Inflammatory cytokines,but not bile acids,regulate expression of murine hepatic anion transporters in endotoxemia

The toxicity of carbon tetrachloride (CCl(4)) and certain other chemicals varies over a 24-h period. Because the metabolism of some drugs follows a diurnal rhythm, it was decided to investigate whether the hepatic metabolic activation of CCl(4) was rhythmic and coincided in time with maximum susceptibility to CCl(4) hepatotoxicity. A related objective was to test the hypothesis that abstinence from food during the sleep cycle results in lipolysis and formation of acetone, which participates in induction of liver microsomal cytochrome P450IIE1 (CYP2E1), resulting in a diurnal increase in CCl(4) metabolic activation and acute liver injury. Groups of fed and fasted male Sprague-Dawley rats were given a single oral dose of 800 mg of CCl(4)/kg at 2- to 4-h intervals over a 24-h period. Serum enzyme activities, measured 24 h post dosing as indices of acute liver injury, exhibited distinct maxima in both fed and fasted animals dosed with CCl(4) near the beginning of their dark/active cycle. Blood acetone, hepatic CYP2E1 activity, and covalent binding of (14)CCl(4)/metabolites to hepatic microsomal proteins in untreated rats fed ad libitum followed circadian rhythms similar to that of susceptibility to CCl(4). Parallel fluctuations of greater amplitude were seen in rats fasted for 24 h. Hepatic glutathione levels were lowest at the time of greatest susceptibility to CCl(4). Acetone dose-response experiments showed high correlations between blood acetone levels, CYP2E1 induction, and CCl(4)-induced liver injury. Pretreatment with diallyl sulfide suppressed CYP2E1 and abolished the circadian rhythmicity of susceptibility to CCl(4). These findings provide additional support for acetone's physiological role in CYP2E1 induction and for CYP2E1's role in modulating CCl(4) chronotoxicity in rats.     

The effect of cycled lighting in the intensive care unit on sleep,activity and physiological parameters: A pilot study

Patients in intensive care suffer from severe illnesses or injuries and from symptoms related to care and treatments. Environmental factors, such as lighting at night, can disturb patients’ circadian rhythms. The aim was to investigate whether patients displayed circadian rhythms and whether a cycled lighting intervention would impact it. In this pilot study (N = 60), a cycled lighting intervention in a two-bed patient room was conducted. An ordinary hospital room functioned as the control. Patient activity, heart rate, mean arterial pressure and body temperature were recorded. All data were collected during the patients’ final 24 h in the intensive care unit. There was a significant difference between day and night patient activity within but not between conditions. Heart rates differed between day and night significantly for patients in the ordinary room but not in the intervention room or between conditions. Body temperature was lowest at night for all patients with no significant difference between conditions. Patients in both conditions had a natural circadian rhythm; and the cycled lighting intervention showed no significant impact. As the sample size was small, a larger repeated measures study should be conducted to determine if other types of lighting or environmental factors can impact patients’ well-being.     

Circadian regulation of human sleep and age-related changes in its timing, consolidation and EEG characteristics.

The light-entrainable circadian pacemaker located in the suprachiasmatic nucleus of the hypothalamus regulates the timing and consolidation of sleep by generating a paradoxical rhythm of sleep propensity; the circadian drive for wakefulness peaks at the end of the day spent awake, ie close to the onset of melatonin secretion at 21.00-22.00 h and the circadian drive for sleep crests shortly before habitual waking-up time. With advancing age, ie after early adulthood, sleep consolidation declines, and time of awakening and the rhythms of body temperature, plasma melatonin and cortisol shift to an earlier clock hour. The variability of the phase relationship between the sleep-wake cycle and circadian rhythms increases, and in old age sleep is more susceptible to internal arousing stimuli associated with circadian misalignment. The propensity to awaken from sleep advances relative to the body temperature nadir in older people, a change that is opposite to the phase delay of awakening relative to internal circadian rhythms associated with morningness in young people. Age-related changes do not appear to be associated with a shortening of the circadian period or a reduction of the circadian drive for wake maintenance. These changes may be related to changes in the sleep process itself, such as reductions in slow-wave sleep and sleep spindles as well as a reduced strength of the circadian signal promoting sleep in the early morning hours. Putative mediators and modulators of circadian sleep regulation are discussed.     

