Dose Of Drug Research Articles

Investigating the effect of LncRNA DLGAP1-AS2 suppression on chemosensitivity of gastric cancer to chemotherapy.

Gastric cancer, as the fifth most frequent disease and the fourth foremost cause of cancer-related death worldwide, remains a main clinical challenge due to its poor prognosis, limited treatment choices, and ability to metastasize. Combining siRNAs to suppress lncRNA with chemotherapeutic medications is a novel treatment approach that eventually increases the therapeutic efficacy of the drug while lessening its adverse effects. This study was performed with the purpose of examining the impact of inhibiting DLGAP1-AS2 expression on gastric cancer cells' drug chemosensitivity. AGS cells were cultured as the study cell line and were transfected with an optimum dose of DLGAP1-AS2 siRNA and then treated with oxaliplatin. Cell viability was examined using the MTT technique. Apoptosis and cell cycle were evaluated using Annexin V/PI staining and flow cytometry. Later, the scratch test was conducted to investigate the ability of cells to migrate, and the inhibition of the stemness of AGS cells was further investigated through the colony formation method. Finally, the qRT-PCR technique was used to assess the expression of Bax, Bcl-2, Caspase-3, p53, MMP-2, and CD44 genes. The MTT test indicated the effect of gene therapy with siRNA and oxaliplatin in combination reduced the chemotherapy drug dose to 29.92µM and increased AGS cells' sensitivity to oxaliplatin. Also, the combination therapy caused a significant increase in apoptosis. However, it reduced the stemness feature, the rate of cell viability, proliferation, and metastasis compared to the effect of each treatment alone; the results also showed the arrest of the cell cycle in the Sub G1 phase after the combined treatment and a further reduction in the number and size of the formed colonies. Suppressing the expression of lncRNA DLGAP1-AS2 by siRNA followed by treatment with oxaliplatin can be utilized as an effective and new therapeutic technique for gastric cancer therapy.

Olaparib maintenance therapy for platinum-sensitive relapsed ovarian cancer at a single institution: A retrospective study.

In this study, we aimed to investigate patient characteristics, efficacy, prognostic factors, and safety of olaparib maintenance therapy for platinum-sensitive recurrent ovarian cancer at our institution. Patients responding to platinum-based therapy and starting olaparib maintenance therapy for recurrent epithelial ovarian, fallopian tube, or peritoneal cancer at Kurume University Hospital between January 2018 and November 2021 were enrolled in the study. Their data were extracted retrospectively from medical records. In all, 50 patients were included. The median (range) age of the patients, follow-up time, and duration of olaparib maintenance therapy were 62 (39-87) years, 21.6 (2.2-45.9) months, and 7.2 (2-45.9) months, respectively. Among the 29 patients tested for homologous recombination (HR) status, 22 (75.9%) were positive for HR deficiency (HRD), 12 (54.5%) of whom had BRCA-positive tumors. The median progression-free survival was 8.9 months (95% confidence interval: 6.2-12.6), and the median overall survival was 27.1 months (95% confidence interval: 22.5-40.3). Multivariate analysis of prognostic factors revealed that HRD was an independent prognostic factor for both progression-free survival and overall survival. The most common adverse event was nausea (any grade, n = 30, 60%), resulting in drug interruption (n = 23, 46%), dose reduction (n = 17, 34%), and discontinuation of treatment (n = 1, 2%). Olaparib maintenance therapy for recurrent platinum-sensitive ovarian cancer at our institution was effective, with acceptable adverse events. HRD was the most significant prognostic factor for patients with recurrent platinum-sensitive ovarian cancer.

Research progress on the prevention and treatment of chemotherapy-induced ovarian damage.

Chemotherapy is a main treatment option for malignant tumors, but it may cause various adverse effects, including dysfunction of female endocrine and fertility. Chemotherapy-induced ovarian damage has been concerned, apart from ovarian preservation, the prevention and treatment of ovarian dysfunction are widely studied. In this article, the mechanisms of ovarian injury caused by chemotherapy, including the apoptosis of follicle and supporting cells, follicle "burn out", ovarian stromal and microvascular damage; and influencing factors, including age at diagnosis and initial low pre-treatment anti-Müllerian hormone levels, toxicity, dose and regimen of chemotherapy drugs are reviewed based on the latest research results and clinical practice. The article also discusses measures and frontier therapies for prevention and treatment of ovarian injury, including the application of gonadotropin releasing hormone agonists or antagonists, tyrosine kinase inhibitors, antioxidants, sphingosine-1-phosphate, ceramide-1-phosphate, mammalian target of rapamycin inhibitors, granulocyte-colony stimulating factor, stem cell therapy and artificial ovary, etc.

