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Journal of Chromatography. A Aug 2024Universal microchip isotachophoresis (μITP) methods were developed for the determination of cationic and anionic macrocomponents (active pharmaceutical ingredients and...
Universal microchip isotachophoresis (μITP) methods were developed for the determination of cationic and anionic macrocomponents (active pharmaceutical ingredients and counterions) in cardiovascular drugs marketed in salt form, amlodipine besylate and perindopril erbumine. The developed methods are characterized by low reagent and sample consumption, waste production and energy consumption, require only minimal sample preparation and provide fast analysis. The greenness of the proposed methods was assessed using AGREE. An internal standard addition was used to improve the quantitative parameters of μITP. The proposed methods were validated according to the ICH guideline. Linearity, precision, accuracy and specificity were evaluated for each of the studied analytes and all set validation criteria were met. Good linearity was observed in the presence of matrix and in the absence of matrix, with a correlation coefficient of at least 0.9993. The developed methods allowed precise and accurate determination of the studied analytes, the RSD of the quantitative and qualitative parameters were less than 1.5% and the recoveries ranged from 98 to 102%. The developed μITP methods were successfully applied to the determination of cationic and anionic macrocomponents in six commercially available pharmaceutical formulations.
Topics: Isotachophoresis; Amlodipine; Reproducibility of Results; Green Chemistry Technology; Quality Control; Pharmaceutical Preparations; Perindopril; Limit of Detection; Electrophoresis, Microchip; Cardiovascular Agents
PubMed: 38852265
DOI: 10.1016/j.chroma.2024.465055 -
Expert Review of Pharmacoeconomics &... Jun 2024To evaluate the cost-effectiveness of a single-pill combination (SPC) of perindopril/amlodipine/indapamide versus its free equivalent combination (FEC) in adults with...
Cost-effectiveness analysis comparing single-pill combination of perindopril/amlodipine/indapamide to the free equivalent combination in patients with hypertension from an Italian national health system perspective.
OBJECTIVE
To evaluate the cost-effectiveness of a single-pill combination (SPC) of perindopril/amlodipine/indapamide versus its free equivalent combination (FEC) in adults with hypertension in Italy.
METHODS
A Markov model was developed to perform a cost-utility analysis with a lifetime horizon and an Italian healthcare payer's perspective. In the model, the additional effect of the SPC on blood pressure level compared with the FEC was translated into a decreased risk of cardiovascular events and CKD, which was modeled via Framingham risk algorithms. Difference in persistence rates of SPC and FEC were modeled via discontinuation rates.
RESULTS
A perindopril/amlodipine/indapamide SPC is associated with lower cost and better health outcomes compared to its FEC. Over a lifetime horizon, it is associated with a 0.050 QALY gain and cost savings of €376, resulting from lower cardiovascular event rates. In the alternative scenario, where different approach for modeling impact of adherence was considered, incremental gain of 0.069 QALY and savings of €1,004 were observed. Results were robust to sensitivity and scenario analyses, indicating that use of this SPC is a cost-effective strategy.
CONCLUSIONS
The findings indicate that a perindopril/amlodipine/indapamide SPC is a cost-saving treatment option for hypertension in Italy, compared to its FEC.
PubMed: 38848115
DOI: 10.1080/14737167.2024.2365988 -
Current Drug Safety May 2024Serotonin syndrome is a potentially life-threatening condition that can occur as a result of the therapeutic use of serotonergic medications or drug interaction. In this...
INTRODUCTION
Serotonin syndrome is a potentially life-threatening condition that can occur as a result of the therapeutic use of serotonergic medications or drug interaction. In this study, we describe two cases of serotonin syndrome-associated hypertensive crisis following linezolid use.
