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“Breakthrough” of psychosis despite good compliance of antipsychotics medication for a long time is a major obstacle to the treatment of schizophrenia, whether the mechanism is caused by dopamine hypersensitivity or insufficient dose of antipsychotics. Researchers advocating “Dopamine Supersensitivity Psychosis” (DSP) emphasize to avoid excessive inhibition of dopamine 2 receptors from the beginning of treatment. On the other hand, researchers advocating “Breakthrough psychosis on Antipsychotic Maintenance Medication” (BAMM) in which psychosis recurs due to insufficient medication despite continuous administration of antipsychotics without non-adherence argue that dose of antipsychotics should be increased to enhance therapeutic effect. In patients using long-acting antipsychotics injection (LAI), non-compliance can be ruled out. We believe that in treating non-affective psychosis, it is necessary to continuously maintain the lowest dose possible using the optimal dose considering the side effects of second-generation antipsychotics and the cycle and stage of psychosis, and the optimal formulation such as LAI.

Objectives: This study examined a case of an 80-year-old woman with extensive ascites and hypervolemic hyponatremia due to decompensated liver cirrhosis.Methods: The patient was first treated with a diuretic to treat her ascites. However, during hospitalization, she developed hypervolemic hyponatremia due to liver cirrhosis. Therefore, we discontinued the diuretic and treated her with Korean herbal medicine (Insamyangyoung-tang with Oryeong-san). We measured her abdominal circumference, followed by radiography, to evaluate the effect of Korean herbal medicine.Result: We treated the patient only with Korean medicine and without diuretics, and her ascites was successfully reduced. No recurrence was observed.Conclusion: Korean herbal medicine can be used as an adjuvant therapy for patients with ascites and hyponatremia.

Objective: In this case report, we address the case of a 22-year-old man complaining of generalized tonic-clonic seizures due to drug-resistant epilepsy.Methods: A patient was treated with Korean medicine, including herbal medication, Shihogyeji-tang (SGT), and acupuncture. We evaluated improvements in symptoms using the Korean version of the Epilepsy Self-Efficacy Scale and quality of life.Results: After 37 days of Korean medicine treatment, there were improvements in the patient’s quality of life and self-efficacy in seizure control.Conclusions: This case report suggests that SGT and acupuncture might be effective in drug-resistant epilepsy via action on neurons. SGT showed excellent tolerability for drug-resistant epilepsy patients. Our experience provides evidence that SGT and acupunctue may be used as alternative treatment options when antiepileptic drugs do not work in epilepsy patients.

The present work explores the pharmaceutical application of a novel seeded granulation to develop properties-improved, high drug-loaded, and sustained-release tablets using hydroxypropylcellulose (HPC) as a binder. Itraconazole, 4-acetamidophenol, and rifaximin were selected as model drugs. They differ significantly with respect to particle size distribution and solubility. As granulated, the correlation among drug properties, binder characteristics, granulation parameters, and product attributes was discussed. Granulation was performed with 11% HPC-L at a constant impeller tip speed of 4.39 m/s and above. The liquid bridge interaction occurred when coarse particles were granulated along with fine particles. The detachment-reattachment process was responsible for the formation of core-shell seeded granules. Such granules showed good mechanical properties, strength, flowability, compactability, sustained release, high drug-loading, and uniformity. In comparison to conventional granulation, this method is cost-effective, gives better compactability, yields a reduced tablet size at a high dose, and facilitates manufacturability using standard batch granulation.

The global COVID-19 pandemic has disrupted every aspect of the healthcare system. Apart from the issues surrounding COVID-19 itself, care for existing patients has met many challenges. One such challenge is caring for patients who are on clozapine treatment and have been confirmed positive for COVID-19. Schizophrenia has been considered to have a deep connection with the immune system, and clozapine can induce further changes in this system. COVID-19 can ravage the compromised immune system and aggravate tissue damage. The intricate relations between schizophrenia, clozapine, and COVID-19 make it difficult to predict the clinical course of COVID-19 in clozapine-treated patients. However, the rigid prohibition on using clozapine if COVID-19 is confirmed may harm patients. Patients who have to use clozapine are often refractory cases with no alternatives. Therefore, the decision to maintain or stop clozapine must be made after a comprehensive review of the patient's unique situation. To do this, theoretical and practical issues surrounding the use of clozapine in COVID-19 should be reviewed and discussed. In this review, we gather useful information surrounding this issue and present an overview. Focusing on the immune system, various theoretical possibilities that could arise from schizophrenia, clozapine, and COVID-19 were carefully examined, and practical checklists for the care of these patients were explored. It is hoped that this review will convince many clinicians to pay attention to this momentous issue and facilitate more active sharing of clinical experiences.