Quantitative analysis of therapeutic peptides by CZE using multiple sample injection in hydrodynamically closed separation system.

Therapeutic peptides have emerged as an innovative and promising class of therapeutic compounds in modern medicine. Synthetic peptide analogs triptorelin and lanreotide are known for their pronounced clinical versatility and potency. In this study, we present the development and validation of novel methods based on capillary zone electrophoresis performed in hydrodynamically closed system (HCS) and paired with ultraviolet detection and repeated injection sample introduction. To the best of our knowledge, we developed the first capillary electrophoresis-based method for the determination of lanreotide, and concurrently, the first HCS method for the determination of triptorelin. Maximal separation efficiency and signal intensity were achieved using background electrolytes composed of 50mM formic acid with the addition of 0.05% (v/v) methyl-hydroxyethyl cellulose. The proposed methods exhibit favorable performance characteristics, namely, calibration curve (r2 exceeding 0.99), low limits of detection (0.25µg/mL in a water matrix and 0.5µg/mL in synthetic urine), acceptable precision (relative standard deviation ranging from 2.2% to 9.6% for intraday repeatability and between 5.2% and 14.9% for interday reproducibility), and accuracy (relative errors falling within the 91.1%-107.8% range). The method for triptorelin determination was then used for its quantification in a commercially available drug dosage form (powder for injection) and in spiked synthetic urine samples. The developed methods were also evaluated according to the novel blue applicability grade index, revealing their superior applicability. The results collectively point out the potential of the proposed methods for both quality control and clinical investigations.

Niosomes as a Promising Therapeutic Approach against Colorectal Cancer: A Focus on the Delivery of Chemotherapeutics and Natural Products.

Nanotechnology has emerged as an effective approach to cancer treatment, including Colorectal Cancer (CRC). While conventional treatments, such as chemotherapeutic agents, are used to manage CRC, their efficacy can be improved using drug delivery systems that enhance their bioavailability and reduce side effects. Niosomes, polymeric nanoparticles, have shown promise as biocompatible vehicles that can transport hydrophilic and lipophilic molecules. This can result in reduced drug dosage and increased efficacy. This review examines the use of niosomal formulations as a delivery platform for treating CRC and provides practical insights into their clinical applications.

Relative bioavailability, immunogenicity, and safety of two adalimumab-adbm formulations in healthy volunteers: a double-blind, randomized, single-dose, parallel-arm phase I trial

ABSTRACT Objective This study compared the relative bioavailability of citrate-free high-concentration and reference formulations of the biosimilar adalimumab-adbm (Cyltezo®), including pharmacokinetic (PK) profiles, immunogenicity, and safety profiles in healthy volunteers. Methods Healthy volunteers (N = 200) aged 18–55 years and with body mass index of 18.5–29.9 kg/m2 and no prior exposure to adalimumab were randomized in a 1:1 ratio to receive a single subcutaneous injection of either adalimumab-adbm 40 mg/0.4 mL (high-concentration formulation) or 40 mg/0.8 mL (reference formulation). Participants completed 13 follow-up visits over 57 days, followed by a safety follow-up period of up to 70 days. Results The main PK parameters were similar for the high-concentration and reference groups. For all primary endpoints, the geometric mean ratios and 90% confidence intervals of AUC0–1344, AUC0–∞, and Cmax for both groups were entirely within the standard 80–125% bioequivalence acceptance range at 101.88% (93.31–111.23%), 105.38% (95.06–116.81%), and 91.29% (84.38–98.76%), respectively. There were no differences in the proportion of anti-drug antibody-positive participants or in the distribution of anti-drug antibody titers between the two formulations at any time point after drug dosing. Participants who were given the high-concentration formulation of adalimumab-adbm experienced a lower incidence of adverse events and local reactions than those who were given the reference formulation. Conclusions Overall, the high-concentration and reference adalimumab-adbm formulations had highly similar PK and immunogenicity profiles and were safe and well tolerated. Clinical trial registration NCT05203289

Quality by design‐engineered reversed‐phase high‐performance liquid chromatography method development and validation for simultaneous estimation of neomycin sulfate and beclomethasone dipropionate in bulk and pharmaceutical dosage form

