RESUMEN
The World Health Organization has warned that substandard and falsified medical products (SFs) can harm patients and fail to treat the diseases for which they were intended, and they affect every region of the world, leading to loss of confidence in medicines, health-care providers, and health systems. Therefore, development of analytical procedures to detect SFs is extremely important. In this study, we investigated the quality of pharmaceutical tablets containing the antihypertensive candesartan cilexetil, collected in China, Indonesia, Japan, and Myanmar, using the Japanese pharmacopeial analytical procedures for quality control, together with principal component analysis (PCA) of Raman spectrum obtained with handheld Raman spectrometer. Some samples showed delayed dissolution and failed to meet the pharmacopeial specification, whereas others failed the assay test. These products appeared to be substandard. Principal component analysis showed that all Raman spectra could be explained in terms of two components: the amount of the active pharmaceutical ingredient and the kinds of excipients. Principal component analysis score plot indicated one substandard, and the falsified tablets have similar principal components in Raman spectra, in contrast to authentic products. The locations of samples within the PCA score plot varied according to the source country, suggesting that manufacturers in different countries use different excipients. Our results indicate that the handheld Raman device will be useful for detection of SFs in the field. Principal component analysis of that Raman data clarify the difference in chemical properties between good quality products and SFs that circulate in the Asian market.
Asunto(s)
Antihipertensivos/normas , Bencimidazoles/normas , Compuestos de Bifenilo/normas , Fraude , Farmacopeas como Asunto/normas , Espectrometría Raman/instrumentación , Comprimidos/normas , Tetrazoles/normas , China , Computadoras de Mano , Fraude/prevención & control , Humanos , Indonesia , Japón , Mianmar , Análisis de Componente Principal , Control de Calidad , Organización Mundial de la SaludRESUMEN
Heart Failure (HF) is one of the main healthcare burdens in the United States and in the world. Many drugs are approved and used in practice for management of this condition; including beta blockers, diuretics, aldosterone antagonists, Angiotensin Converting Enzyme Inhibitors (ACEI's), and Angiotensin Receptor Blockers (ARBs). Recently, the Food and Drug Administration (FDA) approved a drug with brand name Entresto (Sacubitril/Valsartan or LCZ696), an angiotensin receptor neprilysin inhibitor for the use in Heart Failure with Reduced Ejection Fraction (HFrEF) patients instead of ACEI's and ARBs. The drug works through angiotensin receptor blockage via valsartan as well as neprilysin inhibition with sacubitril. This represented a new milestone in managing heart failure patients and provided yet another therapy in our armamentarium. This article reviews the stages that led to the development of this drug, the failure of its preceding agents, the lessons we have learnt, and the current trials of Entresto for new indications.
Asunto(s)
Aminobutiratos/uso terapéutico , Antagonistas de Receptores de Angiotensina , Insuficiencia Cardíaca/tratamiento farmacológico , Tetrazoles/uso terapéutico , Aminobutiratos/normas , Antagonistas de Receptores de Angiotensina/uso terapéutico , Compuestos de Bifenilo , Ensayos Clínicos como Asunto , Combinación de Medicamentos , Humanos , Estructura Molecular , Tetrazoles/normas , Valsartán/química , Valsartán/farmacologíaRESUMEN
A photostability study of Valsartan (VAL) is reported. Exposure of the drug to UV-vis radiation (λ > 320 nm) yielded two previously unknown compounds, which were detected by HPLC. Preparative amounts of the new potential degradation products (DP-1 and DP-2) were obtained by submitting VAL bulk drug to extensive photodegradation. The impurities were isolated by preparative normal phase column chromatography. Analytical information from the infrared, nuclear magnetic resonance and mass spectral data of the degradation products revealed their structures as N-[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-N-isobutylpentanamide (DP-1) and N-(diazirino[1,3-f]phenanthridin-4-ylmethyl)-N-isobutylpentanamide (DP-2). DP-1 arose from decarboxylation of VAL, while DP-2 results from further loss of nitrogen from the tetrazole motif of DP-1, with concomitant cyclization to yield a tetracyclic diazacyclopropene derivative.