Chronopharmacological Approach Research Articles

Glycolysis under Circadian Control.

Glycolysis is considered a main metabolic pathway in highly proliferative cells, including endothelial, epithelial, immune, and cancer cells. Although oxidative phosphorylation (OXPHOS) is more efficient in ATP production per mole of glucose, proliferative cells rely predominantly on aerobic glycolysis, which generates ATP faster compared to OXPHOS and provides anabolic substrates to support cell proliferation and migration. Cellular metabolism, including glucose metabolism, is under strong circadian control. Circadian clocks control a wide array of metabolic processes, including glycolysis, which exhibits a distinct circadian pattern. In this review, we discuss circadian regulations during metabolic reprogramming and key steps of glycolysis in activated, highly proliferative cells. We suggest that the inhibition of metabolic reprogramming in the circadian manner can provide some advantages in the inhibition of oxidative glycolysis and a chronopharmacological approach is a promising way to treat diseases associated with up-regulated glycolysis.

Timing of Novel Drug 1A-116 to Circadian Rhythms Improves Therapeutic Effects against Glioblastoma.

The Ras homologous family of small guanosine triphosphate-binding enzymes (GTPases) is critical for cell migration and proliferation. The novel drug 1A-116 blocks the interaction site of the Ras-related C3 botulinum toxin substrate 1 (RAC1) GTPase with some of its guanine exchange factors (GEFs), such as T-cell lymphoma invasion and metastasis 1 (TIAM1), inhibiting cell motility and proliferation. Knowledge of circadian regulation of targets can improve chemotherapy in glioblastoma. Thus, circadian regulation in the efficacy of 1A-116 was studied in LN229 human glioblastoma cells and tumor-bearing nude mice. Methods. Wild-type LN229 and BMAL1-deficient (i.e., lacking a functional circadian clock) LN229E1 cells were assessed for rhythms in TIAM1, BMAL1, and period circadian protein homolog 1 (PER1), as well as Tiam1, Bmal1, and Rac1 mRNA levels. The effects of 1A-116 on proliferation, apoptosis, and migration were then assessed upon applying the drug at different circadian times. Finally, 1A-116 was administered to tumor-bearing mice at two different circadian times. Results. In LN229 cells, circadian oscillations were found for BMAL1, PER1, and TIAM1 (mRNA and protein), and for the effects of 1A-116 on proliferation, apoptosis, and migration, which were abolished in LN229E1 cells. Increased survival time was observed in tumor-bearing mice when treated with 1A-116 at the end of the light period (zeitgeber time 12, ZT12) compared either to animals treated at the beginning (ZT3) or with vehicle. Conclusions. These results unveil the circadian modulation in the efficacy of 1A-116, likely through RAC1 pathway rhythmicity, suggesting that a chronopharmacological approach is a feasible strategy to improve glioblastoma treatment.

Abstract 620: The response of human glioblastoma cells to the novel drug 1A-116 is dependent on the circadian clock

Abstract Glioblastomas (GBM) account for almost half of the malignant central nervous system tumors and have the highest mortality rates with only about 5% of the adult patients surviving 5 years after diagnosis. Current therapy for GBM is generally very aggressive, combining chemotherapy, radiotherapy, and surgical removal and increased the life expectancy only from 11 to 14 months, but, almost no significant advances were made in the last decades. Taking this into account, more effective compounds and new strategies, such as chronotherapeutic ones, need to be developed. The novel drug 1A-116 specifically blocks the interaction of the Rho GTPase Rac1 with some of its activators (GEFs proteins, such as Tiam1) inhibiting cell motility and proliferation of GBM. To optimize the effectiveness of 1A-116 a chronotherapeutic approach was implemented in vitro by applying the drug at different circadian times to synchronized LN-229 human GBM cells. Cell cultures displayed a functional circadian clock measured by Bmal1-luc activity and BMAL1 protein expression. Expression of Tiam1 was also assessed, finding circadian expression rhythms. The effects of 1A-116 on either cell proliferation, motility and toxicity, were dependent on the circadian cellular clock. The preliminary in vivo studies consisted on treating nude mice with 1A or control at ZT3 or 12. We found that the median survival of the mice treated at ZT3 was 82 days and at ZT12 was 78 days. These results suggest that a chronopharmacological approach based on the drug 1A-116 is a feasible strategy to improve GBM treatment outcomes. Citation Format: Laura Lucia Trebucq, Goergina A. Cardama, Pablo Lorenzano Menna, Diego A. Golombek, Juan J. Chiesa, Luciano Marpegan. The response of human glioblastoma cells to the novel drug 1A-116 is dependent on the circadian clock [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 620.

