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RSC Advances Jan 2024The thermodynamic properties and dissolution of indomethacin (INM) were analyzed as models for poorly water-soluble drugs. Physical mixtures of the most stable γ-form...
Quantification of crystallinity during indomethacin crystalline transformation from α- to γ-polymorphic forms and of the thermodynamic contribution to dissolution in aqueous buffer and solutions of solubilizer.
The thermodynamic properties and dissolution of indomethacin (INM) were analyzed as models for poorly water-soluble drugs. Physical mixtures of the most stable γ-form and metastable α-form of INM at various proportions were prepared, and their individual signal intensities proportional to their mole fractions were observed using X-ray powder diffraction and Fourier transform infrared spectrometry at standard temperature. The endothermic signals of the α-form, with a melting point of 426 K, and that of the γ-form, with a melting point of 433 K, were obtained by differential scanning calorimetry (DSC). Furthermore, an exothermic DSC peak of the α/γ-phase transition at approximately 428 K was obtained. As we computed the melting entropy of the α-form and that of its transformation, the frequency of the transition was quantitatively determined, which indicated the maximum of the α/γ-phase transition at an α-form proportion of 68%. Subsequently, the thermodynamic contributions of the α- and γ-forms were analyzed using a Van't Hoff plot for solubility in aqueous solutions at pH 6.8. The dissolution enthalpies for α- and γ-forms were 28.2 and 31.2 kJ mol, respectively, which are in agreement with the quantitative contribution predicted by the product of the temperature and melting entropy. The contribution of melting entropy was conserved in different dissolution processes with aqueous solvents containing lidocaine, diltiazem, l-carnosine, and aspartame as solubilizers; their γ-form Setschenow coefficients were -39.6, +82.9, -17.3, and +23.2, whereas those of the α-form were -39.7, +80.4, -16.7, and +22.7, respectively. We conclude that the dissolution ability of the solid state and solubilizers indicate their additivity independently.
PubMed: 38292264
DOI: 10.1039/d3ra08481g -
CPT: Pharmacometrics & Systems... Apr 2024Brigatinib is an oral anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive metastatic non-small cell lung cancer. In vitro studies...
Brigatinib is an oral anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive metastatic non-small cell lung cancer. In vitro studies indicated that brigatinib is primarily metabolized by CYP2C8 and CYP3A4 and inhibits P-gp, BCRP, OCT1, MATE1, and MATE2K. Clinical drug-drug interaction (DDI) studies with the strong CYP3A inhibitor itraconazole or the strong CYP3A inducer rifampin demonstrated that CYP3A-mediated metabolism was the primary contributor to overall brigatinib clearance in humans. A physiologically-based pharmacokinetic (PBPK) model for brigatinib was developed to predict potential DDIs, including the effect of moderate CYP3A inhibitors or inducers on brigatinib pharmacokinetics (PK) and the effect of brigatinib on the PK of transporter substrates. The developed model was able to predict clinical DDIs with itraconazole (area under the plasma concentration-time curve from time 0 to infinity [AUC] ratio [with/without itraconazole]: predicted 1.86; observed 2.01) and rifampin (AUC ratio [with/without rifampin]: predicted 0.16; observed 0.20). Simulations using the developed model predicted that moderate CYP3A inhibitors (e.g., verapamil and diltiazem) may increase brigatinib AUC by ~40%, whereas moderate CYP3A inducers (e.g., efavirenz) may decrease brigatinib AUC by ~50%. Simulations of potential transporter-mediated DDIs predicted that brigatinib may increase systemic exposures (AUC) of P-gp substrates (e.g., digoxin and dabigatran) by 15%-43% and MATE1 substrates (e.g., metformin) by up to 29%; however, negligible effects were predicted on BCRP-mediated efflux and OCT1-mediated uptake. The PBPK analysis results informed dosing recommendations for patients receiving moderate CYP3A inhibitors (40% brigatinib dose reduction) or inducers (up to 100% increase in brigatinib dose) during treatment, as reflected in the brigatinib prescribing information.
Topics: Humans; Rifampin; Cytochrome P-450 CYP3A Inhibitors; Itraconazole; Cytochrome P-450 CYP3A; Carcinoma, Non-Small-Cell Lung; ATP Binding Cassette Transporter, Subfamily G, Member 2; Lung Neoplasms; Neoplasm Proteins; Cytochrome P-450 CYP3A Inducers; Drug Interactions; Membrane Transport Proteins; Receptor Protein-Tyrosine Kinases; Models, Biological; Organophosphorus Compounds; Pyrimidines
PubMed: 38288787
DOI: 10.1002/psp4.13106 -
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 -
Cureus Dec 2023Taxanes, in combination with platinum-based drugs, are considered the initial treatment option for certain types of cancer, including ovarian cancer. Here, we report the...
