Oral galactagogues (natural therapies or drugs) for increasing breast milk production in mothers of non-hospitalised term infants.

BACKGROUND: Many women express concern about their ability to produce enough milk, and insufficient milk is frequently cited as the reason for supplementation and early termination of breastfeeding. When addressing this concern, it is important first to consider the influence of maternal and neonatal health, infant suck, proper latch, and feeding frequency on milk production, and that steps be taken to correct or compensate for any contributing issues. Oral galactagogues are substances that stimulate milk production. They may be pharmacological or non-pharmacological (natural). Natural galactagogues are usually botanical or other food agents. The choice between pharmacological or natural galactagogues is often influenced by familiarity and local customs. Evidence for the possible benefits and harms of galactagogues is important for making an informed decision on their use. OBJECTIVES: To assess the effect of oral galactagogues for increasing milk production in non-hospitalised breastfeeding mother-term infant pairs. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register, ClinicalTrials.gov, the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), Health Research and Development Network - Phillippines (HERDIN), Natural Products Alert (Napralert), the personal reference collection of author LM, and reference lists of retrieved studies (4 November 2019). SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs (including published abstracts) comparing oral galactagogues with placebo, no treatment, or another oral galactagogue in mothers breastfeeding healthy term infants. We also included cluster-randomised trials but excluded cross-over trials. DATA COLLECTION AND ANALYSIS: We used standard Cochrane Pregnancy and Childbirth methods for data collection and analysis. Two to four review authors independently selected the studies, assessed the risk of bias, extracted data for analysis and checked accuracy. Where necessary, we contacted the study authors for clarification. MAIN RESULTS: Forty-one RCTs involving 3005 mothers and 3006 infants from at least 17 countries met the inclusion criteria. Studies were conducted either in hospitals immediately postpartum or in the community. There was considerable variation in mothers, particularly in parity and whether or not they had lactation insufficiency. Infants' ages at commencement of the studies ranged from newborn to 6 months. The overall certainty of evidence was low to very low because of high risk of biases (mainly due to lack of blinding), substantial clinical and statistical heterogeneity, and imprecision of measurements. Pharmacological galactagogues Nine studies compared a pharmacological galactagogue (domperidone, metoclopramide, sulpiride, thyrotropin-releasing hormone) with placebo or no treatment. The primary outcome of proportion of mothers who continued breastfeeding at 3, 4 and 6 months was not reported. Only one study (metoclopramide) reported on the outcome of infant weight, finding little or no difference (mean difference (MD) 23.0 grams, 95% confidence interval (CI) -47.71 to 93.71; 1 study, 20 participants; low-certainty evidence). Three studies (metoclopramide, domperidone, sulpiride) reported on milk volume, finding pharmacological galactagogues may increase milk volume (MD 63.82 mL, 95% CI 25.91 to 101.72; I² = 34%; 3 studies, 151 participants; low-certainty evidence). Subgroup analysis indicates there may be increased milk volume with each drug, but with varying CIs. There was limited reporting of adverse effects, none of which could be meta-analysed. Where reported, they were limited to minor complaints, such as tiredness, nausea, headache and dry mouth (very low-certainty evidence). No adverse effects were reported for infants. Natural galactagogues Twenty-seven studies compared natural oral galactagogues (banana flower, fennel, fenugreek, ginger, ixbut, levant cotton, moringa, palm dates, pork knuckle, shatavari, silymarin, torbangun leaves or other natural mixtures) with placebo or no treatment. One study (Mother's Milk Tea) reported breastfeeding rates at six months with a concluding statement of "no significant difference" (no data and no measure of significance provided, 60 participants, very low-certainty evidence). Three studies (fennel, fenugreek, moringa, mixed botanical tea) reported infant weight but could not be meta-analysed due to substantial clinical and statistical heterogeneity (I2 = 60%, 275 participants, very low-certainty evidence). Subgroup analysis shows we are very uncertain whether fennel or fenugreek improves infant weight, whereas moringa and mixed botanical tea may increase infant weight compared to placebo. Thirteen studies (Bu Xue Sheng Ru, Chanbao, Cui Ru, banana flower, fenugreek, ginger, moringa, fenugreek, ginger and turmeric mix, ixbut, mixed botanical tea, Sheng Ru He Ji, silymarin, Xian Tong Ru, palm dates; 962 participants) reported on milk volume, but meta-analysis was not possible due to substantial heterogeneity (I2 = 99%). The subgroup analysis for each intervention suggested either benefit or little or no difference (very low-certainty evidence). There was limited reporting of adverse effects, none of which could be meta-analysed. Where reported, they were limited to minor complaints such as mothers with urine that smelled like maple syrup and urticaria in infants (very low-certainty evidence). Galactagogue versus galactagogue Eight studies (Chanbao; Bue Xue Sheng Ru, domperidone, moringa, fenugreek, palm dates, torbangun, moloco, Mu Er Wu You, Kun Yuan Tong Ru) compared one oral galactagogue with another. We were unable to perform meta-analysis because there was only one small study for each match-up, so we do not know if one galactagogue is better than another for any outcome. AUTHORS' CONCLUSIONS: Due to extremely limited, very low certainty evidence, we do not know whether galactagogues have any effect on proportion of mothers who continued breastfeeding at 3, 4 and 6 months. There is low-certainty evidence that pharmacological galactagogues may increase milk volume. There is some evidence from subgroup analyses that natural galactagogues may benefit infant weight and milk volume in mothers with healthy, term infants, but due to substantial heterogeneity of the studies, imprecision of measurements and incomplete reporting, we are very uncertain about the magnitude of the effect. We are also uncertain if one galactagogue performs better than another. With limited data on adverse effects, we are uncertain if there are any concerning adverse effects with any particular galactagogue; those reported were minor complaints. High-quality RCTs on the efficacy and safety of galactagogues are urgently needed. A set of core outcomes to standardise infant weight and milk volume measurement is also needed, as well as a strong basis for the dose and dosage form used.

