Fentanyl-Norfentanyl Concentrations During Transdermal Patch Application: LC-MS-MS Urine Analysis.

Poklis and Backer published a survey of the concentrations of fentanyl and norfentanyl that could be expected in urine from patients using Duragesic®, a transdermal fentanyl patch. That study employed a relatively small number of patient data points and analysis by Gas Chromatography/Mass Spectrometry. This work examines a larger population of patient positives for fentanyl and norfentanyl to determine whether more than a decade later the original report remains accurate in predicting the range and median levels of fentanyl and norfentanyl concentrations physicians can expect to see from their patients. Additionally, these data were transformed to develop a model that results in a near Gaussian distribution of urine drug test results. This retrospective approach was developed to transform and normalize urine drug testing results to provide a historical picture of expected patient values for this important analgesic. The resulting near Gaussian distribution is dose independent and as such should be of value to physicians in quickly assessing whether their patient is consistent with this historical population in the broad terms of this model. While this comparison alone is not definitive for adherence with a treatment regimen, together with patient interviews, prescription history and other clinical criteria, it can add an idea of expected patient values from urine drug testing.

Treatment of massive phenobarbital overdose with dopamine diuresis.

We report a case of severe phenobarbital sodium overdose with a peak plasma concentration of 253 microgram/mL, normally considered fatal. The patient was successfully treated with forced alkaline diuresis. Treatment was unusual in that dopamine hydrochloride was used to sustain the diuresis.

A fatal case of theophylline intoxication.

A fatal case of theophylline intoxication is presented in which a number of factors leading to a decrease in theophylline clearance and the patient's death were possibly operative. These included advanced age, chronic lung disease, liver disease, and administration of cimetidine. Since early symptoms of the toxic effects of theophylline can mimic peptic ulcer disease, cimetidine might be prescribed for the gastrointestinal symptoms with subsequent worsening of theophylline poisoning. Theophylline plasma concentration should be determined whenever drugs affecting theophylline clearance are administered simultaneously.

Effects of hemodialysis on theophylline kinetics.

Difficulties encountered in controlling theophylline blood concentrations in an asthmatic patient on hemodialysis prompted us to study the effect of hemodialysis on theophylline kinetics. Plasma theophylline extraction ratios, clearances, and half-lives were determined during dialysis for 11 adults given an intravenous infusion of 4 mg/kg aminophylline. For comparison, eight of these patients were evaluated for theophylline half-lives when not dialyzed. Extraction ratios of theophylline during dialysis ranged from 0.22 to 0.51 (0.35 +/- 0.08) for these patients, indicating that a mean of 36 per cent plasma theophylline was removed during each pass through the dialyzer. This compares with a mean extraction ratio of urea of 0.63 +/- 0.07. Plasma clearance of theophylline during dialysis ranged from 52 to 124 ml/min (83 +/ 20 ml/min). Plasma theophylline half-lives during dialysis ranged from 1.6 to 3.4 hours (2.3 +/- 0.5 hours). Theophylline half-lives when not on dialysis ranged from 3.5 to 8.2 hours (5.0 +/- 1.7). Theophylline clearance was significantly faster in every patient during dialysis. Asthmatics requiring hemodialysis should receive additional theophylline during dialysis if therapeutic blood levels are to be maintained. Routine hemodialysis will significantly increase clearance in a toxic patient in whom life-threatening toxicity is occurring and charcoal hemoperfusion is unavailable.

Postinjury scopolamine administration in experimental traumatic brain injury.

A single bolus dose of scopolamine (1.0 mg/kg) or saline (equal volume) was injected (i.p.) at 15, 30 or 60 min after fluid percussion traumatic brain injury in the rat. Scopolamine administered at 15 min postinjury significantly reduced beam walking deficits and body weight loss assessed for 5 days after injury. Scopolamine treatment at 30 or 60 min postinjury had no effect on behavioral outcome assessed for 5 days after injury. Plasma concentrations of scopolamine were measured with a radioreceptor assay. The plasma half-life for scopolamine was 21.6 min in injured rats and 17.3 min in normal rats (P less than 0.05). These results, along with evidence from previous studies, suggest that a brief period of excessive neuronal excitation can produce relatively long-lasting behavioral deficits. The temporal effectiveness of receptor antagonist intervention in this process appears to be brief.