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/química , Azirinas/aislamiento & purificación , Contaminación de Medicamentos , Fenantridinas/aislamiento & purificación , Fotólisis , Tetrazoles/química , Tetrazoles/aislamiento & purificación , Valina/análogos & derivados , Bloqueadores del Receptor Tipo 1 de Angiotensina II/efectos de la radiación , Bloqueadores del Receptor Tipo 1 de Angiotensina II/normas , Cromatografía Líquida de Alta Presión/instrumentación , Cromatografía Líquida de Alta Presión/métodos , Estabilidad de Medicamentos , Espectroscopía de Resonancia Magnética/instrumentación , Espectroscopía de Resonancia Magnética/métodos , Estructura Molecular , Espectroscopía Infrarroja por Transformada de Fourier/instrumentación , Espectroscopía Infrarroja por Transformada de Fourier/métodos , Tetrazoles/efectos de la radiación , Tetrazoles/normas , Valina/química , Valina/efectos de la radiación , Valina/normas , ValsartánRESUMEN
Analytical methods validation is a mandatory step to evaluate the ability of developed methods to provide accurate results for their routine application. Validation usually involves validation standards or quality control samples that are prepared in placebo or reconstituted matrix made of a mixture of all the ingredients composing the drug product except the active substance or the analyte under investigation. However, one of the main concerns that can be made with this approach is that it may lack an important source of variability that come from the manufacturing process. The question that remains at the end of the validation step is about the transferability of the quantitative performance from validation standards to real authentic drug product samples. In this work, this topic is investigated through three case studies. Three analytical methods were validated using the commonly spiked placebo validation standards at several concentration levels as well as using samples coming from authentic batch samples (tablets and syrups). The results showed that, depending on the type of response function used as calibration curve, there were various degrees of differences in the results accuracy obtained with the two types of samples. Nonetheless the use of spiked placebo validation standards was showed to mimic relatively well the quantitative behaviour of the analytical methods with authentic batch samples. Adding these authentic batch samples into the validation design may help the analyst to select and confirm the most fit for purpose calibration curve and thus increase the accuracy and reliability of the results generated by the method in routine application.
Asunto(s)
Preparaciones Farmacéuticas/análisis , Preparaciones Farmacéuticas/normas , Placebos/análisis , Placebos/normas , Calibración , Química Farmacéutica , Cromatografía Líquida de Alta Presión/instrumentación , Cromatografía Líquida de Alta Presión/métodos , Hidroclorotiazida/análisis , Hidroclorotiazida/normas , Metformina/análisis , Metformina/normas , Parabenos/análisis , Parabenos/normas , Control de Calidad , Estándares de Referencia , Reproducibilidad de los Resultados , Espectrofotometría Ultravioleta/instrumentación , Espectrofotometría Ultravioleta/métodos , Comprimidos , Tetrazoles/análisis , Tetrazoles/normas , Valina/análogos & derivados , Valina/análisis , Valina/normas , ValsartánRESUMEN
Angiotensin II receptor blockers (ARBs) are antihypertensive agents with considerable evidence of efficacy and safety for the reduction of cardiovascular (CV) disease risk in numerous patient populations across the CV continuum. There are several agents within this class, all of which have contributed to various degrees, to this evidence base. The evidence with ARBs continues to accumulate, with ongoing trials investigating their role in additional patient populations, potentially expanding their efficacy across a broad spectrum of CV disease states. Cardiovascular disease (CVD) is a leading cause of death around the world, accounting for approximately 29.2% of total global deaths. Of all the deaths attributed to CVD, approximately 43% are due to ischemic heart disease, 33% to cerebrovascular disease, and 23% to hypertensive and other heart conditions. CVD has been represented as a "CV continuum". This continuum concept can be used to describe CVD in general or in specific vascular beds (eg, coronary artery disease or cerebrovascular disease). This review article will discuss the results of the landmark ARB candesartan clinical trials published over the past decade. The evidence presented spans the entire CV continuum, including the effects of ARBs in at-risk patients, stroke, myocardial infarction (MI), and heart failure (HF), as well as a brief discussion of ongoing trials.
