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The Journal of Pharmacy and Pharmacology Jun 2015In this study, the advantages and disadvantages of three salt screening methodologies have been explored, and recommendations are put forward as to when each method is...
OBJECTIVES
In this study, the advantages and disadvantages of three salt screening methodologies have been explored, and recommendations are put forward as to when each method is most appropriate.
METHODS
Three salt screening methodologies have been investigated: the in-situ salt screen, the saturated solution or rational screen approach, and the cooling-evaporative or high-throughput method. Two Active Pharmaceutical Ingredients (APIs) with significant differences in aqueous solubility have been chosen for this study, namely aripiprazole and desvenlafaxine (see Figure 1).
KEY FINDINGS
The in-situ salt formation screen appears to be a good method for early stage salt selection based on aqueous solubility, although this approach does not work for all APIs, as demonstrated in the comparison between aripiprazole and desvenlafaxine. The saturated solution method or rational approach demonstrated a valuable overview of the different salts that can be formed in an efficient and cost-effective manner. The cooling-evaporative screening method involved a complete examination of salt formation, including indication of polymorphism of the salts produced.
CONCLUSIONS
The three salt formation approaches are methods that deliver crystalline salts. The choice of salt screen approach depends on the physical properties of the drug substance, development stage and objective of the screen.
Topics: Aripiprazole; Chemistry, Pharmaceutical; Crystallization; Desvenlafaxine Succinate; Humans; Hydrogen-Ion Concentration; Pharmaceutical Preparations; Salts; Solubility; Technology, Pharmaceutical; Water
PubMed: 25683791
DOI: 10.1111/jphp.12377 -
Journal of the American Association of... Jan 2015To systematically review the evidence related to the efficacy and tolerability of selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake... (Review)
Review
PURPOSE
To systematically review the evidence related to the efficacy and tolerability of selective serotonin reuptake inhibitors (SSRIs) and serotonin/norepinephrine reuptake inhibitors (SNRIs) used for the treatment of vasomotor symptoms in perimenopausal and postmenopausal women.
DATA SOURCES
Medline, CINAHL, and the Cochrane Library databases were searched to identify randomized controlled trials (RCTs). Eighteen trials met the criteria for review.
CONCLUSIONS
Results from these trials indicate that paroxetine, citalopram, escitalopram, venlafaxine, and desvenlafaxine are effective in reducing the frequency and severity of hot flashes. Fluoxetine and sertraline appear to be less effective and should be considered second-line options for treatment.
IMPLICATIONS FOR PRACTICE
The SSRIs and SNRIs can reduce hot flashes by 65% and begin working within the first week. Patient response is variable and if one drug does not improve hot flashes, another can be tried after a 1- to 2-week drug trial. Paroxetine, citalopram, and escitalopram appear to have the fewest adverse effects. Considering cost, paroxetine and citalopram are the most cost-efficient.
Topics: Adult; Aged; Citalopram; Desvenlafaxine Succinate; Female; Fluoxetine; Hot Flashes; Humans; Menopause; Middle Aged; Paroxetine; Serotonin and Noradrenaline Reuptake Inhibitors; Sertraline; Vasomotor System; Venlafaxine Hydrochloride
PubMed: 24944075
DOI: 10.1002/2327-6924.12137 -
Journal of Psychopharmacology (Oxford,... Sep 2017Nine randomized, double-blind, placebo-controlled studies of major depressive disorder were pooled to evaluate the effects of desvenlafaxine 50- and 100-mg/d on energy... (Randomized Controlled Trial)
Randomized Controlled Trial
Nine randomized, double-blind, placebo-controlled studies of major depressive disorder were pooled to evaluate the effects of desvenlafaxine 50- and 100-mg/d on energy and lassitude in adults with major depressive disorder ( n=4279). Changes from baseline to endpoint in 17-item Hamilton Rating Scale for Depression (HAM-D) Work and Activities, Retardation, and Somatic Symptoms General items, HAM-D psychomotor retardation factor, and Montgomery-Åsberg Depression Rating Scale Lassitude item were analyzed with a mixed model for repeated measures analysis of variance. Associations between residual energy measures and functional impairment, based on the Sheehan Disability Scale, were modeled using stepwise multiple linear regression. Improvement from baseline was significantly greater for both desvenlafaxine doses versus placebo on all energy symptom outcomes at week 8 (all p⩽0.005). Both early improvement in HAM-D psychomotor retardation at week 2 and residual energy symptoms at week 8 were associated with Sheehan Disability Scale total score at week 8 (all p⩽0.001). Among Sheehan Disability Scale remitters and responders, the HAM-D psychomotor retardation score at week 8 was significantly lower with desvenlafaxine (both doses) than placebo. Desvenlafaxine 50 and 100 mg/d significantly improved energy and lassitude symptoms in patients with major depressive disorder. Both early improvement in energy and fewer residual energy symptoms were associated with functional improvement.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antidepressive Agents; Depressive Disorder, Major; Desvenlafaxine Succinate; Double-Blind Method; Fatigue; Female; Humans; Male; Middle Aged; Psychiatric Status Rating Scales; Young Adult
PubMed: 28718346
DOI: 10.1177/0269881117719261 -
Current Drug Delivery 2017With its reported side effects Desvenlafaxine succinate (DSV) is a good candidate to prepare prolonged release system. Such prolonged release could decrease the rapid...