Taxanes, in combination with platinum-based drugs, are considered the initial treatment option for certain types of cancer, including ovarian cancer. Here, we report the case of a 59-year-old woman who developed a malar rash on her face, a maculopapular rash on her forearms, and bluish discoloration on her fingers immediately following the end of the third cycle of chemotherapy. After discontinuing paclitaxel and using oral and topical steroids for rash and diltiazem and topical minoxidil for the treatment of Raynaud's phenomenon, the symptoms completely resolved. While taxanes are known to cause drug-induced lupus, there has never been any information on taxanes causing isolated Raynaud's phenomenon. This is the first case report that suggests paclitaxel-induced Raynaud's phenomenon along with paclitaxel-induced lupus.
PubMed: 38259408
DOI: 10.7759/cureus.50974 -
The Korean Journal of Internal Medicine Jan 2024There may be many predictors of anticoagulation-related gastrointestinal bleeding (GIB), but until now, systematic reviews and assessments of the certainty of the... (Meta-Analysis)
Meta-Analysis
BACKGROUND/AIMS
There may be many predictors of anticoagulation-related gastrointestinal bleeding (GIB), but until now, systematic reviews and assessments of the certainty of the evidence have not been published. We conducted a systematic review to identify all risk factors for anticoagulant-associated GIB to inform risk prediction in the management of anticoagulation- related GIB.
METHODS
A systematic review and meta-analysis were conducted to search PubMed, EMBASE, Web of Science, and Cochrane Library databases (from inception through January 21, 2022) using the following search terms: anticoagulants, heparin, warfarin, dabigatran, rivaroxaban, apixaban, DOACs, gastrointestinal hemorrhage, risk factors. According to inclusion and exclusion criteria, studies of risk factors for anticoagulation-related GIB were identified. Risk factors for anticoagulant-associated GIB were used as the outcome index of this review.
RESULTS
We included 34 studies in our analysis. For anticoagulant-associated GIB, moderate-certainty evidence showed a probable association with older age, kidney disease, concomitant use of aspirin, concomitant use of the antiplatelet agent, heart failure, myocardial infarction, hematochezia, renal failure, coronary artery disease, helicobacter pylori infection, social risk factors, alcohol use, smoking, anemia, history of sleep apnea, chronic obstructive pulmonary disease, international normalized ratio (INR), obesity et al. Some of these factors are not included in current GIB risk prediction models. such as anemia, co-administration of gemfibrozil, co-administration of verapamil or diltiazem, INR, heart failure, myocardial infarction, etc.
CONCLUSION
The study found that anemia, co-administration of gemfibrozil, co-administration of verapamil or diltiazem, INR, heart failure, myocardial infarction et al. were associated with anticoagulation-related GIB, and these factors were not in the existing prediction models. This study informs risk prediction for anticoagulant-associated GIB, it also informs guidelines for GIB prevention and future research.
Topics: Humans; Anemia; Anticoagulants; Diltiazem; Gastrointestinal Hemorrhage; Gemfibrozil; Heart Failure; Helicobacter Infections; Helicobacter pylori; Myocardial Infarction; Risk Factors; Verapamil
PubMed: 38062723
DOI: 10.3904/kjim.2023.098 -
RSC Advances Nov 2023Diltiazem (DTZ) is one of the most effective medications for treating cardiovascular diseases. It has been widely used for the treatment of angina pectoris, hypertension...
Diltiazem (DTZ) is one of the most effective medications for treating cardiovascular diseases. It has been widely used for the treatment of angina pectoris, hypertension and some types of arrhythmia. The development and application of a modified carbon paste sensor with improved detection limits for the potentiometric determination of diltiazem are the main goals of the current study. Sensitivity, long-term stability, reproducibility and improving the electrochemical performance are among the characteristics that have undergone careful examination. A modified carbon paste sensor based on β-cyclodextrin (β-CD) as ionophore, a lipophilic anionic additive (NaTPB) and a ZnO-decorated polyaniline/coal nanocomposite (ZnO@PANI/C) dissolved in dibutyl phthalate plasticizer, exhibited the best performance and Nernstian slope. The ZnO@PANI/C based sensor succeeded in lowering the detection limit to 5.0 × 10 through the linear range 1.0 × 10 to 1.0 × 10 mol L with fast response time ≤ 10.0 s. The prepared nanomaterial was characterized using X-ray diffraction (XRD), Fourier transform infrared (FT-IR) spectroscopy and scanning electron microscopy (SEM). The surface properties of the proposed sensor were characterized by electrochemical impedance spectroscopy (EIS). The selectivity behavior of the investigated sensor was tested against a drug with similar chemical structure and biologically important blood electrolytes (Na, K, Mg, and Ca). The proposed analytical method was applied for DTZ analysis in pure drug, pharmaceutical products and industrial water samples with excellent recovery data.