CASE PRESENTATION
The first patient was a 52-year-old female who was admitted due to a diabetic foot infection and pneumonia associated with a decreased consciousness level. Serotonin syndrome occurred 24 hours after starting the linezolid use. Resistant hypertension was the main hemodynamic finding. It could not be controlled with amlodipine, valsartan, prazosin, and nitroglycerin infusion. Resistant hypertension and other symptoms of serotonin syndrome were resolved about 48 hours after discontinuation of linezolid use. The second case was a man with a history of kidney transplant, diabetes, and hypertension. He was admitted to the ICU due to severe COVID-19 broad-spectrum antibiotics [linezolid, cefepime], and remdesivir was initiated. Following intubation, continuous infusion of fentanyl was used for sedation. Within 24 hours after fentanyl and linezolid initiation, severe agitation, eye clonus, hyperreflexia, hypertension [160-186 /90-110 mmHg], and tachycardia [>100/min] were noted. With the possible diagnosis of serotonin syndrome, fentanyl was discontinued, and morphine was initiated. The patient's symptoms improved 48 hours after discontinuation of fentanyl.
CONCLUSION
Both of the patients had a history of controlled hypertension. However, serotonin syndrome occurred following the use of linezolid and concomitant/recent use of serotonergic agents. A thorough evaluation of the patient's medical history and current situation can help clinicians prevent this syndrome in critically ill patients.
PubMed: 38847376
DOI: 10.2174/0115748863299100240507052341 -
Kardiologiia May 2024Based on a clinical case report, the article shows the individual selection of effective therapy for a patient with arterial hypertension and dyslipidemia. Taking into...
Based on a clinical case report, the article shows the individual selection of effective therapy for a patient with arterial hypertension and dyslipidemia. Taking into account the risk factors for cardiovascular diseases, Equamer® was selected as a fixed combination of amlodipine + lisinopril + rosuvastatin capsules 10 mg+20 mg+10 mg (Gedeon Richter Plc, Budapest, Hungary). In the patient with hypertension, ischemic heart disease was verified, and stenting of the anterior descending artery was performed. According to the clinical guidelines, when arterial hypertension is associated with ischemic heart disease, the drug therapy of choice should be a combination of dihydropyridine slow calcium channel blockers with an angiotensin-converting enzyme inhibitor. The fixed triple combination of amlodipine, lisinopril, and rosuvastatin is one of the most appropriate in this clinical situation; this combination targets the two major risk factors for cardiovascular diseases, arterial hypertension and dyslipidemia.
Topics: Humans; Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Drug Combinations; Dyslipidemias; Hypertension; Lisinopril; Rosuvastatin Calcium; Treatment Outcome
PubMed: 38841786
DOI: 10.18087/cardio.2024.5.n2656 -
Prescribed Drug Use and Aneurysmal Subarachnoid Hemorrhage Incidence: A Drug-Wide Association Study.Neurology Jun 2024Current benefits of invasive intracranial aneurysm treatment to prevent aneurysmal subarachnoid hemorrhage (aSAH) rarely outweigh treatment risks. Most intracranial...
BACKGROUND AND OBJECTIVES
Current benefits of invasive intracranial aneurysm treatment to prevent aneurysmal subarachnoid hemorrhage (aSAH) rarely outweigh treatment risks. Most intracranial aneurysms thus remain untreated. Commonly prescribed drugs reducing aSAH incidence may provide leads for drug repurposing. We performed a drug-wide association study (DWAS) to systematically investigate the association between commonly prescribed drugs and aSAH incidence.
METHODS
We defined all aSAH cases between 2000 and 2020 using codes from the Secure Anonymised Information Linkage databank. Each case was matched with 9 controls based on age, sex, and year of database entry. We investigated commonly prescribed drugs (>2% in study population) and defined 3 exposure windows relative to the most recent prescription before index date (i.e., occurrence of aSAH): current (within 3 months), recent (3-12 months), and past (>12 months). A logistic regression model was fitted to compare drug use across these exposure windows vs never use, controlling for age, sex, known aSAH risk factors, and health care utilization. The family-wise error rate was kept at < 0.05 through Bonferroni correction.
