Basis for dosing time-dependent changes in the antiviral activity of interferon-alpha in mice

The influence of dosing time on the pharmacological effect (antiviral activity) of interferon-alpha (IFN-alpha), and the pharmacological and pharmacokinetic mechanisms, were investigated in ICR male mice under a 12-h light/dark cycle (lights on from 7:00 AM to 7:00 PM). 2'-5'Oligoadenylate synthetase activity in plasma at 24 h after IFN-alpha (10 MI.U./kg, i.v.) injection, as an index of antiviral activity, was significantly higher for injections given at 9:00 AM than for injections given at 9:00 PM (P <.05). The uptake of [(3)H]thymidine by lymphocytes after 24-h incubation with IFN-alpha, as an index of lymphocyte-stimulating effect, was significantly higher in cells obtained at 9:00 AM than in the cells obtained at 9:00 PM (P <.01). The number of receptors per cell and the expression of interferon-stimulated gene factor in lymphocytes after 24-h incubation with IFN-alpha were significantly higher in the cells obtained at 9:00 AM than at 9:00 PM (P <.05). A significant dosing time-dependent difference was demonstrated for the pharmacokinetic parameters of IFN-alpha, which showed higher clearance for injections given at 9:00 PM than for those at 9:00 AM (P <.05). The metabolism of IFN-alpha was significantly higher in kidney obtained at 9:00 PM than at 9:00 AM (P <.05). These findings support that choosing the most appropriate time of day for administration of IFN-alpha, associated with the rhythmicity of IFN-alpha receptor function and IFN-alpha pharmacokinetics, may increase the antiviral activity in experimental and clinical situations.     

Influence of feeding schedule on 24-h rhythm of hepatotoxicity induced by acetaminophen in mice

The influence of feeding schedule on the chronopharmacological aspects of acetaminophen (APAP) was examined in mice housed under 12-h light/dark cycle (lights on from 7:00 AM to 7:00 PM) with food and water ad libitum feeding (ALF) or under repeated time-restricted feeding (feeding time between 9:00 AM and 5:00 PM) for 2 weeks before the experiment. For the ALF group, there was a significant 24-h rhythm of mortality after APAP (600 mg/kg i.p.) injection. Peak mortality was observed after APAP injection at 9:00 PM and 1:00 AM, and nadir mortality was observed after drug injection at 9:00 AM. Hepatotoxicity after APAP (300 mg/kg i.p.) injection at 9:00 PM was significantly more severe than that after drug injection at 9:00 AM. Immunohistochemical staining using anti-APAP antibody 2 h after APAP injection was detected in centrilobular hepatocytes after drug injection at 9:00 PM but not after drug injection at 9:00 AM. CYP2E1 activity and hepatic glutathione (GSH) levels in untreated mice showed significant 24-h rhythms associated with APAP toxicity rhythm. The reduction in hepatic GSH levels after APAP injection at 9:00 PM was greater than that after drug injection at 9:00 AM. On the other hand, manipulation of the feeding schedule modified APAP hepatotoxicity rhythmicity, CYP2E1 activity, and GSH levels in the liver. Manipulation of the feeding schedule and choosing the most appropriate time of the day for drug administration may help to achieve rational chronopharmacology of some drugs including APAP in specific experimental and clinical situations.     

Chronopharmacology of analgesic effect and its tolerance induced by morphine in mice

The influence of morphine dosing time on analgesic effect after acute or chronic treatment, recovery of analgesic effect after once developed tolerance, and their pharmacological mechanisms were investigated in ICR male mice under a 12-h light/dark cycle (light on from 7:00 AM to 7:00 PM). There was a significant 24-h rhythm in the latency of thermal response at 30 min after morphine injection. The analgesic effect was significantly greater at the dark phase than at the light phase. The rhythmic pattern resembled overall the rhythm occurring in the latency of thermal response under non-drugged state. The absolute value of morphine analgesic effect (the real time spent on the hot-plate) on days 1 and 2 after morphine daily injection was significantly larger after morphine injection at 9:00 PM than after saline injection at 9:00 PM or after morphine injection at 9:00 AM. The recovery from tolerance of analgesic effect was significantly faster at the dark phase than at the light phase. The time-dependent difference in the analgesic effect after chronic treatment or recovery from tolerance is closely related to that in the expression of mu-opioid receptor. The present study suggests that 24-h rhythm of morphine analgesic effect is consistent with 24-h rhythm of mu-opioid receptor expression.     

