Tobacco and cannabis co-occurrence: Does route of administration matter?

BackgroundQualitative research suggests that a shared route of administration (i.e. via inhalation) for the common forms of both tobacco (i.e. cigarettes) and cannabis (i.e. joints) may contribute to their co-occurring use.MethodsWe used data on 43,093 U.S. adults who participated in the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) to examine whether cannabis use and abuse/dependence were associated with smoked (cigarettes, cigars, pipes) versus smokeless (snuff, chewed tobacco) forms of tobacco use, even after controlling for socio-demographic, psychiatric and substance-related covariates.ResultsTobacco smoking was associated with a 3.3–4.5 times increased risk for cannabis use and abuse/dependence respectively. After covariate adjustment, importantly for nicotine dependence, smoking tobacco (but not smokeless tobacco) was still significantly associated with both cannabis use (multinomial odds-ratio (MOR) 1.99) and cannabis dependence (MOR 1.55). In contrast, use of smokeless tobacco was not significantly correlated with elevated rates of cannabis use (MOR 0.96) or abuse/dependence (MOR 1.04).ConclusionsRoute of administration may play an important role in the observed association between tobacco and cannabis use. This may represent a physiological adaptation of the aero-respiratory system and/or index social and cultural influences surrounding the use of smoked versus smokeless forms of tobacco.     

Pharmacokinetics of zimelidine in humans — Plasma levels and urinary excretion of zimelidine and norzimelidine after intravenous and oral administration of zimelidine

Summary Five healthy adults were administered zimelidine orally (150 mg) and by intravenous infusion (20 mg) in a crossover design. Blood and urine samples were collected for a period of 28 hours after dosing and the concentrations of zimelidine and norzimelidine determined. There was no significant difference in terminal phase half-life of zimelidine after oral (4.7 h±1.3 SD) or intravenous dosing (5.1 h±0.7 SD). An average of 50% of the ingested oral dose reached the systemic circulation. Excretion of unchanged zimelidine in urine was on average 1.26% of the intravenous dose. In appears that zimelidine is completely absorbed from the gastrointestinal tract and first-pass metabolism in the liver reduces the bioavailability to 50%. The mean plasma half-life for norzimelidine was 22.8 h. The area under the plasma concentration time curve for norzimelidine after oral administration was 92% of that after intravenous administration. The plasma concentration of both zimelidine and norzimelidine are predicted to approach steady-state within 3–5 days.     

Effects of isolation housing and timing of drug administration on amikacin kinetics in mice

目的：研究社会环境及给药时刻对小鼠阿米卡星代谢的影响．方法：小鼠按饲养环境：隔离饲养（Ｉ）或集体饲养（Ａ）及给药时间：日中（Ｄ）及午夜（Ｎ）随机分为：Ｉ－Ｄ，Ｉ－Ｎ，Ａ－Ｄ，Ａ－Ｎ４组．饲养４周后于Ｄ（１３∶００）或Ｎ（０１∶００）ｓｃ阿米卡星１５ｍｇ·ｋｇ－１，测定给药后其血浆浓度，以开放一室模型拟合并计算有关药代动力学参数．结果：Ａ－Ｎ组阿米卡星清除率较Ａ－Ｄ及Ｉ－Ｎ组增大，血浆半衰期变短，０－１小时血浆浓度时间曲线下面积（ＡＵＣ（０－１））较Ｉ－Ｎ组减少．隔离饲养两组（Ｉ－Ｄ，Ｉ－Ｎ）间药代动力学参数无显著差异．结论：社会环境及给药时刻均显著影响小鼠阿米卡星代谢动力学．     

Pharmacokinetics and first-pass effects of ϵ-acetamidocaproic acid after administration of zinc acexamate in rats

1. Zinc acexamate (ZAC) is ionized to zinc and ?-acetamidocaproic acid (AACA). Thus, the pharmacokinetics and tissue distribution of zinc and AACA after intravenous (50?mg kg^?1) and oral (100?mg kg^?1) administration of ZAC were evaluated in rats. Also the pharmacokinetics of AACA after intravenous (10, 20, 30, and 50?mg kg^?1) and oral (20, 50, and 100?mg kg^?1) administration of ZAC and the first-pass extractions of AACA at a ZAC dose of 20?mg kg^?1 were evaluated in rats.