Asunto(s)
Antagonistas de Receptores de Angiotensina/uso terapéutico , Antihipertensivos/uso terapéutico , Bencimidazoles/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/prevención & control , Tetrazoles/uso terapéutico , Antagonistas de Receptores de Angiotensina/farmacología , Antihipertensivos/farmacología , Antihipertensivos/normas , Bencimidazoles/farmacología , Bencimidazoles/normas , Compuestos de Bifenilo , Ensayos Clínicos como Asunto , Diabetes Mellitus Tipo 2/prevención & control , Humanos , Hipertensión/tratamiento farmacológico , Hipertensión/prevención & control , Ensayos Clínicos Controlados Aleatorios como Asunto , Tetrazoles/farmacología , Tetrazoles/normas , Resultado del TratamientoRESUMEN
A simple and fast method for the simultaneous determination of the antihypertensive drug Valsartan and its metabolite in human plasma has been validated. The proposed method deals with SPE, followed by an HPLC separation coupled with fluorimetric and photometric detection. The optimization of the SPE-HPLC method was achieved by an experimental design. The separation was performed on an RP C18 Atlantis 100 mmx3.9 mm column. The mobile phase consisted of a mixture of ACN 0.025% TFA and phosphate buffer (5 mM, pH = 2.5) 0.025% TFA and was delivered in gradient mode at a flow rate of 1.30 mL/min. The eluent was monitored with a fluorescence detector at 234 and 378 nm excitation and emission wavelengths, respectively, and at 254 nm using a photometric detector. The full analytical validation was performed according to the Food and Drug Administration (FDA) 'guidance for industry: bioanalytical method validation' and the recoveries obtained for Valsartan and its metabolite ranged from 94.6 to 108.8%. The validated method was successfully applied to 12 plasma samples obtained from patients under antihypertensive treatment with Valsartan.
Asunto(s)
Análisis Químico de la Sangre/métodos , Extracción en Fase Sólida/métodos , Tetrazoles/sangre , Valina/análogos & derivados , Anciano , Antihipertensivos/sangre , Antihipertensivos/normas , Análisis Químico de la Sangre/normas , Análisis Químico de la Sangre/estadística & datos numéricos , Cromatografía Líquida de Alta Presión/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estándares de Referencia , Espectrofotometría Ultravioleta , Tetrazoles/normas , Valina/sangre , Valina/normas , ValsartánRESUMEN
In the Trial of Preventing Hypertension (TROPHY), volunteers with "high normal blood pressure" were randomized to 4 years of placebo (n = 381) or 2 years of 16 mg/d of candesartan (n = 391) followed by 2 years of placebo. At 2 years, there was a 26.8% absolute and a 66.3% relative risk reduction (P < 0.0001) of hypertension in the candesartan group. At study end, the former candesartan group had a 9.8% absolute and a 15.6% relative risk reduction (P < 0.007) of hypertension. The treatment was well tolerated. The Seventh Joint National Committee (JNC 7) changed the nomenclature from "high normal blood pressure" to "prehypertension" and widened the range to 120 to 139 and/or 80 to 89 mm Hg. Our results support the term "prehypertension" only for the 130 to 139 and/or 85 to 89 mm Hg group; in 4 years two thirds of the placebo group developed hypertension. We suggest stratifying the JNC classification into "prehypertension" (130-139 and/or 85-89 mm Hg) and "high normal blood pressure" (120-129 and/or 80-84 mm Hg). By the present JNC definition, only one quarter of adult men have normal blood pressure. Removing the disease label from another 28% would appropriately focus attention on high-risk prehypertension.
Asunto(s)
Comités Consultivos , Antihipertensivos/uso terapéutico , Hipertensión/prevención & control , Antihipertensivos/normas , Bencimidazoles/normas , Bencimidazoles/uso terapéutico , Compuestos de Bifenilo , Presión Sanguínea/efectos de los fármacos , Humanos , Hipertensión/fisiopatología , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Conducta de Reducción del Riesgo , Tetrazoles/normas , Tetrazoles/uso terapéutico , Estados Unidos/epidemiologíaRESUMEN
The continued poor rates of blood pressure (BP) control to the recommended target BP of <140/90 mm Hg in patients with hypertension indicate a persistent need for improved antihypertensive therapy. Angiotensin II receptor blockers (ARBs) constitute the newest approved class of antihypertensive agents. As with angiotensin converting enzyme inhibitors, ARBs block the renin-angiotensin-aldosterone system, but do so through a more specific mechanism. Angiotensin converting enzyme inhibitors block the conversion of angiotensin I to angiotensin II, but angiotensin II may be produced by several alternate pathways. Angiotensin II receptor blockers, by contrast, inhibit the binding of angiotensin II to the angiotensin II type 1 (AT1) receptor, independent of the pathway of angiotensin II production. Comparative safety and efficacy trials indicate that ARBs are similar to other antihypertensive drugs in terms of BP-lowering effectiveness and have superior tolerability. Olmesartan medoxomil is the newest and one of the most effective of the ARBs. In controlled trials, it has been shown to provide 24-h BP control with antihypertensive efficacy at least as good as that of the calcium channel blockers amlodipine besylate and felodipine and the beta-blocker atenolol. In a comparative study, olmesartan medoxomil demonstrated significantly greater reductions in diastolic BP than did three other leading ARBs-losartan potassium, irbesartan, and valsartan. With the convenience of placebo-like tolerability and once-daily dosing, combined with excellent antihypertensive efficacy, olmesartan medoxomil may be a useful addition to our management of hypertension.
