Interaction between different extracts of Hypericum perforatum L. from Serbia and pentobarbital, diazepam and paracetamol.

Herb-drug interactions are an important safety concern and this study was conducted regarding the interaction between the natural top-selling antidepressant remedy Hypericum perforatum (Hypericaceae) and conventional drugs. This study examined the influence of acute pretreatment with different extracts of Hypericum perforatum from Serbia on pentobarbital-induced sleeping time, impairment of motor coordination caused by diazepam and paracetamol pharmacokinetics in mice. Ethanolic extract, aqueous extract, infusion, tablet and capsule of Hypericum perforatum were used in this experiment. The profile of Hypericum perforatum extracts as well as paracetamol plasma concentration was determined using RP-HPLC analysis. By quantitative HPLC analysis of active principles, it has been proven that Hypericum perforatum ethanolic extract has the largest content of naphtodianthrones: hypericin (57.77 µg/mL) and pseudohypericin (155.38 µg/mL). Pretreatment with ethanolic extract of Hypericum perforatum potentiated the hypnotic effect of pentobarbital and impairment of motor coordination caused by diazepam to the greatest extent and also increased paracetamol plasma concentration in comparison to the control group. These results were in correlation with naphtodianthrone concentrations. The obtained results have shown a considerable influence of Hypericum perforatum on pentobarbital and diazepam pharmacodynamics and paracetamol pharmacokinetics.

Population pharmacokinetics of pentobarbital in neonates, infants, and children after open heart surgery.

OBJECTIVES: To determine the pharmacokinetics of pentobarbital in neonates, infants, and young children with congenital heart disease after open-heart surgery. STUDY DESIGN: Thirty-five subjects (3.0 days-4.4 years) after open-heart surgery who received pentobarbital as standard of care were enrolled. Serial pharmacokinetic blood samples were obtained. A population-based, nonlinear mixed-effects modeling approach was used to characterize pentobarbital pharmacokinetics. RESULTS: A two-compartment model with weight as a co-variate allometrically expressed on clearance (CL), inter-compartmental clearance, central (V1) and peripheral volume of distributions, bypass grafting time as a co-variate on CL and V1, and age and ventricular physiology as co-variates on CL best described the pharmacokinetics. A typical infant (two-ventricle physiology, 6.9 kg, 5.2 months, and bypass grafting time of 60 minutes) had a CL of 0.12 L/hr/kg, V1 of 0.45 L/kg, and peripheral volume of distributions of 0.98 L/kg. The bypass grafting effect was poorly estimated. For subjects <12 months age, an age effect on CL remained after accounting for weight and was precisely estimated. CONCLUSIONS: Pentobarbital pharmacokinetics is influenced by age and weight. Subjects with single-ventricle physiology demonstrated a 15% decrease in clearance when compared with subjects with two-ventricle physiology.

Secondary pentobarbital poisoning in two dogs: a cautionary tale.

Two dogs, a 13-year-old spayed female and a 7-year-old neutered male, were diagnosed with pentobarbital poisoning. Follow-up investigation determined that the source of pentobarbital was the carcass of a horse that had been euthanized more than 2 years previously and that was also apparently responsible for the death of a least 1, and possibly 2, other dogs. The fact that the horse carcass remained lethally toxic more than 2 years after it was euthanized reemphasizes the necessity of proper disposal of euthanized animals.

Head injuries, pentobarbital, and the determination of death.

The Bexar County Medical Examiner's Office in San Antonio, Texas, has encountered 3 cases within a 15-month period involving decedents who were pronounced dead by brain death or cardiac death examination and who had elevated, if not toxic concentrations of pentobarbital present at the time of examination. The elevated levels of pentobarbital were discovered during an autopsy examination performed for medicolegal reasons. The diagnosis of brain death and the implications of pentobarbital intoxication during a brain death examination are discussed.

Deliberate Self-poisoning with a Lethal Dose of Pentobarbital with Confirmatory Serum Drug Concentrations: Survival After Cardiac Arrest with Supportive Care.

