Fluoxetine HCl Research Articles

Maillard Reaction of Lactose and Fluoxetine Hydrochloride, a Secondary Amine

□ Analysis of commercially available generic formulations of fluoxetine HCl revealed the presence of lactose as the most common excipient. We show that such formulations are inherently less stable than formulations with starch as the diluent due to the Maillard reaction between the drug, a secondary amine hydrochloride, and lactose. The Amadori rearrangement product was isolated and characterized; the characterization was aided by reduction with sodium borohydride and subsequent characterization of this reduced adduct. The lactose–fluoxetine HCl reaction was examined in aqueous ethanol and in the solid state, in which factors such as water content, lubricant concentration, and temperature were found to influence the degradation. N-Formylfluoxetine was identified as a major product of this Maillard reaction and it is proposed that N-formyl compounds be used as markers for this drug–excipient interaction since they are easy to prepare synthetically. Many characteristic volatile products of the Maillard reaction have been identified by GC/MS, including furaldehyde, maltol, and 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one. Close similarity between the degradation products of simple mixtures and formulated generic products was found; however, at least one product decomposed at a rate nearly 10 times that predicted from the simple models. Maillard products have also been identified in unstressed capsules. The main conclusion is that drugs which are secondary amines (not just primary amines as sometimes reported) undergo the Maillard reaction with lactose under pharmaceutically relevant conditions. This finding should be considered during the selection of excipients and stability protocols for drugs which are secondary amines or their salts, just as it currently is for primary amines.

Adsorption of Fluoxetine HCl by Activated Charcoal

We studied the adsorption of fluoxetine HCl (Prozac) by Norit USP XXIII activated charcoal in vitro, in simulated gastric fluid (USP; pH 1.2), and in simulated intestinal fluid (USP; pH 7.5). The data were fitted to both Langmuir and Freundlich equations. The Langmuir Qm values (maximal adsorption capacities) for pH 1.2 and 7.5 were 0.258 and 0.330g drug/g charcoal, respectively. These excellent capacities suggest that oral charcoal therapy would be effective for fluoxetine overdose.

Modification of Acoustic Startle Reactivity by Cocaine Administration During the Postnatal Period: Comparison With a Specific Serotonin Reuptake Inhibitor

This study investigated whether exposure to cocaine during the postnatal period affects the acoustic startle response (ASR) following administration of the serotonin (5-HT) agonists, 8-OH-DPAT and mCPP , in adulthood. To test the hypothesis that alterations in reactivity may be due to cocaine's effects at the 5-HT carrier, another group of rats was given fluoxetine, a specific 5-HT uptake inhibitor, during the same postnatal period and tested along with the cocaine-treated rats. Male and female rats received 25 mg/kg/day cocaine HCl, fluoxetine HCl, or vehicle SC during postnatal days 11–20. At 75 days of age, subjects were ASR tested for 30 min on 2 consecutive days. On the first test day, there was a significant effect of treatment and gender with post hoc analysis indicating that, overall, the males were more reactive than the females and that the fluoxetine-treated males showed a pattern of reactivity resembling sensitization. On the second test day, subjects received a dose of the 5-HT 1A agonist 8-OH-DPAT, the 5- HT 1 B 2 C agonist, mCPP , or saline prior to being placed in the startle chamber. Cocaine-exposed males showed an enhanced response to 8-OH-DPAT and a reduction in the depression produced by mCPP administration compared to their response to saline. Fluoxetine exposed males showed a significant increase in startle response following saline administration compared to the rats receiving vehicle during the postnatal period and 8-OH-DPAT produced an insignificant enhancement of that startle response. mCPP reduced startle in fluoxetine-treated males as it did in the postnatal vehicle-treated controls. In females, the postnatal cocaine and fluoxetine treatments did not alter the response to 8-OH-DPAT or mCPP compared to females receiving vehicle during the postnatal period. Together these data indicate that, in males, whereas postnatal cocaine alters the development of the 5-HT system as evidenced by an altered startle response to 5-HT agonists, cocaine does not produce the same alteration as that produced by the administration of a specific 5-HT uptake inhibitor during the same period of development.

