Exploring the relationship between bulk Young's Modulus of materials and milling efficiency during wet bead milling of pharmaceutical compounds.

Wet bead milling (WBM) is one of the main approaches for manufacturing long acting injectable (LAI) suspensions, wherein the particle size of an Active Pharmaceutical Ingredient (API) is reduced in a liquid vehicle via grinding. A common challenge observed during WBM is long milling time to achieve target particle size, resulting in poor milling efficiency. The objective of this work was to identify potential API attributes predictive of milling efficiency during WBM. In this study, physical and mechanical properties of nine APIs were characterized. Formulations with these APIs were manufactured using WBM. Bulk Young's Modulus was identified to have a significant influence on the rate of particle attrition. The rank order of Young's Moduli of the APIs was consistent with that of milling efficiency, estimated by an empirical function defined in this study called Milling Resistance (ϕ), representing the holistic impact of milling time, tip speed, bead loading, and batch to chamber volume ratio. The identification of such intrinsic material properties, which provide an early evaluation of potential manufacturing risks, is beneficial to product development, as these assessments can be performed with limited quantities of materials and help identify and design out scale-up challenges.

Current status of pathogen handling in European laboratories: focus on viral inactivation process.

For handling safely infectious agents, European laboratories must comply with specific EC Directives, national regulations and recommendations from the World Health Organization (WHO). To prevent laboratory acquired infections (LAIs) and pathogens dissemination, a key biosafety rule requires that any infectious material (clinical specimens or research samples) manipulated outside a biosafety cabinet (BSC) must be inactivated unless the lack of infectivity is proven. This inactivation process is a crucial step for biosafety and must be guided by a rigorous experimental qualification and validation procedure. However, for diagnostic or research laboratories, this process is not harmonized with common standard operation procedures (SOPs) but based on individual risk assessment and general international guidelines which can pose problems in emergency situations such as major outbreaks or pandemics. This review focuses on viral inactivation method, outlining the current regulatory framework, its limitations and a number of ways in which biosafety can be improved.

Real-world effectiveness of antidepressants, antipsychotics and their combinations in the maintenance treatment of psychotic depression. Evidence from within-subject analyses of two nationwide cohorts.

Psychotic depression (PD) is a severe mental disorder leading to functional disability and high risk of suicide, but very little is known about the comparative effectiveness of medications used in its maintenance treatment. The objective of this study was to investigate the comparative effectiveness of specific antipsychotics and antidepressants, and their combinations, on the risk of psychiatric hospitalization among persons with PD in routine care. Persons aged 16-65 years with a first-time diagnosis of PD were identified from Finnish (years 2000-2018) and Swedish (years 2006-2021) nationwide registers of inpatient care, specialized outpatient care, sickness absence, and disability pension. The main exposures were specific antipsychotics and antidepressants, and the main outcome measure was psychiatric hospitalization as a marker of severe relapse. The risk of hospitalization associated with periods of use vs. non-use of medications (expressed as adjusted hazard ratio, aHR) was assessed by a within-individual design, using each individual as his/her own control, and analyzed with stratified Cox models. The two national cohorts were first analyzed separately, and then combined using a fixed-effect meta-analysis. The Finnish cohort included 19,330 persons (mean age: 39.8±14.7 years; 57.9% women) and the Swedish cohort 13,684 persons (mean age: 41.3±14.0 years; 53.5% women). Individual antidepressants associated with a decreased risk of relapse vs. non-use of antidepressants were bupropion (aHR=0.73, 95% CI: 0.63-0.85), vortioxetine (aHR=0.78, 95% CI: 0.63-0.96) and venlafaxine (aHR=0.92, 95% CI: 0.86-0.98). Any long-acting injectable antipsychotic (LAI) (aHR=0.60, 95% CI: 0.45-0.80) and clozapine (aHR=0.72, 95% CI: 0.57-0.91) were associated with a decreased risk of relapse vs. non-use of antipsychotics. Among monotherapies, only vortioxetine (aHR=0.67, 95% CI: 0.47-0.95) and bupropion (aHR=0.71, 95% CI: 0.56-0.89) were associated with a significantly decreased risk of relapse vs. non-use of both antidepressants and antipsychotics. In an exploratory analysis of antidepressant-antipsychotic combinations, a decreased relapse risk was found for amitriptyline-olanzapine (aHR=0.45, 95% CI: 0.28-0.71), sertraline-quetiapine (aHR=0.79, 95% CI: 0.67-0.93) and venlafaxine-quetiapine (aHR=0.82, 95% CI: 0.73-0.91) vs. non-use of antidepressants and antipsychotics. Benzodiazepines and related drugs (aHR=1.29, 95% CI: 1.24-1.34) and mirtazapine (aHR=1.17, 95% CI: 1.07-1.29) were associated with an increased risk of relapse. These data indicate that, in the maintenance treatment of PD, bupropion, vortioxetine, venlafaxine, any LAI, clozapine, and only few specific antidepressant-antipsychotic combinations are associated with a decreased risk of relapse. These findings challenge the current recommendation by treatment guidelines to combine an antipsychotic with an antidepressant (without further specification) as standard treatment in PD.

