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Biomedical subjects

M Smolensky

Publications and source records attributed to M Smolensky.

At least 19 recordsLinked to original sources
PubMed1995

A phase I-II trial of five-day continuous intravenous infusion of 5-fluorouracil delivered at circadian rhythm modulated rate in patients with metastatic colorectal cancer.

The toxicity of 5-fluorouracil (5-FU) was decreased by two to eight-fold if this drug was injected in mice near the middle of the day (rest span) rather than in the middle of the night (activity span). If the rhythm in 5-FU toxicity is linked to the sleep-wakefulness endogenous circadian cycle across species, the least toxic time in man would correspond to 4.00 hours at night. The availability of a single-reservoir programmable-in-time external ambulatory pump (Chronopump, Autosyringe, Hooksett, USA) allowed us to perform a first test of this hypothesis. Five-FU was infused for 5 consecutive days, via an implanted venous access port, with peak drug delivery at 4.00 hours and no infusion from 18.00 to 22.00 hours. Each course was repeated after a free interval of 16 days. Intrapatient dose escalation was planned from 4 to 9 g/m2/course (800 to 1800 mg/m2/day x 5 days) if toxicity was less than grade 2 according to the World Health Organization (W.H.O.). Thirty-five patients with metastatic colorectal cancer were treated; 15 (41%) had received previous therapy, 22 (63%) had W.H.O. performance status of 2 or greater, and 19 (54%) had two or more sites involved. Grade 2 or greater toxicity was encountered in less than 5% of the courses, indicating an adequate control of toxicity via dose adjustment. Oral mucositis, diarrhea, and/or hand-foot syndrome limited dose escalation, and their incidence was dose dependent. Median maximal tolerated dose was 7.5 mg/m2/course in 30 patients assessed for this endpoint.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

The chronopharmacological application of theophylline therapy in asthma.

It has been known for centuries that asthmatic patients experience a worsening of symptoms at night and early in the morning, thus disturbing sleep and in some compromising daily performance. Nearly 95% of asthmatic patients experience nocturnal symptoms severe enough to awaken them, at least periodically. A more feared consequence of nocturnal asthma than disruption of sleep in death. Patients who suffer from nocturnal asthma require bronchodilator treatment that is effective overnight. The efficacy of therapy depends upon it formulation and the treatment strategy that is employed. An ideal bronchodilator medication should have optimal effect at a time when enhanced bronchoconstriction is known to occur. Certain sustained-release theophylline (SRT) have been formulated as effective chrono-therapies for nocturnal asthma. The use of certain SRTs have proved highly successful in controlling asthma at night after being administered once-daily in the evening.

Asthma↗
PubMed1990

Day-night differences in effects of cosmetic treatments on facial skin. Effects on facial skin appearance.

Two groups of 24 healthy caucasian women, similar with regard to age classes (from 19 to 55) as well as fair and dark complexion of skin and hair, volunteered to use during a 14-day span a conventional facial cream (active placebo: AP) and thereafter, during a 21-day span Noctosome (Noctos). The latter is a new generation of liposome made with non-ionic lipids leading to microspheres which include glycopeptides in the aqueous compartment of the vesicle, alpha-tocopherol ester in the membrane-like structure and sphingo-ceramides at the surface of the microspheres. The aim of the study was to test the beneficial effects of Noctos (vsAP) with respectively morning (7-9-hr) and evening (21-23-hr) applications as facial ointments. Observed differences were validated using several statistical tests: ANOVA, cosinor, etc. Subjects were socially synchronized with a diurnal activity from 7 hr to 23 hr and a nocturnal rest. Each day, at fixed clock hours (7, 10, 20 and 23 hr), each subject used visual analogue scales to self-rate a set of variables characterizing facial aspects. Brilliance of complexion and texture of skin exhibited a circadian rhythm (peak time at 10 hr), both with AP and Noctos. The latter produces a beneficial effect with regard to reference values (AP). The evening application of Noctos is more efficient than the morning one. However, the magnitude of this beneficial effect is related both to age (greater for the age class 25-35 years than for younger and older subjects) and to skin complexion (greater for fair than dark complexioned subjects). Major beneficial effects of Noctos in the evening hours are related neither to fatigue nor to mood of the women since the respective circadian rhythms of these variables appear to vary independently from those of facial skin characteristics.

