylaniline (NMA). We obtained 480 +/- 130 (mean +/- S.E. for 6 mice killed after 30 min) and 380 +/- 40 (for 6 mice killed after 60 min) nmol NMA/mouse. Much lower yields were obtained when AmNO2 was injected i.p. and methylaniline was gavaged. Hence, relatively large amounts of at least one nitrosamine can be produced in vivo from simple nitrite esters.
Amyl Nitrite↗
A novel chronic and detachable indwelling jugular catheterization procedure for mice.
The purpose of this study was to describe and demonstrate the usefulness of a chronic, detachable, indwelling jugular catheterization apparatus in mice that can be applied to acute or chronic I.V. drug administration in freely moving, unrestrained mice. The application of this procedure to the study of abused drugs is particularly advantageous, because the commonly employed intraperitoneal (I.P.), S.C., and per os (P.O.) routes of administration fail to mimic the near complete and instantaneous bioavailability of drugs abused by I.V. injection or inhalation (e.g., cocaine). Compared to current I.V. administration methods, the detachable catheter system presented in this paper is relatively easy to construct, simple to use, and appears to remain patent for an extended period of time. In addition, the utility of this procedure is greatly increased because the subject does not have to remain permanently attached to a complicated tether system. Thus, the test subject can be infused with a drug, detached from the catheter, and then undergo some behavioral test that would otherwise be impossible to undergo with a tethered system. For the purposes of demonstrating catheter patency and the importance of an I.V. route of administration, a conditioned place preference (CPP) paradigm was used to evaluate the reinforcing efficacy of cocaine.
Animals↗
Nitrous oxide (laughing gas) is an NMDA antagonist, neuroprotectant and neurotoxin.
Extensive research has failed to clarify the mechanism of action of nitrous oxide (N2O, laughing gas), a widely used inhalational anesthetic and drug of abuse. Other general anesthetics are thought to act by one of two mechanisms-blockade of NMDA glutamate receptors or enhancement of GABAergic inhibition. Here we show that N2O, at anesthetically-relevant concentrations, inhibits both ionic currents and excitotoxic neurodegeneration mediated through NMDA receptors and, like other NMDA antagonists, produces neurotoxic side effects which can be prevented by drugs that enhance GABAergic inhibition. The favorable safety record of N2O may be explained by the low concentrations typically used and by the fact that it is usually used in combination with GABAergic anesthetics that counteract its neurotoxic potential.
Animals↗
Alcohol and substance use among Japanese high school students.
In the first large-scale survey on the use of alcohol and tobacco and the inhalation of paint thinner by Japanese high school students, a higher percentage of respondents reported past or regular use of these substances than in a 1978 survey. The survey was conducted in 44 high schools. The 14,438 respondents (ages 15-18 years) represented 9 of Japan's 47 geographically distinct urban and rural prefectures. Most (76%) reported that they had consumed alcohol at some time, and 50% reported drinking on a regular basis. Alcohol consumption, drinking partners, and motivation for drinking were compared by student gender, geographic region, and years of education. Fewer students reported smoking cigarettes: 32% had smoked at some time, and 14% smoked regularly. Inhalation of paint thinner was rare: 3% had purposely inhaled it, and 1% had abused it. A significant percentage of the alcohol drinkers also used tobacco and/or thinner, a tendency that was the same despite differences in gender, grade in high school, and urban or rural geographic region. A tendency toward polysubstance use was evident among these high school students.
Adolescent↗
Illicit and licit drugs causing perforation of the nasal septum.
Examination of three patients who were presented for routine physical examinations revealed significant perforations of the anterior nasal septum. A 26-year-old male and 28-year-old female with this defect have been chronic abusers of cocaine by nasal inhalation. A 69-year-old female showed a similar defect by overuse of a common over-the-counter nasal spray containing the decongestant phenylephrine. Both drugs are powerful vasoconstrictors that reduce blood flow to the local area. With prolonged use there is persistent deprivation to the tissue of oxygen necessary for cell viability, with resultant necrosis. Additionally, the physical irritation from the impingement by these drugs on the nasal membranes further hastens the destructive process. Finally, the tissue breakdown is complete with perforations of various sizes.
Adult↗
Inhaled tobramycin in children with acute bacterial rhinopharyngitis.
