Qual o melhor horário da tomada da medicação anti-hipertensiva? / What is the best time to take antihypertensive medication?

A hipertensão arterial é a principal causa de morte precoce no mundo. Existem diversos fatores que contribuem para sua variação dentro da fisiologia do ritmo circadiano, e que exercem forte impacto sobre o controle da pressão arterial (PA). Os valores da PA sofrem interferência de acordo com o horário da medida. Nas primeiras horas da manhã PAS aumenta rapidamente em 20 a 25 mmHg e a PAD em 10 a 15 mmHg. As drogas anti-hipertensivas, sofrem diversas influências na sua absorção, metabolização e excreção dependentes do ritmo circadiano e de suas propriedades físico-químicas. O ciclo circadiano exerce grande impacto no controle da PA, e apenas modificando o horário das prescrições, seguindo o ritmo circadiano, talvez seja possível obter melhor controle pressórico com menor dose da medicação, reduzindo assim, as possíveis reações adversas

Hypertension is the leading cause of early death worldwide. Several factors contribute to its variation within the physiology of circadian rhythm, and these factors have a strong impact on blood pressure (BP) control. BP values are influenced by the measurement time. In the early hours of the morning, SBP increases rapidly by 20 to 25 mmHg and DBP by 10 to 15 mmHg. Antihypertensive drugs suffer from a variety of influences on their absorption, metabolism and excretion, depending on the circadian rhythm and its physical-chemical properties. The circadian cycle has a great impact on BP control, and only by changing the schedule of prescriptions, following the circadian rhythm, it may be possible to obtain better pressure control with a lower dose of medication, thus reducing potential adverse reactions

Chronopharmacology: Tailoring Therapy to Endogenous Rhythms.

Chronopharmacology aims at the use of biological rhythms in the clinical treatment so as to enhance both effectiveness and tolerance and minimize the side effects of a drug by determining the best biological time for its administration. Chronopharmacology is useful to solve problems of drug optimization. In the human organs, the metabolic fate of a pharmacologic agent as well is not constant as a function of time. Thus, the chronobiological approach of drug administration involves a lesser risk of errors than the conventional homeostatic approach. Chronopharmacology is now used as a routine to treat various disorders like hypertension, angina, cancer and various psychotic disorders. The newer drug delivery systems that are designed with the chronopharmacological approach hold great scope for delivering better patient care in terms of efficacy, tolerance and safety parameters of the drug. This review aims at introducing chronopharmacology, the role of the regulatory system of biological clock in pharmacotherapy and the benefits it has conferred in various clinical conditions.