Morphological and Biochemical Characteristics of Prostate Hyperplasia during Sulpiride Treatment.

We studied morphological changes in the prostate ventral lobe, proliferative activity of the epithelium in prostate acini, and the levels of prolactin and prostate-specific antigen in the blood serum of Sprague-Dawley rats after repeated injections of sulpiride in a dose of 40 mg/ kg over 30 and 60 days and in 10 and 30 days after withdrawal. Morphological and morphometrical analysis of hyperplastic changes in the prostate ventral lobe was performed. Ki-67+ proliferating epithelial cells in the acini were counted. The dynamics of serum concentrations of prolactin and prostate-specific antigen was evaluated by ELISA. Morphological and morphometrical analysis and evaluation of the content of Ki-67+ cells demonstrated epithelium hyperplasia in the prostate ventral lobe after sulpiride treatment for 30 or 60 days and in 10 days after withdrawal, but serum level of prostate-specific antigen did not differ from the control. After 60-day sulpiride treatment and in 30 days after withdrawal, pronounced hyperplastic changes of prostate and elevated concentrations of prostate-specific antigen (but not prolactin) were observed. Thus, administration of sulpiride (40 mg/kg) to Sprague-Dawley rats for 60 days allows, by morphological criteria and serum level of prostate-specific antigen, to model stable hyperplastic changes in the prostate corresponding to benign prostatic hyperplasia in humans.

Pharmacokinetics of levosulpiride after single-dose administration in goats (Capra hircus) by different routes of administration.

Levosulpiride (LSP) is the l-enantiomer of sulpiride, and LSP recently replacing sulpiride in several EU countries. Several studies about LSP in humans are present in the literature, but neither pharmacodynamic nor pharmacokinetic data of LSP is present for veterinary species. The aim of this study was to assess the pharmacokinetic profile of LSP after intravenous (IV), intramuscular (IM), and oral (PO) administration in goats. Animals (n = 6) were treated with 50 mg LSP by IV, IM, and PO routes according to a randomized cross-over design (3 × 3 Latin-square). Blood samples were collected prior and up to 24 hr after LSP administration and quantified using a validated HPLC method with fluorescence detection. IV and IM administration gave similar concentration versus time curve profiles. The IM mean bioavailability was 66.97%. After PO administration, the drug plasma concentrations were detectable only in the time range 1.5-4 hr, and the bioavailability (4.73%) was low. When the AUC was related to the administered dose in mg/kg, there was a good correlation in the IV and IM groups, but very low correlation for the PO route. In conclusion, the IM and IV administrations result in very similar plasma concentrations. Oral dosing of LSP in goats is probably not viable as its oral bioavailability was very low.

Development and characterisation of levosulpiride-loaded suppositories with improved bioavailability in vivo.