RESULTS
We investigated exposure to 205 commonly prescribed drugs between 4,879 aSAH cases (mean age 61.4, 61.2% women) and 43,911 matched controls. We found similar trends for lisinopril and amlodipine, with a decreased aSAH risk for current use (lisinopril odds ratio [OR] 0.63, 95% CI 0.44-0.90, amlodipine OR 0.82, 95% CI 0.65-1.04) and an increased aSAH risk for recent use (lisinopril OR 1.30, 95% CI 0.61-2.78, amlodipine OR 1.61, 95% CI 1.04-2.48). A decreased aSAH risk in current use was also found for simvastatin (OR 0.78, 95% CI 0.64-0.96), metformin (OR 0.58, 95% CI 0.43-0.78), and tamsulosin (OR 0.55, 95% CI 0.32-0.93). By contrast, an increased aSAH risk was found for current use of warfarin (OR 1.35, 95% CI 1.02-1.79), venlafaxine (OR 1.67, 95% CI 1.01-2.75), prochlorperazine (OR 2.15, 95% CI 1.45-3.18), and co-codamol (OR 1.31, 95% CI 1.10-1.56).
DISCUSSION
We identified several drugs associated with aSAH, of which 5 drugs (lisinopril and possibly amlodipine, simvastatin, metformin, and tamsulosin) showed a decreased aSAH risk. Future research should build on these signals to further assess the effectiveness of these drugs in reducing aSAH incidence.
CLASSIFICATION OF EVIDENCE
This study provides Class III evidence that some commonly prescribed drugs are associated with subsequent development of aSAH.
Topics: Humans; Subarachnoid Hemorrhage; Female; Male; Middle Aged; Incidence; Adult; Aged; Prescription Drugs; Case-Control Studies; Intracranial Aneurysm; Risk Factors
PubMed: 38838229
DOI: 10.1212/WNL.0000000000209479 -
Journal of Chromatography. B,... Jul 2024A novel and highly sensitive high-performance thin-layer chromatographic (HPTLC) method was developed and validated to quantify a combination of five pharmaceutical...
Enhancing simultaneous determination of some angiotensin II receptor antagonists and amlodipine in plasma using HPTLC with fluorescence densitometry: Independent fluorescence detection of the co-administrative drugs in the mixture across various pH conditions.
A novel and highly sensitive high-performance thin-layer chromatographic (HPTLC) method was developed and validated to quantify a combination of five pharmaceutical mixtures spiked to human plasma. The compounds comprised Amlodipine (AML) along with five angiotensin II receptor antagonist drugs (AIIRAs), namely Olmesartan (OLM), Telmisartan (TLM), Candesartan (CAN), Losartan (LOS), and Irbesartan (IRB). HPTLC was performed on silica gel 60 F254 plates using a mobile phase of Toluene: ethyl acetate: methanol: acetone: acetic acid (6:1.5:1:0.5:1, v/v/v/v/v). In a pioneering move, a reflectance/fluorescence detection mode was employed to identify two concurrently administered drugs at different pH levels for the first time. This method utilized the same chromatographic system, incorporating a specific measurement for AML at a neutral medium to achieve its maximum fluorescence at a 360 nm excitation wavelength, and measuring emission using a 540 nm optical filter. The process involved obtaining a very low fluorescence response from AIIRA. Subsequently, to enhance AIIRA's fluorescence, the plate was sprayed with perchloric acid to transition to a strong acidic medium, ultimately attaining the maximum fluorescence of AIIRA using various excitation wavelengths and a 400 nm emission filter. Through this strategic process, we could optimize the fluorescence signals of both drugs, thereby elevating the sensitivity of detection for this drug combination. AML demonstrated a linear range of 18-300 ng/band, while AIIRAs drugs exhibited a linear range of 6-150 ng/band. The method satisfied the International Conference on Harmonization (ICH) criteria for recovery, precision, repeatability, and robustness, showcasing exceptional sensitivity. The approach was successfully applied to quantify AML and AIIRAs drugs in both bulk drug and plasma samples, achieving high recovery percentages and minimal standard deviations.
