was read the article
array:21 [ "pii" => "X2013251411052028" "issn" => "20132514" "doi" => "10.3265/Nefrologia.pre2010.Nov.10643" "estado" => "S300" "fechaPublicacion" => "2011-05-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2011;31:268-74" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 6516 "formatos" => array:3 [ "EPUB" => 312 "HTML" => 5319 "PDF" => 885 ] ] "Traduccion" => array:1 [ "es" => array:17 [ "pii" => "X0211699511052020" "issn" => "02116995" "doi" => "10.3265/Nefrologia.pre2010.Nov.10643" "estado" => "S300" "fechaPublicacion" => "2011-05-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia. 2011;31:268-74" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 9318 "formatos" => array:3 [ "EPUB" => 296 "HTML" => 8289 "PDF" => 733 ] ] "es" => array:12 [ "idiomaDefecto" => true "titulo" => "Aspectos vasculares y metabólicos de manidipino" "tienePdf" => "es" "tieneTextoCompleto" => "es" "tieneResumen" => array:2 [ 0 => "es" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "268" "paginaFinal" => "274" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Vascular and metabolic properties of manidipine" ] ] "contieneResumen" => array:2 [ "es" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "es" => true ] "contienePdf" => array:1 [ "es" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10643_108_10685_es_10643_f1.jpg" "Alto" => 374 "Ancho" => 504 "Tamanyo" => 94252 ] ] "descripcion" => array:1 [ "es" => "La exposición a manidipino de células preadipocitarias NIH-3T3 activa la expresión del gen aP2 de forma tiempo-dependiente." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Nisa Buset Ríos, N. Buset Ríos, Francisco Rodríguez Esparragón, F. Rodríguez Esparragón, Carlos Fernández-Andrade Rodríguez, C. Fernández-Andrade Rodríguez, José Carlos Rodríguez Pérez, J.C. Rodríguez Pérez" "autores" => array:9 [ 0 => null 1 => array:2 [ "nombre" => "Nisa" "apellidos" => "Buset Ríos" ] 2 => array:2 [ "Iniciales" => "N." "apellidos" => "Buset Ríos" ] 3 => array:2 [ "nombre" => "Francisco" "apellidos" => "Rodríguez Esparragón" ] 4 => array:2 [ "Iniciales" => "F." "apellidos" => "Rodríguez Esparragón" ] 5 => array:2 [ "nombre" => "Carlos" "apellidos" => "Fernández-Andrade Rodríguez" ] 6 => array:2 [ "Iniciales" => "C." "apellidos" => "Fernández-Andrade Rodríguez" ] 7 => array:2 [ "nombre" => "José Carlos" "apellidos" => "Rodríguez Pérez" ] 8 => array:2 [ "Iniciales" => "J.C." "apellidos" => "Rodríguez Pérez" ] ] ] ] ] "idiomaDefecto" => "es" "Traduccion" => array:1 [ "en" => array:9 [ "pii" => "X2013251411052028" "doi" => "10.3265/Nefrologia.pre2010.Nov.10643" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251411052028?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699511052020?idApp=UINPBA000064" "url" => "/02116995/0000003100000003/v0_201502091414/X0211699511052020/v0_201502091414/es/main.assets" ] ] "itemSiguiente" => array:17 [ "pii" => "X201325141105201X" "issn" => "20132514" "doi" => "10.3265/Nefrologia.pre2011.Feb.10820" "estado" => "S300" "fechaPublicacion" => "2011-05-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2011;31:275-85" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 6875 "formatos" => array:3 [ "EPUB" => 295 "HTML" => 4441 "PDF" => 2139 ] ] "en" => array:11 [ "idiomaDefecto" => true "titulo" => "Ethical challenges in transplant practice in Latin America: the Aguascalientes Document" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "275" "paginaFinal" => "285" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Desafíos éticos en la práctica de trasplantes en América Latina: Documento de Aguascalientes" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => " Documento de Aguascalientes, A. Baquero, J. Alberú" "autores" => array:3 [ 0 => array:1 [ "apellidos" => "Documento de Aguascalientes" ] 1 => array:2 [ "Iniciales" => "A." "apellidos" => "Baquero" ] 2 => array:2 [ "Iniciales" => "J." "apellidos" => "Alberú" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "X0211699511052012" "doi" => "10.3265/Nefrologia.pre2011.Feb.10820" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699511052012?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X201325141105201X?idApp=UINPBA000064" "url" => "/20132514/0000003100000003/v0_201502091638/X201325141105201X/v0_201502091638/en/main.assets" ] "itemAnterior" => array:17 [ "pii" => "X2013251411052036" "issn" => "20132514" "doi" => "10.3265/Nefrologia.pre2011.Jan.10768" "estado" => "S300" "fechaPublicacion" => "2011-05-01" "documento" => "article" "licencia" => "http://www.elsevier.com/open-access/userlicense/1.0/" "subdocumento" => "fla" "cita" => "Nefrologia (English Version). 2011;31:260-7" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 5564 "formatos" => array:3 [ "EPUB" => 326 "HTML" => 4448 "PDF" => 790 ] ] "en" => array:12 [ "idiomaDefecto" => true "titulo" => "Management of HCV infection in chronic kidney disease" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "es" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "260" "paginaFinal" => "267" ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Manejo de la infección por el VHC en la enfermedad renal crónica" ] ] "contieneResumen" => array:2 [ "en" => true "es" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10768_16025_14629_en_t1__10768.jpg" "Alto" => 292 "Ancho" => 600 "Tamanyo" => 97787 ] ] "descripcion" => array:1 [ "en" => "Prevalence of HCV infection in haemodialysis" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "S. Aoufi Rabih, R. García Agudo" "autores" => array:2 [ 0 => array:2 [ "Iniciales" => "S." "apellidos" => "Aoufi Rabih" ] 1 => array:2 [ "Iniciales" => "R." "apellidos" => "García Agudo" ] ] ] ] ] "idiomaDefecto" => "en" "Traduccion" => array:1 [ "es" => array:9 [ "pii" => "X0211699511052039" "doi" => "10.3265/Nefrologia.pre2011.Jan.10768" "estado" => "S300" "subdocumento" => "" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "idiomaDefecto" => "es" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X0211699511052039?idApp=UINPBA000064" ] ] "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251411052036?idApp=UINPBA000064" "url" => "/20132514/0000003100000003/v0_201502091638/X2013251411052036/v0_201502091638/en/main.assets" ] "en" => array:15 [ "idiomaDefecto" => true "titulo" => "Vascular and metabolic properties of manidipine" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "268" "paginaFinal" => "274" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Nisa Buset Ríos, N. Buset Ríos, Francisco Rodríguez Esparragón, F. Rodríguez Esparragón, Carlos Fernández-Andrade Rodríguez, C. Fernández-Andrade Rodríguez, José Carlos Rodríguez Pérez, J.C. Rodríguez Pérez" "autores" => array:9 [ 0 => null 1 => array:3 [ "nombre" => "Nisa" "apellidos" => "Buset Ríos" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] 2 => array:3 [ "Iniciales" => "N." "apellidos" => "Buset Ríos" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "affc" ] ] ] 3 => array:3 [ "nombre" => "Francisco" "apellidos" => "Rodríguez Esparragón" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] ] ] 4 => array:3 [ "Iniciales" => "F." "apellidos" => "Rodríguez Esparragón" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "affc" ] ] ] 5 => array:3 [ "nombre" => "Carlos" "apellidos" => "Fernández-Andrade Rodríguez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "affd" ] ] ] 6 => array:3 [ "Iniciales" => "C." "apellidos" => "Fernández-Andrade Rodríguez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "affe" ] ] ] 7 => array:4 [ "nombre" => "José Carlos" "apellidos" => "Rodríguez