Diet-Induced Circadian Enhancer Remodeling Synchronizes Opposing Hepatic Lipid Metabolic Processes

Overnutrition disrupts circadian metabolic rhythms by mechanisms that are not well understood. Here, we show that diet-induced obesity (DIO) causes massive remodeling of circadian enhancer activity in mouse liver, triggering synchronous high-amplitude circadian rhythms of both fatty acid (FA) synthesis and oxidation. SREBP expression was rhythmically induced by DIO, leading to circadian FA synthesis and, surprisingly, FA oxidation (FAO). DIO similarly caused a high-amplitude circadian rhythm of PPARα, which was also required for FAO. Provision of a pharmacological activator of PPARα abrogated the requirement of SREBP for FAO (but not FA synthesis), suggesting that SREBP indirectly controls FAO via production of endogenous PPARα ligands. The high-amplitude rhythm of PPARα imparted time-of-day-dependent responsiveness to lipid-lowering drugs. Thus, acquisition of rhythmicity for non-core clock components PPARα and SREBP1 remodels metabolic gene transcription in response to overnutrition and enables a chronopharmacological approach to metabolic disorders.

Chronopharmacology and drug prescribing pattern of physicians in a tertiary care hospital of North India

Background: Chronopharmacology is the science dealing with the optimization of drug effects and the minimization of adverse effects by timing medication in relation to the biological rhythm. This concept came into picture to make us understand about periodic and predictable changes in both desired effects and tolerance of medication Chronotherapeutics approach gives more accurate determination of the time when patients are at highest risk and in greatest need of therapy. This Chronopharmacological principle is used in the therapy of various diseases like cardiovascular diseases, allergy and many more. The objective of the study was to analyse whether chronopharmacological approach was being applied in clinical practice by comparing chronopharmacology of 4 drugs to their prescribing pattern by the physicians.Methods: This was observational study where 700 prescriptions written by physicians were audited. To study all the drugs would have been tedious so four commonly used drugs were chosen that is, Proton pump inhibitors, statins, Beta blockers and subcutaneous Insulin.Results: Results showed that chronopharmacological approach has been applied in the clinical field though physician didn’t have clear concept about chronopharmacology and it is relation to the prescribing. Despite this, maximum physician prescribing pattern was comparable to the chronopharmacological data except in case of Proton pump inhibitors.Conclusions: It is concluded that Chronotherapeutics approach gives more accurate determination of the time when patients are at highest risk and in greatest need of therapy. Nevertheless, this variation is only seldom considered by clinicians. If drugs are prescribed by following chronopharmacological approach it can prove beneficial to the patients as more of effectiveness of the drug and lesser side effects.

Cocaine modulation of the mammalian circadian clock: potential therapeutic targets