The purpose of this study was to develop and characterize levosulpiride loaded liquid suppository with improved bioavailability. The content of levosulpiride-loaded liquid suppositories were optimized in a series of experiments using various weight ratios of P188, P407, Tween 80, and drug. The suppositories were liquid at room temperature, however, when rectally administered, they became gel at body temperature. Their rheological properties and release characteristics were determined in vitro while pharmacokinetic study was performed after its rectal administration in rats and compared with drug suspension. Poloxamer 188 and Twee 80 decreased the gelation temperature and gelation time, but increased the gel strength and mucoadhesive force of liquid suppositories. Liquid suppository composed of [Levosulpiride/P 188/P 407/Tween 80 (1/15/17/3%)] with a gelation temperature of about 30.7 °C remained liquid at 25 °C, but converted to gel at 30-36.5 °C, resulting in easy administration and rapid gelation inside the body. This liquid suppository gave a considerably increased dissolution rate reflected in a meaningfully higher plasma concentration and 7.1-fold AUC values of levosulpiride in rats as compared to the drug suspension. Hence, liquid suppository system could be used for enhanced bioavailability of levosulpiride-loaded pharmaceutical products.

Effectiveness of Phenolic Antioxidants in Experimental Model of Benign Prostatic Hyperplasia.

Experimental model of sulpiride-provoked benign prostatic hyperplasia was employed to comparatively assess the effect of phenolic antioxidants (dihydroquercetin, p-thyrozol, dibornol, and prostagenin) on prostate morphology. All examined agents decreased the degree of hyperplasia in acinar epithelium; the greatest efficacy was demonstrated by prostagenin. Moreover, dihydroquercetin and p-thyrozol increased the cross-section area of acinar lumina and prostate volume, which is inadmissible in this pathology. These results suggest that the use of phenolic antioxidants in the therapy of benign prostatic hyperplasia should be strictly controlled.

Amisulpride-CD-Loaded Liposomes: Optimization and In Vivo Evaluation.

Amisulpride (AMS) is an atypical antipsychotic agent used for the treatment of schizophrenia. The effect of different variables, i.e., the type of cyclodextrins (CDs), ratio of drug/CDs, and type of loading on the prepared AMS-CD liposomes (single and double loaded) was studied by applying 23 full factorial design. Double-loaded liposomes are loaded with AMS-hydroxyl propyl-ß-cyclodextrin (HP-ß-CD) in the aqueous phase and free drug in the lipophilic bilayer, while single-loaded liposomes are loaded only with AMS-HP-ß-CD in the aqueous phase. Entrapment efficiency, particle size, polydespersibility, and zeta potential were selected as dependent variables. Design Expert® software was used to obtain an optimized formulation with high entrapment efficiency (64.55 ± 1.27%), average particle size of 40.1 ± 2.77 nm, polydespersibility of 0.44 ± 0.37, and zeta potential of - 48.8 ± 0.28. Optimized formula was evaluated for in vitro release, surface morphology and stability study was also conducted. AMS-HP-ß-CD in double-loaded liposomes exhibited higher drug release than those in the conventional liposomes and in the single-loaded liposomes. The maximum plasma concentration (Cmax) of AMS in optimized AMS-HP-ß-CD double-loaded liposomal formulation increased by 1.55- and 1.29-fold, as compared to the commercial tablets and conventional liposomes, respectively. However, the relative bioavailability of AMS double-loaded liposomes was 1.94- and 1.28-folds of commercial tablet and conventional liposomes, respectively.

Dopamine and memory dedifferentiation in aging.

The dedifferentiation theory of aging proposes that a reduction in the specificity of neural representations causes declines in complex cognition as people get older, and may reflect a reduction in dopaminergic signaling. The present pharmacological fMRI study investigated episodic memory-related dedifferentiation in young and older adults, and its relation to dopaminergic function, using a randomized placebo-controlled double-blind crossover design with the agonist Bromocriptine (1.25mg) and the antagonist Sulpiride (400mg). We used multi-voxel pattern analysis to measure memory specificity: the degree to which distributed patterns of activity distinguishing two different task contexts during an encoding phase are reinstated during memory retrieval. As predicted, memory specificity was reduced in older adults in prefrontal cortex and in hippocampus, consistent with an impact of neural dedifferentiation on episodic memory representations. There was also a linear age-dependent dopaminergic modulation of memory specificity in hippocampus reflecting a relative boost to memory specificity on Bromocriptine in older adults whose memory was poorer at baseline, and a relative boost on Sulpiride in older better performers, compared to the young. This differed from generalized effects of both agents on task specificity in the encoding phase. The results demonstrate a link between aging, dopaminergic function and dedifferentiation in the hippocampus.

