Secobarbital Research Articles

Assessment of thiamylal sodium as a euthanasia drug in mice.

Euthanasia agents should rapidly induce death and loss of consciousness without causing pain or distress. Various methods exist for the euthanasia of laboratory animals, and injectable anesthetics, particularly barbiturate derivatives, are widely used due to the rapid onset of unconsciousness induced by these agents. Moreover, pharmaceutical-grade drugs should be used to eliminate undesirable side effects as much as possible. However, in Japan, the sale of pharmaceutical-grade pentobarbital sodium (PB) ended in 2019, and that of secobarbital sodium (SB) ended in 2023, leading to a demand for new pharmaceutical-grade injectable euthanasia drugs. This study evaluates thiamylal sodium (TM), a barbiturate derivative that is available domestically, as a euthanasia agent for mice. The results showed that when administered at dosages of 200 mg/kg or more, TM exhibited effects equivalent to those of PB and SB. In addition, the impact of TM administration on hematological characteristics was examined. In female mice administered TM, decreased blood chloride and calcium levels and increased aspartate aminotransferase and alanine aminotransferase levels, which are markers of liver damage, were observed. These findings suggest that high concentrations of TM may affect renal and liver function. This study revealed that TM is effective as a euthanasia agent at dosages of 200 mg/kg or more. However, considering the potential risks of renal and liver damage due to TM administration, it may be preferable to use alternative euthanasia drugs when these risks could affect the objectives or outcomes of the research.

Liquid chromatography-tandem mass spectrometry to determine sedative hypnotic drugs in river water and wastewater

A method for simultaneous determination of four benzodiazepines (bromazepam (BMZ), carbamazepine (CBZ), diazepam (DZP) and nordiazepam (NDZ)) and four barbiturates (barbital (BTL), pentobarbital (PTB), phenobarbital (PNB) and secobarbital (SCB)) in river water and wastewater using solid-phase extraction (SPE) followed by liquid chromatography-(electrospray) tandem mass spectrometry (LC-(ESI)MS/MS) was developed. LC-(ESI)MS/MS analysis was performed in positive and negative modes for benzodiazepines and barbiturates, respectively, and in selected reaction monitoring (SRM). Limits of detection (LODs) were in the range of 0.2–5 ng/L for benzodiazepines and 2.5–50 ng/L for barbiturates. Precision (repeatability and reproducibility between days) expressed as %RSD (n = 5) was lower than 17% for low concentration (depending on the matrix between 50 and 250 ng/L for barbiturates, and between 5 and 25 ng/L for benzodiazepines), and lower than 15% for high concentration (between 200 and 1250 ng/L for barbiturates, and between 20 and 125 ng/L for benzodiazepines). Low matrix effect was observed for all compounds, except for BTL (75%) and PTB (–48%) in wastewater. The method was applied to water samples from two sewage treatment plants (STPs) and the rivers Ebre, Ter and Llobregat, located in Catalonia. CBZ was the target compound found at the highest concentration in river water (2.1–3.3 ng/L). In both influent and effluent wastewater samples, PNB, BMZ, CBZ, DZP and NDZ were determined at concentration levels ranging from 5.0 to 2337.3 ng/L.

Secobarbital poisoning in an Amur tiger (Panthera tigris altaica)

THE Amur or Siberian tiger ( Panthera tigris altaica ) is one of six subspecies of tiger and is classified as critically endangered by the International Union for Conservation of Nature (IUCN 2008). Captive Amur tigers in European collections are bred in a coordinated manner under the auspices of a European Association of Zoos and Aquaria endangered species breeding programme to increase population numbers, maintain genetic diversity and reduce the risk of extinction. Modern zoo practice generally precludes the feeding of unsuitable or poor-quality food items to captive animals, but cases of barbiturate poisoning in carnivores have occurred on occasion when meat has been contaminated with veterinary barbiturates at the point of slaughter. A product containing a combination of 400 mg/kg cinchocaine hydrochloride and 25 mg/ml of the barbiturate secobarbital sodium (Somulose; Arnolds) is commonly used by veterinary surgeons for the euthanasia of large animals. Secobarbital was formerly known as quinalbarbitone in the UK. This short communication describes a case of secobarbital poisoning in a captive Amur tiger following the ingestion of potentially contaminated horse meat. The report highlights the importance of ensuring that chemically euthanased animals are not used for feed and reminds the wider veterinary profession of the potential risk of secondary barbiturate poisoning in wild, captive and domestic carnivores. A group of three adult female Amur tigers was kept in a large, wooded day enclosure, with separate indoor night quarters, in a safari park in the south of England. All three were fed horse meat on December 26, 2007, at 09.00. At 08.00 the following morning, one nine-year-old tiger was observed to be mildly ataxic and hyporesponsive to auditory and other stimuli. The other two tigers appeared unaffected and all three had been behaving normally during the preceding days. At 16.00 on December 27, the affected animal had become …

Membrane damage by bile salts: the protective function of phospholipids.

