Combination Of Verapamil Research Articles

Chemometric method development for the determination of naringin and verapamil

BackgroundBy resolving complicated spectra from drug combinations, chemometric techniques are valuable for multi-component investigation. The capacity to properly estimate combinations of components without separating drugs from their mixture is one of the benefits of chemometric analysis approaches over traditional analytical methods. These approaches are easy to use and sensitive even to the lowest concentrations. They are also practical, affordable, and cost-effective. In the current study, the chemometric aided spectrophotometric approach was used to evaluate the two drugs naringin and verapamil. The approach is multidimensional and based on chemometrics, which includes an orthogonal partial least square method that is a new refinement of the partial least squares regression analysis method. With this technique, no conversions are made to the spectrum that overlaps the two drugs. The tools UV-PROBE, SIMCA version 17, and excel were used to process the chemometric data.ResultsAccording to results from an orthogonal partial least square model, the mean percent recovery and relative standard deviation for the combination of verapamil with naringin were 100.80/1.19 and 100.836/1.35, respectively.The calibration model was used to predict known synthetic mixtures.This method shows good consistency in recovery ranging between 98.92 and 103.59% for VER and from 96.21 to 101.84% NAR. As saying the synthetic mixture revealed that it had a high percentage of purity.ConclusionsThe proposed chemometric method can estimate the quantitative amount of pharmaceuticals based on their dosage forms. This approach meets the requirements for the international conference on harmonization's (ICH) analytical criteria, such as precision and accuracy.Graphical

Comparing intralesional triamcinolone and verapamil-triamcinolone injections in keloids: A single-blinded randomised clinical trial.

In this clinical trial, we investigated the efficacy of two treatment methods for keloids resulting from surgical incisions: intralesional triamcinolone injections alone versus in combination with verapamil. Patients were divided into two groups: one received triamcinolone alone (Group T) and the other received a triamcinolone-verapamil blend (Group VT). Regular treatments were conducted until the keloids were nearly flat or for a maximum of eight sessions. Both groups showed significant improvements, but Group VT saw quicker resolution of skin redness and needed fewer sessions. Though the Vancouver Scar Scale (VSS) scores were generally similar across both groups, Group VT exhibited greater improvements, leading to lower final scores. The VT group also attained normal scar flexibility faster than the T group. These findings suggest that the combination of verapamil and triamcinolone provides a more effective treatment for keloids, thereby highlighting the potential of verapamil in scar reduction.

Amoebicidal effect of Fluconazole and Verapamil together against trophozoites and cysts of Acanthamoeba castellanii

Acanthamoeba species are an important pathogen that causes Acanthamoeba keratitis, which causes a visual loss, and encephalitis, which lead to the central nervous system infection and death. The options available to successfully treat Acanthamoeba infections have limited success. New therapeutic approaches must thus be developed, and especially combination medication therapy may be a successful and an effective strategy. The aim of this study was to assess the combination efficacy of verapamil and fluconazole against Acanthamoeba trophozoites and cysts. The effects of drugs on growth inhibition against Acanthamoeba were tested using amoebicidal assays. The viability of Acanthamoeba was assessed using Trypan blue and hemocytometer counts. The effect of three different concentrations of fluconazole, verapamil and fluconazole + verapamil combination on growth inhibition against Acanthamoeba trophozoites and cysts was significant compared to the control (p

Treatment pattern and response for cluster headache in Korea: A prospective multicenter observation study.