Topics: Amlodipine; Humans; Chromatography, Thin Layer; Hydrogen-Ion Concentration; Reproducibility of Results; Densitometry; Limit of Detection; Linear Models; Angiotensin Receptor Antagonists; Spectrometry, Fluorescence
PubMed: 38824745
DOI: 10.1016/j.jchromb.2024.124162 -
Georgian Medical News Mar 2024Changing the vision, understanding, interpretation and analysis of certain data or scientific dilemmas is what is able to change the status quo and revitalize a mission,...
(NDMA) METFORMIN AND (NTTP) SITAGLIPTIN INDUCED CUTANEOUS MELANOMAS: LINKS TO NITROSOGENESIS, NITROSO-PHOTOCARCINOGENESIS, ONCOPHARMACOGENESIS AND THE METABOLIC REPROGRAMMING.
Changing the vision, understanding, interpretation and analysis of certain data or scientific dilemmas is what is able to change the status quo and revitalize a mission, an impulse or important thoughts, thus creating the conditions for it to increase immensely the chances of bringing it to success. Or, following Albert Einstein's postulate: ˝We cannot solve our problems with the same thinking we used when we created them˝, we should think: ˝Where does the road to success start? How do we solve or neutralize a problem? ˝ And the answer is: ˝ By taking a consistent and systematic approach, analyzing each component! And we eliminate every possibility of negative influence.˝ These thoughts apply with full force to cancer rates in general, but also to melanoma rates in particular: the murderous tempo of globalization and modernization in medicine has not yet led to the desired decrease in these rates; on the contrary, they are rising headlong and remain largely unpredictable and difficult to regulate. The conclusion is that a solution should be sought by refracting light through another prism: that of Nitrosogenesis and Pharmaco-Oncogenesis. A step-by-step and systematic approach to solving a problem requires patience, determination, and perseverance. As this perseverance is needed mainly to overcome the general ignorance, neglect, disinterest, uneducation and uncertainty of others, rather than doubt in one's own thesis, analysis, and the need for an active approach. Careful analysis of concepts such as ˝Drug Mediated Nitrosogenesis˝ and ˝Onco-pharmacogenesis/Pharmaco-oncogenesis˝ of skin cancer would certainly contribute to the elucidation of skin carcinogenesis in the context of polymedication of the contamination and polymorbidity worldwide. The FDA has already in 2019 taken this much needed first step of universal awareness and its ˝arm˝ has been taken seriously and responsibly solely by dermatologists and dermatosurgeons. It was this guild and only this guild that launched its independent, never-ending observations, logically grounded (hypo)theses, remaining to date confirmatory, unshakable, and enigmatic regarding the unit: intake of potentially contaminated medication and subsequent development of melanomas. It is this and only this branch of the medical guild that has also become the guarantor of safety and objectivity in science, and thus of safety in the fight for survival of a huge number of skin cancer patients. Contaminated oral antidiabetic drugs in the face of Metformin and Sitagliptin do not make an exception in this respect. Similarly to cutaneous melanomas occurring (and published in the scientific literature) after combined intake (or monomedication) of/ between ranitidine, valsartan, olmesartan, candesartan, telmisartan, irbesartan, losartan, enalapril, lisinopril, perindopril, hydrochlorothiazide, nifedipine, amlodipine, propafenone, bisoprolol, nebivolol, melitracen and a number of others, we inform about another rare but not unexpected clinical observation: occurrence of cutaneous melanomas after taking another class of drugs- oral antidiabetic ones. Or after the intake of nitrosamine-contaminated antidiabetic drugs. And whether this contamination is "real or potential" is left to regulators and manufacturers to decide. We accept it as `real-potential' or `potentially-real' because of the fact that neither the regulators nor the manufacturers know what it is or whether it is there or how it arose. The data shared in patients one and two in the presented scientific work are confirmatory in relation to the potential pathogenetic action of nitrosamine contaminated drugs such as 1) bisoprolol/ nebivolol/ candesartan/ hydrochlorothiazide and amlodipine, as well as 2) furosemide in the direction of cutaneous melanoma. Patient 3 in fact also represents the first formally described patient with subsequent melanoma development worldwide, having developed it following intake of potentially/actually nitrosamine-contaminated metformin and metformin/sitagliptin (both drugs are themed in the FDA's Potentially Contaminated Drug Bulletin: 1) metformin, multiple