Antibiotic abuse for treating rhinopharyngitis induces the occurrence of resistant bacteria. As topical drugs might reduce this phenomenon, the aims of our study were to evaluate inhaled tobramycin in children with acute bacterial rhinopharyngitis and to compare it with oral amoxicillin/clavulanate. The trial was conducted as randomized, parallel group and double blind. Children, aged 3-6 years, with acute bacterial rhinopharyngitis were treated with 15 mg of aerosolized tobramycin (Group A) or 50 mg/Kg of amoxicillin/clavulanate (Group B) twice daily for 10 days. The following parameters were assessed: nasal obstruction, mucopurulent rhinorrhea, post-nasal drip, adenoidal hypertrophy, tympanic inflammation, tympanogram, rhinomanometry and cultures. Of 416 patients screened, 311 children (178 females and 133 males), median age 4.5 years, completed the study: 156 in Group A and 155 in Group B. Both treatments improved all parameters (p<0.01 for all). Intergroup analysis showed that inhaled tobramycin induced a better improvement versus amoxicillin/clavulanate concerning nasal obstruction (p<0.05), adenoidal hypertrophy (p<0.01), tympanic inflammation (p<0.01), rhinomanometry (p<0.01) and cultures (p<0.05). In conclusion, inhaled tobramycin may represent a valid treatment for acute bacterial rhinopharyngitis in children, as it is effective, safe, economic and simple to use.
Acute Disease↗
Myocardial infarction after toluene inhalation.
Hydrocarbon exposure occurs through both intentional and nonintentional substance abuse. We present the case of a young male who sustained an acute myocardial infarction temporally related to inhalation of toluene fumes. We propose possible mechanisms for this rare but serious complication of hydrocarbon inhalation and review the literature.
Adolescent↗
Use of nitrite inhalants ("poppers") among American youth.
PURPOSE: We examined the patterns and correlates of nitrite inhalant use among adolescents aged 12 to 17 years. METHODS: Study data were drawn from the 2000 and 2001 National Household Surveys on Drug Abuse. Logistic regression was used to identify the characteristics associated with nitrite inhalant use. RESULTS: Among adolescents aged 12 to 17 years, 1.5% reported any lifetime use of nitrite inhalants. The prevalence of lifetime nitrite inhalant use increased to 12% and 14% among adolescents who were dependent on alcohol and any drug in the past year, respectively. Many nitrite inhalant users used at least three other types of inhalants (68%) and also met the criteria for alcohol (33%) and drug (35%) abuse or dependence. Increased odds of nitrite inhalant use were associated with residing in nonmetropolitan areas, recent utilization of mental health services, delinquent behaviors, past year alcohol and drug abuse and dependence, and multi-drug use. CONCLUSIONS: Adolescents who had used nitrite inhalants at least once in their lifetime tend to engage in delinquent activities and report co-occurring multiple drug abuse and mental health problems in the past year.
Administration, Inhalation↗
Problems of drug abuse and preventive measures in Poland.
An increasing abuse of drugs emerged among young people in Poland at the end of the 1960s and the beginning of the 1970s. According to information provided by the Ministry of Health and Social Welfare, there are currently 35,000 drug abusers, but the actual number is estimated at approximately 200,000. The abuse of extract from poppy straw and the inhalation of volatile solvents, such as glue and paint remover, are the major drug abuse problems. Addicts prepare a decoction of poppy straw for injection, and morphine and heroin have been clandestinely manufactured in very elementary home-made laboratories. Recently, methamphetamine hydrochloride and lysergic acid diethylamide (LSD) have also been illicitly produced in such home-made laboratories. The increasing drug abuse problem has prompted the authorities to prepare new complementary drug control legislation, the Act on the Prevention of Narcotic Addiction, which was adopted on 31 January 1985. The Act provides for more effective preventive and treatment measures, as well as severe punishment for involvement in illicit drug trafficking. Treatment, rehabilitation and social reintegration of drug-dependent persons is provided on a voluntary basis, except for persons convicted of drug-related offences and for persons under 18 years of age, in which case treatment may be compulsory.
Adolescent↗
Solvent abuse associated cortical atrophy.
Eleven of 42 toluene inhalers were evaluated with computed tomography scans because of neurologic abnormalities. Six of the 11 were found to have cerebral cortical atrophy. In addition, two of the six had cerebellar atrophy. All six had been exposed to toluene for at least 10 years. This study suggests that atrophy of the central nervous system may occur in chronic toluene abusers.
Adolescent↗
Drug-induced hyperthermia and rhabdomyolysis during the perioperative period: report of three patients.
Drug-induced hyperthermia is one condition that anesthesiologists may meet even though it is uncommon, it is life threatening. We report 3 cases of patients at Siriraj Hospital, Mahidol University who developed drug-induced hyperthermia and rhabdomyolysis from different mechanisms. In two of them, the diagnosis was suspected malignant hyperthermia. Rigidity, hyperthermia and tachyarrhythmia developed just after inhalation induction (halothane and sevoflurane) and intubation with succinylcholine. The other case was the result of amphetamine abuse. He also had received both succinylcholine and inhalation agent (isoflurane) but no obvious signs or symptoms were detected during anesthesia. He developed a gradual increase in fever over 13 hours post operation and complained of muscle pain (with leg muscle cramps). All of them showed a marked increase in muscle enzymes and had rhabdomyolysis. As a result of early detection and early manangement, these three patients survived without any permanent damage to vital organs. We conclude that Thai anesthesiologists should be more aware and alert to drug-induced hyperthermia especially as nowadays many teenagers abuse stimulant drugs and "triggering" drugs as antidepressant or serotonin reuptake inhibitors are prescribed more frequently. Early detection and management will decrease morbidity and mortality.
