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Channels (Austin, Tex.) Dec 2023Recent years have seen an outpouring of atomic or near atomic resolution structures of cyclic nucleotide-gated (CNG) channels, captured in closed, transition, pre-open,... (Review)
Review
Recent years have seen an outpouring of atomic or near atomic resolution structures of cyclic nucleotide-gated (CNG) channels, captured in closed, transition, pre-open, partially open, and fully open states. These structures provide unprecedented molecular insights into the activation, assembly, architecture, regulation, and channelopathy of CNG channels, as well as mechanistic explanations for CNG channel biophysical and pharmacological properties. This article summarizes recent advances in CNG channel structural biology, describes key structural features and elements, and illuminates a detailed conformational landscape of activation by cyclic nucleotides. The review also correlates structures with findings and properties delineated in functional studies, including nonselective monovalent cation selectivity, Ca permeation and block, block by L--diltiazem, location of the activation gate, lack of voltage-dependent gating, and modulation by lipids and calmodulin. A perspective on future research is also offered.
Topics: Humans; Cyclic Nucleotide-Gated Cation Channels; Channelopathies; Nucleotides, Cyclic; Calmodulin; Cyclic GMP
PubMed: 37905307
DOI: 10.1080/19336950.2023.2273165 -
The Mental Health Clinician Aug 2023Clozapine can be associated with significant side effects and tolerability issues. Hyperhidrosis occurs less commonly and is unanticipated by clinicians because of...
BACKGROUND
Clozapine can be associated with significant side effects and tolerability issues. Hyperhidrosis occurs less commonly and is unanticipated by clinicians because of clozapine's significant anticholinergic activity.
CASE REPORT
A 34-year-old female developed clozapine-induced nocturnal, generalized hyperhidrosis following initial titration to 400 mg/day. Dose reduction did not decrease the side effect. Treatment with an anticholinergic medication could not be initiated because of constipation. Treatment with a beta blocker resulted in worsening of asthma. Treatment with a calcium channel blocker, diltiazem CD 180 mg/day, resulted in a significant reduction in hyperhidrosis.
CONCLUSION
This case supports the use of calcium channel blockers to reduce clozapine-induced hyperhidrosis and offers an alternative to anticholinergic medications that may negatively impact clozapine tolerability.
PubMed: 37860588
DOI: 10.9740/mhc.2023.08.193 -
Clinical and Translational Science Dec 2023Encorafenib is a potent and selective ATP competitive inhibitor of BRAF V600-mutant kinase approved for patients with BRAF-mutant melanoma and colorectal cancer....
Encorafenib is a potent and selective ATP competitive inhibitor of BRAF V600-mutant kinase approved for patients with BRAF-mutant melanoma and colorectal cancer. Encorafenib is mainly metabolized by cytochrome P450 (CYP) 3A4 in vitro and may be susceptible to drug-drug interactions when co-administered with CYP3A inhibitors or inducers. The primary objective was to assess the impact of the strong CYP3A inhibitor posaconazole (part 1) and the moderate CYP3A and P-gp inhibitor diltiazem (part 2) on encorafenib pharmacokinetics in healthy volunteers following a single 50-mg dose. A total of 32 participants were enrolled (16 each in parts 1 and 2). The area under the curve extrapolated to infinity (AUC ) and maximum plasma concentration (C ) geometric mean for encorafenib increased by 183% and 68.4%, respectively, when co-administered with posaconazole. Apparent encorafenib clearance decreased from 26.0 to 9.2 L/h when coadministered with posaconazole, and plasma terminal half-life (t ) of encorafenib increased from 4.3 to 7.3 h. The AUC and C geometric mean for encorafenib increased by 83.0% and 44.7%, respectively, when co-administered with diltiazem. Similarly, the apparent encorafenib clearance decreased from 29.0 to 16.0 L/h when co-administered with diltiazem, and plasma t of encorafenib increased from 6.6 to 7.9 h. There were no deaths, serious adverse events (AEs), or patient discontinuations due to AEs in parts 1 or 2. The most frequently reported treatment-related AEs were erythema (n = 14; 88%) and headache (n = 11; 69%) in part 1 and headache (n = 7; 44%) in part 2. The results of this study indicate that co-administration of encorafenib with strong or moderate CYP3A4 inhibitors should be avoided.