PubMed: 38035231
DOI: 10.1039/d3ra06849h -
Relaxant Effects of Piperine and Piperlongumine from Piper longum Fruits on Porcine Coronary Artery.Biological & Pharmaceutical Bulletin Jan 2024Since ancient times, Piper longum Linn. fruits have been recognized for exhibiting various effects, including the diaphoretic effects linked to enhanced blood flow....
Since ancient times, Piper longum Linn. fruits have been recognized for exhibiting various effects, including the diaphoretic effects linked to enhanced blood flow. Piperine and piperlongumine coexist in Piper longum Linn. fruits, although the cardiovascular effects of both compounds remain elusive. We investigated their action of piperine and piperlongumine in porcine coronary arteries, comparing them to the Ca channel antagonist diltiazem. Piperlongumine, unlike piperine or diltiazem, concentration-dependently inhibited basal contractile tone in endothelium-denuded coronary arteries. All three compounds inhibit tonic contractions induced by high potassium chloride (KCl) concentrations. The order of relaxation potency indexed by the half-maximal effective concentration (EC) were as follows: diltiazem > piperlongumine > piperine. These effects were not different between endothelium-intact and -denuded preparations. In endothelial-denuded preparations, pretreatment with these compounds not only inhibited KCl-induced tonic contractions attenuated calcium chloride (CaCl)-induced ones in a Ca-free medium. Histamine-induced phasic contractions in a Ca-free medium containing intracellular Ca chelator was completely suppressed by selective inositol trisphosphate receptor antagonist and piperlongumine, whereas piperine or diltiazem do not have the same effect. These findings suggest that piperine and piperlongumine similar to diltiazem cause vasorelaxation by inhibiting both KCl- and CaCl-induced contractions in coronary arteries, possibly through the inhibition of voltage-dependent Ca channels. Piperlongumine inhibits histamine-induced contractions in a Ca-free medium, which is associated with the intracellular Ca signaling pathway, suggesting that the relaxant effect of piperlongumine differs from that of piperine.
Topics: Animals; Swine; Diltiazem; Coronary Vessels; Fruit; Calcium Chloride; Histamine; Piper; Calcium; Potassium Chloride; Muscle Contraction
PubMed: 37989300
DOI: 10.1248/bpb.b23-00694 -
Journal of Pharmaceutical and... Jan 2024A number of medical conditions are identified as risk factors for suicide death; in particular, cardiovascular illnesses are recognized as a major suicide risk factor....
A number of medical conditions are identified as risk factors for suicide death; in particular, cardiovascular illnesses are recognized as a major suicide risk factor. In this case, self-poisoning is the common method of suicide and cardiovascular drugs are among the major medications associated with fatal overdose, with calcium channel blockers being one of the most common agents. The present study describes two different fatal suicide cases involving four cardiovascular drugs: carvedilol, doxazosin and amlodipine (case 1) and diltiazem (case 2). The concentrations of the target cardiovascular drugs in the different biological specimens (central and femoral blood, urine, liver, brain) are presented, giving information about the potentially fatal data and the distribution of the drugs in the body. The study led to the implementation of a fast, sensitive and simple method for the detection and quantification of the four commonly prescribed cardiovascular drugs in post-mortem specimens including fluids and tissues for forensic purposes. The method was fully validated. The toxicological results of the studied cases are discussed, along with the autopsy results, histopathological evidence, and circumstances of death. The toxicological findings presented in the study provide new data regarding cardiovascular drugs in different post-mortem specimens, which will contribute to the currently limited knowledge about the toxicological profile of cardiovascular drugs and their distribution.
Topics: Humans; Amlodipine; Diltiazem; Carvedilol; Doxazosin; Cardiovascular Agents; Suicide
PubMed: 37980865
DOI: 10.1016/j.jpba.2023.115831 -
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 -
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