AbstractThe aim of this study was to develop and validate a robust reversed‐phase high‐performance liquid chromatography (RP‐HPLC) method for the simultaneous estimation of neomycin sulfate (NEO) and beclomethasone dipropionate (BECLO) in both bulk drug and pharmaceutical dosage forms. The analysis was conducted using the Box‐Behnken design. The separation of NEO and BECLO was conducted on a Phenomenex Luna C‐18 column (4.6 × 150 mm, 5 µm), employing a mobile phase comprising a mixture of methanol and trifluoroacetic acid in a ratio of 88:12% v/v. The separation was performed at a flow rate of 0.6 mL/min. NEO and BECLO were analyzed at a wavelength of 240 nm employing a photodiode array detector. The validation of the methodology followed the guidelines outlined in the International Council for Harmonization Q2 R (1). The validation process involved assessing critical parameters such as linearity, accuracy, system suitability, precision, and robustness. The results for each parameter were found to be within the acceptable range. The results indicate that the established RP‐HPLC method can effectively be employed for the routine analysis of NEO and BECLO in bulk drug and pharmaceutical dosage forms.

Pharmacodynamic monitoring by residual gene expression of the nuclear factor of activated T cell-regulated genes in lung transplant recipients and its correlation with tacrolimus blood levels

IntroductionTrough blood levels (C0) of tacrolimus are used to adjust drug dosage, but they do not consistently correlate with clinical outcomes. Measurement of residual gene expression of nuclear factor of activated T cell (NFAT)-regulated genes (NFAT-RGE) has been proposed as a pharmacodynamic biomarker to assess the degree of immunosuppression in certain solid organ transplantations, but little is known regarding lung transplant recipients (LTR). Our primary objective is to correlate tacrolimus blood levels with NFAT-RGE.MethodsNFAT-RGE and tacrolimus C0 and peak (C1.5) levels were determined in 42 patients at three, six and 12 months post-transplantation.ResultsTacrolimus C0 did not exhibit a correlation with NFAT-RGE, whereas C1.5 did. Besides, over 20% of measurements indicated high levels of immunosuppression based on the below 30% NFAT-RGE threshold observed in many studies. Among those measurements within the therapeutic range, 19% had an NFAT-RGE<30%.ConclusionConsequently, a subset of patients within the tacrolimus therapeutic range may be more susceptible to infection or cancer, potentially benefiting from NFAT-RGE and tacrolimus peak level monitoring to tailor their dosage. Further quantitative risk assessment studies are needed to elucidate the relationship between NFAT-RGE and the risk of infection, cancer, or rejection.

Complete Remission with Partial Hematological Recovery as a Palliative Endpoint for Treatment of Acute Myeloid Leukemia

Complete remission with partial hematological recovery (CRh) has been used as an efficacy endpoint in clinical trials of nonmyelosuppressive drugs for acute myeloid leukemia (AML). We conducted a pooled analysis to characterize the clinical outcomes for patients with AML who achieved CRh after treatment with ivosidenib, olutasidenib, enasidenib, or gilteritinib monotherapy in clinical trials used to support marketing applications. The study cohort included 841 adult patients treated at the recommended drug dosage; 64.6% were red blood cell or platelet transfusion dependent at study baseline. Correlations between disease response and outcomes were assessed by logistic regression modeling for categorical variables and by Cox proportional hazards modeling for time-to-event variables. In comparison to patients with no response (NR), those with CRh had a higher proportion with transfusion independence (TI) for at least 56 days (92.3% vs 22.3%, p < 0.0001) or TI for at least 112 days (63.5% vs 8.7%, p < 0.0001), a reduced risk over time for severe infection (HR 0.43, p = 0.0007) or severe bleeding (HR 0.17, p = 0.01), and a longer overall survival (OS) (HR 0.31, p < 0.0001). The effects were consistent across drugs. In comparison to patients with CR, the effect sizes for CRh were similar for TI-56 and for risk over time of infection or bleeding but less for TI-112 and OS. CRh is associated with clinical benefits consistent with clinically meaningful palliative effects for treatment of AML with nonmyelosuppressive drugs, although less robustly than for CR.