Modification of acoustic startle reactivity by cocaine administration during the postnatal period: Comparison with a specific serotonin reuptake inhibitor

This study investigated whether exposure to cocaine during the postnatal period affects the acoustic startle response (ASR) following administration of the serotonin (5-HT) agonists, 8-OH-DPAT and mCPP, in adulthood. To test the hypothesis that alterations in reactivity may be due to cocaine's effects at the 5-HT carrier, another group of rats was given fluoxetine, a specific 5-HT uptake inhibitor, during the same postnatal period and tested along with the cocaine-treated rats. Male and female rats received 25 mg/kg/day cocaine HCl, fluoxetine HCl, or vehicle SC during postnatal days 11–20. At 75 days of age, subjects were ASR tested for 30 min on 2 consecutive days. On the first test day, there was a significant effect of treatment and gender with post hoc analysis indicating that, overall, the males were more reactive than the females and that the fluoxetine-treated males showed a pattern of reactivity resembling sensitization. On the second test day, subjects received a dose of the 5-HT 1A agonist 8-OH-DPAT, the 5- HT 1 B 2 C agonist, mCPP, or saline prior to being placed in the startle chamber. Cocaine-exposed males showed an enhanced response to 8-OH-DPAT and a reduction in the depression produced by mCPP administration compared to their response to saline. Fluoxetine exposed males showed a significant increase in startle response following saline administration compared to the rats receiving vehicle during the postnatal period and 8-OH-DPAT produced an insignificant enhancement of that startle response. mCPP reduced startle in fluoxetine-treated males as it did in the postnatal vehicle-treated controls. In females, the postnatal cocaine and fluoxetine treatments did not alter the response to 8-OH-DPAT or mCPP compared to females receiving vehicle during the postnatal period. Together these data indicate that, in males, whereas postnatal cocaine alters the development of the 5-HT system as evidenced by an altered startle response to 5-HT agonists, cocaine does not produce the same alteration as that produced by the administration of a specific 5-HT uptake inhibitor during the same period of development.

Short-term fluoxetine treatment alters monoamine levels and turnover in discrete brain nuclei

The effects of short-term fluoxetine administration on monoamine levels and turnover were assessed in discrete brain nuclei. Adult male rats received fluoxetine HCl (10 mg/kg) or saline injections intraperitoneally for 4 days and monoamine levels determined by high performance liquid chromatography. The major metabolite of 5-HT, 5-hydroxyindoleacetic acid (5-HIAA), was decreased by fluoxetine treatment in the ventromedial hypothalamic nucleus (VMN), the lateral hypothalamic area and the CA1 region of the hippocampus. Fluoxetine treatment significantly increased serotonin (5-HT) levels in the VMN but did not change 5-HT levels in any other area examined. Norepinephrine (NE) levels were higher in fluoxetine-treated rats in the dorsomedial hypothalamic nucleus, dorsal raphe nucleus and parietal motor cortex (MCTX). 5-HT and NE turnover were also determined by the pargyline method. Fluoxetine treatment decreased 5-HT turnover in the VMN and increased 5-HT turnover in the median raphe. NE turnover was decreased in the preoptic area, the MCTX and parietal sensory cortex by fluoxetine administration. These results demonstrate that brain areas with similar 5-HT innervation respond differently to fluoxetine administration and fluoxetine, which selectively alters 5-HT uptake, also affects NE levels and turnover in several brain nuclei.

In utero exposure to fluoxetine HCl increases hematoma frequency at birth

The present study was undertaken to determine if fluoxetine HCl (Prozac, Dista Products Ltd., Liverpool, UK) might cause adverse vascular effects, such as hematomas, in rats exposed in utero. Gravid Sprague-Dawley rats were administered 5.62 mg/kg fluoxetine HCl by oral gavage beginning on day 7 of gestation and ending the day of birth. A control group received distilled water by oral gavage during gestation. At birth, offspring of both groups were assessed for visible adverse vascular effects. Fluoxetine HCl-exposed offspring showed a statistically higher frequency of skin hematomas when compared to water controls. This result is consistent with known adverse effects of fluoxetine and lends support to a recently published report that attempted to link fluoxetine HCl use to bleeding episodes in eight patients being treated for obsessive-compulsive disorder. The results of this study suggest caution in the prolonged use of this medication during pregnancy and in patients with predisposing conditions that may increase the chances of bleeding.

