Clinical Significance and Therapeutic Implication of Nocturnal Hypertension: Relationship between Nighttime Blood Pressure and Quality of Sleep

Recent global hypertension guidelines recommend an early, strict and 24-hour blood pressure (BP) control for the prevention of target organ damage and cardiovascular events. Out-of-office BP measurement such as ambulatory BP monitoring and home BP monitoring is now widely utilized to rule out white-coat hypertension, to detect masked hypertension, to evaluate the effects of antihypertensive medication, to analyze diurnal BP variation, and to increase drug adherence. Nocturnal hypertension has been neglected in the management of hypertension despite of its clinical significance. Nighttime BP and non-dipping patterns of BP are stronger risk predictors for the future cardiovascular mortality and morbidity than clinic or daytime BP. In addition to ambulatory or home daytime BP and 24-hour mean BP, nocturnal BP should be a new therapeutic target for the optimal treatment of hypertension to improve prognosis in hypertensive patients. This review will provide an overview of epidemiology, characteristics, and pathophysiology of nocturnal hypertension and clinical significance, therapeutic implication and future perspectives of nocturnal hypertension will be discussed.

Development and evaluation of multiparticulate biphasic system for the treatment of circadian diseases

Multiparticulate systems have biopharmaceutical advantages when compared to the monolithic systems, once they allow different patterns of drug release and can be used in different treatments. The aim of the present work was to develop a biphasic controlled release delivery system, using propranolol hydrochloride (PROP) that can be used for the treatment of circadian diseases. This system was obtained by the combination of cellulosic polymers hydroxypropyl methylcellulose (HPMC) and ethylcellulose (EC) in a 2² factorial experimental design, which allowed the optimization of the development stage. The pellets produced and used in biphasic formulations were evaluated for physical and chemical characteristics and presented acceptable results. The immediate fraction obtained showed the complete release in 30 min while the others kept the release of the drug for 24 h. This study showed that the combination of beads with different releasing characteristics allowed to obtain different release profiles, which can be modulated according to the pathological needs, especially with regard to circadian diseases that suffer alterations throughout the day.

Importancia de la cronoterapia en la hipertensión arterial / Importance Of Chronotherapy In Blood Hypertension

Antecedentes: La presión arterial presenta una marcada variación a lo largo del día. En los últimos años se ha evidenciado que la falta de descenso de la presión arterial sistólica durante la noche representa un factor de riesgo cardiovascular independiente. En respuesta a ello ha surgido la cronoterapia como estrategia que ha demostrado reducir dicho riesgo en los hipertensos. Caso Clínico: Mujer de 72 años hipertensa desde hace 5 años, con Dislipidemia, y Obesidad central. Al examen físico, biotipo pícnico, índice de masa corporal 37 Kg/M 2 . Presión arterial clínica (PAC) 161/81 mmHg. Auscultación cardiopulmonar normal. Resto del examen físico normal. Se realizó Monitorización Ambulatoria de la Presión Arterial (MAPA) de 24 h que reflejó patrón circadiano Riser. Ante este hallazgo, el alto riesgo cardiovascular y el efecto de la bata blanca que presenta la paciente, se decidió aplicar cronoterapia. Se realizó un MAPA de control a las 8 semanas que reveló cambio en el patrón circadiano y mejor control de la PAC Conclusión: El fin último del tratamiento antihipertensivo es reducir la morbimortalidad cardiovascular, por lo tanto, para establecer la terapia se debe tomar en cuenta el perfil circadiano de cada paciente, la farmacocinética del fármaco a elegir y el horario en que deberá ser administrado...(AU)

Cronobiología del sistema inmune / Immune system chronobiology

La cronobiología es la disciplina que ha estudiado la organización temporal de los procesos que ocurren en los seres vivos, los mecanismos que las originan y sus alteraciones. En 1832, Agustín de Candolle demostró que bajo condiciones constantes el período de los ciclos de movimientos de las plantas duraba unas 24 horas, con lo que añadió una evidencia de la naturaleza endógena de los ritmos biológicos. En los mamíferos, se ha estimado que aproximadamente el 10 por ciento del genoma está bajo un control circadiano. Desde la década de los años 70´s se observó que la respuesta inmune dependía de la hora del día en la cual se analizaba y que la susceptibilidad a las infecciones dependía también de la hora en la cual el organismo fuera infectado. Recientemente se ha establecido una relación entre el ciclo circadiano y la respuesta inmune. Este trabajo trata las ventajas del conocimiento del ritmo circadiana de los mecanismos inmunitarios y la importancia del uso de la cronoterapia sobre los osciladores de las células del sistema inmune en los trastornos inmunitarios, lo cual pudiera evitar complicaciones en los pacientes(AU)

