Evidence-based treatments for low sexual desire in women

Low sexual desire is the most common sexual complaint in women, with multinational studies finding that at least a third of women experience low sexual desire. No single etiology for the development of Female Sexual Interest/Arousal Disorder, the diagnosis laid out by the 5th edition of the Diagnostic and Statistical Manual of Mental Disorders, has been established. There has been considerable interest in pharmacological approaches to improving low desire, and agents targeting a range of neurotransmitters have been examined. To date, only flibanserin, a centrally acting medication targeting the serotonin, dopamine, and norepinephrine systems, has been approved by the Food and Drug Administration (FDA). Despite statistically significant effects on sexual desire, sexual distress, and sexually satisfying events, side-effects are significant, and flibanserin is completely contraindicated with alcohol. As such, there has been renewed interest in advancing the science of psychological approaches to low desire, including cognitive behavioral and mindfulness therapies.     

Flibanserin toxicity in a toddler following ingestion

Introduction: Flibanserin is a medication recently approved by the FDA for treatment of generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Its mechanism of action is not fully understood but is thought to modulate serotonin receptors and increase levels of norepinephrine and dopamine. While much is known about toxicity of other drugs which affect these systems, there is little information about toxicity of flibanserin at this time.

Case: We present a case of a 2-year-old boy who ingested an estimated 600?mg of his mother’s flibanserin. Following ingestion, the child developed facial twitching and unresponsiveness to pain, concerning for seizure-like activity. In the emergency department (ED) he was found to have hypertension, mydriasis, slurred speech, and normal labs. He responded well to supportive care including administration of benzodiazepines. Shortly after admission to the hospital, his temperature increased to 38.4?°C. Toxicology testing revealed the presence of 1-(3-trifluoromethylphenyl)-piperazine (TFMPP), a flibanserin metabolite. TFMPP is a recreational drug used as an alternative to 3,4-methylenedioxymethamphetamine (more commonly known as “MDMA” or “ecstasy”).

Discussion: This case highlights potential toxicity associated with ingestion of flibanserin.     

Further characterisation of potential antidepressant action of flibanserin

RATIONALE: Flibanserin has shown antidepressant-like properties in some animal models. In order to better define the probability that flibanserin may act as an antidepressant, its effects were tested in additional tests. OBJECTIVES: To assess the activity of flibanserin in the forced swimming test in rats, in the distress call frequency in isolated chicks, in the tail suspension test in mice and in muricidal rats. Flibanserin was also tested in mice performing an operant schedule of a food reinforcement fixed at an interval of 2 min. METHODS: Flibanserin was given intraperitoneally at a dose range between 0.5 and 32 mg/kg, 60 min before the muricidal test, 30 min before the tail suspension test, once (30 min) or three times (24, 5 and 1 h) before the forced swimming test, or just before testing (distress-induced calls in chicks). In the food reinforcement test in mice, flibanserin was given orally 60 min before testing. RESULTS: Flibanserin showed an antidepressant-like effect in the distress-induced calls in chicks (5 mg/kg) and in the muricidal test (16 and 32 mg/kg), but not in the tail suspension test (from 7.5 to 30 mg/kg). Flibanserin (8 and 16 mg/kg) increased immobility in the forced swimming test, either when administered once or for three times. Flibanserin increased the operant responses in the food reinforcement test (40 mg/kg). CONCLUSIONS: Flibanserin showed antidepressant-like effects in two out of four tests, and increased animal drive in the operant paradigm. These findings, together with others already published, may suggest that flibanserin will exert antidepressant activity in humans.     

Effects of Alcohol Administered With Flibanserin in Healthy Premenopausal Women: A Randomized,Double-Blind,Single-Dose Crossover Study

