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.
Biological Clocks ; Chronobiology Phenomena ; Circadian Rhythm ; physiology ; Drug Chronotherapy ; Jet Lag Syndrome

OBJECTIVETo 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.

METHODThe 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.

RESULTThe 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.

CONCLUSIONThe 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.

Chemistry, Pharmaceutical ; Drug Chronotherapy ; Drug Delivery Systems ; methods ; Humans ; Morphinans ; chemistry ; pharmacokinetics ; Stomach ; drug effects ; Tablets, Enteric-Coated ; chemistry ; pharmacokinetics

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.
Cardiovascular Diseases ; drug therapy ; Cerebrovascular Disorders ; drug therapy ; Chronotherapy ; Drugs, Chinese Herbal ; therapeutic use ; Humans ; Medicine, Chinese Traditional ; methods ; Phytotherapy ; Time Factors

PURPOSE: To determine the efficacy and tolerability of a modified chronomodulated infusion of oxaliplatin, 5-fluorouracil (5-FU) and leucovorin in the treatment of advanced colorectal cancer. MATERIALS AND METHODS: Sixteen patients with relapsed or metastatic colorectal cancer were treated with an intravenous infusion of oxaliplatin 25 mg/m(2), 5-FU 700 mg/m(2) and leucovorin 20 mg/m(2) on days 1 to 5. The infusion of oxaliplatin was chronomodulated with a peak delivery rate at 16: 00 p.m., with 5-FU infused constantly overnight. Each course was repeated every 21 days. RESULTS: The response rate was 38.5% (95% confidence interval [CI], 13.9% to 68.4%) in the 13 measurable patients, including 1 complete response (7.7%) and 4 partial responses (30.8%). Five patients (38.5%) had a stable disease and 3 (23.0%) a progressive disease. Three patients without a measurable lesion had improved status. The median time to progression and overall survival were 29 weeks and 85 weeks, respectively. Grade 3 thrombocytopenia occurred in 2.5% (2 cycles) and grade 3 vomiting in 12.5% (2 patients). Anorexia, stomatitis, diarrhea, pruritus, alopecia and peripheral neuropathy were mild and tolerable. CONCLUSION: The modified chronomodulated infusion of oxaliplatin, 5-FU and leucovorin is effective and tolerable, but the number of patients was too small. Further study will be needed to confirm the efficacy of this regimen with a larger population of patients.
Alopecia ; Anorexia ; Chronotherapy ; Colorectal Neoplasms* ; Diarrhea ; Drug Therapy ; Fluorouracil* ; Humans ; Infusions, Intravenous ; Leucovorin* ; Peripheral Nervous System Diseases ; Pruritus ; Stomatitis ; Thrombocytopenia ; Vomiting

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.
Animals ; Antihypertensive Agents ; administration & dosage ; Benzazepines ; administration & dosage ; CLOCK Proteins ; metabolism ; Circadian Rhythm ; Drug Chronotherapy ; Gene Expression Profiling ; Hypertension, Renal ; drug therapy ; physiopathology ; Kidney ; drug effects ; physiopathology ; surgery ; Male ; Nephrectomy ; Rats ; Rats, Wistar ; Renin-Angiotensin System ; drug effects ; Treatment Outcome

OBJECTIVEThe 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.

METHODSTwenty-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.

RESULTSTwenty-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.

CONCLUSIONChronomodulated intravenous chemotherapy of oxaliplatin, 5-fluorouracil and folinic acid is effective and safe in the treatment of advanced gastric cancer.

Adenocarcinoma ; drug therapy ; Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Chronotherapy ; Drug Administration Schedule ; Female ; Fluorouracil ; administration & dosage ; Humans ; Leucovorin ; administration & dosage ; Male ; Middle Aged ; Organoplatinum Compounds ; administration & dosage ; Stomach Neoplasms ; drug therapy ; Treatment Outcome

OBJECTIVETo 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).

METHODSSeventy 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.

RESULTSSixty-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.

CONCLUSIONSCompared 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.

Antineoplastic Combined Chemotherapy Protocols ; administration & dosage ; Carcinoma ; Chemoradiotherapy ; Cisplatin ; administration & dosage ; Drug Chronotherapy ; Fluorouracil ; administration & dosage ; Humans ; Induction Chemotherapy ; methods ; Nasopharyngeal Neoplasms ; drug therapy ; pathology ; radiotherapy ; Nausea ; Neoplasm Staging ; Radiotherapy, Intensity-Modulated ; Taxoids ; administration & dosage ; Treatment Outcome

Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; administration & dosage ; adverse effects ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; pathology ; Cisplatin ; administration & dosage ; adverse effects ; Deoxycytidine ; administration & dosage ; adverse effects ; analogs & derivatives ; Drug Chronotherapy ; Female ; Humans ; Leukopenia ; chemically induced ; Lung Neoplasms ; drug therapy ; pathology ; Male ; Middle Aged ; Nausea ; chemically induced ; Neoplasm Staging ; Neutropenia ; chemically induced ; Remission Induction ; Taxoids ; administration & dosage ; adverse effects

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.
Adult ; Antineoplastic Combined Chemotherapy Protocols ; adverse effects ; therapeutic use ; Carcinoma ; Cisplatin ; administration & dosage ; Disease-Free Survival ; Dose Fractionation ; Drug Chronotherapy ; Female ; Fluorouracil ; administration & dosage ; Humans ; Induction Chemotherapy ; adverse effects ; Male ; Middle Aged ; Nasopharyngeal Neoplasms ; drug therapy ; pathology ; radiotherapy ; Neoplasm Staging ; Neutropenia ; chemically induced ; Radiotherapy, High-Energy ; Stomatitis ; etiology ; Survival Rate ; Young Adult