Only limited data are available regarding the treatment status and response to cluster headache in an Asian population. Therefore, this study aimed to provide a real-world treatment pattern of cluster headache and the response rate of each treatment in an Asian population. Patients with cluster headache were recruited between September 2016 and January 2019 from 16 hospitals in Korea. At the baseline visit, we surveyed the patients about their previous experience of cluster headache treatment, and acute and/or preventive treatments were prescribed at the physician's discretion. Treatment response was prospectively evaluated using a structured case-report form at 2 ± 2 weeks after baseline visit and reassessed after three months. Among 295 recruited patients, 262 experiencing active bouts were included. Only one-third of patients reported a previous experience of evidence-based treatment. At the baseline visit, oral triptans (73.4%), verapamil (68.3%), and systemic steroids (55.6%) were the three most common treatments prescribed by the investigators. Most treatments were given as combination. For acute treatment, oral triptans and oxygen were effective in 90.1% and 86.8% of the patients, respectively; for preventive treatment, evidence-based treatments, i.e. monotherapy or different combinations of verapamil, lithium, systemic steroids, and suboccipital steroid injection, helped 75.0% to 91.8% of patients. Our data provide the first prospective analysis of treatment responses in an Asian population with cluster headache. The patients responded well to treatment despite the limited availability of treatment options, and this might be attributed at least in part by combination of medications. Most patients were previously undertreated, suggesting a need to raise awareness of cluster headache among primary physicians.

Efficacy and safety of intracoronary epinephrine for the management of the no-reflow phenomenon following percutaneous coronary interventions: a systematic-review study.

Currently, no pharmacological or device-based intervention has been fully proven to reverse the no-reflow phenomenon. To assess the efficacy and safety of intracoronary (IC) epinephrine in the management of no-reflow phenomenon following percutaneous coronary intervention (PCI), either as first-line treatment or after the failure of conventional agents. Systematic review. PubMed and Scopus databases were systematically searched up to 28 May 2022, with additional manual search on the Google Scholar and review of the reference lists of the relevant studies to identify all published studies. Cohort studies, case series, and interventional studies written in English which evaluated the efficacy and safety of IC epinephrine in patients with no-flow phenomenon were included in our review. Six of the 646 articles identified in the initial search met our inclusion criteria. IC epinephrine was used either as a first-line treatment [two randomized clinical trials (RCTs)] or after the failure of conventional agents (two cohort studies and two case series) for restoring the coronary flow, mainly after primary PCI. As first-line therapy, IC epinephrine successfully restored coronary flow in over 90% of patients in both RCTs, which significantly outperformed IC adenosine (78%) but lagged behind combination of verapamil and tirofiban (100%) in this regard. In the refractory no-flow phenomenon, successful reperfusion [thrombolysis in myocardial infarction (TIMI) flow grade = 3] was achieved in three out of four patients after the administration of IC epinephrine based on the results from both case series. Their findings were confirmed by a recent cohort study that further compared IC epinephrine with IC adenosine and found significant differences between them in terms of efficacy [% TIMI flow grade 3: (69.1% versus 52.7%, respectively; p value = 0.04)] and 1-year major adverse cardiac event (MACE) outcomes (11.3% versus 26.7%, respectively; p value ⩽ 0.01). Overall, malignant ventricular arrhythmias were reported in none of the patients treated with IC epinephrine. Results from available evidence suggest that IC epinephrine might be an effective and safe agent in managing the no-reflow phenomenon.

Carvacrol Enhance Apoptotic Effect of 5-FU on MCF-7 Cell Line via inhibiting P-glycoprotein: An In-silco and In-vitro Study.

P-glycoprotein (P-gp), is an ATP-dependent efflux transporter and overexpressed in cancer cells which is responsible for drug resistance and transportation of anticancer agents out of cells. Hence, P-gp inhibition is a promising way to reverse multi-drug resistance, finding a suitable inhibitor is essential. Carvacrol, an active compound of thyme, has been shown anticancer properties in several types of cancers but the mechanisms underlying this effect remain unclear. Here, we evaluated the inhibitory effects of carvacrol on P-gp by In-silco and in-vitro studies. carvacrol was docked against P-gp via autodock vina software to identify the potential binding of this agent. Verapamil, a well-known P-gp inhibitor, was selected as the control ligands. Cell proliferation and apoptosis were assessed using MTT assay and ELISA cell death assay, respectively. It was observed that carvacrol exhibited appropriate affinity (-7 kcal/mol) to drug binding pocket of P-gp when compared with verapamil that showed binding affinities of -8 kcal/mol. The result of MTT assay showed a dose-dependent inhibitory effect of carvacrol and 5-FU. Data of apoptosis assay showed that combining carvacrol with 5-FU increased apoptotic effect of 5-FU 6.7-Fold rather than the control group. This ability to enhance apoptosis is more than the combination of verapamil and 5-FU (4.26-Fold). These results provide important evidence that carvacrol may be a promising agent able to overcome P-gp-mediated MDR.