Topics: Humans; Antineoplastic Agents; Colorectal Neoplasms; Cytochrome P-450 CYP3A Inhibitors; Diltiazem; Drug Interactions; Headache; Melanoma; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf
PubMed: 37837178
DOI: 10.1111/cts.13662 -
The Annals of Pharmacotherapy Jul 2024To review treatment options and updates that exist for the management of paroxysmal supraventricular tachycardia (PSVT). (Review)
Review
OBJECTIVE
To review treatment options and updates that exist for the management of paroxysmal supraventricular tachycardia (PSVT).
DATA SOURCES
A literature search of PubMed was performed including articles from 1974 to June 2023 using the terms: , , , , , , , , , , , , , , , . Primary literature and guidelines were reviewed.
STUDY SELECTION AND DATA EXTRACTION
Studies were considered if they were available in English and conducted in humans.
DATA SYNTHESIS
PSVT is a subset of supraventricular tachycardia (SVT) that presents as a rapid, regular tachycardia with an abrupt onset and termination. Due to frequent emergency department (ED) visits annually with symptoms of PSVT, appropriate and efficient management of these patients is vital. This review provides an overview of the pathophysiology of PSVT, while also describing the literature behind nonpharmacologic and pharmacologic management of PSVT.
RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE
This review describes new literature regarding the improved success of the modified Valsalva maneuver as a nonpharmacologic therapy in PSVT. In addition, it describes a new technique in administration of adenosine that has improved outcomes, defines dose adjustments needed for drug interactions with adenosine, compares the utilization of nondihydropyridine calcium channel blockers with adenosine, and provides management recommendations for patients in special populations.
CONCLUSIONS
With high annual rates of ED visits for SVT, providers should be aware of the data behind management and modifications of therapy based on patient-specific factors (ie, patient preference, pharmacokinetics/pharmacodynamics, drug interactions, and special populations).
Topics: Humans; Tachycardia, Supraventricular; Anti-Arrhythmia Agents
PubMed: 37743672
DOI: 10.1177/10600280231199136 -
Genes & Diseases Jan 2024Exosomes are small membrane vesicles containing microRNA, RNA, DNA fragments, and proteins that are transferred from donor cells to recipient cells. Tumor cells release... (Review)
Review
Exosomes are small membrane vesicles containing microRNA, RNA, DNA fragments, and proteins that are transferred from donor cells to recipient cells. Tumor cells release exosomes to reprogram the factors associated with the tumor microenvironment (TME) causing tumor metastasis and immune escape. Emerging evidence revealed that cancer cell-derived exosomes carry immune inhibitory molecule program death ligand 1 (PD-L1) that binds with receptor program death protein 1 (PD-1) and promote tumor progression by escaping immune response. Currently, some FDA-approved monoclonal antibodies are clinically used for cancer treatment by blocking PD-1/PD-L1 interaction. Despite notable treatment outcomes, some patients show poor drug response. Exosomal PD-L1 plays a vital role in lowering the treatment response, showing resistance to PD-1/PD-L1 blockage therapy through recapitulating the effect of cell surface PD-L1. To enhance therapeutic response, inhibition of exosomal PD-L1 is required. Calcium signaling is the central regulator of tumorigenesis and can regulate exosome biogenesis and secretion by modulating Rab GTPase family and membrane fusion factors. Immune checkpoints are also connected with calcium signaling and calcium channel blockers like amlodipine, nifedipine, lercanidipine, diltiazem, and verapamil were also reported to suppress cellular PD-L1 expression. Therefore, to enhance the PD-1/PD-L1 blockage therapy response, the reduction of exosomal PD-L1 secretion from cancer cells is in our therapeutic consideration. In this review, we proposed a therapeutic strategy by targeting calcium signaling to inhibit the expression of PD-L1-containing exosome levels that could reduce the anti-PD-1/PD-L1 therapy resistance and increase the patient's drug response rate.