Impact of long-acting injectable antipsychotics vs. oral medication on relapses of patients with psychosis and bipolar disorder.

Relapse associated with multiple hospital readmissions of patients with chronic and severe mental disorders, such as psychosis and bipolar disorder, is frequently associated with non-adherence to treatment. The primary aim of the study was to compare the effectiveness of long-acting injectable (LAI) treatment, vs. oral medication in reducing readmissions of patients with psychotic or bipolar disorder in a community sample of 164 patients with psychosis and 29 patients with bipolar disorder (n = 193), with poor adherence to oral medication. The mean follow up period was 5.6 years and the number of readmissions were compared for an equal-length period of oral treatment preceding the onset of LAI administration. We observed a significant decrease of 45.2 % in total hospital readmissions after receiving LAIs treatment. The effect was significant both for patients with a pre-LAI treatment history of predominantly voluntary hospitalizations and with predominantly involuntary admissions. In addition, we observed equal effectiveness of first- vs. second-generation LAIs in reducing total hospital readmissions regardless of type of pre-treatment admission history (voluntary vs. involuntary). LAIs appear to be effective in reducing both voluntary and involuntary hospital readmissions in patients with psychosis and bipolar disorder with a history of poor adherence to treatment.

Long-Acting Injectable Antipsychotics-A Review on Formulation and In Vitro Dissolution.

Long-acting injectable (LAI) neuroleptics constitute an effective therapeutical alternative for individuals suffering from persistent mental illness. These injectable pharmaceuticals help patients manage their condition better and improve long-term outcomes by preventing relapses and improving compliance. This review aims to analyse the current formulation aspects of LAI neuroleptics, with particular emphasis on analysis of drug release profiles as a critical test to guarantee drug quality and relevant therapeutical activity. While there is no officially approved procedure for depot parenteral drug formulations, various dissolution tests which were developed by LAI manufacturers are described. In vitro dissolution tests also possess a critical function in the estimation of the in vivo performance of a drug formulation. For that reason, thorough inspection of the in vitro-in vivo correlation (IVIVC) is also discussed.

Attitude and influencing factors of patients with schizophrenia toward long-acting injections: A community-based cross-sectional investigation in China.

Background: Low prescription rates of antipsychotic long-acting injections (LAIs) may be a major challenge in the prevention and treatment of schizophrenia. However, there are few studies on the usage and attitude toward LAIs among community-based patients with schizophrenia. Methods: A large community-based cross-sectional investigation was conducted among 6,336 patients with schizophrenia from Shanghai, China from March 1 to June 30, 2021. The structured Attitude and Status toward Treatment of Community Patients with Schizophrenia Questionnaire (AST-CSQ) was used to investigate the attitude and influencing factors of community-dwelling patients with schizophrenia toward LAIs. Results: Among the 6,336 participants, the average age was 49.28 ± 11.23. The rate of agreement to LAI antipsychotics among participants was 3.16% (n = 200). The family financial resources, care ability, and disease course of the LAIs group were less than those of the non-LAIs group. However, the LAIs group had higher immediate family guardianship, social activity, previous hospitalization, number of hospitalization, outpatient adherence, previous antipsychotic use, antipsychotic adherence, and attitude toward oral antipsychotics than the non-LAIs group, with significant differences between the two groups (p < 0.05). Furthermore, age (ß = -0.036, OR 0.964, 95% CI 0.947-0.982), marital status (ß = 0.237, OR 1.267, 95% CI 1.002-1.602), care ability (ß = 0.709, OR 2.032, 95% CI 1.437-2.875), outpatient adherence (ß = -0.674, OR 0.510, 95% CI 0.358-0.725), antipsychotic adherence (ß = 0.920, OR 2.509, 95% CI 1.092-5.764), and attitude toward oral antipsychotics (ß = -1.357, OR 0.258, 95% CI 0.103-0.646) were significant predictors of attitude toward LAI antipsychotics (p < 0.05). Conclusions: The community-dwelling patients with schizophrenia in China had a low willingness to use LAIs. Patients of a younger age, more hospitalizations, and a shorter course of disease were prone to be more willing to accept LAIs. The patients' age, marital status, care ability, outpatient adherence, antipsychotic adherence, and attitude toward oral antipsychotics were important predictor of patients' attitudes toward LAIs. Under the global deinstitutionalized management model of mental disorders, these results highlight an urgent problems for public mental health service providers and policy-makers and provide more solutions for them.