The circadian system plays an integral role in regulating physiological and behavioral responses to cocaine, which contribute to abuse and relapse. To date, however, little is known of the mechanism(s) underlying cocaine effects on biological timing, and in particular, how this drug may impact the regulation of the master circadian clock of the suprachiasmatic nucleus (SCN). This review summarizes our current research into the chronotypic actions of acute and chronic cocaine. In initial experiments, it was shown that acute systemic and in vitro cocaine blocks the nocturnal SCN photic phase-resetting response critical for circadian entrainment to the light-dark cycle (LD). Cocaine treatment at midday also advances circadian clock phase, showing that this drug possess non-photic circadian phase-resetting properties. Next, chronic (weeks-months) cocaine regimens were used to model human drug abuse patterns. Such long-term oral drug exposures caused dramatic alterations in intrinsic circadian period and entrainment to LD that persisted long after cocaine withdrawal, suggesting long-term (possibly permanent) circadian disruptive effects. Lastly, we found that the acute systemic cocaine effects described above are blocked using a serotonin receptor antagonist (metergoline) targeted to the SCN in vivo, as well as in vitro , suggesting involvement of a serotonergic mechanism. Consistent with this hypothesis, mutant mice with a cocaine-insensitive serotonin transporter exhibited little or no circadian response to cocaine. Collectively, these results indicate that cocaine-induced perturbations of clock timing could produce chronic psychological and physiological stress, contributing to increased cocaine use and dependence. Earmarking the serotonergic system in mediating these cocaine effects offers a potential chrono-pharmacological approach for the treatment of cocaine abuse and addiction.

The molecular clock: a focus on chronopharmacological strategies for a possible control of aminoglycoside renal toxicity

Chronotherapy applies biological rhythmicity in order to optimize clinical treatments, relating the dosing time of the drugs to the daily variations of their therapeutic and unwanted side effects due to the fluctuations in physiological processes involved in their pharmacokinetics and/or pharmacodynamics. The goal of chronotherapy is to administer treatments at the time of day that enhances both their effectiveness and tolerance. This review intends to (1) provide the theoretical rationale behind the use of aminoglycosides during extended interval schedule chronotherapy in clinical practice and (2) target the underlying molecular mechanisms of renal toxicity, the main unwanted side effect. Previous reports suggest that aminoglycoside therapy may benefit from a chronopharmacological approach. Temporal variations in the renal blood flow and glomerular filtration rate and several clock-dependent molecular mechanisms contributing to the daily changes in electrolyte and water urinary excretion have been reported. Daily differences in aminoglycoside toxicity and kinetic disposition have been found in laboratory animals and human patients. Nephrotoxicity and renal cortical accumulation are higher when drugs are administered during the rest phase than during the active phase. Active translocation of aminoglycosides into renal cells is mediated by the megalin/cubilin receptor complex located at the luminal epithelial cell membrane. The complex regulation of this endocytic mechanism deserves further study, in order to dilucidate the molecular bases that may be involved in chrono- therapeutic strategies developed for minimizing aminoglycoside accumulation in the renal cells, and thus, increasing their tolerance.

Circadian aspects of post‐operative morbidity and mortality

It has been well established that there exists a circadian concentration of cardiovascular, cerebrovascular and cardiopulmonary events. The aim was to describe aspects of circadian variation in relation to cardiovascular, cerebrovascular and thromboembolic diseases and to describe the literature concerning post-operative circadian disturbances. We also present the literature concerning circadian variation in post-operative morbidity and mortality. PubMed and the Cochrane database were searched for papers using a combination of 'circadian,''surgery,''post-operative,''mortality' and 'morbidity.' Eleven relevant studies were found, and seven of these were excluded due to the use of time of surgery and not time of morbidity or mortality as the main variable. The results from the four articles showed a circadian distribution of morbidity and mortality that mimics the one seen without surgery. There is a peak incidence of myocardial ischemia, fatal thromboembolism and sudden unexpected death in the morning hours. A circadian variation exists in post-operative morbidity and mortality. The observed circadian variation in post-operative morbidity and mortality may warrant a chronopharmacological approach to patients in the perioperative period. The underlying pathophysiological mechanisms should be the focus for future studies.