Adult↗
Phencyclidine- and diazepam-like discriminative stimulus effects of inhalants in mice.
It has been shown that abused solvents, such as 1,1,1-trichloroethane (TCE) and toluene, share certain pharmacological properties with central nervous system depressants, such as alcohol and anesthetic vapors. Several vapors were tested for diazepam (DZ)- and phencyclidine (PCP)-like discriminative stimulus effects to further explore their pharmacological specificity. In DZ-trained mice, methoxyflurane fully substituted, and TCE produced partial substitution. Fluorothyl and toluene produced no appreciable DZ-lever responding at any concentration tested. On the other hand, toluene produced concentration-related partial substitution for PCP, whereas methoxyflurane, TCE, and fluorothyl did not substitute. The substitution of some these vapors for DZ or PCP suggests that, like ethanol, the discriminative stimulus effects of abused solvents partially overlap those of N-methyl-D-aspartate antagonists as well as those of gamma amino butyric acid agonists.
Animals↗
Pharmacokinetics of a model organic nitrite inhalant and its alcohol metabolite in rats.
Volatile organic nitrites were originally used to relieve the chest pain that is associated with angina pectoris. Today, these inhalants are predominantly used as drugs of abuse. Little is known regarding the bioavailability and disposition of volatile nitrites. In this study, the pharmacokinetics of a major organic nitrite inhalant, isobutyl nitrite (ISBN), and its primary metabolite, isobutyl alcohol (ISBA), were investigated after inhalation and i.v. administration. ISBN blood concentrations in the rat declined mono-exponentially with a half-life of 1.4 min and a blood clearance of 2.9 l/min/kg that vastly exceeded cardiac output (0.3 l/min/kg). Approximately 98% of ISBN was metabolized to ISBA, which declined monoexponentially with a half-life of 5.3 min when the infusion of ISBN was terminated. The bioavailability of inhaled ISBN, over a range of 300 to 900 ppm, was estimated to be 43%. After inhaled ISBN, the half-life of ISBA decreased approximately 4-fold (t(1/2) inh = 1.5 min versus t(1/2) i.v. = 5.3 min; P <.001), whereas no pharmacokinetic difference was observed for ISBN. Inhalation of another nitrite, isoamyl nitrite, accelerated the apparent clearance of ISBA, suggesting that nitrite inhalation could change the disposition of another compound. A pharmacokinetic model was developed to describe the concentration-time profile of ISBA and ISBN after inhalation and i.v. administration.
Administration, Inhalation↗
Successful resuscitation from recurrent ventricular fibrillation secondary to butane inhalation.
Resuscitation from cardiac arrest caused by volatile substance abuse is rarely successful. Large doses of catecholamines given during resuscitation, in the presence of butane, may cause recurrent ventricular fibrillation. We report a case of prolonged resuscitation in a young man who had inhaled butane. Cardiac output was restored 10 min after the administration of intravenous amiodarone. We suggest that antiarrhythmic agents should be used early during resuscitation to prevent recurrent arrhythmias.
Adolescent↗
Substance abuse and cerebral blood flow.
OBJECTIVE AND METHOD: This paper reviews acute and chronic effects of drugs of abuse on cerebral blood flow (CBF) and metabolism and their clinical significance. The most important source of information for the review is human research reports published in refereed journals. A few animal studies, book chapters, and abstracts that are especially relevant are also included. RESULTS: In humans, ethanol in small doses produces cerebral vasodilation; higher doses induce cerebral vasoconstriction. Chronic alcoholism is associated with reduced CBF and cerebral metabolism. Sedatives and antianxiety drugs lead to global reduction in CBF and cerebral metabolism. Caffeine, even in small doses, is a potent cerebral vasoconstrictor. Cerebral vasodilation is seen immediately after cigarette smoking, but chronic smokers show global reduction in CBF. Changes in CBF after marijuana smoking are variable; both increases and decreases are seen. Chronic marijuana smoking, however, seems to reduce CBF. Most inhalants and solvents are vasodilators; chronic abuse is accompanied by a decrease in CBF. A number of drugs of abuse, including ethanol, amphetamines, cocaine, nicotine, and caffeine-phenylpropanolamine combinations, increase the risk for stroke. Reduction in CBF associated with chronic use of ethanol, nicotine, inhalants, and solvents is at least partially reversible upon abstinence. CONCLUSIONS: Topics for future research include regional brain function, which mediates drug-induced mood changes (euphoria); CBF concomitants of psychological and physiological characteristics that increase addiction potential; changes in CBF that accompany withdrawal syndromes; mechanisms responsible for drug-induced stroke; and effects of functional and organic complications on CBF.
Adolescent↗