CNS Stimulant Drugs Research Articles

Intranasal transfersomal based in situ gel for augmenting methylphenidate bioavailability and brain delivery: In vitro and in vivo evaluation

Methylphenidate, a CNS stimulant drug, has poor oral bioavailability due to extensive first-pass effect. In this study, Methylphenidate loaded transfersomes based in situ gel (MPH-TFs Gel) was prepared for brain targeting through intranasal (IN) drug delivery. Methylphenidate transfersomes (MPH-TFs) were prepared using the thin film hydration method. Box-Behnken Design expert software was utilized for the optimization by assessing the effect of independent variables phospholipon 90-G, Tween-80, and Methylphenidate (MPH) on particle size (PS), zeta potential (ZP), Polydispersity index (PDI), and Entrapment Efficiency (EE). The observed mean particle size of the optimized MPH-TFs was found to be 139.7 ± 3.75 nm, mono dispersion with PDI (0.208 ± 0.002), negatively charged (−27.9 ± 0.287 mV) and had an excellent entrapment efficiency (86 ± 3 %). Fourier-Transform Infrared (FTIR) spectra have depicted the compatibility of the components. X-r Diffraction analysis showed the conversion of crystalline structure methylphenidate to amorphous. The optimized MPH-TFs were then subsequently incorporated into an already optimized MPH-TFs Gel. MPH-TFs Gel was then characterized for its physicochemical properties, in vitro and in vivo studies. In vitro release and ex vivo permeation analysis showed sustained release and improved permeation of the MPH-TFs Gel, respectively. Additionally, histopathological studies of nasal membrane affirmed the safety of MPH-TFs Gel after intranasal application. In vivo pharmacokinetic study demonstrated improved brain bioavailability of MPH-TFs Gel compared to orally administered Methylphenidate solution (MPH-Sol).

Analytical method development and validation of UV-visible spectrophotometric method for the estimation of CNS stimulant drug in bulk

A simple, rapid, accurate, economical and precise UV/VIS method has been developed and validated. Choices of a common solvent were essential so various solvent ranges including methanol, ethanol, acetonitrile, and 0.1 N HCL, and various concentrations ranges of various buffers were analyzed. Hence 0.1 N HCL was selected as a solvent for the proposed method. Caffeine showed maximum absorbance at 273nm.Drug obey Beer Lambert’s law in the concentration range of 3-18 μg/mL for Caffeine. The LOD and LOQ were found to be 0.5476 μg/mL and 1.6594 μg/mL for Caffeine. The method was quantitatively evaluated in terms of linearity, precision, precision, LOD, LOQ and recovery. The method is simple, convenient and suitable for the analysis of Caffeine in bulk drugs.

The Psychobiological Problems of Continued Nicotine Dependency in E-Cigarette 'Vapers'. Commentary: "Electronic Cigarettes".

The Psychobiological Problems of Continued Nicotine Dependency in E-Cigarette 'Vapers'. Commentary: "Electronic Cigarettes".

Stimulant-Related Psychosis in ADHD Treatment: An Update for Past 10 Years

Although it is considered rare, stimulant-induced psychosis is one of the most serious and unpleasant adverse events during attention deficit/hyperactivity disorder (ADHD) treatment. There is a need to update regularly the current state of knowledge on this topic to improve quality of care. For this reason, we reviewed relevant publications using Pubmed database, for the period 2003-2012. It came out that the amount of publications, which are predominantly case reports, on this topic are limited for this period. Previous trend of publication and state of knowledge continues. Newer atypical antipsychotics, which complicate stimulant treatment in ADHD, is an emerging dimension. We suggest more research and ongoing clinical vigilance to reach an advanced understanding of the topic. Keywords: Adverse effect, ADHD, CNS stimulant drugs, drug-induced psychosis, mania, methylphenidate, psychoactive drugs.