Adult↗
PubMed1988

Circadian and circannual rhythms of allergic rhinitis: an epidemiologic study involving chronobiologic methods.

Seven hundred sixty-five patients, living in France and suffering from allergic rhinitis (eg, with positive skin tests to various antigens), agreed to self-rate (visual analog scales), four times daily, symptoms such as sneezing, stuffy or blocked nose, runny nose, itchy nose, itchy eyes, wheeze, or cough. Despite acute symptoms, patients did not take medications of any kind by any route during 36 hours. Several statistical methods (eg, Student's t test, analysis of variance, cosinor, chi-square, etc.) were used to validate both circadian and circannual rhythms of these symptoms in the group as a whole, as well as in subgroups related to age, sex, etc. Large-amplitude circadian rhythms with early morning peak times (eg, approximately 6 AM) were validated for sneezing, stuffy nose, and runny nose (with p less than 0.0001) but not for wheeze or cough. Such time-dependent changes were related neither to age (from 10 to 80 years) nor to sex. However, small differences were observed in subgroups sorted with regard to duration of disease (old versus new cases), smoking habits, and geographic location (north versus south France). Reanalysis of data taking into account interindividual differences revealed that the respective peak times of the three major symptoms occurred in the early morning in about 60% to 70% of the patients. Annual changes were validated as well with the annual peak time being January to April. The proposed interpretation of both circadian and circannual rhythms suggests taking into account endogenous component rhythms (eg, involving metabolic, immunologic, and endocrine systems), since they contribute to time-dependent changes in the human susceptibility to antigens. In addition, the elevated severity of symptoms in the morning experienced by 60% to 70% of patients should serve as a guide to individually optimize dosing time(s) of medications, such as antihistamines.

Age Factors↗
PubMed1987

Aspects of chronopharmacology and chronotherapy in pediatrics.

Pediatric chronopharmacological findings until now have been limited to circadian changes in children from ages 6 to 15 years. This means that data in newborns and even in infants of 1 year are not available and other bioperiodicities with periods of about-1-year (infradian rhythms) have not been explored in older children. Biologic time-related changes have been documented for phenytoin and theophylline with regard to pharmacokinetics, for orciprenaline with regard to bronchodilation, and for corticosteroids as well as anticancer agents with regard to their effectiveness. Despite the limited number of experiments performed to date, it is already possible to state that a chronopharmacological approach provides better precision in pharmacologic study than the conventional approach not using time-related data and better therapeutics can be achieved with the help of chronopharmacological facts since appropriate timing in administration of medicine usually enhances its desired and/or reduces its undesired effects.

Adrenal Cortex Hormones↗
PubMed1985

Seasonal variations in socially and legally unacceptable sexual behaviour.

The calendar dates, over the 15-year span 1966-1980, of committed rapes by eight male recidivists and offences of sexually indecent or immoral behaviour by eight other male recidivists were gathered from the files of the Préfecture de Police, Paris, France. Each offender of the first group had committed from two to six rapes, while each offender of the second had committed from two to 16 incidences of indecent behaviour. Although the reported rapes took place during several calendar years, almost all, 18 out of 22 offences, were committed by the eight rape-recidivists during the 4-month span of July-October. Single cosinor analysis of these data revealed a circannual rhythmicity (P less than 0.03) with luminal diameter being 10 August +/- 34 days (the 95% CL). The peak time of indecent sexual behaviour, exclusive of rape, against females occurred during September with secondary peaks in February and June; such offences directed against males peaked in October. 'Bootstrap' and 'Jackknife' methods confirmed seasonality within all data sets, except for the offences of indecent behaviour.

