Post-marketing surveillance of quetiapine fumarate extended-release tablets in patients with bipolar depression.

AIM: This study aimed to verify the real-world efficacy and safety of quetiapine fumarate extended-release tablets (Bipresso® 50 mg and 150 mg; marketing authorization holder is KYOWA Pharmaceutical Industry Co., Ltd., Osaka, Japan) in patients with bipolar depression. METHODS: We performed a post-marketing surveillance with an observation period of 12 weeks. RESULTS: In the safety analysis group (n = 345), adverse drug reactions (ADRs) occurred in 111 patients (32.17%). The most common ADRs (>1%) were somnolence in 55 patients (15.94%), akathisia in 11 (3.19%), dizziness in 10 (2.90%), weight increase in 6 (1.74%), thirst in 5 (1.45%), and hypersomnia, constipation, and nausea in 4 patients each (1.16%). The only severe ADR was one patient of suicidal ideation, and "longer time since the onset of the first episode" (p = 0.011) and "presence of complications" (p < 0.001) were identified as significant risk factors for the occurrence of ADRs. In the efficacy analysis group (n = 265), the average changes from baseline in the total Montgomery-Åsberg Depression Rating Scale (MADRS) score were -7.3 ± 8.8, -12.2 ± 10.7, -16.8 ± 12.7, and -13.2 ± 12.7 points after 4, 8, and 12 weeks, and at the last evaluation, respectively. The mean MADRS total score decrease had no significant association with maximum daily dose, diagnosis, and presence or absence of prior or concomitant treatment for bipolar disorder with mood stabilizers/antipsychotics/antidepressants. CONCLUSION: The efficacy of quetiapine fumarate extended-release tablets was confirmed in clinical practice, and no new safety concerns or risks were identified.

Preventive effect of aripiprazole once monthly on rehospitalization for bipolar disorder: A multicenter 1-year retrospective mirror image study.

AIM: We conducted a 1-year retrospective mirror-image study to investigate the effect of aripiprazole once monthly (AOM) on rehospitalization for bipolar disorder. METHODS: Participants were recruited from psychiatric emergency and acute care hospitals in western Japan. We included 39 participants with bipolar disorder who had been administered AOM for at least 1 year with no missing medical records during the observational period. The primary outcomes were rehospitalization rate, number of rehospitalizations, total hospitalization days, and time to rehospitalization in the context of overall psychiatric readmissions. The significance level was set at p < 0.05. RESULTS: AOM significantly reduced the rehospitalization rate from 23/39 (59%) to 7/39 (18%) (p = 0.001). The number of rehospitalizations decreased significantly from a mean of 0.85 per person-year to 0.41 per person-year (p = 0.048). The total hospitalization days significantly decreased from a mean of 34.9 days to 14.4 days (p = 0.008). AOM significantly prolonged the time to rehospitalization (p < 0.001). CONCLUSION: This study found that AOM reduces overall psychiatric rehospitalization for bipolar disorder based on data from 1 year before and after AOM administration in the real-world setting. Future studies should examine the robustness and persistence of the rehospitalization preventive effect of AOM with larger sample sizes and longer observation periods beyond 1 year.

U.S. patient preferences for long-acting HIV treatment: a discrete choice experiment.

INTRODUCTION: Recent advances in long-acting antiretroviral therapy (LA-ART) could provide new options for HIV treatment and reduce adherence barriers, if regimens are acceptable to patients. We elicited preferences for key attributes of potential LA-ART regimens among people with HIV (PWH) in the United States, focusing on four treatment modes (oral tablets, subcutaneous injections, intramuscular injections, and implants), product characteristics and location of administration. METHODS: A discrete choice experiment was conducted among PWH aged ≥18 years recruited from HIV clinics in Washington State and Atlanta, Georgia from March 2021 to June 2022. Participants responded to 17 choice scenarios, each with three options: two systematically generated hypothetical LA-ART regimens and a constant opt-out (their current daily oral treatment). LA-ART regimen descriptions included treatment mode, pain, dosing frequency, location, pre-treatment time with undetectable viral load, pre-treatment negative reaction testing and "late-dose leeway" (i.e. flexibility or forgiveness in timing the next dose). We used conditional logistic regression, with an interaction between treatment mode and pain, to estimate preference weights for all attribute levels. RESULTS: Seven hundred participants (350 at each site) enrolled, with median age 51 years (range 18-73); 70% identified as cisgender male, 24% as cisgender female and 6% as non-binary or transgender. LA oral tablets were the only mode preferred over current daily oral treatment, with annual implants and injections the next most preferred LA-ART option. Longer time between doses was preferred, and administration at home was preferred to clinics, which were preferred to pharmacies. Attributes with less impact on preferences included oral lead-in treatment to achieve viral suppression or test for negative reactions and late-dose leeway around the prescribed dosing interval. Participants in Atlanta were more likely to prefer their current daily oral ART than participants from Seattle. CONCLUSIONS: PWH in the United States may soon have several options for LA-ART. Our results suggest that LA oral tablets will be preferred by many patients over their current daily oral treatment, while implants and injections with longer duration may be acceptable to some. Future research should investigate sources of preference heterogeneity and actual uptake of and adherence to LA-ART products, when available.