Chronopharmacological study of antidepressants in forced swimming test of mice

The influence of dosing time on the anti-immobility effect of antidepressants and mechanisms underlying this phenomenon were investigated in mice. In the forced swimming test (FST), the immobility time of mice treated with amitriptyline (15 mg/kg) and fluvoxamine (30 mg/kg) showed a significant 24-h rhythm. The anti-immobility effect of fluvoxamine in FST was potent at the early part of the dark phase without increasing locomotor activity. Concerning pharmacokinetics, although K(e) of fluvoxamine was approximately 1.3-fold higher in mice injected with fluvoxamine at 9:00 PM than at 9:00 AM, no dosing time dependence was demonstrated for either plasma or brain fluvoxamine concentration at 0.5 h after the drug injection. On the other hand, serotonin transporter (SERT) mRNA expression and 5-hydroxytryptamine (5-HT) uptake activity in the mouse midbrain showed significant time-dependent changes with higher levels during the dark phase and lower levels during the light phase. These results suggest that the reuptake of 5-HT might be more increased during the dark phase. Since the reuptake of 5-HT is inhibited almost completely by injection with 30 mg/kg fluvoxamine at any time, the extracellular 5-HT level may be more increased by the injection of fluvoxamine at the early part of the dark phase. The present results suggest that the anti-immobility effect of fluvoxamine in FST increases depending on dosing time. Furthermore, the time-dependent change of SERT mRNA expression and uptake activity in the midbrain is suggested to be the mechanism underlying the 24-h rhythm of anti-immobility effect of fluvoxamine.     

Altered diurnal rhythm of intestinal peptide transporter by fasting and its effects on the pharmacokinetics of ceftibuten

We previously demonstrated that H+/peptide cotransporter PEPT1 shows a diurnal rhythm in the rat small intestine. In the present study, we examined the effect of food intake on the diurnal rhythm of intestinal PEPT1 using fed and fasted rats and also determined whether such variation affected the pharmacokinetics of peptide-like drugs. In fed rats, PEPT1 protein level was significantly higher at 8:00 PM than at 8:00 AM. However, during fasting for 2 to 4 days, the differences of PEPT1 protein levels between 8:00 AM and 8:00 PM gradually disappeared. Intestinal absorption of an oral antibiotic ceftibuten (CETB), a pharmacological substrate for PEPT1, was also greater at 8:00 PM than at 8:00 AM in fed rats, but not different in 4-day fasted rats. In contrast to PEPT1 protein levels, PEPT1 mRNA levels retained a diurnal rhythm after 4 days of fasting. Pharmacokinetic analyses of CETB after intraintestinal administration demonstrated that both Cmax and area under the plasma concentration-time curve from 0 to 3 h were greater at 8:00 PM than at 8:00 AM in fed rats. In contrast, pharmacokinetic parameters showed no significant difference between 8:00 AM and 8:00 PM for intraintestinal administration in 4-day fasted rats and for intravenous administration in fed and 4-day fasted rats. These findings suggested that the diurnal rhythm of intestinal PEPT1 transport activity was disrupted by fasting and that diurnal variation of intestinal PEPT1 functionality could influence the pharmacokinetics of peptide-like drugs such as CETB.     