Chronobiology is the science that studies temporary organization of the processes that happen in organisms, the mechanisms that originate them and its disorders. Austin of Candolle demonstrated that under constant conditions the period of the cycles of the plants' movements it lasted some 24 hour, adding an evidence of the endogenous nature of the biological rhythms in 1832. In mammals, has been considered approximately 10 percent of genome under circadian control. Since decade of 70´s, was observed that immune response depends of day´s hours in which it was analyzed, and the susceptibility to infections also depends of the hour in which an organism is infected. It has begun to establish relationship between circadian cycle and immune response recently. This work intends to give us the advantages of the knowledge of circadian rhythms of immune mechanisms and the importance of the chronotherapy´s use on the oscillators of the immune system´s cells in immunity dysfunctions and it would avoid complications in the patients(AU)

Los ritmos circadianos en cáncer y la cronoterapia / The circadian rhythms in cancer and chronotherapy / Os ritmos circadianos em câncer e a cronoterapia

Los ritmos circadianos, períodos fisiológicos de 24 horas aproximadamente, coordinan la actividad temporal de la mayoría, si no, de todos los seres vivos del planeta. Uno de los procesos más importantes del cuerpo, la proliferación celular, también está regulado por el reloj biológico cuya alteración puede tener repercusiones directas en el desarrollo del cáncer. El concepto de cronoterapia ha surgido a partir de la evidencia que tanto la proliferación de las células, como los mecanismos responsables de la farmacocinética y la farmacodinamia de los antineoplásicos ocurren a horas específicas del día. En esta revisión se presentan las generalidades del ciclo circadiano y su relación con el ciclo celular y el cáncer. Además, se expone evidencia del uso de la cronoterapia en pacientes con leucemia linfocítica aguda y en estudios clínicos de cáncer de colon, endometrio y ovario con asignación aleatoria. Se concluye que la hora de administración de la quimioterapia debe tener en cuenta los ritmos circadianos de los pacientes. Se enfatiza en la necesidad de hacer estudios clínicos enfocados en la quimioterapia cronomodulada, con el fin de aumentar la tolerancia y efectividad de los medicamentos con los protocolos existentes.

Circadian rhythms, physiological periods of about 24 hours, coordinate the temporal processes of most, or maybe all, living beings on the planet. Cell proliferation, one of the most important events in the body, is also regulated by the biological clock, whose alteration may have a direct impact on cancer development. The concept of chronotherapy comes from evidence showing that both cell proliferation and the mechanisms responsible for pharmacokinetics and pharmacodynamics of antineoplastic drugs occur at specific times of the day. This review presents an overview of the circadian cycle and its relation to cell cycle and cancer. Also, it presents evidence for the use of chronotherapy in patients with acute lymphocytic leukemia and in randomized clinical trials for colon, endometrial and ovarian cancer. As a conclusion, the time of chemotherapy administration should take into account the circadian rhythms of patients. We emphasize on the need to conduct clinical trials focused on chronomodulated chemotherapy, in order to increase the tolerance and effectiveness of drugs under the existing protocols.

Os ritmos circadianos, períodos fisiológicos de 24 horas aproximadamente, coordenam a atividade temporal da maioria, se não, de todos os seres vivos do planeta. Um dos processos mais importantes do corpo, a proliferação celular, também está regulada pelo relógio biológico cuja alteração pode ter repercussões diretas no desenvolvimento do câncer O conceito de cronoterapia há surgido a partir da evidência que tanto a proliferação das células, como os mecanismos responsáveis da farmacocinética e a farmacodinâmica dos antineoplásicos ocorrem a horas específicas do dia. Nesta revisão se apresentam as generalidades do ciclo circadiano e sua relação com o ciclo celular e o câncer. Ademais, se expõe evidência do uso da cronoterapia em pacientes com leucemia linfocítica aguda e em estudos clínicos de câncer de cólon, endométrio e ovário com designação aleatória. Se conclui que na hora de administração da quimioterapia deve ter em conta os ritmos circadianos dos pacientes. Se enfatiza na necessidade de fazer estudos clínicos enfocados na quimioterapia cronomodulada, com o fim de aumentar a tolerância e efetividade dos medicamentos com os protocolos existentes.