times between 2020-21, due to its contamination with NDMA and 2) sitagliptin, as of September 2022, due to its contamination with NTTP). It should not be seen as surprising to anyone that the intake of relatively similar carcinogens/nitrosamines or NDSRIs, but as an unofficial component of heterogeneous drugs, produces a relatively monomorphic clinical picture- that of cutaneous melanoma. Or to put it metaphorically: ˝The wolf changes its hair, but not its mood˝. A carcinogen remains a carcinogen, regardless of whether it is ingested in a lemonade, a tablet, a sandwich, or a bonbon. Similarly to the intake of nitrosamines in food. Future studies should address the important tasks/dilemmas to elucidate 1) the phototoxic/photocarcinogenic effect of unmetabolized nitrosamines identified in drug formulations; 2) the phototoxic/photocarcinogenic effect of DNA adducts generated after their metabolization, and 3) the availability of specific DNA adducts in lesional/tumor tissue and blood of patients after ingestion of nitroso-containing drug formulations. This level of evidence is likely to lead to a reconsideration of the arguments for the introduction of permanent elimination regimes for nitrosamines in medicines. Metabolic reprogramming (and its relationship to UVB radiation) due to the availability of nitrosamines in cigarette smoke is also currently a proven reality. Based on the available clinicopathological correlations, we believe that nitrosamines in drugs have a similar effect and are part of the key pathway activating skin carcinogenesis under the influence of solar radiation. Intake of contaminated medication is associated with skin cancer generation and progression. It is up to regulators and manufacturers to justify the merits and benefits of the self-imposed presence of carcinogens in drugs or the benefits of such drugs. Apart from the "cancer-generating benefit", of course, which is already widely known. And let us not forget that: "A lie stops being a lie and becomes a truth the moment it is officially refuted".
Topics: Humans; Melanoma; Skin Neoplasms; Metformin; Sitagliptin Phosphate; Carcinogenesis; Melanoma, Cutaneous Malignant; Hypoglycemic Agents; Metabolic Reprogramming
PubMed: 38807407
DOI: No ID Found -
Regulatory Toxicology and Pharmacology... Jun 2024Permitted Daily Exposure Limits (PDEs) are set for Active Pharmaceutical Ingredients (APIs) to control cross-contamination when manufacturing medicinal products in... (Comparative Study)
Comparative Study
Permitted Daily Exposure Limits (PDEs) are set for Active Pharmaceutical Ingredients (APIs) to control cross-contamination when manufacturing medicinal products in shared facilities. With the lack of official PDE lists for pharmaceuticals, PDEs have to be set by each company separately. Although general rules and guidelines for the setting of PDEs exist, inter-company variations in the setting of PDEs occur and are considered acceptable within a certain range. To evaluate the robustness of the PDE approach between different pharmaceutical companies, data on PDE setting of five marketed APIs (amlodipine, hydrochlorothiazide, metformin, morphine, and omeprazole) were collected and compared. Findings show that the variability between PDE values is within acceptable ranges (below 10-fold) for all compounds, with the highest difference for morphine due to different Point of Departures (PODs) and Adjustment Factors (AFs). Factors of PDE variability identified and further discussed are: (1) availability of data, (2) selection of POD, (3) assignment of AFs, (4) route-to-route extrapolation, and (5) expert judgement and differences in company policies. We conclude that the investigated PDE methods and calculations are robust and scientifically defensible. Additionally, we provide further recommendations to harmonize PDE calculation approaches across the pharmaceutical industry.
Topics: Humans; Drug Industry; Pharmaceutical Preparations; Risk Assessment; Drug Contamination; Occupational Exposure; Bulk Drugs
PubMed: 38782234
DOI: 10.1016/j.yrtph.2024.105649 -
Sleep Medicine Jul 2024Obstructive sleep apnea (OSA) and hypertension are common conditions that may be linked through sympathetic activation and water retention. We hypothesized that... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Obstructive sleep apnea (OSA) and hypertension are common conditions that may be linked through sympathetic activation and water retention. We hypothesized that diuretics, which reduce the body water content, may be more effective than amlodipine, a blood pressure (BP)-lowering agent implicated with edema, in controlling OSA in patients with hypertension. We also aimed to compare the effects of these treatments on ambulatory blood pressure monitoring (ABPM).