Phase II clinical trial of two different modes of administration of the induction chemotherapy for locally advanced nasopharyngeal carcinoma / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To compare the therapeutic effects, toxic side effects and influence on the immune function in patients treated with TPF [docetaxel (DOC) + cisplatin (DDP) + 5-fluorouracil (5-Fu)] induction chronochemotherapy and conventional chemotherapy for locally advanced nasopharyngeal (NPC).</p><p><b>METHODS</b>Seventy patients with locally advanced nasopharyngeal carcinoma were treated in our department at their first visit from April 2013 to December 2013. They were divided randomly into two groups: the chronochemotherapy group (38 patients) and conventional chemotherapy group (32 patients). All of the patients were treated with TPF regimen with 2 cycles of induction chemotherapy in a 21-28-days/cycle. The chronochemotherapy group: DOC: 75 mg/m2, i. v. gtt, d1 (03: 30-04: 30); DDP: 75 mg/m2, 10 am-10 pm, c.i.v, d1-d5; 5-Fu: 750 mg·m(-2)·d(-1), 10 pm-10 am, c. i.v., d1-d5, both chemotherapies were administered by intravenous infusion using an automatic electric pump. The conventional chemotherapy group: Both DOC and DDP were administered intravenously at a dose of 75 mg/m2 on d1. 5-Fu was given at a dose of 750 mg/m2 for 24 hours from d1-d5 with continuous infusion in a total of 120 hours. In this procedure, prescribing the conventional intravenous infusion, intensity modulated radiation therapy was used after the induction chemotherapy. The prescribed nasopharyngeal lesion dose (GTVnx) was 69.96 Gy/33 fractions for the T1-T2 nasopharygeal cancer, while 73.92 Gy/33 fractions nasopharynx lesion dose (GTVnx) for the T3-T4 nasopharyngeal cancer. The planning target volume (PTV) of positive lymph node (PTVnd) dose was 69.96 Gy/33 fractions. Concurrent chemoradiotherapy: cisplatin 100 mg/m2, i. v. gtt. d1-d2, and there were two cycles in total and 21 days each cycle.</p><p><b>RESULTS</b>Sixty-six patients were evaluable for the response assessment. There were 36 patients in the chronochemotherapy group and 30 patients in the conventional chemotherapy group. After the induction chemotherapy, no CR case was found in both of the two groups. The PR was 80.6% in the chronochemotherapy group and 50.0% in the conventional chemotherapy group (P=0.009). After concurrent chemoradiotherapy, the CR rate in the chronocheotherapy group was 45.5%, significantly higher than 20.7% in the conventional chemotherapy group (P=0.040). Secondly, the incidence rates of adverse reactions including bone marrow suppression, nausea, vomiting, diarrhea, constipation, oral mucositis, fatigue, anorexia in the chrono-chemotherapy group were significantly lower than that in the conventional group (P<0.05 for all). Finally, compared the two groups, the CD4+ /CD8+ ratio was significantly lower in the chronochemotherapy group than that in the conventional chemotherapy group (P<0.05). The lymphocytes CD19+ and CD4+/CD8+ were decreased and CD3+, CD4+, CD8+, CD16++CD56+ were increased in the chronochemotherapy group, while only CD3+ and CD8+ were increased in the conventional chemotherapy group.</p><p><b>CONCLUSIONS</b>Compared with the conventional chemotherapy, the chronochemotherapy may be more favorable in the treatment of NPC, with a better therapeutic effects and effectiveness than that of conventional chemotherapy after induction chemotherapy, with less side effects, and can improve the immune function in the patients.</p>

Design and optimization of self-microemulsifying drug delivery system (SMEDDS) of felodipine for chronotherapeutic application

The objective of this research work was to design, develop and optimize the self micro-emulsifying drug delivery system (SMEDDS) of Felodipine (FL) filled in hard gelatine capsule coated with polymer in order to achieve rapid drug release after a desired time lag in the management of hypertension. Microemulsion is composed of a FL, Lauroglycol FCC, Transcutol P and Cremophor EL. The optimum surfactant to co-surfactant ratio was found to be 2:1. The resultant microemulsions have a particle size in the range of 65-85 nm and zeta potential value of -13.71 mV. FL release was adequately adjusted by using pH independent polymer i.e. ethyl cellulose along with dibutyl phthalate as plasticizer. Influence of formulation variables like viscosity of polymer, type of plasticizer and percent coating weight gain was investigated to characterize the time lag. The developed formulation of FL SMEDDS capsules coated with ethyl cellulose showed time lag of 5-7 h which is desirable for chronotherapeutic application.

O objetivo desse trabalho de pesquisa foi planejar, desenvolver e otimizar sistema de liberação de fármaco auto-microemulsificante(SMEDDS) de felodipino (FL) em cápsulas de gelatina dura revestidas com polímero, a fim de obter liberação rápida após tempo desejado no manejo da hipertensão. A microemulsão é composta de FL, lauroglilcol FCC, Transcutol P e Cremophor EL. A proporção ótima de tensoativo e de co-tensoativo foi de 2:1. As microemulsões resultantes têm tamanho de partícula na faixa de 65-85 nm com potencial zeta de -13,71 mV. A liberação de FL foi ajustada adequadamente, utilizando-se polímero independente de pH, como etilcelulose com ftalato de dibutila como plastificante. A influência das variáveis da formulação, como viscosidade do polímero, tipo de plastificante e ganho percentual de peso do revestimento foi investigada para caracterizar o intervalo de tempo de liberação. A formulação de cápsulas de FL SMEDDS revestidas com etilcelulose mostrou intervalo de tempo de liberação de 5 a 7 horas, o que é desejável para uma aplicação cronoterapêutica.

Cronoterapia y psiquiatría: aspectos a considerar en la clínica / Chronotherapy and psychiatry: issues to consider clinic

Se ha demostrado que las funciones fisiológicas oscilan durante ciclos de 24 horas (circadianos), menos de 24 horas (ultradianos) y mayores de 24 horas (infradianos), lo que se denomina ritmos biológicos (cronobiología). El presente artículo hace énfasis en cómo los ritmos biológicos pueden incidir en la respuesta a los medicamentos y la terapéutica psiquiátrica (cronofarmacología, cronoterapia). Esta variable de estudio podría ofrecer nuevos márgenes en la eficacia y seguridad de los medicamentos y hacer su uso más racional.

