Prozac
MDMA (ecstasy) inhibition of MAO type A and type B: comparisons with fenfluramine and fluoxetine (Prozac).

Leonardi ET, Azmitia EC.

Department of Biology, New York University, NY 10003.

3,4-Methylenedioxymethamphetamine (MDMA), a serotonin (5-HT) neurotoxin, has been shown to promote the release of serotonin (5-HT) and block its reuptake. The increased buildup of extracellular 5-HT should normally be degraded by monoamine oxidase (MAO). The effects of both enantiomers of MDMA were examined on MAO-A and monoamine oxidase-B (MAO-B) activity in rat brain homogenates. Both enantiomers competitively inhibited 5-HT catabolism by rat brain MAO-A. The Ki of MDMA for MAO-A was 22 mumol/L. A mixed type of inhibition by MDMA was observed for phenethylamine catabolism by MAO-B for both optical antipodes. Logistical analysis of concentration response curves for MDMA inhibition of MAO-A and MAO-B show an IC50 of 44 mumol/L for inhibition of MAO-A by MDMA. The IC50 value of MDMA inhibition of MAO-B was 370 mumol/L, showing a selective potency for MAO-A inhibition. The MAO inhibitory properties of fenfluramine (FEN) and fluoxetine (FLUOX) were compared to those of MDMA. The rank order potency of these drugs for MAO-A inhibition was MDMA > FLUOX > FEN, whereas for MAO-B inhibition, FLUOX > MDMA > FEN. A combination of FLUOX and MDMA at their respective IC50 did not inhibit MAO activity more than either drug alone at equivalent concentrations. These results indicate that the actions of FEN do not appear to involve MAO inhibition. MDMA (ecstasy) produced a preferential inhibition of MAO-A (IC50 = 44 mumol/L), which should increase extracellular 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7945733&dopt=Abstract fluoxetine Prozac



Prozac
Stress and hunger alter the anorectic efficacy of fluoxetine in binge-eating rats with a history of caloric restriction.

Placidi RJ, Chandler PC, Oswald KD, Maldonado C, Wauford PK, Boggiano MM.

Department of Psychology, Division of Behavioral Neuroscience, The University of Alabama at Birmingham, Alabama 35294-1170, USA.

OBJECTIVE: We examined the effect of fluoxetine to suppress binge eating in rats with a history of caloric restriction (CR) and the extent to which this effect was altered by stress and hunger. METHOD: To detect heightened sensitivity to fluoxetine, young female rats were used to determine a subthreshold anorectic dose (2 mg/kg, intraperitonally). Another group of rats was either fed ad libitum or given multiple CR (to 90% body weight) and refeeding-to-satiety cycles. One half of the rats were then either spared or subjected to foot shock stress before fluoxetine treatment. RESULTS: A history of CR alone produced bingelike eating on palatable food (p < .001) and, although stress did not affect intake, it rendered CR rats hypersensitive to the satiety effect of fluoxetine. The feeding-suppression was mainly for chow (p < .05) and the effect was abolished if the rats were in negative energy balance. DISCUSSION: Results support the utility of this animal model to elucidate serotonergic changes linking dieting to binge eating. The diverse effects of fluoxetine on the type of food, and in hungry versus sated rats, suggest alternate brain mechanisms should be concomitantly targeted for improved treatment of binge eating disorders.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15478135&dopt=Abstract fluoxetine Prozac



Prozac
Crystal engineering approach to forming cocrystals of amine hydrochlorides with organic acids. Molecular complexes of fluoxetine hydrochloride with benzoic, succinic, and fumaric acids.

Childs SL, Chyall LJ, Dunlap JT, Smolenskaya VN, Stahly BC, Stahly GP.

