Systematic review of preclinical, clinical, and post-marketing evidence of bupropion misuse potential.

Background: Bupropion is a substituted cathinone compound widely used as a first line or add-on treatment for depression, smoking cessation, and more recently in combination with naltrexone for weight loss. As abuse of synthetic cathinone compounds has received more attention in recent years, concern about the misuse potential of bupropion has grown as well. Objectives: We review bupropion pharmacology and assessments of misuse potential including preclinical evidence, human studies, and post-marketing surveillance of bupropion misuse. Methods: This review reports the results of a systematic review of publications evaluating the potential for bupropion to be misused. Publications were identified using PubMed and Medline through Ovid® as well as iterative bibliographic searches. A summary of data from informal sources of information including substance-user experience from online forum entries is included. Results: Preclinical evidence demonstrates some potential for misuse based on psychomotor, discrimination, self-administration, and conditioned place preference tasks. However, this potential is less than that of commonly misused stimulants. Studies in human populations similarly indicate that bupropion shares interoceptive effects with other stimulants, but lacks some key reinforcing effects of other stimulants. In the real-world setting, misuse of bupropion occurs, but is uncommon. Adverse effects of bupropion misuse are frequently cited as significant barriers to obtaining any desired interoceptive effect. Conclusions: While bupropion demonstrates some potential for misuse, pharmacological differences from other structurally-related stimulants limit bupropion's reinforcing effects. Without additional data indicating susceptibility of specific populations to bupropion misuse, there is no empirical data suggesting a need to modify bupropion prescribing patterns.

Composite carbohydrate interpenetrating polyelectrolyte nano-complexes (IPNC) as a controlled oral delivery system of citalopram HCl for pediatric use: in-vitro/in-vivo evaluation and histopathological examination.

Citalopram HCl (CH) is one of the few drugs which can be used safely in childhood psychiatric disorders. This study was focused on the preparation of interpenetrating polyelectrolytes nano-complexes (IPNC) to transform the hydrophilic carbohydrate polymers into an insoluble form. The IPNCs were loaded with CH to sustain its effect. The IPNC2 (composed of chitosan:pectin in a 3:1 ratio) showed the most extended drug release pattern (P < 0.05) and followed a Higuchi-order kinetics model. It was characterized using SEM, X-rays diffractometry, and FTIR. In-vivo studies were performed using immature rats with induced depression, and were based on the investigation of behavioral, biochemical, and histopathological changes at different time intervals up to 24 h. Rats treated with IPNC2 showed a significant more rapid onset of action and more extended effect in the behavioral tests, in addition to a significantly higher serotonin brain level up to 24 h, compared to rats treated with the market product (P < 0.05). The histopathological examination showed a profound amelioration of the cerebral cortex features of the depressed rats after IPNC2 administration. This study proves the higher efficacy and more extended effect of the new polyelectrolytes nano-complexes compared to the market product.

A dearth of data: the problem of phosphorus in prescription medications.

A high dietary intake of phosphorus is considered by most to be a significant health threat for dialysis patients. Efforts to include the phosphorus content of foods on the nutrition label in the US have, to date, been fruitless. Another source of phosphorus, largely unrecognized, is prescription medications. These may contain phosphorus as indicated on their package label; the amount is not quantified. We examined the labels of the branded forms of 200 of the most widely prescribed medications in Dialysis Clinic centers in the United States and found that 23 (11.5%) contained phosphorus. A sampling of different doses and manufacturers (generic and branded) of these drugs was analyzed for phosphorus content and found levels as high as 111.5 mg/dose (40 mg paroxetine). Notable were the phosphorus content of a generic 10 mg lisinopril (32.6 mg) and a generic 10 mg amlodipine (40.1 mg). The significant potential for iatrogenic injury accruing from the use of these drugs warrants efforts at remediation. Specific information on the phosphorus content of medications used by dialysis population needs to be made available to the dialysis community.

Mianserin, an antidepressant kills Leishmania donovani by depleting ergosterol levels.