Chronic fluoxetine treatment up‐regulates dopamine receptors in the mesolimbic forebrain of the rat

AbstractThe mechanism of antidepressant function is still largely unknown. The authors examined the binding of [H] SCH 23390 and [3H] spiperone to dopantine D1‐ and D2‐like receptors, respectively, using quantitative in vitro receptor autoradiogra‐phy inforebrain sections front rats treated for 8 weeks with 5 mg/kg fluoxetine HCl or vehicle. Fluoxetine treatment significantly increased dopamine D1 receptor density in the nucleus accumbens and D2 density in the nucleus accumbens, olfactory tubercle and islands of Calleja region. Neither D1 nor D2 receptors were significantly affected in the striatum. The results are discussed in light of additional evidence that antidepressants alter mesolimbic dopamine function. Although fluoxetine (Prozac) selectively inhibits reuptake of serotonin, its indirect effects on mesolimbic dopamine systems might underlie its potent efficacy as an antidepressant. Depression 1:82–87 (1993). © 1993 Wiley‐Liss, Inc.

Fluoxetine reduces intravenous cocaine self-administration in rats

Rats self-administered intravenously delivered cocaine (0.2 mg/kg) under a fixed-ratio (FR) 4 schedule during 24-hr sessions. Water was freely available from both a drinkometer and a standard water bottle. After behavior had stabilized,the rats were injected with fluoxetine HCl at 10:00 a.m. and 4:00 p.m. for 5 consecutive days. Three groups of 5 rats each received a different dose of fluoxetine (2.5, 5 or 10 mg/kg) via the IV cannula. In three other groups of rats a glucose and saccharin solution (G+S) was substituted for water in the automatic drinking device and saline was substituted for cocaine. These three groups of rats received the same fluoxetine doses as the cocaine self-injecting groups. In two additional groups of 5 rats each, the cocaine dose was changed to 0.1 or 0.4 mg/kg, and 5 mg/kg fluoxetine injections were given. The two higher doses of fluoxetine (5 and 10 mg/kg) reduced cocaine infusions (0.2 mg/kg) by at least 50 percent on all 5 days of treatment, and cocaine infusions returned to baseline levels within 48 hr after fluoxetine treatments were terminated. Behavior maintained by the G+S solution was also reduced by the two higher fluoxetine doses; however, this reduction did not reliably occur until the last two days of fluoxetine administration. The G+S intakes returned to baseline levels within 24 hr after fluoxetine treatment. Fluoxetine also reduced cocaine infusions in the group of rats that received the lower unit dose of cocaine (0.1 mg/kg); however, it had almost no effect on behavior maintained by a higher cocaine dose (0.4 mg/kg). Food and water intake, responding on an inactive lever, and the number of saline infusions were not reliably altered by the fluoxetine treatments. These results suggest that fluoxetine alters the reinforcing effects of cocaine as well as a nondrug substance.

Reduction in oral ethanol self-administration in the rat by the 5-HT uptake blocker fluoxetine

Long-Evans rats (N=4) maintained on ad lib food and water were initiated to self-administer ethanol using the sucrose-substitution procedure. Following initiation, the rats received IP injections of fluoxetine HCl in sterile water 30 minutes before selected daily self-administration sessions. On other sessions, the rats were injected with sterile water only. Doses of 1, 2, 3, and 5 mg/kg were tested in a random order. Only one drug dose was given each week and each dose was tested at least twice except the 5 mg/kg dose. As dose increased, responding for ethanol decreased with significant reductions at both the 3 and 5 mg/kg dose. The nature of the decrease was such that the duration of continuous responding at the beginning of the session was reduced respective to control and noninjection performance. Overall, the findings of this study support prior work with fluoxetine and other 5-Ht blockers which appear to affect satiety mechanisms and possibly reinforcement efficacy.

Fluoxetine subsensitizes a nicotinic mechanism involved in the regulation of core temperature

Fluoxetine HCl, 10 mg/kg ip, twice daily produced subsensitivity to the hypothermic effects of nicotine (base), 1 mg/kg ip, after 1 ( p<0.02) and 2 ( p<0.002) weeks of treatment. Phenelzine sulfate, desipramine HCl and bright artificial light produced the same effect. The capacity of three chemically distinct classes of antidepressants and bright artificial light (a treatment for seasonal depression) to produce this result suggestss that effects on nicotinic mechanisms may be involved in the mechanism of action of these treatments.

