Current Therapeutic Research-clinical and Experimental最新文献

Background

There is an urgent need for pharmacological treatment for cocaine (COC) use disorder (CUD). Glutamatergic transmission in the prefrontal cortex is affected by addictive behaviors. Clavulanic acid (CLAV), a glutamate transporter GLT-1 (excitatory amino acid transporter) activator, is a clinical-stage medication that has potential for treating CUD.

Methods

In a pilot study, nine participants with CUD received 500 mg CLAV with dose escalations to 750 mg and 1000 mg over 10 days. In 5 separate magnetic resonance imaging (MRI) sessions, brain anterior cingulate cortex (ACC) glutamate level and resting state network (RSN) functional connectivity (FC) were assessed using MR spectroscopy and functional MRI. Craving was assessed at the same time points, between baseline (before CLAV), 6 days, and 10 days of CLAV. Independent component analysis with dual regression was used to identify RSN FC changes from baseline to Days 6 and 10. Relationships among glutamate, craving, and resting state FC values were analyzed.

Results

Participants who achieved high ACC glutamate levels after CLAV treatment had robust decreases in COC craving (r = −0.90, P = 0.0009, n = 9). The salience network (SN) and executive control network (ECN) demonstrated an association between increased FC after CLAV treatment and low baseline ACC Glu levels (SN CLAV 750 mg, r = −0.82, P = 0.007) (ECN CLAV 1000 mg, r = −0.667, P = 0.050; n = 9).

Conclusions

Glutamate associated changes in craving and FC of the salience and executive control brain networks support CLAV as a potentially efficacious pharmacological treatment for CUD.

Objectives

Natural killer (NK) cells are important immune system effector cells providing innate defenses against intracellular infections, including viral infections, immune surveillance, and cancer immunoediting. The primary purpose of this study was to investigate whether modified ultra-filtrated colostrum (UC) and hydrolyzed whey (W) products or their combinations with other natural products with reported immunomodulatory properties will stimulate NK cell cytotoxic activity by activation of granzyme B and IFN-γ production.

Methods

The ability of study products to stimulate the cytotoxic activity of human-purified CD56⁺ NK cells and the production of granzyme B and IFN-γ by activated NK cells was evaluated in the cytotoxic assay.

Results

All study products significantly increased NK-cell cytotoxic activity at an E: T ratio of 20:1. Treatment of cells with UC had a maximal cytotoxic effect at the minimal dose of 10 µg/ml, which exceeded the cytotoxic activity of IL-2. In contrast, the addition of egg yolk (CE) or CE + botanical blend (CEB) to UC resulted in a dose-dependent cytotoxic response with a maximal response at 1000 µg/ml. The maximal activity of blend products was comparable to UC activity. W exerted minimal stimulatory activity on NK cells. The magnitude of granzyme B and IFN-γ production was closely associated with the cytotoxic activity of NK cells stimulated with the study products.

Conclusions

All study products demonstrated stimulatory activity on NK cells, with UC having a maximal effect on NK cell cytotoxicity. The study products can be used as dietary supplements to support NK cell activity in healthy individuals.

Background

Hypertension and dyslipidemia significantly contribute to cardiovascular disease development. Their coexistence poses challenges in managing multiple medications, influencing treatment adherence.

Objective

This study aimed to assess the efficacy and safety of a combined treatment approach using a fixed-dose combination therapy.

Methods

This multicenter, 8-week, randomized, double-blind, Phase IV trial was named Telmisartan/Amlodipine/Rosuvastatin from Samjin Pharmaceuticals and evaluated the efficacy and safety of fixed-dose combination treatment in patients with essential hypertension and dyslipidemia. They were randomly assigned to 2 fixed-dose combination therapy groups, telmisartan 40 mg/amlodipine 5 mg/rosuvastatin 10 mg (TEL/ALD/RSV) or amlodipine 5 mg/atorvastatin 10 mg (ALD/ATV) after washout/run-in period. The primary outcomes were the change in mean sitting systolic blood pressure and the percentage change of LDL-C after 8 weeks of medical treatment. Adverse drug reactions and events were assessed.