EFFECTS OF L-DOPA ON CIRCADIAN RHYTHMS OF 6-OHDA STRIATAL LESIONED RATS: A RADIOTELEMETRIC STUDY

Temporal variation in the motor function of Parkinson's disease (PD) patients suggests the potential importance of a chronobiological and chronopharmacological approach in its clinical management. We previously documented the effects of striatal injection of 6-OHDA (as an animal model of PD) on the circadian rhythms of temperature (T), heart rate (HR), and locomotor activity (A). The present work assessed the possible influence of L-Dopa on these same rhythms in the 6-OHDA animal model of PD. The study began after a four-week recovery period following surgical implantation of telemetric devices to monitor the study variables and/or anaesthesia. The study was divided into an initial one-week control period (W1) for baseline measurement of T, HR, and A rhythms. Thereafter, stereotaxic 6-OHDA lesioning was done. and a second monitoring for two weeks followed (W2, W3). Rats were then randomly divided into two groups: eight control rats received, via a mini-osmotic pump implanted subcutaneously, the excipient saline; the other eight rats received L-Dopa (100 mg/kg SC/day). After a seven-day period (W4), the pumps were removed and the T, HR, and A rhythms were monitored for two weeks (W5 and W6). To control for 6-OHDA striatal dopamine-induced depletion, 12 other rats were injected by identical methods (eight rats with 6-OHDA and four controls with saline) and sacrificed at W1, W3, and W5 for dopamine striatal content determination. To verify the delivery of levodopa from the osmotic pumps, plasma levels of levodopa and its main metabolites 3-OMD, DOPAC, and HVA were determined on separate group of rats receiving the drug under the same experimental conditions (osmotic pumps delivering continuously 10 µl/h for seven days, 100 mg/kg/subcutaneously). Our results agree with previously reported rhythmic changes induced by 6-OHDA—loss of circadian rhythmicity or changes in the main parameters of the registered rhythms. When circadian rhythmicity was abolished, L-Dopa treatment improved or accelerated recovery of the circadian rhythms, the effect being more pronounced for the HR rhythm. When circadian rhythms were not abolished but perturbed, L-Dopa treatment did not improve the 6-OHDA-induced changes in the T and A mesor (24 h mean level), while a significant effect was observed for HR. It appears that constant-rate L-Dopa infusion is unable to totally balance dopamine depletion; taking into account the circadian pattern of many structures implicated in drug effect, a sinusoidal delivery of L-Dopa must be evaluated in future experiments. (Author correspondence: bernard.bruguerolle@univmed.fr)

Construction of Optimal Combined Chemotherapy of Anti-tumor Drugs Based on Chronotherapy

Metastatic breast cancer (MBC) is almost always incurable, and the median survival is of the order on 18-24 months. Combination therapy with adriamycin (ADR) and docetaxel (DOC) is more effective against MBC than the previous therapy due to differences between their mechanisms. However, the combination of ADR and DOC induces severe adverse effects, limiting its clinical use in many patients with MBC. The biologic functions of most living organisms are organized along an approximate 24 h time cycle or circadian rhythm. Chronotherapy is defined as the administration of medications using biological rhythms to optimize the therapeutic outcomes and/or control adverse effects. To decrease adverse effects, many antitumor drugs have been particularly studied in humans and animals. The toxicities of ADR and DOC have also been found to depend on dosing-time in animals and humans. This study was to establish the most suitable dosing schedule to relieve severe adverse effects and improve antitumor effects by considering a chronopharmacological approach, dosing-interval and dosing-sequence to the combination chemotherapy of ADR and DOC in mice. In the results, we demonstrate that the dosing schedule based on dosing-sequence, dosing-interval and dosing-time not only significantly reduced leukopenia and toxic death but also significantly increased the inhibition rate of tumor growth compared with the dosing schedule without an interval between each injection, commonly used in clinical practice. These findings suggest that the therapeutic index of combined chemotherapy can be improved by choosing an optimal dosing-schedule (dosing-interval, dosing-sequence and dosing-time).

Therapeutic Index by Combination of Adriamycin and Docetaxel Depends on Dosing Time in Mice

