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The following drugs have been demonstrated to be secreted by the parotid glands of rats and human beings: amobarbital, chlorpromazine, codeine, glutethimide, meprobamate, pentobarbital, phenobarbital, and secobarbital. Methadone could not be detected in the parotid saliva of either rats or human beings, and morphine has been demonstrated only in parotid saliva of rats.
Acute and chronic ethanol ingestion can alter both the pharmacodynamics and pharmacokinetics of other drugs. For psychotherapeutic drugs, modification of drug action by alcohol is much more important than kinetic interaction, such as ethanol induced drug metabolism. In contrast, the importance of the effects of alcohol on the kinetics of other classes of drug is incomplete. The probability and mechanism of alcohol kinetic interactions with other drugs can nevertheless be anticipated, in part, on the basis of the extent of binding of the drug to plasma proteins, the capacity of the liver for extracting the drug from blood passing through the liver and the true distribution space of the drug. Highly bound drugs with low intrinsic hepatic clearance are among the most commonly reported to have their kinetics altered by ethanol (e.g. benzodiazepines, phenytoin, tolbutamide and warfarin). Less highly bound drugs are less consistently affected (e.g. meprobamate, glutethimide, pentobarbitone and phenobarbitone). Acute administration of ethanol to laboratory animals or incubation of microsomal preparations with ethanol inhibits the mixed function oxidase activity. In the human, the elimination half-life of meprobamate, pentobarbitone and tolbutamide is increased by acute ethanol administration. Chronic administration of ethanol to rats and humans causes proliferation of the smooth endoplasmic reticulum, increase in microsomal protein content and cytochrome P450 and results in an augmentation in drug metabolising ability of the microsomes in vitro. Even though the plasma half-life of some drugs is decreased by chronic ethanol ingestion, the clinical determination of the mechanism is incomplete because few studies have measured drug metabolite levels. In addition, alcohol effects on drug distribution have not been studied very extensively. The effects of chronic alcohol ingestion on drugs with low and high hepatic extraction, high and low binding, important tissue localisation and microsomal and non-microsomal metabolism will be quite different. Systematic studies of the mechanism of alcohol kinetic interactions are needed. Such kinetic studies should be combined with pharmacodynamic measures in order to establish the clinical importance of changes in drug kinetics.
This report discusses characteristics of a custom-designed vidicon spectrometer and evaluates its applicability to several clinical analysis problems. Data show that the vidicon detector response is linear with intensity over about four orders of magnitude and that the uncertainty in absorbance measurements can approach 0.001 absorbance units in the range from 0 to 2 absorbance units. Applications include the enzymatic determination of glucose, the determination of lactate dehydrogenase, and determinations of barbital, chlordiazepoxide, and glutethimide. Capabilities of the instrument system for first-derivative spectroscopy are also discussed. The discussion included a critical evaluation of the potential advantages and limitations of the concept.
Procedures have been developed for the determination in serum and urine of 21 drugs which include all of the barbiturates, methyprylon, glutethimide, meprobamate, propoxyphene, methaqualone, primidone, diphenylhydantoin, methadone, codeine, morphine, amphetamine and methamphetamine. The method involves pipeting 1.0 ml of serum or urine into an extraction tube, adding an internal standard together with either a pH 4.9 or pH 8.3 buffer and extracting with chloroform. The drugs in the extract are concentrated by exaporation of the organic layer and identified and quantitated by gas-liquid chromatography (GLC) using a column packed with 3 percent OV 17. GLC analysis times are kept below seven minutes by using temperature programming which allows good separations of drugs of widely varying volatilities. All calculations are based on peak areas determined by an electronic integrator. Losses of drugs during extraction, evaporation and chromatography steps are compensated for by the use of internal standards. Actual extraction efficiencies of drugs from serum or urine range from 75 to 100 percent although recoveries, based on standards carried through the entire procedures, are quantitative. Precision (s.d.) based on replicate determinations is approximately plus or minus 0.2 mg per dl.
The New York State Department of Health has conducted a proficiency evaluation program in quantitative toxicology since 1974. Serum samples containing a barbiturate and phenytoin, together with either glutethimide, procainamide, or theophylline, are sent to participating laboratories quarterly. Within the first two years of the program the percentage of laboratories able to quantitate 75% of the test samples to within 25% of the gravimetric values increased from 25 (1974-1975) to 40% (1975-1976). This improvement was partly due to licensure requirements, improved technology for sample preparation and analysis, and the availability of better quality-control practice. An obstacle to obtaining uniform accuracy is the lack of adequate calibration or testing materials. To overcome these obstacles, pure drugs are weighed into a bovine serum matrix, and the weights are confirmed by reference laboratories and used as the target values in the testing program. Comparison of the methods used by participants in this program for barbiturate and phenytoin yielded equations different from those found in other method evaluations.