METHODS
In a randomized, double-blind clinical trial, we compared the effects of chlorthalidone/amiloride 25/5 mg with amlodipine 10 mg on OSA measured by portable sleep monitor and BP measured by ABPM. The study included participants older than 40 who had moderate OSA (10-40 apneas/hour of sleep) and BP within the systolic range of 140-159 mmHg or diastolic range of 90-99 mmHg.
RESULTS
The individuals in the experimental groups were comparable in age, gender, and other relevant characteristics. Neither the combination of diuretics nor amlodipine alone reduced the AHI after 8 weeks of treatment (AHI 26.3 with diuretics and 25.0 with amlodipine. P = 0.713). Both treatments significantly lowered office, 24-h, and nighttime ABP, but the two groups had no significant difference.
CONCLUSION
Chlorthalidone associated with amiloride and amlodipine are ineffective in decreasing the frequency of sleep apnea episodes in patients with moderate OSA and hypertension. Both treatments have comparable effects in lowering both office and ambulatory blood pressure. The notion that treatments could offer benefits for both OSA and hypertension remains to be demonstrated. TRIAL REGISTRATION CLINICALTRIALS.
GOV IDENTIFIER
NCT01896661.
Topics: Humans; Male; Female; Double-Blind Method; Hypertension; Middle Aged; Blood Pressure Monitoring, Ambulatory; Antihypertensive Agents; Chlorthalidone; Amlodipine; Sleep Apnea, Obstructive; Amiloride; Diuretics; Blood Pressure; Polysomnography; Aged
PubMed: 38781664
DOI: 10.1016/j.sleep.2024.05.035 -
Drugs in R&D May 2024This study aimed to assess and compare the pharmacokinetics, safety, and tolerability of a fixed-dose combination product (FDCP) comprising four different drugs (two...
Pharmacokinetics of a Fixed-Dose Combination Product of Amlodipine, Losartan, Ezetimibe, and Rosuvastatin and Its Comparison with Co-administration of Four Individual Components in Healthy Participants.
BACKGROUND AND OBJECTIVE
This study aimed to assess and compare the pharmacokinetics, safety, and tolerability of a fixed-dose combination product (FDCP) comprising four different drugs (two antihypertensive drugs, amlodipine and losartan, and two lipid-lowering agents, ezetimibe and rosuvastatin) with their separate tablets.
METHODS
A total of 60 participants were enrolled in this open-label, randomized, single-dose crossover study. Each participant received a single dose of FDCP and individual tablets during each period, with a 14-day washout period between the periods. The pharmacokinetic parameters of amlodipine, losartan, EXP3174 (an active metabolite of losartan), rosuvastatin, free ezetimibe, and total ezetimibe were evaluated and compared.
RESULTS
The pharmacokinetic profiles of amlodipine, losartan, rosuvastatin, and ezetimibe after administration of the individual products were similar to those of FDCP. The geometric mean ratios and 90% confidence intervals for maximum concentration (C) and area under the curve (AUC) of FDCP to individual tablets were within 0.8-1.25 for all six analytes. No clinically relevant changes were observed in the vital signs or physical, biochemical, hematological, electrocardiographic, or urinalysis findings during the study, and no serious adverse events were reported.
CONCLUSION
This study demonstrated that a newly developed FDCP containing amlodipine, losartan, ezetimibe, and rosuvastatin exhibited pharmacokinetic equivalence with the individual products and met the regulatory criteria. Both formulations were well tolerated.
CLINICAL TRIAL REGISTRATION
This trial (NCT04322266) was retrospectively registered on 9 September 2019.
PubMed: 38775910
DOI: 10.1007/s40268-024-00460-y