Dose selection for investigations of intrinsic and extrinsic factors of pharmacokinetic variability as well as safety is a challenging question in the early clinical stage of drug development. The dose of an investigational product is chosen considering the compound information available to date, feasibility of the assessments, regulatory requirements, and the intent to maximize information for later regulatory submission. This review selected 37 programs as case examples of recently approved drugs to explore the doses selected with focus on studies of drug interaction, renal and hepatic impairment, food effect and concentration-QTc assessment.The review found that regulatory agencies may consider alternative approaches if justified and safe as illustrated in these examples. It is thus recommendable to use the first in human trial as an opportunity to assess QT-prolongation and drug interactions using probes or endogenous markers while maximizing the DDI potential, increasing sensitivity and ensuring safety. Early understanding of dose proportionality assists dose finding and simple and fast to conduct DDI study designs are advantageous. Single dose impairment studies despite non-proportional/time-dependent PK are often acceptability.Overall, the early understanding of the drug\'s safety profile is essential to ensure the safety of doses selected while preventing clinical trials with unnecessary exposure when using high doses or multiple doses. The information collected in this retrospective survey is a good reminder to tailor the early clinical program to the profile and needs of the molecule and consider regulatory opportunities to streamline the development path.

Resveratrol (3, 5, 4\'-trihydroxystilbene) is a polyphenolic derivative with herbal origin. It has attracted considerable attention in recent decades. Many studies have revealed the benefits of Resveratrol over several human disease models, including heart and neurological diseases, nephroprotective, immune regulation, antidiabetic, anti-obesity, age-related diseases, antiviral, and anticancer in experimental and clinical conditions. Recently, the antioxidant and anti-inflammatory activities of Resveratrol have been observed, and it has been shown that Resveratrol reduces inflammatory biomarkers, such as tissue degradation factor, cyclooxygenase 2, nitric oxide synthase, and interleukins. All of these activities appear to be dependent on its structural properties, such as the number and position of the hydroxyl group, which regulates oxidative stress, cell death, and inflammation. Resveratrol is well tolerated and safe even at higher pharmacological doses and desirably affects cardiovascular, neurological, and diabetic diseases. Consequently, it is plausible that Resveratrol can be regarded as a beneficial nutritional additive and a complementary drug, particularly for therapeutic applications. The present review provides an overview of currently available investigations on preventive and therapeutic characteristics and the main molecular mechanisms of Resveratrol and its potent derivatives in various diseases. Thus, this review would enhance knowledge and information about Resveratrol and encourage researchers worldwide to consider it as a pharmaceutical drug to struggle with future health crises against different human disorders.

To investigate the therapeutic dose and long-term efficacy of high-intensity focused ultrasound (HIFU) ablation for different types of uterine fibroids based on signal intensity on T2-weighted MR images (T2WI).
Four hundred and one patients with a solitary uterine fibroid treated with HIFU were classified into four groups consisting of extremely hypointense, hypointense, isointense and hyperintense fibroids. Each group was further classified into two subtypes: homogeneous and heterogeneous, based on signal homogeneity of fibroids. The therapeutic dose and long-term follow-up results were compared.
There were significant differences in treatment time, sonication time, treatment intensity, total treatment dosage, treatment efficiency, energy-efficiency factor (EEF) and non-perfused volume (NPV) ratio among the four groups (p<.05). The average NPV ratio achieved in patients with extremely hypointense, hypointense, isointense and hyperintense fibroids was 75.2 ± 14.6%, 71.1 ± 15.6%, 68.2 ± 17.3% and 67.8 ± 16.6%, respectively; the re-intervention rates at 36 months after HIFU were 8.4%, 10.3%, 12.5% and 6.1%, respectively. Sonication time, treatment intensity and total energy for heterogeneous fibroids were greater than that for homogeneous fibroids in patients with extremely hypointense fibroids (p<.05). The treatment time for heterogeneous fibroids was significantly longer than that for homogeneous fibroids in patients with isointense fibroids (p<.05). Multivariate ordered logistic regression analysis showed that the ablation volume of fibroids and treatment time were related to NPV ratio (p<.05).
Every group of patients obtained satisfactory long-term results. Hyperintense fibroids are difficult to treat by HIFU. Heterogeneous fibroids are more difficult to treat with HIFU than homogeneity fibroids.

