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The aim of the present study was to develop and evaluate intranasal formulations of the thermoreversible fluoxetine cubosomal in situ gel. This gel was intended for permeation and bioavailability enhancement to target the brain effectively by bypassing the blood-brain barrier (BBB). Fluoxetine-loaded cubosomes were prepared by the homogenization method followed by the cold method approach to develop in situ gel. Fluoxetine-loaded cubosomes displayed a higher encapsulation efficiency (82.60 ± 1.25%) than fluoxetine. This might be due to the solubilizing activity of the polymer to cause partitioning of the lipophilic drug into the aqueous phase during the change from the cubic gel phase to cubosomes. In vitro analysis of fluoxetine-loaded cubosomal in situ gel showed a sustained release profile (93.22 ± 2.47%) due to limited diffusion of fluoxetine. The formation of strong affinity bonds of the drug with GMO (drug transporter) decreased the drug release in comparison to that with fluoxetine-loaded cubosomes (90.68 ± 1.74%). The ex vivo drug release profile revealed the drug release of 96.31 ± 2.88% by the end of 24 h. This is attributed to the higher capability of the intranasal cubosomal in situ gel to prolong the retention and enable better permeation through the nasal mucosa. In male Wistar rats, in vivo biodistribution studies for cubosomal in situ gel administered via the intranasal route at a dose of 3.5 mg/kg demonstrated an increase in pharmacokinetic parameters like the AUC (406 ± 75.35 μg/mL), C max (368.07 ± 0.23 μg/mL), T max (4 h), and t 1/2 (14.06 h). The mucoadhesive nature of the in situ gel led to an increase in the residence time of the gel in the nasal mucosa. The biodistribution study of intranasal in situ cubosomal gel improved the bioavailability 2.21-fold in comparison to that with the cubosomal dispersion but 2.83-fold in comparison to that with the drug solution. Therefore, fluoxetine-loaded cubosomal in situ gel proved as a promising carrier for effective transportation of fluoxetine via the intranasal route with significant brain bioavailability.

Synergistic effects of the exo- and endocyclic chiral centers of an imidazolidinone-based auxiliary were investigated in the perspective of acetate aldol reactions. The reversal in diastereoselectivity was accomplished by lithium and titanium enolate reactions, which proceed through proposed open and closed transitions states, respectively. The aldol adducts were used in the stereoselective synthesis of fluoxetine.

Understanding the removal of trace organic contaminants is critical for membrane applications in water recycling. This study investigates the relationship between trace contaminant sorption and their rejection by nanofiltration (NF) membranes. A mass balance is developed that quantitatively links the rejection decline over time seen with some sorbing compounds to the total mass found sorbed on the membrane. The sorbed mass of perfluorooctane sulfonamide (FOSA) and fluoxetine evaluated from the mass balance agreed to within approximately 30% of the quantity analytically determined via extraction. Static sorption experiments show that sorption takes place predominantly within the polyamide separating layer of the membrane. Finally, the relationship between the steady-state rejection and sorption tendency of ten trace organic compounds is elucidated. A greater tendency to sorb results in lower steady-state rejection, both when comparing compounds of similar size, as well as when comparing the same compound under different conditions. As a result, a major finding is that in the presence of competitive sorption, that is, the presence of other trace organic compounds in the membrane matrix, some compounds sorb less and are therefore rejected more than when these compounds are alone in the feed. At no point during experimentation was any effect on the water flux observed.

The present investigation reports the importance of the S and R forms of fluoxetine, as an antidepressant with regards to the chirality taking different types of interactions associated with the neurotransmitter, serotonin. The goal of the present study is to provide predictions and to help experimental and theoretical studies toward understanding the chirality of fluoxetine in drug-ligand interaction, associated with serotonin-reuptake inhibitor drug design studies. Several different conformations for serotonin and fluoxetine complexes have been considered for quantum mechanical calculations. Both the S and R forms of fluoxetine associated with serotonin and fluoxetine complexes are found to be similar in total energy and binding energy values. The present study also supports the conformational effect of the 3-phenyl group of fluoxetine as stereo independent and is consistent with in vitro and in vivo data which indicates that the the eudismic ratio of fluoxetine enantiomers is near unity. The calculated highest stabilization energy values, binding energy values, both in the gas and aqueous phases at MP2/6-31+G*//B3LYP/6-31+G* identify the most possible stable conformer for the serotonin-fluoxetine complex.