CLUSTER AND TRIGEMINAL AUTONOMIC CEPHALALGIAS

The suprachiasmatic nucleus (SCN) of the hypothalamus has been termed the master circadian pacemaker of mammals. Recent discoveries of damped circadian oscillators in other tissues have led to the hypothesis that the SCN synchronizes and sustains daily rhythms in these tissues. We studied the effects of constant lighting (LL) and of SCN lesions on behavioral rhythmicity and Period 1 (Per 1) gene activity in the SCN and olfactory bulb (OB). We found that LL had similar effects on cyclic locomotor and feeding behaviors and Per 1 expression in the SCN but had no effect on rhythmic Per 1 expression in the OB. LL lengthened the period of locomotor and SCN rhythms by approximately 1.6 hr. After 2 weeks in LL, nearly 35% of rats lost behavioral rhythmicity. Of these, 90% showed no rhythm in Per 1-driven expression in their SCN. Returning the animals to constant darkness rapidly restored their daily cycles of running wheel activity and gene expression in the SCN. In contrast, the OB remained rhythmic with no significant change in period, even when cultured from animals that had been behaviorally arrhythmic for 1 month. Similarly, we found that lesions of the SCN abolished circadian rhythms in behavior but not in the OB. Together, these results suggest that LL causes the SCN to lose circadian rhythmicity and its ability to coordinate daily locomotor and feeding rhythms. The SCN, however, is not required to sustain all rhythms because the OB continues to oscillate in vivo when the SCN is arrhythmic or ablated.
Comments: As the central generator for cluster appears to be near the hypothalamic circadian nuclei (May A, Bahra A, Buchel C, Frackowiak RS, Goadsby PJ. PET and MRA findings in cluster headache and MRA in experimental pain. Neurology. 2000;55:1328-1335), it behooves us to follow the work on understanding the training of circadian and circannual rhythms in order to better understand cluster. Stewart J. Tepper     

Circadian phase resetting in older people by ocular bright light exposure.

BACKGROUND: Aging is associated with frequent complaints about earlier bedtimes and waketimes. These changes in sleep timing are associated with an earlier timing of multiple endogenous rhythms, including core body temperature (CBT) and plasma melatonin, driven by the circadian pacemaker. One possible cause of the age-related shift of endogenous circadian rhythms and the timing of sleep relative to clock time is a change in the phase-shifting capacity of the circadian pacemaker in response to the environmental light-dark cycle, the principal synchronizer of the human circadian system. METHODS: We studied the response of the circadian system of 24 older men and women and 23 young men to scheduled exposure to ocular bright light stimuli. Light stimuli were 5 hours in duration, administered for 3 consecutive days at an illuminance of approximately 10,000 lux. Light stimuli were scheduled 1.5 or 3.5 hours after the CBT nadir to induce shifts of endogenous circadian pacemaker to an earlier hour (phase advances) or were scheduled 1.5 hours before the CBT nadir to induce shifts to a later hour (phase delays). The rhythms of CBT and plasma melatonin assessed under constant conditions served as markers of circadian phase. RESULTS: Bright light stimuli elicited robust responses of the circadian timing system in older people; both phase advances and phase delays were induced. The magnitude of the phase delays did not differ significantly between older and younger individuals, but the phase advances were significantly attenuated in older people. CONCLUSIONS: The attenuated response to light stimuli that induce phase advances does not explain the advanced phase of the circadian pacemaker in older people. The maintained responsiveness of the circadian pacemaker to light implies that scheduled bright light exposure can be used to treat circadian phase disturbances in older people.     

