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It is established that dopamine (DA) neurotransmission plays a critical role in the behavioral (e.g. discriminative stimulus) effects of cocaine in rodents. Nonetheless, research has also demonstrated that reciprocal signaling between DA and monoamine neurotransmitters, i.e. serotonin (5-HT) and norepinephrine (NE) has important implication for understanding the actions of cocaine. The present study was focussed on the ability of novel antidepressant drugs (milnacipram, reboxetine and venlafaxine), which affect either NE or both 5-HT and NE reuptake mechanism, to alter (enhance or antagonize) the discriminative stimulus effects of cocaine. Moreover, we investigated if the combined treatment with those drugs and a DA D3 receptor agonist (pramipexole) could reproduce cocaine discrimination. Male Wistar rats were trained to discriminate cocaine (10 mg/kg, ip) from saline (ip) in a two-choice, water-reinforced fixed-ratio 20 drug discrimination paradigm. Given alone, none of antidepressant drugs induced substitution for the cocaine-lever responses. Pramipexole (0.25 mg/kg) produced a partial substitution for cocaine (i.e. 43-52% cocaine-lever responding). In combination experiments, milnacipram (10 mg/kg) or reboxetine (10 mg/kg) given with submaximal doses of cocaine (1.25-5 mg/kg) did not affect the cocaine dose-response curve or its ED50 values. Venlafaxine (10 mg/kg) given in combination with submaximal doses of cocaine (0.6-5 mg/kg) produced significant enhancement of cocaine discrimination with a leftward shift in the cocaine dose-response curve and a decrease in its ED50 value. Pretreatment with either milnacipram (10 mg/kg) or reboxetine (10 mg/kg) failed to modulate the partial substitution evoked by pramipexole (0.25 mg/kg). On the other hand, venlafaxine (10 mg/kg) given in combination with a submaximal dose of pramipexole (0.25 mg/kg), which separately elicited 16 and 42% the cocaine-lever responses, produced significant enhancement of cocaine discrimination (up to 99% of the drug-lever responding). These results indicate that the discriminative stimulus effects of cocaine in rats can be enhanced by venlafaxine or mimicked by the combination with this antidepressant drug and the DA D3 receptor agonist. This finding, together with the recent data reporting the lack of rewarding properties of venlafaxine and the attenuation of morphine dependence and withdrwal signs in rats by the drug, may indicate a possible therapeutic use of this antidepressant in cocaine abuse.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11985331&dopt=Abstract

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Prog Neuropsychopharmacol Biol Psychiatry. 2002 Apr;26(3):585-9.
Venlafaxine versus stimulant therapy in patients with dual diagnosis ADD and depression.

Hornig-Rohan M, Amsterdam JD.

Depression Research Unit, University Science Center, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia 19104, USA.

BACKGROUND: Adult attention-deficit disorder (ADD) may either present as chronic depression or be comorbid with major depressive disorder (MDD). The present study examined treatment outcome with antidepressants and/or stimulants in adults with ADD who initially presented with a diagnosis of MDD. METHOD: Seventeen patients with comorbid MDD and ADD were identified: 65% had a history of hyperactivity in childhood, and 41% had a history of treatment nonresponse to two or more antidepressants. Retrospective analysis was performed with patients who received one of three treatments: (i) venlafaxine, bupropion, or tricyclic antidepressant (TCA) monotherapy; (ii) stimulant monotherapy; or (iii) stimulant plus antidepressant therapy. Outcome was based upon change in both MDD and ADD symptoms. RESULTS: Venlafaxine-treated patients (80%) versus patients taking stimulant therapy alone (33%) had at least a moderate reduction in both MDD and ADD symptoms (chi2=2.40, Fisher exact P=.13). Similarly, 88% of patients on stimulants plus antidepressant therapy also showed a reduction in both MDD and ADD symptoms (versus stimulant monotherapy) (chi2 = 7.22, Fisher exact P=.018). There was no difference in response rates between venlafaxine monotherapy and combination stimulant plus antidepressant therapy (chi2=0.13, Fisher exact p=ns). CONCLUSION: Although preliminary in nature, these data suggest that venlafaxine monotherapy may have similar efficacy to a treatment with a combination of stimulant plus antidepressant therapy, and superior to stimulant therapy alone, in patients with comorbid MDD and ADD. Controlled, prospective trials with larger patient samples will be needed to confirm these preliminary observations.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11999912&dopt=Abstract

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J Pharm Biomed Anal. 2002 Jun 15;28(6):1055-9.
Stability indicating LC method for the estimation of venlafaxine in pharmaceutical formulations.

Makhija SN, Vavia PR.

Pharmaceutical Division, University Department of Chemical Technology (Autonomous), University of Mumbai, Nathalal Parikh Marg, Matunga, Mumbai, India.

A rapid, selective and stability indicating high performance liquid chromatographic method was developed and validated for the estimation of venlafaxine in pharmaceutical dosage forms. The analysis was done on a Spherisorb C8 (4.6 x 250 mm, 5 microm) column. The mobile phase consisted of acetonitrile:sodium dihydrogen orthophosphate [0.04 M], pH 6.8 (75:25) at a flow rate of 1.5 ml/min. Detection was carried out at a wavelength of 224 nm. The developed method was found to give good separation between the pure drug and the degraded product. The polynomial regression data for the calibration plots showed good linear relationship in the concentration range of 1-10 microg/ml with r=0.9999. The method was validated for precision, accuracy, ruggedness and recovery. The minimum detectable and minimum quantifiable amounts were found to be 150 and 600 ng/ml, respectively. The drug was stable under basic and oxidative conditions. However, the sample treated with acid showed an additional peak at a retention time of 4.32 min other than the main peak at a retention time of 5.32 min. Statistical analysis proves that the method is reproducible and selective for the estimation of venlafaxine. As the method could effectively separate the drug from the degradation product, it can be employed as a stability indicating one.

online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12049970&dopt=Abstract

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