The extent to which humans and wildlife are exposed to the vast array of anthropogenic chemicals and their degradation products, along with related naturally occurring compounds, is nowadays an important issue. The study of the physical-chemical properties of the compounds and/or degradation products is an important subject because some of them are intrinsically related to its resistance to degradation and/or bioaccumulation. Accordingly, the study of the electrochemical behavior of the selective serotonin reuptake inhibitor fluoxetine and its main metabolite norfluoxetine was investigated. The identification of the oxidation processes was done via two fluoxetine analogues, 1-(benzyloxy)-4-(trifluoromethyl)benzene and N-methyl-3-phenylpropan-1-amine hydrochloride. The oxidative processes occurring in fluoxetine are pH-dependent and were ascribed to the chemical moieties present in the molecule: the secondary amine group and the substituted aromatic nucleus. To perform an unequivocal ascription, the structural preferences of the drug and metabolite were also determined, by Raman spectroscopy coupled to quantum mechanical calculations (at the DFT level). The analytical data obtained in this work will allow the development of a rapid and unequivocal spectroscopic procedure suitable for fluoxetine identification, as well as to distinguish between the drug and its main metabolite.

Fluoxetine, the active ingredient of many antidepressants, was identified as specifically toxic toward algae in a quantitative structure-activity relationship (QSAR) analysis with literature data for algae, daphnia, and fish. The goal of this study was to elucidate the mode of action in algae and to evaluate the toxicity of the major human metabolites of fluoxetine using two different algae tests. The time dependence and sensitivity of thedifferenteffectendpointsyield information on the physiological mode of action. Baseline toxicity was predicted with QSARs based on measured liposome-water partition coefficients. The ratio of predicted baseline toxicity to experimental toxicity (toxic ratio TR) gives information on the intrinsic potency (extent of specificity of effect). The metabolite p-trifluoromethylphenol was classified to act as baseline toxicant Fluoxetine (TR 60-150) and its pharmacologically active metabolite norfluoxetine (TR 10-80) exhibited specific toxicity. By comparison with reference compounds we conclude that fluoxetine and norfluoxetine have an effect on the energy budget of algal cells since the time pattern of these two compounds is most similar to that observed for norflurazon, but they act less specifically as indicated by lower TR values and the similarity of the effect pattern to baseline toxicants. The mixture toxicity of fluoxetine and its human metabolites norfluoxetine and p-TFMP can be predicted using the model of concentration addition for practical purposes of risk assessment despite small deviations from this model for the specific endpoints like PSII inhibition because the integrative endpoints like growth rate and reproduction in all cases gave agreement with the predictions for concentration addition.

The GABA amides of the antidepressants nortriptyline and fluoxetine, 1 and 2, were compared to their respective parent compounds in rodent models of pain. The amides significantly reduced early nociceptive and late inflammatory responses compared to nortriptyline or fluoxetine, where 1 exhibited overall better efficacy than 2. Amide 1 was most efficacious in lowering cytokine secretion, edema and hyperalgesia induced by formalin and lambda-carrageenan, respectively. Thus, 1 is a promising candidate for the treatment of pain.

A method to perform nanoscale automated CYP450-based drug metabolism studies using a capillary as a reaction vessel is described. In-capillary assays consumed only approximately 30 nL of recombinant human CYP450 solution. Ultrafast analysis of substrates and metabolites was achieved off-line by ultrahigh-pressure liquid chromatography coupled to mass spectrometry. This approach was successfully applied to qualitative metabolism studies of six major CYP450 isozymes and CYP2D6 inhibition experiments.