Clinical presentations of substance abuse in bipolar heroin addicts at time of treatment entry

BackgroundStudies on the ‘self-medication hypothesis’ have focused on substance abuse as an attempt to alleviate emotional suffering.MethodsWe have investigated concomitant substances of abuse in 150 bipolar heroin addicts clustered according to their clinical presentation at treatment entry (depressive episode, hypomanic episode, manic episode and mixed episode). Bipolar heroin addicted patients were chosen because they tend to have a concomitant poly-substance abuse and because, as compared with patients suffering for other mental illnesses, they more clearly reveal a variety of identifiable affective states.ResultsPatients with a depressive episode more frequently used non-prescribed anxiolytic-hypnotics. They were found to use cocaine-amphetamines more frequently during a hypomanic episode, whereas the use of cannabis and cocaine-amphetamines occurred more frequently during a manic episode. The associated use of alcohol, cocaine-amphetamines and cannabinoids was more frequently encountered during a mixed episode. Limitations: apart from the difficulty in determining whether the substance use modifies the mood or the mood state determines the substance used, this is a report on a retrospective analysis, rather than a study specifically designed to elucidate the issue; in addition, no information was available on the temperament of our subjects. Assessments of the same subject in various clinical presentations would have provided a better level of information.ConclusionsBesides one expected result – the prominent use of CNS stimulants during a depressive phase of bipolar patients – this study supports the hypothesis that mood elation is a pleasurable, rewarding experience that, in bipolar patients, can be started or prolonged by means of CNS stimulant drugs. Stimulant use was, therefore, more prevalent during the ‘up’ rather than the ‘down’ phase of the illness.

Microwave assisted enzyme catalysis for synthesis of n-butyl dipheyl methyl mercapto acetate in non-aqueous media

n-Butyl dipheyl methyl mercapto acetate is an important pharmaceutical intermediate, having applications in the synthesis of Modafinil, a CNS stimulant drug. The current process is highly polluting and requires alternate green processes. Synthesis of it was carried out via lipase in the presence of microwave irradiation. Optimization of reaction conditions, such as catalyst loading, mole ratio of reactants, reaction temperature, water concentration and reusability of catalysts under the microwave irradiation was done. Among all, the commercially available lipases Novozym 435 was found best and gives the conversion 34% in 24 h at 60°C. A ping–pong bi–bi model with substrate n-butanol inhibition at higher concentration was found to be suitable for kinetics of the reaction.

Evaluation of sedative and anticonvulsant activities of Unmadnashak Ghrita

‘Unmadnashak Ghrita’ (UG) is a ayurvedic formulation containing Ferula narthex (6 g), Gardenia gummifera (6 g), Ellataria cardamom (6 g), Bacopa monneri (6 g), and cow’s ghee (clarified butter fat) (76 g). In the present study, neuropharmacological activities of UG were evaluated for its gross behavioural effect, pentobarbitone sleeping time, spontaneous locomotor activity, antagonism to amphetamine induced hyperlocomotor activity, analgesic activity by tail flick test, rota-rod performance (motor coordination test), maximal electroshock (MES) induced seizures, and pentylenetetrazol (PTZ) induced convulsions in mice. The formulation showed CNS-depressant activity in gross behavioural test, potentiated pentobarbitone sleeping time and there was significant decrease in spontaneous locomotor count in mice. The formulation also antagonized the behavioral effects of CNS-stimulant drug amphetamine, and showed analgesic effect in mice. UG failed to affect the motor coordination test. The formulation also protected mice from MES and PTZ induced convulsions. These results suggest that UG has CNS-depressant and anticonvulsant activity in mice.