2. After oral administration of ZAC (20?mg kg^?1), approximately 0.408% of the oral dose was not absorbed, the F value was approximately 47.1%, and the hepatic and gastrointestinal (GI) first-pass extractions of AACA were approximately 8.50% and 46.4% of the oral dose, respectively. The incomplete F value of AACA was mainly due to the considerable GI first-pass extraction in rats.

3. Affinity of rat tissues to zinc and AACA was low—the tissue-to-plasma (T/P) ratios were less than unity. The equilibrium plasma-to-blood cells partition ratios of AACA were independent of initial blood ZAC concentrations of 1, 5, and 10?µg ml^?1—the mean values were 0.481, 0.490, and 0.499, respectively. The bound fractions of zinc and AACA to rat plasma were 96.6% and 39.0%, respectively.

     

Concomitant administration of zoster and pneumococcal vaccines in adults ≥60 years old

This study evaluated safety & immunogenicity of ZOSTAVAX? (zoster vaccine: ZV) administered concomitantly versus nonconcomitantly with PNEUMOVAX? 23 (pneumococcal vaccine: PPV23). This randomized, double-blind, placebo-controlled study enrolled 473 subjects ≥60 years old in 1:1 ratio to receive ZV & PPV23 concomitantly (Day 1) or nonconcomitantly (PPV23 Day 1, ZV Week 4). Blood samples obtained for pneumococcal polysaccharide (PnPs) antibody (Ab) testing by enzyme-linked immunosorbent assay (ELISA) and varicella-zoster virus (VZV) Ab testing by glycoprotein ELISA. Subjects followed for adverse experiences (AEs) for 28 days postvaccination. Mean baseline VZV geometric mean titers (GMT) in nonconcomitant group were lower than concomitant group. Four weeks postvaccination with ZV, VZV Ab response in concomitant group was not similar to nonconcomitant group; estimated VZV GMT ratio [concomitant/nonconcomitant] was 0.70 (95% CI, 0.61-0.80). VZV Ab response was acceptable in concomitant group; estimated geometric mean foldrise (GMFR) from baseline was 1.9 (95% CI, 1.7-2.1). PnPs serotype-specific Ab responses were similar in both groups. All 6 reported serious AEs were deemed not related to study vaccine. Postvaccination of ZV, incidence of injection-site AEs was similar in both groups; clinical AEs were numerically but not significantly higher in nonconcomitant group. In summary, VZV GMT Ab response induced by ZV administered concomitantly with PPV23 was inferior to that induced nonconcomitantly. These results indicate that, to avoid a potential decrease in ZV immunogenicity, ZV & PPV23 should not be given concomitantly. Concomitant administration did not affect response to PPV23 serotypes tested. When administered concomitantly, ZV & PPV23 vaccines were generally well tolerated.     

Bioavailability and pharmacokinetics of isradipine after oral and intravenous administration: half-life shorter than expected?

Isradipine is a calcium channel-blocking agent of the dihydropyridine type, used in the treatment of hypertension. A terminal half-life of 8-9 hr has been reported, in several pharmacokinetic studies after oral administration of isradipine. In a yet unpublished study a much shorter half-life was observed, and the present trial was therefore conducted in order to estimate the half-life after intravenous administration of isradipine. The bioavailability was estimated as well. In a randomised cross-over design ten healthy young volunteers were given either isradipine orally or an intravenous infusion. The two study periods were separated by at least 3 days. Blood samples for measurement of isradipine concentration were collected for 10-12 hr after administration and half-life and bioavailability were estimated. Mean terminal half-life after intravenous administration was calculated to be 2.8 hr, and the bioavailability to be 0.28. None of the 10 subjects suffered from side effects. In the present intravenous study the half-life of isradipine seems to be of much shorter than demonstrated in previous oral studies.     