Cronoterapia en la enfermedad pulmonar obstructiva crónica: ¿es factible? / Chronotherapy in the disease Chronic obstructive pulmonary disease Is it feasible?

La cronoterapia se define como el tratamiento médico temporalmente adecuado para poder alcanzar su mayor eficacia. Su concepto está estrechamente unido al de ritmo circadiano, el cual se refiere al ritmo biológico autónomo de un ser vivo, con una duración aproximada de 24 horas, que se acopla a las oscilaciones del ambiente. El conocimiento de las variaciones fisiológicas que ocurren durante un día, tanto en salud como enfermedad, nos permite una aproximación terapéutica más acertada cuando queremos indicar uno o varios fármacos a un individuo. Para ello, debemos reconocer un ritmo circadiano respiratorio e intentar incidir en las variables más prominentes

Formulation and evaluation of mini-tablets-filled-pulsincap delivery of lornoxicam in the chronotherapeutic treatment of rheumatoid arthritis

In this present research work, we have designed a pulsincap formulation comprising mini-tablets, which to the best of our knowledge this combination has not been reported yet. We successfully combined the advantages of minitablets technology to meet the optimized requirements of our pulsincap formulation. Our main aim was to target lornoxicam to treat rheumatoid arthritis as per the chronotherapeutic pattern of the disease. Directly compressing method was used to prepare mini-tablets. The drug, polymers and combine mixtures of drug and polymers was evaluated for preformulation testing. Prepared mini-tablets were also evaluated for physicochemical, dissolution and stability studies. From FTIR and DSC evaluation, we found no interaction between the drug and polymers used. For mini-tablets, all the physico-chemical parameters were in limit. The mini-tablets of lornoxicam were filled into an insoluble body of capsule, and its opening was sealed by plugging it with a polymer. The complete capsule body after sealing with a cap was given enteric coating. Different polymers in various concentrations were used as a plug, to identify the most suitable which gives a complete lag time of 5 hours when combined with 5% CAP coating. HPMC-K100M in 30% and sodium alginate in 40% concentrations were identified as the most suitable plugs. Our optimized pulsincap formulations releases lornoxicam after a lag time of 5 hrs and maximum portion of the drug will be released in the early morning hours. It was also found to be stable for a period of 6 months as per ICH guidelines

Clinical Experience with Low-dose Modified-release Prednisone Chronotherapy in Asian Patients with Rheumatoid Arthritis in Singapore

OBJECTIVE: To examine the demographic profile and treatment patterns in patients with rheumatoid arthritis (RA) prescribed low-dose modified-release prednisone (LODOTRA(R)) on a named patient basis in Singapore and to evaluate safety and clinical outcome of the treatment. METHODS: Medical records of adult patients with RA who had inadequate responses to prior RA treatment and were prescribed low-dose modified-release prednisone between January and December 2012 at a specialist clinic were reviewed retrospectively. Demographics, treatment information, relevant laboratory evaluations, and disease condition, prior to and after the start of treatment, were collected. RESULTS: Thirty-eight patients were enrolled. The mean age was 52.8 years and median disease duration was 1.3 years (0.04 to 8.2 years). Patients received a mean daily dose of 5.0+/-1.0 mg of modified-release prednisone for a median period of 4.4 months (0.2 to 11.8 months). Before treatment, the majority of patients received disease-modifying anti-rheumatic drugs (78.9%), glucocorticoids (71.0%), and non-steroidal anti-inflammatory drugs (NSAIDs) (68.4%). After the start of treatment, prescription of NSAIDs declined from 68.4% to 28.9%. Similar laboratory findings were observed before and after treatment. The median C-reactive protein level decreased substantially from 9.8 mg/L (0.2 to 77.7 mg/L) to 3.9 mg/L (0.4 to 27.6 mg/L). High proportions of patients reported improvement or recovery from morning stiffness (94.7%) or joint pain (70.0 to 100.0%) after treatment. The median number of painful joints decreased from 4 (1 to 8) to 0 (0 to 4) after treatment. CONCLUSION: Our clinical experience in Asian patients with RA suggests that low-dose modified-release prednisone chronotherapy is associated with similar treatment patterns, safety profile, and clinical outcomes as in Western populations.