Time to Discontinuation of Second-Generation Antipsychotics Versus Haloperidol and Sulpiride in People With Schizophrenia: A Naturalistic, Comparative Study.

PURPOSE: A retrospective study was conducted to evaluate the time to discontinuation (TTD) of the first- (FGAs) and second-generation antipsychotics (SGAs). METHODS: In total, 918 treatment episodes of patients with schizophrenia, initiated on one of the investigated drugs on an outpatient basis during 2004-2006, were entered into the study. The primary outcome was the duration of the investigated treatment episode. Discontinuation was defined when either patients were admitted or the investigated drug had been stopped for more than 28 days. We used the Cox proportional hazard model to compare hazards of discontinuations among 8 SGAs versus 2 FGAs (haloperidol and sulpiride). The follow-up period was up to 18 months. RESULTS: During the follow-up period, clozapine had the highest rate of continuous treatment in the primary analysis: clozapine, 40.6%; olanzapine, 23.4%; aripiprazole, 22.9%; amisulpride, 21.9%; zotepine, 21.3%; sulpiride, 17.0%; risperidone, 12.8%; quetiapine, 12.5%; haloperidol, 10.6%; and ziprasidone, 10.4%. Compared with haloperidol, 5 SGAs had significantly longer TTD (adjusted hazard ratios and 95% confidence intervals): clozapine (0.403, 0.267-0.607), olanzapine (0.611, 0.439-0.849), aripiprazole (0.570, 0.407-0.795), amisulpride (0.680, 0.487-0.947), and zotepine (0.687, 0.497-0.948), but only clozapine had significantly longer TTD compared with sulpiride (0.519, 0.342-0.786). The sensitivity analysis showed similar results. IMPLICATIONS/CONCLUSIONS: The current findings suggested that SGAs or FGAs are not homogeneous groups. Clozapine has the highest rate of continuous treatment among SGAs, and haloperidol is not the representative drug for all FGAs. Furthermore, antipsychotics dropout rate is high in naturalistic situation. A good service model needs to be constructed to enhance antipsychotic treatment adherence of people with schizophrenia.

Intravenous Amisulpride for the Prevention of Postoperative Nausea and Vomiting: Two Concurrent, Randomized, Double-blind, Placebo-controlled Trials.

BACKGROUND: Two essentially identical, randomized, double-blind, placebo-controlled, parallel-group phase III studies evaluated the efficacy of intravenous amisulpride, a dopamine D2/D3 antagonist, in the prevention of postoperative nausea and vomiting in adult surgical patients. METHODS: Adult inpatients undergoing elective surgery during general anesthesia and having at least two of the four Apfel risk factors for postoperative nausea and vomiting were enrolled at 9 U.S. and 10 European sites. A single 5-mg dose of amisulpride or matching placebo was given at induction of anesthesia. The primary endpoint was complete response, defined as no vomiting/retching and no use of antiemetic rescue medication in the 24-h postoperative period. Nausea incidence was a secondary endpoint. RESULTS: Across the two studies, 689 patients were randomized and dosed with study medication, of whom 626 were evaluable per protocol. In the U.S. study, 46.9% (95% CI, 39.0 to 54.9) of patients achieved complete response in the amisulpride group compared to 33.8% (95% CI, 26.2 to 42.0) in the placebo group (P = 0.026). In the European study, complete response rates were 57.4% (95% CI, 49.2 to 65.3) for amisulpride and 46.6% (95% CI, 38.8 to 54.6) for placebo (P = 0.070). Nausea occurred less often in patients who received amisulpride than those who received placebo. There was no clinically significant difference in the safety profile of amisulpride and placebo; in particular, there were no differences in terms of QT prolongation, extrapyramidal side effects, or sedation. CONCLUSIONS: One of the two trials demonstrated superiority, while pooling both in a post hoc change to the plan of analysis supported the hypothesis that amisulpride was safe and superior to placebo in reducing the incidence of postoperative nausea and vomiting in a population of adult inpatients at moderate to high risk of postoperative nausea and vomiting.

Thorough QT study of the effect of intravenous amisulpride on QTc interval in Caucasian and Japanese healthy subjects.