Investigation of the effect of the calcium channel blocker, verapamil, on the parasite burden, inflammatory response and angiogenesis in experimental Trichinella spiralis infection in mice

Trichinella spiralis larvae have very special characters that make them able to completely transform the function of the affected muscle cells towards a self-serving environment, offering them nourishment and protection via what is known as “nurse cells”. This setting may be affected by drugs that are used for the treatment of co-morbidities and co-infections as calcium channel blockers, which are widely used in clinical practice. In the present study, the effects of verapamil, ivermectin (IVM), and their combined administration on the parasitic burden, immuno-pathology and angiogenesis were investigated during experimental trichinellosis. Estimation of intestinal adult parasitic stages and muscle larvae was done. VEGF gene expression and CD31 immunohistochemical local expression were measured to investigate angiogenesis, in addition to histopathological examination to explore the extent of inflammation. Although verapamil did not have an effect on the adult worm count during the intestinal phase, it induced an anti-inflammatory effect on intestinal pathology. During the muscle phase, it was very effective in reducing the larval count by 93.78%. IVM effectively reduced the worm count by 85.34%, and the muscle larval count by 97.84%, while combined verapamil and IVM administration resulted in a significant reduction in both adult parasites by 69.5% and larval stages by 99%. Both verapamil and IVM and their combination induced a potent decrease in local CD31 protein expression and VEGF gene expression. The important role of calcium and calcium channels during the pathology of trichinellosis, in addition to the pivotal role of calcium on biological processes such as immunity and angiogenesis, make calcium-channel blockers promising candidates for drug repurposing in the management of helminthic infection.

Dual intra-arterial vasodilators in the management of post-aneurysmal subarachnoid haemorrhage vasospasm

ObjectiveEndovascular chemical angioplasty has been in practice in patients with symptomatic cerebral vasospasm secondary to aneurysmal subarachnoid haemorrhage in many neurosurgical centres. However, the evidence base is derived from clinical case series and expert consensus. The aim of this retrospective cohort study is to evaluate the immediate and functional outcomes of endovascular intervention in aneurysmal subarachnoid haemorrhage cerebral vasospasm treated with a combination of vasodilators. MethodsA cohort of 25 patients was identified. Each patient underwent surgical clipping, and endovascular treatment for vasospasm. A combination of Verapamil and Nimodipine was intra-arterially administered. Statistical analysis was performed to determine the rate of response. The angiographic response and functional outcome on discharge (modified Rankin score - MRS) were used as markers of outcome. ResultsThe study cohort consisted of 25 patients with a mean age of 50.3 (SD 11.2). A total of 135 therapeutic DSA’s were performed. There was an associated between MRS outcomes and number of vasodilation’s each patient received. For each additional vasodilation episode, the odds of a poor outcome increased by 1.190. An angiographic response was demonstrated in 88% of patients, a clinical response in 27%. A good functional outcome was achieved in 17/25, 71% at discharge. ConclusionThe combination therapy of Intra-arterial nimodipine and verapamil in patients with aneurysmal subarachnoid haemorrhage vasospasm appears to have a synergistic, if not comparable, outcome to from solitary vasodilatory treatment results and potentially promote future studies with prospective designs to measure the outcomes.