UNASSIGNED: Clozapine has well-documented inter-ethnic variations in pharmacokinetics. There is a paucity of data about clozapine use and associated adverse events such as seizures, obsessive compulsive symptoms, neutropenia, and agranulocytosis, from India.
UNASSIGNED: This retrospective cohort study followed up 228 patients initiated on clozapine in a tertiary care referral center in India for an average of 10 years. We calculated incidence rates of new-onset seizures, new-onset obsessive compulsive symptoms, agranulocytosis, and neutropenia. We collected data on doses of clozapine used and serum assays and calculated concentration-to-dose (C/D) ratios. We also collected relevant clinical details about clozapine-induced seizures.
UNASSIGNED: In the sample, 16.8% had new-onset seizures, 12.3% had new-onset OC symptoms, 2.7% had neutropenia, and 0.9% had agranulocytosis. The mean C/D ratio was 2.09 (SD = 1.8). Almost half (46.3%) of available serum assays were in the supra-therapeutic range. Seizures were associated with a higher clozapine dose at one year (OR = 1.003; 95%CI = 1.000-1.006; P value = 0.045) and the presence of positive psychotic symptoms at one year (OR = 4.214; 95%CI = 1.894-9.373; P < 0.001).
UNASSIGNED: Compared to existing literature, Indians have a higher rate of clozapine- related seizures and need lower doses to reach therapeutic serum levels.

Several studies have suggested genetic variants associated with acetaminophen induced liver injury (DILI) following overdose. Genetic variation associated with acetaminophen-induced alanine aminotransferase elevation during therapeutic dosing has not been examined.
We performed genetic analyses on patients that ingested therapeutic doses of 4 grams of acetaminophen for up to 16 days. We examined 20 genes previously implicated in the metabolism of acetaminophen or the development of immune-mediated DILI using the Illumina Multi-Ethnic Global Array 2. Autosomes were aligned and imputed using TOPMed. A candidate gene region analysis was performed by testing each gene individually using linkage disequilibrium (LD) pruned variants with the adaptive sum of powered scores (aSPU) test from the aSPU R package. The highest measured ALT during therapy, the maximum ALT, was used as the outcome.
192 subjects taking therapeutic APAP were included in the genetic analysis. 136 (70.8%) were female, 133 (69.2%) were Caucasian race, and the median age was 34 years (IQR: 26, 46). Age > 50 years was the only clinical factor associated with maximum ALT increase. Variants in SULT1E1, the gene responsible for Sulfotransferase Family 1E Member 1 enzyme production, were associated with maximum ALT. No single variant drove this association, but rather the association was due to the additive effects of numerous variants within the gene. No other genes were associated with maximum ALT increase in this cohort.
Acetaminophen induced ALT elevation at therapeutic doses was not associated with variation in most genes associated with acetaminophen metabolism or immune-induced DILI in this cohort. The role of SULT1E1 polymorphism in acetaminophen-induced elevated ALT needs further examination.