BACKGROUND
With its reported side effects Desvenlafaxine succinate (DSV) is a good candidate to prepare prolonged release system. Such prolonged release could decrease the rapid DSV absorption after oral administration and reduce its exaggerated side effects.
METHODS
A prolonged release Desvenlafaxine succinate (DSV) multilayered system was prepared by ionotropic gelation using sodium alginate (SA) and calcium chloride as a cross-linker. DSV was incorporated simultaneously during the gelation stage and the formed beads were evaluated for shape and particle size. Thirteen formulation variables including pH, DSV: polymer ratio, cross-linker concentration and curing time were optimized for optimal drug entrapment. The optimized formula was evaluated ex vivo using the everted sac technique to predict DSV absorption through intestinal mucosal cells, follow the permeation and calculate its apparent permeability coefficient.
RESULTS
The optimum formulation variables were: pH (8-9), DSV: SA ratio (2:1), cross-linker concentration (5%w/v) and 30 min curing time. Multilayered beads coating using chitosan and SA was compared with uncoated beads or the innovator for DSV release. Coating of the beads greatly retarded DSV release with a release profile similar to that of the innovator. An optimized formula (T13) coated with 0.04% w/v of each of chitosan and SA was selected. The developed system gave rise to a prolonged release pattern with high similarity factor with the innovator.
CONCLUSION
The results of the current work can be applied to prepare controlled release systems of similar drugs that have intense side effects associated with their initial burst after oral administration.
Topics: Administration, Oral; Alginates; Chemistry, Pharmaceutical; Chitosan; Desvenlafaxine Succinate; Drug Carriers; Drug Liberation; Excipients; Glucuronic Acid; Hexuronic Acids; Particle Size
PubMed: 27211103
DOI: 10.2174/1567201813666160523143111 -
Journal of Child and Adolescent... Feb 2018To evaluate the short-term efficacy and safety of desvenlafaxine versus placebo in the treatment of children and adolescents with major depressive disorder (MDD).
OBJECTIVE
To evaluate the short-term efficacy and safety of desvenlafaxine versus placebo in the treatment of children and adolescents with major depressive disorder (MDD).
METHODS
Outpatient children (7-11 years) and adolescents (12-17 years) who met DSM-IV-TR criteria for MDD and had screening and baseline Children's Depression Rating Scale-Revised (CDRS-R) total scores >40 were randomly assigned to 8 weeks of treatment with placebo, low exposure desvenlafaxine (20, 30, or 35 mg/day based on baseline weight), or higher exposure desvenlafaxine (25, 35, or 50 mg/day based on baseline weight). The primary efficacy endpoint was change from baseline in CDRS-R total score at week 8, analyzed using a mixed-effects model for repeated measures. Secondary efficacy assessments included Clinical Global Impressions-Severity and Clinical Global Impressions-Improvement scales. Safety assessments included adverse events and the Columbia-Suicide Severity Rating Scale.
RESULTS
The safety population included 363 patients (children, n = 109; adolescents, n = 254). No statistical separation from placebo was observed for either desvenlafaxine group for CDRS-R total score or for any secondary efficacy endpoint. At week 8, adjusted mean (standard error) changes from baseline in CDRS-R total score for the desvenlafaxine low exposure, desvenlafaxine high exposure, and placebo groups were -23.7 (1.1), -24.4 (1.1), and -22.9 (1.1), respectively. The incidence of adverse events was similar among groups.
CONCLUSION
Low and high exposure desvenlafaxine groups did not demonstrate efficacy for the treatment of MDD in children and adolescents in this double-blind, placebo-controlled trial. Desvenlafaxine (20-50 mg/day) was generally safe and well tolerated with no new safety signals identified in pediatric patients with MDD in this study.
Topics: Adolescent; Antidepressive Agents; Child; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Psychiatric Status Rating Scales; Treatment Outcome
PubMed: 29185786
DOI: 10.1089/cap.2017.0099 -
The Mental Health Clinician May 2020Desvenlafaxine is a potent selective serotonin and norepinephrine reuptake inhibitor used to treat depression and anxiety. Several antidepressants have been associated...