AIM: The D2 /D3 antagonist amisulpride has shown promising efficacy against postoperative nausea and vomiting (PONV) at low doses. We investigated whether intravenous amisulpride has an effect on the QTc interval in a formal Thorough QT study (TQT). METHODS: This was a randomized, double-blind, placebo and positive-controlled, four-way crossover study. Forty healthy Caucasian and Japanese subjects were included to receive a single administration of 5 mg and 40 mg of i.v. amisulpride or a single oral dose of moxifloxacin or placebo per period. RESULTS: The therapeutic dose of 5 mg amisulpride was associated with a slight, transient increase in mean ΔΔQTcF, from 2.0 ms prior to dosing to a peak of 5 ms (90% CI: 2.8, 7.1 ms) at 8 min, decreasing to 2.1 ms at 30 min after dosing. The supra-therapeutic dose of 40 mg given at twice the infusion rate was associated with prolongation in ΔΔQTcF peaking at 23.4 ms (90% CI: 21.3, 25.5 ms) at the end of infusion (8 min), returning below 10 ms within 1.5 h. Assay sensitivity was confirmed; ΔΔQTcF had increased by 12.3 ms (90% CI 10.1, 14.6 ms) at 4 h post-dose. The PK-PD relationship revealed no differences between Caucasian and Japanese subjects (p-value > 0.5). CONCLUSIONS: Amisulpride has a plasma concentration-dependent effect on the QTc interval. The proposed therapeutic dose for management of PONV does not lead to a prolongation of QTcF above the threshold of regulatory concern, while such effect could not be excluded for the supratherapeutic dose.

Bioequivalence of a New Oral Levosulpiride Formulation Compared With a Standard One in Healthy Volunteers.

BACKGROUND: A monocentric, single-dose, open-label, 2-way, crossover randomized study was conducted by the San Matteo Phase I Clinical Trial Unit and Experimental Therapy (Pavia, Italy) to assess the bioequivalence and the systemic tolerability of a new oral formulation of levosulpiride (tablet 25 mg: test) versus a commercially available formulation on the Italian market (tablet 25 mg: reference). METHODS: Thirty-five healthy adult volunteers, men (n = 19) and women (n = 16), aged between 18 and 55 years were screened and 32 of them were enrolled in the study. After having signed the written informed consent, each subject received a single oral dose of Test or Reference product with 250 mL of natural mineral water, in fasting conditions, interspersed with a 6-day washout period Blood samples were collected up to 36 hours after drug administration: the drug plasma levels were determined by high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry. The pharmacokinetic parameters included peak plasma concentration (Cmax), time corresponding to Cmax (tmax), area under the plasma concentration-time curve from zero to infinity (AUC0-∞) or to the last sampling time assessment (AUC0-36), the elimination rate constant (ke), and the terminal half-life (t1/2). Safety was measured by pre- and post-treatment specific biochemical investigations, physical examination, electrocardiogram, occurrence of adverse events, and any information on patients' withdrawal. RESULTS: The geometric mean ratio Test/Reference (90% confidence interval) for levosulpiride was 103.0% (95.8-110.8) for AUC0-36, 103.6% (95.9-111.9) for AUC0-∞, and 104.3% (94.9-114.6) for Cmax. ke and t1/2 were 0.07 (SD: 0.02) and 9 hours (8-12) for both the formulations. Clearance (L/h) was 29.6 (±13.5) and 30.7 (±14.2) for the test and the reference product, respectively. CONCLUSIONS: Because the acceptance criteria required by the drug regulatory agency (European Medicines Agency, EMA) for bioequivalence prescribe limits of 80%-120% for untransformed data and 80%-125% for "ln" transformed data, we can confirm that the 2 formulations are bioequivalent, in terms of the rate and extent of absorption.

Multiple organic cation transporters contribute to the renal transport of sulpiride.