Fluoxetine (FLX) was shown to be photoreactive in sunlit surface waters. FLX degraded in deionized water when exposed to simulated sunlight with a half-life of 55.2+/-3.6 h(-1). Photodegradation products were identified using high performance liquid chromatography-UV (HPLC-UV) and liquid chromatography tandem mass spectrometry (LC-MS-MS) using electrospray (ES) ionization. Defluorination of the trifluoromethyl group in FLX and in fluometuron and flutalanil,two other compounds containing this functional group, is suggested to be a common direct photolysis pathway for trifluoromethylated compounds. Products resulting from O-dealkylation of FLX were also observed. The rate of degradation was faster in synthetic field water where .OH was the likely dominant oxidant in the system. The bimolecular rate constant for the reaction between FLX and .OH was measured as (8.4+/-0.5) x 10(9) and (9.6 +/-0.8) x 10(9) M(-1) s(-1) using two different methods of competition kinetics. Indirect photodegradation reactions could lead to the production of hydroxylated and O-dealkylated compounds. Although direct photolysis could potentially limitthe persistence of FLX in surface waters, its degradation by indirect photolysis would proceed faster. Thus, this latter process could be important in the elimination of FLX in surface waters.

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.

In a wide search program toward new, efficient, and fast-acting antidepressant drugs, we have prepared series of new compounds having an (aryl)(aryloxy)methyl moiety linked directly or through a methylene chain to different substituted and unsubstituted cycles (isoquinoline, piperazine, piperidine, tetrahydropyran, or cyclopentane). These compounds have been evaluated for their affinities for serotonin (5-HT) transporter (SERT) and 5-HT(1A) and 5-HT(2A) receptors. Racemic mixtures of 4-[(aryl)(aryloxy)methyl]piperidine derivatives showed much higher affinity values for SERT than fluoxetine and resulted in lack of affinity for 5-HT(1A) and 5-HT(2A) receptors. Some of these racemic mixtures were resolved to their enantiomers and tested for binding to norepinephrine (NE) transporter (NET), dopamine (DA) transporter (DAT), and alpha(2) receptor. Several of these enantiomers [(-)-15b, (-)-15j, (-)-15t, (+)-15u] displayed a dual binding profile with affinities for SERT and NET with K(i) < 25 nM and a NET/SERT ratio <10. Compound (-)-15j (coded as F-98214-TA for development studies) showed a dual binding profile with very high affinity values for SERT and NET (K(i) = 1.9 and 13.5 nM, respectively), and further pharmacological characterization is in progress for its evaluation as a antidepressant.

Allopregnanolone is a neurosteroid which exhibits anxiolytic and anticonvulsant activities through potentiation of the GABA(A) receptor. The reduction of 5alpha-dihydroprogesterone (5alpha-DHP), the last step in allopregnanolone biosynthesis, is catalyzed by 3alpha-hydroxysteroid dehydrogenases (3alpha-HSDs). While the mechanism of action of allopregnanolone and the physiological and pharmacological modulation of allopregnanolone concentrations in vivo have been extensively studied, there has been little characterization of the kinetics of human 3alpha-HSD catalyzed allopregnanolone formation. We report here determination of the kinetic mechanism for 5alpha-DHP reduction catalyzed by human 3alpha-HSD type III by using steady-state kinetics studies and assessment of the ability of fluoxetine and various other small molecules to activate 3alpha-HSD type III catalyzed allopregnanolone formation. Enzyme-catalyzed 5alpha-DHP reduction yielded two products, allopregnanolone and 5alpha,20alpha-tetrahydroprogesterone, as measured by using a radiometric thin-layer chromatography assay, while 5beta-DHP reduction yielded the neurosteroid pregnanolone as the only product. 5Beta-DHP reduction proceeded with a catalytic efficiency 10 times higher than that of 5alpha-DHP reduction. Two-substrate kinetic analysis and dead-end inhibition studies for 5alpha-DHP reduction and allopregnanolone oxidation indicated that 3alpha-HSD type III utilized a ternary complex (sequential) kinetic mechanism, with nicotinamide adenine dinucleotide cofactor binding before steroid substrate and leaving after steroid product. Since previous reports suggested that fluoxetine and certain other small molecules increased allopregnanolone concentrations in vivo by activating 3alpha-HSD type III, we investigated whether these small molecules were able to activate human 3alpha-HSD type III. Our results showed that, at concentrations up to 50 microM, fluoxetine, paroxetine, sertraline, norfluoxetine, carbamazepine, clozapine, flurbiprofen, and sulfobromophthalein did not activate the enzyme. These results characterize the role of 3alpha-HSD type III in allopregnanolone formation and suggest that activation of this enzyme by fluoxetine is likely not the mechanism by which fluoxetine increases allopregnanolone concentrations.