Comparative efficacy of intralesional verapamil hydrochloride, triamcinolone acetonide and combination of both drug in hypertrophic scars and keloids at tertiary care center

Background: Keloids and hypertrophic scars are still a therapeutic problem. Despite numerous proposed therapies reported in the literature, the management of keloid and hypertrophic scars is still challenging as there is no universally accepted treatment regimen. Compare the efficacy intralesional verapamil hydrochloride and triamcinolone acetonide separately as well as combination of both drug in treatment of hypertrophic scars and keloids.Methods: A retrospective study was carried out at the general surgery department (plastic surgery unit) at the JNUIMSRC Jaipur, Rajasthan. Total of 150 patients (60 males and 90 females) between 18 to 60 years of age were enrolled fulfilling the inclusion criteria. They were randomly categorized in to three groups (group A, B and C), based on treatment they received viz. verapamil alone, triamcinolone alone and combination of both drugs respectively. Assessment of the scars were done prior to or on the day of the first injection and at 24 weeks after the end of injection scheme by Vancouver scar scale (VSS). The decreasing values reflected clinical improvement of the scar.Results: Better improvement observed in all four parameters: height, vascularity, pliability and pigmentation among patients receiving combination of both triamcinolone-verapamil drugs as compare to those patients receiving drugs separately either verapamil or triamcinolone alone. For parameters height, pliability and pigmentation, the improvement was found to be statistically significant (p<0.05)Conclusions: Study highlights that the combined verapamil and triamcinolone therapy scheme causes remarkable scar improvement in keloid and hypertrophic scars in comparison to single drug scheme.

Amlodipine and Verapamil, Voltage-Gated Ca2+ Channel Inhibitors, Suppressed the Growth of Gastric Cancer Stem Cells.

The membrane transporters activated in cancer stem cells (CSCs) are the target of novel cancer therapies for gastric cancer. The present study investigated ion channel expression profiles in gastric CSCs (GCSCs). Cells strongly expressing CD44 were separated from MKN74 cells, a human gastric cancer cell line, by fluorescence-activated cell sorting (FACS), and GCSCs were identified based on tumorsphere formation. Gene expression profiles in GCSCs were examined by a microarray analysis. Among MKN74 cells, CD44 messenger RNA levels were higher in CSCs than in non-CSCs. These CSCs also exhibited resistance to cisplatin. The microarray analysis revealed that the expression of several genes related to voltage-gated Ca2+ channels (VGCCs), including CACNA2D1 and CACNB4, was upregulated. The cytotoxicities of the CACNA2D1 inhibitor amlodipine and the CACNB4 inhibitor verapamil were greater at lower concentrations in CSCs than in non-CSCs, and markedly reduced tumorsphere numbers. Tumor volumes were significantly smaller in a xenograft nude mouse model treated with amlodipine or verapamil in combination with cisplatin than in that treated with cisplatin alone. The present results indicate that VGCCs play a role in maintaining CSCs, and demonstrated the potential of their specific inhibitors, amlodipine and verapamil, as targeted therapeutic agents against gastric cancer.

Verapamil inhibits efflux pumps in Candida albicans, exhibits synergism with fluconazole, and increases survival of Galleria mellonella

ABSTRACT The emergence of resistance requires alternative methods to treat Candida albicans infections. We evaluated efficacy of the efflux pump inhibitor (EPI) verapamil (VER) with fluconazole (FLC) against FLC-resistant (CaR) and -susceptible C. albicans (CaS). The susceptibility of both strains to VER and FLC was determined, as well as the synergism of VER with FLC. Experiments were performed in vitro for planktonic cultures and biofilms and in vivo using Galleria mellonella. Larval survival and fungal recovery were evaluated after treatment with VER and FLC. Data were analyzed by analysis of variance and Kaplan-Meier tests. The combination of VER with FLC at sub-lethal concentrations reduced fungal growth. VER inhibited the efflux of rhodamine 123 and showed synergism with FLC against CaR. For biofilms, FLC and VER alone reduced fungal viability. The combination of VER with FLC at sub-lethal concentrations also reduced biofilm viability. In the in vivo assays, VER and FLC used alone or in combination increased the survival of larvae infected with CaR. Reduction of fungal recovery was observed only for larvae infected with CaR and treated with VER with FLC. VER reverted the FLC-resistance of C. albicans. Based on the results obtained, VER reverted the FLC-resistance of C. albicans and showed synergism with FLC against CaR. VER also increased the survival of G. mellonella infected with CaR and reduced the fungal recovery.