Although the combination of adriamycin and docetaxel showed a better cure rate against metastatic breast cancer, severe myelosuppression and cardiotoxicity were dose-limiting factors. The purpose of this study was to establish a suitable dosing schedule, based on a chronopharmacologic approach, to relieve severe adverse effects. In experiment 1, adriamycin or docetaxel was injected i.p. at 2, 6, 10, 14, 18, or 22 hours after light onset (HALO) to estimate toxicities. In experiment 2, the dosing time dependency of toxicity and pharmacokinetics were assessed in the combination of adriamycin and docetaxel. In addition, G2-M phase in myelocyte cells was determined in nontreated mice. Adverse effects caused by adriamycin were shown to be the worst at 2 HALO and the best at 14 HALO. On the other hand, docetaxel-induced adverse effects were more severe at 14 HALO than at 2 HALO. In the combination study, the D(2)-A(1)4 group, in which docetaxel was administered at 2 HALO followed by adriamycin at 14 HALO, showed the most toxicity relief of all the treated groups. In the pharmacokinetic study, the dosing time dependency of toxicities was not related to the daily variation of pharmacokinetics of adriamycin and docetaxel. A significant 24-hour rhythm of G2-M phase distribution was found in myelocyte cells of nontreated mice. The daily variation of leukopenia caused by docetaxel corresponded to the 24-hour rhythm of G2-M phase distribution. These findings reveal that the therapeutic index of the combined chemotherapy can be improved by administering adriamycin and docetaxel at the time when the most adverse effects are relieved in each drug.

Biologic rhythms and Parkinson's disease: a chronopharmacologic approach to considering fluctuations in function.

The existence of circadian rhythms and their implication in many pathologic processes have been underlined in several diseases but have not been evaluated in Parkinson's disease. The aim of this paper is to review diurnal variations of clinical, biologic, or experimental factors described with Parkinson's disease. Clinical data often report daily fluctuations of motor activity pattern, but the effect of the stage of the disease and the respective roles of drugs are difficult to evaluate. Sleep disturbances in Parkinson's disease patients also reveal alterations of circadian rhythms. Autonomic dysfunction, described in Parkinson's disease, reveals numerous alterations in circadian regulations including loss of circadian rhythm of blood pressure, increased diurnal blood pressure variability, and postprandial hypotension. Many biologic indices such as cortisol, catecholamines, and melatonin are also altered. Circadian rhythms in dopaminergic systems as well as possible daily fluctuations in kinetics of drug treatments are likely involved in such variations. Few clinical studies have been devoted to circadian patterns of drug response. As for other diseases where biologic rhythms are concerned Parkinson's disease therapy may be influenced by further understanding of circadian influence.

Chronotherapy with active vitamin D3 in aged stroke-prone spontaneously hypertensive rats, a model of osteoporosis

The chronotherapeutic effects of 1-α-(OH) vitamin D3, a pro-drug of 1,25(OH)2 vitamin D3 (1,25(OH)2D3), were evaluated by repeated dosing of the drug in aged stroke-prone spontaneously hypertensive male rats, a model of osteoporosis. Animals (7 months old) were kept in rooms with a 12-h light/dark cycle. Drug (0.5 μg/kg) or vehicle was given once daily at 2 or 14 h after lights on for 3 months. The severity of adverse effects such as body weight loss, hypercalcemia and hyperphosphatemia was significantly less when the drug was given at 14 h after lights on (14 HALO). Serum 1,25(OH)2 vitamin D3 concentrations of 2 h after lights on (2 HALO) group and 14 HALO group did not differ significantly after dosing. The decrease in parathyroid hormone (PTH) level 12 weeks after the start of the study was greater in the 14 HALO group than in the 2 HALO group. Urinary excretion of inorganic Ca and P in the 2 HALO group was greater than that in the 14 HALO group. Urinary excretion of deoxypyridiniline, an index of the bone resorption capacity of osteoclasts, was much suppressed in the 14 HALO group, suggesting that the efficacy of vitamin D3 for suppressing bone resorption might vary with the dosing time. The increase in bone density of both femurs, determined by dual-energy X-ray absorption at the end of the study, was greater in the 14 HALO group than in the 2 HALO group. This is the first study to show the dosing time-dependent efficacy and toxicity of active vitamin D3 in an animal model of osteoporosis. These results indicate that a chronopharmacological approach is beneficial for establishing a more effective and/or safer regimen of active vitamin D3 for the treatment of osteoporosis.