Crosstalk between central and peripheral biological clocks

Mammalian circadian system is multi-oscillator system. Clock gene expression analysis revealed that central clock, suprachiasmatic nucleus, organizes and synchronizes the peripheral oscillators in the whole body cells. Similarly, human circadian system is considered to be dual oscillation system because of internal desynchronization between melatonin, body temperature rhythms(driven by oscillator I) and sleep-wake rhythm (driven by oscillator II) under temporal isolation of dim light conditions. These oscillators control their periods mutually which means there is crosstalk of oscillators. Although the effect from oscillator II to oscillator I is weak under experimental dim light conditions, sleep-wake behavior controls light input to light sensitive oscillator I and feedbacks to sleep-wake driving oscillator II under lighting condition we live. To understand these mechanisms is important for prevention of circadian rhythm related diseases.     

A circadian rhythm of proteinuria in patients with a nephrotic syndrome

Circadian variations in proteinuria were studied in 17 patients with different types of glomerulopathies. During 3-4 successive days urine was collected over periods of 3 h under standardized conditions. Thirteen of the 17 patients showed a circadian rhythm of their proteinuria with a maximum excretion in daytime around 16.00 hours and a minimum excretion at night around 03.00 hours. In the majority of patients the urinary excretory rhythms of albumin, transferrin and immunoglobulin G were 'in phase' with each other and with the circadian rhythm of total protein excretion. Nine patients had a larger degree of rhythmicity for immunoglobulin G than for transferrin excretion. In eight of them a circadian rhythm of the selectivity index of proteinuria was seen with the lowest index at night. No relation was observed between the circadian rhythm of proteinuria and the type of glomerulopathy.     

Circadian and circannual rhythms of several enzymes of lysosomal origin in human plasma

The circadian and circannual group rhythms in the plasma concentrations of the following lysosomal enzymes were studied in women and men: beta-D-N-acetylglucosaminidase, beta-D-glucuronidase, beta-D-glucosidase, beta-D-galactosidase, alpha-D-galactosidase, alpha-L-fucosidase and alpha-D-mannosidase. The circadian rhythm was detected in all the tested enzymes of women, and only in alpha-D-galactosidase, beta-D-glucosidase, alpha-D-mannosidase and beta-D-N-acetylglucosaminidase of men. A statistically significant difference between genders in the circadian rhythm was exhibited by beta-D-galactosidase, beta-D-glucosidase, beta-D-N-acetylglucosaminidase, beta-D-glucuronidase, alpha-D-galactosidase and alpha-L-fucosidase. A circannual rhythm was detected in all the tested enzymes, with the exception of beta-D-glucuronidase and beta-D-N-acetylglucosaminidase, without any statistically significant difference between genders. The group rhythms of some of the enzymes (alpha-D-galactosidase, beta-D-glucosidase, beta-D-galactosidase) showed similar values of both circadian and circannual acrophases, suggesting that they may be subjected as a group to the same chronobiological coordination. The chronobiological rhythms of lysosomal enzymes were different from those of lactate dehydrogenase and alpha 1-antitrypsin, indicating that these rhythms are not merely reflecting fluctuations of the water content of plasma. No in-phase relationship was observed between the circadian and circannual rhythms of plasma cortisol and those of the tested lysosomal enzymes, excluding a direct chronobiological relationship between this hormone and lysosomal enzymes.     

Circadian regulation of cardiac metabolism

Circadian rhythm evolved to allow organisms to coordinate intrinsic physiological functions in anticipation of recurring environmental changes. The importance of this coordination is exemplified by the tight temporal control of cardiac metabolism. Levels of metabolites, metabolic flux, and response to nutrients all oscillate in a time-of-day–dependent fashion. While these rhythms are affected by oscillatory behavior (feeding/fasting, wake/sleep) and neurohormonal changes, recent data have unequivocally demonstrated an intrinsic circadian regulation at the tissue and cellular level. The circadian clock — through a network of a core clock, slave clock, and effectors — exerts intricate temporal control of cardiac metabolism, which is also integrated with environmental cues. The combined anticipation and adaptability that the circadian clock enables provide maximum advantage to cardiac function. Disruption of the circadian rhythm, or dyssynchrony, leads to cardiometabolic disorders seen not only in shift workers but in most individuals in modern society. In this Review, we describe current findings on rhythmic cardiac metabolism and discuss the intricate regulation of circadian rhythm and the consequences of rhythm disruption. An in-depth understanding of the circadian biology in cardiac metabolism is critical in translating preclinical findings from nocturnal-animal models as well as in developing novel chronotherapeutic strategies.     