Combined Growth Factor Hydrogel Enhances Rotator Cuff Enthesis Healing in Rat But Not Sheep Model.

We hypothesized that a combined growth factor hydrogel would improve chronic rotator cuff tear healing in a rat and sheep model. Insulin-like growth factor 1, transforming growth factor ß1, and parathyroid hormone were combined into a tyraminated poly-vinyl-alcohol (PVA-Tyr) hydrogel and applied directly at the enthesis. In total, 30 Sprague-Dawley rats and 16 Romney ewes underwent unilateral rotator cuff tenotomy and then delayed repairs were performed after 3-4 weeks. The animals were divided into a control group (repair alone) and treatment group. The rotator cuffs were harvested at 12 weeks after surgery for biomechanical and histological analyses of the repair site. In the rat model, the stress at failure and Young's modulus were higher in the treatment group in comparison with the control group (73% improvement, p = 0.010 and 56% improvement, p = 0.028, respectively). Histologically, the repaired entheses in the treatment group demonstrated improved healing with higher semi-quantitative scores (10.1 vs. 6.55 of 15, p = 0.032). In the large animal model, there was no observable treatment effect. This PVA-Tyr bound growth factor system holds promise for improving rotator cuff healing. However, our approach was not scalable from a small to a large animal model. Further tailoring of this growth factor delivery system is still required. Level of Evidence: Basic Science Study; Biomechanics and Histology; Animal Model Impact Statement Previous studies using single-growth factor treatment to improve enthesis healing after rotator cuff repair have reported promising, but inconsistent results. A novel approach is to combine multiple growth factors using controlled-release hydrogels that mimic the normal healing process. In this study, we report that a combined growth factor hydrogel can improve the histological quality and strength of rotator cuff repair in a rat chronic tear model. This novel hydrogel growth factor treatment has the potential to be used in human clinical applications to improve healing after rotator cuff repair.

Pharmacokinetic properties of a new sustained-release pregabalin tablet in subjects with reduced renal function.

A new sustained-release (SR) pregabalin tablet, YHD1119, was formulated for once-daily dosing. In the current study, we aimed to evaluate the pharmacokinetics of YHD1119 tablets in patients with reduced renal function. Subjects were grouped by creatinine clearance: > 60 mL/min/1.73m2 (Cohort A) and 30-60 mL/min/1.73m2 (Cohort B). Eight subjects in Cohort A received a YHD1119 75 mg tablet (Y75T) and a YHD1119 150 mg tablet (Y150T) in each period, and eight subjects in Cohort B received a Y75T. Non-compartment analysis and population pharmacokinetic analysis using a one-compartment model with first-order elimination and first-order absorption with lag time were performed. Sixteen subjects completed the study. The geometric mean ratio (GMR) (90% confidence intervals [CI]) for maximum concentration (Cmax), and area under the concentration-time profile from 0 to the last measurable time (AUClast) after Y75T of Cohort B to those of Y75T of Cohort A were 1.2273 (1.0245-1.4701), and 2.4146 (1.8142-3.2138), respectively. The GMR (90% CI) for Cmax, and AUClast after Y75T of Cohort B to those of Y150T of Cohort A were 0.6476 (0.5229-0.8021), and 1.1471 (0.8418-1.5632), respectively. Simulated steady-steady pregabalin concentrations after once-daily Y75T dosing in subjects with eGFR 45 mL/min/1.73 m2 were within the range of steady-state concentrations simulated after once-daily Y150T dosing in subjects with eGFR 90 mL/min/1.73 m2. The total pregabalin exposure of Y75T in patients with moderate renal impairment was comparable with that of Y150T in subjects with near-normal renal function. Trial Registration: ClinicalTrials.gov Identifier: NCT05012436.

Concerns regarding tablet splitting: a systematic review.