Can the use of long-acting injectable antipsychotic preparations be increased in routine clinical practice and the benefits realised?

BACKGROUND: The use of continuing antipsychotic medication is an established evidence-based strategy for preventing relapse in people with schizophrenia, but medication adherence is known to be suboptimal. Covert non-adherence can be eliminated by the use of long-acting injectable (LAI) formulations. We sought to (1) raise awareness among clinicians of the potential benefits of LAI antipsychotic formulations, (2) increase use of these formulations for the treatment of schizophrenia in routine clinical practice and thereby (3) reduce the number of relapses requiring hospitalisation in patients with schizophrenia under our care. METHOD: Educational initiatives, promotion of reflective practice and patient-specific reminders were used to prompt increased use of LAI antipsychotic medication for patients with schizophrenia. Data relating to the use of these medications and the number of acute admissions for schizophrenia spectrum disorders (F20-29, ICD-10) over time were extracted from existing clinical information systems. RESULTS: Over the 3-year time frame of our local initiative, the use of LAI antipsychotic preparations increased by 11%, the number of acute admissions for schizophrenia/schizoaffective disorder (F20 and F25) decreased by 26% and the number of acute bed days occupied by patients with these diagnoses decreased by 8%. The number of admissions for other psychosis diagnoses (F21-24 and F28-29) did not show the same pattern of improvement. CONCLUSION: In our health care organisation, raising clinicians' awareness of the evidence base relating to the potentially favourable benefit-risk balance for LAI antipsychotic medication compared with oral formulations resulted in more use of the former. There were accompanying reductions in acute admissions and occupied bed days for patients with schizophrenia.

Rehospitalization Rates Among Patients with Psychotic Disorders During Covid-19 Pandemic: Oral Versus Long-Acting Injectable Antipsychotics.

Objective: The superiority of long-acting injectable antipsychotics (LAIs) versus oral antipsychotics is often emphasized, even in terms of adherence and rehospitaliza-tion rates. As such, LAIs are particularly recommended during the COVID-19 pandemic. The goal of our research was to determine whether there are differences in the number of rehospitalizations in patients treated for schizophrenia, schizophrenia-like disorders, and delusional states (psychotic disorders) with LAI antispychotics versus oral antispychotics. Method: Subjects with schizophrenia, schizophrenia-like disorders and delusional states participated in our retrospective study. 124 subjects were treated with oral anti-psychotics, while 72 received LAIs along with oral antipsychotics. We collected their sociodemographic data and psychiatric history data. Our main outcome measure was the number of rehospitalizations. Results: Statistical analysis showed that the studied groups did not differ according to sociodemographic parameters, except that in the group of patients with LAIs there was a significantly higher percentage of men (65 (52.4) vs 50 (69.4), p=0.029)). Also, the groups do not differ according to the psychiatric history data. There is no difference in the duration of the current hospitalization nor in the composition of the patients, considering the order of the current hospitalization. The difference in the number of rehospitalizations is not significant neither in the first year of follow-up (p=0.144), nor in the second (p=0.142), nor after two years of follow-up (p=0.083). Conclusions: Our research has shown that there is no difference in the number of rehospitalizations in patients with schizophrenia, schizophrenia-like disorders and delusional states, considering whether they take oral antipsychotics or they also take LAIs along with them. We can therefore conclude that it is particularly important to work on improving patient adherence. We must make psychiatrists aware that the pandemic, like other threats, can be our ally in improving adherence ("perceived threat as a health belief").

The Steady-State Comparative Bioavailability of Intramuscular Risperidone ISM and Oral Risperidone: An Open-Label, One-Sequence Study.