Patterns of cocaine and opioid co-use and polyroutes of administration among street-based cocaine users in Montréal,Canada

BackgroundEffective public health programs aimed at problematic cocaine users are challenged by the fact that they can have complex patterns of drug use with respect to polysubstance use and routes of drug administration. This study was carried out to explore the presence of subgroups of cocaine users on the basis of their concurrent use of opioids and their routes of cocaine and opioid administration, and to determine if subgroups could be differentiated in terms of sociodemographic factors and risk behaviours.MethodsRegular cocaine users (≥1 per week) were recruited in low-threshold services located in the Montréal downtown area. The following variables were examined: demographic characteristics, types of drug used, routes of drug administration, and condom use with occasional or commercial sexual partners. Latent class analysis and multinomial logistic regression modeling were carried out.Results886 cocaine users were recruited (83.5% male: mean age 35.38 years). A 5-class model was identified: (1) “cocaine smokers” (CSs) (n = 161; membership probability (MP) = 0.183); (2) “cocaine smokers/sniffers” (CSSs) (n = 201; MP = 0.218); (3) “cocaine injectors” (CIs) (n = 207; MP = 0.231); (4) “cocaine-opioid injectors” (COIs) (n = 277; MP = 0.291); (5) “cocaine-opioid polyroute users” (COPs) (n = 40; MP = 0.077). Compared with COIs, other subtypes were significantly different in terms of either age, duration of cocaine use, ethnic background, homelessness, polydrug use or condom use.ConclusionThe heterogeneity of consumption patterns supports the importance of offering an array of interventions aimed at problematic cocaine users. These should include the provision of clean injecting and smoking material, the promotion of safe sexual behaviours and the prevention of initiation to drug injection. In the absence of specific treatment, cocaine users should have access to primary health care services and addiction treatment based on innovative behavioural and pharmacological approaches.     

Effect of hypertriglyceridemia on the pharmacokinetics and blood–brain barrier penetration of clozapine and norclozapine following administration to rats

There is a long-term discussion in the literature concerning the possible link between the improved efficacy of clozapine treatment and elevated plasma triglyceride levels, but no mechanistic studies have been performed to date. The aim of this work was to investigate whether the postprandial hypertriglyceridemia affects the pharmacokinetics and brain distribution of clozapine and norclozapine. Experimental hypertriglyceridemia in rats was induced by oral administration of peanut oil and the pharmacokinetic parameters and brain penetration of clozapine and norclozapine following administration of clozapine were compared to normotriglyceridemic control animals. Moderately increased clearance of clozapine was found in hypertriglyceridemic animals compared to control group. No changes were found in penetration of compounds across the blood–brain barrier (BBB). Taken together, the results do not support the hypothesis that hypertriglyceridemia improves the effect of clozapine by altered pharmacokinetics of clozapine and norclozapine and their increased penetration across the BBB.     

Combined administration of anisodamine and neostigmine produces anti-shock effects: involvement of α7 nicotinic acetylcholine receptors

Aim:

To evaluate the anti-effects of anisodamine and neostigmine in animal models of endotoxic and hemorrhagic shock.

Methods:

Kunming mice were injected with lipopolysaccharide (LPS 30 mg/kg, ip) to induce endotoxic shock. Anisodamine (12.5, 25, and 50 mg/kg, ip) and neostigmine (12.5, 25, and 50 μg/kg, ip) were administered immediately after LPS injection. Survival rate was monitored, and the serum levels of TNF-α and IL-1β were analyzed using ELISA assays. The effects of anisodamine and neostigmine were also examined in α7 nicotinic acetylcholine receptor (α7 nAChR) knockout mice with endotoxic shock and in Beagle dogs with hemorrhagic shock.

Results:

In mice with experimental endotoxemia, combined administration of anisodamine and neostigmine significantly increased the survival rate and decreased the serum levels of inflammatory cytokines, as compared to those produced by either drug alone. The anti-shock effect of combined anisodamine and neostigmine was abolished in α7 nAChR knockout mice. On the other hand, intravenous injection of the combined anisodamine and neostigmine, or the selective α7 nAChR agonist PNU282987 exerted similar anti-shock effects in dogs with hemorrhagic shock.

Conclusion:

The results demonstrate that combined administration of anisodamine and neostigmine produces significant anti-shock effects, which involves activation of α7 nAChRs.     