Follicle inhibition at the primordial stage without increasing apoptosis, with a combination of everolimus, verapamil.

The aim of the present study was to test whether inhibition of ovarian primordial follicles and subsequent activation can be achieved by transient mTOR inhibition. In this preclinical investigation, forty-five female immature Wistar rats were randomized in 5 groups. The control group received subcutaneous saline injections. The other groups received Everolimus, Everolimus plus Verapamil, Everolimus plus Fisetin, and Fisetin alone. Primary and secondary outcomes were measured in the left ovary after a treatment period of 8weeks. Ten days later, animals received 35IU FSH for 4days and 35IU of hCG on the 5th day. The same parameters were examined in the right ovary. AMH, estradiol, and progesterone levels were assessed at the end of both interventions. Significantly, more primordial and less atretic follicles were observed in the Everolimus plus Verapamil group. AMH and progesterone levels were substantially lower in the Everolimus group. Interestingly, after ovarian stimulation higher levels of AMH and progesterone were observed in the Everolimus plus Verapamil group. Immunoblot analysis of ovarian extracts revealed that the administration of Everolimus led to a significant reduction in the mTORC1-mediated phosphorylation of the 70-kDa ribosomal protein S6 kinase 1. This decrease was reversed in the presence of FSH after stopping drug administration. The expression of the anti-apoptotic molecule Bcl2 as well as of LC3-II and ATG12 was increased after removal of the Everolimus plus Verapamil combination, indicating reduced apoptosis and increased autophagy, whereas the levels of the proliferation marker PCNA in the granulosa cells were elevated, consistent with initiation of follicular growth.Thus, the combination of Everolimus plus Verapamil is capable of increasing the number of competent primordial follicles while reducing atresia.

Metabolomics analysis of multidrug resistance in colorectal cancer cell and multidrug resistance reversal effect of verapamil.

Multidrug resistance remains a huge challenge in the chemotherapy of cancer and numerous studies have reported that P-glycoprotein is the most common mechanism of multidrug resistance. Verapamil has been shown to be able to reverse development of multidrug resistance mediated by P-glycoprotein. However, the mechanism of action for verapamil in reversing multidrug resistance at the metabolic level has been rarely reported. In this research, we report the reversal effect of verapamil on multidrug resistance and its mechanisms of action using metabolomics. The results show that the P-glycoprotein-mediated chemotherapy drug resistance was significantly reversed by verapamil in resistant SW620/Ad300 cells. In-depth studies demonstrated that verapamil at reversal concentration had no effect on the P-glycoprotein expression level, but increased intramolecular accumulation of paclitaxel in SW620/Ad300 cells. Metabolomics revealed that the multidrug resistance of SW620/Ad300 cells was related to changes in glycerophospholipid metabolism, sphingolipid metabolism and citric acid cycle, and verapamil could antagonize the multidrug resistance by reversing the above-mentioned glycerophospholipid metabolism and sphingolipid metabolism. This research shows the multidrug resistance reversal mechanism of verapamil at the metabolic level, which helps in understanding the exact multidrug resistance mechanism of verapamil and might be potentially useful to find new multidrug resistance reversal agents. The combination of verapamil (VRP) and paclitaxel (PTX) yielded synergistic effects. VRP had no effect on the expression of P-gp, but increased intramolecular accumulation of PTX. VRP antagonized the MDR by regulating glycerophospholipid metabolism and sphingolipid metabolism.