INTRODUCTION: This open-label, one-sequence study evaluated the steady-state comparative bioavailability of risperidone in situ microimplants (ISM®) and oral risperidone in patients stabilized on oral risperidone treatment. METHODS: Repeat oral administration of once daily 4 mg risperidone for 7 days was followed by 4 monthly (once every four weeks) intramuscular (IM) doses of risperidone ISM 100 mg. Mean steady-state concentration versus time profiles for risperidone, 9-OH risperidone, and risperidone active moiety was characterized. RESULTS: A total of 104 subjects were enrolled, 81 were included in the safety population and 58 completed the study. Intersubject variability for the steady-state concentrations versus time profiles for risperidone active moiety presented a greater variability range for oral risperidone versus risperidone ISM (% coefficient of variation [CV] range: 40-65% and 38-52%, respectively). Minimum plasma concentration at steady-state (Cmin, ss) and fluctuation in plasma concentrations (Fluc) of risperidone active moiety after risperidone ISM administration met bioequivalence criteria compared to the reference oral risperidone (geometric mean ratio [GMR] = 1.09 and 0.96, respectively; both 90% CIs were within 0.80-1.25). Area under the curve during the dosing interval (AUCtau), maximum plasma concentration at steady-state (Cmax, ss) and average plasma concentration (Cave) were only slightly higher (GMR [90% CI] = 1.25 [1.16-1.34], 1.17 [1.08-1.27], and 1.25 [1.16-1.34], respectively). Overall, once daily oral risperidone 4 mg and once monthly IM risperidone ISM 100 mg were generally safe and well tolerated in the participating subjects with schizophrenia previously stabilized with oral risperidone. CONCLUSION: The rapid release of risperidone ISM allows the achievement of the desired levels similar to those observed at the steady-state after oral risperidone treatment. Therefore, direct switch after 24 hours from the last oral risperidone dose to risperidone ISM treatment can be done in schizophrenia patients with no time lag, maintaining steady-state levels of the active moiety throughout treatment and without the need for oral risperidone supplementation or loading doses.

Comparison of Sublingual Immunotherapy in Patients With Allergic Rhinitis Sensitive to House Dust Mites in Korea.

The aim of this study was to investigate the clinical outcomes of sublingual immunotherapy (SLIT) using 2 kinds of SLIT medications (LAIS and Staloral) in patients with allergic rhinitis for Dermatophagoides pteronyssinus and Dermatophagoides farinae. We have evaluated the patient's characteristics, safety, and compliance in 293 patients and also analyzed the symptom score, medication score, satisfaction rate, and immunologic measurement in 84 patients who have continued the treatment over 1 year. The symptom scores were significantly improved in both treatment groups, 51% versus 44% (LAIS vs Starloral) at 1 year (P < .05). The medication score was also significantly decreased in both treatment groups (P < .05), 50.8% versus 60%. The subjective improvement score was 44.4% versus 46.1%, and satisfaction rate was 29% versus 40% (P < .05). The serum immunoglobulin G4 (IgG4) level was significantly increased in Staloral group (P < .05). The adverse events were 6.2% versus 33.3% and the compliance was 37.7% versus 25.1%. In conclusion, the improvements in symptom score and medication scores were not significant different between 2 SLIT medications at 1 year. LAIS was more compliant, less side effects and Staloral has shown increased satisfaction rate and IgG4 level.

[Some current trends in the use of prolonged injectable antipsychotics in the conditions of modernization of the psychiatric service]. / Nekotorye sovremennye tendentsii primeneniya prolongirovannykh in"ektsionnykh antipsikhotikov v usloviyakh modernizatsii psikhiatricheskoi sluzhby.

OBJECTIVE: A pharmacoeconomical analysis of the use of prolonged injectable antipsychotics in the treatment of patients with schizophrenia in Moscow over 2015-2019 in the context of the reform of the psychiatric service. MATERIAL AND METHODS: The authors studied the economic costs of treatment of psychiatric patients with prolonged injectable antipsychotics on the pharmaceutical market in Moscow for five years on the example of patients diagnosed with paranoid schizophrenia (ICD-10 F20.0) based on the dynamics of the registered contingent of patients with schizophrenic spectrum disorders over the past fifteen years including the period of active modernization of the psychiatric service. RESULTS AND CONCLUSION: A constant increase in public spending on treatment, including therapy with prolonged injectable neuroleptics (both first-generation drugs and atypical antipsychotics), was shown. At the same time, the increase in the use of atypical antipsychotics is ahead of schedule. The number of patients receiving treatment with prolonged injectable haloperidol and zupentixol increased approximately twice during this period, the number of patients receiving treatment with injectable risperidone and paliperidone palmitate increased by more than 3 and 13 times, respectively. There is a significant increase in public spending on the purchase and use of these drugs for the treatment of privileged categories of patients, most of this applies to injectable forms of paliperidone, the cost of using these drugs has increased more than 20 times over a five-year period. These trends indicate a shift in emphasis towards outpatient psychiatric care and improvement of approaches to treatment of patients with schizophrenia, which indicate a new stage in the development of out-of-hospital treatment and rehabilitation systems based on the latest achievements of psychopharmacology and the development of social support systems for patients with schizophrenia spectrum disorders.