It has been shown that physiological functions oscillate during cycles of 24 hours (circadian), of less than 24 (ultradian) and larger than 24 hours (infradian). These are called biological rhythms (chronobiology). This article emphasizes on how biological rhythms may influence response to drugs and psychiatric treatment (chronopharmacology, chronotherapy). The study of this variable could offer new perspectives on efficacy and safety of drugs in order to pursue a more rational use of them.

Effects of chronotherapy of benazepril on the diurnal profile of RAAS and clock genes in the kidney of 5/6 nephrectomy rats / 华中科技大学学报（医学）（英德文版）

This study investigated the effects of benazepril administered in the morning or evening on the diurnal variation of renin-angiotensin-aldosterone system (RAAS) and clock genes in the kidney. The male Wistar rat models of 5/6 subtotal nephrectomy (STNx) were established. Animals were randomly divided into 4 groups: sham STNx group (control), STNx group, morning benazepril group (MB) and evening benazepril group (EB). Benazepril was intragastrically administered at a dose of 10 mg/kg/day at 07:00 and 19:00 in the MB group and EB group respectively for 12 weeks. All the animals were synchronized to the light:dark cycle of 12:12 for 12 weeks. Systolic blood pressure (SBP), 24-h urinary protein excretion and renal function were measured at 11 weeks. Blood samples and kidneys were collected every 4 h throughout a day to detect the expression pattern of renin activity (RA), angiotensin II (AngII) and aldosterone (Ald) by radioimmunoassay (RIA) and the mRNA expression profile of clock genes (bmal1, dbp and per2) by real-time PCR at 12 weeks. Our results showed that no significant differences were noted in the SBP, 24-h urine protein excretion and renal function between the MB and EB groups. There were no significant differences in average Ald and RA content of a day between the MB group and EB group. The expression peak of bmal1 mRNA was phase-delayed by 4 to 8 h, and the diurnal variation of per2 and dbp mRNA diminished in the MB and EB groups compared with the control and STNx groups. It was concluded when the similar SBP reduction, RAAS inhibition and clock gene profile were achieved with optimal dose of benazepril, morning versus evening dosing of benazepril has the same renoprotection effects.

Randomized study of sinusoidal chronomodulated versus flat intermittent induction chemotherapy with cisplatin and 5-fluorouracil followed by traditional radiotherapy for locoregionally advanced nasopharyngeal carcinoma / 癌症

Neoadjuvant chemotherapy plus radiotherapy is the most common treatment regimen for advanced nasopharyngeal carcinoma (NPC). Whether chronomodulated infusion of chemotherapy can reduce its toxicity is unclear. This study aimed to evaluate the toxic and therapeutic effects of sinusoidal chronomodulated infusion versus flat intermittent infusion of cisplatin (DDP) and 5-fluorouracil (5-FU) followed by radiotherapy in patients with locoregionally advanced NPC. Patients with biopsy-diagnosed untreated stages III and IV NPC (according to the 2002 UICC staging system) were randomized to undergo 2 cycles of sinusoidal chronomodulated infusion (Arm A) or flat intermittent constant rate infusion (Arm B) of DDP and 5-FU followed by radical radiotherapy. Using a "MELODIE" multi-channel programmed pump, the patients were given 12-hour continuous infusions of DDP (20 mg/m2) and 5-FU (750 mg/m2) for 5 days, repeated every 3 weeks for 2 cycles. DDP was administered from 10:00 am to 10:00 pm, and 5-FU was administered from 10:00 pm to 10:00 am each day. Chronomodulated infusion was performed in Arm A, with the peak deliveries of 5-FU at 4:00 am and DDP at 4:00 pm. The patients in Arm B underwent a constant rate of infusion. Radiotherapy was initiated in the fifth week, and both arms were treated with the same radiotherapy techniques and dose fractions. Between June 2004 and June 2006, 125 patients were registered, and 124 were eligible for analysis of response and toxicity. The major toxicity observed during neoadjuvant chemotherapy was neutropenia. The incidence of acute toxicity was similar in both arms. During radiotherapy, the incidence of stomatitis was significantly lower in Arm A than in Arm B (38.1% vs. 59.0%, P = 0.020). No significant differences were observed for other toxicities. The 1-, 3-, and 5-year overall survival rates were 88.9%, 82.4%, and 74.8% for Arm A and 91.8%, 90.2%, and 82.1% for Arm B. The 1-, 3-, and 5-year progression-free survival rates were 91.7%, 88.1%, and 85.2% for Arm A and 100%, 94.5%, and 86.9% for Arm B. The 1-, 3-, and 5-year distant metastasis-free survival rates were 82.5%, 79.1%, and 79.1% for Arm A and 90.2%, 85.2%, and 81.7% for Arm B. Chronochemotherapy significantly reduced stomatitis but was not superior to standard chemotherapy in terms of hematologic toxicities and therapeutic response.