INTRODUCTION: Pentobarbital (PB) is a euthanasia drug in doses of 2 to 10 grams, causing death within 15-30 minutes. We report a case of recovery from lethal pentobarbital deliberate self-poisoning with confirmatory serum drug concentrations. CASE REPORT: A 45-year-old male purchased 20 grams of PB powder over the Internet. He ingested this powder and then alerted his mother 10 minutes later. She found him unresponsive and commenced cardiopulmonary resuscitation (CPR). Within 20 minutes of ingestion, emergency medical services arrived and initiated advanced life support. On arrival to the emergency department, heart rate was 116 bpm, BP 117/62 mmHg, on an epinephrine infusion. He was hypotonic and hypothermic, with absent brainstem reflexes. ECG and CT brain were normal. Activated charcoal was administered and he was admitted to ICU. He remained comatose with absent brainstem reflexes until day 5. Cerebral angiogram on day 3 was normal. Qualitative urine testing detected pentobarbital suggesting ongoing drug effects as the cause of coma. He was extubated on day 10, eventually making a full recovery. At 2.5 hours post-ingestion, PB concentration was 112 mg/L; PB peaked at 116 mg/L at 29 hours; PB was 2 mg/L at 190 hours and undetectable over 200 hours post-ingestion. DISCUSSION: Average PB concentration in fatalities is reported around 30 mg/L. This patient survived higher serum concentrations with early CPR and prolonged cardiorespiratory support in the ICU. Assessment of brainstem death should be deferred until PB has been adequately eliminated.

Suicide by Fatal Pentobarbital Intoxication in Ontario, Canada, from 2012 to 2015.

A fatal concentration of pentobarbital found in a coroner's case where the history had not indicated use of this drug prompted a review of fatalities in Ontario from 2012 to 2015. Coroner's case files, including police and toxicology reports, were reviewed in twenty deaths, in which pentobarbital was identified as the primary cause of death. In all of the deaths (11 females, 9 males), the blood concentration of pentobarbital was greater than 10 mg/L. There were three to eight deaths per year and each was classified as suicide. In 11 cases, there was clear evidence that the drug was purchased over the internet from Mexico or China and imported into Canada. In four cases, it appears that the pentobarbital was labeled as a different, innocuous chemical to facilitate crossing the border without scrutiny. The findings underscore the value of a thorough scene investigation, including details of evidence that may be considered unrelated.

Usefulness of serum concentration measurement for acute pentobarbital intoxication in patients.

Toxicokinetic parameters were analyzed in 25 patients who were acutely intoxicated with pentobarbital. The serum pentobarbital concentrations were at hypnotic / therapeutic levels (1- 10 microg/mL) in 11 patients, at toxic levels (10-24 microg/mL) in 10 patients, and at lethal levels (>24 microg/mL) in 4 patients. One fatal case was encountered with a serum pentobarbital concentration of 37.27 microg/ mL. The relationships between serum pentobarbital concentrations and the drug, the induced toxic symptoms, such as respiratory / cardiac depression and hypotension, were in good correlation. The therapy of direct hemoperfusion carried out for many pentobarbital-intoxicated patients was highly effective.

More reliable brain death diagnosis with chromatographic analysis of midazolam, diazepam, thiopentone, and active metabolites.

Brain death diagnosis may be confounded by centrally acting drugs. The certainty of brain death diagnosis can be enhanced by demonstrating that the concentrations of such drugs are well below the therapeutic range. A combined high-performance liquid chromatography-based method was developed for the benzodiazepines midazolam, 1-hydroxymidazolam, 1-hydroxymidazolam glucuronide, diazepam, and nordiazepam and for the barbiturates thiopentone and pentobarbitone in serum or plasma of critically ill patients. The lower limits of detection of the assays for benzodiazepines and barbiturates were 2.5 ng/mL and 0.05 microg/mL. The lower limits of the working ranges of these assays were set at 25 ng/mL and 0.5 microg/mL, respectively, and are below the lowest pharmacologically active plasma concentrations of these drugs. Intra- and interday coefficients of variations were less than 2.5% and 11.0% throughout, as determined with six replicates (n = 6). These assays were accurate in that the relative difference between actually measured and expected concentration never exceeded 12%. Utilization of these assays will render the diagnosis of brain death more reliable.

Physiological disposition of pentobarbital in tumor-bearing mice.