Results

Of a total of 304 patients who underwent screening, 252 were randomized to the TEL/ALD/RSV group (125 patients) and the ALD/ATV group (127 patients). The mean (SD) ages of the TEL/ALD/RSV group and the ALD/ATV group were 67.4 (11.3) and 68.2 (10.6) years, respectively (P = 0.563). The least-squares mean (SE) in mean sitting systolic blood pressure changes between the 2 groups were –16.27 (0.93) mm Hg in the TEL/ALD/RSV group, –6.85 (0.92) mm Hg in the ALD/ATV group (LSM difference = –9.42 mm Hg; 95% CI, –11.99 to –6.84; P < .001). For LDL-C level changes, a significant difference was noted between the 2 groups: –50.03% (1.18%) in the TEL/ALD/RSV group, –39.60% (1.17%) in the ALD/ATV group (LSM difference = –10.43%; 95% CI, –13.70 to –7.16; P < .001). No severe adverse events were observed.

Conclusions

TEL/ALD/RSV proved to be more efficient than ALD/ATV in lowering blood pressure and reducing LDL-C levels among patients with hypertension and dyslipidemia, with no notable safety concerns. (Curr Ther Res Clin Exp. 2024; XX:XXX–XXX). ClinicalTrials.gov identifier: NCT03860220.

Background

A new oral paracetamol formulation with the same paracetamol quantity (24 mg/mL) as a marketed formulation but with finer active ingredient particle size and lower amounts of maltitol (5.85 g/dose in the test formulation vs 7.25 g/dose in the reference formulation) and sorbitol (2.4 g/dose vs 2.83 g/dose) was developed.

Objective

Establish the bioequivalence of the new pediatric formulation (test treatment) compared with the marketed formulation (reference treatment).

Methods

This Phase I, open-label trial assigned healthy adult volunteers to a single 42-mL (1 g para-cetamol) dose of test or reference treatment. Participants received both treatments in a randomized order separated by a 72-hour washout period. The primary endpoints were AUC_0–tlast (AUC vs time curve from time 0 to last measurable sampling timepoint), C_max, and t_max. Safety assessments included adverse event, clinical laboratory, and physical examination data.

Results

Thirty-five participants were randomized and treated. The study population was 42.9% women (57.1% men) with a median age of 30 years; most participants were non-Hispanic White. Mean C_max values were comparable between test and reference products, with a median t_max of 1.00 hour for both. The test/reference ratios (%) (90% CI) for AUC_0–tlast and C_max were 98.69% (96.46, 100.97) and 100.73% (95.63, 106.10), respectively. There were no adverse events or deaths.

Conclusions

The new paracetamol formulation is bioequivalent to the marketed formulation.

Background

Objectives

Methods

Results

Conclusions

Background

Belimumab is the first antibody drug approved for systemic lupus erythematosus (SLE), and is a fully human monoclonal antibody that inhibits soluble B lymphocyte stimulator protein. In clinical trials, a composite index was used to assess efficacy of belimumab. However, clinical guidelines on SLE treatment currently use single efficacy indexes.

Objective

The main objective of this study was to perform a meta-analysis to evaluate the efficacy of belimumab utilizing single indexes used in routine clinical practice, rather than the composite efficacy index used in clinical trials during the development phase. As a secondary endpoint, safety was also evaluated.

Methods

Several databases were searched to identify reports published up to December 1, 2021 on randomized controlled trials examining the efficacy of belimumab in adult patients with SLE. From the clinical trial data, efficacy was evaluated using single indexes including the SLE Disease Activity Index (SLEDAI), British Isles Lupus Assessment Group Index, and Physician Global Assessment. Safety was also assessed. Data were synthesized and analyzed using Review Manager 5.4. This study protocol was registered in the UMIN Clinical Trials Registry (Registration number: UMIN000052846).