The direct toxicity of sodium deoxycholate (SDC) and lysophosphatidylcholine (LPC) to biological membranes was assessed by measurement of goldfish overturn time. When phosphatidylcholine (PC) was incorporated into the aqueous media, the toxicity of both SDC and LPC was reduced, as indicated by increased overturn time. Fish were also pretreated for various times in media containing (a) 1 mM SDC and (b) 1 mM SDC with 1 mM PC. Subsequent transfer to solution, 100 mg litre-1 quinalbarbitone sodium showed that reciprocal overturn times for fish treated using method (a) increased linearly with duration of pretreatment up to a limiting value, obtained after 20 min exposure; 40 min exposure to 1 mM SDC was directly toxic. Fish pretreated using regimen (b) survived longer when challenged with barbiturate, and the reciprocal overturn times were a linear function of time of pretreatment up to at least 40 min. PC also provided protection against membrane damage caused by the synthetic surfactant sodium dodecyl sulphate. Mixed micelle formation between PC and surfactant is thought to account for the protective effects. The results are of significance in the consideration of reflux hypothesis for the aetiology of gastric ulceration and also the possible formulation of drug delivery systems intended to enhance absorption whilst minimizing gastrointestinal damage.

Barbiturate Detection in Oral Fluid, Plasma, and Urine

Although current abuse of barbiturates is low compared with other classes of abused drugs, their narrow margin of safety, risk of dependence, and abuse liability remain a health concern. Limited information is available on the disposition of barbiturates in different biologic matrices. The authors conducted a clinical study of the disposition of barbiturates in oral fluid, plasma, and urine after single-dose administration to healthy subjects. Three parallel groups of 15 subjects were administered a single oral dose of one barbiturate: butalbital (50 mg), Phenobarbital (30 mg), or sodium secobarbital (100 mg). Subjects remained at the clinic for two confinement periods; the first was -1 to 36 hours postdose and again at 48 to 52 hours. Oral fluid specimens were collected by bilateral collection (Intercept; one on each side of the mouth simultaneously). Blood specimens were obtained by venipuncture and urine specimens were collected through separate collection pools of varying periods. Oral fluid specimens were analyzed for barbiturates by liquid chromatography-tandem mass spectroscopy with a limit of quantitation of 8 ng/mL. Plasma and urine specimens were analyzed by gas chromatography-mass spectroscopy with a limit of quantitation of 100 ng/mL. Barbiturate side effects included dizziness, drowsiness, and somnolence. All effects resolved spontaneously without medical intervention. The three barbiturates were detectable in oral fluid and plasma within 15 to 60 minutes of administration and in the first urine pooled collection at 2 hours. Butalbital and Phenobarbital remained detectable in all specimens through 48 to 52 hours, whereas secobarbital was frequently negative in the last collection. Oral fluid to plasma ratios appeared stable over the 1- to 48-hour collection period. This study demonstrated that single, oral therapeutic doses of butalbital, Phenobarbital, and secobarbital were excreted in readily detectable concentrations in oral fluid over a period of approximately 2 days. Oral fluid patterns of appearance and elimination were similar to that observed for plasma and urine.

Detector response and intensity cross-contribution as contributing factors to the observed non-linear calibration curves in mass spectrometric analysis

It is a common knowledge that detector fatigue causes a calibration curve to deviate from the preferred linear relationship at the higher concentration end. With the adaptation of an isotopically labeled analog of the analyte as the internal standard (IS), cross-contribution (CC) of the intensities monitored for the ions designating the analyte and the IS can also result in a non-linear relationship at both ends. A novel approach developed to assess 'the extent and the effect of [CC]… in quantitative GC-MS analysis' can be extended (a) to examine whether a specific set of CC values is accurate; and (b) to differentiate whether the observed non-linear calibration curve is caused by detector fatigue or the CC phenomenon. Data derived from the exemplar secobarbital (SB)/SB-d(5) system (as di-butyl-derivatives) are used to illustrate this novel approach. Comparing the non-linear nature of calibration data that are empirically observed to that derived from theoretical calculation (with the incorporation of adjustment resulting from the ion CC phenomenon), supports the conclusions that (a) both CC and detector fatigue contribute significantly to the observed non-linear nature of the calibration curve based on ion-pair m/z 207/212; and (b) detector fatigue is the dominating contributor when the calibration curve is based on ion-pair m/z 263/268.