Comparison of RR-interval scaling exponents derived from long and short segments at different wake periods

Heartbeat fluctuations show fractal-like correlations that are associated with highly adaptive cardiovascular regulatory systems. Moreover, the short-range fractal or scaling exponent alpha(1) extracted from these correlations has been found to be a predictor of mortality for subjects with an impaired left ventricular function. In general, the RR-interval data required for this analysis are derived from long-term ECG recordings during free-running conditions. Yet short-term recordings are more likely to be obtained in some practical circumstances, so becoming relevant to assess the possibility of obtaining representative alpha(1) exponents from these recordings. Here, we compare the alpha(1) exponents extracted from the RR-interval series (9:00 AM-6:00 PM) of 51 healthy adults in normal sinus rhythm and the alpha(1) calculated from three shorted segments of only 700 beats obtained from the same series at 9:00 AM, 1:30 PM and 5:00 PM. We found no significant differences between the scaling exponents derived from the whole 9 h series and the short segments at 9:00 AM and 5:00 PM, but did find significant differences when comparing the whole series with the short segment at 1:30 PM. Thus, only if the time of day is taken into consideration can short segments of heartbeat fluctuation data be used to obtain representative alpha(1) exponents.     

Role of adenosine and N-methyl-D-aspartate receptors in mediating haloperidol-induced gene expression and catalepsy.

Acute blockade of dopamine D(2) receptors by the typical antipsychotic drug haloperidol leads to alterations in neuronal gene expression and behavior. In the dorsolateral striatum, the levels of mRNA for the immediate-early gene c-fos and the neuropeptide gene neurotensin/neuromedin N (NT/N) are significantly increased by haloperidol. An acute behavioral response to haloperidol is catalepsy, considered to be a rodent correlate of some of the immediate extrapyramidal motor side effects seen in humans. Several lines of evidence suggest a link between neurotensin induction in the dorsolateral striatum and catalepsy. We hypothesize that both striatal gene induction and catalepsy elicited by haloperidol arise from the combined effect of excitatory adenosinergic and glutamatergic inputs acting at adenosine A(2A) and N-methyl-D-aspartate (NMDA) receptors, respectively. In agreement with our previous reports, adenosine antagonists reduced haloperidol-induced c-fos and neurotensin gene expression as well as catalepsy. In agreement with other reports, the noncompetitive NMDA receptor antagonist MK-801 also reduced gene expression and catalepsy in response to haloperidol. The competitive NMDA receptor antagonist LY235959 decreased haloperidol-induced catalepsy. We show here that blocking both A(2A) and NMDA receptors simultaneously in conjunction with haloperidol resulted in a combined effect on gene expression and behavior that was greater than that for block of either receptor alone. Both c-fos and NT/N mRNA levels were reduced, and catalepsy was completely abolished. These results indicate that the haloperidol-induced increases in c-fos and NT gene expression in the dorsolateral striatum and catalepsy are driven largely by adenosine and glutamatergic inputs acting at A(2A) and NMDA receptors.     

Optimizing the dosing schedule of TNP-470 [O-(chloroacetyl-carbamoyl) fumagillol] enhances its antitumor and antiangiogenic efficacies

Many drugs vary in potency and/or toxicity according to the time of day when they are administered. In this study, we investigated whether antitumor efficacy of angiogenesis inhibitor, TNP-470 [O-(chloroacetyl-carbamoyl) fumagillol], could be improved by optimizing the dosing schedule. Tumor-bearing mice were housed under standardized light/dark cycle conditions (lights on at 7:00 AM, off at 7:00 PM) with food and water ad libitum. The antitumor effect of TNP-470 (30 mg/kg s.c.) was more potent in mice injected with the drug at the early light phase than it was when administered at the early dark phase. The diurnal change in the antitumor effect of TNP-470 was parallel to that in its antiangiogenic activity. The variation in the effects of TNP-470 was closely related to the diurnal variations in its inhibitory action on methionine aminopeptidase activity in tumor masses. There was a significant dosing time-dependent change in the concentration of TNP-470 in plasma. The higher concentration of TNP-470 in plasma was observed when its antitumor and antiangiogenic activities were increased. These results suggest that therapeutic efficacy of TNP-470 can be enhanced by choosing the most appropriate time of day to administer the drug.     