BACKGROUND: Tablet splitting can provide dose flexibility and cost savings; however, pharmaceutical representatives typically discourage the practice. AIM: To identify and summarise all published concerns related to tablet splitting and to present the experimental evidence that investigates those concerns. DESIGN & SETTING: Systematic review and qualitative synthesis of tablet-splitting concerns and evidence. METHOD: Medline and EMBASE databases were searched over all years of publication for articles in English discussing the splitting of tablets. Eligible articles included original research, narrative reviews, systematic reviews, and expert opinion. RESULTS: After removing duplicates, 1837 potentially relevant articles underwent dual review, whereupon 1612 articles were excluded based on title and abstract. After examination of 225 full texts, 138 articles were included (one systematic review, four narrative reviews, 101 original research articles, and 32 opinion articles). The described concerns included difficulty breaking tablets, loss of mass, weight variability, chemical instability, overly rapid dosing if sustained-release medications are split, non-compliance, and patient confusion resulting in medication errors. No substantive evidence was found to support concerns regarding loss of mass, weight variability, chemical instability, or non-compliance. Evidence does support some older adults struggling to split tablets without tablet splitters, and the inappropriateness of splitting sustained-release preparations, given the potential for alteration of the rate of drug release for some products. CONCLUSION: With the exception of sustained-release tablets, which should not be split, and excepting those older people who may struggle to split tablets based on physical limitations, there is little evidence to support tablet-splitting concerns.

Aripiprazole Lauroxil Dosing Regimens: Understanding Dosage Strengths and Injection Intervals.

Aripiprazole lauroxil (AL) is a long-acting atypical antipsychotic approved for the treatment of schizophrenia in adults. AL has five regimen options that offer three different injection intervals using four different dosage strengths. The relationship between dosage strength (milligram injected), injection interval (time between injection visits), and expected steady-state plasma aripiprazole concentrations may not be readily apparent. This article illustrates the relationship by providing visual scenarios of steady-state plasma aripiprazole concentrations for the five AL regimens. The efficacy of AL was originally demonstrated in a pivotal study of two AL regimens (approved as 441 mg monthly and 882 mg monthly). The three additional regimens (662 mg monthly, 882 mg every 6 weeks, and 1064 mg every 2 months) were approved based on pharmacokinetic bridging studies and population pharmacokinetic models. For this paper, expected steady-state concentrations for each AL regimen were derived from the published population pharmacokinetic models and compared using median values and ranges. The five labeled AL regimens differ in dosage strength and injection interval; however, model-simulated concentrations illustrate that each regimen produces steady-state plasma aripiprazole concentrations within the upper and lower bounds associated with known efficacy for AL 441 mg and 882 mg administered monthly. This visual presentation of the relationship between dosage strength of the AL injection, the interval between successive injections, and steady-state aripiprazole plasma concentrations may demonstrate for clinicians how dosage strength and injection interval can be considered in selecting the AL regimen option that best fits the clinical circumstances of the individual patient.

Liproca Depot: A New Antiandrogen Treatment for Active Surveillance Patients.

BACKGROUND: There is increasing interest in nonmorbid treatments for low- and intermediate-risk prostate cancer with fewer side effects than surgery or radiotherapy. OBJECTIVE: To investigate the tolerability, safety, and antitumor effects of the intraprostatic NanoZolid depot formulation Liproca Depot (LIDDS AB, Uppsala, Sweden) with antiandrogen 2-hydroxyflutamide (2-HOF) in men with low- or intermediate-risk localized prostate cancer managed with active surveillance. DESIGN, SETTING, AND PARTICIPANTS: This clinical phase 2b trial, LPC-004, involved 61 patients. The 2-HOF-containing formulation Liproca Depot was injected transrectally into the prostate under ultrasound guidance. A single dose of 35% or 45% of the prostate volume (study part 1) and a fixed dose of 16 or 20 ml (study part 2) of the formulation were evaluated. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: The primary endpoints were tolerability and the reduction in serum prostate-specific antigen (PSA) 5 mo after injection. Antitumor effects were evaluated with magnetic resonance imaging (MRI) and prostate biopsies. Quality of life was assessed using a validated questionnaire (International Prostate Symptom Score). RESULTS AND LIMITATIONS: All doses were safe and well tolerated, without hormonal side effects. In part 2 of the study, the PSA reduction was greatest for the group receiving 16 ml, with an average decrease of 14%, and 95% of patients had a PSA reduction. Some 78% of patients showed a prostate volume decrease compared to baseline. Prostate MRI and biopsies confirmed stable or reduced lesion size. However, post treatment biopsies were performed at the discretion of the investigator, and not routinely. Most patients were amenable to a second injection. CONCLUSIONS: PSA and prostate volume decreased in most patients. Indications of efficacy were shown by post-treatment MRI and biopsies demonstrating stabilization or regression in the majority of cases. PATIENT SUMMARY: Liproca Depot is a safe, minimally invasive treatment that offers the potential for cancer control in patients with intermediate-risk prostate cancer. Further clinical evaluation is warranted.

