Background: Fingolimod is approved in relapsing-remitting multiple sclerosis (RRMS) with the recommended dose of 0.5 mg daily. To tackle possible adverse events, some clinicians may reduce the dose of fingolimod, mainly in the alternate-day form. We systematically reviewed the literature for efficacy measures of this method. Methods: PubMed (Medline®), Web of Science, Embase, Scopus, and the Cochrane Library databases were searched until April 9, 2021. Clinical studies (other than case reports and case series), in English, were included. Then, publications concerning alternate dose fingolimod (including every other day, every two or three days) were selected. Those studies concerning reduced daily dose (any daily dose less than 0.5 mg/day) were excluded to focus on alternate dosing. Results: Four observational studies were included. Data on Ohtani et al. study were limited. Three other studies were of good quality based on the Newcastle-Ottawa Scale. A total of 296 patients on the standard dose were compared to 276 patients on the alternate dosage. The most common reason for switching to the alternate dose was lymphopenia, followed by elevated liver enzymes. Two studies concluded that the alternate dosing could be a safe, yet effective strategy in patients with intolerable adverse effects of daily dose. However, Zecca et al. warned about the high possibility of disease reactivation. Due to the differences in outcome measures of the studies, meta-analysis was not applicable. Conclusion: This systematic review highlights the ambiguity of evidence on safety and efficacy of alternate dosing of fingolimod, encouraging further research on the subject.

Clozapine is the most effective drug for treatment-resistant schizophrenia, and the dosage and concentration of clozapine in the treatment of mental illness vary greatly in different populations and are affected by many factors.
The serum clozapine concentration of 3734 psychiatric patients was detected, and data on daily dose, sex, age and other medical records were collected for statistical analysis.
The mean daily dose, mean serum concentration and mean C/D (concentration/dose) ratio of clozapine were 191.02 ± 113.47 mg/day, 326.15 ± 235.66 ng/mL and 1.94 ± 1.25 ng/mL per mg/day, respectively. There was difference in daily dose between sexes, and females had higher daily dose (p <0.01), higher serum clozapine concentrations (p < 0.01) and higher C/D ratios (p < 0.01). There were significant differences in daily dose (p < 0.001), serum drug concentration (p < 0.001) and C/D ratio (p < 0.001) among different age groups. The daily dose decreased with age (p for trend < 0.001), and the C/D ratio increased with age (p for trend < 0.001). Inpatients and outpatients had no difference in daily dose, but inpatients had higher serum concentration (p < 0.001) and C/D ratio (p < 0.001). There was no difference in daily dose among different occupations, but there were significant differences in serum concentration (p < 0.001) and C/D ratio (p < 0.001), and unemployed patients may have higher serum concentration and C/D ratio. Duration of disease, comorbidity, marital status, and psychotic type may influence the daily dose and serum concentration.
The effective daily dose and serum concentration of clozapine in the study area may be lower than recommended levels, and women have higher serum concentrations and slower metabolic rates. With increasing age, the daily dose decreases, and the metabolic rate slows. Inpatient status and occupation of patients may influence the serum concentration and metabolic rate of clozapine.

UNASSIGNED: Worldwide, the leading cause of invasive candidiasis and the fourth leading cause of hospital-acquired infections are the Candida species (spp.) group. One of the most important tools in fighting such drug-resistant fungi is the appropriate use of antifungal agents.
UNASSIGNED: The study aimed to determine echinocandins\' general prescribing patterns and how they are associated with the treatment period.
UNASSIGNED: A quantitative, observational, and descriptive was used, and included patients receiving antifungal treatment in a private hospital in Gauteng, South Africa between 01 January 2015 to 31 December 2015.
UNASSIGNED: Of the 146 patient files included, 102 patients (69.9%) received caspofungin and 44 patients (30.1%) were treated with anidulafungin. For the former, 99 (97.1%) patients received a loading dose (LD) of 70 mg, while 200 mg anidulafungin was only prescribed to 30 patients (68.2%). In line with maintenance dose guidelines, the majority (98.1%) of caspofungin-treated patients received 50 mg IV daily, whereas 4 (3.9%) patients were treated at higher doses (70 mg daily). Anidulafungin was administered at various maintenance doses, including 400 mg (2.3% of patients), 200 mg (52.3%), 100 mg (43.2%) and 50 mg (2.3%) IV daily.
UNASSIGNED: Our results can be utilised to produce a hospital-specific algorithm in terms of Candida-infected patients.
UNASSIGNED: These findings contribute to our understanding of prescribing patterns of antifungal agents and the impact thereof on treating Candida spp. Infections.