Characteristics of infradian and circadian rhythms in the persistent vegetative state

This retrospective study investigated the circadian and infradian characteristics of blood pressure and heart rate in 26 patients with traumatic head injury in a persistent vegetative state (PVS). Systolic and diastolic blood pressures and heart rate were measured every hour for the first 240 h (10 days) following hospital admission. These data were analysed for the presence of circadian and infradian rhythms using the least-squares fit of the cosine function with the single cosinor method. Infradian rhythms were defined as biological rhythms with a period of approximately 7 days (circaseptan rhythms). All the patients studied had circadian and circaseptan rhythms of systolic and diastolic blood pressures and heart rate. The amplitudes of all the circaseptan rhythms were significantly greater than those of the corresponding circadian rhythms. It was concluded that there was an altered association between circadian and infradian blood pressure and heart rate rhythms in patients in a PVS. Circadian and infradian rhythms were present, but the infradian rhythm had a greater amplitude than the circadian rhythm.     

Relationship of endogenous circadian melatonin and temperature rhythms to self-reported preference for morning or evening activity in young and older people.

BACKGROUND: Morningness-eveningness refers to interindividual differences in preferred timing of behavior (i.e., bed and wake times). Older people have earlier wake times and rate themselves as more morning-like than young adults. It has been reported that the phase of circadian rhythms is earlier in morning-types than in evening types, and that older people have earlier phases than young adults. These changes in phase have been considered to be the chronobiological basis of differences in preferred bed and wake times and age-related changes therein. Whether such differences in phase are associated with changes in the phase relationship between endogenous circadian rhythms and the sleep-wake cycle has not been investigated previously. METHODS: We investigated the association between circadian phase, the phase relationship between the sleep-wake cycle and circadian rhythms, and morningness-eveningness, and their interaction with aging. In this circadian rhythm study, 68 young and 40 older subjects participated. RESULTS: Among the young subjects, the phase of the melatonin and core temperature rhythms occurred earlier in morning than in evening types and the interval between circadian phase and usual wake time was longer in morning types. Thus, while evening types woke at a later clock hour than morning types, morning types actually woke at a later circadian phase. Comparing young and older morning types we found that older morning types had an earlier circadian phase and a shorter phase-wake time interval. The shorter phase-waketime interval in older "morning types" is opposite to the change associated with morningness in young people, and is more similar to young evening types. CONCLUSIONS: These findings demonstrate an association between circadian phase, the relationship between the sleep-wake cycle and circadian phase, and morningness-eveningness in young adults. Furthermore, they demonstrate that age-related changes in phase angle cannot be attributed fully to an age-related shift toward morningness. These findings have important implications for understanding individual preferences in sleep-wake timing and age-related changes in the timing of sleep.     