Pérez" "email" => array:1 [ 0 => "jrodperd@gobiernodecanarias.org" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">f</span>" "identificador" => "afff" ] ] ] 8 => array:4 [ "Iniciales" => "J.C." "apellidos" => "Rodríguez Pérez" "email" => array:1 [ 0 => "jrodperd@gobiernodecanarias.org" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">g</span>" "identificador" => "affg" ] ] ] ] "afiliaciones" => array:6 [ 0 => array:3 [ "entidad" => "Unidad de Investigación, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas de Gran Canaria Las Palmas, Spain, " "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "affb" ] 1 => array:3 [ "entidad" => "Unidad de Investigación, Hospital Universitario de Gran Canaria Dr. Negrín, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria " "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "affc" ] 2 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Universitario Virgen del Rocío, Sevilla, Sevilla, Spain, " "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "affd" ] 3 => array:3 [ "entidad" => "Servicio de Nefrología, Hospital Universitario Virgen del Rocío, Sevilla, " "etiqueta" => "<span class="elsevierStyleSup">e</span>" "identificador" => "affe" ] 4 => array:3 [ "entidad" => "Servicio de Nefrología y Unidad de Investigación, Hospital Universitario de Gran Canaria Dr. Negrín, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria Las Palmas Spain, " "etiqueta" => "<span class="elsevierStyleSup">f</span>" "identificador" => "afff" ] 5 => array:3 [ "entidad" => "Servicio de Nefrología y Unidad de Investigación, Hospital Universitario de Gran Canaria Dr. Negrín, Universidad de Las Palmas de Gran Canaria, Las Palmas de Gran Canaria " "etiqueta" => "<span class="elsevierStyleSup">g</span>" "identificador" => "affg" ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Aspectos vasculares y metabólicos de manidipino" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10643_108_14369_en_10643_f1.jpg" "Alto" => 485 "Ancho" => 686 "Tamanyo" => 30753 ] ] "descripcion" => array:1 [ "en" => "Exposure of NIH-3T3 preadipocyte cells to manidipine activates the expression of the aP2 gene in a time-dependent manner." ] ] ] "textoCompleto" => "<p class="elsevierStylePara"><span class="elsevierStyleBold">CALCIUM CHANNELS </span></p><p class="elsevierStylePara">Voltage-dependent calcium channels mediate the flow of calcium in response to the depolarisation of the cell membrane and regulate intracellular processes such as contraction, secretion, neurotransmission, and gene expression, in which calcium acts as a second messenger.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">The channels are composed of multiple heteromeric subunits: α, β, γ and δ, which are coded for by several different genes. They are named using the chemical symbol of the principal ion they regulate the passage of (Ca) and the primary physiological regulator, voltage (v). The numerical identifier corresponds to the gene subfamily to which the channel corresponds (1-3), and the letter (A-I) indicates the order in which it was identified, except subunit a1S, which was assigned the letter S due to its presence in skeletal muscle.</p><p class="elsevierStylePara">Subunit α<span class="elsevierStyleSup">1</span>, which is coded for by CACNA1, appears to be responsible for the main characteristics of these channels, since it is involved in ion selectivity and conductivity and sensitivity to voltage.<span class="elsevierStyleSup">1-3 </span></p><p class="elsevierStylePara">The calcium currents registered in different cell types have multiple pharmacological and physiological properties, so it is possible to group calcium channels into L, P/Q, N, R, and T types.<span class="elsevierStyleSup">1 </span></p><p class="elsevierStylePara">L-type (long-lasting) calcium channels are activated by strong depolarisations, mediated by the prolonged flow of calcium into a wide variety of cell types. In this manner, these channels play a central role in the contraction and excitation of skeletal, cardiac, and smooth muscle4 (Cav 1.2 [a<span class="elsevierStyleInf">1C</span>]). They are responsible for muscle tone in arterial smooth muscles, and have become a target for drugs to treat hypertension and angina. In the kidney (Cav1.2 [a<span class="elsevierStyleInf">1C</span>] and Cav1.3 [a<span class="elsevierStyleInf">1D</span>]), these channels promote the dilation of preglomerular (afferent) arterioles, ostensibly increasing intraglomerular pressure. Additionally, other L-type channels are found in the skeletal muscle (Cav1.1 [a<span class="elsevierStyleInf">1S</span>]), brain and kidney (Cav1.2 [a<span class="elsevierStyleInf">1C</span>], Cav1.3 [a<span class="elsevierStyleInf">1D</span>]), pancreas (Cav1.3 [a<span class="elsevierStyleInf">1D</span>]), and retina (Cav1.4 [a1F]).<span class="elsevierStyleSup">1</span></p><p class="elsevierStylePara">Other lesser-known channel types are P/Q, N, and R, and these also require strong depolarisation in order to be activated.<span class="elsevierStyleSup">1</span></p><p class="elsevierStylePara">Contrary to the previously mentioned channel types, T-type (transient) channels are activated by weak depolarisations, and provoke a transitory flow of calcium.5 T-type channels are present in the nervous system (Cav3.1 [a<span class="elsevierStyleInf">1G</span>]), brain (Cav3.1 [a1G,] Cav3.2 [a1H] and (Cav3.3 [a<span class="elsevierStyleInf">1D</span>]), heart (Cav3.2 [(a1H]), kidneys (Cav3.1 [a<span class="elsevierStyleInf">1G</span>], Cav3.2 [a<span class="elsevierStyleInf">1H</span>]) and liver (Cav3.2 [a<span class="elsevierStyleInf">1H</span>]).1 These are involved in heart rate, vascular smooth muscle contraction, and cell growth.4 T-type channels have been implicated on several occasions in the secretion of hormones such as renin, aldosterone, atrial natriuretic peptide, and insulin. Only T-type channels (not L-type) are found in postglomerular (efferent) arterioles, and so the tone of these vascular muscles must be controlled by T-type channels and angiotensin II AT1 receptors.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">In principle, L-type channel blocking is considered to be the most important type in the regulation of vascular functioning, since Cav1.2 is the major route of calcium entry into skeletal muscle, heart, and kidney cells.<span class="elsevierStyleSup">1,6 </span>However, the non-haemodynamic action of T-type channel blockers could have multiple beneficial effects by inhibiting inflammatory processes (inhibition of Rho kinases, NF-kB, leukocyte adhesion), blocking the renin-angiotensin system, and blocking the sympathetic nervous system (Table 1).<span class="elsevierStyleInf">7</span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">TYPES OF CALCIUM CHANNEL BLOCKERS </span></p><p class="elsevierStylePara">Calcium channel blockers (CCB) are highly heterogeneous molecules that can be grouped into: derived from phenylalkylamine, such as verapamil; derived from benzodiazepines, whose prototype is diltiazem; and derived from 1,4-dihydropyridines, such as manidipine.<span class="elsevierStyleSup">8 </span>These molecules mainly block L-type channels.</p><p class="elsevierStylePara">The first generation of dihydropyridine calcium channel blockers, such as nifedipine, are characterised by instantaneous release, a short lifetime, and quick absorption. In spite of a favourable metabolic profile, these drugs cause some adverse effects such as sharp drops in blood pressure, tachycardia, and sympathetic activation. In the second generation of drugs, including nimodipine, the release of the molecule is slower.