Tacrolimus is a major immunosuppressor against post-transplant rejection in kidney transplant recipients. However, the narrow therapeutic index of tacrolimus and considerable variability among individuals are challenges for therapeutic outcomes. The aim of this study was to compare different machine learning and deep learning algorithms and establish individualized dose prediction models by using the best performing algorithm. Therefore, among the 10 commonly used algorithms we compared, the TabNet algorithm outperformed other algorithms with the highest R2 (0.824), the lowest prediction error [mean absolute error (MAE) 0.468, mean square error (MSE) 0.558, and root mean square error (RMSE) 0.745], and good performance of overestimated (5.29%) or underestimated dose percentage (8.52%). In the final prediction model, the last tacrolimus daily dose, the last tacrolimus therapeutic drug monitoring value, time after transplantation, hematocrit, serum creatinine, aspartate aminotransferase, weight, CYP3A5, body mass index, and uric acid were the most influential variables on tacrolimus daily dose. Our study provides a reference for the application of deep learning technique in tacrolimus dose estimation, and the TabNet model with desirable predictive performance is expected to be expanded and applied in future clinical practice.

In this work, antimicrobial usage data from 2,546 commercial broiler chicken flocks originating from 37 farms are presented. Antimicrobial usage data at the flock level were based on mandatory documentation of antibiotic treatments in livestock in Germany, collected retrospectively for the time period of 2013-2018. The data encompasses all antimicrobial treatments during the fattening period of each flock, starting with the placement of day-old chicks at the barn. The aim of this analysis was to investigate antibiotic usage patterns in broiler chicken flocks in Germany, temporal trends in treatment frequency, the proportions of different antimicrobial classes and the weights of the broiler chickens at the time of treatment. The median treatment frequency over all flocks was six, and veterinary medicinal products belonging to nine different antimicrobial classes were used. Overall, the most frequently used classes were aminoglycosides (25.6%) and lincosamides (25.6%), followed by polypeptides (21.4%) and beta-lactams (16.2%). Over the 6 years evaluated, a considerable increase in the relative usage of lincosamides and aminoglycosides was observed. Compared to the first year of data collection, the percentage of treatments with fluoroquinolones, macrolides and polypeptides decreased in consecutive years. The median age of the broiler chickens at the time of treatment was 5 days, which corresponded to a median body weight at the time of treatment of 111 g, with substantial differences among various antimicrobial classes. We showed that in Germany, the median weight of broiler chickens at the time of treatment was substantially lower than the standard weight of broilers of 1,000 g proposed by the European Surveillance of Veterinary Antimicrobial Consumption. The median weight at treatment is very much influenced by the frequency of age-specific diseases. As different antimicrobial classes are used to combat these diseases, variations in the weight at treatment may have a considerable impact on the estimated treatment indicators. Additionally, a decrease in the relative usage of the highest-priority critically important antimicrobials, such as fluoroquinolones, macrolides and polypeptides, was shown, which might be the consequence of increasing awareness of the antibiotic resistance situation as well as of antibiotic monitoring and benchmarking systems currently running in Germany.

The study aims were to investigate adherence to methadone maintenance treatment (MMT) and to identify associated clinical factors in patients who inject drugs diagnosed with human immunodeficiency virus (HIV) infection in Taiwan.
Data were from the National Health Surveillance System on HIV and the National Drug Treatment System on MMT. HIV-positive people who inject drugs (HIVPWID) were defined as the study population. Information obtained included age, sex, education, marital status, employment, methadone dose, and date of diagnosis of HIV infection. Adherence was defined as taking methadone for the past 90, 180 and 365 days, then categorized as high (> 90%), moderate (51 to 90%), or low (<=50%) adherent respectively.
Of 1641 HIVPWID registered in the datasets from 2007 to 2012, 961 (58.56%) had received MMT. For HIVPWID evaluated at 90 days (n = 951), 271 (28.5%), 382 (40.2%), and 298 (31.3%) were classified as high, moderate, and low adherent respectively. For HIVPWID evaluated at 180 days (n = 936), 190 (20.3%), 349 (37.3%), and 397 (42.4%) were classified as high, moderate, and low adherent respectively. For HIVPWID evaluated at 365 days (n = 919), 133 (14.5%), 271 (29.5%), and 515 (56.0%) were classified as high, moderate, and low adherent respectively. After controlling for sociodemographics, results showed that methadone dose, location of MMT clinic, and date of HIV diagnosis were significantly associated with MMT adherence.
Study findings underscore the importance to MMT adherence of methadone dosage, early diagnosis of patient\'s HIV infection, and area of patient residence.

BACKGROUND: Systemic lupus erythematosus (SLE) is a multisystem disease with very diverse developments. Corticosteroid is mostly used for the treatment of SLE as antiinflammatory and immunosuppressant, but its long-term use and high dose can cause the side effects such as Cushing habitus.
OBJECTIVE: Analyze the risk factors of Cushing habitus occurrence in patients with SLE comprising pulse dose, duration of therapy, daily dose, and total dose of methylprednisolone.
METHODS: Case Control study.
METHODS: 40 patients with SLE treated at Rheumatology outpatient clinic at Hasan Sadikin Hospital in Bandung was conducted. Each of these patients were divided into case and control groups. The design of this study was a case control study, the data was retrieved from medical record of patients with and without cushing habitus.
METHODS: Chi-squared test was used to test the relationship between independent variables followed by linear logistic regression analysis to determine the influence of the most influential variable in causing Cushing habitus.
RESULTS: The results of this study showed that the use of total dose of methylprednisolon (> 8040 mg) has a significant effect on the incidence of Cushing habitus p = 0.029; odds ratio [OR] = 3.55). In addition, daily dose of methylprednisolone >9.4 mg has a significant effect on Cushing habitus (p = 0.012; OR = 2.98).
CONCLUSIONS: Significant relationship between daily dose and total dose of methylprednisolone on the occurrence of Cushing.

