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At least 19 recordsLinked to original sources
PubMed1998

Rapid simultaneous capillary electrophoretic determination of (R)- and (S)-secobarbital from serum and prediction of hydroxypropyl-gamma-cyclodextrin-secobarbital stereoselective interaction using molecular mechanics simulation.

Secobarbital is a hypnotic sedative that is used in the treatment of preoperative anxiety and to manage elevated intracranial pressures and cerebral ischemia due to neurosurgical procedures. Stereoselective resolution is first predicted using hydroxypropyl-gamma-cyclodextrin (HPGCD)-(R)- and (S)-secobarbital transient complex energy calculations using SYBYL 6.01 molecular modeling software. Separation is accomplished as predicted using 40 mM HPGCD in 50 mM phosphate buffer (pH 9.0), resulting in a rapid, sensitive method for the determination of (S)- and (R)-enantiomers of secobarbital from serum using solid-phase extraction, capillary electrophoresis (CE), and ultraviolet detection. The method involves extraction of both enantiomers and the internal standard, aprobarbital, from serum using C18 Bond-Elut solid-phase cartridges. The CE system consists of fused-silica capillary (52 cm x 75-microns i.d.) maintained at a run voltage of 15 kV with detection performed at a wavelength of 254 nm. The detection and quantitation limits from serum for (S)- and (R)-secobarbital are 1 microgram/mL. Linear calibration curves from 1 to 60 micrograms of both (S)- and (R)-secobarbital show a coefficient of determination of more than 0.999. The precision and accuracy of the method, calculated as relative standard deviation (%) and percent error, are 0.35-4.48% and 0.71-8.67%, respectively, for (R)-secobarbital and 0.39-4.08% and 2.16-3.70%, respectively, for (S)-secobarbital.

Circadian Rhythm↗
PubMed2000

13C4-secobarbital as the internal standard for the quantitative determination of secobarbital--a critical evaluation

In this study, 13C4-secobarbital was used as an exemplar compound to illustrate the mechanism based on which the effectiveness of a proposed internal standard (IS) could be evaluated. A deuterated analog, 2H5-secobarbital, was also studied in parallel for comparison purposes. Well-established solid-phase extraction and methylation procedures were used prior to the GC/MS measurement step. The contribution of the intensity of an ion designated for the analyte (secobarbital) by the proposed IS, and similarly, the contribution of the intensity of an ion designated for the IS by the analyte--a phenomenon termed "cross-contribution"-were evaluated based on a "direct measurement" procedure in which equimolar amounts of the analyte and the IS were used to generate intensity data. These intensity data were then used as the basis for the calculation of "cross-contribution" (in percentages) of ions designated for the analyte and the IS. Cross-contribution data were compared with the linearity data resulting from two series of standards containing 25 to 9600 ng/mL secobarbital using two sets of quantitation ion pairs--m/z 196/200 and 195/199 with 13C4-secobarbital as the IS and m/z 196/201 and 195/200 with 2HS-secobarbital as the IS. 13C4-secobarbital was found to be much less problematic and thus can serve as a very effective IS. Cross-contribution data alone cannot fully explain the observed differences resulting from the use of these two ISs; further systematic study is needed to provide better understanding of the underlying interference mechanism.

Journal Article↗
PubMed1983

Effect of the degradation of cytochrome P-450 heme by secobarbital on polychlorinated biphenyls (PCB)-induced hepatic vitamin A reduction and lipid peroxide formation in rats.