Asunto(s)
Antagonistas de Receptores de Angiotensina , Antihipertensivos/normas , Antihipertensivos/uso terapéutico , Hipertensión/tratamiento farmacológico , Imidazoles/normas , Imidazoles/uso terapéutico , Tetrazoles/normas , Tetrazoles/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Humanos , Olmesartán MedoxomiloRESUMEN
OBJECTIVE: This study was designed mainly to establish the rates of response to valsartan 80mg once daily (qd) and to valsartan 160mg qd given to non-responders to 80mg qd, as well as to determine the safety of valsartan and the blood pressure control achieved using valsartan over a period of 24 h or more, using ambulatory blood pressure monitoring (ABPM) devices. METHODS: This was a single-blind, single-arm, multicenter study involving 256 out-patients with mild-to-moderate essential hypertension. After previous antihypertensive treatments had been 'washed out', the patients were entered into a 2-week placebo run-in period to confirm the diagnosis of mild-to-moderate hypertension. Patients who, at the end of the placebo run-in period, had a mean sitting diastolic blood pressure of between 95 and 115mmHg inclusive received valsartan 80mg qd for 4 weeks. Non-responders (those not demonstrating a diastolic blood pressure of less than 90mmHg or a decrease in diastolic blood pressure of 10mmHg or more compared with baseline) received valsartan 160mg qd for another 4 weeks. In selected centers, patients who agreed also had their blood pressure monitored for 24 h, provided their blood pressure was shown to be controlled. Of these patients, half skipped one dose of valsartan and were monitored for an additional 24h period. RESULTS: The rate of response to valsartan 80mg was 45.4%, and of those not responding to this dose, 36.3% responded to valsartan 160mg. The response rate to one or other dose was 63.2%. The ambulatory blood pressure data support a consistent reduction of blood pressure with valsartan over a 24h period and for up to 32 h after dosing in those who missed a dose. The overall incidence of adverse experiences per person-year, treatment related or otherwise, was 6.3 and 10.6 for the valsartan and placebo study periods respectively. CONCLUSION: Antihypertensive treatment with valsartan for 8 weeks produced a significant decrease in diastolic blood pressure in hypertensive patients. In addition, the drug may be safely administered, and the results of 24 h/48 h ambulatory monitoring demonstrate that valsartan is a true once-a-day antihypertensive.
Asunto(s)
Antihipertensivos/administración & dosificación , Hipertensión/tratamiento farmacológico , Tetrazoles/administración & dosificación , Valina/administración & dosificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antagonistas de Receptores de Angiotensina , Antihipertensivos/normas , Antihipertensivos/toxicidad , Presión Sanguínea/efectos de los fármacos , Monitoreo Ambulatorio de la Presión Arterial , Canadá , Cronoterapia , Femenino , Humanos , Hipertensión/complicaciones , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Grupos Raciales , Factores Sexuales , Método Simple Ciego , Tetrazoles/normas , Tetrazoles/toxicidad , Valina/análogos & derivados , Valina/normas , Valina/toxicidad , ValsartánRESUMEN
The nonpeptide angiotensin II (AII)-receptor antagonist losartan is a selective blocker of the pressor effects of AII. It is now being evaluated as an anti-hypertensive drug in multicenter clinical trials in the United States and other countries. Preliminary inpatient studies have shown that after 5 days of treatment, losartan--in doses of 50, 100, and 150 mg--is significantly more effective than placebo in decreasing blood pressure, and has efficacy similar to that of the angiotensin-converting enzyme (ACE) inhibitor enalapril. Large-scale dose-ranging studies in ambulatory hypertensive patients have shown that 10- and 25-mg losartan doses have brief effects in lowering blood pressure, but when given once daily, 50 mg is the minimal dose needed to produce significant day-long decreases in blood pressure. Interestingly, higher doses do not appear to exhibit greater efficacy; however, the effects of these doses are all similar to those of enalapril (20 mg once daily). Losartan's long duration of action is documented by ratios of trough (end of 24-h dosing interval) to peak antihypertensive effects, which are consistently above 50%. Clinical experiences thus far have indicated a low incidence of adverse events. Preliminary animal and in vitro investigations have shown that losartan produces beneficial effects on cardiac function, renal function, and survival that are similar to those of ACE inhibitors. Additional studies are now under way to define more fully the cardiovascular and metabolic profiles of losartan.