Electronic prescription systems in Greece: a large-scale survey of healthcare professionals’ perceptions

BackgroundThe national e-prescription system in Greece is one of the most important achievements in the e-health sector. Healthcare professionals’ feedback is essential to ensure the introduced system tends to their needs and reduces their everyday workload. The number of surveys collecting the users’ views is limited, while the existing studies include only a small number of participants.MethodsIn this study, healthcare professionals’ perceptions on e-prescription are explored. For this, a questionnaire was distributed online, containing closed- and open-ended questions aiming to address strengths and identify drawbacks in e-prescription. Answers were collected from primary health care physicians, specialized medical doctors and pharmacists.ResultsIn total, 430 answers were collected (129 from primary health care physicians, 164 responses from specialized medical doctors and 137 pharmacists). Analysis of the collected answers reveals that the views of the three groups of healthcare professionals mostly converge. The positive impact e-prescribing systems have on the overall prescribing procedure in preventing errors and providing automation is commented. Among gaps identified and proposed improvements, health care professionals note the need for access to information on adverse drug reactions, side effects, drug-to-drug interactions and allergies. Flexible interaction with Therapeutic Prescription Protocols is desired to ameliorate monitoring and decision-making, while drug dosing features, and simplified procedures for copying, repeating, canceling a prescription, are perceived as useful to incorporate.ConclusionsCollecting healthcare professionals’ feedback is important, as their views can be transcribed to system requirements, to further promote e-prescribing and improve the provided health care services by facilitating decision making through safer and more efficient e-prescription. Introduction of the identified improvements can simplify the everyday workflow of healthcare professionals. To the best of our knowledge, a survey with more than 400 answered questionnaires on the use of e-prescription systems by healthcare professionals has never been conducted in Greece before.

Recommended dosages of analgesic and sedative drugs in intensive care result in a low incidence of potentially toxic blood concentrations

Background: Standard dosages of analgesic and sedative drugs are given to intensive care patients. The resulting range of blood concentrations and corresponding clinical responses need to be better examined. The purpose of this study was to describe daily dosages, measured blood concentrations, and clinical responses in critically ill patients. The purpose was also to contribute to establishing whole blood concentration reference values of the drugs investigated. Methods: A descriptive study of prospectively collected data from 302 admissions to a general intensive care unit (ICU) at a university hospital. Ten drugs (clonidine, fentanyl, morphine, dexmedetomidine, ketamine, ketobemidone, midazolam, paracetamol, propofol, and thiopental) were investigated, and daily dosages recorded. Blood samples were collected twice daily, and drug concentrations were measured. Clinical responses were registered using Richmond agitation-sedation scale (RASS) and Numeric rating scale (NRS). Results: Drug dosages were within recommended dose ranges. Blood concentrations for all 10 drugs showed a wide variation within the cohort, but only 3% were above therapeutic interval where clonidine (57 of 122) and midazolam (38 of 122) dominated. RASS and NRS were not correlated to drug concentrations. Conclusion: Using recommended dose intervals for analgesic and sedative drugs in the ICU setting combined with regular monitoring of clinical responses such as RASS and NRS leads to 97% of concentrations being below the upper limit in the therapeutic interval. This study contributes to whole blood drug concentration reference values regarding these 10 drugs.

Characteristics of expression of proteomic markers in women with “thin” endometrium and their importance for the therapeutic effects of the use of exogenous estradiol: A prospective cohort comparative study