Serotonin and the regulation of mammalian circadian rhythmicity

The suprachiasmatic nucleus (SCN), the site of the primary mammalian circadian clock, contains one of the densest serotonergic terminal plexes in the brain. Although this fact has been appreciated for some time, only in the last decade has there been substantial approach toward the understanding of the function of serotonin in the circadian rhythm system. The intergeniculate leaflet, which projects to the SCN via the geniculohypothalamic tract, receives serotonergic innervation from the dorsal raphe nucleus, and the SCN receives its serotonergic input from the median raphe nucleus. This separation of serotonergic origins provides the opportunity to investigate the function of the two projections. Loss of serotonergic neurones of the median raphe yields earlier onset and later offset of the nocturnal activity phase, longer duration of the activity phase, and increased sensitivity of circadian rhythm response to light. Despite the simplicity of the origins of serotonergic anatomy with respect to the circadian rhythm system, the actual involvement of serotonin in rhythm modulation is not so obvious. A variety of pharmacological studies have clearly implicated serotonin as a direct regulator of circadian rhythm phase, but others employing different methods suggest that simple elevation of SCN serotonin concentrations does not modify rhythm phase. The most convincing role of serotonin is its apparent ability to modulate sensitivity of the circadian rhythm to light. The putative method for such modulation is via a presynaptic 5-HT1B receptor on the retinohypothalamic tract, the activation of which attenuates photic input to the SCN thereby reducing phase response to light. Serotonin may modulate phase response to benzodiazepines, but does not appear to modify such response to environmentally induced locomotor activity. Current interest in serotonergic modulation of circadian rhythmicity is strong and the research is vigorous. There is an abundance of information about serotonin and circadian rhythm function that lacks a satisfactory framework for its interpretation. The next decade is likely to see the gradual evolution of this framework as the role of serotonin in circadian rhythm regulation is further elucidated.     

Reducing disruption of circadian temperature rhythm following surgery

Temperature and other circadian rhythms are disrupted following surgery and other traumatic events. During recovery, coordination between temperature rhythms and other rhythmic physiologic processes is reduced. Studies of animals and humans have shown that return of synchrony is not immediate, but that it is important in the recovery process. The purpose of this study was to test a combination of cues that have been shown to adjust the timing of circadian temperature rhythm. The combined cues consisted of timed ingestion of caffeine and protein foods and adjustment of the sleep/wake cycle. The intervention was tested in 26 age- and gender-matched maxillofacial surgery patients. Patients were randomly assigned to control or experimental groups. Circadian temperature rhythm was measured by continuous monitoring with axillary probes and miniature recorders before and after surgery. Following surgery, both experimental and control subjects displayed 24-hour circadian temperature rhythms; however, the peak-to-trough difference was decreased more following surgery in the control subjects than in the subjects who had prepared for surgery by practicing the intervention. Control subjects also had less day-to-day stability in the phase of their rhythms following surgery. These results suggest that the intervention reduced circadian disruption following surgery and provides a way for patients to prepare themselves to resist rhythm changes.     

Circadian and extracircadian exploration during daytime hours of circulating corticosterone and other endocrine chronomes

During 7 consecutive days, blood and several tissues were collected during daytime working hours only, three times per day at 4-h intervals from inbred Wistar rats, which had been previously standardized for 1 month in two rooms on a regimen of 12 h of light (L) alternating with 12 h of darkness (LD12:12). In one room, lights were on from 09:00 to 21:00 and in the other room, lights were on from 21:00 to 09:00 (DL12:12; reversed lighting regimen). This setup provides a convenient design to study circadian and extracircadian variations over long (e.g., 7-day) spans. Prior checking of certain circadian rhythms in animals reared in the room on reversed lighting (DL) as compared with animals in the usual (LD) regimen provided evidence that the 180° phase-shift had occurred. These measurements were limited to the circadian (and not extended to infradian) variation. As marker rhythm, the core temperature of a subsample of rats was measured every 4 h around the clock (by night as well as by day) before the start of the 7-day sampling. An antiphase of the circadian rhythm in core temperature was thus demonstrated between rats in the LD vs. DL rooms. A sex difference in core temperature was also found in each room. A reversed rhythm in animals kept in DL and an antiphase between rats kept in DL vs. LD was again shown for the circulating corticosterone rhythm documented in subsamples of 8 animals of each sex sampled around the clock during the first ∼1.5 day of the 7-day sampling. The findings were in keeping with the proposition that sampling rats at three timepoints 4 h apart during daytime from two rooms on opposite lighting regimens allows the assessment of circadian changes, the daytime samples from animals kept on the reversed lighting regimen accounting for the samples that would have to be obtained by night from animals kept in the room with the usual lighting regimen. During the 7-day-long follow-up, circadian and extracircadian spectral components were mapped for serum corticosterone, taking into account the large day-to-day variability. A third check on the synchronization of the animals to their respective lighting regimen was a comparison (and a good agreement) between studies carried out earlier on the same variables and the circadian results obtained on core temperature and serum corticosterone in this study as a whole. The present study happened to start on the day of the second extremum of a moderate double magnetic storm. The study of any associations of corticosterone with the storm is beyond our scope herein, as are the results on circulating prolactin, characterized by a greater variability and a larger sex difference than corticosterone. Sex differences and extracircadian aspects of prolactin and endothelin determined in the same samples are reported elsewhere, as are results on melatonin. Prior studies on melatonin were confirmed insofar as a circadian profile is concerned by sampling on two antiphasic lighting regimens, as also reported elsewhere. Accordingly, a circadian map for the rat will eventually be extended by the result of this study and aligned with other maps with the qualification of the unassessed contribution in this study of a magnetic storm.     

