What Do We Know About Medical Cannabis in Neurological Disorders and What Are the Next Steps?

Medical use of cannabis has been receiving growing attention over the last few decades in modern medicine. As we know that the endocannabinoid system is largely involved in neurological disorders, we focused on the scientific rationale of medical cannabis in three neurological disorders: amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease through pharmacological plausibility, clinical studies, and patients' view. Clinical studies (randomized controlled trials, open-label studies, cohorts, and case reports) exploring medical cannabis in these disorders show different results depending on the methods and outcomes.

Effect of desipramine on patients with breathing disorders in RETT syndrome.

Objective: Rett Syndrome (RTT) is a severe neurodevelopmental condition with breathing disorders, affecting around one in 10,000 female births. Desipramine, a noradrenaline reuptake inhibitor, reduced the number of apneas in Mecp2-deficient mice, a model of RTT. We planned a phase 2 trial to test its efficacy and its safety on breathing patterns in 36 girls with RTT.

Population pharmacokinetics model of THC used by pulmonary route in occasional cannabis smokers.

Cannabis is the most widely used illegal drug in the world. Delta-9-tetrahydrocannabinol (THC) is the main source of the pharmacological effect. Some studies have been carried out and showed significant variability in the described models as the values of the estimated pharmacokinetic parameters.

Comparison of Cannabinoid Concentrations in Plasma, Oral Fluid and Urine in Occasional Cannabis Smokers After Smoking Cannabis Cigarette.

Purpose: A randomized cross-over, double blind placebo controlled study of smoked cannabis was carried out on occasional cannabis smokers. The objective of this research was to describe the pharmacokinetic parameters of THC and its metabolites in plasma, oral fluid and urine, from samples obtained simultaneously to provide estimations of THC and metabolites concentrations after smoking a cannabis cigarette.

Methods: Blood, oral fluid and urine samples were collected until up to 72 h after smoking the cannabis cigarette (4% of delta-9-tetrathydrocannabinol (THC)).

Effect of ascorbic acid in patients with Charcot-Marie-Tooth disease type 1A: a multicentre, randomised, double-blind, placebo-controlled trial.

Background: Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary peripheral neuropathy that affects roughly one in 5000 births. No specific therapy currently exists for this degenerative disorder, which is characterised by distal progressive muscle atrophy and sensory loss, although ascorbic acid has been shown to reduce demyelination and improve muscle function in a transgenic mouse model of CMT1A. We tested the safety and efficacy of ascorbic acid in adults with CMT1A.

Oxidative metabolism of bupivacaine into pipecolylxylidine in humans is mainly catalyzed by CYP3A.

Bupivacaine is used to provide prolonged anesthesia and postoperative analgesia. The human cytochrome P450 (CYP) involved in bupivacaine degradation into pipecolylxylidine (PPX), its major metabolite, has, to our knowledge, never been described. Microsome samples were prepared from six human livers and incubated in the presence of bupivacaine.

Nicorandil affects diurnal rhythms of body temperature, heart rate and locomotor activity in rats.

The effects of nicorandil, a K+ channel opener with a potent vasodilator action, on diurnal rhythms of body temperature, heart rate and locomotor activity were assessed in rats. Transmitters were intraperitoneally implanted under ether anaesthesia. After recovery from surgery, body temperature, heart rate and locomotor activity were recorded during control, saline or nicorandil (10 mg x kg(-1) administered orally) treatment and for 5 days after treatment.

Tobacco smoke influence on heart rate, body temperature, and locomotor activity daily rhythms as assessed by radiotelemetry in rats.

Using radiotelemetry, this study aimed to evaluate the influence of tobacco smoke on heart rate (H), body temperature (T) and locomotor activity (A) daily rhythms in rats. The tobacco smoke intoxication was produced with a smoking apparatus. H, T, and A data were captured by radiotelemetry.

Effect of cigarette smoke on UDP-glucuronosyltransferase activity and cytochrome P450 content in liver, lung and kidney microsomes in mice.

The effect of cigarette smoke on the expression of several cytochromes P450 (CYP) and UDP-glucuronosyl-transferases (UGT) was studied in mice. The animals were exposed to cigarette smoke for 4 to 30 days. Enzymatic activities supported by CYP1A1, 1A2, 2B, 2E1 and the glucuronidation activity toward phenols were measured in lung, liver and kidney microsomes.

Effects of tobacco smoke on the gene expression of the Cyp1a, Cyp2b, Cyp2e, and Cyp3a subfamilies in mouse liver and lung: relation to single strand breaks of DNA.

Cigarette smoking is a worldwide health problem and is the greatest risk factor for lung cancer. By activating procarcinogens, hepatic and extrahepatic cytochromes P450 can participate in lung carcinogenesis. Tobacco smoke contains numerous cytochrome P450 inducers, substrates, and inhibitors.

Daily rhythms of heart rate, temperature and locomotor activity are modified by anaesthetics in rats: a telemetric study.

The aim of this study was to evaluate the effect of anaesthesia (ether or ketamine) on daily rhythms of temperature (T), heart rate (H) and locomotor activity (A) in unrestrained rats by using implanted radio-telemetry transmitters. T, H and A were measured every 10 min, in Wistar male rats, and analysed using Cosinor. The mean +/- SEM days needed, after surgical implantation, to detect a daily rhythm in H, T and A were also assessed.

Kinetics of bupivacaine after levcromakalim treatment in mice.