Differences in the regional and cellular localization of c- fos messenger RNA induced by amphetamine, cocaine and caffeine in the rat

Male rats were treated i.p. with either 5 mg/kg amphetamine, 3 and 30 mg/kg cocaine or 100 mg/kg caffeine and killed after 30 min. Brains were sectioned and processed for radioactive in situ hybridization histochemistry for the labelling of either c- fos, enkephalin, substance P, neurokinin B, choline acetyltransferase, somatostatin or adenosine A 2A receptor messenger RNA. The distribution of c- fos messenger RNA was investigated both at the regional level using film autoradiography, and at the cellular level using emulsion autoradiography. All drug treatments except 3 mg/kg cocaine induced an increased level of c- fos messenger RNA in cells that had a neuron-like morphology. The cells that contained the c- fos messenger RNA were identified by making pairs of 5-μm sections in which one section was processed for c- fos messenger RNA and the other was processed for one of the other messenger RNA species. After amphetamine treatment, only some 10% of the cells in the striatum were labelled, and to a variable extent. Instead there was prominent labelling of a band in the cortex that runs parallel to the cortical surface. There was also a moderate degree of labelling in the nucleus accumbens. c- fos -positive cells were substance P-positive and negative for enkephalin or A 2A receptor messenger RNA. Cocaine (30 mg/kg) induced a modest labelling in the caudate-putamen, as well as in the accumbens. With cocaine treatment (30 mg/kg), about 30% of striatal neuron-like cells were c- fos labelled. Most c- fos -positive cells were substance P-positive, but none of the c- fos -positive cells were enkephalin-positive or A 2A-receptor-positive. Cocaine (3 mg/kg) had no significant effect on c- fos. Caffeine gave rise to a strong hybridization signal in the caudate-putamen, particularly the dorsolateral part. No other region examined differed significantly from control. With caffeine treatment, about 73% of neuron-like cells were c- fos labelled in the lateral striatum, but labelling was much less pronounced in the medial part or in the accumbens. c- fos -labelled cells were found in enkephalin-positive and enkephalin-negative, substance P-positive and substance P-negative, neurokinin B-positive and neurokinin B-negative groups. No choline acetyltransferase-positive or somatostatin-positive cells were found that were also c- fos -positive with any of the treatments. We conclude that each of the different CNS stimulant drugs induces a highly specific pattern of c- fos messenger RNA. Furthermore, caffeine induces a pattern of c- fos induction that differs markedly from that of amphetamine and cocaine.

Effects of CNS stimulants on the in vivo release of the colocalized transmitters, dopamine and neurotensin, from rat prefrontal cortex

The effect of CNS stimulant drugs on the in vivo release of the colocalized neurotransmitters dopamine and neurotensin in rat prefrontal cortex was studied using microdialysis. Amphetamine, methylphenidate and nomifensine all increased extracellular fluid (ECF) levels of dopamine; however, their effects on neurotensin varied. Amphetamine increased both ECF dopamine (514 ± 82% of basal) and neurotensin (350 ± 49% of basal); however, the neurotensin increase lagged behind the increase in dopamine suggesting a possible trans-synaptic effect. Methylphenidate increased both dopamine and neurotensin (226 ± 26% and 151 ± 14% of basal respectively) co-synchronously, suggesting exocytosis of vesicles containing both dopamine and neurotensin. The nomifensine-induced increase in dopamine (202 ± 23% of basal) was similar to that of methylphenidate, whereas the increase in neurotensin was significantly delayed and of lower magnitude (134 ± 20% of basal). These data suggest that dopamine and neurotensin in part share a common releaseable pool in the prefrontal cortex. Moreover, dopamine may act presynaptically to increase neurotensin release and the different behavioral profiles of these psychostimulants may in part relate to their different effects on neurotensin release.

Central nervous system stimulants: neuropharmacological mechanisms.

The mechanisms underlying CNS-stimulant drug discrimination are discussed. Although different doses of CNS stimulants may produce qualitatively different cues, it appears that a relatively low dose of d-amphetamine (e.g., 1 mg/kg) elicits a "general" CNS-stimulant cue. Presynaptically, this cue may primarily depend on release of endogenous dopamine whereas inhibition of dopamine reuptake, per se, is insufficient to elicit the cue. Postsynaptically, the involvement of both dopamine D-1 and D-2 receptors is implicated. Furthermore, in the drug discrimination situation, D-1/D-2 receptors may be coupled differently than in dopamine-dependent locomotor activation. Anatomically, CNS-stimulant drug discrimination may depend primarily on mesolimbic dopamine systems.