Micafungin (MCFG) is an echinocandin antifungal drug used for prophylaxis and treatment of fungal infections after allogeneic hematopoietic cell transplantation (HCT). However, its efficacy and safety in patients undergoing cord blood transplantation (CBT) has not been clarified. We retrospectively analyzed the efficacy and safety of MCFG in 92 adult patients undergoing CBT in our institute. Of the entire cohort, 83 patients (90%) received MCFG for empirical or preemptive therapy. Documented breakthrough fungal infection occurred in 2 patients during MCFG treatment. Among the 49 patients who received MCFG as empirical therapy for febrile neutropenia, 41 (84%) patients had resolution of fever during neutropenia. Elevation of serum levels of hepatobiliary parameters during MCFG treatment was commonly observed, but grade 3 or higher elevation was rare. We also compared the efficacy and safety of 2 different initial daily doses of MCFG (150 mg vs. 300 mg). There were no significant differences of efficacy and safety between the two groups. These data suggest that MCFG was effective and safe for adult patients undergoing CBT. The optimal daily dose of MCFG treatment is a matter of future investigation for adult patients undergoing CBT.

Drug-induced liver injury (DILI) is a major safety concern; it occurs frequently; it is idiosyncratic; it cannot be adequately predicted; and a multitude of underlying mechanisms has been postulated. A number of experimental approaches to predict human DILI have been proposed utilizing in vitro screening such as inhibition of mitochondrial function, hepatobiliary transporter inhibition, reactive metabolite formation with and without covalent binding, and cellular health, but they have achieved only minimal success. Several studies have shown total administered dose alone or in combination with drug lipophilicity to be correlated with a higher risk of DILI. However, it would be best to have a predictive DILI methodology early in drug development, long before the clinical dose is known. Here we discuss the extent to which Biopharmaceutics Drug Disposition Classification System (BDDCS) defining characteristics, independent of knowing actual drug pharmacokinetics/pharmacodynamics and dose, can be used to evaluate prior published predictive proposals. Our results show that BDDCS Class 2 drugs exhibit the highest DILI severity, and that all of the short-lived published methodologies evaluated here, except when daily dose is known, do not yield markedly better predictions than BDDCS. The assertion that extensively metabolized compounds are at higher risk of developing DILI is confirmed, but can be enhanced by differentiating BDDCS Class 2 from Class 1 drugs.
CONCLUSIONS: Our published analyses suggest that comparison of proposed DILI prediction methodologies with BDDCS classification is a useful tool to evaluate the potential reliability of newly proposed algorithms, although BDDCS classification itself is not sufficiently predictive. Almost all of the predictive DILI metrics do no better than just avoiding BDDCS Class 2 drugs, although some early data with microliver platforms enabling long-enduring metabolic competency show promising results.

UNASSIGNED: Although the worldwide prevalence of attention-deficit/hyperactivity disorder (ADHD) in adults is estimated to be between 2% and 5%, it is considered to be underdiagnosed. This register study explored the prevalence of diagnosed ADHD and incidence of newly diagnosed ADHD in Swedish adults over time, and assessed comorbidities and pharmacologic treatment.
UNASSIGNED: National Patient Register data were used to estimate the overall prevalence of adults (≥18 years) with a registered ADHD diagnosis from 2006 to 2011, and the incidence of newly registered diagnoses from 2007 to 2011. Data from the Prescribed Drug Register were used to estimate the mean dose of the most frequently prescribed ADHD medication.
UNASSIGNED: The estimated annual prevalence (N=44,364) of diagnosed ADHD increased from 0.58 per 1,000 persons in 2006 to 3.54 per 1,000 persons in 2011. The estimated annual incidence of newly diagnosed ADHD (N=24,921) increased from 0.39 per 1,000 persons to 0.90 per 1,000 persons between 2007 and 2011. At least one comorbidity was diagnosed in 52.6% of adults with ADHD (54.0% of newly diagnosed adults), with anxiety, substance use disorders, and depression being the most common. Among all adults with ADHD, 78.9% (65.7% of newly diagnosed adults) were prescribed ADHD medication and one-third were prescribed more than one add-on medication. Osmotic release oral system methylphenidate was the most commonly used medication. The mean daily dose was 51.5 mg, and was significantly higher in males, patients with substance use disorders, patients with drug holidays, and patients with at least one add-on medication. The most frequent concomitant medications were anxiolytics and hypnotics.
UNASSIGNED: In Sweden, the number of adults diagnosed with ADHD increased between 2006 and 2011, and the majority of patients were prescribed ADHD-specific medication. Over one-half of patients had psychiatric comorbidities; one-third were prescribed more than one add-on medication. Consumption of pharmacologic ADHD medication was high in specific patient subpopulations.