Capsaicin Causes Vasorelaxation of Rat Aorta through Blocking of L-type Ca2+ Channels and Activation of CB1 Receptors.

The aim of this work was to determine whether Capsaicin may exert a vascular regulation through the activation of CB1 and/or CB2 receptors causing vasorelaxation in the rat aorta. Our results show the location of TRPV1 mainly in the endothelial and smooth muscle cells membrane. Nevertheless, Capsaicin caused vasorelaxation of this artery through a mechanism independent of TRPV1, since the specific antagonists Capsazepine and SB-366791 did not block the effect of Capsaicin. Because the significant expression of CB1 and CB2 receptors has been previously reported in the rat aorta, we used antagonists for these two receptors prior to the addition of Capsaicin. In these experiments, we found that the inhibition of CB1 using AM281, decreases the vasorelaxant effect caused by Capsaicin. On the other hand, the vasorelaxant effect is not altered in the presence of the CB2 receptor antagonist AM630. Furthermore, a partial decrease of the effect of Capsaicin was also seen when L-type calcium channels are blocked. A complete block of Capsaicin-induced vasorelaxation was achieved using a combination of Verapamil and AM281. In accordance to our results, Capsaicin-induced vasorelaxation of the rat aorta is neither dependent of TRPV1 or CB2 receptors, but rather it is strongly suggested that a tandem mechanism between inactivation of L-type calcium channels and the direct activation of CB1 receptors is involved. These findings are supported by CB1 docking simulation which predicted a binding site on CB1 receptors for Capsaicin.

Development and Validation of a Liquid Chromatographic Method for Concurrent Assay of Weakly Basic Drug Verapamil and Amphoteric Drug Trandolapril inPharmaceutical Formulations

The analysis of weakly basic drugs such as verapamil by reverse-phase liquid chromatography remains a problem, particularly when present in combination with other drugs such as amphoteric compounds like trandolapril. In this study, the simple, accurate, precise and fully validated RP-LC method for the simultaneous determination of verapamil and trandolapril in combined dosage forms has been developed. The LC method allowed quantitation over the ranges of 0.50-18.00 μg/mL and 0.05-1.00μg/mL for verapamil and trandolapril, respectively. The detection limits were found to be 0.008μg/mL and 0.018μg/mL for verapamil and trandolapril, respectively. Moreover, pKa values of verapamil and trandolapril were determined via the dependence of the retention factor on the pH of the mobile phase for ionizable substances. The effect of the mobile phase composition on the ionization constant was studied by measuring the pKa at different methanol-water mixtures, ranging 50-65% (v/v). It was shown that RP-HPLC was sllitab1e for the high throughput analysis of the combination of verapamil and trandolapril. The method also allows a number of cost and time saving benefits and can be readily employed for the analysis of pharmaceutical formulations. The method has been verified, without any interference from excipients, for the concurrent analysis of these compounds in tablets.

The effects of verapamil and heparin co-administration on sperm parameters and oxidative stress in prevention of testicular torsion/detorsion damage in rats.

In this research, the impacts of combined administration of verapamil and heparin on testicular torsion damage were examined. In this experimental study, 30 sexually mature male Wistar albino rats were divided into five equal groups haphazardly (n=6): Group 1 was the sham group. In group 2, a 2-hr testicular torsion was induced, and thereafter, detorsion was done. Rats in group 3 and group 4 experienced an identical surgical procedure like group 2, but verapamil and heparin were administered in 0.3mg/kg and 800IU/kg doses respectively, and in group 5, a combination of verapamil and heparin were administered. Intraperitoneal drug injection in all treatment groups was done 30min before testicular detorsion. Testicular torsion significantly changed sperm parameters, oxidative stress biomarkers and Cosentino's histological score compared to the sham group (p<.05). All treatment groups reduced testicular damage by decreasing oxidative stress and improving sperm parameters, but heparin and co-administration of verapamil and heparin were significantly better than verapamil injection alone. However, heparin injected groupwas more effective than other treatment groups (p<.05). Overall, an anticoagulant like heparin is more effective than a calcium channel blocker such as verapamil, and it is more likely to reduce testicular torsion injuries.