Time-dependent changes in receptor/G-protein coupling in rat brain following chronic monoamine transporter blockade

The potent tropane analog, WF-23 [2beta-propanoyl-3beta-(2-naphthyl) tropane], blocks dopamine, serotonin, and norepinephrine transporters with high affinity in vitro and blocks transporters for at least 2 days following a single in vivo administration. Previous studies demonstrated desensitization of monoamine receptor-coupled G-proteins in brain following chronic treatment of rats with WF-23. The current study sought to determine the time course of this desensitization and the behavioral effects of receptor desensitization. Rats were treated with 1 mg/kg WF-23 and injected i.p. every 48 h for 1 to 21 days. Receptor activation of G-proteins was determined by guanosine 5'-O-(3-[(35)S]thiotriphosphate) ([(35)S]GTPgammaS) binding in brain sections for monoamine receptors, as well as mu opioid receptors as a nonmonoamine receptor control. Chronic treatment with WF-23 produced significant reductions in D(2), 5-hydroxytryptamine 1A, and alpha(2)-adrenergic receptor-stimulated [(35)S]GTPgammaS binding; however, the time course of desensitization varied with different receptors. There was no effect of WF-23 treatment on mu opioid-stimulated [(35)S]GTPgammaS binding at any time point. Consistent with previous studies, there was no effect of WF-23 treatment on D(2) receptor binding, as determined by [(3)H]spiperone autoradiography. Locomotor activity was significantly increased for up to 48 h following acute administration of WF-23, demonstrated by increased photocell beam interruptions. WF-23-induced increases in locomotor activity occurred following repeated administration, as above, for up to 7 days. Following 7 days of treatment, there was a significant decrease in WF-23-increased locomotor activity. This reduction occurred at the same time point as the decrease in D(2) receptor/G-protein coupling, suggesting a role of D(2) desensitization in producing tolerance to WF-23-mediated behavior.     

Loratadine versus cetirizine: assessment of somnolence and motivation during the workday

OBJECTIVE: This parallel-group, double-blind study compared the somnolence and motivation profiles of 2 second-generation antihistamines, loratadine and cetirizine, in patients with allergic rhinitis. BACKGROUND: Second-generation antihistamines were developed to provide symptomatic relief from allergic disorders without the unwanted side effects of first-generation antihistamines, including somnolence. Recent research has indicated that not all second-generation antihistamines are comparable with respect to somnolence and other cognitive processes. METHODS: Patients aged > or = 12 years and actively exhibiting symptoms of allergic rhinitis were randomized to 2 treatment groups to receive 10 mg loratadine or 10 mg cetirizine daily at 8:00 AM for 1 week. After patients took the medication, their somnolence and degree of motivation to perform activities were recorded in an electronic diary using a visual analog scale 4 times during the workday (8:00 AM, 10:00 AM, noon, and 3:00 PM). RESULTS: Sixty patients (31 men, 29 women) were randomized to treatment. Somnolence scores were similar for both groups at baseline and at the time of dosing (8:00 AM). However, there was a statistically significant difference in somnolence scores between the loratadine and cetirizine groups at 10:00 AM (P = 0.008), noon (P = 0.001), and 3:00 PM (P < 0.001), with the cetirizine group showing a greater degree of somnolence. The scores on motivation to perform activities were similar for both groups at the baseline and 8:00-AM measurements. In parallel with the somnolence scores, there were statistically significant differences in motivation scores between the loratadine and cetirizine groups at 10:00 AM (P = 0.014), noon (P = 0.001), and 3:00 PM (P < 0.001), indicating that patients taking loratadine were relatively more motivated during the workday. CONCLUSION: The results of this study demonstrate that in patients aged > or = 12 years who had allergic rhinitis, cetirizine use promoted somnolence and decreased motivation to perform activities during the workday compared with loratadine.     

Chronotherapy of high-dose 1,25-dihydroxyvitamin D3 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 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. 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. 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. 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.     