The clinical efficiency and complication analysis of dexamethasone sustained release intraocular implantation in macular edema after vitrectomy / 中国医师杂志

Objective:To investigate the efficiency, safety and complication of 0.7 mg dexamethasone sustained release agent (Ozurdex ?) vitreous cavity implantation for macular edema secondary to vitrectomy. Methods:A total of 15 patients (16 eyes) were included in this retrospective case series study. There were 7 males (8 eyes) and 8 females (8 eyes). Age ranged from 47 to 72 years old with an average age of (60.2±8.6)years. Among them, 8 cases were diabetic retinopathy (6 cases combined cataract surgery). 4 cases were silicone oil removal after retinal detachment surgery (all combined cataract surgery). 2 cases were epi-macular membrane (all combined with cataract surgery) and 1 case was vitreous hemorrhage (combined with cataract surgery). Ozurdex ? was implanted for macular edema after vitrectomy. The number of implantation was from 1 to 3 times (mean 1.67 times). The follow-up time was from 3 to 12 months, with an average of (7.33±3.50)months. Results:The best corrected visual acuity (BCVA) was improved in 10 cases (11 eyes), unchanged in 4 cases and decreased in 1 case within 3 months after Ozurdex ? implantation in the 15 cases (16 eyes). The macular edema was significantly improved in all cases. The central macular thickness (CMT) measured by optical coherence tomography (OCT) was from 350 to 1 370 γm before surgery with average thickness (621.60±235.48)γm, and the CMT postoperative was 118 to 556 γm with average thickness (269.87±118.14)γm, with statistically significant difference ( P<0.001). Cataract was not progressive after Ozurdex ? implantation. Macular edema was recurrent in 7 cases after first implantation and stable for additional 1-2 injections. Intraocular pressure elevation occurred in 3 cases 1 to 2 months after implantation with the highest intraocular pressure of 36 mmHg, which were controlled by local anti-glaucoma eye drops. Drugs entered into the anterior chamber in 2 cases and was taken out in 1 case. Conclusions:The efficiency of Ozurdex ? vitreous cavity implantation is definite and the complications are controllable, so it is a safe and effective method to treat macular edema after vitrectomy.

Preparation, Synergism, and Biocompatibility of in situ Liquid Crystals Loaded with Sinomenine and 5-Fluorouracil for Treatment of Liver Cancer.

PURPOSE: Transarterial chemoembolization is the preferred treatment for patients with middle and advanced-stage hepatocellular carcinoma (HCC); however, most hepatic artery embolization agents have various disadvantages. The purpose of this study was to evaluate phytantriol-based liquid crystal injections for potential use in treatment of HCC. METHODS: Using sinomenine (SN) and 5-fluorouracil (5-FU) as model drugs, three precursor in situ liquid crystal injections based on phytantriol (P1, P2, and P3) were prepared, and their in vitro biocompatibility, anticancer activity, and drug release investigated, to evaluate their feasibility for use in treatment of HCC. The properties of the precursor injections and subsequent cubic liquid crystal gels were observed by visual and polarizing microscopy, in an in vitro gelation experiment. Biocompatibility was evaluated by in vitro hemolysis, histocompatibility, and cytotoxicity assays. RESULTS: Precursor injections were colorless liquids that formed transparent cubic liquid crystal gels on addition of excess water. The three precursor injections all caused slight hemolysis, without agglutination, and were mildly cytotoxic. Histocompatibility experiments showed that P1 had good histocompatibility, while P2 and P3 resulted in strong inflammatory responses, which subsequently resolved spontaneously. In vitro anti-cancer testing showed that SN and 5-FU inhibited HepG2 cells in a time- and concentration-dependent manner and had synergistic effects. Further, in vitro release assays indicated that all three preparations had sustained release effects, with cumulative release of >80% within 48 h. CONCLUSION: These results indicate that SN and 5-FU have synergistic inhibitory effects on HepG2 cells, which has not previously been reported. Moreover, we describe a biocompatible precursor injection, useful as a drug carrier for the treatment of liver cancer, which can achieve targeting, sustained release, synergistic chemotherapy, and embolization. These data indicate that precursor injections containing SN and 5-FU have great potential for use in therapy for liver cancer.

Successful Treatment of Delusional Infestation with Olanzapine Depot.

Delusional infestation (DI) is a rare psychiatric disorder characterized by a persistent false belief that one is infected with nonliving or living pathogens, usually accompanied by formication. Other psychotic features, such as disorganized speech or hallucinations unrelated to the core delusion itself, are never present, and the delusional belief does not extend into other areas of life. Secondary DI, when one needs to address the underlying condition in order to achieve adequate treatment, is also possible. We present the case of a 42-year-old male with a 2-year history of having a persistent and firm belief that his house was infested with tiny insects that were constantly biting him and laying their eggs under his skin. His delusional belief was preceded by a complex, years-long substance use disorder, which confronted us with a differential diagnostic dilemma between primary and secondary DI. He was successfully treated with olanzapine pamoate depot, which was introduced to address his lack of insight and unsatisfactory compliance, and his delusion faded away after his symptoms subsided.