In the extract of the serum, prepared as described by Külpmann (1979) (this J. 17, 89-96), other hypnotics, in addition to the barbiturates can be determined by gas chromatography; these are: carbromal, 2,2-diethylallylacetamide, ethinamate, glutethimide, methyprylone and pyrithyldione. Methaqualone can be detected qualitatively. The coefficient of variation for the precision in the series is dependent on the hypnotic investigated and ranges from 2.1 to 8.5%, the recovery from 76 to 92%; the detection limit is estimated to be 1.6 up to 4.6 mumol/l. The specificity was proved by comparison 1) of analyses of sera from poisoned patients or animals before and after the additional purification of the extract by thin-layer chromatography, 2) with the retention times of about 100 drugs under the gas chromatographic conditions that were used. The method allows the determination of 18 barbiturates and 7 non-barbiturates within one to two hours.
The adsorptive capacities of some ion-exchange resins and activated charcoal towards the hypnotic drugs, phenobarbital, glutethimide, carbromal, and methaqualone, have been investigated. Furthermore, the properties of some of these resins and charcoal, encapsulated in an agarose matrix in the form of beads, have been compared with those of the adsorbent phases in their native states. In general, the adsorptive capacities of charcoal were at least as good as, and frequently better than those of the resins. Amberlite XAD-type resins had a higher affinity than Dowex-type resins for all the drugs tested, except for phenobarbital, which was not adsorbed to a satisfactory extent onto Amberlite XAD-4. The encapsulation of adsorbent phases into agarose beads of diameter 5-10 mm results in a reduction of the adsorbtion of the drugs. Nonetheless, the remaining adsorptive capacity is sufficient for application in an extracorporeal detoxification system. Moreover, the overwhelming advantage of good haemocompatibility is provided by the agarose-encapsulated adsorbents.
The microcapsule artificial kidney was used in the treatment of three patients with acute drug intoxication. The apparatus contains 300 g. of microencapsulated activated charcoal with a total membrane area available for diffusion of more than 2m.(2) The membrane thickness is only 500 A. These properties make possible a compact artificial kidney whose efficiency for the removal of uremic metabolites and drugs is much higher than standard hemodialysis apparatus. The microcapsules are made blood-compatible by coating with human albumin. A roller pump was used to propel the blood through the microcapsule artificial kidney at a flow rate of 300 ml./min. for two to three hours. The clearance values for glutethimide, methyprylon and methaqualone were much higher than those achieved by standard hemodialysis. Hemoperfusion quickly lowered the drug level in the blood with resulting clinical improvement.
"Loads," a combination of glutethimide and codeine, are a relatively new form of drug abuse that is increasing in popularity in the Los Angeles area as a heroin-substitute. Preliminary findings based on interviews and treatment of a group of preferential Loads abusers seen over a one-year period suggest that this combination has a potential for serious intoxications and withdrawal complications. The common withdrawal symptoms include those produced by both a sedative-hypnotic and a major narcotic and necessitate a detoxification plan based on the pharmacologic rationale of the abused combination.
Fixed-bed activated charcoal cartridges were used for hemoperfusion in the treatment of 54 patients with overdose of one or more drugs, including barbiturate, glutethimide, ethchloryvnol, meprobamate, methyprylon, methaqualone, salicylate, and diazepam. The most dramatic improvement was noticed in patients with phenobarbitol intoxication; they were admitted in stage 3-4 coma and were either awake or arousable by verbal communication at the end of 1 1/2 to 3 1/2 hours of hemoperfusion. Other intoxications improved slowly and required longer duration of treatment. The clearance rates of the drugs with hemoperfusion were greater than those usually achieved with hemodialysis. The data demonstrate the efficacy and usefulness of charcoal hemoperfusion for the management of drug overdose.