Mise au point d'un indice EEG de vigilance diurne. Application aux essais pharmacologiques

Theta/alpha spectral powers ratio was used to quantify physiological decrease of vigilance occurring after 5 min recording eyes closed, at different times of the day, in normal volunteers with 'high alpha'. Maximum decrease of vigilance occurred at about 2 or 4 p.m. Theta/alpha ratio fluctuations were similar on the homologous right and left scalp areas. This ratio is useful in psychopharmacology to quantify the antagonist activity of a CNS stimulant drug on the physiological decrease of vigilance after 5 min as well as the sedative effect of a drug. It allows to follow the kinetics of the drug action at receptor level.

Computerized CFF: Reliability and Validity of Two Psychophysical Techniques

Two computerized CFF measures have been implemented in our laboratory and used in several studies. One method is based on the traditional "method of limits" threshold determination technique (CFF-ML). Process-controlled optimization of individual stimulus parameters (starting points and center frequency of ascending and descending sweeps) were shown to give a significant increase in test-retest reliability as compared with a non-computerized version. In subsequent studies, test-retest reliabilities (> 24 h) for CFF-ML have regularly exceeded .90. Criticism against the method of limits for not separating sensory and response factors was the basis for the design of a forced choice, three-alternative, process-controlled CFF method (CFF-3). The reliability of CFF-3 appears to be high (.90-.95), there are virtually no order effects (even after 20 retest sessions of four minutes each), and the "exposure time" for a reliable threshold determination can be made short enough to study fast drug onset effects, for instance after smoking. Both CFF methods appear to have a satisfactory validity, allowing demonstration of significant effects in small samples of subjects, of e.g. variations in cerebral blood flow, effects of thyroxine substitution therapy in hypothyroid patients, and effects of sedative and CNS stimulant drugs.

Use of CNS Stimulant Medication in Averaged Electroencephalic Audiometru with Children with MBD

Averaged electroencephalic audiometry (AEA) was conducted on 12 children diagnosed as having minimal brain dysfunction (MBD). Each child was tested on three separate days to permit a double-blind evaluation of responsiveness to no-drug, placebo and CNS stimulant drug conditions. In addition, 9 of the 72 children were tested a fourth time to permit an examination of the two dosage levels. Lower thresholds were recorded when the subjects were tested on medication. This finding suggests that AEA with MBD children can be enhanced by taking advantage of the medication prescribed to counteract hyperactivity. It was also observed that the AEA performance of children on whom medication had a favorable behavioral effect was different from that of poor drug responders, even in the no-medication conditions.

Chromatographic screening for drugs of abuse using capillary columns II. Peak identification on support coated open tubular columns for a series of central nervous system stimulant drugs

A system based on Kovats' Retention Indices is described for the identification of CNS stimulant drugs recovered from body fluids. Use is made of the difference in retention indices found on polar and non-polar GLC columns (Δl values) and the effect of operating temperature is discussed.