Preliminary efficacy and tolerability profiles of first versus second-generation Long-Acting Injectable Antipsychotics in schizophrenia: A systematic review and meta-analysis.

We performed a systematic review and meta-analysis of the efficacy and safety of second generation (SG) long-acting antipsychotics (LAIAs) versus first generation (FG) LAIAs in schizophrenia. We conducted a comprehensive search in PubMed, MEDLINE, EMBASE and PsycINFO until May 2019. Inclusion criteria for randomized trials included: (1) patients ≥18 years with schizophrenia, (2) efficacy evaluated through the Positive and Negative Syndrome Scale (PANSS), (3) safety assessment through clinimetry, laboratory analysis, somatometry or adverse events, and (4) treatment duration ≥12 weeks. Data was synthesized using mean differences (MD) for continuous outcomes and risk ratios (RR) for dichotomous outcomes using a random-effect model. Of 1872 citations, 17 trials were included, and direct comparisons of SG vs FG-LAIAs were observed in 3 (n = 459). SG and FG-LAIAs had similar effects on PANSS scores (MD -1.35; 95% CI -8.33-5.64), tardive dyskinesia (RR 0.99; 95% CI, 0.47-2.07), all-cause discontinuation (RR 1.01; 95% CI 0.75-1.36), discontinuation due to inadequate efficacy (RR 1.13; 95% CI 0.81-1.59) or adverse events (RR 1.08; 95% CI 0.55-2.11). SG-LAIAs reduced the risk of using antiparkinsonian drugs (RR 0.54; 95% CI 0.54-0.76) but significantly increased serum prolactin, weight and BMI. For long-term management, depot preparations of paliperidone, haloperidol, risperidone and fluphenazine were equally effective at symptom control and adherence, with significant differences in their safety profiles. These results however are considerably limited due to the small number of included studies and are therefore preliminary, not generalizable. More clinical trials are required to obtain a broader perspective of SG-LAIAs compared to FG-LAIAs.

Desarrollo de implantes subcutáneos de liberación controlada de Carvedilol para la reducción sostenida de la presión arterial en modelos experimentales de hipertensión arterial / Development of Subcutaneous Implants of Controlled Release Formulations of Carvedilol for Sustained Blood Pressure Reduction in Experimental Models of Hypertension

RESUMEN Objetivo: El objetivo del presente estudio fue el desarrollo y la evaluación farmacocinética y farmacodinámica de la liberación in vivo de implantes subcutáneos de carvedilol capaces de aportar niveles tisulares estables en modelos experimentales de hipertensión arterial. La incorporación del polímero hidrofílico SoluPlus (SP) en los implantes PCL:SP 150:150 y 50:250 favorece un incremento de la liberación de carvedilol dado que aporta concentraciones plasmáticas en el rango de 100-200 ng/mL durante 2 semanas, lo que tiene como resultado una reducción sostenida de la presión arterial sistólica indirecta en animales SHR. Material y métodos: Se prepararon implantes subcutáneos de poli (epsilon-caprolactona) (PCL) con diferentes proporciones del polímero hidrofílico SoluPlus (300:0; 250:50; 150:150 y 50:250 mg) cargados con 100 mg de carvedilol. Se evaluó el perfil plasmático y el efecto sobre la presión arterial sistólica (PAS) luego del implante de cada formulación en el tejido subcutáneo de ratas espontáneamente hipertensas (REH) macho. Resultados: Las formulaciones PCL:SP 50:250 y 150:150 aportaron niveles en el rango de 100-200 ng/mL. Las formulaciones PCL:SP 250:50 y 300:0 aportaron concentraciones inferiores de carvedilol comprendidas en el rango de los 0-100 ng/mL durante el transcurso del tratamiento. Los animales espontáneamente hipertensos tratados con PCL:SP 50:250 y 150:150 experimentaron un descenso significativo de la presión arterial sistólica (PCL:SP 50:250: DPAS: -36,6 ± 2,0 mmHg; PCL:SP150:150: 35,7 ± 2,2 mmHg; p <0,05 vs. basal). Conclusiones: La incorporación del polímero hidrofílico SoluPlus en los implantes PCL:SP 150:150 y 50:250 favorece un incremento de la liberación de carvedilol, ya que aporta concentraciones plasmáticas del β-bloqueante que aseguran una reducción sostenida de la PAS indirecta en animales espontáneamente hipertensos.