Sulpiride, a selective dopamine D2 receptor blocker, is used widely for the treatment of schizophrenia, depression and gastric/duodenal ulcers. Because the great majority of sulpiride is positively charged at physiological pH 7.4, and ~70% of the dose recovered in urine is in the unchanged form after human intravenous administration of sulpiride, it is believed that transporters play an important role in the renal excretion of sulpiride. The aim of the present study was to explore which transporters contribute to the renal disposition of sulpiride. The results demonstrated that sulpiride was a substrate of human carnitine/organic cation transporter 1 (hOCTN1) and 2 (hOCTN2), human organic cation transporter 2 (hOCT2), human multidrug and toxin efflux extrusion protein 1 (hMATE1) and 2-K (hMATE2-K). Sulpiride accumulation from the basolateral (BL) to the apical (AP) side in MDCK-hOCT2/pcDNA3.1 cell monolayers was much greater than that in MDCK-hOCT2/hMATE1 cells, and cimetidine dramatically reduced the intracellular accumulation of sulpiride from BL to AP. In addition, the accumulation of sulpiride in mouse primary renal tubular cells (mPRTCs) was markedly reduced by inhibitors of Oct2 and Octns. The results implied that OCTN1, OCTN2, OCT2, MATE1 and MATE2-K probably contributed to the renal transfer of sulpiride, in which OCT2 mediated the uptake of sulpiride from the bloodstream to the proximal tubular cells, while MATEs contributed to the sulpiride efflux from the proximal tubular cells to the renal lumen, and OCTNs participated in both renal secretion and reabsorption.

Development of novel amisulpride-loaded liquid self-nanoemulsifying drug delivery systems via dual tackling of its solubility and intestinal permeability.

OBJECTIVE: The aim of the current investigation was at enhancing the oral biopharmaceutical behavior; solubility and intestinal permeability of amisulpride (AMS) via development of liquid self-nanoemulsifying drug delivery systems (L-SNEDDS) containing bioenhancing excipients. METHODS: The components of L-SNEDDS were identified via solubility studies and emulsification efficiency tests, and ternary phase diagrams were constructed to identify the efficient self-emulsification regions. The formulated systems were assessed for their thermodynamic stability, globule size, self-emulsification time, optical clarity and in vitro drug release. Ex vivo evaluation using non-everted gut sac technique was adopted for uncovering the permeability enhancing effect of the formulated systems. RESULTS: The optimum formulations were composed of different ratios of Capryol™ 90 as an oil phase, Cremophor® RH40 as a surfactant, and Transcutol® HP as a co-surfactant. All tested formulations were thermodynamically stable with globule sizes ranging from 13.74 to 29.19 nm and emulsification time not exceeding 1 min, indicating the formation of homogenous stable nanoemulsions. In vitro drug release showed significant enhancement from L-SNEDDS formulations compared to aqueous drug suspension. Optimized L-SNEDDS showed significantly higher intestinal permeation compared to plain drug solution with nearly 1.6-2.9 folds increase in the apparent permeability coefficient as demonstrated by the ex vivo studies. CONCLUSIONS: The present study proved that AMS could be successfully incorporated into L-SNEDDS for improved dissolution and intestinal permeation leading to enhanced oral delivery.

Development of novel amisulpride-loaded solid self-nanoemulsifying tablets: preparation and pharmacokinetic evaluation in rabbits.

OBJECTIVE: The current investigation is focused on the formulation and in vivo evaluation of optimized solid self-nanoemulsifying drug delivery systems (S-SNEDDS) of amisulpride (AMS) for improving its oral dissolution and bioavailability. METHODS: Liquid SNEDDS (L-SNEDDS) composed of Capryol™ 90 (oil), Cremophor® RH40 (surfactant), and Transcutol® HP (co-surfactant) were transformed to solid systems via physical adsorption onto magnesium aluminometasilicate (Neusilin US2). Micromeretic studies and solid-state characterization of formulated S-SNEDDS were carried out, followed by tableting, tablet evaluation, and pharmacokinetic studies in rabbits. RESULTS: Micromeretic properties and solid-state characterization proved satisfactory flow properties with AMS present in a completely amorphous state. Formulated self-nanoemulsifying tablets revealed significant improvement in AMS dissolution compared with either directly compressed or commercial AMS tablets. In vivo pharmacokinetic study in rabbits emphasized significant improvements in tmax, AUC(0-12), and AUC(0-∞) at p < .05 with 1.26-folds improvement in relative bioavailability from the optimized self-nanoemulsifying tablets compared with the commercial product. CONCLUSIONS: S-SNEDDS can be a very useful approach for providing patient acceptable dosage forms with improved oral dissolution and biovailability.

Pregnancy outcomes in women reporting ingestion of levosulpiride in early pregnancy.