Adolescent↗
PubMed1984

[Clinical chronopharmacokinetics].

Circadian (approximately or equal to 24 hours) and other endogenous biological rhythms, detectable at all levels of organisation, constitute a temporal structure in all species, including man. Circadian, circannual, 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. A better understanding of periodic and thus predictable changes in drug effects can be attained through consideration of three complementary concepts: the chronopharmacokinetics of a drug (rhythmic changes in its pharmacokinetics), the chronesthesy (rhythmic changes in susceptibility of target biosystems to the drug), and the chronergy (the drug-integrated overall effects). The chronopharmacokinetics of many drugs have been evaluated in man (tables I-IV) including sodium salicylate, aspirin, indomethacin (fig. 1), sustained-release indomethacin, paracetamol (acetaminophen), phenacetin, amidopyrine, theophylline sustained-release theophylline (fig. 2), aminophylline, sustained-release aminophylline, digitalis, propranolol, clorazepate, hexobarbitone (hexobarbital), diazepam, midazolam, lithium, phenytoin (diphenylhydantoin), nortriptyline, ethanol, erythromycine , ampicillin, sulfasymazine , sulphanilamide, cis-diammine-dichloroplatinum (fig. 3), mequitazine (fig. 4), d-xylose, ferrous sulphate, potassium chloride, hydrocortisone and prednisolone, among others. The roles presumably played by circadium rhythms in drug metabolizing liver enzymes (fig. 5), and kidney function are summarized, and the practical implications of chronopharmacokinetics, aiming both to improve in a quantitative manner the metabolic fate of a drug and its effectiveness, are discussed.

Anesthesia↗
PubMed1983

Aspects of clinical chronopharmacology.

Circadian (congruent to 24 h), circannual (congruent to 1 year) and other biological rhythms of endogenous origin, detectable at all levels of organization, constitute a temporal structure in all animal species, including man. Circadian, circannual and other rhythmic changes in biological susceptibility and response of organisms to a large variety of physical as well as chemical agents including medications and foods are rather common phenomena. Modern chronopharmacology investigates drug effects: (a) as a function of biological timing, and (b) upon parameters characterizing the endogenous bioperiodicities. A better understanding of periodic and thus predictable changes in drug effects can be attained through consideration of three complementary concepts: the chronokinetics of a drug (rhythmic changes in its pharmacokinetics); the chronesthesy (rhythmic changes in susceptibility of target biosystems to this drug), and the chronergy (the drug integrated overall effects). One of the aims of chronopharmacology is solving problems of drug optimization. Knowledge of those administration times coinciding with best effectiveness or tolerance is required to optimize both timing(s) and dosage(s) of a medication. Illustrative examples of both experimental and clinical investigative chronopharmacology are corticosteroids and anticancerous agents.

Adult↗
PubMed1981

Circadian changes in the bioavailability and effects of indomethacin in healthy subjects.

Nine subjects, 19 to 29 years old (2 females) synchronized with activity from 07.00 to 00.00 received a single daily oral dose (100 mg) of indomethacin at fixed hours: 07.00, 11.00, 15.00, 19.00 and 23.00, in random order and at weekly intervals. 1) Chronopharmacokinetics: Venous blood (sampled at: 0, 0.33, 0.67, 1.0, 1.5, 2.0, 4.0, 6.0, 8.0 and 10.0 h post ingestion) was used for plasma drug determination. Circadian changes in peak height, time to peak, area under the concentration-time curve and the disappearance rate were used to characterize indomethacin chronopharmacokinetics. A circadian rhythm of both peak height and time to peak was validated. An evening ingestion led to smallest peak height and longest time to peak. 2) Circadian changes in a set of effects: Eleven physiologic variables were investigated (post absorption) at delta t = 2 h. Circadian rhythms were detected: i) on control day and ii) with evening ingestion for ten of the eleven variables indicating that the subjects' temporal structure did not become altered by an evening ingestion, whereas it did become so by morning ones. Transient changes (n minutes post absorption) measured as T240 min post absorption/Tcontrol day, same clock hour ratio were also circadian rhythmic for most variables. Again, evening ingestion appeared least disturbing.