<span class="elsevierStyleSup">9 </span></p><p class="elsevierStylePara">The latest-generation CCB have a long lifetime and prolonged action that significantly reduces blood pressure, thus notably diminishing the secondary side effects of the drug (Table 2). In contrast with traditional blockers, this new group of molecules, including manidipine, blocks both L-type and T-type channels.<span class="elsevierStyleSup">10 </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">THE EFFECTS OF CCB ON CARDIOVASCULAR MORBIDITY </span></p><p class="elsevierStylePara">Cardiovascular disease is clearly and consistently related to blood pressure. The main objective of antihypertensive therapy is to reduce both cardiovascular and renal morbidity and mortality. In order to achieve this, a target blood pressure level was established at below 140/90mm Hg, although in patients with diabetes or kidney disease, it appears that this limit should be less than 130/80mm Hg.<span class="elsevierStyleSup">11 </span></p><p class="elsevierStylePara">According to the guidelines for the management of arterial hypertension,<span class="elsevierStyleSup">12 </span>thiazide diuretics should be the treatment of choice, although certain high-risk cases could be treated with angiotensin II receptor antagonists (ARA-II), CCB, or angiotensin-converting enzyme (ACE) inhibitors as a first choice.<span class="elsevierStyleSup">11 </span>Precise indications exist for the use of antihypertensive agents such as CCB, ACE inhibitors, and ARA-II in order to prevent the development of diabetes in hypertensive patients.<span class="elsevierStyleSup">11 </span></p><p class="elsevierStylePara">The CAMELOT study concluded that, as a monotherapy, CCB are more efficient at diminishing cardiovascular events and slowing the progression of atherosclerosis than ACE inhibitors.<span class="elsevierStyleSup">13 </span>With regard to CCB combined with other drugs, Fogari et al. demonstrated that manidipine (CCB) and delapril (ACE inhibitor) provide increased benefit over olmesartan (ARA II) and hydrochlorothiazide, as this combination reduces orthostatic blood pressure and does not cause adverse metabolic effects.<span class="elsevierStyleSup">14 </span></p><p class="elsevierStylePara">Other studies, such as the one carried out by the Japanese Hypertension Society, affirm that CCB possess greater antihypertensive efficacy than all other preferred antihypertensive drugs available, without affecting blood flow to the body’s organs. This characteristic makes this group of drugs particularly indicated in elderly patients and those with complications such as left ventricular hypertrophy, tachycardia, angina pectoris, and chronic cerebrovascular disease.<span class="elsevierStyleSup">15 </span></p><p class="elsevierStylePara">In this respect, one trial treated 30 obese hypertensive patients with amlodipine, manidipine, and cilnidipine, revealing that these long-acting CCB reduce blood pressure and also diminish resistance to insulin, suggesting valuable cardio-metabolic properties.<span class="elsevierStyleSup">16 </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara">However, other studies have not observed significant differences in the efficacy of reducing blood pressure between different latest generation calcium channel blockers.<span class="elsevierStyleSup">17,18 </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">CCB AND INSULIN RESISTANCE. MANIDIPINE AND THE EXPRESSION OF AP2 </span></p><p class="elsevierStylePara">In terms of cardiovascular morbidity and mortality, arterial hypertension and diabetes are key risk factors. These are interrelated in a complex and multifactorial manner. Hypertensive patients with metabolic syndromes (MS) have an elevated risk of diabetes mellitus (DM). The incidence of DM appears to increase in patients with AHT, partly due to the high percentage of obese patients in both groups. The UKPDS study demonstrated that high blood pressure and glycaemia independently and additively increase the risk of cardiovascular disease.<span class="elsevierStyleSup">19,20 </span></p><p class="elsevierStylePara">In this respect, the MARIMBA study compared the effects of administering manidipine and amlodipine<span class="elsevierStyleSup">21 </span>in non-diabetic MS patients, and found that blood pressure and C-reactive protein (CRP) levels decreased with both types of treatment, although manidipine also significantly reduced albuminuria and insulin resistance, associated with an increase in serum adiponectin levels. Manidipine also caused fewer adverse effects.</p><p class="elsevierStylePara">By comparing manidipine with another CCB with similar kinetic and lipophilic characteristics, such as lercanidipine, manidipine is more effective in reducing insulin resistance in obese and hypertensive patients.<span class="elsevierStyleSup">22 </span>In other studies, manidipine proves itself to be just as effective as pioglitazone in reducing the expression of RAGE and the production of ROS, as well as reducing CRP levels. These experiments with specific inhibitors have concluded that the mechanism depends on PPAR-γ. This mechanism could explain the reduced inflammatory effect of hyperglycaemia and vascular damage.<span class="elsevierStyleSup">23 </span></p><p class="elsevierStylePara">The “lipotoxicity hypothesis” correlates type 2 diabetes with a loss in capacity of adipose tissue to accommodate excess calories. The loss in adipocyte differentiation makes the excess calories accumulate primarily in the liver, pancreas, and muscles, contributing to the development of insulin resistance.<span class="elsevierStyleSup">24 </span>We know that small adipocytes are sensitive to insulin, as opposed to mature cells, which undergo hypertrophy and become resistant to the hormone. For this reason, favouring adipogenesis would contribute to reducing insulin resistance in type 2 diabetes patients.</p><p class="elsevierStylePara">The improvement produced in insulin sensitivity by dihydropyrimidine CCB is almost imperceptible. In the case of nifedipine, which blocks only L-type channels, the body becomes even more desensitised to insulin, and glucose release is inhibited.<span class="elsevierStyleSup">16 </span>However, studies with manidipine have reported surprising results in this respect. Although some of these studies were already taken into account, a clinical trial performed with 64 hypertensive MS patients. The patients were evaluated using NCEP/ATPIII criteria and randomly assigned to manidipine or amlodipine treatments for 12 weeks. Similar reductions in blood pressure were observed with both treatments, and the patients treated with manidipine also experienced significant reductions in insulin resistance.<span class="elsevierStyleSup">25 </span>In this same manner, a more recent analysis on insulin sensitivity and plasma fibrinogen in obese and hypertensive patients compared the combination of manidipine and delapril versus olmesartan and hydrochlorothiazide. It demonstrated that the first combination significantly reduced insulin resistance and plasma fibrinogen levels, in spite of the fact that the reduction in blood pressure values would indicate similar efficacy between both combinations.<span class="elsevierStyleSup">26 </span>A later study compared the combination of manidipine and delapril with losartan and hydrochlorothiazide in patients with diabetes and microalbuminuria, and concluded that the first combination was the more useful therapeutic option for these patients.