Savings on High-Cost Drugs Such as Atypical Long-Acting Injectable Antipsychotics: Switching to Billing Under the Pharmacy Benefit in Outpatient Settings.

OBJECTIVE: Access to health care can be improved by controlling and optimizing expenditures, specifically the high-cost drugs such as atypical long-acting injectable (LAI) antipsychotics. This type of LAI is usually covered under the medical benefit and/or pharmacy benefit. We sought to compare financial outcomes of the medical benefit billing option with the pharmacy benefit billing option for atypical LAIs in an adult outpatient psychiatric clinic and to determine insurance companies' reasons for nonpayment when the medical benefit billing model was utilized. METHODS: A retrospective chart review with patients 18 years of age and older who were receiving atypical LAI antipsychotics in the outpatient psychiatric department during two time periods--January 7 through February 6, 2016 and August 15 through September 14, 2016--to evaluate medical (N = 31) and pharmacy (N = 23) benefit study periods, respectively. RESULTS: The estimated loss when using the medical benefit billing option was $14,520 per month. Switching to billing under the pharmacy benefit resulted in a monthly gain of $2,100. The net savings from the switch were estimated at $16,620 per month. No patient lost access to treatment or was switched to another medication solely because of the change in billing option. The reasons for nonpayment (N = 10) provided by medical insurance companies were prior authorization/step therapy required (40%), insurance terminated (30%), and coverage through Medicaid Rx only (30%). CONCLUSION: This study revealed a significant financial loss related to atypical LAI antipsychotics when the medical benefit model was utilized. By switching to billing under the pharmacy benefit, potential savings for high-cost drugs such as LAIs can be realized.

Maritime over the Horizon Sensor Integration: High Frequency Surface-Wave-Radar and Automatic Identification System Data Integration Algorithm.

To obtain the complete operational picture of the maritime situation in the Exclusive Economic Zone (EEZ) which lies over the horizon (OTH) requires the integration of data obtained from various sensors. These sensors include: high frequency surface-wave-radar (HFSWR), satellite automatic identification system (SAIS) and land automatic identification system (LAIS). The algorithm proposed in this paper utilizes radar tracks obtained from the network of HFSWRs, which are already processed by a multi-target tracking algorithm and associates SAIS and LAIS data to the corresponding radar tracks, thus forming an integrated data pair. During the integration process, all HFSWR targets in the vicinity of AIS data are evaluated and the one which has the highest matching factor is used for data association. On the other hand, if there is multiple AIS data in the vicinity of a single HFSWR track, the algorithm still makes only one data pair which consists of AIS and HFSWR data with the highest mutual matching factor. During the design and testing, special attention is given to the latency of AIS data, which could be very high in the EEZs of developing countries. The algorithm is designed, implemented and tested in a real working environment. The testing environment is located in the Gulf of Guinea and includes a network of HFSWRs consisting of two HFSWRs, several coastal sites with LAIS receivers and SAIS data provided by provider of SAIS data.

Discontinuing financial incentives for adherence to antipsychotic depot medication: long-term outcomes of a cluster randomised controlled trial.

OBJECTIVES: In a cluster randomised controlled trial, offering financial incentives improved adherence to antipsychotic depot medication over a 1-year period. Yet, it is unknown whether this positive effect is sustained once the incentives stop. METHODS AND ANALYSES: Patients in the intervention and control group were followed up for 2 years after the intervention. Primary and secondary outcomes were assessed at 6 months and 24 months post intervention. Assessments were conducted between September 2011 and November 2014. RESULTS: After the intervention period, intervention and control groups did not show any statistically significant differences in adherence, neither in the first 6 months (71% and 77%, respectively) nor in the following 18 months (68%, 74%). There were no statistically significant differences in secondary outcomes, that is, adherence ≥95% and untoward incidents either. CONCLUSIONS: It may be concluded that incentives to improve adherence to antipsychotic maintenance medication are effective only for as long as they are provided. Once they are stopped, adherence returns to approximately baseline level with no sustained benefit. TRIAL REGISTRATION NUMBER: ISRCTN77769281; Results.