Previous workers have reported that 0.01 mg kg-1 of levcromakalim injected intraperitoneally did not modify bupivacaine-induced neurotoxicity but increased the duration of action of bupivacaine. This study was designed to document possible changes in the pharmacokinetic behaviour of bupivacaine and its main metabolite, N-desbutylbupivacaine in mice after a single 0.

Ketamine effects on bupivacaine local anaesthetic activity and pharmacokinetics of bupivacaine in mice.

This study was designed to document possible changes in bupivacaine (B) local anaesthetic activity and pharmacokinetics in mice after a ketamine (K) injection. In the experiments, bupivacaine (8.25 mg.

Effects of tobacco smoke exposure on the kinetics of bupivacaine in mice.

The aim of this work was to determine the effects of different time of tobacco smoke exposure on pharmacokinetics of bupivacaine in mice. Mice were exposed to tobacco smoke during 4 days (group T4) or 8 days (group T8) using the Hamburg II smoking machine. Controls were exposed under the same experimental conditions but without tobacco smoke.

Effects of calcium antagonists on binding of local anesthetics to plasma proteins and erythrocytes in mice.

This study was designed to document possible changes in the binding of bupivacaine (BV), lidocaine (LC) and their main metabolites desbutylbupivacaine (PPX) and monoethylglycinexylydide (MEGX), respectively, to plasma proteins and erythrocytes in mice after acute treatment with the calcium antagonists diltiazem (DZ), nicardipine (NP) and verapamil (VP). A significant plasma protein binding of BV, LC and PPX was measured, whereas no binding could be detected for MEGX. The binding of BV was not modified by DZ, NP and VP, however, the total plasma level was increased in the presence of VP.

Potassium channel agonists modify the local anaesthetic activity of bupivacaine in mice.

Purpose: The mechanisms of action of local anaesthetics and potassium channel agonists (PCAs) may interfere by acting in a direct or indirect manner on the same ion channels. In a previously reported study, the bupivacaine-induced mortality was shown to be modified in different ways by four PCAs tested (diazoxide (D), levcromakalim (L), nicorandil (N) and pinacidil (P)) since bupivacaine-induced mortality was increased by high doses of P and L, decreased by N and stayed unchanged by D. The present study was designed to document the changes in bupivacaine (B) local anaesthetic activity in mice after a single injection of one of the four PCAs (D, L, N and P).

Effects of different exposure times to tobacco smoke intoxication on carboxyhemoglobin and hepatic enzymate activities in mice.

The aim of this work was to determine the effects of different exposure times to smoke on carboxyhemoglobin (HbCO) and hepatic enzymate activities in order to adapt a tobacco smoke intoxication model in mice. Mice were exposed to tobacco smoke for various durations of either 2 (group S2), 4 (group S4), 8 (group S8), or 31 days (group S31) using the Hamburg II machine. Controls (nonexposed animals) were used under the same experimental conditions.

Seasonal variations in the kinetics of bupivacaine in the mouse.

Very few studies have been devoted to the influence of the time of the year, i.e. seasonal variations, on drug kinetics.

Kinetics of bupivacaine after nicorandil treatment in mice.

Previous studies have reported interactions between potassium-channel agonists and bupivacaine. This study was designed to document possible changes in the pharmacokinetic behaviour of bupivacaine and its main metabolite, N-desbutylbupivacaine, in mice after a single 1 mg kg-1 intraperitoneal injection of nicorandil. The kinetic variables of bupivacaine were determined after a single 20 mg kg-1 intraperitoneal dose of bupivacaine in controls (group 1) and in nicorandil-treated mice (group 2).

High inducibility of mouse renal CYP2E1 gene by tobacco smoke and its possible effect on DNA single strand breaks.

Several studies have shown in humans an association between renal carcinoma and cigarette smoking. Cigarette smoke contains numerous cytochrome P450 inducers and substrates. In the present study we investigated the effect of cigarette smoke on the regulation of murine cytochrome P450 expression in kidney and its possible role in the induction of single strand breaks in DNA.

Effects of clonidine pretreatment on the local anaesthetic activity of bupivacaine in mice.

This study was designed to document possible changes in bupivacaine local anaesthetic activity in mice after a single injection of clonidine (0.1 or 1 mgkg-1, i.p.

Kinetics of bupivacaine after clonidine pretreatment in mice.

Previous studies have reported that clonidine pretreatment causes an increase in the local anaesthetic activity of bupivacaine. This study was designed to document possible changes in the pharmacokinetic behaviour of bupivacaine and its main metabolite, desbutylbupivacaine, PPX, in mice after a single, 0.1 mg.

Effect of four potassium channel agonists on bupivacaine-induced toxicity in mice.

The influence of four potassium channel agonists i.e. diazoxide (D), levcromakalim (L), nicorandil (N) and pinacidil (P) on bupivacaine-induced acute toxicity was evaluated by measuring the convulsant activity, the time of latency to convulse and the mortality rate.

Rapid simultaneous determination of lidocaine, bupivacaine, and their two main metabolites using capillary gas-liquid chromatography with nitrogen phosphorus detector.

A gas-liquid chromatographic method for the simultaneous measurement in serum of bupivacaine, lidocaine, and their main metabolites, 2,6-pipecolylxylidide (PPX) and monoethylglycine xylidide (MEGX), respectively, is described. The procedure involves a one-step extraction and injection of the extract into a gas chromatograph equipped with a capillary column and nitrogen phosphorus detector under constant temperature conditions. Recovery of all components averaged 94%, with the lowest detection limit of 15 ng/ml for the four drugs.