The 5-HT(3) serotonin receptor plays an important role in regulating communication between cells in the central and peripheral nervous systems. It is the target of many different therapeutic agents and abused drugs. A rapid chemical kinetic method with a time resolution of 10 ms in combination with the whole-cell current-recording technique was employed to study the receptor in NIE-115 mouse neuroblastoma cells. The mechanism of the channel-opening process, receptor desensitization, and receptor inhibition by nicotine, cocaine, and fluoxetine were investigated. Two different forms of the 5-HT(3) serotonin receptor, each with a different desensitization rate, were observed. The inhibition of the receptor by nicotine has not previously been reported. Both nicotine and cocaine compete with serotonin for the receptor site that controls channel opening, with observed dissociation constants of 25 and 7 microM, respectively. Fluoxetine (Prozac), a widely used antidepressant, occupies a different regulatory site on the receptor with an apparent K(i) value of 244 microM.

A combined protein and pharmacophore model for cytochrome P450 2D6 (CYP2D6) has been extended with a second pharmacophore in order to explain CYP2D6 catalyzed N-dealkylation reactions. A group of 14 experimentally verified N-dealkylation reactions form the basis of this second pharmacophore. The combined model can now accommodate both the usual hydroxylation and O-demethylation reactions catalyzed by CYP2D6, as well as the less common N-dealkylation reactions. The combined model now contains 72 metabolic pathways catalyzed by CYP2D6 in 51 substrates. The model was then used to predict the involvement of CYP2D6 in the metabolism of a "test set" of seven compounds. Molecular orbital calculations were used to suggest energetically favorable sites of metabolism, which were then examined using modeling techniques. The combined model correctly predicted 6 of the 8 observed metabolites. For the well-established CYP2D6 metabolic routes, the predictive value of the current combined protein and pharmacophore model is good. Except for the highly unusual metabolism of procainamide and ritonavir, the known metabolites not included in the development of the model were all predicted by the current model. Two possible metabolites have been predicted by the current model, which have not been detected experimentally. In these cases, the model may be able to guide experiments. P450 models, like the one presented here, have wide applications in the drug design process which will contribute to the prediction and elimination of polymorphic metabolism and drug-drug interactions.

Radiolabeled m-iodobenzylguanidine (MIBG) is a tumor-seeking radioactive drug used in the diagnosis and treatment of pheochromocytomas and neuroblastomas. It is transported into the tumor cells by the neuronal norepinephrine (NE) transporter (NET) which is expressed in almost all neuroblastoma cells. Here, we describe the synthesis and some pharmacological properties of a series of fluorescent compounds structurally related to the NET substrate, MIBG, or to the NET inhibitors, (-)-(2R,3S)-cocaine and nisoxetine. Three of 10 synthesized fluorescent compounds, 1-(1-naphthylmethyl)guanidinium sulfate (1), 1-[2-(dibenz[b, f]azepin-5-yl)ethyl]guanidinium sulfate (2), and (2R, 3S)-2beta-ethoxycarbonyl-3beta-tropanyl 5-(dimethylamino)naphthalene-1-sulfonate (6), exhibited high affinity (IC(50) about 50 nM) for the NET. The nisoxetine derivatives 8 (rac-N-[(3-methylamino-1-phenyl)propyl]-5-(dimethylamino)-1-naphthale nesulfonamide) and 9 (rac-4-[(3-methylamino-1-phenyl)propyl]amino-7-nitro-2,1, 3-benzoxadiazole) and especially the guanidine derivative 4 (1-[4-(4-phenyl-1,3-butadienyl)benzyl]guanidinium sulfate) which are characterized by intermediate affinity for the NET (IC(50) 370-850 nM) caused significant and nisoxetine-sensitive cell fluorescence. At least the guanidine derivative 4 might represent a potentially useful agent for imaging of neuroblastoma cells.