Pentobarbital depressed macromolecular synthesis in Ehrlich ascites cells in vitro, and this depression was proportional to a decrease in oxygen consumption. However, survival time of animals bearing Ehrlich ascites cells was unaffected by pentobarbital. The acute toxicity of the drug was greatly enhanced by the presence of the tumor. Sleeping time was prolonged in mice carrying the following tumors: Ehrlich ascites, Sarcoma 180 ascites, and Yancy plasma cell solid. Seven-day Ehrlich ascites tumor-bearing animals treated with pentobarbital slept about three times longer than normal mice, but both groups awoke at the same plasma levels of the unbound drug. The plasma half-life of unchanged pentobarbital was about four times as long in tumor-bearing mice as it was in controls. No qualitative difference in catabolism other than rate was detected. Renal excretion of unchanged pentobarbital in tumor-bearing animals was 50% of control animals during the first 4 hr. In tumor-bearing mice the sleeping time of the nonmetabo ble barbiturate, barbital, was identical with that in normal animals. These data suggest that the tumor affected mainly pentobarbital metabolism. Tumor-bearing mice still responded to the pharmacological challenge of phenobarbital with the apparent induction of drug metabolizing enzymes. The prolonged pentobarbital sleeping time in tumor-bearing mice required the development of some type of tumor-host relationship.

Pharmacokinetics of high-dose pentobarbital in severe head trauma.

High-dose pentobarbital infusion has been advocated as an effective adjunct in controlling persistent intracranial hypertension after severe head trauma in patients refractory to conventional therapy. Pentobarbital disposition was assessed in 10 adults with severe nonpenetrating head injury after an intravenous loading dose of sodium pentobarbital, 10 mg/kg, infused over 1 hour, followed by a continuous infusion at 0.5 to 3.0 mg/kg/hr provided the cerebral perfusion pressure remained greater than 50 torr. Pharmacokinetic parameters of volume of distribution at steady state (Vss), total body clearance (CL), and t1/2 for the patients with trauma were statistically compared with similar estimates reported for seven adult subjects without head injury. On discontinuation of the pentobarbital infusion, serum concentrations in the patients followed a monoexponential decline with a mean (+/- SD) t1/2 and Vss that were significantly less than values reported for the control subjects (15.6 +/- 3.9 vs. 22.3 +/- 4.0 hours and 44.0 +/- 11.7 vs. 63.4 +/- 15.2 L, respectively). However, there was no significant difference between the mean pentobarbital CL of the patients (2.0 +/- 0.7 L/hr) and the subjects (2.0 +/- 0.4 L/hr). To our knowledge this is the first report on the disposition, elimination, and intrasubject variability of high-dose pentobarbital infusion in adult patients with head trauma.

The effect of age on the plasma protein binding of pentobarbitone in the mouse. A brief note.

Old mice show an increased sensitivity to parenteral pentobarbitone compared with young adult mice, despite similar plasma concentrations of the drug. One factor may be an alteration in the binding of barbiturate to the plasma protein, perhaps consequent on reduced hepatic synthesis of plasma protein with advancing age. As part of a study of the effect of age upon the pharmacological and adaptive response to barbiturates, binding of pentobarbitone to plasma proteins from mice of different ages was measured by equilibrium dialysis in the presence of a standard concentration of the drug. The total plasma protein concentration was measured and found to be the same in both age groups. The plasma protein binding of pentobarbitone was found to correlate significantly with the plasma albumin concentration, which was lower in the older mice. However, there was no significant overall difference in pentobarbitone binding between old and young mice. Pretreatment of the mice with phenobarbitone for 21 days had no effect upon the capacity for plasma protein binding of pentobarbitone in either age group. Thus, it seems unlikely that the increased sensitivity of older mice to pentobarbitone can be explained in terms of altered plasma protein binding of the drug.

Barbiturate anesthesia in the treatment of status epilepticus: clinical experience with 14 patients.