<span class="elsevierStyleSup">27 </span></p><p class="elsevierStylePara">Experiments have shown that manidipine, but not amlodipine or lercanidipine, activates PPAR-γin 3T3-L1 rat adipocytes.<span class="elsevierStyleSup">23,28 </span>In our studies, we have observed that NIH3T3 cells treated with manidipine<span class="elsevierStyleSup">29 </span>experience increased PPAR-γ(Peroxisome Proliferator-activated Receptor gamma) expression and adipocyte differentiation 2 (aP2) gene expression, which can be considered as evidence of the expression of the first (Figure 1). These results indicate mechanisms that link manidipine to the increase observed in insulin sensitivity in hypertensive, diabetic patients and with <span class="elsevierStyleItalic">de novo </span>adipocyte formation. In this sense, the increase in intracellular calcium levels has been observed to inhibit preadipocyte differentiation.<span class="elsevierStyleSup">30 </span>This contrasts with the normal role of calcium in faster processes, such as neurosecretion, excitation, and contraction.</p><p class="elsevierStylePara">Adipogenesis, as other differentiation processes, depends on stimulating transcription factors, such as PPAR-γ, and inhibitors such as the GATA family, which in turn is activated by extracellular signals. Calcium homeostasis has been studied with special emphasis on calreticulin, which is one of the main calcium binding proteins in the lumen of the endoplasmic reticulum, and is largely responsible for a rapid calcium exchange. One study performed with stem cells and 3T3-L1 preadipocytes demonstrated how calreticulin can modulate adipogenesis through a negative feedback mechanism. PPAR-γis a potent transcription activator for calreticulin, as it binds to its promoter. In this manner, it increases the expression of calreticulin, but once this protein is over-expressed, calreticulin inhibits the <span class="elsevierStyleItalic">cis</span>-bond of the PPAR-γ-RxR heterodimer to PPAR-γresponse elements (PPRE), thus cancelling the transcriptional activation of PPAR-γby fatty acids. Through this mechanism, calreticulin negatively regulates both the expression of PPAR-γand other critical proadipogenic transcription factors such as C/EBPa.<span class="elsevierStyleSup">31 </span></p><p class="elsevierStylePara">Manidipine’s calcium channel blocking activity could impede the entrance of calcium into the cells, thus reducing calcium concentrations in the endoplasmic reticulum, and in turn, that of calreticulin, favouring the differentiation of adipocytes.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">EFFECTS OF CCB ON MICROALBUMINURIA </span></p><p class="elsevierStylePara">The renal protection is associated with cardiovascular protection as well, and the evolution of albuminuria is an excellent predictor of both the evolution of renal function and the development of cardiovascular complications.<span class="elsevierStyleSup">32 </span>The presence of microalbuminuria makes the use of ACE inhibitors or ARA-II necessary, even as CCB are still considered for combined therapy. In the absence of albuminuria, and with maintained or diminished glomerular filtration rate, CCB could be the first pharmacological option. However, a high percentage of patients do require ACE inhibitors and/or ARA-II.<span class="elsevierStyleSup">33 </span></p><p class="elsevierStylePara">Contrary to other dihydropyridines, manidipine blocks T-type channels of efferent arterioles, which diminishes glomerular pressure and, consequently, albumin excretion, but at the same time it blocks L-type channels, thus favouring the dilation of the afferent arteriole. In this manner, T-type calcium channel blockers (CCB)<span class="elsevierStyleSup">1,7,34 </span>influence haemodynamics through their antihypertensive effect. Thus, we could consider their effect as protective against kidney damage, since the kidney is one of the target organs in hypertensive and diabetic patients. The AMANDHA study (Efficacy and Safety Assessment of Manidipine in Type 2 Diabetic Patients with Hypertension and Microalbuminuria Uncontrolled with Renin-Angiotensin System Blockers)<span class="elsevierStyleSup">35 </span>compared manidipine and amlodipine in diabetic patients with uncontrolled hypertension and microalbuminuria. Although both CCB are equally effective in reducing CRP and blood pressure, the first implies fewer adverse effects. Also, the reduction in albuminuria and insulin resistance was significantly higher in patients treated with manidipine. A recent study demonstrated yet again that manidipine is capable of significantly reducing albumin urine excretion in patients with essential hypertension without causing adverse effects, and so the combination of manidipine with renin-angiotensin antagonists could be beneficial in these cases.<span class="elsevierStyleSup">36 </span></p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">MANIDIPINE AND OXIDATIVE STRESS </span></p><p class="elsevierStylePara">Endothelial structure and function could improve considerably with the use of CCB. Research such as the INSIGHT study (International Nifedipine Intervention as a Goal in Hypertension Treatment) and MIDAS study (Myocardial Infarction Data Acquisition System) demonstrates the superiority of these drugs as compared to thiazide diuretics in terms of lower increases in intimal thickness.<span class="elsevierStyleSup">33,37,38 </span></p><p class="elsevierStylePara">The beneficial effects of calcium blockers in macrovascular endothelial cells must be demonstrated and justified through mechanisms that do not include calcium channels, since these are not expressed in endothelial cells.<span class="elsevierStyleSup">39,40 </span>To this end, some authors have postulated that the action of DHP in this type of tissue are related to their lipophilicity.<span class="elsevierStyleSup">41 </span></p><p class="elsevierStylePara">Oxidative stress plays a fundamental role in the development of atherosclerosis. Toba et al. pointed out the antioxidant and anti-inflammatory effects of manidipine and other CCB such as amlodipine, mediated by the increased expression of endothelial nitric oxide synthase (eNOS) and the inhibition of angiotensin converting enzyme (ACE) expression, but not their possible activity in reducing blood pressure. In this study, the authors observed how manidipine normalises the reduction in the expression of both the eNOS gene and protein, and reduces the over-expression of NADPH oxidase, VCAM, and MCP-1 in hypertensive rat aortas.<span class="elsevierStyleSup">41 </span>Furthermore, manidipine has another beneficial effect on atherogenesis, as it inhibits the expression of LOX-1, a low-density lipoprotein receptor induced into action by angiotensin II.<span class="elsevierStyleSup">43 </span></p><p class="elsevierStylePara">Sun X et al.<span class="elsevierStyleSup">44 </span>recently demonstrated that both in mature differentiated adipocytes and 3T3-L1 cells, and in co-cultures of both cell types, calcitrol increases the expression of inflammatory molecules such as MCP-1, MIF, M-CSF, MIP, IL-6<span class="elsevierStyleSup">45</span>, TNF and CD14. Treatment with nifedipine or dinitrophenol inhibits the activity of calcitrol, which could reveal a calcium-dependent mechanism that requires mitochondrial uncoupling. As such, we could expect the blockage of calcium channels with manidipine to also show anti-oxidative and · anti-inflammatory effect by reducing intracellular calcium levels.