The present studies were conducted to characterize the relevance of a microsomal mixed function oxidase system to the polychlorinated biphenyls (PCB)-induced vitamin A reduction and endogenous lipid peroxide formation in the liver of rats. And also, this study dealt with an influence of scavengers on the hepatic lipid peroxide formation stimulated by PCB. Rats were given a 0.01% PCB diet supplemented with adequate nutrients, for 14 days. In an experiment, secobarbital was injected subcutaneously for the degradation of hepatic microsomal cytochrome P-450 heme. A marked liver enlargement and a significant increase of total liver lipid content were observed in the PCB group. The secobarbital enhanced the PCB-induced liver enlargement but no effect of secobarbital on the lipid content was recognized. PCB significantly induced hepatic microsomal cytochrome P-450, but not both cytochrome b5 and NADPH-cytochrome c reductase. The secobarbital suppressed the induction of cytochrome P-450 caused by PCB to approximately one-half. The hepatic vitamin A content significantly decreased on PCB administration and the secobarbital slightly enhanced the PCB-induced vitamin A reduction. However, the vitamin A content in the secobarbital-injected control group decreased to nearly the same levels as in the PCB groups. Therefore, it was presumed that the hepatic microsomal mixed function oxidase system, especially the cytochrome P-450, was possibly not directly involved in the PCB-induced hepatic vitamin A reduction or that a metabolic system related to mixed function oxidase system was involved in the reduction. On the other hand, the hepatic lipid peroxide content tended to increase on PCB administration though no significant difference was recognized. In contrast, the hepatic lipid peroxide content significantly increased in the secobarbital-injected PCB group as compared with the secobarbital-injected control group. However, there was no difference in the lipid peroxide contents between the control groups with and without the injection of secobarbital, and also between the PCB groups. The hepatic vitamin E contents lowered in the secobarbital-injected groups but no effect was observed on PCB administration. The glutathione peroxidase activity decreased significantly on PCB administration and the secobarbital further decreased the activity. Therefore, it was suggested that the significant increase and tendency of increase in hepatic lipid peroxide contents in the PCB groups with and without injection of secobarbital were ascribed to an insufficiency of lipid peroxide scavengers in the liver.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1982

Rectal absorption and disposition of secobarbital in epileptic children.

The absorption and disposition of rectally administered secobarbital was studied in ten epileptic children, ages 2-13 yrs. Five subjects received secobarbital rectally in solution, and the other five received secobarbital suppositories. Concentration of secobarbital in serum was serially determined during 48 hrs after a single rectal dose of about 5 mg/kg. The rate of absorption of secobarbital, as measured by the time to reach peak serum concentration, was much more rapid from the solution than the suppository (0.92 +/- 0.47 hr vs 4.60 +/ 2.30 hr). The peak serum concentration of secobarbital in the solution group was consistently higher than in the suppository group (2.26 +/- 0.37 micrograms/ml vs 1.35 +/- 0.24 microgram/ml). None of the individual peak serum concentrations exceeded 3 micrograms/ml, which is well below the previously reported minimum toxic concentration of secobarbital (ie, 6 microgram/ml). The elimination half-life of secobarbital varied over a wide range, from 2.7 to 13.5 hr, and is, on the average, shorter than estimates previously reported for adult volunteers or poly-drug abusers. Also, the mean elimination half-life did not differ between the solution and the suppository groups. The extent of rectal absorption of secobarbital, as assessed by the area under the serum concentration time curve, was not significantly different between the solution and the suppository treatments. If rectal secobarbital is considered for treatment of prolonged seizure, a rectal solution may offer a more rapid and consistent onset of action than with the suppository preparation.

Adolescent↗
PubMed1976

Influence of cannabidiol on secobarbital effects and plasma kinetics.

To investigate the possible metabolic interaction between cannabidiol (CBD) and secobarbital, 6 male volunteers received 150 mg/70 kg sodium secobarbital orally immediately after smoking a marihuana cigarette prepared to deliver 0, 150, or 500 mug/kg CBD. The study was performed in a double-blind manner with each of the three treatments being assigned to every subject. Clinical effects and plasma secobarbital concentrations were recorded at periodic intervals. CBD did not alter the summary parameters which describe the secobarbital plasma concentration time curve. Secobarbital half-life, peak concentration, time of peak concentration, and area under the curve were unchanged by the coadministration of CBD. Clinical effects of secobarbital were also unaltered by CBD pretreatment. Thus at the doses administered, CBD does not appear to inhibit secobarbital metabolism in man.

Adult↗
PubMed1991

Prolonged sedation associated with secobarbital in newborn infants receiving ventilatory support.