Desvenlafaxine is a potent selective serotonin and norepinephrine reuptake inhibitor used to treat depression and anxiety. Several antidepressants have been associated with drug-induced hyperglycemia, but currently there are no reports for desvenlafaxine. A case of suspected desvenlafaxine-induced hyperglycemia is presented involving a 59-year-old female with type 2 diabetes whose average blood glucose increased by 30 mg/dL for fasting blood glucose and 75 mg/dL for postprandial blood glucose 1 month after switching from venlafaxine to desvenlafaxine. Prior to starting desvenlafaxine, she was stable on metformin 1000 mg twice daily, insulin glargine 8 units daily, and dulaglutide 1.5 mg once weekly. Over the course of 3 months after desvenlafaxine initiation, insulin glargine was increased and insulin lispro was initiated as the patient refused alternative antidepressant therapy due to favorable improvements in anxiety and depression. No other cause for elevated blood glucose could be elucidated. The Naranjo scale resulted in a score of 3, indicating a possible cause for the adverse drug reaction. Antidepressants have been associated with glucose dysregulation. However, literature also demonstrates improved glycemic control in treated versus untreated depression. If altered glucose levels are noted, all potential causative factors should be evaluated and risks and benefits weighed to guide therapy.
PubMed: 32420005
DOI: 10.9740/mhc.2020.05.085 -
International Journal of Molecular... Sep 2022Drug metabolizing enzyme activity is affected by various factors such as drug-drug interactions, and a method to quantify drug metabolizing enzyme activity in real time...
Drug metabolizing enzyme activity is affected by various factors such as drug-drug interactions, and a method to quantify drug metabolizing enzyme activity in real time is needed. In this study, we developed a novel radiopharmaceutical for quantitative imaging to estimate hepatic CYP3A4 and CYP2D6 activity. Iodine-123- and 125-labeled -desmethylvenlafaxine (I-ODV) was obtained with high labeling and purity, and its metabolism was found to strongly involve CYP3A4 and CYP2D6. SPECT imaging in normal mice showed that the administered I-ODV accumulated early in the liver and was excreted into the gallbladder, as evaluated by time activity curves. In its biological distribution, I-ODV administered to mice accumulated early in the liver, and only the metabolite of I-ODV was quickly excreted into the bile. In CYP3A4- and CYP2D6-inhibited model mice, the accumulation in bile decreased more than in normal mice, indicating inhibition of metabolite production. These results indicated that imaging and quantifying the accumulation of radioactive metabolites in excretory organs will aid in determining the dosages of various drugs metabolized by CYP3A4 and CYP2D6 for individualized medicine. Thus, I-ODV has the potential to direct, comprehensive detection and measurement of hepatic CYP3A4 and CYP2D6 activity by a simple and less invasive approach.
Topics: Animals; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Desvenlafaxine Succinate; Iodine Radioisotopes; Liver; Mice; Radiopharmaceuticals; Venlafaxine Hydrochloride
PubMed: 36232758
DOI: 10.3390/ijms231911458 -
Journal of Chromatography. B,... Aug 2022The majority of women have health problems that require medication after giving birth. Complications such as allergies, postpartum depression, and diabetes are often...
The majority of women have health problems that require medication after giving birth. Complications such as allergies, postpartum depression, and diabetes are often treated with drugs such as cetirizine, venlafaxine, and metformin, respectively. These treatments are considered safe during lactation, but information of the transfer of drugs to breast milk and possible effects on the infant is scarce. Therefore, this needs to be systematically investigated in larger populations. To enable the determination of drug transfer, we here describe the validation of two rapid, sensitive, and high-throughput analysis methods for 1) simultaneous quantification of cetirizine, venlafaxine, and O-desmethylvenlafaxine in human breast milk, and 2) metformin in human breast milk and plasma. In both methods, a simple protein precipitation protocol with acetonitrile and benchtop-centrifugation was used prior to compound analysis with liquid-chromatography tandem mass spectrometry. The methods had linear ranges between 0.39 - 194.5 ng/mL for cetirizine, 0.28 - 138.7 ng/mL for venlafaxine, 0.26 - 131.7 ng/mL for O-desmethylvenlafaxine, in milk, and 0.65 - 193.7 ng/mL for metformin in both milk and plasma. Intra-run and inter-run precision and accuracy were ≤ 9% for cetirizine, venlafaxine, and O-desmethylvenlafaxine in milk, and ≤ 7% for metformin in milk and plasma. Cetirizine was measured to median milk concentrations of 13 ng/mL (range: 0.65 - 65 ng/mL) in 228 donor samples from breast-feeding women.