Heme- and tin-chelated metalloporphyrins are known to decrease the activity of hepatic delta-amino-levulinate synthase, the rate-controlling enzyme of heme synthesis. We performed experiments in primary chick embryo liver cells with tin-, zinc- and copper-chelated porphyrins to assess their effects on activities of delta-aminolevulinate synthase induced by prior treatment of cells with glutethimide and ferric nitrilotriacetate. These different metalloporphyrins were tested to form the experimental foundation for eventual studies in patients with acute porphyrias, in which uncontrolled induction of hepatic delta-amino-levulinate synthase, which plays a key role in pathogenesis of disease. Zinc and tin porphyrins reduced delta-aminolevulinate synthase activities, whereas copper-chelated porphyrins did not. When heme (iron protoporphyrin) was added with zinc or tin porphyrins, delta-aminolevulinate synthase activity was further reduced. Effects of the nonheme metalloporphyrins on delta-aminolevulinate synthase were closely correlated with their abilities to inhibit heme oxygenase (r = 0.78). The largest decrease of delta-aminolevulinate synthase (67%) was obtained with zinc mesoporphyrin and heme. Dose-response data indicated that only nanomolar concentrations of zinc mesoporphyrin and heme are required to obtain this effect. We found no effect of exposure to heme (10 mumol/L) or heme (200 nmol/L) plus zinc mesoporphyrin (50 nmol/L) on the half-life of activity of delta-aminolevulinate synthase (1.9 to 2.1 hr, regardless of treatment). This result suggests that the repressive effect of heme is directed toward decreasing synthesis, increasing breakdown or decreasing the translation of the messenger RNA of delta-aminolevulinate synthase.(ABSTRACT TRUNCATED AT 250 WORDS)
Hemoperfusion with coated activated charcoal is a novel procedure for treating acute poisoning. It enables the elimination of both, water-soluble and liposoluble toxins. Hemoperfusion with coated activated charcoal has proved to be superior to hemodialysis in the treatment of barbiturate or bromocarbamide poisoning both under experimental conditions as well as in the ward. Analogous statements may be made for the therapy of glutethimide poisoning. Methaqualone, on the other hand, could not be eliminated sufficiently well in animal trials. Intoxications by "mild" analgetics, such as paracetamol and acetylsalicylic acid, may be treated successfully with hemoperfusion. Treatment of acetylsalicylic acid poisoning is equally effective with hemoperfusion as with hemodialysis. Prospects for the success of hemoperfusion in treating intoxication from tricyclic antidepressants and neuroliptics are slight. It is simply the danger of antidepressant poisoning that justifies using this method of treatment in the first few hours after ingestion in order to reduced the flow of the psychopharmaceutical substance into the tissue.
Mitomycin C (MMC) is a DNA cross-linking agent that has been used in cancer chemotherapy for over 20 years, yet little is known either qualitatively or quantitatively about MMC-induced DNA adduct formation and repair in vivo. As an initial means of investigating this, we used a recently developed 32P-postlabeling assay to examine the formation and loss of MMC-DNA adducts in the tissues of a simple in vivo model test system, the chick embryo, following treatment with a chemotherapeutic dose of MMC. As early as 15 min after MMC treatment, four adducts could be detected in the liver which were tentatively identified as the (CpG) N2G-MMC-N2G interstrand cross-link, the bifunctionally activated MMC-N2G monoadduct, and two isomers (alpha and beta) of the monofunctionally activated MMC-N2G monoadduct. The (GpG) N2G-MMC-N2G intrastrand cross-link appears to be a poor substrate for nuclease P1 and/or T4 kinase and was not evaluable by this assay. Levels of all four detectable adducts increased substantially within the first 2 h after MMC treatment, reached maximal levels by 6 h, and decreased progressively thereafter through 24 h, although low levels of certain adducts persisted beyond 24 h. Lung and kidney had comparable levels of total MMC adducts, which were approximately 60% those of the liver, and there were no significant differences in the proportion of specific adducts among the three tissues. The interstrand cross-link represented approximately 13-14% of the total MMC adducts, which is approximately 5-fold greater than the proportion of CpG sites in the genome. In addition, the interstrand cross-link was selectively decreased after 16 h relative to the three monoadducts, suggesting preferential repair. The effect of modulating different components of the Phase I and Phase II drug metabolism on MMC adduct formation, using either glutethimide, 3,4,3',4'-tetrachlorobiphenyl, dexamethasone, buthionine sulfoximine, ethacrynic acid, or N-acetylcysteine pretreatments, was examined to characterize the possible pathways of MMC metabolism and adduct formation in vivo. Surprisingly, none of these pretreatments had a significant effect on individual or total adducts with the exception of dexamethasone, which caused an almost 2-fold proportional increase in all four adducts in the liver.