We report our experience using barbiturate anesthesia for the treatment of refractory status epilepticus. Following a retrospective review of eight patients treated with a variety of barbiturates and dosing regimens, we established a specific protocol employing pentobarbital and evaluated it prospectively in six patients. Among the 14 patients, intravenous barbiturates, when administered with a loading dose followed by continuous infusion, were uniformly effective in aborting seizures and producing a burst-suppression EEG pattern. Other than the pupillary light reflex, most patients lost all brainstem reflexes and motor responses during therapy. Barbiturate-induced hypotension was observed in 9 of the 14 patients, and required treatment with pressors in seven cases. Three patients died early as a consequence of their underlying illness, while three others died late for reasons unrelated to the status itself or to anticonvulsant therapy. The time to recovery of function following anesthesia varied highly, spanning hours to days for return of motor function and days to weeks for cognition. Of the eight survivors, four were left with mild cognitive deficits, one returned to his baseline dementia, and three had residual encephalopathies (severe in two). We conclude that barbiturate anesthesia is an extremely effective therapy for refractory seizures. However, its use necessitates recognition of untoward cardiovascular responses and prolonged intensive care.

Biliary excretion of barbiturates.

1. Pentobarbitone and phenobarbitone are excreted into the bile of rats.2. The concentration of pentobarbitone and/or its metabolites in the bile is 22-fold higher than in the plasma; the concentration of phenobarbitone and/or its metabolites in bile is 10-fold higher than in the plasma.3. Probenecid decreases the excretion of the barbiturates into the bile.4. Twenty-eight per cent of a 35 mg/kg dose of pentobarbitone and 18% of a 75 mg/kg dose of phenobarbitone is excreted in the bile in 6 hours.5. Most of the pentobarbitone and phenobarbitone excreted into the bile is not in the form of the parent compound but rather as a more polar metabolite or metabolites.

Interactions of cholinesterase inhibitors and glucocorticoids with ketamine and pentobarbitone-induced general anaesthesia in the rat: possible effects on central cholinergic activity.

Doses of 100, 150 and 200 micrograms kg-1 of the cholinesterase inhibitor neostigmine reverse the anaesthetic action of ketamine. The antagonistic effect is increased as the dose is increased. The duration of anaesthesia induced by pentobarbitone is reversed by the cholinesterase inhibitor in doses of 150, 200 and 250 micrograms kg-1. Choline, in a dose of 50 mg kg-1, significantly antagonizes the action of the two anaesthetics, whereas hemicholinium-3, an inhibitor of the uptake of choline and the synthesis of acetylcholine, markedly potentiates their action. Dexamethasone induces a significant reduction of the duration of anaesthesia produced by ketamine and pentobarbitone. The potentiation of the anaesthetic effect caused by hemicholinium-3 is also reversed by dexamethasone. The acetylcholine content in rat cerebral cortex is increased after treatment with ketamine and pentobarbitone. Measurements of the course of the plasma level of pentobarbitone do not reveal alterations in the pharmacokinetic profile by either neostigmine or dexamethasone. These results indicate that central cholinergic systems may somehow be involved in the anaesthesia induced by ketamine and pentobarbitone and that the interactions described in this paper may be the result of modification by neostigmine and dexamethasone of the alterations in cholinergic activity caused by the two anaesthetics.

The effects of pentobarbitone and chloralose anaesthesia on the vagal component of bronchoconstriction produced by histamine aerosol in the anaesthetized dog.

1 Total lung resistance (R(L)) and dynamic lung compliance (C(dyn)) were measured in dogs anaesthetized with pentobarbitone or chloralose and subjected to aerosols of histamine during 4 successive inspirations.2 Histamine caused concentration-dependent increases in R(L) and decreases in C(dyn). A significant vagal component was involved, but only when chloralose was employed and then only in the R(L) response.3 The resting values of R(L) and C(dyn) were similar regardless of which anaesthetic was used and remained essentially the same if the vagi were cooled.4 Electrical stimulation of the efferent vagi caused large increases in R(L) of dogs given chloralose and these effects were attenuated by the administration of pentobarbitone. Such stimulation was relatively ineffective in dogs given pentobarbitone alone.5In vitro, electrical field stimulation caused contractions of dog trachealis muscle. The responses were reduced by pentobarbitone in concentrations approximating to plasma levels in the anaesthetized dogs (1 to 5 x 10(-4) M), but the effects of exogenous acetylcholine were unaltered. The inhibition was dose-dependent, reversed by washing and unaltered by hexamethonium.6 The results suggest that pentobarbitone inhibits the vagal component of histamine-induced bronchoconstriction in the dog by an action on the efferent pathway. Furthermore, pentobarbitone acts either by blocking transmission along postganglionic parasympathetic nerves or by preventing the release of acetylcholine from the nerve endings in the lung.