Topics: Cetirizine; Chromatography, High Pressure Liquid; Desvenlafaxine Succinate; Female; Humans; Infant; Metformin; Milk, Human; Pregnancy; Reproducibility of Results; Tandem Mass Spectrometry; Venlafaxine Hydrochloride
PubMed: 35732105
DOI: 10.1016/j.jchromb.2022.123340 -
Journal of Child and Adolescent... Dec 2016To investigate the safety and pharmacokinetic profile of ascending doses of desvenlafaxine in children and adolescents with major depressive disorder. Assessment of the...
OBJECTIVE
To investigate the safety and pharmacokinetic profile of ascending doses of desvenlafaxine in children and adolescents with major depressive disorder. Assessment of the effect of desvenlafaxine on depression symptoms was exploratory.
METHODS
The 8-week, open-label study included an initial 3.5-day inpatient period followed by a 7.5-week outpatient period. Children (7-11 years) received a single desvenlafaxine dose of 10, 25, 50, or 100 mg on day 1; adolescents (12-17 years) received desvenlafaxine 25, 50, 100, or 200 mg/day. Plasma and urine samples were collected over the initial 72-hour inpatient period. Evaluations included treatment-emergent adverse events (TEAEs), physical examinations (including Tanner Staging), vital signs, laboratory assessments, 12-lead electrocardiogram, Columbia-Suicide Severity Rating Scale, and the Children's Depression Rating Scale-Revised (CDRS-R).
RESULTS
In all, 29 children and 30 adolescents took at least one dose of desvenlafaxine and were included in the safety population (children: 10 mg, n = 6; 25 mg, n = 7; 50 mg, n = 9; 100 mg, n = 7; adolescents: 25 mg, n = 7; 50 mg, n = 7; 100 mg, n = 8; 200 mg, n = 8). Total area under the drug concentration-time curve from 0 to infinity (AUC) appeared to increase linearly with increasing dose. Mean (standard deviation [SD]) AUC ranged from 628 (346) ng/mL (desvenlafaxine 10 mg) to 6732 (3031) ng/mL (100 mg) in children and from 1123 (361) ng/mL (25 mg) to 11,730 (3113) ng/mL (200 mg) in adolescents. During the combined inpatient and outpatient period, 16/29 (55%) children and 21/30 (70%) adolescents reported at least one TEAE. One serious adverse event (suicidal behavior) was reported. Mean (SD) change from baseline in CDRS-R total scores at week 8 was -19.00 (9.87) for children and -21.57 (11.50) for adolescents.
CONCLUSIONS
Desvenlafaxine AUC values increased linearly with dose; body weight alone provided an adequate prediction for dose-normalized AUC. Desvenlafaxine was generally safe and well tolerated in children and adolescents for treatment up to 8 weeks.
Topics: Adolescent; Antidepressive Agents; Area Under Curve; Body Weight; Child; Depressive Disorder, Major; Desvenlafaxine Succinate; Dose-Response Relationship, Drug; Electrocardiography; Female; Humans; Male; Psychiatric Status Rating Scales; Severity of Illness Index; Suicide
PubMed: 27428303
DOI: 10.1089/cap.2016.0009 -
Journal of Biochemical and Molecular... Jul 2022Depression during pregnancy adversely affects fetal development. Desvenlafaxine drug is used for the treatment of gestational depression. In light of the...
Depression during pregnancy adversely affects fetal development. Desvenlafaxine drug is used for the treatment of gestational depression. In light of the well-established role of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in regulating neurogenesis and neural survival, the role of S100b in nerve cell energetic metabolism, differentiation of neurons and glial cells, an aberrant increase in NGF, BDNF and S100b expression in the fetal brain may contribute to desvenlafaxine cognitive disorders by altering brain development. This study is trying to determine the effect of desvenlafaxine on brain development. Thirty timed pregnant rats (from the 5th to the 20th day) were divided into three groups: control, low dose (5.14 mg/kg/day) and high dose (10.28 mg/kg/day) of desvenlafaxine where all animals received the corresponding doses by gavage. Maternal and fetal brain samples were fixed for histological, immunohistochemical (IHC) study of NGF and evaluated for BDNF and S100b genes expression. Desvenlafaxine induced some of the histopathological alterations in maternal and fetal rat brains. Moreover, IHC analysis of maternal and fetal rat brains showed that groups treated with desvenlafaxine demonstrated a significant increase of NGF protein immunoreactivity compared with that in the controls. Gene expression results revealed upregulation of messenger RNA BDNF and S100B expression. According to developmental changes in the brain, desvenlafaxine affects neonatal growth during pregnancy, which may lead to delay of brain development. So, it is essential to survey the roles of antidepressant drugs on neonatal development during pregnancy.
Topics: Animals; Brain; Brain-Derived Neurotrophic Factor; Desvenlafaxine Succinate; Female; Fetus; Maternal Exposure; Nerve Growth Factor; Pregnancy; Rats
PubMed: 35363936
DOI: 10.1002/jbt.23062