Circadian patterns of emergency asthma presentations: implications for staffing and treatment

Are there circadian patterns for time of presentation and clinical status in asthmatic patients admitted to an emergency department for acute exacerbations? DESIGN: Prospective observational study. SETTING: Urban community teaching hospital emergency department. PARTICIPANTS: 279 consecutive patients who presented a total of 310 times with asthma exacerbations between October 19 and December 31, 1993. We grouped patients aged 16 years and above as adults and patients younger than 16 years of age as children. INFORMATION COLLECTED: Time of emergency department presentation, time attack began (for adult patients), peak expiratory flowrate prior to emergency department treatment (for adult patients), need for hospital admission, ventilatory failure during an acute attack, and death during an acute attack. RESULTS: Circadian patterns were demonstrated for time of presentation. For the total study group, the peak time of presentation was 8:00 PM to 11:59 PM (p < 0.05) and the trough time of presentation was 4:00 AM to 7:59 AM (p < 0.01). There were differences in peak time of presentation for patients grouped by age. For adult patients only, the peak time of presentation was 8:00 AM to 11:59 AM (p < 0.01), whereas for children only, the peak time of presentation was 8:00 PM to 11:59 PM (p < 0.001). No statistically significant patterns in time of attack onset, hospital admission rates, or peak flow measurements were observed. CONCLUSIONS: There are circadian patterns for the time at which patients with acute asthmatic exacerbations present to our emergency department. Adult patients have a peak time of presentation between 8:00 AM and 11:59 AM, whereas children have an apparent peak time of presentation between 8:00 PM and 11:59 PM. For all age groups, there is a trough in presentation between 4:00 AM and 7:59 AM.     

Chronokinetics of Pravastatin Administered in the PM Compared with AM Dosing

Pravastatin, an HMG CoA reductase inhibitor used in the treatment of hypercholesterolemia, is recommended for bedtime (PM) dosing. Bedtime dosing with pravastatin is slightly more efficacious but not significantly different than morning (AM) dosing in lowering LDL-C and total cholesterol. The pharmacokinetics of pravastatin and its major metabolite SQ 31,906 were determined in 20 healthy men administered a single 20-mg dose either in the morning or at bedtime in an open, randomized, crossover study. Concentrations of pravastatin and SQ 31,906 were measured in serum and urine by gas chromatograph/mass spectrometry methodology. The area under the serum concentration time curve (AUC) of pravastatin was significantly less (40%) following PM dosing compared with AM dosing. Urinary excretion of pravastatin following PM dosing was also significantly decreased. Bioavailability of SQ 31,906 was somewhat higher in the PM group (20% greater following PM administration), and urinary excretion of SQ 31,906 was significantly increased by 60% following PM dosing. The lower AUC of pravastatin following PM dosing does not diminish its efficacy, possibly because PM dosing immediately precedes the diurnal peak period of hepatic cholesterol synthesis. Lower blood levels of pravastatin following PM dosing may contribute to its favorable safety profile.     

Long-term pharmacokinetics of an extract of isoflavones from red clover (Trifolium pratense)

OBJECTIVES: To study the pharmacokinetics of isoflavones from red clover (Trifolium pratense) after long-term administration as a once-daily dietary supplementary. DESIGN: Fourteen (14) subjects who had been consuming a low-isoflavone diet for 2 weeks were given an oral dose of two isoflavone tablets (approximately 80 mg of total isoflavones) daily for 2 weeks and appeared for a study day at 9:00 AM after an overnight fast on the day that they were to receive the last dose. Plasma samples were collected for a 48-hour period after the last dose. Plasma isoflavones were assayed by high-performance liquid chromatography (HPLC). RESULTS: Trough plasma levels were significantly higher for daidzein and genistein after long-term dosing than levels taken prior to the commencement of the study and plasma levels of isoflavones after long-term dosing were in the range previously reported in populations that consume an isoflavone-rich diet. The plasma half-lives observed after long-term administration were, in most cases, consistent with once-daily administration. CONCLUSIONS: Isoflavones have pharmacokinetic characteristics that suggest that once-daily administration is adequate when they are administered long-term as dietary supplements.     