Development and evaluation of a chronotherapeutic drug delivery system of torsemide / Desenvolvimento e avaliação de um sistema de entrega de drogas cronoterapêuticas de torsemida

The objective of this study was to prepare and evaluate chronotherapeutic drug delivery systems (ChrDDs) of torsemide. Compression coated tablets (CCT) containing torsemide in the core tablet were prepared by the compression coating technique with different grades of polyethylene oxide (PEO WSR 301 & 1105). The optimized formulations were characterised for tabletting parameters and drug polymer interaction by Fourier-Transform Infrared Spectroscopy (FTIR).The hardness of all the CCT using PEO WSR 301 & PEO WSR 1105 were in the range 6-8 kg/cm² & 5.5 to 7 kg/cm² respectively. Their friability values were <0.3 percent. All the CCT showed a clear lag time but finalized as per the predetermined lag time. As the amount of PEO was increased in the outer layer the drug released was delayed. The drug content of all the CCT was >99 percent. The FTIR studies showed no interaction throughout the process of development. Formulations of F7 and of P7 were considered optimized formulations since they yielded a predetermined lag time of 6h before burst release. Hence, these formulations can be exploited to achieve chronotherapeutic drug delivery systems of Torsemide for the treatment of hypertension at the time the patient needs it.

O objetivo deste estudo foi preparar e avaliar sistemas cronoterapêuticos de liberação de fármacos (ChrDDs) de torsemida. Comprimidos revestidos por compressão (CCT) contendo torsemida no (núcleo) foram preparados pela técnica de revestimento por compressão, com diferentes categorias de óxido de polietileno (PEO WSR 301 & 1105). As formulações otimizadas foram caracterizadas por parâmetros de compressão e interação fármaco polímero por Infravermelho com Transformada de Fourier (FTIR). A dureza dos CCT utilizando PEO WSR 301 e PEO WSR 1105 foi entre 6-8 kg/cm² e 5,5 a 7 kg/cm², respectivamente. Os valores de friabilidade foram <0,3 por cento. Todos os CCT mostraram claro tempo de retardo, mas finalizaram de acordo com o tempo de retardo pré-determinado. À medida que a quantidade de PEO aumentava na camada mais externa, a liberação do fármaco era retardada. O teor de fármaco em todos os CCT foi >99 por cento. Os estudos de FTIR mostraram que não h[a interação durante o processo de desenvolvimento. As formulações F7 e P7 foram consideradas otimizadas, uma vez que resultaram em tempo de retardo pré-determinado de 6 h antes da liberação por meio de explosão. Dessa forma, estas formulações podem ser exploradas para se obter sistemas de liberação.

Preparation of gastric retenting and chronopharmacologic drug delivery tablets of sinomenine hydrochloride / 中国中药杂志

<p><b>OBJECTIVE</b>To prepare the gastric retenting and chronopharmacologic drug delivery tablets containing sinomenine hydrochloride as a model drug, evaluate the effects of the coating layers formulation and technics on drug release behavior, and to elucidate the mechanism of drug release based on obtained results.</p><p><b>METHOD</b>The gastric retenting and chronopharmacologic drug delivery tablets were prepared by press-coated technics. The types of disintegrants were chosen according to the expanding rate and the lag-time. The effects of formulation and technics of coating layer on the release characteristic of the drug were investigated by dissolution testing. The mechanism of drug release was proved by erosion test.</p><p><b>RESULT</b>The tablets had typical chronopharmacologic drug delivery properties with a lag time followed by a rapid release phase. CMS-Na was selected as the disintegrant. The lag-time was prolonged with the increase of the ratio of HPMC/carrrageenan and the amount of matrix material in coating layer. The compressing pressure and preparation method of coat material had minor influence on the lag-time of the tablets. Coating layer erosion and tablet core swelling were involved in the mechanism of drug release.</p><p><b>CONCLUSION</b>The tablets had typical chronopharmacologic drug delivery properties. A suitable lag-time can be achieved by adjusting formulation of coating layer to meet the requirement of chronotherapy.</p>