ABSTRACT Objective: The aim of this study was the development and pharmacokinetic/pharmacodynamic evaluation of the in vivo release of subcutaneous implants of carvedilol capable of providing stable tissue levels in experimental models of hypertension. Methods: The subcutaneous implants were prepared with poly (epsilon-caprolactone) (PCL) and different proportions of the SoluPlus (SP) hydrophilic polymer (300:0; 250:50; 150:150 and 50:250 mg) loaded with 100 mg carvedilol. The plasma profile and the effect on systolic blood pressure (SBP) after subcutaneous implantation of each formulation was evaluated in male spontaneously hypertensive rats (SHR). Results: The PCL:SP 50:250 and 150:150 formulations provided levels ranging from 100 to 200 ng/mL and the PCL:SP 250:50 and 300:0 formulations provided lower concentrations of carvedilol ranging from 0 to 100 ng/mL during the treatment period. Spontaneously hypertensive animals treated with the PCL:SP 50:250 y 150:150 implants presented a significant decrease in SBP (PCL:SP 50:250: DPAS: -36.6 ± 2.0 mm Hg; PCL:SP150:150: -35.7 ± 2.2 mmHg; p <0.05 vs. baseline values) Conclusions: The incorporation of the SoluPlus hydrophilic polymer in PC:SP 150:150 and 50:250 implants increases the release of carvedilol, since it provides plasma concentrations ranging from 100 to 200 ng/ml, resulting in a sustained reduction of indirect SBP in SHR.

Personalizing dosing of risperidone, paliperidone and clozapine using therapeutic drug monitoring and pharmacogenetics.

By combining knowledge of pharmacogenetics, therapeutic drug monitoring (TDM) and drug-drug interactions (DDIs) the author developed a model for personalizing antipsychotic dosing, which is applied to risperidone, 9-hydroxyrisperidone or paliperidone, and clozapine. Drugs are approved using an average dose for an ideal average patient, but pharmacologists have described outliers: genetic poor metabolizers (PMs) and ultrarapid metabolizers (UMs). Environmental and personal variables can also make patients behave as PMs or UMs. Drug clearance is represented by the concentration-to-dose (C/D) ratio under steady-state and trough conditions. A very low C/D ratio indicates a UM, while a very high C/D ratio indicates a PM. Total risperidone C/D ratio for the oral formulation is around 7 ng/ml per mg/day and can be influenced by CYP2D6 polymorphism, DDIs with inducers and inhibitors, and renal function. Oral paliperidone has low availability; its C/D ratio is around 4.1 ng/ml per mg/d and can be influenced by inducers and renal impairment. Once-a-month long-acting paliperidone provides a C/D ratio around 7.7 ng/ml per mg/day at steady state, which is expected to be in the 8th month (before the 9th injection). TDM is particularly important for long-acting paliperidone formulations that may accumulate once steady state is reached (after years for the 3- and 6-month formulations). In the US, clozapine C/D ratios typically range from 0.6 (male smokers) to 1.2 (female non-smokers) ng/ml per mg/day. East Asians' clozapine C/D ratios appear to be twice as high. Inhibitors (including fluvoxamine and oral contraceptives) and inflammation can also increase clozapine C/D ratios. This article is part of the issue entitled 'Special Issue on Antipsychotics'.

Prevalence of Dyskinesia and OFF by 30-Minute Intervals Through the Day and Assessment of Daily Episodes of Dyskinesia and OFF: Novel Analyses of Diary Data from Gocovri Pivotal Trials.

BACKGROUND: Parkinson's disease (PD) patients using levodopa commonly develop dyskinesia and OFF episodes that reduce quality of life. OBJECTIVE: Evaluate prevalence of troublesome dyskinesia and OFF through the day, assessed by 30-minute intervals, as well as the mean number and duration of troublesome dyskinesia and OFF episodes, transitions between PD states, and effects of Gocovri® (amantadine) extended release capsules on these episodes. METHODS: Evaluate diary data from pooled Gocovri phase 3, placebo-controlled trials-analyzed for 17 hours following wake-up-at baseline and week 12. RESULTS: Diaries were evaluable for 162 patients. At baseline, 67% of patients woke up OFF, with prevalence decreasing to 13% at 2 hours and then remaining relatively steady at ∼12% (range, 6-17%) across half-hour intervals thereafter. Troublesome dyskinesia prevalence rose steadily from 5% to 24% over the first 2 hours, then fluctuated between 20% and 44% through the rest of the waking day. At baseline, patients experienced a mean of 3.0 daily episodes of troublesome dyskinesia (average duration 2.0 hours each), and 2.2 daily episodes of OFF (average duration 1.1 hour each). At week 12, Gocovri-treated patients showed greater reductions than placebo in troublesome dyskinesia and OFF episodes per day (treatment difference: -1.0 episodes and -0.4 episodes, respectively) and average episode duration (treatment difference: -0.6 hours and -0.3 hours, respectively). Mean duration of individual episodes of ON without troublesome dyskinesia (Good ON) increased by 5.0 hours for Gocovri, compared with 2.0 hours for placebo. Patients taking Gocovri experienced 2.2 fewer transitions between states than patients taking placebo. CONCLUSIONS: Troublesome dyskinesia and OFF occurred in the morning and throughout the waking day. Gocovri-treated patients experienced fewer, shorter episodes of both troublesome dyskinesia and OFF, thereby increasing the duration of continuous Good ON episodes and reducing the frequency of transitions between motor states.