Wada test using secobarbital sodium (Ional) to determine language dominance

The intracarotid sodium amobarbital (Amytal) test, the Wada test, remains an efficient test for evaluation of language and memory function. However, due to a world shortage of amobarbital, it has become necessary to investigate the use of alternatives. We report the efficacy of the Wada test using secobarbital sodium (Ional) in determining language dominance. An accurate determination of language dominance was required in 43 patients preoperatively at our institution. Patients underwent the Wada test using secobarbital sodium, effectiveness and safety were assessed. Patients were monitored for vital signs (blood pressure, respiratory rates, heart rates and saturation of oxygen). Ten patients were further monitored for continuous intra-arterial blood pressure and monitored with scalp electroencephalography (EEG). Language dominance was determined by the Wada test with secobarbital sodium in all patients. Total volume of secobarbital sodium injected was 10–25 mg (mean 16.5 ± 3.2 mg). Changes in vital signs were minimal and any induced neurological deficits completely disappeared within 8 min. On EEG records, induced theta waves immediately appeared on the ipsilateral side of the intra-arterial injection and disappeared within 6 min. One patient described a scintillating scotoma (sensation of shimmering light in his eyes) at the moment of injection; another experienced an epileptic episode during the test and recovered after 6 min. No adverse events were observed in the remaining 41 cases. We propose secobarbital sodium as a safe and reliable alternative to sodium amobarbital used in the Wada test to determine language dominance.

5-(1-Methylbutyl)-5-propenylbarbituric acid (quinal barbitone)

The title compound, C12H18N2O3, also known as quinal barbitone, crystallizes from aqueous solution in an anhydrous form, with one mol­ecule in the asymmetric unit. Inter­molecular N—H⋯O hydrogen bonding forms a one-dimensional tape structure.

Multimodal Inclusion Complexes Between Barbiturates and 2‐Hydroxypropyl‐β‐Cyclodextrin in Aqueous Solution: Isothermal Titration Microcalorimetry, 13C NMR Spectrometry, and Molecular Dynamics Simulation

Multiple types (structures) of inclusion complexes between barbiturates and 2‐hydroxypropyl‐β‐cyclodextrin (HPCD) were evaluated by isothermal titration microcalorimetry and 13C NMR spectroscopy. The geometries of the inclusion complexes were suggested by molecular dynamics simulation. Barbituric acid (BA), barbital (B), amobarbital (AB), pentobarbital (PB), secobarbital (SB), cyclobarbital (CB), and phenobarbital (PHB) were used as barbiturates with different substituents on the barbituric acid ring and compared for inclusion types in aqueous solution. The association constants (K), stoichiometries, and thermodynamic parameters change in free energy (ΔG) change in enthalpy (ΔH), and change in entropy [ΔS] for each type of complex were determined from the calorimetric data. The inclusion complexation was largely entropy driven because of hydrophobic interactions. The values of K increased in the order BA<B<AB<PB<SB<CB<PHB. Barbiturates, except B and BA, form two types of inclusion complex with a 1:1 stoichiometry in the un‐ionized forms. The first type of inclusion complex with high affinity (K1) was characterized by small negative values of ΔH1 and large positive ΔS1, where the substituent R2 of the barbiturate was initially inserted into the cavity of HPCD through hydrophobic interactions. There was a good relationship between ΔG1 obtained from the calorimetric data for the first type of inclusion complex and ΔGR2 calculated from the changes in 13C Nuclear Magnetic Resonance (NMR) chemical shifts for the substituent R2 of barbiturates. These types were very stable in aqueous solution at various pHs. The second type of complex, with low affinity (K2), was characterized by large negative values of ΔH2 and small positive ΔS2, reflecting van der Waals' interactions in the un‐ionized forms of barbiturates at pH values less than pKa. The values of K2 were markedly decreased to <103 M−1 as the barbiturates were ionized over pH 8. Thus, in the second type, the barbituric acid ring contributed to forming the complexes. The geometries were stabilized by hydrogen bond formation between the hetero atoms in the barbituric acid ring and the secondary hydroxyl groups on the rim of the cyclodextrin. The 13C NMR chemical shifts of C4 and C6 carbons in the barbituric acid ring were moved upfield significantly by the inclusion complexation. On the other hand, B and BA could form only one type of complex, the lid‐type supramolecular complex with small association constants. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1186–1197, 2001