</p><p class="elsevierStylePara">Our preliminary studies on smooth muscle cells revealed an increase in endothelial nitric oxide synthase (eNOS) gene after being treated with manidipine. In response to many types of aggression, the expression of eNOS in cells treated with manidipine is essentially stable, compared to the control culture. This data may reveal a beneficial effect of CCB against endothelial dysfunction (Figure 2).</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">CONCLUSIONS </span></p><p class="elsevierStylePara">T-type calcium channel blockers provide protection to the kidneys, as they improve glomerular microcirculation due to their vasodilatory effect both on afferent and efferent arterioles. Manidipine stands out from among these types of calcium channel blockers due to its anti-inflammatory activity, which does not rely on the renin-angiotensin system, and because of its possible beneficial effects against endothelial dysfunction.</p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"> </p><p class="elsevierStylePara"><span class="elsevierStyleBold">Acknowledgements </span></p><p class="elsevierStylePara">This manuscript was developed with the aid of authors from the Fundación Mapfre-Guanarteme (Mapfre-Guanarteme Foundation) and Laboratorios Chiesi (Chiesi Laboratories), who we thank for their support and collaboration. The authors declare a Research Agreement between Chiesi Farmaceuti­ca S.p.A. and the Research Unit of the Dr. Negrín Gran Canaria</p><p class="elsevierStylePara"><a href="grande/10643_108_14369_en_10643_f1.jpg" class="elsevierStyleCrossRefs"><img src="10643_108_14369_en_10643_f1.jpg" alt="Exposure of NIH-3T3 preadipocyte cells to manidipine activates the expression of the aP2 gene in a time-dependent manner."></img></a></p><p class="elsevierStylePara">Figure 1. Exposure of NIH-3T3 preadipocyte cells to manidipine activates the expression of the aP2 gene in a time-dependent manner.</p><p class="elsevierStylePara"><a href="grande/10643_108_14370_en_10643_f2.jpg" class="elsevierStyleCrossRefs"><img src="10643_108_14370_en_10643_f2.jpg" alt="The Expression of eNOS in cells treated with angiotensin II and manidipine is significantly greater than in cells treated with just angiotensin II "></img></a></p><p class="elsevierStylePara">Figure 2. The Expression of eNOS in cells treated with angiotensin II and manidipine is significantly greater than in cells treated with just angiotensin II </p><p class="elsevierStylePara"><a href="10643_108_14367_en_10643tabla_1.doc" class="elsevierStyleCrossRefs">10643_108_14367_en_10643tabla_1.doc</a></p><p class="elsevierStylePara">Table 1. Calcium channels </p><p class="elsevierStylePara"><a href="10643_108_14368_en_10643tabla_2.doc" class="elsevierStyleCrossRefs">10643_108_14368_en_10643tabla_2.doc</a></p><p class="elsevierStylePara">Table 2. Calcium channel blockers </p>" "pdfFichero" => "P1-E521-S2953-A10643-EN.pdf" "tienePdf" => true "PalabrasClave" => array:2 [ "es" => array:3 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441061" "palabras" => array:1 [ 0 => "Canales de calcio tipo T" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441063" "palabras" => array:1 [ 0 => "Manidipino" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec441065" "palabras" => array:1 [ 0 => "Bloqueantes de canales de calcio" ] ] ] "en" => array:3 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441062" "palabras" => array:1 [ 0 => "T-type calcium channels" ] ] 1 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441064" "palabras" => array:1 [ 0 => "Manidipine" ] ] 2 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec441066" "palabras" => array:1 [ 0 => "Calcium channel blockers" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:1 [ "resumen" => "<p class="elsevierStylePara"><span class="elsevierStyleItalic">In the treatment of hypertension and diabetes, the combination of blockers of the renin-angiotensin system with calcium channel blockers appears as one of the most effective options. Nevertheless, all calcium blockers do not behave similarly. Manidipine, unlike other third-generation dihydropyridine derivatives, blocks T-type calcium channels present in the efferent glomerular arterioles, reducing glomerular pressure and microalbuminuria. In addition, T-type channels are related with proliferation, inflammation, fibrosis, vasoconstriction and activation of the renin-angiotensin system. Inhibition of these factors could explain manidipine non-hemodynamic actions compared to other blockers.</span></p> <p class="elsevierStylePara"><span class="elsevierStyleItalic"> </span></p> <p class="elsevierStylePara"><span class="elsevierStyleBold"><br /></span></p>" ] "es" => array:1 [ "resumen" => "<p class="elsevierStylePara">En el tratamiento de la hipertensión y la diabetes, la combinación de bloqueantes del sistema renina-angiotensina y de los canales de calcio se presenta como una de las opciones más eficaces. Sin embargo, no todos los bloqueantes de calcio se comportan del mismo modo. Manidipino, a diferencia de otros derivados dihidropiridínicos de tercera generación, bloquea los canales de calcio T presentes en las arteriolas glomerulares eferentes, disminuyendo la presión intraglomerular y la microalbuminuria. Además, los canales T están relacionados con proliferación, inflamación, fibrosis, vasoconstricción y activación del sistema renina-angiotensina. La inhibición de estos factores podría explicar la acción no hemodinámica del manidipino frente a otros bloqueantes. </p> <p class="elsevierStylePara"><span class="elsevierStyleBold"> </span></p>" ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "fig1" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10643_108_14369_en_10643_f1.jpg" "Alto" => 485 "Ancho" => 686 "Tamanyo" => 30753 ] ] "descripcion" => array:1 [ "en" => "Exposure of NIH-3T3 preadipocyte cells to manidipine activates the expression of the aP2 gene in a time-dependent manner." ] ] 1 => array:8 [ "identificador" => "fig2" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "figura" => array:1 [ 0 => array:4 [ "imagen" => "10643_108_14370_en_10643_f2.jpg" "Alto" => 482 "Ancho" => 686 "Tamanyo" => 26855 ] ] "descripcion" => array:1 [ "en" => "The Expression of eNOS in cells treated with angiotensin II and manidipine is significantly greater than in cells treated with just angiotensin II" ] ] 2 => array:8 [ "identificador" => "mmc1" "etiqueta" => "Tab. 1" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "Ecomponente" => array:2 [ "fichero" => "10643_108_14367_en_10643tabla_1.doc" "ficheroTamanyo" => 37376 ] "descripcion" => array:1 [ "en" => "Calcium channels " ] ] 3 => array:8 [ "identificador" => "mmc2" "etiqueta" => "Tab. 2" "tipo" => "MULTIMEDIAECOMPONENTE" "mostrarFloat" => true "mostrarDisplay" => false "copyright" => "Elsevier España" "Ecomponente" => array:2 [ "fichero" => "10643_108_14368_en_10643tabla_2.doc" "ficheroTamanyo" => 37888 ] "descripcion" => array:1 [ "en" => "Calcium channel blockers " ] ] ] "bibliografia" => array:2 [ "titulo" => "Bibliography" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:50 [ 0 => array:3 [ "identificador" => "bib1" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "1.\u{A0}Hayashi K, Wakino S, Sugano N, et al. Ca2 channel subtypes and pharmacology in the kidney. Circ Res 2007;100:342-53. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17307972" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S0735109711018742" "estado" => "S300" "issn" => "07351097" ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib2" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "2.