Adult↗
PubMed1981

Clinical chronopharmacology.

Circadian (approximately or equal to 24 h), circannual (approximately or equal to 1 year) and other biological rhythms of endogenous origin, detectable at all levels of organization, constitute a temporal structure in all animal species, including man. Circadian, circannual and other rhythmic changes in biological susceptibility and response of organisms to a large variety of physical as well as chemical agents including medications and foods are rather common phenomena. Modern chronopharmacology investigates drug effects: a) as a function of biological timing and b) upon parameters characterising the endogenous bioperiodicities. A better understanding of periodic and thus predictable changes in drug effects can be attained through consideration of three complementary concepts: the chronokinetics of a drug (rhythmic changes in its pharmacokinetics): the chronesthesy (rhythmic changes in susceptibility of target biosystem to this drug), and the chronergy (the drug-integrated overall effects). One of the aims of chronopharmacology is solving problems of drug optimization. Knowledge of those administration times coinciding with best effectiveness or tolerance is required to optimize both timing(s) and dosage(s) of a medication. Illustrative examples of both experimental and clinical investigative chronopharmacology are corticosteroids and anticancerous agents.

Adult↗
PubMed1977

Twenty-four-hour rhythm in the bronchial hyperreactivity to house dust in asthmatics.

Four subjects, 2 males (17 and 35 yr of age) and 2 females (24 and 47 yr of age) suffering from allergic asthma were studied for 10 days in allergen-shielded rooms and without medication. Synchronization of subjects to activity was by light on at 7 A.M. and sleep by light off at midnight. A single bronchial challenge to the threshold concentration of house dust, predetermined for each subject, was presented every other day at designated clock hours such that during a 10-day study span tests were presented at the following times: 8 A.M., 3 P.M., 7 P.M., and 11 P.M. The effect upon bronchial patency determined by FEV 1.0 15 min after house dust inhalation resulted in greatest effect at 11 P.M., while that at 8 A.M. resulted in least effect. The differences were statistically significant (p less than 0.025). Peak expiratory flow (PEF), self-measured at 3-hr intervals throughout the 10-day span, revealed practically no persistence of effect for inhalation of the house dust preparations at 8 A.M.; on the other hand, considerable persistence of effect on airway patency occurred from tests carried out at 11 P.M. The differences between the 24-hr rhythm-adjusted means (mesors) in the PEF for the (24-hr) spans following house dust inhalation at 8 A.M. and 11 P.M. were statistically significant (p less than 0.025) as well.

Adolescent↗
PubMed1977

Meteorologic factors and temporal variations of cardiac mortality in an urban setting in a desert climatic zone.

The aim of this investigation was to study, by use of the unbiased and rigorous techniques of lagged cross-covariance and spectral analyses, the associations between daily cardiac mortality and weather conditions in Beersheba, an urban center situated in a hot and dry climatic zone. The results of the analyses point to the existence of seasonal differences in mortality, with a peak in winter. Of greater interest is the statistical documentation of temporal associations between short-term increases in daily mortality and certain weather situations corresponding to the transitional periods of turbulent atmosphere with below normal air temperatures, strong gusty winds and a drop in relative humidity, i.e., conditions accompanying the intrusion of a winter cold wave. The crests in short-term mortality occurred most often within a week of the intrusion of the cold air masses. No consistent cross association was found between high summer temperatures and mortality. The results of this investigation are discussed in the light of those previously reported for Tel Aviv (a coastal city) and Jerusalem (a city situated at a high altitude).

Atmospheric Pressure↗