Biological determinants of P300: the effects of a barbiturate on latency and amplitude

Polich & Kok (1995) ( Biological Psychology, 41, 103–146) have recently argued that P300 is not only sensitive to specific ‘cognitive’ variables, but also to non-specific biological processes such as arousal. Fluctuations in arousal are said to be indexed by an inverse relationship between latency and amplitude. We tested this hypothesis with a drug that decreases arousal — the barbiturate secobarbital sodium. Twelve subjects performed a visual 80-20% oddball task at two levels of stimulus quality and after ingesting the drug (2.9 mg/kg body weight) or a placebo. Reaction time (RT) and P300 were collected simultaneously and the latter was analyzed on both a single trial and average basis. The RT results confirmed that secobarbital interacts with stimulus quality. Secobarbital slowed single trial P300 by about half as much as RT, and this slowing was additive with stimulus quality. Thus the two measures dissociated. Secobarbital did not influence P300 amplitude. Average P300 revealed the same pattern of results, although the size of the latency effects was somewhat attenuated. RT and P300 latency were more strongly correlated than P300 latency and amplitude. We propose that P300 latency reflected the slowing of stimulus evaluation produced by the depressant properties of the drug, and that fluctuations in arousal are not necessarily associated with a simple inverse relationship between P300 latency and amplitude.

Secobarbital-mediated Inactivation of Cytochrome P450 2B1 and Its Active Site Mutants: PARTITIONING BETWEEN HEME AND PROTEIN ALKYLATION AND EPOXIDATION

Secobarbital (SB) is a relatively selective mechanism-based inactivator of cytochrome P450 2B1, that partitions between epoxidation and heme and protein modification during its enzyme inactivation. The SB-2B1 heme adduct formed in situ in a functionally reconstituted system has been spectrally documented and structurally characterized as N-(5-(2-hydroxypropyl)-5-(1-methylbutyl)barbituric acid)protoporphyrin IX. The SB-protein modification has been localized to 2B1 peptide 277-323 corresponding to the active site helix I of cytochrome P450 101. The targeting of heme and this active site peptide suggests that the 2B1 active site topology could influence the course of its inactivation. To explore this possibility, the individual SB epoxidation, heme and protein modification, and corresponding molar partition ratios of the wild type and seven structural 2B1 mutants, site-directed at specific substrate recognition sites, and known to influence 2B1 catalysis were examined after Escherichia coli expression. These studies reveal that Thr-302 is critical for SB-mediated heme N-alkylation, whereas Val-367 is a critical determinant of 2B1 protein modification, and Val-363 is important for SB epoxidation. SB docking into a refined 2B1 homology model coupled with molecular dynamics analyses provide a logical rationale for these findings.

Identification of the heme adduct and an active site peptide modified during mechanism-based inactivation of rat liver cytochrome P450 2B1 by secobarbital.

The olefinic barbiturate secobarbital (SB) is a sedative hypnotic known to be a relatively selective mechanism-based inactivator of rat liver cytochrome P450 2B1. Previous studies have demonstrated that such inactivation results in prosthetic heme destruction and irreversible drug-induced protein modification, events most likely triggered by P450 2B1-dependent oxidative activation of the olefinic pi-bond. However, the precise structure of the SB-modified heme and/or the protein site targeted for attack remained to be elucidated. We have now isolated the SB-heme adduct from P450 2B1 inactivated by [14C]SB in a functionally reconstituted system and structurally characterized it by electronic absorption spectroscopy and tandem collision-induced dissociation (CID), matrix-assisted laser desorption ionization on time of flight (MALDI-TOF), and liquid secondary ion mass spectrometry in the positive mode (+ LSIMS) as the N-(5-(2-hydroxypropyl)-5-(1-methylbutyl)barbituric acid)protoporphyrin IX adduct. The [14C]SB-modified 2B1 protein has also been isolated from similar inactivation systems and subjected to lysyl endopeptidase C (Lys-C) digestion and HPLC-peptide mapping. A [14C]SB-modified 2B1 peptide was thus isolated, purified, electrotransferred onto a poly-(vinylidene) membrane, and identified by micro Edman degradation of its first N-terminal 17 residues (S277NH(H)TEFH(H)ENLMISLL293) as the Lys-C peptide domain comprised of amino acids 277-323. This peptide thus includes the peptide domain corresponding to the distal helix I of P450 101, a region highly conserved through evolution, and which is known not only to flank the heme moiety but also to intimately contact the substrates. This finding thus suggests that SB-induced protein modification of P450 2B1 also occurs at the active site and, together with heme N-alkylation, contributes to the SB-induced mechanism-based inactivation of P450 2B1.