Effects of phototherapy in neonates on circadian sleep-wake and saliva cortisol level rhythms

The influence of phototherapy treatment during the neonatal period on sleep-wake rhythm, and its long-term effects on biological rhythms, was evaluated in preterm and full-term infants. Forty-three infants treated with phototherapy during the neonatal period and 47 untreated infants were examined for entrainment of sleep-wake rhythms between 16 and 52 weeks and for sleep-wake and saliva cortisol rhythms at 2.5 years of age. The age of sleep-wake rhythm entrainment was not significantly different between the 2 groups. No correlations between duration of exposure to phototherapy and corrected age of entrainment of sleep-wake rhythm were observed. At follow-up, no significant differences in sleep-wake and saliva cortisol rhythms were observed between the 2 groups, indicating that circadian variations were similar to those in adults.     

Circadian rhythms of hypophysis-thyroid hormones secretion in patients with bronchial asthma

AIM: To examine circadian rhythms of hypophysiothyroid system in patients with bronchial asthma and effects of exogenic glucocorticoids on thyroid function. MATERIALS AND METHODS: Free T3, T4 and TTH were measured in plasma using immunochemiluminescence in 16 patients with nonallergic bronchial asthma running a severe course. The plasma samples were taken each 6 hours for 48 hours. RESULTS: In patients with severe bronchial asthma (SBA) thyroid functional activity changed. Production of T3 increased while that of T4 dropped at night. TTH concentration rhythm for 24 hours was like that in healthy subjects. Glucocorticoids induced no significant changes in circadian rhythms of hypophysiothyroid system in SBA patients. CONCLUSION: In SBA functional activity of the hypophysiothyroid system changes with rearrangement of hormonal production at night.     

Desynchronization of daily rest-activity rhythm in the days following light propofol anesthesia for colonoscopy

Anesthesia and surgery are associated with fatigue and sleep disorders, suggestive of disturbance of the circadian rest-activity rhythm. Previous studies on circadian rhythm disturbance were focused on patients undergoing general anesthesia associated with surgery. This does not permit one to draw valid conclusions about the effects of general anesthesia per se on circadian rhythms. Our study was set up to determine the impact of a hypnotic dose of propofol on the circadian rest-activity rhythm in humans under real-life conditions. Seventeen healthy subjects scheduled to receive light propofol anesthesia for ambulatory colonoscopy were investigated. Their rest-activity rhythms were assessed using actigraphic monitoring. Diurnal rest was increased, whereas nocturnal sleep was unchanged in the days following anesthesia. Nonparametric analyses showed a decrease in the strength of coupling of the rhythm to stable environmental zeitgebers and increase of fragmentation of the rhythm after anesthesia. Light general anesthesia itself impairs synchronization of the circadian rest-activity rhythm to local time in patients by acting directly on the circadian clock.     