Pharmacokinetics and pharmacodynamics of cicaprost in healthy volunteers after oral administration of 5 to 20 μG

Summary In a Phase I study, the tolerability, pharmacodynamics and pharmacokinetics of cicaprost have been investigated in 6 male volunteers given 5, 10, 15 and 20 g as tablets of the -cyclodextrin clathrate.Individual inhibition of platelet aggregation and changes in facial colour (measured by chromametry) were dose-dependent and reached a maximum 30 to 60 min post-dose. The maximum inhibition of platelet aggregation was about 40%. After 3 to 4 h pre-treatment values had returned. Blood pressure remained within the normal range. The peak plasma level of cicaprost was reached within 15 to 90 min after drug intake. Both C_max-and AUC were individually dose-dependent. The terminal half-life in plasma of cicaprost was approx. 1 h, and its total clearance amounted to 4–7 ml·min^–1·kg^–1. The time courses of the plasma levels and of the pharmacodynamic actions were in agreement. Interindividual differences were observed in the occurrence of unwanted effects (e.g. headache).Thus, cicaprost is an orally available PGI₂-mimetic, for which effects on platelet aggregation and vascular perfusion have been demonstrated in healthy volunteers after doses of 5 to 15 g.The results will form part of the M.D. thesis of T.Staks. Some of the findings were presented at the CPT meeting, Mannheim/Heidelberg, 1989     

Design and in vitro evaluation of gentamicin–Eudragit microspheres intended for intra-ocular administration

The conditions of preparation of gentamicin sulfate microspheres with high drug loading and a particle size less than 5?µm, using a double-emulsion-solvent evaporation technique, intended for intra-ocular administration are described. The microspheres were prepared from poly methacrylate (Eudragit RS and RL) polymers cross-linked with polyvinyl alcohol. The parameters that improved the incorporation efficiency of gentamicin in the microspheres and controlled the particle size and surface morphology were investigated. Modifying the secondary aqueous phase by partially saturating it with various concentrations of either KCl or gentamicin increased the incorporation efficiency of the drug and affected the mean diameters of the microspheres. However, these characteristics were not altered when the initial drug loading was increased in the formulations. The modified gentamicin microspheres exhibited a smooth surface with an incorporation efficiency rate of 12.59% and a mean diameter of 4.06?µm. The antimicrobial efficiency of gentamicin released from the modified particles against selected Gram-positive and -negative organisms including Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa confirmed that the entrapped gentamicin seemed to remain unaltered by the encapsulation process.     

Sensory,perceptual, motor and cognitive functioning and subjective reports following oral administration ofΔ 9-Tetrahydrocannabinol

Three dose levels, 0.2, 0.4 and 0.6 mg/kg, of ⁹-tetrahydrocannabinol (THC) and a placebo were orally administered to 10 frequent and 10 occasional marijuana users. Following ingestion of each dose and the placebo, objective tests selected from a battery of sensory and perceptual motor tests routinely used to evaluate cerebral dysfunction in hospitalized patients were administered. The influence of ⁹-THC on proficiency and variability of performance was minimal. However, when individual test scores and variabilities were combined and converted to standard scores, allowing for analysis of overall performance, THC had a small but consistent detrimental effect on both proficiency and variability of performance. In contrast, THC exerted profound effects on the subjective experiences of the volunteers as assessed by the Subjective Drug Effects Questionnaire. Subjective changes in mood, feeling, perception and somatic sensations were reported by all subjects but were more pronounced in the occasional user group. It was proposed that the small impairment noted in objective test performance after ingestion of ⁹-THC as contrasted to the large effects on subjective responses suggests that the principal effects of marijuana are on the autonomic nervous system rather than on higher cortical functions.Veterans Administration approved Research Project 0864-03. Also supported by U.S. Public Health Service Research Grant No. DA000.56 from the National Institute of Mental Health.     