Correlation between cytochrome p450 2b1 induction by barbiturates and toxicity in the chick embryoin ovo

Using the highly sensitive probe‐substrate pentoxyresorufin towards cytochrome P450 2B1 isozymes, the relationship between the induction of this set of hemoproteins by barbiturates and toxicity was studied. Each chemical, allobarbital (AB), amobarbital (AM), barbital (BA), butobarbital (BB), buthetal (BU), cyclobarbital (CB), heptobarbital (HE), hexobarbital (HX), mephobarbital (ME), pentobarbital (PA), pentotal (PT), phenobarbital (PB), secobarbital (SE) and vinbarbital (VB) was injected in the chick embryo at the 16–18 day of embryonic incubation in equivalent doses (50, 25, 12.5, 6.25 and 3.12% of the respective LD50) and the mixed function monooxygenase activity examined in purified hepatic microsomes. For each barbiturate, linear regression was performed for both the inductive and toxic slope related to P450 2B1‐like activity in order to evaluate the IC100 in μmol/egg [the dose producing a 100 % increase of pentoxyresorufin dealkylation (PROD) during the induction phase] and the TC100, (the dose prod...

Fast and slow skeletal muscles: effect of ethanol on contractility of muscles from mice.

We examined in vitro the effect of ethanol at four concentrations (0g%, 0.1g%, 0.2g%, and 0.4g%) on contractile parameters of 40 fast extensor digitorum longus (EDL) and 40 slow soleus muscles from healthy mice at 35C. Preparations were curarized to avoid the possible effect of ethanol on the terminal axons or skeletal neuromuscular junction. Contractile parameters measured included: (1) twitch and tetanic tension; (2) rate of tension development; (3) time to peak tension and half relaxation for twitch; (4) time to first evidence of relaxation in the tetanus; and (5) maximum rate of relaxation. The three lower concentrations of ethanol had no significant effect on muscle contractility; however, the 0.4g% dose reduced EDL twitch tension by 9%. High doses of ethanol (2.5g%) reduced the tetanic tension produced by the EDL and soleus muscles 31% and 26%, respectively. Ethanol at 2.5g% also reduced the twitch tension of the EDL and soleus by 50% and 38%, respectively. The data suggested that the 0.4g% is the highest dose of ethanol that should be used to dilute drugs in a solution that will bathe directly stimulated curarized muscle without confounding effects. In addition, it is highly unlikely that a direct effect of ethanol on muscle contractility in humans is related to an impairment in driving.

Correlation of sedative effects with brain levels of barbiturates in LS and SS mice

Long-sleep (LS) and short-sleep (SS) mice, genetically selected for their differential CNS sensitivity to ethanol, have also been shown to differ in their response to other sedative-hypnotics, including the barbiturates. We have applied a gas-chromatographic method of analysis of brain barbiturate concentrations following IP administration of either the water-soluble barbiturate diethylbarbital (DB) or the lipid-soluble barbiturate secobarbital (SB). Brain barbiturate levels were assessed at loss of righting response, and at regaining righting response (waking). In addition, latency to loss of righting response and duration of loss of righting response were measured following IP barbiturate administration. We have observed a differential sensitivity of LS and SS mice to the sedative effects of DB, with LS mice having greater sensitivity compared to SS. This differential sensitivity to DB, as measured by a lower concentration of DB which caused loss of righting in LS, was accompanied by an equal rate of water-soluble barbiturate brain distribution and elimination in the two lines. With the lipid-soluble barbiturate SB, LS and SS mice did not differ in brain SB concentration at loss of righting response or at waking. However, sleep time was much longer in SS mice than LS due to slower brain clearance of the barbiturate in SS. Therefore, duration of loss of righting (sleep time) did not adequately reflect central sensitivity to the lipid-soluble barbiturate. These data suggest the importance of quantifying brain concentrations at loss of righting reflex when assessing central sensitivity to sedative-hypnotic agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Modeling Multiple Agent Interactions in Behavioral Pharmacology