Comparison between different isoelectric points of biodegradable gelatin sponges incorporating ß-tricalcium phosphate and recombinant human fibroblast growth factor-2 for ridge augmentation: A preclinical study of saddle-type defects in dogs.

BACKGROUND AND OBJECTIVE: It is well known that recombinant human fibroblast growth factor-2 (rhFGF-2) signaling plays an important role in tissue repair and regeneration. rhFGF-2 strongly binds to acidic gelatin via ionic linkages and is gradually released upon gelatin decomposition. On the other hand, the linkage between rhFGF-2 and basic gelatin is so weak that most rhFGF-2 is rapidly released from basic gelatin by simple desorption. Gelatin/ß-tricalcium phosphate (ß-TCP) sponges, which comprise 50 wt% gelatin and 50 wt% ß-TCP in a cross-linked structure, can release rhFGF-2 gradually owing to their electrical features. In a previous study, we reported that new bone height in the test group using rhFGF-2 with acidic gelatin/ß-TCP sponges was significantly greater than that in the control group using acidic gelatin/ß-TCP sponges alone in a ridge augmentation model in dogs. However, whether these results depend on controlled release by the gelatin/ß-TCP sponges remains controversial. In this study, we evaluated the effects of controlled release by comparing acidic and basic gelatin/ß-TCP sponges with different isoelectric points (IEP) on ridge augmentation in dogs. MATERIALS AND METHODS: Twelve weeks after extraction of the maxillary second and third incisors of six dogs, critically sized saddle-type defects (8 mm length × 4 mm depth) were surgically created bilaterally 2 mm from the mesial side of the canine. Acidic gelatin/ß-TCP sponges (IEP 5.0) soaked with 0.3% rhFGF-2 were applied to the defect in the acidic group, whereas basic gelatin/ß-TCP sponges (IEP 9.0) soaked with 0.3% rhFGF-2 were applied to the defect in the basic group. Twelve weeks after surgery, biopsy specimens were obtained and subjected to microcomputed tomography (micro-CT) and histological analyses. RESULTS: New bone area detected by micro-CT analysis was significantly smaller in the basic group than in the acidic group. New bone height calculated by histologic sections was significantly lower in the basic group than in the acidic group. The total tissue height was lower in the basic group than in the acidic group. However, the differences between both sites were not significant. CONCLUSIONS: These findings suggest that in ridge augmentation of saddle-type defects, controlled release of rhFGF-2 induces notably more alveolar bone formation than does short-term application of rhFGF-2.

Pharmacokinetics and bioequivalence of gliclazide modified release tablets in Beagle dogs / 第二军医大学学报

Objective: To explore the pharmacokinetics of self-made gliclazide modified release tablets in Beagle dogs and to evaluate the in vivo and in vitro correlation. Methods: Six Beagle dogs were orally given self-made gliclazide modified release tablets or reference preparation (DaMeiKang) at a dose of 30 mg with self-control cross-over method. Blood samples were collected at different time points after administration. The gliclazide concentration in plasma was determined by high-performance liquid chromatography, and the pharmacokinetic parameters were calculated. The pharmacokinetic characteristics and relative bioavailability of self-made gliclazide modified release tablets were investigated, the bioequivalence was evaluated, and the in vivo and in vitro correlation was calculated. Results: Area under curve (AUC0-∞) of DaMeiKang was (101.74 ± 20.29) μg/(mL · h), and AUC0-∞ of self-made gliclazide modified release tablets was (95.40 ± 28.68) μg/(mL · h). There were no significant differences in the pharmacokinetic parameters between the test and reference formulations (P>0.05). The relative bioavailability of self-made gliclazide modified release tablets was 93.77%, which was bioequivalent with the reference preparation. The in vitro and in vivo correlation analysis showed that the correlation coefficients of DaMeiKang and self-made gliclazide modified release tablets were 0.912 and 0.894, respectively, which were higher than the critical value (r005.7=0.754). The in vitro release rates of the two preparations were correlated with the in vivo absorption rates. Conclusion: The self-made gliclazide modified release tablets have sustained-release characteristics and bioequivalence with reference preparation. The in vivo absorption behavior of gliclazide modified release tablets can be predicted by the in vitro release assay established in this study.

A systematic review and combined analysis of therapeutic drug monitoring studies for long-acting paliperidone.