Kinetic profile of N,N-dimethyltryptamine and β-carbolines in saliva and serum after oral administration of ayahuasca in a religious context

Ayahuasca is a beverage obtained from Banisteriopsis caapi plus Psychotria viridis. B. caapi contains the β-carbolines harmine, harmaline, and tetrahydroharmine that are monoamine oxidase inhibitors and P. viridis contains N,N-dimethyltryptamine (DMT) that is responsible for the visionary effects of the beverage. Ayahuasca use is becoming a global phenomenon, and the recreational use of DMT and similar alkaloids has also increased in recent years; such uncontrolled use can lead to severe intoxications. In this investigation, liquid chromatography–tandem mass spectrometry (LC–MS/MS) was used to study the kinetics of alkaloids over a 24 h period in saliva and serum of 14 volunteers who consumed ayahuasca twice a month in a religious context. We compared the area under the curve (AUC), maximum concentration (C_max), time to reach C_max (T_max), mean residence time (MRT), and half-life (t_1/2), as well as the serum/saliva ratios of these parameters. DMT and β-carboline concentrations (C_max) and AUC were higher in saliva than in serum and the MRT was 1.5–3.0 times higher in serum. A generalized estimation equations (GEEs) model suggested that serum concentrations could be predicted by saliva concentrations, despite large individual variability in the saliva and serum alkaloid concentrations. The possibility of using saliva as a biological matrix to detect DMT, β-carbolines, and their derivatives is very interesting because it allows fast noninvasive sample collection and could be useful for detecting similar alkaloids used recreationally that have considerable potential for intoxication.     

Altered magnetic resonance images of brain and social behaviors of hatchling, and expression of thyroid hormone receptor βmRNA in cerebellum of embryos after Methimazole administration

Rationale and objectives

The effects of low thyroid hormone level during embryogenesis on MRI of the brain and social behaviors of hatchlings were examined using “fertilized hen's egg–embryo–chick” system.

Methods and results

Control and hatchlings treated with methimazole (20 μmol/egg), which hatched 3 days later than controls were examined. The results are as follows:

1. The MRI examination of the midsagittal section of the brain on hatch day showed that the sizes, by T1- and ADC values by diffusion-weighted images, of the optic lobe and cerebellum of the MMI-hatchlings were significantly bigger than those of the controls.
2. The social behaviors on post-hatch day 3 were based on the following tests:
   1. Aggregation test: The speed of four chicks, individually isolated by cardboard barriers in a box, to make a group upon the removal of barriers.
   2. Belongingness tests: The speed of a chick isolated at a corner to join the group of three chicks placed at the opposite corner.
   3. Vocalization test: The number of decibel produced by a chick isolated at a corner using a sound meter. These tests demonstrated that MMI-hatchlings took longer times and had weaker vocalization than the controls, significantly.
3. Upregulation of THRβ mRNA after MMI treatment suggested that THR was necessary for cerebellum development.

Conclusions

The MMI exposure during the last week of embryogenesis possibly delayed the myelination of certain brain regions and impaired the social behaviors of hatchlings. The chick embryos can be easily induced with hypothyroidism without maternal influences, and the hatchling's behaviors were analyzed using a video camera. The present method will be useful for assessing the effects of unfavorable influences during embryogenesis on social behaviors in later life.     

Effects of chronic Δ9-tetrahyrocannabinol administration on schedule-controlled behavior of pigeons: Cross-tolerance to pentobarbital and barbital

Pigeons responding under a variable-interval (VI) 75-s schedule of food presentation were used to study cross-tolerance from ⁹-tetrahyrocannabinol (⁹-THC) to pentobarbital and barbital. After initial dose-effect functions for pentobarbital and barbital were determined, the birds received ⁹-THC injections for 6 weeks. This chronic administration regimen resulted in a greater than 100-fold tolerance to ⁹-THC. Redetermination of the pentobarbital and barbital dose-effect functions during the chronic ⁹-THC regimen revealed statistically significant shifts to the right for the pentobarbital (0.191 log unit) and barbital (0.078 log unit) dose-effect curves. All six birds showed tolerance to pentobarbital, while four of the six showed tolerance to barbital. Blood barbital levels before and after chronic ⁹-THC administration did not differ significantly. Tolerance to ⁹-THC was more prolonged and of much greater magnitude than the cross-tolerance to pentobarbital or barbital. The results demonstrate that cross-tolerance can develop from ⁹-THC to a barbiturate that normally undergoes little metabolism.