Acute and subchronic effects of MJ-13859, a potential antipsychotic drug, on rat brain dopaminergic function

The potential antipsychotic drug, MJ-13859, was tested for its acute and subchronic effects on rat brain dopaminergic neurotransmission and function. This drug exhibited an IC50 for displacement of [3H]spiperone binding of 6.35 nM which was similar to trifluoperazine, a potent classical antipsychotic drug. In female rats, MJ-13859 was slightly less potent than trifluoperazine for induction of catalepsy, inhibition of stimulant-induced hyperactivity and for increasing striatal, frontal cortical and olfactory tubercule dopamine metabolism. Both drugs also blocked dopamine autoreceptors on striatal dopamine nerve endings. When administered i.p., rather than s.c., the effect of MJ-13859 on dopamine metabolism was reduced significantly. When administered to male rats, the response of dopamine metabolism to drug was reduced, but a similar inhibition of stimulated activity occurred as in female rats. These results suggest a rapid first pass metabolism of MJ-13859 in the rat and that the antistimulant effect may be partly independent of the antidopaminergic effects. Osmotic minipumps were implanted s.c. for 2 week continuous infusion of MJ-13859 at doses of 1.0 or 3.0 mg/kg/day. Unlike classical antipsychotic drugs, MJ-13859 did not cause a subsensitivity to the ability of acute haloperidol challenge (0.1 mg/kg s.c.) to increase dopamine metabolism. After allowing a 4-day drug washout period before [3H]spiperone binding assay for D2 receptors, neither the maximum binding nor Kd were altered in rats treated for 2 weeks with 3.0 mg/kg/day of MJ-13859. Haloperidol at 1.0 mg/kg/day for 2 weeks caused a 57% increase in D2 receptor maximum binding.(ABSTRACT TRUNCATED AT 250 WORDS)     

The dopamine D3/D2 agonist (+)-PD-128,907 [(R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol)] protects against acute and cocaine-kindled seizures in mice: further evidence for the involvement of D3 receptors

Previous findings have demonstrated a protective role for dopamine D(3)/D(2) receptor agonists in the convulsant and lethal effects of acutely administered cocaine. Data are provided here to establish that the protection occurs through a D(3)-linked mechanism and that protection is extended to seizure kindling. The D(3) antagonist SB-277011-A [4-quinolinecarboxamide,N-[trans-4-[2-(6-cyano-3,4-dihydro-2(1H)-isoquinolinyl)ethyl]-cyclohexyl]-(9CI)] prevented the anticonvulsant effect of the D(3)/D(2) receptor agonist (+)-PD-128,907 [(R-(+)-trans-3,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-ol)] on cocaine-induced seizures. The protection afforded by the D(3)/D(2) agonist, (+)-PD-128,907, was eliminated in D(3) receptor-deficient mice. In D(2) receptor knockout mice, the anticonvulsant effects of (+)-PD-128,907 were preserved. (+)-PD-128,907 also prevented the acquisition and expression of cocaine-kindled seizures engendered by repeated daily dosing with 60 mg/kg cocaine. (+)-PD-128,907 also blocked the seizures induced in mice fully seizure kindled to cocaine. Although repeated dosing with cocaine increased the potency of cocaine to produce seizures and lethality (decreased ED(50) values), daily coadministration of (+)-PD-128,907 significantly prevented this potency shift. In mice treated daily with cocaine and (+)-PD-128,907, the density, but not the affinity, of D(3) receptors was increased. The specificity with which (+)-PD-128,907 acts upon this cocaine-driven process was demonstrated by the lack of a significant effect of (+)-PD-128,907 on seizure kindling to a GABA(A) receptor antagonist, pentylenetetrazol. Taken together and with literature findings, the data indicate that dopamine D(3) receptors function in the initiation of a dampening mechanism against the toxic effects of cocaine, a finding that might have relevance to psychiatric disorders of drug dependence, schizophrenia, and bipolar depression.     