Uso del monitoreo ambulatorio de la presión arterial en la evaluación clínica de la hipertensión arterial / Ambulatory blood pressure monitoring in the clinic evaluation of arterial hypertension

La presión arterial, al igual que otros eventos de importancia biológica en nuestro organismo, sigue un ritmo circadiano normalmente, por lo que ésta fluctúa durante las 24 horas del día. Para establecer la eficacia del tratamiento antihipertensivo, se deberá demostrar que dicho tratamiento mantiene controlada la presión arterial en los diferentes momentos del día y la noche, por lo cual se ha utilizado el monitoreo ambulatorio de la presión arterial (MAPA) o “holter de presión,” como una herramienta indispensable en la evaluación clínica de la hipertensión arterial.

The arterial pressure, the same as others events of biologic importance in our organism, follow a normally circadian rhythm, and fluctuate during 24 hours of day. For establish the efficiency ofantihypertensive treatment, should be demonstrated that treatment keep under control the arterial pressure in the different moments of day and night, this is the reason why used an ambulatory blood pressure monitoring like a essential tool in the evaluation of arterial hypertension.

Chronotherapeutic effect of fluvastatin on lipid profile in rats

Dyslipidemia is a major risk factor for coronary heart disease [CHD], and its management is important in preventing the occurrence of cardiovascular events. Lipid-altering drug treatment, targeted to patients at high risk for cardiovascular disease, has been shown [in clinical trials] to reduce the incidence of first and recurrent CHD events. Statins are used widely for the treatment of dyslipidemia. They act through reversible competitive inhibition of the hepatic 3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase, the enzyme that catalyzes the rate-limiting step in cholesterol biosynthesis. The early use of statin in management of dyslipidemia recommended their morning administration. However, this strategy should be re-evaluated in light of reports showing that the biosynthesis of cholesterol exhibits diurnal periodicity with nocturnal increase in the level of cholesterol precursors. The experiments were performed on forty male albino rats divided after estimation of basic lipid profile into four equal groups, each composed of 10 animals: control normocholesterolemic, hypercholesterolemic non-treated, hypercholesterolemic treated with morning fluvastatin [8mg/kg, for 12[th] weeks] and hypercholesterolemic treated with evening fluvastatin [8mg/kg for 12[th] weeks]. Lipid profile was estimated at the end of the 4[th], 8[th], 12[th] and 16[th] weeks for all animals using spectrophotometeric assay kits and the results were expressed in mg/dl. Both morning and evening treatment with fluvastatin significantly reduced blood cholesterol level and low-density lipoprotein. Significant increase of plasma high density lipoprotein level was observed in evening treated group in comparison with non-treated hypercholesterolemic animals. Interestingly, all these beneficial effects of fluvastatin treatment were more significant when administered in the evening rather than in the morning pattern of treatment. On the other hand, fluvastatin treatment whether given in the morning or in the evening for hypercholesterolemic animals, produced no significant effect on plasma triglyceride level and total lipid level in comparison with non-treated hypercholesterolemic animals. It is concluded that therapeutic efficiency of fluvastatin is best obtained when the drug was administered in the evening rather than in the morning. This most likely occurred due to the circadian rhythm of cholesterol biosynthesis. This chronotherapeutic pattern of fluvastatin recommends its night administration to ensure introduction of the drug at the proper timing thus achieving the best therapeutic effect

Developments of chronobiology abroad / 生物医学工程学杂志

Developments of chronobiology abroad are forging ahead in elucidating the cellular and molecular basis and the influential factors of circadian clock such as light, jet lag, pharmaceutical. This article also reviews the influence of circadian system on human physiology and disease occurrence. The circadian-based therapy holds promising future and the research emphasis is on prognosis and prevention.