Newborn infants receiving ventilatory support often require sedation. Secobarbital is commonly used in these patients, but dosage guidelines to avoid prolonged sedation are not available. Seventeen infants (gestational age, 30 to 40 weeks; postnatal age, 0 to 3 days) with hyaline membrane disease or persistent pulmonary hypertension on mechanical ventilation were studied. These patients received secobarbital, 4 to 14 mg/kg/day intravenously for 1 to 10 days to produce sedation. Sedation was considered prolonged if it lasted more than 24 hours after the last dose. Nine of 17 infants experienced prolonged sedation. The mean daily secobarbital dose was 11.2 mg/kg/day in patients with prolonged sedation and 6.9 mg/kg/day in those patients without (p less than 0.05); the cumulative mean dose in the respective groups was 33.3 and 21.3 mg/kg (p less than 0.05). Four infants were sedated for 3 to 4 days after stopping secobarbital; the mean daily and cumulative dose was 13 mg/kg/day and 53 mg/kg in these patients. Duration of sedation was related to both daily and cumulative doses of secobarbital. Based on our results, the daily dose of secobarbital should not exceed 7 mg/kg/day to avoid prolonged sedation in infants. Frequent monitoring appears necessary to ensure efficacy with the lowest cumulative dose of secobarbital in newborn infants.

Humans↗
PubMed1993

Effect of secobarbital and morphine on arterial blood gases in healthy human volunteers.

Secobarbital is still widely used as a hypnotic and morphine as an analgesic perioperatively in surgical patients. Their combination is often used as a preanesthetic medication. Although their ventilatory depressant effect is recognized, the resulting blood gas changes have not been studied as yet adequately in a sufficiently large population of healthy volunteers. Therefore this study was undertaken. Thirty healthy volunteers who gave valid written consent were studied. Secobarbital 2.0 mg/kg intravenously caused a significant (P < .05) decrease in arterial oxygen pressure (PaO2), peaking at 10 minutes (n = 10; mean age, 23.4 years). Morphine, 0.2 mg/kg intravenously also caused a significant decrease in PaO2 at 5 minutes (n = 10; mean age, 26.3 years). The combination of the same doses of morphine and secobarbital caused a significantly (P < .01) greater decrease in PaO2 at 5 and 10 minutes than the sole administration of either drug (n = 10; mean age, 23.5 years). Arterial oxygen pressure remained significantly (P < .05) reduced for 30 minutes. Although the PaCO2 increases after secobarbital and morphine did not reach statistical significance, their combination caused a significant (P < .05) increase in PaCO2. Both secobarbital and morphine alone caused significant (P < .05) decrease in pHa at 30 minutes. Their combination caused a significant (P < .01) reduction in pHa from 5 minutes until 60 minutes. In conclusion, both secobarbital and morphine alone caused ventilatory depression. The duration of ventilatory depression was greater with the intravenous combination than with either drug alone.

Adult↗
PubMed1986

Behavioral effects of the isomers of pentobarbital and secobarbital in mice and rats.

To determine what stereoselective differences there may be in the behavioral effects of the isomers of pentobarbital and secobarbital, the effect of each isomer was determined on the spontaneous motor activity (SMA) and multiple fixed-ratio 30, fixed-interval 600-sec (mult FR30 FI600) responding of mice, and on the variable-interval 60-sec (VI60) responding of rats. The S-(-) isomers of pentobarbital and secobarbital decreased SMA at lower doses than those required for the R-(+) isomers. At moderate to high doses of R-(+)-pentobarbital (30-42.5 mg/kg) and low to moderate doses of S-(-)-secobarbital (5.6-17.5 mg/kg) SMA was increased. An increase in SMA following R-(+)-secobarbital was only observed at 30 mg/kg, and no increases were observed with S-(-)-pentobarbital. No potency differences were observed between the isomers of pentobarbital and secobarbital on the responding of mice under the mult FR30 FI600 schedule over a dose range of 1-30 mg/kg. Increases in FI600 responding were only observed following moderate doses of the S-(-) isomer of pentobarbital (5.6-17.5 mg/kg). In rats responding under the VI60 schedule of food presentation, no qualitative stereoselective differences were observed in the behavioral effects of the isomers of pentobarbital (1-13 mg/kg) and secobarbital (1-13 mg/kg), but small differences in potency were observed. Thus, differences in the effects of the isomers were usually restricted to differences in potency, but in some cases differences in efficacy were observed.