In the present study, we have investigated the antileishmanial potential of mianserin, an antidepressant. Mianserin was found to inhibit both the promastigote and amastigote forms of the parasite in a dose dependant manner. The IC50 values for promastigotes and amastigotes were 21 µM and 46 µM respectively. Interestingly, mianserin failed to inhibit THP-1 differentiated macrophages up to 100 µM concentration thus, exhibiting parasite selectivity. When mianserin was incubated with recombinant Leishmania donovani 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) enzyme, it exhibited an IC50 value of 19.8 µM. Inhibition kinetics revealed competitive mode of enzyme inhibition as the Km increased with no change in Vmax. Further structural investigation of enzyme-inhibitor interaction revealed quenching of HMGR tryptophan intrinsic fluorescence with a K(sv) value of 3.025±0.37 M(-1) and an apparent binding constant of 0.0954 mM. We further estimated ergosterol levels which is a major component of Leishmania cell membrane. It is synthesized by HMGR enzyme, the first rate limiting enzyme of the sterol biosynthetic pathway. Analysis of ergosterol levels by HPLC revealed ∼2.5-fold depletion in mianserin treated promastigotes with respect to untreated parasites. This data was further validated by exogenous supplementation of mianserin treated cells with ergosterol and cholesterol. Reversal of growth inhibition was observed only upon ergosterol addition though it was refractory to cholesterol supplementation. Overall, our results demonstrate the possibility of repositioning of an antidepressant for the treatment of Visceral Leishmaniasis.

Fluoxetine: a case history of its discovery and preclinical development.

INTRODUCTION: Depression is a multifactorial mood disorder with a high prevalence worldwide. Until now, treatments for depression have focused on the inhibition of monoaminergic reuptake sites, which augment the bioavailability of monoamines in the CNS. Advances in drug discovery have widened the therapeutic options with the synthesis of so-called selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine. AREAS COVERED: The aim of this case history is to describe and discuss the pharmacokinetic and pharmacodynamic profiles of fluoxetine, including its acute effects and the adaptive changes induced after long-term treatment. Furthermore, the authors review the effect of fluoxetine on neuroplasticity and adult neurogenesis. In addition, the article summarises the preclinical behavioural data available on fluoxetine's effects on depressive-like behaviour, anxiety and cognition as well as its effects on other diseases. Finally, the article describes the seminal studies validating the antidepressant effects of fluoxetine. EXPERT OPINION: Fluoxetine is the first selective SSRI that has a recognised clinical efficacy and safety profile. Since its discovery, other molecules that mimic its mechanism of action have been developed, commencing a new age in the treatment of depression. Fluoxetine has also demonstrated utility in the treatment of other disorders for which its prescription has now been approved.

Characterization of the trace-level impurities in the bulk drug citalopram by high-performance liquid chromatography/tandem multistage mass spectrometry.

Five trace impurities were detected in the bulk drug citalopram using high-performance liquid chromatography with UV detection. A simple and sensitive method suitable for liquid chromatography tandem multistage mass spectrometry (HPLC/MS(n)) analysis was developed. Using this method, the fragmentation behavior of citalopram and the impurities was investigated. Four impurities were rapidly characterized, and an unknown impurity was elucidated as 3-(3-dimethylaminopropyl)-N-(1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-yl)-3-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carboxamide on the basis of the MS(n) and exact mass evidence, and the proposed structure was further confirmed by nuclear magnetic resonance (NMR) experiments after preparative isolation.

Drug evaluation: Vilazodone--a combined SSRI and 5-HT1A partial agonist for the treatment of depression.

Vilazodone is a combined selective serotonin reuptake inhibitor (SSRI) and a 5-HT(1A) receptor partial agonist that is being developed by Clinical Data Inc for the treatment of depression. In preclinical studies, vilazodone compared favorably to other antidepressants such as paroxetine and fluoxetine. Orally administered vilazodone inhibited ultrasonic vocalization in the rat after electrical foot shock (a model of anxiolytic activity). Yet, in the forced swimming test model of depression in rats, vilazodone administered intraperitoneally was active at 1 mg/kg but not at 3 or 10 mg/kg. During clinical trials, vilazodone completely abolished REM sleep for 8 h and demonstrated antidepressant efficacy that was equal to that of current antidepressant therapeutics. The author concludes that the success of vilazodone as an effective antidepressant agent will depend on whether the drug can produce a more rapid antidepressant effect than other SSRI agents, or if specific genetic markers of patients can be associated with clinical efficacy.