This study aimed to evaluate pregnancy outcomes of women who were inadvertently exposed to levosulpiride in early pregnancy. All 162 consecutive singleton pregnant women counselled through the Korean Motherisk Program, Cheil General Hospital, between April 2001 and April 2014, on teratogenic risk after inadvertent exposure to levosulpiride in early pregnancy were enrolled in this study. The women were exposed to levosulpiride at median 4.8 gestational weeks. The rate of miscarriage was not significantly different between groups (9.2% in those exposed and 5.5% in the non-exposed; p = .084). The rate of major malformations was not significantly different between exposed (2.7%) and non-exposed pregnancies (4.4%) (p = .481). All other pregnancy outcomes between the two groups were comparable (p > .05). Our data suggest that levosulpiride causes no significant adverse effects on pregnancy outcomes and therefore may be not a major teratogen.

Large Variation in Brain Exposure of Reference CNS Drugs: a PET Study in Nonhuman Primates.

BACKGROUND: Positron emission tomography microdosing of radiolabeled drugs allows for noninvasive studies of organ exposure in vivo. The aim of the present study was to examine and compare the brain exposure of 12 commercially available CNS drugs and one non-CNS drug. METHODS: The drugs were radiolabeled with (11)C (t 1/2 = 20.4 minutes) and examined using a high resolution research tomograph. In cynomolgus monkeys, each drug was examined twice. In rhesus monkeys, a first positron emission tomography microdosing measurement was repeated after preadministration with unlabeled drug to examine potential dose-dependent effects on brain exposure. Partition coefficients between brain and plasma (KP) were calculated by dividing the AUC0-90 min for brain with that for plasma or by a compartmental analysis (VT). Unbound KP (KP u,u) was obtained by correction for the free fraction in brain and plasma. RESULTS: After intravenous injection, the maximum radioactivity concentration (C max, %ID) in brain ranged from 0.01% to 6.2%. For 10 of the 12 CNS drugs, C max, %ID was >2%, indicating a preferential distribution to brain. A lower C max, %ID was observed for morphine, sulpiride, and verapamil. K P ranged from 0.002 (sulpiride) to 68 (sertraline) and 7 of 13 drugs had KP u,u close to unity. For morphine, sulpiride, and verapamil, K P u,u was <0.3, indicating impaired diffusion and/or active efflux. Brain exposure at microdosing agreed with pharmacological dosing conditions for the investigated drugs. CONCLUSIONS: This study represents the largest positron emission tomography study on brain exposure of commercially available CNS drugs in nonhuman primates and may guide interpretation of positron emission tomography microdosing data for novel drug candidates.

Acute Effects of Haloperidol, Amisulpride, and Quetiapine on Bone Turnover Markers in Patients With Schizophrenia.

OBJECTIVE: This prospective study sought to compare the acute effects of haloperidol, amisulpride, and quetiapine on serum markers of bone formation and resorption in relatively young patients with minimal previous exposure to antipsychotic drugs. METHODS: Patients included in the study were randomly assigned to receive haloperidol, amisulpride, or quetiapine monotherapy in an open-label manner. Serum osteocalcin (OC, a marker of bone formation), C-terminal peptide of type I collagen (CTX, a marker of bone resorption), prolactin (PRL), estradiol, and testosterone were measured in 70 patients at baseline and after 4 weeks of antipsychotic treatment. RESULTS: A repeated-measures analysis of variance revealed a significant difference in CTX levels and in the OC to CTX ratio between treatment groups (F = 4.481, P < 0.05; F = 8.114, P < 0.01). After 4 weeks of treatment, only the amisulpride group had significantly increased CTX levels and decreased OC/CTX. In addition, an obvious increase in PRL level and a reduction of sex hormone secretion after amisulpride treatment were found. No significant changes in bone turnover were observed in the haloperidol or quetiapine groups. Notably, a positive correlation between the CTX change to the change in PRL after treatment (r = 0.255, P < 0.05) was observed. CONCLUSIONS: The PRL-raising antipsychotic drug amisulpride influenced bone turnover balance very early in the course of treatment, which may require long-term monitoring of bone metabolism. Bone resorption marker changes induced by acute antipsychotic drug treatment are likely related to increased PRL levels.

Skating on thin ice: pragmatic prescribing for medication refractory schizophrenia.