Effect of raphe lesions on the development of acute tolerance to ethanol and pentobarbital.

The effect of electrolytic lesions in the median and dorsal raphe nuclei was tested on acute tolerance development to ethanol and pentobarbital in the rat, as measured by motor impairment on the moving belt test. Acute tolerance to ethanol (1.7 g/kg, IP) or pentobarbital (17.5 mg/kg, IP) was monitored at 12.5, 25, or 50 min in separate subgroups tested only once each. One week of recovery was allowed between ethanol and pentobarbital tests. Median raphe lesions delayed the development of acute tolerance, whereas dorsal raphe lesions produced a negligible effect. These results were seen with both ethanol and pentobarbital. The mesolimbic 5-HT pathway from the median raphe nucleus is important in the development of acute tolerance to ethanol and pentobarbital, as was shown to be the case previously for chronic tolerance.

Use of simple tasks to test for impairment of complex skills by a sedative.

Examination of the effect of three doses of pentobarbital on the comparative performance of a complex psychomotor task with two simple neuromotor tasks, i. e., standing steady and pendulum eye tracking, revealed a high correlation. These simple tasks could be used as measures of intoxication since they do not require extensive training. Examination of the complex task impairment blood level ratio revealed that impairment relative to blood level was much greater in the absorption phase. This changing ratio underscores the point that blood levels alone are not an adequate estimate of intoxication.

Differential sensitivity to ethanol, pentobarbital, and barbital in spontaneously hypertensive and normotensive Wistar-Kyoto rats.

Ethanol, pentobarbital, and barbital sleep times and blood levels on awakening were determined in female spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WK) rats. Ethanol-induced sleep times were significantly longer for SH than for WK and blood ethanol concentrations on awakening were significantly lower in SH than in WK rats. By contrast, pentobarbital and barbital sleep times for SH rats were significantly less than for WK rats and barbiturate blood levels at awakening were significantly higher in SH than in WK rats. No differences were observed between SH and WK rats with respect to the disappearance of ethanol, pentobarbital, and barbital from blood and in the apparent volume of distribution of these drugs. These observations suggest differential CNS sensitivity of the SH and WK rats to ethanol and barbiturates and provide additional support for the notion that there exist differences in the modes of acute action of these drugs.

Effect of raphe lesions on the development of chronic tolerance to pentobarbital and cross-tolerance to ethanol.

Sham and electrolytic lesions of the dorsal, median, and median + dorsal raphe nuclei were made in different groups of rats, and the differential patterns of regional 5-HT depletion were verified chemically. One week later, an initial dose-response curve for the motor impairment effect (moving belt test) of pentobarbital was obtained. Matched subgroups of the animals in each lesioned group received daily gavage with either pentobarbital (50 mg/kg) or water for 36 days. Tolerance to the motor impairment effect of pentobarbital was measured at 4-day intervals. Lesions of the dorsal raphe nucleus had no influence on the development of tolerance, whereas median and median + dorsal raphe lesions resulted in slower development of tolerance, though plasma pentobarbital levels were unaltered. The effect of the combined lesion was similar to that of the median raphe lesion alone. A separate study revealed a similar differential effect of median versus dorsal raphe lesions on the development of cross-tolerance to ethanol.

Factors involved in the differential response to ethanol, barbital and pentobarbital in rats selectively bred for ethanol sensitivity.

Two lines of rats, 'least affected' (LA) and 'most affected' (MA), had been selectively bred for their differential sensitivity to ethanol. Both males and females of the LA strain were observed to be less sensitive than their MA counterparts to the acute hypnotic and motor-impairing effects of ethanol. However, a lower ethanol metabolic rate of the MA males suggests that both CNS and metabolic factors contribute to their enhanced sensitivity to ethanol. By contrast, no differences were observed between the LA and MA males with respect to the hypnotic and subhypnotic effects of pentobarbital or to the clearance of this drug. MA females were more sensitive only to the hypnotic effects of pentobarbital, probably because of a smaller apparent volume of distribution. No strain difference was observed in the hypnotic effect or clearance of barbital. These observations suggest that, in spite of a differential sensitivity to ethanol, the LA and MA lines do not differ in their response to the barbiturates tested.