A REVIEW ON ANALYTICAL METHOD DEVELOPMENT AND VALIDATION OF CALCIUM CHANNEL BLOCKERS AND ANGIOTENSIN- CONVERTING ENZYME INHIBITORS IN BULK AND PHARMACETICAL FORMULATION

A simple, economical and rapid by UV detector and PDA Detector was used for Estimation of Trandolapril and Verapamil in combination and other drugs in various Pharmaceutical formulation. Calcium channel blockers(CCBs) and angiotensin- converting enzyme (ACE) inhibitors has been developed and fully validated by High performance liquid Chromatographic Methods. Calcium channel blockers (CCBs) or Calcium antagonists are among the most widely used drugs in cardiovascular medicine and hypertension also in angina. CCBs promote vasodilator activity by reducing calcium influx into vascular smooth muscle cells by interfering with calcium channels in the cell membrane. Trandolapril is a potent nonsulfhydryl and dicarboxyl containing Angiotensin converting inhibitor (ACE). Trandolapril used to treatment of hypertension appears to result the inhibition of tissue ACE activity and to improve survival myocardial infarction thereby reduce angiotensin II formation.&#x0D; It includes drugs like Trandolapril, Norverapamil, Nifedipine, Verapamil. This Review enlists different method Developed, Validated and determination of Calcium channel blockers and angiotensin- converting enzyme inhibitors Like, RP-HPLC, LC-MS/MS and HPLC UV- Spectophotometric method. This method was also validated for various validation terms indicates that precise, accurate, linearly, and limit of Detection and limit of Quantitation as per ICH guidelines.&#x0D; Keywords: HPLC Chromatography, Calcium Channel blocker, angiotensin- converting enzyme (ACE) inhibitors, Hypertension, Validation etc.

Beta-blocker Use in Moderate and Severe Chronic Obstructive Pulmonary Disease.

Introduction:The most appropriate choice of pharmacological treatment of heart rhythm disorders occurring in patients with chronic obstructive pulmonary disease (COPD) and cardiovascular comorbidity is often a topic of debate between pulmonologists and cardiologists in clinical practice, although numerous studies and clinical trials have demonstrated evidence to support the use of selective beta-blockers (BBs) in these patients.Aim:To examine the difference in the number of exacerbations in patients treated with a combination of verapamil and digoxin or BB alone in patients with different COPD stages.Patients and methods:The study included 68 patients (n = 68) diagnosed with COPD who were followed-up during a 12-month period, and the number of exacerbations were analyzed. The patients were divided into two groups according to the stage of COPD: GOLD II (moderate), and GOLD III (severe), and in each group a subdivision was established in relation to the use of either a combination of verapamil and digoxin or the use of BBs alone in pharmacological treatment. The inclusion criteria for patients were defined as following: a) established diagnosis of COPD according to present or deteriorated relevant clinical symptoms and signs, b) the ejection fraction (EF) of a left ventricle (LV) >35%, and c) spirometric cut-points classified as GOLD II (FEV1 / FVC <0.7, FEV1 predicted 50-80%), or GOLD III (FEV1/FVC <0.7, FEV1 predicted 30-50%) stage of the COPD. The exclusion criteria were EF of LV <35% and a lethal outcome during a follow-up period (2 patients were encountered). Exacerbation was defined as functional deterioration of the COPD symptoms verified by spirometric functional testing, frequency of hospitalizations according to GOLD stage assignment or verified clinical symptoms deterioration.Results:Regardless the pharmacological treatment, there is a statistically significant increase in the number of COPD exacerbations, in a 12-month period follow-up, in the GOLD III group (severe) compared to the GOLD II group (moderate). In the group of patients taking verapamil and digoxin, a two-tailed t-test was used to analyze the results between the GOLD II and GOLD III stage groups, p = 0.01, and 2. In the group of patients taking BBs, a two-tailed t-test was also used to analyze the results between the GOLD II and GOLD III stage groups, p = 0.003). Within the COPD GOLD II stage group, there appears to be no statistically significant difference in the number of exacerbations between the patients taking verapamil and digoxin (n = 24) and the patients taking BBs alone (n = 15), although, in patients taking BBs alone, there appears to be a trend towards a decrease in the exacerbations compared to the number of exacerbations in patients taking verapamil and digoxin (p = 0.007). Within the COPD GOLD III stage group, there is no difference in the number of exacerbations between the patients taking verapamil and digoxin (n = 20), and the patients taking BBs alone (n = 9), as analyzed by a two-tailed t-test, p = 0.577.Conclusion:Use of selective BBs in the treatment of cardiovascular comorbidity in patients with COPD represents a far better choice of pharmacological approach in the treatment of patients diagnosed with COPD GOLD II (moderate) stage.