INTRODUCTION: This is a combined analysis of therapeutic drug monitoring (TDM) studies of long-acting injectable paliperidone formulations: monthly (PP1M) and three-month (PP3M) injections. Areas covered: Fourteen PP1M articles and one PP3M article were identified. Using the paliperidone concentration/dose (C/D) ratio as a measure of clearance provided a weighted mean of 7.7 ng/ml per mg/day among 69 patients from three steady-state PP1M studies (twice as high as oral paliperidone). C/D ratios were: 1) higher by a factor of 1.26 in 12 geriatric patients, 2) lower in obese patients, and 3) 50% lower in three patients taking carbamazepine. No clinically meaningful PP3M pharmacokinetic data have been published. Expert commentary: Half-life studies and more TDM PP1M studies using steady state are urgently needed. Early TDM studies may help orient PP1M dosing but steady state may not be reached until after the ninth injection (8 months). PP3M may take > 1 year to reach steady state. Any clinician considering switching patients to PP1M: 1) should switch from oral risperidone to PP1M rather than from oral paliperidone to PP1M, and 2) become proficient in paliperidone TDM to use during switches. TDM is highly recommended for patients with abnormal clearance (from obesity, geriatric age, or potent inducers).

A Historical Report on Preparing Sustained Release Dosage Forms for Addicts in Medieval Persia, 16th Century AD.

For several centuries, opium addiction has been a social problem all over the world. It has been prevalent in Iran from the Safavid era (1501-1736 A.D). During this period, Hakim Imad al-Din Mahmud ibn-Mas'ud Shirazi (1515-1592 A.D), also known as Imad was one of the Persian physicians who wrote one of the earliest books in the field of opium and addiction (called Afiounieh) in history. In this book, he introduced two sustained release rectal (suppository) and oral (pill) dosage forms for Muslim addicts who fast in the month of Ramadan. He aimed to formulate them for these people so that they could keep fasting by using the slow release drugs. In these formulations, his innovation has important impacts in the history of both addiction and pharmaceutical sciences.

Fabrication and biological effect investigation of the antibacterial drug delivery system with PEG-hydrogel and gentamicin-loaded-CSt on titanium surface / 中华骨科杂志

Objective To fabricate an antibacterial controlled drug delivery system with PEG-hydrogel and gentamicin-loaded-CSt on titanium surface,and to investigate its surface characteristics,swelling behavior,drug release behavior in vitro,antiinfection performance in vivo,and tissue biocompatibility.Methods Cross-linked starch (CSt) was synthesized first and then CSt was loaded with gentamicin (GEN) as a carrier (GEN@CSt),then 4-arm-polyethylene glycol (PEG) was added to it which was mixed by ultrasound.The surface of titanium (Ti) was covered with a layer of poly dopamine (PDA).The drug-loaded hydrogel was fixed to the titanium surface,subsequently capped by poly lactic-co-glycolic acid (PLGA) membranes,and then the Ti-PDA-PEG (GEN@CSt)-PLGA composite coating was fabricated finally.Surface morphology of the system was observed,while the swelling behavior was characterized;release behavior of the composite coating was detected;the bacteriostatic experiments were carried out with staphylococcus aureus (SAU),staphylococcus epidermidis (SEP) and escherichia coli (ECO) in vitro.The animal models of infected bone defect was established in 36 New Zealand white rabbits.These animals were randomly divided into three groups.Group 1 animals were implanted with drug-loaded composite coatings.Group 2 animals were implanted with drug-free composite coatings.Group 3 animals were implanted with bare titanium rods.The infection data were collected periodically to carry out antiinfection experiments in vivo.Another 12 rabbits were divided into the experimental group and the control group randomly.Biocompatibility of the materials was observed by histopathology after implantation of the corresponding materials into the femoral condyle.Results The composite coating adhered to the titanium surface firmly,presenting a smooth and translucent shape.The ratio of CSt/PEG affects swelling behavior varied,starch-free gels maintained an equilibrium swelling of 7.4,after the ratio reached 1 ∶ 1,the equilibrium swelling ratio remained at 3.0.In-vitro the release rate of the first 8 h was fast,and the cumulative release amount accounted for 83％ of the total in the first 7 days,lasting more than 13 d.In vitro antibacterial test,the average diameter of the inhibition ring was 3.6±0.13 cm (SAU),3.4±0.11 cm (SEP),3.7±0.10 cm (ECO).In-vivo anti-infection experiment,the infection situation of the group 1 was better than the control groups 2 and 3.The pathological results indicated that inflammatory reaction in the experimental group was basically the same as the control group.Conclusion The study successfully fabricated the antibacterial controlled drug delivery system with PEG-hydrogel and gentamicin-loaded-CSt on titanium surface.The system has a reasonable drug release behavior,and effectively inhibited the growth of bacteria in vivo and in vitro.It also has good biocompatibility to stand a promising strategy to improve the orthopedics anti-infection.