\u{A0}Tiwari S, Zhang Y, Heller J, Abernethy DR, Soldatov NM. Atherosclerosis-related molecular alteration of the human CaV1.2 calcium channel alpha1C subunit. Proc Natl Acad Sci USA 2006;103:17024-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17071743" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 2 => array:3 [ "identificador" => "bib3" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "3.\u{A0}Bergh JJ, Shao Y, Puente E, Duncan RL, Farach-Carson MC. Osteoblast Ca(2 ) permeability and voltage-sensitive Ca(2 ) channel expression is temporally regulated by 1,25-dihydroxyvitamin D(3). Am J Physiol Cell Physiol 2006;290:C822-C31." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S0735109710025234" "estado" => "S300" "issn" => "07351097" ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib4" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "4.\u{A0}Tanaka H, Shigenobu K. Pathophysiological significance of T-type Ca2 channels: T-type Ca2 channels and drug development. J Pharmacol Sci 2005;99:214-20. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16293935" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 4 => array:3 [ "identificador" => "bib5" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "5.\u{A0}Catterall WA, Striessing J, Terrance P, Snutch P, Perez-Reyes E. International Union of pharmacology. XL. Compedium of Voltage-Gated Ion Channels: Calcium channels. Pharmacol Rev 2003;55:579-81. <a href="http://www.ncbi.nlm.nih.gov/pubmed/14657414" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 5 => array:3 [ "identificador" => "bib6" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "6.\u{A0}Cheng X, Liu J, Asuncion-Chin M, et al. A novel Ca(V)1.2 N terminus expressed in smooth muscle cells of resistance size arteries modifies channel regulation by auxiliary subunits. J Biol Chem 2007;282:29211-21." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 6 => array:3 [ "identificador" => "bib7" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "7.\u{A0}Hayashi K, Wakino S, Homma K, Sugano N, Saruta T. Pathophysiological significance of T-type Ca2 channels: role of T-type Ca2 channels in renal microcirculation. J Pharmacol Sci 2005;99:221-7. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16293936" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 7 => array:3 [ "identificador" => "bib8" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "8.\u{A0}Abernethy DR, Schwartz JB. Calcium-antagonist drugs. N Engl J Med 1999;341:1447-57. <a href="http://www.ncbi.nlm.nih.gov/pubmed/10547409" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 8 => array:3 [ "identificador" => "bib9" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "9.\u{A0}Gojanovic B, Feihl F, Liaudet L, Waeber B. Concomitant calcium entry blockade and inhibition of the renin-angiotensin system: a rational and effective means for treating hypertension. J Renin Angiotensin Aldosterone Syst 2008;9:1-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18404602" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 9 => array:3 [ "identificador" => "bib10" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Hayashi K, Nagahama T, Oka K, Epstein M, Saruta T. Disparate effects of calcium antagonists on renal microcirculation. Hypertens Res 1996;19:31-6. <a href="http://www.ncbi.nlm.nih.gov/pubmed/8829821" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 10 => array:3 [ "identificador" => "bib11" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "11.\u{A0}Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42:1206-52." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 11 => array:3 [ "identificador" => "bib12" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "12.\u{A0}Bonny A, Lacombe F, Yitemben M, et al. The 2007 ESH/ESC guidelines for the management of arterial hypertension. J Hypertens 2008;26:825-6." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 12 => array:3 [ "identificador" => "bib13" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "13.\u{A0}Nissen SE, Tuzcu EM, Libby P, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA 2004;292:2217-25. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15536108" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 13 => array:3 [ "identificador" => "bib14" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "14.\u{A0}Fogari R, Derosa G, Zoppi A, et al. Effects of manidipine/delapril versus olmesartan/hydrochlorothiazide combination therapy in elderly hypertensive patients with type 2 diabetes mellitus. Hypertens Res 2008;31:43-50. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18360017" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 14 => array:3 [ "identificador" => "bib15" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "15.\u{A0}Ebina T, Kimura K, Umemura S. Calcium antagonists: current and future applications based on new evidence. Calcium channel blockers and JSH 2009. Clin Calcium 2010;20:16-22." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 15 => array:3 [ "identificador" => "bib16" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "16.\u{A0}Ueshiba H, Miyachi Y. Effects of the long-acting calcium channel blockers, amlodipine, manidipine and cilnidipine on steroid hormones and insulin resistance in hypertensive obese patients. Intern Med 2004;43:561-5. <a href="http://www.ncbi.nlm.nih.gov/pubmed/15335180" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S0021915014000768" "estado" => "S300" "issn" => "00219150" ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib17" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "17.\u{A0}Payeras AC, Sladek K, Lembo G, Alberici M. Antihypertensive efficacy and safety of manidipine versus amlodipine in elderly subjects with isolated systolic hypertension: MAISH study. Clin Drug Invest 2007;27:623-32." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 17 => array:3 [ "identificador" => "bib18" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "18.\u{A0}Zanchetti A, Omboni S, La Commare P, De Cesaris R, Palatini P. Efficacy, tolerability, and impact on quality of life of long-term treatment with manidipine or amlodipine in patients with essential hypertension. J Cardiovasc Pharmacol 2001;38:642-50. <a href="http://www.ncbi.nlm.nih.gov/pubmed/11588535" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 18 => array:3 [ "identificador" => "bib19" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "19.\u{A0}Scheen AJ, Paquot N, Lefebvre PJ. United Kingdom Prospective Diabetes Study (UKPDS): 10 years later. Rev Med Liege 2008;63:624-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19009971" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 19 => array:3 [ "identificador" => "bib20" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "20.\u{A0}Gore MO, McGuire DK. The 10-year post-trial follow-up of the United Kingdom Prospective Diabetes Study (UKPDS): cardiovascular observations in context. Diab Vasc Dis Res 2009;6:53-5. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19156632" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 20 => array:3 [ "identificador" => "bib21" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "21.\u{A0}Martínez Martín FJ. Manidipine in hypertensive patients with metabolic syndrome: the MARIMBA study. Expert Review of Cardiovascular Therapy 2009;7:863-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19589122" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 21 => array:3 [ "identificador" => "bib22" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "22.