Animals↗
PubMed1989

Monologue speech: effects of d-amphetamine, secobarbital and diazepam.

Drugs of abuse from different pharmacological classes increase social conversation. Alcohol and d-amphetamine also increase rates of talking in subjects producing speech monologues in an isolated context. This latter finding suggests that the increases observed during dyadic social conversation may represent general increases in talking and not specific effects on social interaction. The present study was conducted to assess whether other abused drugs also increase monologue speaking. The acute effects of secobarbital (0, 50, 150, 250 mg), d-amphetamine (0, 25 mg) (Experiment 1), and diazepam (0, 10, 20, 40 mg) (Experiment 2) were investigated in healthy, adult volunteers. Secobarbital and d-amphetamine both increased the total amount of speech emitted, while diazepam generally had no effect or decreased talking. Experiment 3 was conducted to further compare the effects of secobarbital (0, 50, 150, 250 mg) and diazepam (0, 5, 15, 25 mg) using a within-subject, crossover design. Secobarbital increased talking in three of the four subjects studied, while diazepam, again, had no effect or decreased talking. In contrast to the differences noted with talking, secobarbital and diazepam both decreased response rates in a nonverbal performance task (i.e., circular-lights procedure); they also produced many similar effects on various subject-rated measures of drug effect. Thus, the differences in the effects of these two compounds on talking are not the result of a general difference in their overall profile of behavioral effects. In summary, the results obtained with secobarbital and d-amphetamine further demonstrate that an explicitly social context is not a necessary condition to observe drug-produced increases in speech quantity. The failure of diazepam to reliably increase talking in the present study illustrates the existence of some pharmacological specificity in the effect of drugs on human speech, and suggests another way in which the behavioral effects of the barbiturates and benzodiazepines may differ.

Administration, Oral↗
PubMed1988

Discriminative stimulus properties of the isomers of pentobarbital and secobarbital in pigeons.

To date there have been no reports on the discriminative stimulus properties of barbiturate isomers in laboratory animals or man in which the individual isomers were used in the development of the discrimination. To determine what stereospecificity might exist for the stimulus properties of barbiturate isomers, one group of pigeons was trained to discriminate 5 mg/kg of (S)-(-)-pentobarbital from saline and another group was trained to discriminate 8 mg/kg of (R)-(+)-pentobarbital from saline. After responding had stabilized, dose-response curves were determined in both groups for (S)-(-)-pentobarbital (0.3-10 mg/kg), (R)-(+)-pentobarbital (1-17.5 mg/kg), (S)-(-)-secobarbital (0.3-10 mg/kg), (R)-(+)-secobarbital (1-17.5 mg/kg), racemic Na.pentobarbital (1-17.5 mg/kg) and racemic Na.secobarbital (1-17.5 mg/kg). In both groups of pigeons, both isomers of pentobarbital and secobarbital, as well as racemic pentobarbital and racemic secobarbital, showed complete generalization to the training stimulus. For both pentobarbital and secobarbital, the S-(-) isomers showed generalization to the training drug at lower doses than the corresponding R-(+) isomers. No differences were observed in the dose-response curves for the racemic mixtures as a function of the training drug. Thus, no stereoselective differences other than potency could be demonstrated for the stimulus properties of the isomers of pentobarbital and secobarbital.

Animals↗
PubMed1976

Effectiveness of intermediate-term use of secobarbital.

Secobarbital, 100 mg, was evaluated in two separate sleep laboratory drug evaluation studies, each with 4 insomniac patients. In both studies, the effect of secobarbital in inducing and maintaining sleep was evaluated, as well as the effects of the drug on sleep stages. Statistical analysis demonstrated that the results of the two studies could be combined. With short-term drug administration of secobarbital (up to 3 nights), there was an improvement in both sleep induction and sleep maintenance. Total wake time was decreased 43% below baseline and was consistently decreased in each third of the night. With intermediate-term drug administration (2 wk), total wake time was decreased only 14% (not statistically significant). Following drug withdrawal, the degree of sleep difficulty returned to baseline levels. The results indicate that secobarbital 100 mg is effective for short-term use but loses much of its effectiveness with intermediate use and suggest that the drug is of limited value for insomniac patients who require nightly medication beyond a period of 1 wk. With short-term administration, secobarbital induced a slight decrease in rapid eye movement (REM) and slow-wave sleep and a significant increase in stage 2 sleep. With intermediate administration, sleep stage values were similar to baseline levels. Following withdrawal, there was only a minimal increase in REM sleep above baseline levels, a significant increase in stage 3 sleep, and a significant decrease in stage 2 sleep. The rebound increase in stage 3 sleep is similar to that reported following withdrawal of pentobarbital.