Antimicrobial activity assessment of time-dependent release bilayer tablets of amoxicillin trihydrate

The aim of present study was the assessment of antimicrobial activity of prepared time-dependent release bilayer tablets of amoxicillin trihydrate and in vitro evaluation of drug release by antimicrobial assay using agar plate diffusion method. The bilayer tablets comprised of a delayed and sustained release layer. Direct compression method was used for the preparation of bilayer tablets containing Eudragit-L100 D55 as delayed release polymer, and HPMCK4M and HPMCK15 as sustained release polymers. The prepared bilayer tablets containing amoxicillin trihydrate were evaluated for hardness, thickness, friability, weight variation and drug content. Further, in vitro drug release was assessed by antimicrobial assay using S. aureus and E. coli as test microorganisms. The aliquot samples of in vitro drug release study were found to be effective against both microorganisms for 16 hours due to sustained action. The in vitro drug release study and antimicrobial assay showed that bilayer tablets have sustained release profile of drug delivery with time-dependent burst release after a lag-time of 2 hours. The lower MIC value (2 µg/mL) of prepared bilayer tablets vis-à-vis marketed preparation (5 µg/mL) represented its good antimicrobial activity.

O objetivo do presente estudo foi avaliar a atividade antimicrobiana de formulações de comprimidos de dupla camada contendo amoxicilina triidratada para liberação tempo dependente e avaliação da liberação in vitro do fármaco pelo ensaio de atividade antimicrobiana utilizando o método de difusão em placa de ágar. Os comprimidos de dupla camada consistem em uma camada para liberação retardada e outra sustentada. O método de compressão direta foi usado para a preparação dos comprimidos de dupla camada contendo Eudragit-L 100 D55 como polímero para liberação retardada e HPMCK4M ou HPMCK15 como polímeros para liberação sustentada. As formulações de comprimidos de dupla camada contendo amoxicilina triidratada foram avaliadas quanto a dureza, espessura, friabilidade, variação de peso e conteúdo de fármaco. Além disso, a liberação do fármaco in vitro foi avaliada por ensaio de atividade antimicrobiana usando S. aureus e E. coli como microrganismos teste. A alíquota das amostras do estudo de liberação do fármaco in vitro demonstrou ser efetiva contra ambos os microrganismos por um período de 16 horas devido à ação sustentada. O estudo de liberação do fármaco in vitro e o ensaio de atividade antimicrobiana mostraram que os comprimidos de dupla camada tiveram um perfil de liberação sustentada do fármaco com um pico de liberação após 2 horas de ensaio. O menor valor de MIC (2 ug/mL) dos comprimidos de dupla camada quando comparados à formulação comercial (5 ug/mL) representa uma boa atividade antimicrobiana.

Clinical Significance of Nighttime Blood Pressure / 대한내과학회지

It was impossible to measure the nighttime blood pressure in patients with hypertension for more than one hundred years. The introduction of ambulatory blood pressure monitoring made it possible to evaluate the nighttime blood pressure and clinical significances in recent 40 years. There are tremendous evidences for proving that the nighttime blood pressure is the more powerful predictor in cardiovascular morbidity and mortality than conventional office and ambulatory daytime blood pressure. The cardiovascular mortality can be reduced when 5% of nighttime blood pressure decreased from Ohasama registry report. So investigators should reevaluate the antihypertensive drugs in the view points of nighttime blood pressure reduction. And changing the administration schedule of antihypertensive drugs, so called chronotherapy, is effective for controlling the nighttime blood pressure and modifying the blood pressure circadian rhythm. Korean Ambulatory Blood Pressure (KORABP), nationwide ambulatory blood pressure monitoring registry in Korea, may answer unproved questions for controlling nighttime blood pressure.

Treatment of circadian rhythm sleep disorders with light

The human circadian system is normally synchronised with the solar day, insuring that alertness and performance peak during daytime hours and consolidated sleep occurs during the night. In circadian rhythm sleep disorders, the pattern of sleep-wake is misaligned with the patient's circadian system or the external environment, resulting in insomnia, fatigue, and deterioration in performance. Appropriately-timed exposure to bright light can reset the timing of sleep and wake to the desired times, and improve sleep quality and daytime alertness. The efficacy of bright light therapy, however, is dependent on the time-of-day of the circadian cycle that the light is administered. In this article, we examine the physiological basis for bright light therapy, and we discuss the application of light in the treatment of circadian rhythm sleep disorders including advanced and delayed sleep-phase disorder, free-running disorder (nonentrained type), shiftwork disorder and jet lag disorder. We review the laboratory and field studies which have established bright light therapy as an effective treatment for sleep-wake and circadian misalignment, and we also provide guidelines for the appropriate timing and safe use of bright light therapy.