Chronotherapy of high-dose 1,25-dihydroxyvitamin D in hemodialysis patients with secondary hyperparathyroidism: A single-dose study

A high-dose oral intermittent vitamin D (pulse therapy) is widely used for the treatment of secondary hyperparathyroidism associated with kidney failure. However, hypercalcemia by vitamin D sometimes interrupts this treatment. Because serum calcium concentration possesses a circadian rhythm, a chronopharmacologic approach of vitamin D may have merit for avoidance of adverse reactions. Six female secondary hyperparathyroidism patients receiving maintenance hemodialysis received a single oral dose of 2 microg 1,25-dihydroxyvitamin D3 at either 8 AM or 8 PM in a crossover design. Serum concentrations of ionized and total calcium, phosphate, and vitamin D3 were determined for a 48-hour period after administration. We also measured serum intact parathyroid hormone before and 48 hours after dosing as an index for efficacy. A single oral administration of the drug caused an increase in concentration of ionized calcium, serum calcium, and phosphate. However, the area under concentration-time curve from zero to 48 hours [AUC(0-48)] and peak concentration of these variables were markedly lower after dosing at 8 PM. Pre-dose concentrations of these variables were lower at night. The AUC(0-48) of serum vitamin D3 of the morning and night trials did not differ significantly. Reduction of intact parathyroid hormone concentration was also similar between the two trials. The administration of vitamin D3 at night may reduce the occurrence of hypercalcemia and hyperphosphatemia in patients with secondary hyperparathyroidism, whereas the pharmacokinetics and intact parathyroid hormone-lowering effect of the drug does not vary with dosing time.

Chronotherapy of high-dose 1,25-dihydroxyvitamin D in hemodialysis patients with secondary hyperparathyroidism: A single-dose study

Background A high-dose oral intermittent vitamin D (pulse therapy) is widely used for the treatment of secondary hyperparathyroidism associated with kidney failure. However, hypercalcemia by vitamin D sometimes interrupts this treatment. Because serum calcium concentration possesses a circadian rhythm, a chronopharmacologic approach of vitamin D may have merit for avoidance of adverse reactions. Methods Six female secondary hyperparathyroidism patients receiving maintenance hemodialysis received a single oral dose of 2 μg 1,25-dihydroxyvitamin D3 at either 8 AM or 8 PM in a crossover design. Serum concentrations of ionized and total calcium, phosphate, and vitamin D3 were determined for a 48-hour period after administration. We also measured serum intact parathyroid hormone before and 48 hours after dosing as an index for efficacy. Results A single oral administration of the drug caused an increase in concentration of ionized calcium, serum calcium, and phosphate. However, the area under concentration–time curve from zero to 48 hours [AUC(0-48)] and peak concentration of these variables were markedly lower after dosing at 8 PM. Predose concentrations of these variables were lower at night. The AUC(0-48) of serum vitamin D3 of the morning and night trials did not differ significantly. Reduction of intact parathyroid hormone concentration was also similar between the two trials. Conclusion The administration of vitamin D3 at night may reduce the occurrence of hypercalcemia and hyperphosphatemia in patients with secondary hyperparathyroidism, whereas the pharmacokinetics and intact parathyroid hormone–lowering effect of the drug does not vary with dosing time. Clinical Pharmacology & Therapeutics (1999) 66, 609–616; doi: 10.1053/cp.1999.v66.103169001

Chronopharmacology for deoxyspergualin: toxicity and efficacy in the rat.

Deoxyspergualin (DSG), a potent immunosuppressive drug, has been clinically used as a rescue therapy for acute graft rejection. However, DSG has severe adverse effects that limits its use. Here, we examined the optimized therapeutic protocol for DSG using chronopharmacological profiles of it. First, a dosing time-dependent difference in the toxicity and efficacy of DSG was determined using a heterotopic heart transplantation model. Second, chronokinetics of DSG were examined to reveal the mechanism for dosing time-dependent differences in the effect. In rats treated with DSG at the active period, bone marrow suppression and damage of small intestine were significantly severe. However, no significant difference was found in cardiac allograft survival and pharmacokinetics according to the timing of drug administration. The toxicity of DSG varied with the dosing time, whereas its efficacy did not. The chronopharmacological approach may provide merits for immunosuppressive therapy with DSG in clinical organ transplantation.