Adult↗
PubMed1983

Secobarbital effects on recall and recognition in a levels-of-processing paradigm.

Dose effects of secobarbital on free recall and recognition of words were examined in levels-of-processing paradigms. Secobarbital significantly impaired recall, even when initial item processing was guided with appropriate orienting tasks. However, when processing was guided both at input (with orienting tasks) and at retrieval (with recognition testing), secobarbital-related retention deficits reported in conventional 'learn these words' experiments were not found. Levels-of-processing theory suggests at least two possible mediators for retention deficits associated with drug intoxication, a production deficit at encoding or reduced processing capacity. Neither of these hypotheses can account for the data. A third hypothesis suggests that the intoxicated subject adopts a cautious response-decision strategy, thus failing to emit available items in recall testing or to endorse correct items on recognition. The results of signal detection analysis offered no support for this hypothesis. Considered together with earlier studies, the data indicate that when processing is guided only at retrieval, secobarbital produces both recall and recognition decrements. On the other hand, when processing is guided only at input, the drug produces recall deficits. Apparently, when secobarbital-intoxicated subjects are left to generate their own responses at retrieval, they fail to undertake optimal retrieval strategies. When their processing is guided both at input and retrieval, their drug-induced retention decrements can be corrected.

Adult↗
PubMed1984

Effects of acute and chronic exposure to secobarbital on the activity of hepatic synthesized clotting factors.

Male Sprague-Dawley rats were injected with either a single subcutaneous dose of 75 mg of secobarbital, or once daily injections of 20 mg of secobarbital for 7 days. Plasma was collected prior to treatment and 18 hours later (75 mg) or 8 and 15 days later (20 mg). Plasma was analyzed for the platelet count (PLT), prothrombin time (PT), fibrinogen (FIB), and coagulation factor activities for factors II, V, VII, IX, and X. Treatment with a single subcutaneous injection of 75 mg of secobarbital caused statistically significant alterations in every clotting activity measured whereas 7 days of treatment with 20 mg once daily resulted in only 2 clotting factors being abnormal. These two factors returned to pretreatment levels following 7 days of withdrawal of secobarbital. The data indicates that a single larger dose of secobarbital is more influential on hepatic synthesized clotting factor activity than is longer treatment with a lesser dose.

Animals↗
PubMed1980

Interaction of secobarbital with warfarin pseudoracemates.

To evaluate the interaction of secobarbital with racemic warfarin or R,S(+/-)-warfarin, S(-)-warfarin was synthesized with 13C-label in the 2-position of the coumarin nucleus and added to 12C-R(+)-warfarin to form a 12C-/13C-warfarin pseudoracemate. Six normal subjects received 1.5 mg/kg of this "cold-labeled" pseudoracemate. It was given with and without a daily oral dose of secobarbital, 100 mg, beginning 7 days before the warfarin and continuing throughout the hypoprothrombinemia. Plasma samples were obtained daily and analyzed for warfarin and for one-stage prothrombin activity. Unchanged warfarin in plasma was fractionated by forward-phase high-pressure liquid chromatography, and enantiomorphic ratios were determined by chemical ionization-mass spectrometry with pentadeuterio-warfarin as the internal standard. There was a reduction of the hypoprothrombinemia of the pseuoracemate during the secobarbital regimen over that on warfarin alone (p < 0.001). There was an increase in plasma clearance of R-warfarin (p < 0.05) and an increase in plasma clearance of S-warfarin (p < 0.003) during the secobarbital regimen over that on warfarin alone. It was concluded that secobarbital diminished the hypoprothrombinemia of pseudoracemic warfarin by increasing plasma clearance of the more hypoprothrombinemic S-warfarin and by increasing plasma clearance of the less hypoprothombinemic R-warfarin.