Analysis of factors associated with the extinction of a conditioned response

Among the numerous forms of treatment which have been applied to the problem of childhood enuresis nocturna , conditioning therapy has yielded the most satisfactory results ( Young, 1965a ; Yates, 1970 ; Morgan and Young, 1972 ). A major drawback to the use of conditioning techniques has been the high relapse rate; reported rates vary according to the period of follow-up employed, but percentages ranging from 8 to 52 per cent have been recorded ( Lovibond, 1964 ; Young, 1969 ). Statistics available for the years 1967-1970 for the Vale Drive special investigation clinic indicate a relapse rate of approximately 30 per cent. Attempts to reduce this rate by the use of CNS stimulant drugs during initial treatment have proved unsuccessful ( Young and Turner, 1965 ; Turner and Young, 1966 ), while the use of intermittent reinforcement schedules has yet to be found to reduce relapse to a significant extent ( Lovibond, 1964 ; Turner, Young and Rachman, 1970 ). Overlearning procedures, brought about by increased fluid intake, have, however, been found successful at a significant level in the counteraction of the relapse problem ( Young and Morgan, 1972 ). Few investigators have attempted to identify the type of child whose learned responses are most susceptible to the extinction which represents relapse, although Lovibond and Coote (1970) found a significant increase in the relapse rate among children whose nocturnal enuresis was accompanied by diurnal urinary symptoms. Young (1965b) , in accord with the hypothesis relating personality structure and conditioning ( Eysenck, 1957 , Eysenck, 1960 ), found extraverted children to be significantly more susceptible to relapse than introverts.

Overlearning in the conditioning treatment of enuresis: A long-term follow-up study

V arious studies have reported high rates of relapse following the otherwise highly successful conditioning treatment of childhood enuresis nocturna (Young, 1969). Relapse would seem to be a hazard inherent in this form of treatment, and to be independent of patient variables (Young and Morgan, 1972a). Use of the technique of intermittent reinforcement schedules (Lovibond, 1964; Turner, Young and Rachman, 1970) and of CNS stimulant drugs (Young and Turner, 1965; Turner and Young, 1966) to counteract the problem of relapse have failed to achieve satisfactory results. Young and Morgan (1972b) have demonstrated the success of overlearning therapy in reducing the relapse rate. This regime requires the child to maintain or regain his learned nocturnal bladder control, to a success criterion of 14 consecutive dry nights, while drinking up to 2 pints of liquid in the hour before retiring. The present paper reports the experience gained in the counteraction of relapse by the use of overlearning therapy over approximately 4 yr at the Vale Drive Clinic, at which enuresis is treated by conditioning techniques (Young, 1965; Morgan and Young, 1972).

The effect of immunosympathectomy on the responses of the mouse to reserpine and various antidepressant and stimulant drugs.

The technique of immunosympathectomy was used to investigate the relative importance of sympathetically mediated processes in the body temperature responses of mice to reserpine treatment and the thermogenic effects of subsequently administered anti-depressant and CNS stimulant drugs. It was found that immunosympathectomized mice were less sensitive to the temperature lowering effects of reserpine but exhibited, unexpectedly, an enhanced thermogenic response to each of the representative antidepressant and stimulant drugs tested. These findings appear to exclude the sympathetic division of the autonomic nervous system as an essential prerequisite for the thermogenic effects of anti-depressant and stimulant drugs in reserpine treated mice. It is suggested that the observed effects could be accounted for in terms of a possible hyperfunctional adrenal gland.

CNS stimulant drugs and conditioning treatment of nocturnal enuresis: A long term follow-up study

The results of a long term follow-up of enuretics treated by conditioning techniques are presented. A high relapse rate has occurred after treatment with a combination of the “bell and pad” and stimulant drugs. The frequency of relapse is particularly high in the group of patients to whom Dexedrine had been administered. The importance of the relapse rate associated with conditioning treatment is discussed, and explanations and further research are considered.

CNS stimulant drugs and conditioning treatment of nocturnal enuresis: A long term follow-up study

The results of a long term follow-up of enuretics treated by conditioning techniques are presented. A high relapse rate has occurred after treatment with a combination of the “bell and pad” and stimulant drugs. The frequency of relapse is particularly high in the group of patients to whom Dexedrine had been administered. The importance of the relapse rate associated with conditioning treatment is discussed, and explanations and further research are considered.

CNS stimulant drugs and conditioning treatment of nocturnal enuresis

CNS stimulant drugs and conditioning treatment of nocturnal enuresis