Design Science Research, LLC, 1256 Briarcliff Road, Atlanta, Georgia 30306, USA. scott design-science.info

A crystal engineering strategy for designing cocrystals of pharmaceuticals is presented. The strategy increases the probability of discovering useful cocrystals and decreases the number of experiments that are needed by selecting API:guest combinations that have the greatest potential of forming energetically and structurally robust interactions. Our approach involves multicomponent cocrystallization of hydrochloride salts, wherein strong hydrogen bond donors are introduced to interact with chloride ions that are underutilized as hydrogen bond acceptors. The strategy is particularly effective in producing cocrystals of amine hydrochlorides with neutral organic acid guests. As an example of the approach, we report the discovery of three cocrystals containing fluoxetine hydrochloride (1), which is the active ingredient in the popular antidepressant Prozac. A 1:1 cocrystal was prepared with 1 and benzoic acid (2), while succinic acid and fumaric acid were each cocrystallized with 1 to provide 2:1 cocrystals of fluoxetine hydrochloride:succinic acid (3) and fluoxetine hydrochloride:fumaric acid (4). The presence of a guest molecule along with fluoxetine hydrochloride in the same crystal structure results in a solid phase with altered physical properties when compared to the known crystalline form of fluoxetine hydrochloride. On the basis of intrinsic dissolution rate experiments, cocrystals 2 and 4 dissolve more slowly than 1, and 3 dissolves more quickly than 1. Powder dissolution experiments demonstrated that the solid present at equilibrium corresponds to the cocrystal for 2 and 4, while 3 completely converted to 1 upon prolonged slurry in water.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15479089&dopt=Abstract fluoxetine Prozac



Prozac
A developmental neurotoxicity evaluation of the effects of prenatal exposure to fluoxetine in rats.

Vorhees CV, Acuff-Smith KD, Schilling MA, Fisher JE, Moran MS, Buelke-Sam J.

Division of Basic Science Research, Children's Hospital Research Foundation, Cincinnati, OH 45229-3039.

Fluoxetine is a widely used serotonin reuptake inhibitor effective in the treatment of depression. This experiment assessed the potential developmental neurotoxicity of fluoxetine. Sprague-Dawley CD rats were treated once per day on Days 7-20 of gestation with 0, 1, 5, or 12 mg/kg of fluoxetine (free base) dissolved in distilled water. One control group received water by gavage; animals in this group were provided food and water ad libitum. The second control group (PF) also received water by gavage; animals in this group had their food and water restricted by pair-feeding and watering them to the 12 mg/kg fluoxetine group. Litters were culled to 12 after birth and offspring (male/female pairs) were tested neurobehaviorally at three developmental stages (preweaning, juvenile, and adult). At each stage, two pairs per litter received tests of locomotor activity, acoustic startle, and startle after administration of one of two pharmacological challenges (one pair each receiving fluoxetine or apomorphine). Two pairs were also tested for spontaneous alternation, passive avoidance, and complex learning in a water maze. At the highest dose, fluoxetine caused maternal weight loss during pregnancy, reduced litter sizes at birth, and increased neonatal mortality. No effects on long-term growth or survival were seen. Prenatal fluoxetine exposure produced no significant effects on locomotor activity, spontaneous alternation, passive avoidance, or water maze performance. A few scattered interactions involving treatment group were obtained on startle, but no pattern of treatment-related changes was evident. Regional wet and dry brain weights taken at each stage were not affected by prenatal fluoxetine exposure. The data suggest that fluoxetine is not developmentally neurotoxic in the rat.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7982528&dopt=Abstract fluoxetine Prozac



Prozac
Revisiting fluoxetine (Proxac) and suicidal preoccupations.

Tueth MJ.

Department of Psychiatry, University of Florida, Gainesville 32608.