A protein precipitation technique was optimized to produce biophysically stable ‘protein microbeads’, applicable to highly concentrated protein formulation. Initially, production of BSA microbeads was performed using rapid dehydration by vortexing in organic solvents followed by cold ethanol treatment and a vacuum drying. Out of four solvents, n-octanol produced the most reversible microbeads upon reconstitution. A Shirasu porous glass (SPG) membrane emulsification technique was utilized to enhance the size distribution and manufacturing process of the protein microbeads with a marketized human IgG solution. Process variants such as dehydration time, temperature, excipients, drying conditions, and initial protein concentration were evaluated in terms of the quality of IgG microbeads and their reversibility. The hydrophobized SPG membrane produced a narrow size distribution of the microbeads, which were further enhanced by shorter dehydration time, low temperature, minimized the residual solvents, lower initial protein concentration, and addition of trehalose to the IgG solution. Final reversibility of the IgG microbeads with trehalose was over 99% at both low and high protein concentrations. Moreover, the formulation was highly stable under repeated mechanical shocks and at an elevated temperature compared to its liquid state. Its in vivo pharmacokinetic profiles in rats were consistent before and after the ‘microbeadification’.

Methiozolin is a novel herbicide used to control annual bluegrass. It has low vapor pressure and high hydrophobicity, which could result in persistence in water and bioaccumulation. We measured the bioconcentration factors (BCFs) of methiozolin in ricefish (Oryzias latipes). Two radiolabels were used to quantify the parent compound and identify its metabolites. Ricefish were exposed to 2.0 and 20.0 ng/L methiozolin for 28 days in the uptake phase with a 96-h LC50 of 2.2 mg/L(95% confidence limit: 2.1-2.5 mg/L) and water solubility of 4.2 mg/L after 48 h was observed. On the basis of total radioactivity residues (TRRs), BCFss and BCFk values of 797.0-851.9 and 992.9-1077.4 were observed, respectively, while BCFss values for methiozolin were 251.9-257.5. Several minor metabolites with TRR < 3.4% were detected. Among them, 4-(2,6-difluorobenzyloxy-methyl)-3-hydroxy-3-methyl-1-(3-methylthiophen-2-yl)butan-1-one, 2,6-difluorobenzyl alcohol, and 4,5-dihydro-5-methyl-3-(3-methylthiophen-2-yl)isoxazol-5-yl)methanol were identified. Methiozolin is metabolized into numerous minor metabolites with potentially low bioaccumulation capacity in ricefish. These findings can facilitate risk assessments regarding methiozolin use, particularly its movements and final stages in aquatic environments.

This study aimed to develop a solid dispersion (SD) of MT-102, a new anti-inflammatory agent, to improve its oral bioavailability. The ternary SD formulations of MT-102 (a poorly soluble extract of Isatis indigotica and Juglans mandshurica) were prepared using a solvent evaporation method with various drug/excipient ratios. Following that, the effectiveness of various SDs as an oral formulation of MT-102 was investigated using indirubin as a marker component. By forming SDs with hydrophilic polymers, the aqueous solubility of indirubin was significantly increased. SD-F4, containing drug, poloxamer 407 (P407), and povidone K30 (PVP K30) at a 1:2:2 weight ratio, exhibited the optimal dissolution profiles in the acidic to neutral pH range. Compared to pure MT-102 and a physical mixture, SD-F4 increased indirubin’s dissolution from MT-102 by approximately 9.86-fold and 2.21-fold, respectively. Additionally, SD-F4 caused the sticky extract to solidify, resulting in improved flowability and handling. As a result, compared to pure MT-102, the oral administration of SD-F4 significantly improved the systemic exposure of MT-102 in rats. Overall, the ternary SD formulation of MT-102 with a blended mixture of P407 and PVP K30 appeared to be effective at improving the dissolution and oral absorption of MT-102.