Results

The search identified 12 reports that met the inclusion criteria. Five reports were included in efficacy evaluation and 9 in safety evaluation. The primary endpoint was SLEDAI. Significantly more belimumab-treated patients achieved a ≥4-point reduction in SLEDAI (relative risk 1.28; 95% confidence interval, 1.16–1.40; P < 0.00001) compared with placebo. Other efficacy endpoints were also improved significantly in the belimumab group. No difference in safety was found between belimumab and placebo.

Conclusions

The present meta-analysis evaluating clinical trial data using various single indexes recommended by clinical guidelines for SLE verifies that addition of belimumab to standard of care is efficacious for moderate-to-severe SLE.

Objective

This study aims to analyze a severe adverse reaction of pulmonary fibrosis induced by dronedarone hydrochloride tablets, and to provide a reference for clinical rational medication through drug precautions.

Methods

A case of pulmonary fibrosis induced by dronedarone hydrochloride tablets, along with related literature was retrospectively analyzed.

Results

Patients over 65 years old with a history of exposure to amiodarone may increase the incidence of pulmonary toxicity induced by dronedarone, and dronedarone should not be selected as a substitute treatment drug for patients with amiodarone-induced pulmonary toxicity.

Conclusions

It is recommended that clinicians monitor the diffusion capacity of carbon monoxide and lung ventilation function of patients before and after using dronedarone for treatment. For patients with a history of amiodarone exposure, intermittent monitoring of chest X-rays and lung function is necessary. If lung function decreases, dronedarone should be immediately discontinued.

Background

Slow insulin absorption prevents the development of a fully automated artificial pancreas with subcutaneous insulin delivery.

Objective

We have hypothesized that glucagon could be used as a vasodilator to accelerate insulin absorption in a bihormonal subcutaneous artificial pancreas. The present proof-of-concept study is the first study to investigate the pharmacokinetics of insulin after subcutaneous administration of a low dose of glucagon at the site of subcutaneous insulin injection.

Methods

Twelve anesthetized pigs were randomized to receive a subcutaneous injection of 10 IU insulin aspart with either 100 µg glucagon or the equivalent volume of placebo (0.9% saline solution) injected at the same site. Arterial samples were collected for 180 minutes to determine insulin, glucagon, and glucose concentrations.

Results

Glucagon did not influence the insulin concentration T_max in plasma. The plasma insulin AUC_0–∞ was significantly larger after glucagon administration (P < 0.01). The glucagon group had significantly higher glucose concentrations in the first 30 minutes after insulin administration (P < 0.05).

Conclusions

This proof-of-concept study indicates that glucagon may increase the total absorption of a single dose of subcutaneously injected insulin. This is a novel observation. However, we did not observe any reduction in insulin concentration T_max, as we had hypothesized. Further, glucagon induced a significant, undesirable increase in early blood glucose concentrations.

Purpose

Methods

Findings

Implications

Background

The Kingdom of Bahrain has reported more than 696,000 cases of coronavirus disease 2019 (COVID-19) and 1548 associated deaths as of December 26, 2022.

Objectives

To better inform responses to future public health threats, this narrative review documents the challenges and responses to the COVID-19 pandemic in the Kingdom of Bahrain.

Methods

A PubMed search was conducted focusing on severe acute respiratory syndrome or COVID-19 in Bahrain. Additional relevant references were also included from the authors’ personal reference collections.

Results

The search indicated that Bahrain achieved well-established control of the pandemic through robust public health measures, including an early, comprehensive vaccination program. Bahrain was among the first countries to grant emergency authorization for COVID-19 vaccines; as of December 2022, nearly 73% of the eligible population has been fully vaccinated, and approximately 60% has been boosted. Low case rates in recent months highlight Bahrain's successful response to the COVID-19 pandemic.

Conclusions

Early organization, robust and systematic protective measures, and a comprehensive vaccination program were key components of the Kingdom's response to the pandemic; traveler quarantines and attempts to combat misinformation were of little or no benefit. These lessons provide guidance for future preparedness to minimize the public health impacts of another pandemic. (Curr Ther Res Clin Exp. 2024; XX:XXX–XXX).