IntroductionFlibanserin is approved in the United States and Canada for the treatment of hypoactive sexual desire disorder in premenopausal women.AimThe purpose of this trial was to evaluate the safety of concomitant administration of flibanserin with alcohol.MethodsIn this single-center, randomized, double-blind, single-dose, crossover study, participants were randomly assigned to 1 of 12 sequences to receive each of 7 treatments: flibanserin 100 mg or placebo with ethanol 0.2 g/kg, 0.4 g/kg, or 0.6 g/kg, or flibanserin 100 mg only. Treatments were administered using a worst-case approach that included morning dosing and consumption of alcohol within 10 minutes.Main Outcome MeasureThe primary end point was the proportion of participants who experienced dizziness, syncope, or hypotension. Safety end points included orthostatic vital signs.ResultsThe study included 96 premenopausal women (mean age 31 ± 8 years). The incidence of dizziness for ethanol + flibanserin was 39.8% for ethanol 0.6 g/kg, 34.1% for 0.4 g/kg, and 27.4% for 0.2 g/kg compared with 31.1% for flibanserin without ethanol. Based on the available vital signs data, there was no effect of ethanol concentration on orthostatic blood pressure, vertigo, or hypotension; no instances of syncope were observed. The overall incidence of adverse events (AEs) was similar when flibanserin was administered alone (96.7%) or with ethanol (90.5–97.6%).Clinical ImplicationsConsumption of the tested amounts of alcohol (0.2–0.6 g/kg) does not have an additive effect on the AE profile of flibanserin 100 mg in healthy premenopausal women.Strengths & LimitationsStrengths include the study population (premenopausal women, as indicated for flibanserin) and range of ethanol doses. Limitations include the morning dosing of study medication, which is inconsistent with the bedtime dosing recommended for flibanserin, and the method of handling missing vital sign measurements.ConclusionCo-administration of flibanserin 100 mg with varying doses of ethanol resulted in few AEs of special interest, with no notable alcohol dose response. However, a significantly greater percentage of participants administered flibanserin with 0.6 g/kg and 0.4 g/kg of alcohol were characterized as “Participants in Whom Standing Blood Pressure Was Not Obtained” compared with participants administered flibanserin alone.Simon JA, Clayton AH, Parish SJ, et al. Effects of Alcohol Administered With Flibanserin in Healthy Premenopausal Women: A Randomized, Double-Blind, Single-Dose Crossover Study. J Sex Med 2020;17:83–93.     

Anti-anhedonic actions of the novel serotonergic agent flibanserin, a potential rapidly-acting antidepressant

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of palatable sweet solutions and to block the formation of conditioned place preferences; these effects are reversed by chronic treatment with tricyclic or atypical antidepressant drugs. The present study was designed to evaluate the antidepressant-like activity in this model of flibaserin (BIMT-17), a novel serotonergic agent with 5-HT_1A receptor agonist and 5-HT₂ receptor antagonist properties. Two experiments were conducted, using rats (experiment 1) and mice (experiment 2). In experiment 1, decreases in sucrose intake were seen in rats exposed to chronic mild stress, but the effect was unreliable in this study, and sucrose testing was terminated after 7 weeks of stress. Beginning after 5 weeks of stress, groups of control and stressed animals were treated daily with vehicle, fluoxetine (5 mg/kg) or flibanserin (5, 10 or 20 mg/kg). After 6 weeks of treatment, all animals were tested for acquisition of food-reinforced place preference conditioning. Conditioning was seen in all groups other than the vehicle-treated stressed animals. We also tested the locomotor stimulant effect of a single injection of the dopamine D₂/D₃ receptor agonist quinpirole (0.2 mg/kg). The effect of quinpirole was potentiated by fluoxetine in control animals, and by both fluoxetine and flibanserin (all doses) in stressed animals. In experiment 2, long-lasting decreases in sucrose intake were seen in mice exposed to chronic mild stress. The effects were reversed by chronic (4 weeks) treatment with fluoxetine (5 mg/kg) or flibanserin (2.5 or 5 mg/kg); the full effect of flibanserin was seen after the first injection. All animals received a single injection of raclopride (0.1 mg/kg) immediately prior to a sucrose intake test on day 27 of drug treatment. Raclopride decreased sucrose intake only in the three drug-treated stressed groups. The results support a rapid antidepressant-like action of flibanserin, and suggest that this effect involves sensitization of dopamine D₂/D₃ receptor-mediated transmission.     