BACKGROUND: Clozapine is the treatment of choice for medication refractory psychosis, but it does not benefit half of those put on it. There are numerous studies of potential post-clozapine strategies, but little data to guide the order of such treatment in this common clinical challenge. We describe a naturalistic observational study in 153 patients treated by a specialist psychosis service to identify optimal pharmacotherapy practice, based on outcomes. METHODS: Medication and clinical data, based on the OPCRIT tool, were examined on admission and discharge from the national psychosis service. The primary outcome measure was the percentage change in mental state examination symptoms between admission and discharge and the association with medication on discharge. Exploratory analyses evaluated the specificity of individual medication effects on symptom clusters. RESULTS: There were fewer drugs prescribed at discharge relative to admission, suggesting an optimisation of medication, and a doubling of the number of patients treated with clozapine. Treatment with clozapine on discharge was associated with maximal decrease in symptoms from admission. In the group of patients that did not respond to clozapine monotherapy, the most effective drug combinations were clozapine augmentation with 1) sodium valproate, 2) lithium, 3) amisulpride, and 4) quetiapine. There was no support for a dose-response relationship for any drug combination. CONCLUSIONS: Clozapine monotherapy is clearly the optimal medication in medication refractory schizophrenia and it is possible to maximise its use. In patients unresponsive to clozapine monotherapy, augmentation with sodium valproate, lithium, amisulpride and quetiapine, in that order, is a reasonable treatment algorithm. Reducing the number of ineffective drugs is possible without a detrimental effect on symptoms. Exploratory data indicated that clozapine was beneficial across a range of symptoms domains, whereas olanzapine was beneficial specifically for hallucinations and lamotrigine for comorbid affective symptoms.

Dosage and duration of antipsychotic treatment in demented outpatients with agitation or psychosis.

BACKGROUND/PURPOSE: The USA Food and Drug Administration (FDA) issued warnings regarding the use of antipsychotics in patients with dementia in 2003 and 2005. We aimed to study the dose and duration of antipsychotic treatment in dementia, and to examine whether physicians' prescription behaviors changed after the FDA warnings. METHODS: Medical charts of outpatients who had Alzheimer's disease, vascular dementia, or mixed dementia were reviewed. Patients must have achieved a clinically stable state for at least 4 weeks after receiving antipsychotic treatment for agitation or psychosis. Demographics, clinical correlates, and duration of antipsychotic treatment were compared among different antipsychotic groups. Because the quetiapine group had the largest sample size, the optimal dose and duration of quetiapine treatment were compared among three time periods (before 2003, 2003-2005, after 2005). RESULTS: Stable state was achieved in 215 patients (80 had Alzheimer's disease, 117 vascular dementia, and 18 mixed dementia). Most patients (177) took quetiapine, 25 took risperidone, and 13 took sulpiride. The whole sample had a long total duration of antipsychotic treatment (median 525 days, mean 707 days). The median dose and total duration of antipsychotic treatment were 1.0mg/day and 238 days for risperidone, 100mg/day and 390 days for sulpiride, and 25mg/day and 611 days for quetiapine, respectively. The optimal dose and total duration of quetiapine treatment decreased significantly after FDA warning in 2005, although the duration remained long. CONCLUSION: The optimal doses of antipsychotics were not higher than those of western reports, but the total duration of antipsychotic treatment was quite long. Although our study suggests the prescription dosage and duration of antipsychotic treatment decreased significantly after FDA warning in 2005, the duration of treatment was still long. Given the serious safety concerns, more effort should be made to avoid unnecessary and prolonged prescription.

Heat stroke during treatment with olanzapine, trihexyphenidyl, and trazodone in a patient with schizophrenia.

OBJECTIVE: Heat stroke is a medical emergency. Psychiatric patients are particularly susceptible to heat stroke. Therefore, awareness and preventive measures of heat stroke are important for both clinicians and patients. Case description A 49-year-old man with schizophrenia, who was under maintenance treatment with olanzapine 20 mg/day, trihexyphenidyl 4 mg/day, and trazodone 50 mg/day, suffered from heat stroke in a heat wave and required intensive care. He recovered with the medical treatment provided. Discussion Several factors could have contributed to the impaired thermoregulation and the occurrence of heat stroke in this case: schizophrenia, the psychotropic regimen, and lack of preventive measures. Possible differential diagnoses of heat stroke in this case include infection, neuroleptic malignant syndrome, and serotonin syndrome. CONCLUSION: Heat stroke can occur during the maintenance treatment of olanzapine, trihexyphenidyl, and trazodone for schizophrenia. Clinicians should be proactive to reduce the risk of heat stroke in psychiatric patients.