Several reports were published in the psychiatric literature in 1990 and 1991 documenting fluoxetine (Prozac) causing patients to consider or attempt suicide. During the following 2 years, retrospective studies appeared in the medical literature that seemed to indicate that suicidal preoccupation was not related to the antidepressant fluoxetine (Prozac) but was probably a symptom of the depressive illness. Recent studies have suggested, however, that fluoxetine (Prozac) may in fact lead to suicidal behavior because the drug appears to adversely affect serotonergic neuronal discharge and induce an akathisia-like extrapyramidal reaction. While fluoxetine (Prozac) has a very favorable side effect profile compared to the tricyclic antidepressants, it may cause akathisia and induce a small subset of patients to consider or attempt suicide.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7989697&dopt=Abstract fluoxetine Prozac



Prozac
[Clinical evaluation of fluoxetine]

[Article in Polish]

Puzynski S, Rybakowski J, Kocur J, Rydzynski Z, Beresewicz M, Bogdanowicz E, Duszyk S, Gruszczynski W, Kalinowski A, Koszewska I, et al.

II Kliniki Psychiatrycznej, Instytutu Psychiatrii i Neurologii w Warszawie.

The multicenter trials were performed in a group of 86 depressive inpatients (among them 64 with endogenous depression) managed with fluoxetine (Prozac). It was established that the drug is most effective in managing psychogenic depressions and may also be of use in endogenous depressions, among them in drug resistant ones. Tolerance to the drug was satisfactory, 62% did not show any unwanted side-effects. The rest of the group displayed sleep disorders, increased anxiety, lost of appetite and nausea. Changes in the laboratory parameters and non-specific changes in the electrocardiogram were observed sporadically. Fluoxetine seemed not to have any direct cholinolytic effect.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7991712&dopt=Abstract fluoxetine Prozac



Prozac
Attenuation of hormone responses to the 5-HT1A agonist ipsapirone by long-term treatment with fluoxetine, but not desipramine, in male rats.

Li Q, Brownfield MS, Levy AD, Battaglia G, Cabrera TM, Van de Kar LD.

Department of Pharmacology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL.

The present study had two objectives: (1) to provide information on neuroendocrine challenge tests that can lead to diagnostic tests in humans; and (2) to confirm our previous observation that chronic fluoxetine selectively inhibits serotonin (5-HT1A) receptor function. We determined the effect of chronic fluoxetine and desipramine (DMI) on the hormone response to ipsapirone, a 5-HT1A agonist and a potential anxiolytic drug. Ipsapirone increased oxytocin, adrenocorticotropic hormone (ACTH), corticosterone, and prolactin, but not renin or vasopressin concentrations in plasma. Chronic fluoxetine, but not DMI, significantly inhibited the effect of ipsapirone on plasma oxytocin, ACTH and corticosterone concentrations. Chronic fluoxetine also reduced the Bmax for 3H-8-hydroxy-2-(dipropylamino) tetralin (3H-8-OH-DPAT) labelled 5-HT1A receptors in the midbrain. Neither antidepressant altered the density or affinity of 5-HT uptake sites. In conclusion, the present results confirm our previous results using 8-OH-DPAT as a challenge, and suggest that chronic 5-HT uptake inhibition results in adaptive changes leading to decreased function of the 5-HT1A receptor system. Finally, because ipsapirone may be administered to humans, it might be usable to evaluate 5-HT1A receptor function in depressed patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7993956&dopt=Abstract fluoxetine Prozac



Prozac
Lack of potentiation of anticonvulsant effect by fluoxetine in drug-resistant epilepsy.

Gigli GL, Diomedi M, Troisi A, Baldinetti F, Marciani MG, Girolami E, Pasini A.

Department of Neurology, University of Rome Tor Vergata, Italy.

To test the hypothesis that fluoxetine may be a useful adjunct to antiepileptic therapy, we treated with fluoxetine (20-40 mg/day) nine patients suffering from medically intractable epilepsy with daily seizures. Five patients remained unchanged and four worsened. Worsening was more evident at 40 mg/day. One patient improved when receiving the lower dose (20 mg/day) and worsened with the higher dose (40 mg/day). These data suggest: (1) that fluoxetine is not effective as add-on antiepileptic treatment; (2) that caution should be exerted when using fluoxetine as an antidepressive treatment in epileptic patients.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8000717&dopt=Abstract fluoxetine Prozac