Amelioration of Enalapril-Induced Dry Cough by Changing Dosing Time from Morning to Evening; A Preliminary Trial.

Objective: To determine whether the severity and frequency of dry cough induced by enalapril, an angiotensin-converting enzyme (ACE) inhibitor, might be altered by changing its administration time.Methods: Twenty-one patients with hypertension and three with chronic heart failure received enalapril (5 mg) once daily in the morning for more than 2 weeks and complained of persistent, non-productive dry cough. After the severity and frequency of cough were evaluated using a questionnaire, enalapril (5 mg) was given once daily in the evening for more than 2 weeks. At the end of this period, patients were asked to specify any changes in their cough during the evening treatment regimen, according to the following 5-point response scale: 1 (much worse), 2 (moderately worse), 3 (no change), 4 (moderately improved) and 5 (much improved).Results: The severity of dry cough was attenuated [mean change (and 95% CI): 3.75 (3.37-4.13)] and the frequency was reduced [mean change: 3.79 (3.44-4.14)] after the administraiton time was changed to evening.Conclusion: Dry cough is the most common adverse effect of ACE inhibitors. The present findings suggest that a chronopharmacological approach might ameliorate enalapril-induced dry cough and, consequently, improve QOL in treated patients.

Nocturnal Asthma: Circadian Rhythms and Therapeutic Interventions

The pathophysiology of nocturnal asthma is closely associated with chronobiology, the science of biologic processes that have time-related rhythms. The 24-h cycle (circadian rhythm) is especially important in understanding the changes in pulmonary function that occur in sleeping asthmatics. Nocturnal asthma can be seen as representing an exaggerated amplitude of normal circadian patterns, including increased airway responsiveness and decreased lung function at night and in the early morning. Circadian changes in epinephrine, AMP, histamine and other inflammatory mediators, cortisol, vagal tone, body temperature, and lower airway secretions are potential mechanisms that favor nocturnal bronchoconstriction. Circadian variation in pulmonary function, as well as the effect of therapeutic interventions, can be readily demonstrated by having patients record peak expiratory flow rate values at different times of the day and night, using a peak flow meter. The treatment of nocturnal asthma requires a chronopharmacologic approach, in which more intense therapy is targeted to coincide with the time that the disease is the worst. Chronopharmacology includes the strategic use of longer-acting beta-agonists, theophylline, corticosteroids, and anticholinergics. Understanding the kinetics of the different drug preparations is necessary for most effective timing of dose. Future treatment of nocturnal asthma will continue to be guided by increased understanding of circadian and sleep-related events.

Concepts in chronopharmacology.

Circadian and other rhythmic changes in biological susceptibility and response of organisms to a large variety of physical and chemical agents including medications and foods are rather common phenomena. Time-related differences in drug effects depend upon endogenous circadian rhythms, which include metabolic pathways. In addition, chronopharmacology investigates drug effects on parameters (e.g. circadian period, peak time, amplitude, and adjusted mean) used to characterize biological rhythms. A better understanding of periodic and thus predictable changes in drug effects can be attained by consideration of complementary concepts: (a) The chronokinetics for a drug, i.e. dosing time-dependent and predictable (rhythmic) changes in parameters used to characterize the pharmacokinetics (or the bioavailability) of a drug, e.g. Cmax, tmax, AUC, and t1/2; (b) the chronesthesy, i.e. rhythmic changes in susceptibility of the target biosystem to this drug, including CR in pharmacodynamic processes; and (c) the chronergy, i.e. the drug-integrated overall effect. One of the aims of chronopharmacology refers to the use of a chronopharmacological approach to clinical treatment so as to enhance both effectiveness and tolerance of a drug by determining the best biological time for its administration.

P-523 - Efficacy of amikacin against mica infected with Pseudotonas aeruginosa: Chronopharmacologic approach

P-523 - Efficacy of amikacin against mica infected with Pseudotonas aeruginosa: Chronopharmacologic approach