PubMed: 37588227
DOI: 10.1016/j.gendis.2023.01.026 -
Hypertension in Pregnancy Dec 2024Preeclampsia (PE) is a pregnancy disorder that represents a major cause of maternal and perinatal morbidity and mortality. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Preeclampsia (PE) is a pregnancy disorder that represents a major cause of maternal and perinatal morbidity and mortality.
METHODS
This network meta-analysis was registered with PROSPERO. We searched the PubMed, ClinicalTrials.gov. and Embase databases for studies published from inception to the 31 of March 2023. RevMan5.3 software provided by the Cochrane Collaboration was used for direct meta-analysis (DMA) statistical analysis. Funnel maps, network meta-analysis (NMA), the surface under the cumulative ranking curve (SUCRA) to rank the different interventions and publication bias were generated by STATA 17.0 software.
RESULTS
We included eight randomized controlled trials (RCTs) involving a total of 1192 women with PE; two studies were of high quality and six were of moderate quality. Eight interventions were addressed in the NMA. In the DMA, we found that blood pressure in the Ketanserin group were significantly higher than those in the Nicardipine group. NMA showed that blood pressure in the Dihydralazine group was significantly higher than that in the Methyldopa, Labetalol, Nicardipine and Diltiazem groups. And the blood pressure in the Labetalol group was significantly lower than that in the Nicardipine group. SUCRA values showed that Diltiazem was more effective in lowering blood pressure than other drugs looked at in this study.
CONCLUSION
According to the eight RCTs included in this study, Diltiazem was the most effective in reducing blood pressure in PE patients; Labetalol and Nicardipine also had good effects. Diltiazem is preferred for the treatment of patients with severe PE and high blood pressure.
Topics: Pregnancy; Female; Humans; Antihypertensive Agents; Labetalol; Pre-Eclampsia; Diltiazem; Nicardipine; Network Meta-Analysis
PubMed: 38488570
DOI: 10.1080/10641955.2024.2329068 -
Medicine Oct 2023Currently, there is no gold standard for monitoring noxious stimulation during surgery, and the surgical pleth index (SPI) is only one of many monitoring methods. It is... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Currently, there is no gold standard for monitoring noxious stimulation during surgery, and the surgical pleth index (SPI) is only one of many monitoring methods. It is commonly used in the monitoring of conventional opiate anesthesia, but its effectiveness in opioid-free anesthesia (OFA) has not been evaluated. Therefore, the aim of this study was to observe the guidance value of the surgical pleth index in opioid-free anesthesia for patients undergoing lower abdominal or pelvic surgery.
METHODS
A total of 122 patients who underwent lower abdominal or pelvic surgery in our hospital between March 2021 and July 2022 were selected and equally divided into OFA (F) and control (C) groups according to the random number table method. Both groups underwent ultrasound-guided unilateral/bilateral quadratus lumborum block in the supine position according to the surgical field. In group F, 0.50% lidocaine and 0.20% ropivacaine (in 20 mL of 0.9% normal saline) were injected on each side. In group C, 20 mL 0.9% normal saline was injected on each side. Group F received general anesthesia without opioids and group C received general anesthesia with opioids. BP, pulse oxygen saturation, PETCO2, reactionentropy, stateentropy, and SPI values; Steward score; dosage of propofol, dexmedetomidine, rocuronium, and diltiazem; extubation time; and awake time were monitored in both groups.
RESULTS
There were no significant differences in the general data between the 2 groups (P > .05). There were no significant differences in SPI values at T0, T1, T2, T3, T4, and T5 or the number of cases requiring additional remifentanil, propofol, and diltiazem between the 2 groups (P > .05). The stateentropy, reactionentropy, and Steward scores were higher in group F than in group C at T4 and T5, while the extubation and awake times were lower in group F than in group C (P < .05). The heart rate and SPI of group F were lower than that of group C at T3 (P < .05).
CONCLUSION
The guiding value of SPI in OFA was similar to its use in opiated anesthesia. Its clinical efficacy is exact, vital signs are stable, enabling rapid, and complete regaining of consciousness.