Effects of testosterone and cortisol in sports fatigued organism by Chinese material medica of shixiang yaofa / 中国中药杂志

<p><b>OBJECTIVE</b>To study the endogenous hormone of testosterone and cortisol that secretes volume and rhythm in sports fatigued human bodies and animals. To determine secretory volume and rhythm in sports fatigued human bodies and animals when Shixiang yaofa's drug are used.</p><p><b>METHOD</b>Radio-immunity method was used to determine secretory volume and rhythm in sports fatigued human bodies and animals and to analyze secretory volume and rhythm. According to the secretory volume and rhythm of testosterone and cortisol, the Shixiang Yaofa's drugs were used. Doses: wenyang jihuo bead 10 g/sack 2 sack, ziyin xiuyang capsule 0.5 g/pill 8 pill pd in human bodies for 28 days. Wenyang jihuo bead 10 g x kg(-1) of crude drug, ziyin xiuyang capsule 4 g x kg(-1) of crude drug pd for hight doses in animals. Other groups for low doses 5 g x kg(-1) and 2 g x kg(-1) of crude drug pd for 15 days. The blood samples were collected for determination.</p><p><b>RESULT</b>(1) In human bodies the peak value of testosterone was appeared in 8:00 and valley value was appeared in 18:00, ranges: 176.93-281.73 x 10(-5) mg x L(-1). The peak value of cortisol was appeared in 8:00 and valley value was appeared in 22:00, ranges: 1.31-16.13 x 10(-3) mg x L(-1). In the same condition, the mouse peak value of testosterone was appeared in 20:00 and valley value was appeared in 0:00, ranges: (0.56 x 10(-5) - 124.0 x 10(-5)) mg x L(-1). The rhythm in animals was compatible with human bodies, howerer, the peak value was delayed for 12 hours. (2) The testosterone was step up and the cortisol was cut down in sports fatigued human bodies and animals when shixiang yaofa's drug were used (P < 0.05, P < 0.01).</p><p><b>CONCLUSION</b>The secretion of testosterone and cortisol in sports fatigued human bodies and animals are existed conclusive biologic rhythm. The secretory volume can be available accommodation by shixiang yaofa's drugs.</p>

Chronotherapeutics of intrathecal fentanyl added to bupivacaine for labour analgesia

Chronotherapeutics is the optimization of pharmacotherapies, taking into consideration rhythm-dependence in the kinetics and dynamics of medications plus predictable-in-time variability in the manifestations and severity of human disease. The aim of the present work was to determine whether the efficacy and side-effects of intrathecally administered mixture of a small dose of fentanyl and bupivacaine, to relieve labour pain, is influenced by the hour of administration. One hundred parturients requesting neuroaxial labour analgesia were assigned to one of four equal groups based on the time period when the intrathecal mixture was administered. Group E= evening, group N= night, group M= morning and group AN= afternoon. Maternal demographic and obstetric data, and the characteristics of the intrathecal blocks were recorded Demographic data, gestational age and cervical dilatation were similar in the four groups. The incidence of oxytocin use was lower in E and N groups than M and AN groups. The base-line visual analog pain score [VAPS] was higher in E and N groups than in M and AN groups. The onset of analgesia was delayed in E and N groups than M and AN groups [8.6 [3.4], 8.2 [3.1] Vs 6.5 [2.5], 6.6 [2.6], mm respectively]. There were no significant cant differences between groups as regard the upper sensory level, the number of parturients with detectable motor block or side effects. The duration of analgesia was shorter in groups E and N than in groups M and AN [75 [22] and 71 [19] Vs 108 [33] and 102 [31] mm respectively]. Maternal and midwife satisfaction scores were lower in groups E and N than in groups M and AN but no significant difference at 30 mm and at reinjection. Fentanyl and bupivacaine exhibit a temporal pattern of kinetics and dynamics when administered intrathecally for labour analgesia and this should be considered in future comparative studies and in analysis of previous studies and clinically to administer the suitable dose over the 24 hours of the day

Progress of therapeutic research on cardiovascular and cerebrovascular diseases with chrono-medicine / 中国中西医结合杂志

Comformed with the natural biological universal view of "harmony of human and nature", the clinical and experimental researches and the achievements on chrono-medicine for cardiovascular and cerebrovascular diseases in recent 10 odd years were analyzed and summarized, and the problems in the current researches and the stressed spots of the future research were put forward in this paper.