Aim. To analyze the relationship between the expression of proteomic markers [estrogen (ER) and progesterone (PR) receptors, LIF, FOXA1, FOXA2] of endometrial receptivity and indicators of the levels of sex steroids [estradiol (E2) and progesterone (P)] in the peripheral blood during the “implantation window” in women with a history of reproductive dysfunction with “thin” endometrium (TE) and evaluate their significance for the therapeutic effect of using estradiol drugs. Materials and methods. The prospective cohort comparative study was conducted. The main group included 52 patients with TE (7 mm according to ultrasound on preovulatory days), the comparison group consisted of 62 women with normal endometrial thickness (≥7 mm according to ultrasound), women of both groups with reproductive dysfunctions of unknown reason; the control group included 16 healthy women. Aspiration biopsy of the endometrium was performed on the 6–8 days after ovulation (LH +6–8), as well as venipuncture to obtain a sample of peripheral blood to determine the E2, P levels. A combined histological and immunohistochemical study of endometrial samples was performed (ER, PR, LIF, FOXA1, FOXA2). The therapeutic effects of estradiol drugs were assessed in a cohort of women from the main group with TE (n=16 out of 26, those who have not changed their reproductive plans). Results. All women had ovulatory values of progesterone [P≥16.1 nmol/l (LH +6–8)] and normoestrogenemia in the blood (p0.05). According to the results of the correlation analysis, there were no associations between the E2, P levels and the value of M-echo, and no relationships were found between the E2, P levels and the expression of ER, PR, LIF, FOX-proteins. It was revealed that there are significant positive relationships between M-echo and FOXA2 expression in the endometrium (r=0.422; p0.001). Conditional threshold values for the ER, PR expression (LH +6–8) were determined, the excess of which is associated with abnormal expression of LIF, FOX-proteins: for PR in the glands – 105 and 285, for ER in glands – 145, for ER in the stroma – 155. It was found that usual doses of estradiol drugs (1–1.5 mg/day) are capable of increasing endometrial proliferation in women with TE, provided that the expression of ER, PR, LIF, FOX-proteins in their endometrium is similar to healthy women. Increased doses of estradiol drugs (4 mg/day) in women with TE had a significant effect in the form of an increase M-echo value and/or pregnancy in cases where the endometrial expression of LIF, FOX-proteins was comparable with healthy women, even in the presence of hormone-receptor interactions in the endometrium that are different from healthy women. Spontaneous pregnancy in participants of the main group with hypoplastic endometrium in our study occurred in 5 women in whom the expression characteristics of FOXA1 and/or FOXA2 in the endometrium were comparable to healthy women. Conclusion. TE is not the only marker of an imbalance of proteomic molecules, but it determines a greater likelihood of impaired expression of ER, PR, LIF, FOX-proteins in the endometrium. In women with an unclear reason of fertility disorders, it is necessary to conduct an in-depth examination of endometrial samples. Characteristics of endometrial expression ER, PR, LIF, FOX-proteins and the usefulness of hormone-receptor interactions in the TE in women with a history of reproductive disorders can be markers for predicting the effectiveness of the use of exogenous estradiol drugs in women in order to enhance endometrial proliferation with an initially low M-echo.

A goal-oriented reinforcement learning for optimal drug dosage control

A goal-oriented reinforcement learning for optimal drug dosage control

Challenges of Super-Super Obese Patient Presenting for Neurosurgery: A Case-Based Review

AbstractWith the rising prevalence of extreme obesity, their perioperative neurosurgical management demands special attention. We report the case of an acromegalic male with a body mass index as high as 64.12 kg/m2 who presented for craniotomy and resection of a pituitary tumor under general anesthesia. Through this report, we introduce the readers to this newer concept of the highest grade of obesity in the context of neurosurgery, explain the perioperative concerns, and reiterate the need for careful drug dosing, ventilation targets, positioning requirements, thorough cardiac and airway evaluation, and preparedness for adverse events. This report also highlights the fact that a well-planned and managed case can still turn out uneventful in the presence of multiple comorbidities like diabetes mellitus, adrenocortical insufficiency, hypothyroidism, and acromegaly. Advances in airway management, regional anesthesia, and perioperative point-of-care ultrasound have made it possible to formulate a safe anesthetic plan tailored to the patient's needs.

A Prospective Randomized Controlled Clinical Study to Investigate the Efficacy and Safety of Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitors in Non-Dialysis Patients with Chronic Heart Failure and Renal Anemia Switched from Continuous Erythropoietin Receptor Activator Treatment

Background/Objectives: Chronic kidney disease (CKD) and anemia are independent prognostic factors for heart failure. In recent years, hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors have become available for the treatment of renal anemia. This prospective randomized controlled study aimed to investigate the effects of switching from a continuous erythropoietin receptor activator (CERA) to one of four HIF-PH inhibitors in patients with chronic heart failure and renal anemia. Methods: Forty patients were randomized by the envelop method to receive treatment with roxadustat, daprodustat, vadadustat, or molidustat. The primary endpoint was the change in the hemoglobin (Hb) level. Secondary endpoints included changes in erythropoietin, changes in free T3, free T4, and thyroid-stimulating hormone (TSH), adverse effects, and drug dose increases and decreases. This study was preregistered in the University Hospital Medical Information Network Clinical Trials Registry (study ID: UMIN000041651). Results: We found no statistically significant difference between Hb levels with HIF-PH inhibitors and CERA, but at month 6, the Hb level was significantly higher with roxadustat than with vadadustat and daprodustat. Erythropoietin decreased significantly after switching to HIF-PH inhibitors. HIF-PH inhibitors had various significant effects on free T3, free T4, and TSH. No adverse events occurred. The doses of some drugs had to be increased or decreased. Conclusions: In patients with heart failure and renal anemia receiving CERA, Hb, NT-ProBNP, and renal function were similar after switching from CERA to HIF-PH inhibitors. The individual HIF-PH inhibitors appear to have different effects on anemia and thyroid function. However, because this was a single-center study with a limited sample size, the efficacy and potential limitations of HIF-PH inhibitors need to be further clarified.