Study of New Therapeutic Strategies to Combat Breast Cancer Using Drug Combinations.

Cancer is a disease that affects and kills millions of people worldwide. Breast cancer, especially, has a high incidence and mortality, and is challenging to treat. Due to its high impact on the health sector, oncological therapy is the subject of an intense and very expensive research. To improve this therapy and reduce its costs, strategies such as drug repurposing and drug combinations have been extensively studied. Drug repurposing means giving new usefulness to drugs which are approved for the therapy of various diseases, but, in this case, are not approved for cancer therapy. On the other hand, the purpose of combining drugs is that the response that is obtained is more advantageous than the response obtained by the single drugs. Using drugs with potential to be repurposed, combined with 5-fluorouracil, the aim of this project was to investigate whether this combination led to therapeutic benefits, comparing with the isolated drugs. We started with a screening of the most promising drugs, with verapamil and itraconazole being chosen. Several cellular viability studies, cell death and proliferation studies, mainly in MCF-7 cells (Michigan Cancer Foundation-7, human breast adenocarcinoma cells) were performed. Studies were also carried out to understand the effect of the drugs at the level of possible therapeutic resistance, evaluating the epithelial-mesenchymal transition. Combining all the results, the conclusion is that the combination of verapamil and itraconazole with 5-fluorouracil had benefits, mainly by decreasing cell viability and proliferation. Furthermore, the combination of itraconazole and 5-fluorouracil seemed to be the most effective, being an interesting focus in future studies.

Simultaneous spectrophotometric determination of drugs lacking peak maxima in their zero-order profiles by graphical or statistical representation of data

Trandolapril has no sharp peak in its zero-order spectrum, therefore it is difficult to be measured by direct spectrophotometry. In this study, direct univariate spectrophotometric methods were developed and validated for determination of Trandolapril and Verapamil combination in pure and tablet dosage forms. The first method for measuring both Trandolapril and Verapamil is Absorbance Subtraction (AS), this method depends on the presence of iso-absorptive point in the zero-order curve at 217 nm. It has the advantage of measuring the concentration of both Trandolapril and Verapamil from unified regression equation at the iso-absorptive point. The second, third and fourth methods were applied on the first order spectra of the studied drugs. Second method is Derivative Subtraction (DS) for Trandolapril and Derivative subtraction followed by spectrum subtraction (DS-SS) for Verapamil. The third and fourth methods are constant value and concentration value methods. In the concentration value method, the concentration of the drugs is determined from the graphical representation without the use of regression equations. All the developed methods were validated as per International Conference on Harmonization guidelines and the results proved that the developed methods are simple, accurate, and selective. Moreover, a statistical comparison between the developed methods and a reference method was done. Also, One-way ANOVA statistical test was done between all the proposed spectrophoto-metric methods and results showed no significant differences.