\u{A0}Li CJ, Shi ZD. Calcium channel blockers. Clin Ther 2009;31:1652-63. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19808126" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 22 => array:3 [ "identificador" => "bib23" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "23.\u{A0}Nakami T, Martinez MFJ. Manidipine prevents hepatic C-reactive protein production and reactive oxygen species generation by down-regulation of the age receptor expression, dependent on PPAR-gamma activation. J Hypertens 2007;25:S119-S20." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 23 => array:3 [ "identificador" => "bib24" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "24.\u{A0}Sharma AM, Janke J, Gorzelniak K, Engeli S, Luft FC. Angiotensin blockade prevents type 2 diabetes by formation of fat cells. Hypertens 2002;40:609-11." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 24 => array:3 [ "identificador" => "bib25" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "25.\u{A0}Martínez Martín FJ. Manidipine (but not amlodipine), increases insulin sensitivity and rises plasma adiponectin cocentrations in hypertensive non-diabetic patients with metabolic syndrome and impaired fasting glucose. Diabetologia 2005;48(Suppl 1):A374." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 25 => array:3 [ "identificador" => "bib26" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "26.\u{A0}Fogari R, Derosa G, Zoppi A, et al. Effect of delapril/manidipine vs olmesartan/ hydrochlorothiazide combination on insulin sensitivity and fibrinogen in obese hypertensive patients. Intern Med 2008;47:361-6. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18310964" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 26 => array:3 [ "identificador" => "bib27" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "27.\u{A0}Kohlmann O, Jr., Roca-Cusachs A, Laurent S, et al. Fixed-dose manidipine/delapril versus losartan/hydrochlorothiazide in hypertensive patients with type 2 diabetes and microalbuminuria. Adv Ther 2009;26:313-24. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19330493" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 27 => array:3 [ "identificador" => "bib28" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "28.\u{A0}Oshimura H, Nakami T, Javier MF. Manidipine has a marked non-haemodynamic nephroprotective action; Partly dependent on PPAR-gamma activation, and synergistic with angiotensin receptor blockade. J Hypertens 2007;25(Suppl):S8." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 28 => array:3 [ "identificador" => "bib29" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "Buset Ríos N, Rodríguez Esparragón F, Rodríguez Pérez J. Cardio-metabolic properties of manidipine: beyond lowering arterial pressure?. Nefrologia 2009;29(3):203-7. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19554052" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 29 => array:3 [ "identificador" => "bib30" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "30.\u{A0}Meldolesi J. Inhibition of adipogenesis: a new job for the ER Ca2 pool. J Cell Biol 2008;182:11-3. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18606853" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 30 => array:3 [ "identificador" => "bib31" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "31.\u{A0}Szabo E, Qiu Y, Baksh S, Michalak M, Opas M. Calreticulin inhibits commitment to adipocyte differentiation. J Cell Biol 2008;182:103-16. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18606846" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 31 => array:3 [ "identificador" => "bib32" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "32.\u{A0}Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis 2000;36:646-61." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 32 => array:3 [ "identificador" => "bib33" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "33.\u{A0}Segura J, García-Donaire JA, Ruilope LM. Calcium channel blockers and renal protection: insights from the latest clinical trials. J Am Soc Nephrol 2005;16 (Suppl 1):S64-S6." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 33 => array:3 [ "identificador" => "bib34" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "34.\u{A0}Sabbatini M, Leonardi A, Testa R, Vitaioli L, Amenta F. Effect of calcium antagonists on glomerular arterioles in spontaneously hypertensive rats. Hypertension 2000;35:775-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/10720594" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 34 => array:3 [ "identificador" => "bib35" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "35.\u{A0}Martínez-Martín FJ, Saiz-Satjes M. Add-on manidipine versus amlodipine in diabetic patients with hypertension and microalbuminuria: the AMANDHA study. Expert Review Cardiovascular Therapy 2008;6:1347-55." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 35 => array:3 [ "identificador" => "bib36" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "36.\u{A0}Galceran J, Plana J, Felip A, et al. Manidipine treatment in patients with albuminuria not sufficiently reduced with renin-angiotensin system blockers. Expert Review\u{A0}Cardiovascular Therapy 2010;8:751-7." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 36 => array:3 [ "identificador" => "bib37" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "37.\u{A0}Rosenthal T. Role of calcium channel blockers in the future, in view of the INSIGHT Study. Kidney Int\u{A0}2002;82(Suppl):S32-S5." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 37 => array:3 [ "identificador" => "bib38" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "38.\u{A0}Borhani NO, Mercuri M, Borhani PA, et al. Final outcome results of the Multicenter Isradipine Diuretic Atherosclerosis Study (MIDAS). A randomized controlled trial. JAMA 1996;276:785-91. <a href="http://www.ncbi.nlm.nih.gov/pubmed/8769587" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 38 => array:3 [ "identificador" => "bib39" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "39.\u{A0}Simon A, Levenson J. Effects of calcium channel blockers on atherosclerosis: new insights. Acta Cardiol 2002;57:249-55. <a href="http://www.ncbi.nlm.nih.gov/pubmed/12222691" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 39 => array:3 [ "identificador" => "bib40" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "40.\u{A0}Adams DJ, Barakeh J, Laskey R, Van Breemen C. Ion channels and regulation of intracellular calcium in vascular endothelial cells. FASEB J 1989;3:2389-400. <a href="http://www.ncbi.nlm.nih.gov/pubmed/2477294" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 40 => array:3 [ "identificador" => "bib41" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "41.\u{A0}Berkels R, Breitenbach T, Bartels H, et al. Different antioxidative potencies of dihydropyridine calcium channel modulators in various models. Vasc Pharmacol 2005;42:145-52." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 41 => array:3 [ "identificador" => "bib42" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "42.\u{A0}Toba H, Nakagawa Y, Miki S, et al. Calcium channel blockades exhibit anti-inflammatory and antioxidative effects by augmentation of endothelial nitric oxide synthase and the inhibition of angiotensin converting enzyme in the N(G)-nitro-L-arginine methyl ester-induced hypertensive rat aorta: vasoprotective effects beyond the blood pressure-lowering effects of amlodipine and manidipine. Hypertens Res 2005;28:689-700. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16392774" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 42 => array:3 [ "identificador" => "bib43" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "43.\u{A0}Toba H, Shimizu T, Miki S, et al. Calcium [corrected] channel blockers reduce angiotensin II-induced superoxide generation and inhibit lectin-like oxidized low-density lipoprotein receptor-1 expression in endothelial cells. Hypertens Res 2006;29:105-16. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16755144" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 43 => array:3 [ "identificador" => "bib44" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "44.\u{A0}Sun X, Zemel MB. Calcitriol and calcium regulate cytokine production and adipocyte-macrophage cross-talk. J Nutr Biochem 2008;19:392-9. <a href="http://www.ncbi.nlm.nih.gov/pubmed/17869082" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 44 => array:3 [ "identificador" => "bib45" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "45.\u{A0}Costa S, Zimetti F, Pedrelli M, Cremonesi G, Bernini F. Manidipine reduces pro-inflammatory cytokines secretion in human endothelial cells and macrophages. Pharmacol Res 2010;62:265-70. <a href="http://www.ncbi.nlm.nih.gov/pubmed/20347984" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 45 => array:3 [ "identificador" => "bib46" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "46.\u{A0}Moosmang S, Haider N, Bruderl B, Welling A, Hofmann F. Antihypertensive effects of the putative T-type calcium channel antagonist mibefradil are mediated by the L-type calcium channel Cav1.2. Circ Res 2006;98:105-10. <a href="http://www.ncbi.nlm.nih.gov/pubmed/16306443" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 46 => array:3 [ "identificador" => "bib47" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "47.\u{A0}Peltz A, Sherwani SI, Kotha SR, et al. Calcium and calmodulin regulate mercury-induced phospholipase D activation in vascular endothelial cells. Int J Toxicol 2009;28:190-206. <a href="http://www.ncbi.nlm.nih.gov/pubmed/19546257" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:1 [ "itemHostRev" => array:3 [ "pii" => "S0735109710002809" "estado" => "S300" "issn" => "07351097" ] ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib48" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "48.\u{A0}Martínez Martín FJ. Calcium channel-blockers for managing metabolic syndrome-associated hypertension. Trials with manidipine. Nefrologia 2007;27 (Suppl 6):26-35. <a href="http://www.ncbi.nlm.nih.gov/pubmed/18225601" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 48 => array:3 [ "identificador" => "bib49" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "49.\u{A0}Patel RJ, Patel PD, Patel MM, Patel NJ, Thyagarajan B. Mechanisms of potentiation of Angiotensin II-induced contractile response of isolated rat aorta by hydrogen peroxide and tert-butyryl hydroperoxide. Indian J Pharmacol 2009;41:140-3. <a href="http://www.ncbi.nlm.nih.gov/pubmed/20442823" target="_blank">[Pubmed]</a>" "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] 49 => array:3 [ "identificador" => "bib50" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:3 [ "referenciaCompleta" => "50.\u{A0}Nakano N, Ishimitsu T, Takahashi T, et al. Effects of efonidipine, an L- and T-type calcium channel blocker, on the renin-angiotensin-aldosterone system in chronic hemodialysis patients. Int Heart J 2010;51:188-92." "contribucion" => array:1 [ 0 => null ] "host" => array:1 [ 0 => null ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/20132514/0000003100000003/v0_201502091638/X2013251411052028/v0_201502091638/en/main.assets" "Apartado" => array:4 [ "identificador" => "35445" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Short Reviews" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/20132514/0000003100000003/v0_201502091638/X2013251411052028/v0_201502091638/en/P1-E521-S2953-A10643-EN.pdf?idApp=UINPBA000064&text.app=https://revistanefrologia.com/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/X2013251411052028?idApp=UINPBA000064" ]
Year/Month | Html | Total | |
---|---|---|---|
2024 November | 8 | 9 | 17 |
2024 October | 88 | 342 | 430 |
2024 September | 96 | 60 | 156 |
2024 August | 118 | 83 | 201 |
2024 July | 101 | 34 | 135 |
2024 June | 103 | 57 | 160 |
2024 May | 103 | 57 | 160 |
2024 April | 83 | 66 | 149 |
2024 March | 94 | 44 | 138 |
2024 February | 78 | 47 | 125 |
2024 January | 80 | 25 | 105 |
2023 December | 52 | 33 | 85 |
2023 November | 57 | 46 | 103 |
2023 October | 63 | 36 | 99 |
2023 September | 71 | 31 | 102 |
2023 August | 75 | 25 | 100 |
2023 July | 99 | 36 | 135 |
2023 June | 73 | 21 | 94 |
2023 May | 81 | 42 | 123 |
2023 April | 46 | 16 | 62 |
2023 March | 63 | 24 | 87 |
2023 February | 55 | 24 | 79 |
2023 January | 56 | 27 | 83 |
2022 December | 61 | 38 | 99 |
2022 November | 73 | 28 | 101 |
2022 October | 87 | 55 | 142 |
2022 September | 106 | 43 | 149 |
2022 August | 99 | 52 | 151 |
2022 July | 60 | 41 | 101 |
2022 June | 87 | 53 | 140 |
2022 May | 125 | 37 | 162 |
2022 April | 93 | 53 | 146 |
2022 March | 102 | 60 | 162 |
2022 February | 107 | 51 | 158 |
2022 January | 93 | 70 | 163 |
2021 December | 58 | 58 | 116 |
2021 November | 102 | 47 | 149 |
2021 October | 125 | 59 | 184 |
2021 September | 114 | 47 | 161 |
2021 August | 94 | 48 | 142 |
2021 July | 42 | 38 | 80 |
2021 June | 92 | 42 | 134 |
2021 May | 81 | 51 | 132 |
2021 April | 164 | 118 | 282 |
2021 March | 94 | 45 | 139 |
2021 February | 95 | 38 | 133 |
2021 January | 71 | 31 | 102 |
2020 December | 63 | 20 | 83 |
2020 November | 55 | 33 | 88 |
2020 October | 54 | 20 | 74 |
2020 September | 93 | 11 | 104 |
2020 August | 64 | 13 | 77 |
2020 July | 60 | 17 | 77 |
2020 June | 68 | 23 | 91 |
2020 May | 76 | 21 | 97 |
2020 April | 76 | 22 | 98 |
2020 March | 86 | 28 | 114 |
2020 February | 83 | 27 | 110 |
2020 January | 127 | 32 | 159 |
2019 December | 106 | 30 | 136 |
2019 November | 104 | 36 | 140 |
2019 October | 86 | 25 | 111 |
2019 September | 87 | 26 | 113 |
2019 August | 74 | 50 | 124 |
2019 July | 83 | 27 | 110 |
2019 June | 55 | 21 | 76 |
2019 May | 94 | 39 | 133 |
2019 April | 123 | 48 | 171 |
2019 March | 50 | 22 | 72 |
2019 February | 51 | 21 | 72 |
2019 January | 85 | 24 | 109 |
2018 December | 148 | 38 | 186 |
2018 November | 150 | 23 | 173 |
2018 October | 116 | 17 | 133 |
2018 September | 119 | 25 | 144 |
2018 August | 68 | 19 | 87 |
2018 July | 59 | 18 | 77 |
2018 June | 65 | 13 | 78 |
2018 May | 51 | 21 | 72 |
2018 April | 54 | 7 | 61 |
2018 March | 48 | 8 | 56 |
2018 February | 44 | 3 | 47 |
2018 January | 44 | 11 | 55 |
2017 December | 55 | 11 | 66 |
2017 November | 46 | 20 | 66 |
2017 October | 53 | 10 | 63 |
2017 September | 54 | 10 | 64 |
2017 August | 70 | 14 | 84 |
2017 July | 61 | 13 | 74 |
2017 June | 61 | 20 | 81 |
2017 May | 65 | 14 | 79 |
2017 April | 72 | 17 | 89 |
2017 March | 54 | 16 | 70 |
2017 February | 39 | 23 | 62 |
2017 January | 39 | 13 | 52 |
2016 December | 99 | 7 | 106 |
2016 November | 128 | 17 | 145 |
2016 October | 127 | 9 | 136 |
2016 September | 149 | 23 | 172 |
2016 August | 228 | 12 | 240 |
2016 July | 220 | 19 | 239 |
2016 June | 148 | 0 | 148 |
2016 May | 171 | 0 | 171 |
2016 April | 123 | 0 | 123 |
2016 March | 118 | 0 | 118 |
2016 February | 147 | 0 | 147 |
2016 January | 142 | 0 | 142 |
2015 December | 150 | 0 | 150 |
2015 November | 115 | 0 | 115 |
2015 October | 98 | 0 | 98 |
2015 September | 92 | 0 | 92 |
2015 August | 79 | 0 | 79 |
2015 July | 67 | 0 | 67 |
2015 June | 41 | 0 | 41 |
2015 May | 60 | 0 | 60 |
2015 April | 5 | 0 | 5 |