UNASSIGNED: Adropin is a hormone encoded by the Enho gene, which is associated with energy homeostasis. Preclinical studies using animal models have shown that adropin plays a role in enhancing glucose homeostasis and dyslipidemia. Lately, several studies on animal models have been performed to examine the therapeutic and pathophysiological effects of adropin in many disorders. The aim of this systematic review was to identify the ideal adropin dose in mice and rat animal models.
UNASSIGNED: We systematically searched PubMed, Science Direct, and Scopus databases from 2008 to 2020. The terms used in the search were \"adropin,\" \"adropin doses in animal models,\" \"glucose homeostasis related to adropin,\" and \"adropin therapeutic effects on rats and mice.\" Articles that included non-adropin doses, in vitro studies, and factors affecting adropin levels were excluded from the study.
UNASSIGNED: Of the total 179 qualified studies, six studies were included. We found that a daily injection of 450 nmol/kg of adropin for 3 days might be considered the optimum dose of effect in mice, whereas injection of 2.1 mg/kg once a day for 10 successive days might be the optimal effective dose in rats.
UNASSIGNED: Additional investigations are needed to determine the optimum dose of adropin to be used as a therapeutic intervention depending on the animal model.

An 86-year-old female was found unconscious the day after taking a prescribed tablet containing a combination of tramadol and acetaminophen. At admission to the hospital, marked hypoglycemia (blood glucose: 4 mg/dL) was confirmed, but serum insulin and C-peptide were within the normal range, which suggested that neither endogenous hyperinsulinemia nor exogenous insulin administration was responsible for the hypoglycemia. Despite resuscitation efforts, the woman subsequently died. At autopsy, there was renal disorder, but any pathological abnormalities that could have caused hypoglycemia were not observed. Blood tramadol and acetaminophen were in the therapeutic range. We speculate that the cause of fatal hypoglycemia was tramadol intake at the therapeutic dose. Older age and renal insufficiency are factors that could have potentially caused the fatal hypoglycemia in this case despite tramadol having been taken at a therapeutic dose. This is the first case report of fatal hypoglycemia following ingestion of a therapeutic dose of tramadol.

In real-world pragmatic administrative databases, patient reported remission is often missing.
We evaluate if, in administrative data, five features of antidepressant use patterns can replace patient-reported symptom remission.
We re-examined data from Sequence Treatment Alternatives to Relieve Depression (STAR*D) study. Remission was measured using 50% reduction in Hamilton index. Pattern of antidepressant use was examined through five variables: (a) number of prior ineffective antidepressants, (b) duration of taking current antidepressant, (c) receiving therapeutic dose of the medication, and (d) switching to another medication, or (e) augmenting with another antidepressant. The likelihood ratio (LR) associated with each of these predictors was assessed in 90% of data (3329 cases) and evaluated in 10% of data (350 cases) set-aside for evaluation. The accuracy of predictions was calculated using Area under the Receiver Operating Curve (AROC).
Patients who took antidepressants for 14 weeks (LR = 2.007) were more likely to have symptom remission. Prior use of 3 antidepressants reduced the odds of remission (LR = 0.771). Patients who received antidepressants below therapeutic dose were 5 times less likely to experience remission (LR = 0.204). Antidepressant that were augment or switched, almost never led to remission (LR = 0.008, LR = 0.002 respectively). Patterns of antidepressant use accurately (AROC = 0.93) predicted symptom remission.
Within the first 100 days, antidepressants use patterns could serve as a surrogate measure for patient-reported remission of symptoms.

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UNASSIGNED: Irisin, a novel myocyte-secreted hormone, was proposed to mediate some of the beneficial effects of exercise such as browning of adipocytes, thermogenesis, and metabolic homeostasis. Recently, several animals\' models\' studies have been performed to investigate the therapeutic impact of irisin in several disorders. Several interventional trials used different doses. However, optimum dose was not determined. This systematic review aims to identify the optimal dose of interventional irisin in mice and rat animal models.
UNASSIGNED: Online databases PubMed, Google Scholar, and Springer were systematically searched from 2012 to 2019. The words searched were irisin, irisin and animal model, physical activity, and irisin and irisin dosage. Non-irisin doses, in vitro studies, and factors influencing irisin levels were excluded.
UNASSIGNED: Eleven of the total 391 qualifying studies were included. A daily injection of 500 μg/kg irisin may be the optimum dose of effect in mice and rats.
UNASSIGNED: More studies are required to determine the optimum dose of irisin to be used as a therapeutic intervention based on animal model.