Withdrawal-like behaviour induced by inhibitors of biogenic amine reuptake in rats treated chronically with delta 9-tetrahydrocannabinol.

The effects of the biogenic amine reuptake inhibitors fluoxetine, clomipramine and imipramine on the behaviour of rats after chronic treatment with delta 9-tetrahydrocannabinol (delta 9-THC) for 5 and 10 days were examined. Rats with permanently in-dwelling IV cannulae were injected twice daily with doses of delta 9-THC (2-6 mg/kg). delta 9-THC treatment reduced the rate of body weight gain and induced the typical biphasic modifications of behaviour. Tolerance developed to both of these effects. On days 6 and 11 of the experiment, rats were injected IP with 15 mg/kg imipramine HCl, clomipramine HCl or fluoxetine HCl, and behaviour, consisting of writhes, backward kicks, jumps and wet shakes, was observed for the next 30 min. Each of the amine reuptake inhibitors induced changes in behaviour, the severity of which appeared to correlate with their ability to inhibit the reuptake of 5-hydroxytryptamine (5-HT). It is suggested that tryptaminergic mechanisms are involved in the production of a withdrawal-like behaviour after chronic delta 9-THC treatment.

Potentiation of morphine hyperthermia in cats by pimozide and fluoxetine hydrochloride

Administration of morphine sulfate (1–4 mg/kg i.v.) to cats produces changes in body temperature, with hyperthermia appearing with larger doses. Since the central neurotransmitters dopamine and serotonin have been implicated in thermoregulation, studies were done to determine whether morphine's action could be mediated via these transmitters. Temperature responses were measured in freely moving cats by means of rectal thermometer probes. Either pimozide, 0.5 mg/kg i.p., a specific DA receptor blocker, or fluoxetine HCl, 10 mg/kg i.p., a specific inhibitor of 5-HT uptake, was administered 2—3 h prior to morphine injection. Temperatures were monitored for 3.5 h after morphine administration. Both agents were found to enhance the hyperthermic response to morphine with the maximum morphine effect occurring in most cases by 2h. The results indicate that a balance in the ratio of 5-HT : DA may be involved in cat thermoregulation and that the hyperthermic responses in the cat to morphine may be affected by shifting this 5-HT : DA ratio.

Intracranial reward after Lilly 110140 (fluoxetine HCl): Evidence for an inhibitory role for serotonin

The 5-hydroxytryptamine (5-HT, serotonin) specific presynaptic reuptake inhibitor Lilly 110140 (fluoxetine hydroxhloride) was injected systemically in rats trained to bar-press for rewarding stimulation to the caudal portion of the medial forebrain bundle. Rates of self stimulation were reduced in proportion to drug dosage, and these reductions were partially reversible by methysergide. These findings are consistent with previous reports suggesting an inhibitory role for 5-HT in self stimulation.

Serotonin involvement in the blockade of bulbospinal inhibition of the spinal monosynaptic reflex

Bulbospinal inhibition of the extensor quadriceps monosynaptic reflex (MSR) was antagonized by the serotinin precursor, 5-hydroxytryptophan (5-HTP, 75 mg/kg), in unanesthetized, mid-collicular, decerebrate cats. Fluoxetine HCl (Lilly 110140, 0.25 – 6 mg/kg), a specific serotonin neuronal uptake blocker, also blocked this inhibition as well as bulbospinal inhibition of the flexor posterior biceps-semitendinosus MSR. The serotonin antagonist, cyproheptadine HCl (5 mg/kg), partially reversed the above blocking actions of 5-HTP and fluoxetine and enhanced bulbospinal inhibition when administered alone in doses of 2.5–5 mg/kg. Imipramine HCl (0.125 – 4 mg/kg) was more potent in antagonizing bulbospinal inhibition of the dorsal root-ventral root MSR when administered intra-arterially to the spinal cord than when injected intra-arterially to the brain stem or intravenously, indicating that the spinal cord is the site of imipramine's action. These results support our earlier proposal 16 that a 5-HT system antagonizes bulbospinal inhibition of the MSR. They also indicate that the 5-HT system is tonically active and exerts its blocking action in the spinal cord.