Effects of sotalol on ambulatory electrocardiography in volunteers

The effects of sotalol dosing, 160, 240, and 320 mg/day, for 10 days in seven healthy volunteers were studied. Twenty-four-hour ECG was recorded continuously under placebo and on days 2, 4, 6, 8, 10, 11, 13, and 14. Sotalol at the three doses significantly lowered mean heart rate, reducing mean diurnal heart rate significantly between noon and 6:00 PM and decreasing mean nocturnal heart rate between midnight and 6:00 AM at 320 mg/day. Although there was no change in plasma sotalol between days 4 and 10, at high doses a significant decrease in bradycardiac effect occurred. PR intervals and QTc intervals were lengthened at all doses during the daytime. At the highest dose, the PR interval was lengthened during the nighttime.     

Are daytime arterial blood gases a good reflection of nighttime gas exchange in patients on long-term oxygen therapy?

OBJECTIVE: Compare nighttime and daytime arterial blood gas values in patients undergoing long-term oxygen therapy (LTOT). METHODS: We studied 39 LTOT patients with chronic airflow limitation. Oxygen from an oxygen concentrator was administered via nasal prongs until daytime blood oxygen saturation (measured via pulse oximetry [S(pO2)]) was > or = 90%. Arterial blood samples were drawn at 6:00 PM, while the subject breathed room air, and also during oxygen administration at night (3:00 AM), early in the morning (7:00 AM), and at noon. S(pO2) was measured throughout the night. RESULTS: Mean patient age was 70 +/- 7 yr. All patients suffered severe chronic airflow limitation (mean forced expiratory volume in the first second 28 +/- 9% of predicted). The mean oxygen flow administered was 1.41 +/- 0.6 L/min. Mean overnight S(pO2) was 92 +/- 2.5%, with 21.5 +/- 28% of recording time under 90%. There were statistically significant differences between P(aO2), P(aCO2), and pH obtained at 3:00 AM and noon and between 7:00 AM and noon, while the patients breathed the same oxygen concentration. The differences between the 3:00 and 7:00 AM values were not significant. In 23 patients (59%) we observed a P(aCO2) increase > 10 mm Hg and/or a pH decrease to < 7.33 during that period, indicating poor response to LTOT. CONCLUSIONS: Daytime arterial blood gas measurements do not reflect nighttime gas exchange. However, samples taken early in the morning (7:00 AM) do seem to reflect arterial blood gases during the night and can therefore be used for setting and monitoring nighttime oxygen flow.     

Behavioral and neurochemical responses to haloperidol and SCH-23390 in rats treated neonatally or as adults with 6-hydroxydopamine

Behavioral and neurochemical effects of haloperidol (D2-dopamine antagonist) and SCH-23390 (D1-dopamine antagonist) were examined in unlesioned rats and in rats lesioned with 6-hydroxy-dopamine (6-OHDA) as adults or as neonates. In unlesioned rats, chronic haloperidol treatment (15 days) resulted in an increase in D2-dopamine receptor density, as measured with [3H]spiperone, in the nucleus accumbens and in the caudate-putamen. Rats treated as adults with 6-OHDA responded to chronic haloperidol similarly to controls. However, adult rats treated with 6-OHDA as neonates did not exhibit an increase in [3H]spiperone binding in response to chronic haloperidol treatment. Control and adult 6-OHDA-treated rats given haloperidol exhibited a profound akinesia. In contrast, rats that received 6-OHDA as neonates and were tested as adults did not display a significant behavioral response to haloperidol at doses as high as 2 mg/kg. Results similar to those for haloperidol were also found for SCH-23390. Chronic treatment (15 days) with this D1-dopamine antagonist increased [3H]SCH-23390 binding in the nucleus accumbens and caudate-putamen in unlesioned rats as well as in adult 6-OHDA-treated rats. However, after neonatal 6-OHDA treatment, an elevation in [3H]SCH-23390 binding did not occur after chronic SCH-23390 treatment. SCH-23390 produced akinesia similar to that produced by haloperidol in unlesioned and in adult 6-OHDA-treated rats. In contrast, rats lesioned with 6-OHDA as neonates and tested as adults did not exhibit a significant behavioral response to SCH-23390 under our test conditions.(ABSTRACT TRUNCATED AT 250 WORDS)