Chronobiological and chronopharmacological studies of ketoprofen and its solid dispersion form using adjuvant arthritis model in rats.

Chronobiology of rheumatoid arthritis (RA) was studied using a standard adjuvant arthritis animal model. Chronopharmacology of ketoprofen, and its solid dispersion forms was also studied. Temporal variations in the degree of articular inflammation (paw volume) and progression of articular destruction were studied by injecting Freund's Complete Adjuvant (FCA) at 0800 and 2000 hrs. Temporal variations in anti-inflammatory effects and ulcerogenic effect were also studied by administration of plain ketoprofen (20 mg/kg) and its solid dispersion with hydroxypropyl beta-cyclodextrin (equivalent to 20 mg/kg of ketoprofen) at the same time points (0800 and 2000 hrs) twice weekly for 22 days. Solid dispersion of ketoprofen was found to be more effective in inhibiting progression of RA. The incidence and severity of ulcers was found to be less with the solid dispersion. The protective effect of ketoprofen and its solid dispersion was significantly higher when these were administered at 0800 hrs. The incidence of ulceration was more in 2000 hrs group. Thus, it was observed that in the adjuvant induced arthritis model, inflammation and articular damage was significantly greater in the rest period of diurnally active rats than in the activity phase. KPF and its solid dispersion showed better protection from inflammation in the morning than in the evening.

Scientometrics and bibliometrics of chronotherapy / 生物医学工程学杂志

In order to retrieve Chinese and foreign articles of chronotherapy, we searched Chinese databases of CBM, CMCC and foreign series databases in OVID and hence revealed and assessed the current status, research trend and level of chronotherapy in China and in foreign countries by means of scientometric and bibliometric parameters. ProCite5 software and handsearching were used to manage, check and statistically analyze the searched papers so as to find the parameters which included distributions of databases, years, authors, periodicals, subject headings, organizations and nations. 91 Chinese papers were identified which were distributed in 73 kinds of journals and in subject headings, e.g., Traditional Chinese medicine, cardiovascular diseases, neoplasms, asthma, peptic ulcer, diabetes mellitus, general review of chronotherapy, etc. 480 foreign articles were identified which mainly came from EMBASE and MEDLINE and were distributed in 285 types of journals and 35 nations and regions. There were 14 journals which recorded five or more articles. 12 researchers published more than five articles. Paul Brousse Hospital, University of Texas, University of Connecticut School of Medicine, Jichi Medical School and University of Minnesota were the core research institutes. There was no core author or core journal or core institute in China up till now. However, core authors, core journals and core research institutes had come into being in foreign countries; they were mainly from the Euro-American developed countries and had done well in chronotherapy.

Chronomodulated chemotherapy of oxaliplatin, 5-fluorouracil and folinic acid for advanced gastric cancer / 中华肿瘤杂志

<p><b>OBJECTIVE</b>The combination of oxaliplatin (L-OHP), 5-fluorouracil (5-Fu) and folinic acid (FA), being one of the effective regimens for advanced gastric cancer, is used in form of chronomodulated chemotherapy for advanced gastric cancer to investigate its efficacy and safety.</p><p><b>METHODS</b>Twenty-six patients received a 4-day chronomodulated infusion of L-OHP, 5-Fu and FA. L-OHP (25 mg.m(-2).d(-1)) infused from 10:00 am to 22:00 pm, and followed by 5-Fu (600 mg.m(-2).d(-1)) and FA (300 mg.m(-2).d(-1)) from 22:00 pm to 10:00 am for 4 days using a multichannel programmable pump, every 2 weeks as an cycle for at least 2 cycles.</p><p><b>RESULTS</b>Twenty-six patients with previously untreated advanced gastric cancer were eligible. Two complete and 13 partial remissions were observed with an overall response rate of 57.7%. Stable disease was observed in 6 patients (23.1%) and progressive disease in five (19.2%). Four of these patients underwent surgery. The median remission time was 3.5 months and time to tumor progression (TTP) was 4.5 months. The median overall survival time was 8 months. A total of 80 cycles were given without any grade 4 toxicity observed, but grade 3 thrombocytopenia (1.3%) and mucositis (1.3%) in one patient, two grade 3 neutropenia (2.5%) and nausea/vomiting (2.5%) in 2.</p><p><b>CONCLUSION</b>Chronomodulated intravenous chemotherapy of oxaliplatin, 5-fluorouracil and folinic acid is effective and safe in the treatment of advanced gastric cancer.</p>