[Analysis of the application effect and safety of transnasal humidified rapid insufflation ventilatory exchange technique in hysteroscopic diagnostic and therapeutic surgery].

Objective: To investigate the effect and safety of transnasal humidified rapid insufflation ventilatory exchange (THRIVE) technique in hysteroscopic diagnostic and therapeutic surgery. Methods: This study was a randomized controlled trial. A total of 100 female patients undergoing hysteroscopy surgery at Beijing Tongren Hospital from September to December 2023 were selected and randomly divided into two groups by the random number table method: the THRIVE group and the mask oxygen group, with 50 patients in each group. Patients in both groups were given total intravenous anesthesia with propofol combined with remifentanil and preserved spontaneous respiration. The THRIVE group was given oxygen by the THRIVE device with an oxygen flow rate of 50 L/min, while the mask oxygen group was given oxygen by the mask with an oxygen flow rate of 5 L/min; the oxygen concentration of both groups was set at 100%. The general condition of the patients, vital signs during the operation, the amount of anesthesia drugs used and the operation time were recorded. The primary observation index was the incidence of hypoxic events in the two groups; the secondary observation indexes were the incidence and time of intraoperative apnea as well as the corresponding oxygenation interventions and the incidence of non-hypoxic adverse events. Results: The age of the THRIVE group was (42±14) years, and the age of the mask oxygen group was (43±15) years. The duration of surgery in the THRIVE group was (15.9±3.4) min, which was statistically lower than that of the mask oxygen group (16.3±4.5) min (P=0.041), and there were no differences observed in the duration of awakening time and anesthesia time (both P>0.05). There was no significant difference in the dosage of propofol, remifentanil, and intraoperative vasoactive drugs between the two groups (all P>0.05). The SpO2 of the patients in the THRIVE group at the end of the operation was (99.7±1.1) %, which was higher than that of the mask-oxygen group (99.1±1.1) % (P<0.05). There was no difference in SpO2 of the two groups at the other time points (all P>0.05). There were no differences in HR and MAP of two group patients at each time point (all P>0.05). The incidence of hypoxic events in the THRIVE group was 12.0% (6/50), which was lower than that of 28.0% (14/50) in the mask oxygen group (P=0.045). The difference in the incidence and duration of apnea between the two groups was not statistically significant (all P>0.05). There were no cases of temporary need for laryngeal mask or tracheal intubation during surgery in both groups. There was no statistically significant difference in the incidence of intraoperative body movement, dizziness, nausea and vomiting between the two groups (all P>0.05), and no cardiac, cerebral, renal or other important organ insufficiency occurred in the two weeks after surgery. Conclusion: THRIVE technology can provide effective oxygenation for patients undergoing hysteroscopic diagnosis and treatment, maintain patients' circulatory stability, and improve the safety and efficiency of surgery.

Thyroid Hormone Status in Children Taking Antiepileptic Drugs (AEDs): An Experience in a Tertiary Care Hospital of Bangladesh.

Introduction: Antiepileptic drugs (AEDs) may alter thyroid hormone homeostasis at the level of biosynthesis, release, transport, metabolism and excretion of thyroid hormones. The purpose of the study was to see the thyroid hormone status in children with epilepsy treating with common antiepileptic drugs. Materials &amp; Method: The cross-sectional study was carried out in department of pediatric neurology, National Institute of Neurosciences and Hospital (NINS), Dhaka. One hundred and sixty epileptic children aged 1 year to 14 years who were on monotherapy or polytherapy with the most commonly used Antiepileptic drugs (AEDs) for at least 6 months or more were enrolled. Serum TSH and FT4 were measured in all selected patients with early morning serum sample. Result: Nearly one third of study subjects had thyroid dysfunction, most of which were Subclinical hypothyroidism (SCH). The frequency of SCH was 29.2% in carbamazepine(CBZ), 50% in oxcabazepine (OXC), 28.6% in phenobarbitone(PHB) and 13% in valproic acid (VPA) treated epileptic children. No child was found to have subclinical hypothyroidism with topiramate and ethosuximide monotherapy. Antiepileptic drugs (AEDs) monotherapy or polytherapy had no significant difference in alteration on thyroid hormone level. Use of CBZ for long duration significantly altered thyroid function. Doses of Antiepileptic drugs (AEDs) didn’t show any significant thyroid dysfunction. Conclusion: Commonly used Antiepileptic drugs (AEDs) in children with epilepsy were associated with alteration of thyroid hormones, most commonly subclinical hypothyroidism. BANGLADESH J CHILD HEALTH 2022; VOL 46 (2) : 58-64