Even though arginine hydrochloride has been recognized as a protein aggregation suppressor in the biopharmaceutical industry, its use has been questioned due to decreasing transition unfolding temperatures (Tm). Four compounds were designed to enhance the role of arginine by changing the length of the carbon chain with removal or N-acetylation of α-amino group. Biophysical properties were observed by differential scanning calorimetry (DSC), dynamic light scattering (DLS), size-exclusion chromatography (SEC), and flow imaging (FI). N-Acetyl-L-arginine (NALA) performed the best at minimizing decrease in Tm with arginine at different pH. NALA also demonstrated relatively higher colloidal stability than arginine hydrochloride, especially in the acidic pH, thereby reducing agitation stress of IgG. Moreover, NALA exhibited a cooperative effect with commercially used glycine buffer for IVIG to maintain the monomer contents with almost no change and suppressed larger particle formation after agitation with heat. The study concludes that the decreasing Tm of proteins by arginine hydrochloride is due to amide group in the α-carbon chain. Moreover, chemical modification on the group compared to removing it will be a breakthrough of arginine's limitations and optimize storage stability of protein therapeutics.

Even though butein can be a promising candidate for anti-inflammatory and anti-diabetic activities, it is poorly soluble limiting its availability for product development. Size reduction and solid dispersion (SD) were adopted independently to evaluate their feasibility for enhancement in solubility as well as bioavailability. To reduce the particle size, milling method was carried out under dry and wet conditions. For solid dispersion preparation, simple solvent evaporation method was used with hydrophilic excipients including PVP K-30 and Poloxamer 407. Physicochemical properties such as crystallinity, size, and kinetic solubility of prepared formulations were assessed using dynamic light scattering, X-ray powder diffraction, differential scanning calorimetry, and solubility. In vivo pharmacokinetic study was also conducted with selected samples. Butein is weakly basic with its pKa 6.76 and log P 3.81 based on the Henderson-Hasselbalch equation. High temperature and basic pH were degradative stresses as significant color change in solution. Milling decreased the size distribution down to 4.2 μm without dramatic change in the solubility. However, the solubility of solid dispersion increased from 3.15 up to 114.57 μg/mL, suggesting amorphous state increased solubility significantly. Its amorphous state was confirmed by DSC and PXRD. In addition, oral absorption of SD in vivo confirmed its enhanced pharmacokinetic parameters; faster Tmax, higher Cmax and AUC. Solid dispersion exhibited enhancement in pharmacokinetic parameters compared to size reduction, suggesting its feasibility for solid dispersion formulation.

Seeded granulation is one of the recently adopted wet granulation techniques. The seeded granules consist of high-density core nuclei and low-density particles layered on the outside. It depends on various process and formulation factors. The mechanism of granule formation will be clarified and the methods to predict the suitable conditions for the optimum granules. Moreover, measurement tools and models need to be explored to understand the granulation process. Computational modeling will be introduced such as discrete element method (DEM) to evaluate granules, and computational fluid dynamics (CFD) to study binder fluid interactions. Both can be coupled and CFD-DEM-PBM framework can relate the effects of particle–fluid interactions. The state-of-the-art simulation methods may bridge the gap between micro and meso scales of seeded granulation process. Measurement techniques are also discussed to obtain reliable experimental data and this review assesses the prospective of on-line soft sensing measurement and application to continuous granulation.

Previously, N-acetyl-l-arginine (NALA) suppressed the aggregation of intravenous immunoglobulins (IVIG) more effectively and with a minimum decrease in transition temperature (T

Objective The nature of physical comorbidities in patients with mental illness may differ according to diagnosis and personal characteristics. We investigated this complexity by conventional logistic regression and network analysis.Methods A health insurance claims data in Korea was analyzed. For every combination of psychiatric and physical diagnoses, odds ratios were calculated adjusting age and sex. From the patient-diagnosis data, a network of diagnoses was constructed using Jaccard coefficient as the index of comorbidity.Results In 1,017,024 individuals, 77,447 (7.6%) were diagnosed with mental illnesses. The number of physical diagnoses among them was 11.2, which was 1.6 times higher than non-psychiatric groups. The most noticeable associations were 1) neurotic illnesses with gastrointestinal/pain disorders and 2) dementia with fracture, Parkinson’s disease, and cerebrovascular accidents. Unexpectedly, the diagnosis of metabolic syndrome was only scarcely found in patients with severe mental illnesses (SMIs). However, implicit associations between metabolic syndrome and SMIs were suggested in comorbidity networks.Conclusion Physical comorbidities in patients with mental illnesses were more extensive than those with other disease categories. However, the result raised questions as to whether the medical resources were being diverted to less serious conditions than more urgent conditions in patients with SMIs.