HPLC-DAD法测定氟班色林原料药的含量及有关物质

摘 要 目的：建立高效液相色谱法测定氟班色林原料药的含量及有关物质。方法: 采用Phenomenex Luna C18色谱柱(150 mm×4.6 mm, 5 μm),流动相：0.02 mol·L^-1磷酸二氢钾(氢氧化钠调pH至6.0) 甲醇：乙腈(4〖KG*9〗∶〖KG-*2〗1),流速：1.0 ml·min^-1,柱温：30℃,检测波长：260 nm,进样量：10 μl。结果: 氟班色林与各有关物质均能良好地分离,氟班色林的质量浓度在20～500 μg·ml^-1内线性关系良好(r=0.999 8),平均回收率为100.0%（RSD=0.90%,n=9）,4批样品中主成分含量分别为99.6%、 99.8%、100.4%及99.4%;单个杂质限量定为0.1%,杂质总量为0.5%。结论: 本法专属性好,准确性高,可用于氟班色林原料药含量测定和有关物质检测。     

Preparation,characterization, dissolution,and permeation of flibanserin − 2-HP-β-cyclodextrin inclusion complexes

Flibanserin (FLB), an antiserotonin drug, is used to treat women with hypoactive sexual appetite disorder. FLB shows low bioavailability (~33%) probably due to its low water solubility. The current study investigated the impact of hydroxypropyl-β-cyclodextrin (HP-β-CD) and sodium lauryl sulfate (SLS) on the dissolution and permeation of FLB. HP-β-CD–FLB inclusion complexes were prepared using physical mixing and kneading at 1:1 and 1:2 M ratios and characterized using differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder X-ray diffractometry. The dissolution and permeation of the complexes through a cellophane membrane were performed in, 0.1, 0.3 and 0.5% SLS in phosphate buffer (pH 6.8).Derived from the slope of the linear phase solubility diagram, the apparent stability constant (K_1:1) was 372.54 M⁻¹. Kneading changed the crystalline form of FLB to an amorphous appearance characterized by minimal crystalline peaks, indicating successful inclusion complex formation. In addition, the HP-β-CD–FLB inclusion complexes showed twofold increased dissolution efficiency at 6 h. The cumulative FLB amount permeated at 6 h increased from 14.1% to 21.88% and 34.56% in the presence of 0.1% and 0.3% of SLS, respectively. However, increasing SLS to 0.5% did not show an increase in FLB permeation. Therefore, the HP-β-CD–FLB inclusion complex has an improved dissolution rate compared to FLB alone. The presence of SLS in the dissolution medium increases the dissolution rate of pure FLB and its complex with HP-β-CD. kneaded 1:1 complex was formulated bioadhesive buccal tablets and showed enhanced drug release.     

Preparation,characterization, dissolution,and permeation of flibanserin − 2-HP-β-cyclodextrin inclusion complexes

Flibanserin (FLB), an antiserotonin drug, is used to treat women with hypoactive sexual appetite disorder. FLB shows low bioavailability (~33%) probably due to its low water solubility. The current study investigated the impact of hydroxypropyl-β-cyclodextrin (HP-β-CD) and sodium lauryl sulfate (SLS) on the dissolution and permeation of FLB. HP-β-CD–FLB inclusion complexes were prepared using physical mixing and kneading at 1:1 and 1:2 M ratios and characterized using differential scanning calorimetry, Fourier transform infrared spectroscopy, and powder X-ray diffractometry. The dissolution and permeation of the complexes through a cellophane membrane were performed in, 0.1, 0.3 and 0.5% SLS in phosphate buffer (pH 6.8).Derived from the slope of the linear phase solubility diagram, the apparent stability constant (K_1:1) was 372.54 M⁻¹. Kneading changed the crystalline form of FLB to an amorphous appearance characterized by minimal crystalline peaks, indicating successful inclusion complex formation. In addition, the HP-β-CD–FLB inclusion complexes showed twofold increased dissolution efficiency at 6 h. The cumulative FLB amount permeated at 6 h increased from 14.1% to 21.88% and 34.56% in the presence of 0.1% and 0.3% of SLS, respectively. However, increasing SLS to 0.5% did not show an increase in FLB permeation. Therefore, the HP-β-CD–FLB inclusion complex has an improved dissolution rate compared to FLB alone. The presence of SLS in the dissolution medium increases the dissolution rate of pure FLB and its complex with HP-β-CD. kneaded 1:1 complex was formulated bioadhesive buccal tablets and showed enhanced drug release.