Maralixibat in progressive familial intrahepatic cholestasis (MARCH-PFIC): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive disorders, the most prevalent being BSEP deficiency, resulting in disrupted bile formation, cholestasis, and pruritus. Building on a previous phase 2 study, we aimed to evaluate the efficacy and safety of maralixibat-an ileal bile acid transporter inhibitor-in participants with all types of PFIC. MARCH-PFIC was a multicentre, randomised, double-blind, placebo-controlled, phase 3 study conducted in 29 community and hospital centres across 16 countries in Europe, the Americas, and Asia. We recruited participants aged 1-17 years with PFIC with persistent pruritus (>6 months; average of ≥1·5 on morning Itch-Reported Outcome [Observer; ItchRO(Obs)] during the last 4 weeks of screening) and biochemical abnormalities or pathological evidence of progressive liver disease, or both. We defined three analysis cohorts. The BSEP (or primary) cohort included only those with biallelic, non-truncated BSEP deficiency without low or fluctuating serum bile acids or previous biliary surgery. The all-PFIC cohort combined the BSEP cohort with participants with biallelic FIC1, MDR3, TJP2, or MYO5B deficiencies without previous surgery but regardless of bile acids. The full cohort had no exclusions. Participants were randomly assigned (1:1) to receive oral maralixibat (starting dose 142·5 μg/kg, then escalated to 570 μg/kg) or placebo twice daily for 26 weeks. The primary endpoint was the mean change in average morning ItchRO(Obs) severity score between baseline and weeks 15-26 in the BSEP cohort. The key secondary efficacy endpoint was the mean change in total serum bile acids between baseline and the average of weeks 18, 22, and 26 in the BSEP cohort. Efficacy analyses were done in the intention-to-treat population (all those randomly assigned) and safety analyses were done in all participants who received at least one dose of study drug. This completed trial is registered with ClinicalTrials.gov, NCT03905330, and EudraCT, 2019-001211-22. Between July 9, 2019, and March 4, 2022, 125 patients were screened, of whom 93 were randomly assigned to maralixibat (n=47; 14 in the BSEP cohort and 33 in the all-PFIC cohort) or placebo (n=46; 17 in the BSEP cohort and 31 in the all-PFIC cohort), received at least one dose of study drug, and were included in the intention-to-treat and safety populations. The median age was 3·0 years (IQR 2·0-7·0) and 51 (55%) of 93 participants were female and 42 (45%) were male. In the BSEP cohort, least-squares mean change from baseline in morning ItchRO(Obs) was -1·7 (95% CI -2·3 to -1·2) with maralixibat versus -0·6 (-1·1 to -0·1) with placebo, with a significant between-group difference of -1·1 (95% CI -1·8 to -0·3; p=0·0063). Least-squares mean change from baseline in total serum bile acids was -176 μmol/L (95% CI -257 to -94) for maralixibat versus 11 μmol/L (-58 to 80) for placebo, also representing a significant difference of -187 μmol/L (95% CI -293 to -80; p=0·0013). The most common adverse event was diarrhoea (27 [57%] of 47 patients on maralixibat vs nine [20%] of 46 patients on placebo; all mild or moderate and mostly transient). There were five (11%) participants with serious treatment-emergent adverse events in the maralixibat group versus three (7%) in the placebo group. No treatment-related deaths occurred. Maralixibat improved pruritus and predictors of native liver survival in PFIC (eg, serum bile acids). Maralixibat represents a non-surgical, pharmacological option to interrupt the enterohepatic circulation and improve the standard of care in patients with PFIC. Mirum Pharmaceuticals.

Cutaneous biomarkers of therapeutic efficacy in early treatment of hereditary ATTR amyloid polyneuropathy with tafamidis.