Topics: Humans; Analgesics, Opioid; Anesthesia, General; Diltiazem; Propofol; Saline Solution
PubMed: 37904423
DOI: 10.1097/MD.0000000000035172 -
Cureus Sep 2023The current guidelines state that propafenone can be used in combination with a beta-blocker or a calcium channel blocker for pharmacologic cardioversion of recent-onset...
The current guidelines state that propafenone can be used in combination with a beta-blocker or a calcium channel blocker for pharmacologic cardioversion of recent-onset atrial fibrillation in patients without structural heart disease. To prevent the conversion from atrial fibrillation to atrial flutter with a rapid ventricular rate, it is recommended to administer propafenone following the administration of a beta-blocker or a calcium channel blocker. However, this combination carries the potential risk of cardiogenic shock. There are several scenarios where this combination can lead to shock, attributed to the variable pharmacokinetics of propafenone among individuals and its significant drug interactions with commonly used AV nodal blockers, such as metoprolol and diltiazem. Additionally, a significant proportion of the population has genetic polymorphisms that affect the metabolism of these medications. While pill-in-the-pocket propafenone is also employed in outpatient settings, unexpected severe and life-threatening reactions have been reported. In this context, we present a case report of severe propafenone toxicity in a closely monitored inpatient setting aimed at converting atrial fibrillation.
PubMed: 37908936
DOI: 10.7759/cureus.46282 -
International Journal of Dermatology Sep 2023
Topics: Humans; Mitragyna; Diltiazem; Calcium Channel Blockers; Hyperpigmentation; Eating
PubMed: 36942835
DOI: 10.1111/ijd.16650 -
Europace : European Pacing,... Dec 2023Chronic obstructive pulmonary disease (COPD) may influence management and prognosis of atrial fibrillation (AF), but this relationship has been scarcely explored in...
AIMS
Chronic obstructive pulmonary disease (COPD) may influence management and prognosis of atrial fibrillation (AF), but this relationship has been scarcely explored in contemporary global cohorts. We aimed to investigate the association between AF and COPD, in relation to treatment patterns and major outcomes.
METHODS AND RESULTS
From the prospective, global GLORIA-AF registry, we analysed factors associated with COPD diagnosis, as well as treatment patterns and risk of major outcomes in relation to COPD. The primary outcome was the composite of all-cause death and major adverse cardiovascular events (MACEs). A total of 36 263 patients (mean age 70.1 ± 10.5 years, 45.2% females) were included; 2,261 (6.2%) had COPD. The prevalence of COPD was lower in Asia and higher in North America. Age, female sex, smoking, body mass index, and cardiovascular comorbidities were associated with the presence of COPD. Chronic obstructive pulmonary disease was associated with higher use of oral anticoagulant (OAC) [adjusted odds ratio (aOR) and 95% confidence interval (CI): 1.29 (1.13-1.47)] and higher OAC discontinuation [adjusted hazard ratio (aHR) and 95% CI: 1.12 (1.01-1.25)]. Chronic obstructive pulmonary disease was associated with less use of beta-blocker [aOR (95% CI): 0.79 (0.72-0.87)], amiodarone and propafenone, and higher use of digoxin and verapamil/diltiazem. Patients with COPD had a higher hazard of primary composite outcome [aHR (95% CI): 1.78 (1.58-2.00)]; no interaction was observed regarding beta-blocker use. Chronic obstructive pulmonary disease was also associated with all-cause death [aHR (95% CI): 2.01 (1.77-2.28)], MACEs [aHR (95% CI): 1.41 (1.18-1.68)], and major bleeding [aHR (95% CI): 1.48 (1.16-1.88)].
CONCLUSION
In AF patients, COPD was associated with differences in OAC treatment and use of other drugs; Patients with AF and COPD had worse outcomes, including higher mortality, MACE, and major bleeding.
Topics: Humans; Female; Middle Aged; Aged; Aged, 80 and over; Male; Atrial Fibrillation; Prospective Studies; Risk Factors; Pulmonary Disease, Chronic Obstructive; Hemorrhage; Anticoagulants; Registries; Stroke
PubMed: 38266129
DOI: 10.1093/europace/euae021