Absorption↗
PubMed1980

Inhibitory action of the combination of aminopyrine and secobarbital on EEG activation, neocortical recruiting and augmenting responses in rabbits.

The effect of the combination of aminopyrine and secobarbital at a molar ratio of 2:1, the mixture and molecular compound, on rabbit EEG activation was examined. Secobarbital 40 mg/kg p.o. elevated threshold voltages in the neocortical and hippocampal EEG activation by high frequency electrical stimulation of the midbrain reticular formation (MRF), nucleus centralis medialis (CM) of the thalamus, and posterior hypothalamus (PHA) by 40, 40 and 80% respectively. Aminopyrine 80 mg/kg p.o. alone did not affect the arousal responses. The molecular compound 120 mg/kg p.o. has more potent and long-lasting actions in inhibiting the arousal responses induced by the stimulation of MRF (80%) and CM (50%) than with secobarbital alone. The inhibitory action of the mixture 120 mg/kg p.o. on the PHA-arousal response (40%) was significantly weaker than that of the molecular compound (80%). Secobarbital and the molecular compound slightly inhibited the neocortical augmenting and recruiting responses. Our findings suggest that although aminopyrine exerts a synergistic effect with secobarbital in inhibiting the EEG activation produced by MRF stimulation, in inhibiting the PHA-arousal response, there is no synergistic effect of the two drugs when they were given as the mixture. Moreover, the molecular compound rather than the mixture has a more potent inhibitory action on the EEG activation, particularly with PHA stimulation.

Aminopyrine↗
PubMed1975

Pharmacokinetics of secobarbital in rabbit.

The pharmacokinetic study of secobarbital in the rabbit utilizing gas chromatography (GC) indicated a correlation between blood levels and brain tissue levels; and that the distribution of the drug appears to be more complex than a first order process is suggested by the compartmental simulation midel. The liver and kidney which eliminate the drug into bile and urine, respectively, tend to follow first order elimination kinetics more closely than those which act as depots for drug storage such as muscle and fat. The two dose levels of secobarbital indicate the same relationship with blood and tissues, therefore an increase or decrease in the dosage has no effect on the pharmacokinetics of secobarbital. The termination of action of secobarbital is due to the combination of rapid uptake by liver and its disposition there and a slower uptake by muscle. Computer simulation of secobarbital distribution has strongly suggested the elimination of this drug in bile and that the rebound rise in liver amy be due to enterohepatic circulation.

Adipose Tissue↗
PubMed1986

Stereoselective behavioral effects of the isomers of pentobarbital and secobarbital in the pigeon.

Little information is available on the contribution of the isomers of pentobarbital and secobarbital to the behavioral effects of the racemic mixtures. To determine the contribution of each isomer on food-maintained behavior, pigeons were trained to respond under either a multiple fixed-ratio 30, fixed-interval 600 (mult FR30 FI600) schedule, or a multiple fixed-ratio 30, variable-interval 60-sec (mult FR30 VI60) schedule under which every response under both the FR and VI components also produced a brief electrical shock (punishment). Dose-response curves were determined separately for each isomer of pentobarbital (1-17.5 mg/kg i.m.) and secobarbital (1-17.5 mg/kg i.m.). Under the mult FR30 FI600 schedule, the S-(-)-isomers of pentobarbital and secobarbital were slightly less than 2-fold more potent than the R-(+)-isomers, but both isomers produced qualitatively similar effects on responding. The S-(-)-isomers of both barbiturates produced increases in punished responding under the mult FR30 VI60 at lower doses than the R-(+)-isomers. At high doses (greater than 10 mg/kg), the S-(-)-isomers suppressed responding early in the session resulting in a lower average rate of punished responding for the session than the R-(+)-isomers. The peak increase in punished responding was observed after 10 mg/kg of the R-(+)-isomers of pentobarbital and secobarbital. These results indicate that the effect of the isomers of pentobarbital and secobarbital on mult FR30 FI600 responding and on suppressed responding are qualitatively similar.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