ATTR (ATTRv) amyloidosis neuropathy is characterized by progressive sensorimotor and autonomic nerve degeneration secondary to amyloid deposition caused by a misfolded transthyretin protein (TTR). Small nerve fiber neuropathy is an early clinical manifestation of this disease resulting from the dysfunction of the Aδ and C small nerve fibers. Tafamidis, a selective TTR stabilizer, has proven its efficacy in the earlier stages of hATTR. To evaluate the clinical course and utility of cutaneous pathological biomarkers in patients with ATTR amyloidosis treated with tafamidis compared to control patients. Forty patients diagnosed with early stages of ATTRv amyloidosis (polyneuropathy disability [PND] scores 0-II) underwent small and large nerve fiber neurological evaluations, and annual skin biopsies for intraepidermal nerve fiber density (IENFD) and amyloid deposition index (ADI) estimation. Thirty patients were allocated to receive tafamidis, and 10 patients served as controls. Tafamidis pharmacokinetics analysis was performed in patients who received the treatment. At baseline, 12% of patients in stage PND 0 and 28% in PND I displayed small nerve fiber denervation in the distal thigh, whereas 23% and 38%, respectively, in the distal leg. Similarly, 72% and 84% had amyloid deposition in the distal thigh and 56% and 69% in the distal leg. Following 1 year of treatment, the tafamidis group showed significant clinical improvement compared to the control group, revealed by the following mean differences (1) -9.3 versus -4 points (p = <.00) in the patient's neuropathy total symptom score 6 (NTSS-6) questionnaire, (2) -2.5 versus +2.8 points (p = <.00) in the Utah Early Neuropathy Score (UENS), and (3) +1.2°C versus -0.6 (p = .01) in cold detection thresholds. Among the patients who received tafamidis, 65% had stable or increased IENFD in their distal thigh and 27% in the distal leg. In contrast, all patients in the control group underwent denervation. The ADI either decreased or remained constant in 31% of the biopsies in the distal thigh and in 24% of the biopsies in the distal leg of the tafamidis-treated patients, whereas it rose across all the biopsies in the control group. At the 4-year follow-up, the tafamidis group continued to display less denervation in the distal thigh (mean difference [MD] of -3.0 vs. -9.3 fibers/mm) and the distal leg (mean difference [MD] -4.9 vs. -8.6 fibers/mm). ADI in tafamidis-treated patients was also lower in the distal thigh (10 vs. 30 amyloid/mm2) and the distal leg (23 vs. 40 amyloid/mm2) compared to control patients. Plasma tafamidis concentrations were higher in patients with IENFD improvement and in patients with reduced amyloid deposition. Patients without amyloid deposition in the distal leg at baseline displayed delayed disease progression at 4 years. Cutaneous IENFD and amyloid deposition assessments in the skin of the distal thigh and distal leg are valuable biomarkers for early diagnosis of ATTR amyloidosis and for measuring the progression of small nerve fiber neuropathy. Early treatment with tafamidis slows the clinical progression of the disease, skin denervation, and amyloid deposition in the skin. Higher plasma concentrations of tafamidis are associated with better disease outcomes, suggesting that increasing the drug dose could achieve better plasma concentrations and response rates. This study describes the longest small nerve fiber neuropathy therapeutic trial with tafamidis and is the first to report small fiber symptoms, function, and structural assessments as outcomes.

Assessment of antifungal drugs’ activity against some Candida albicans isolates in the presence or absence of human albumin: a study employing an in vitro pharmacokinetics / pharmacodynamics model

Invasive candidiasis associated with the dissemination of endogenous Candida species is a fatal condition linked to high rates of morbidity and mortality. Progressive drug resistance necessitates the need for prompt and effective therapy. Therefore, choosing a specific and effective treatment is crucial. A two-compartment in vitro pharmacokinetics (PK) / pharmacodynamics (PD) model has been used for this purpose, and the PD behaviours of amphotericin B (AMB; at 2.5 and 5 mg/L), voriconazole (VOR; at 1.5 and 3 mg/L), and itraconazole (ITR; at 1.5 and 3 mg/L) were assessed against two Candida albicans isolates (a sensitive and resistant one; ATCC-90028 and ATCC-10231, re¬spectively) with or without the addition of human albumin (2%). PK were simulated as time-concentration profiles, while the PD susceptibility of all drug doses has been assessed through the minimum inhibitory concentration (MIC), the relative optical density of fungal growth, and the exposure - effect relationship (fAUC0–24/MIC). A fungicidal activity without the presence of albumin was seen against both isolates of C. albicans at the highest dose of VOR, while the addition of albumin potentiated the efficacies of AMB and of VOR against both isolates, with no effect for ITR. Finally, human albumin exerted a variable and dose-dependent effect on the activities of some antifungal agents.