The synthesis of 5'-substituted thalidomide analogs is described. The amino acids 2 necessary to synthesize the target compounds were prepared by Michael reaction. Condensation of 2 with phthalic anhydrides followed by reaction with urea yielded 4 as diastereomeric mixtures. Furthermore glutethimide (5) was brominated by an improved method and the resulting compound 6 was reacted in several steps with sodium azide, hydrogen, and phthalic anhydride to give 8. In a similar manner, 6 was reacted with sodium azide and various phthalic anhydrides to give 9, 10, and 11. All final compounds were tested in vitro for their inhibitory activity on the release of TNF-alpha, using stimulated peripheral mononuclear blood cells (PBMCs). Compounds with an additional aromatic substituent in position 5' of the thalidomide molecule were more active than thalidomide. Compound 11 was able to reduce increased levels of IL-2 in vitro.
The effect of orally administered activated charcoal (AC) on the sleep times of mice following intravenous injection of various hypnotics was investigated. Preliminary studies with phenobarbital (Pb) showed that a linear relationship exists between the Pb-induced sleep time and the logarithm of the Pb dose in both control and AC treated mice. Half-lives of Pb in the two groups were estimated to be 8.1 and 0.9 h, respectively. A linear decline in Pb-induced sleep time with increasing dose of AC was observed up to a maximum effective dose of AC beyond which dose increments caused no further reduction in sleep time. A similar relationship was observed between sleep time and the concentration of sodium sulfate in which the AC was suspended. AC treatment resulted in an 82-88 per cent reduction in sleep time induced by administration of phenobarbital, methyprylon, glutethimide, ethchlorvynol, and methaqualone. AC had no significant effect on sleep time following amobarbital or pentobarbital administration.
The response of chronic insomniacs to 100 mg pentobarbital, 300 mg methyprylon, 500 mg glutethimide, and placebo was assessed using our previously described subjective and objective techniques. The purpose of the study was to examine (1) the presence or absence of the subjects' reported insomnia; (2) the subjects' ability to discriminate between active hypnotic drugs and placebo; and (3) whether any preference existed among active medications. Statistically significant findings included a high degree of correlation (P less than 0.001) between subjective and objective data and greater response to active medications as compared to placebo shown on all parameters except objective onset of sleep. In no case was there significant difference between the two nights of placebo. Although methyprylon was most frequently superior to placebo, there was no significant patient preference for any of the active medications.
The abilities of structural congeners of phenobarbital to induce immunoreactive hepatic cytochrome P450 2B (CYP2B) protein and associated catalytic activity (benzyloxyresorufin O-dealkylation) in the male B6C3F1 mouse were examined. Interspecies differences in inducing ability were examined through comparison of the results with induction data obtained previously with the male F344/NCr rat. The congeners were administered in the diet for 2 weeks at concentrations equimolar to 500 ppm of the prototype CYP2B inducer, phenobarbital. Of the series of compounds tested, phenobarbital was the most effective inducer of benzyloxyresorufin O-dealkylation and immunoreactive CYP2B protein, with 2-ethyl-2-phenylsuccinimide, 5-ethyl-5-phenylhydantoin, primidone, and glutethimide being only 19-42% as effective. 5-Ethyl-5-phenyloxazolidinedione and the ring-opened and decarboxylated congeners, N-(2-ethyl-2-phenylacetyl)urea and 2-ethyl-2-phenylmalonamide, displayed minimal induction of these catalytic activities. Dose-response experiments performed with 5-ethyl-5-phenylhydantoin indicated that the intrinsic CYP2B-inducing activity of this congener was as great as that of phenobarbital in the mouse, although a fourfold greater dietary concentration of this hydantoin (2000 ppm) was required to elicit a response equivalent to that caused by 500 ppm phenobarbital. When extent of induction was related to serum total xenobiotic concentration rather than to administered dietary concentration, the potencies of the two congeners were determined to be more similar (58 vs. > or = 78 microM for phenobarbital and 5-ethyl-5-phenylhydantoin, respectively).
Comparative in vitro studies were carried out to determine the adsorption characteristics of 12 drugs on activated charcoal. At pH 1.3 and 37 degrees, the adsorption capacity of activated charcoal (milligrams per gram of charcoal) was: aspirin, 262; glutethimide, 252; methaqualone, 179; chlordiazepoxide, 157; propoxyphene napsylate, 137; diazepam, 136; amitriptyline, 133; propoxyphene hydrochloride, 127; secobarbital, 124, pentobarbital, 103; phenobarbital, 70; and amobarbital, 51. The adsorption of the weak acids was most markedly decreased at pH 10.8. In patients, actual drug adsorption probably is lower than these maxima because of the presence of mucus, bile salts, and other drugs. In patients investing large amounts of poorly adsorbed drugs, activated charcoal would not be helpful.