2,2,2-Tribromoethanol phase-shifts the circadian rhythm of the liver clock in Per2::Luciferase knockin mice: lack of dependence on anesthetic activity

Comprehensive gene expression profiling in mice in response to the inhalation of sevoflurane has revealed that circadian clock gene expression is affected strongly in the liver, heart, lung, and kidney, in this order, but moderately in the spleen and slightly in the brain. Therefore, we examined whether the administration of general anesthetics at different times of the day induces phase shifts of the liver clock in Per2::Luciferase knockin mice. One to 4 days of intraperitoneal injection of 2,2,2-tribromoethanol (240 mg/kg, anesthetic time 60 min) or 2,2,2-trichloroethanol (240 mg/kg, 60 min), common anesthetics in veterinary surgery, caused phase delays when injected during the daytime and phase advances when injected during the nighttime. Inhalation administration of isoflurane for 30 or 60 min during the daytime did not induce a phase delay. Injection of propofol (300 mg/kg, 17 min) during the daytime induced an insignificant phase delay of the Per2 bioluminescence rhythm. Injection of 2,2,2-tribromoethanol did not induce a phase shift in the suprachiasmatic nucleus, the main oscillator, or in behavioral locomotor rhythms, suggesting that 2,2,2-tribromoethanol induced phase shifts of the liver clock independent of the main suprachiasmatic clock. The expression of clock genes, such as Bmal1 and Clock, in mouse liver was decreased strongly 1 and 4 h after a single injection of 2,2,2-tribromoethanol. These results demonstrate that 2,2,2-tribromoethanol or 2,2,2-trichloroethanol produce phase shifts of the peripheral clock, independent of anesthetic activity. These anesthetics may cause circadian rhythm disorders in peripheral organs when administered as general anesthetics several times during the day.     

The potentiation of barbiturate-induced narcosis by procarbazine.

Procarbazine (MIH), N-isopropyl-alpha-(2-methylhydrazino)-p-toluamide (NSC-77213), a clinically effective antineoplastic agent, induced sleep in mice at its optimally effective dose (400 mg/kg) and prolongs hexobarbital sleeping times. MIH (400 mg/kg) increased the period of sleep following hexobarbital (100 mg/kg) nearly 10-fold. Nonhypnotic doses of MIH also significantly prolonged hexobarbital-induced sleep. Hexobarbital half-life in plasma was prolonged 6 to 7 times by prior treatment with MIH (400 mg/kg). Liver microsomes from mice treated with MIH exhibited decreased metabolism of the following substrates in vitro: hexobarbital, aminopyrine, ethylmorphine, and aniline. Cytochrome P-450 levels were also decreased by MIH treatment. Maximal decreases in enzyme activity and P-450 content occurred between 4 and 8 hours following treatment. Pretreatment with phenobarbital decreased the effectiveness of MIH to prolong hexobarbital sleeping times while pretreatment with SKF 525A added to the potentiating effect of MIH. Two major metabolites of MIH had neither central nervous system hypnotic effect nor inhibited hepatic microsomal mixed-function oxidases. Therefore, MIH potentiation of hexobarbital-induces sleep is probably due both to its direct hypnotic effect and inhibition of mixed-function oxidase activity.     

Acetaminophen injection: a review of clinical information

Acetaminophen injection is an antipyretic and analgesic agent recently marketed in the United States as Ofirmev. Five published trials directly compare acetaminophen injection to drugs available in the United States. For management of pain in adults, acetaminophen injection was at least as effective as morphine injection in renal colic, oral ibuprofen after cesarean delivery, and oral acetaminophen after coronary artery bypass surgery. In children (3 to 16 years old), single-dose acetaminophen injection was similar to meperidine intramuscular (i.m.) for pain after tonsillectomy; readiness for discharge from the recovery room was shorter with acetaminophen injection (median 15 minutes) compared with meperidine i.m. (median 25 minutes), P = .005. In children (2 to 5 years old) postoperative adenotonsillectomy or adenoidectomy, the time to rescue analgesia was superior with high-dose acetaminophen rectal suppository (median 10 hours) compared with acetaminophen injection (median 7 hours), P = .01. One published trial demonstrated acetaminophen injection is noninferior to propacetamol injection for fever related to infection in pediatric patients. Dosing adjustments are not required when switching between oral and injectable acetaminophen formulations in adult and adolescent patients. Acetaminophen injection represents another agent for multimodal pain management.