The solubility of glibenclamide was evaluated in DMSO, NMP, 1,4-dioxane, PEG 400, Transcutol® HP, water, and aqueous mixtures (T = 293.15~323.15 K). It was then recrystallized to solvate and compressed into tablets, of which 30-day stability and dissolution was studied. It had a higher solubility in 1,4-dioxane, DMSO, NMP (Xexp = 2.30 × 103, 3.08 × 104, 2.90 × 104) at 323.15 K, its mixture (Xexp = 1.93 × 103, 1.89 × 104, 1.58 × 104) at 298.15 K, and 1,4-dioxane (w) + water (1−w) mixture ratio of w = 0.8 (Xexp = 3.74 × 103) at 323.15 K. Modified Apelblat (RMSD ≤ 0.519) and CNIBS/R-K model (RMSD ≤ 0.358) suggested good comparability with the experimental solubility. The minimum value of ΔG° vs ΔH° at 0.70 < x2 < 0.80 suggested higher solubility at that molar concentration. Based on the solubility, it was recrystallized into the solvate, which was granulated and compressed into tablets. Among the studied solvates, the tablets of glibenclamide dioxane solvate had a higher initial (95.51%) and 30-day (93.74%) dissolution compared to glibenclamide reference (28.93%). There was no stability issue even after granulation, drying, or at pH 7.4. Thus, glibenclamide dioxane solvate could be an alternative form to improve the molecule’s properties.

Biophysical characterization of type A botulinum neurotoxin (BoNT/A) complex along with its thermodynamic stability was assessed through a combination of various methods. BoNT/A exists as large complexes in association with neurotoxin associated proteins (NAPs). To evaluate its biophysical behavior, size-exclusion chromatography (SEC), multi-angled light scattering (MALS), enzyme linked immunosorbent assay (ELISA), and dynamic light scattering (DLS) were utilized. Initially, a single peak (peak 1) of SEC was observed at pH 6.0, and an additional peak (peak 2) appeared at pH 7.4 with a decrement of peak 1. Through MALS and ELISA, the peak 2 was determined to be BoNT/A dissociated from its complex. The dissociation was accelerated by time and temperature. At 37°C, dissociated BoNT/A self-associated at pH 7.4 in the presence of polysorbate 20. On the other hand, the dissociation was partly reversible when titrated back to pH 6.0. Overall, BoNT/A was more stable when associated with NAPs at pH 6.0 compared to its dissociated state at pH 7.4. The conventional analytical methods could be utilized to relatively quantify its amount in different formulations.

One of the primary challenges in developing highly concentrated protein formulations is ensuring adequate stability of the protein product. Among the many available methods, cold solvent precipitation is useful, and it has been adopted for protein purification. This study aimed to characterize protein stability under various precipitation conditions and to determine the most stable precipitation conditions. Lysozyme was used as a model protein to investigate the effects of various solvents and temperature conditions on the physicochemical properties. Size exclusion chromatography, dynamic light scattering, circular dichroism, and thermodynamic analysis are the primary tools for the protein characterization. Changes in the rehydrated particle size, secondary structure, thermodynamic stability, and in vitro activity of lysozyme were observed under various conditions. By analyzing the effect of temperature on protein characteristics, it has been discovered that protein precipitation at a temperature of 4 °C or below is optimal. During the precipitation at – 20 °C, the secondary structures of proteins are adversely affected by the formation of ice crystals. None of the solvents used as precipitants in this study affected the activity of the protein. However, changes in the secondary structure were minimal when ethanol and octanol were used. In this study, the feasibility of various precipitation conditions was evaluated for stable reversible precipitation formation. Although further studies are needed, precipitation of proteins using various organic solvents could be used in the development of formulations that purify and concentrate proteins.

Objective The present study aimed to report the initial seizure threshold (IST) of a brief-pulse bilateral electroconvulsive therapy (BP-BL ECT) in Korean patients with schizophrenia/schizoaffective disorder and to identify IST predictors. Methods Among 67 patients who received ECT and diagnosed with schizophrenia/schizoaffective disorder based on the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, we included 56 patients who received 1-millisecond BP-BL ECT after anesthesia with sodium thiopental between March 2012 and June 2018. Demographic and clinical information was gathered from electronic medical records, and a multiple regression analysis was conducted to identify predictors of the IST. Results The mean age of the patients was 36.9±12.0 years and 30 (53.6%) patients were male. The mean and median IST were 105.9±54.5 and 96 millicoulombs (mC), respectively. The IST was predicted by age, gender, and dose (mg/kg) of sodium thiopental. Other physical and clinical variables were not associated with the IST. Conclusion The present study demonstrated that the IST of 1-ms BP-BL ECT following sodium thiopental anesthesia in Korean patients was comparable to those reported in previous literature. The IST was associated with age, gender, and dose of sodium thiopental.