Drugs of abuse frequently are self-administered in combinations, thus the study of the behavioral pharmacology of drug interactions has important public health implications. The effect-addition and the dose-addition models are predictive models frequently used to interpret such investigations. The aims of the present study were to empirically validate these predictive models using simple drug combinations. The effects of combinations of pentobarbital (PB) with itself or PB with secobarbital (SB) were studied using an inverted screen test in mice and a milk consumption test in rats. When evaluated using the effect-addition model the interactions between PB and itself were generally greater than effect-additive, suggesting that greater effects were obtained when giving the drug by two separate injections. In contrast, when evaluated using the dose-addition model, the interactions between PB and PB were dose-additive as would be expected for a drug interacting with itself. Similar results were obtained for the interaction of PB and SB using the mouse inverted screen test. These results suggest that the dose-addition model is a better model for evaluating drug interactions. The interactions observed for PB and SB using the rat milk drinking test generally were greater than effect-additive when analyzed using the effect-addition model. In contrast, using the dose-addition model, the interactions between PB and SB were generally infra-additive, suggesting that these two drugs have different mechanisms in decreasing milk consumption.

The discriminative stimulus properties of barbiturate stereoisomers.

Pigeons were trained to discriminate an IM injection of racemic pentobarbital sodium (5.0 mg/kg) from saline under a second-order color-tracking schedule of mixed grain presentation. In a time-course study, maximal pentobarbital-appropriate responding occurred 15 min after administration of 5.0 mg/kg racemic pentobarbital sodium, the pretreatment time used for subsequent experiments. Racemic pentobarbital sodium, the R(+) and S(-) isomers of pentobarbital, racemic secobarbital sodium, and the R(+) and S(-) isomers of secobarbital all produced dose-dependent increases in pentobarbital-appropriate responding. Racemic secobarbital sodium, the secobarbital isomers, and the R(+) isomer of pentobarbital were equipotent to each other and slightly less potent than racemic pentobarbital and the S(-)-pentobarbital isomer in this regard. Except for R(+)-pentobarbital, all barbiturates caused dose-dependent decreases in response rate over the dose range tested.

Liquid Chromatographic Assays for Barbiturate Injections

Precise, rugged, stability-indicating HPLC assays were developed for phenobarbital, pentobarbital, and secobarbital sodium injections. Degradation products of the three barbiturates were prepared and chromatographed to demonstrate method specificity. The degradation products were also used to demonstrate specificity of official GC methods for pentobarbital and secobarbital sodium capsules. The acetylurea degradation products of pentobarbital and secobarbital were characterized following the separation of their diastereoisomers by HPLC.

The effects of dihydropyridine calcium antagonists on heme biosynthesis in chick embryo liver cell culture.

A variety of 1,4-dihydropyridine calcium antagonists were tested for porphyrinogenic activity in chick embryo liver cell culture. 3,5-Dimethoxycarbonyl-1,4-dihydro-2, 6-dimethyl-4-(ortho-nitrophenyl)pyridine (nifedipine) was shown to be a potent porphyrinogenic agent. This activity was shared by a number of related analogues, viz., the 4-phenyl, 4-(meta-nitrophenyl), 4-(para-nitrophenyl), 4-(ortho-methoxyphenyl), 4-(meta-trifluoromethylphenyl), and 4-(para-trifluoromethylphenyl) analogues and nitrendipine; nicardipine exhibited very weak activity. The porphyrinogenic potency of the 1,4-dihydropyridines did not parallel their calcium antagonist activity. Nifedipine did not exhibit ferrochelatase-lowering activity in chick embryo liver cell culture and uroporphyrin and heptacarboxylic acid porphyrin were the major porphyrins to accumulate. Nifedipine did not cause suicidal destruction of cytochrome P-450 in chick embryo hepatic microsomes. Because nifedipine possesses comparable porphyrinogenic activity to sodium secobarbital in chick embryo liver cell culture, caution is required if nifedipine or related drugs are administered to patients with hereditary hepatic porphyria.

Exposure to quinalbarbitone sodium in pharmaceutical workers.

Exposure to quinalbarbitone sodium in pharmaceutical workers.