Pharmacological characterization of BNMPA (alpha-benzyl-N-methylphenethylamine), an impurity of illicit methamphetamine synthesis.

alpha-Benzyl-N-methylphenethylamine (BNMPA), an impurity of illicit methamphetamine synthesis, has previously been reported to produce convulsions in mice without affecting spontaneous locomotor activity or altering methamphetamine-induced increases in spontaneous activity. In this study the in vitro effects of BNMPA on a variety of neuronal receptor types was determined to better characterize the pharmacological actions of this novel compound. BNMPA and N-demethyl-BNMPA fully displaced the dopamine transporter selective ligand [3H]CFT (2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane) from rat striatal membranes with Ki values (mean +/- S.E.M) of 6.05 microM +/- 0.15 and 8.73 microM +/- 1.66, respectively. BNMPA also inhibited [3H]dopamine uptake into striatal synaptosomes with an IC50 value of 5.1 +/- 1.4 microM. The basal efflux of [3H]dopamine from striatal slices was slightly enhanced by BNMPA only at concentrations > or = 100 microM. BNMPA had no effect on [3H]norepinephrine efflux from hippocampal slices. BNMPA displaced tritiated paroxetine and prazosin binding from rat cortical membranes with Ki values of 14.5 microM and 11.7 microM respectively. In electrophysiological studies, BNMPA (100 microM) had no significant effects on either GABAA Cl- currents in cultured neurons or non-NMDA glutamate receptors expressed in oocytes. However, BNMPA significantly inhibited NMDA-stimulated currents in oocytes expressing the NR1/2A or NR1/2C receptor subunit combinations (IC50 values = 24.6 +/- 1.8 and 24.0 +/- 1.5 microM, respectively). This inhibition was rapid, reversible and voltage-dependent. These results indicate that BNMPA has multiple sites of action in the CNS that could be important in modulating a variety of behavioral effects upon exposure to this synthetic byproduct of illicit methamphetamine synthesis.

Pharmacological evaluation of aerosolized cannabinoids in mice.

The reemergence on the debate of the use of marijuana for medicinal purposes has been the impetus for developing an acceptable delivery form of aerosolized cannabinoids. The goals of the present study were to: (1) develop and characterize the physical properties of an aerosolized form of Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive constituent present in marijuana; and (2) assess the pharmacological effects of cannabinoid inhalation in mice. A Small Particle Aerosol Generator (SPAG) nebulizer, used to generate the aerosol, had an output of approximately 0.154 mg/l of aerosolized Delta(9)-THC with a 2.0 microm mass median aerodynamic diameter and a 2.2 geometric standard deviation (GSD). Virtually all the particles were less than 5.0 microm in diameter suggesting that they were sufficiently small to penetrate deeply into the lungs. Inhalation exposure to aerosolized Delta(9)-THC in mice elicited antinociceptive effects that were dependent on concentration and exposure time with an estimated Delta(9)-THC dose of 1.8 mg/kg. On the other hand, inhalation exposure to Delta(9)-THC failed to produce two other indices indicative of cannabinoid activity, hypothermia and decreases in spontaneous locomotor activity. The antinociceptive effects occurred within 5 min of exposure and lasted approximately 40 min in duration. The cannabinoid receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR 141716A), but not naloxone, blocked these antinociceptive effects (AD(50)=0.09 mg/kg) indicating a cannabinoid receptor mechanism of action. Similarly, inhalation exposure to a water soluble cannabinoid analog, 3-(5'-cyano-1', 1'dimethylheptyl)-1-(4-N-morpholinobutyrloxy)-Delta(8)-te trahydrocann abinol (O-1057), produced antinociception that was blocked by SR 141716A. These results demonstrate that the development of an aerosolized form of cannabinoids for human medicinal use is feasible.

Decline in abuse of pentazocine/tripelennamine (T's and Blues) associated with the addition of naloxone to pentazocine tablets.

From 1977 to 1982, the intravenous use of the combination pentazocine/tripelennamine (T's and Blues) had become a major drug abuse problem in St. Louis, MO, U.S.A. In 1983, the manufacturer of pentazocine tablets removed the drug from the pharmaceutical market and released a new tablet formulation of pentazocine and the narcotic antagonist naloxone. Since 1983 there has been a continuous decline in T's and Blues abuse whereby (a) the new pentazocine tablets do not produce the euphoria sought by addicts; (b) the price of old pentazocine tablets has greatly increased and (c) the availability of heroin and other narcotics has increased.

Pentazocine/tripelennamine (T's and blues) abuse: a five year survey of St. Louis, Missouri.

From 1977 to 1981, the intravenous use of a pentazocine/tripelennamine combination (T's and Blues) has become a major drug abuse problem in the city of St. Louis, Missouri, U.S.A. There has been a continuous increase in the involvement of these drugs in (a) sudden and violent deaths (62 homicides, 7 fatal intoxications), (b) emergency room visits (137 in 1980), (c) admissions to drug treatment programs (7.7% in 1978 up to 64% in 1981), and (d) police laboratory cases (100 in 1977 - 78 up to 700 in 1981). Initial popularity of the drugs was related to the decline in the quality of street heroin (2.5% in 1977 reduced to 0.5% by 1979) and the lack of strict legal controls. Serious adverse reactions include clonic-tonic seizures and pulmonary foreign body granulomatosis. Ethanol and diazepam were present in 53% and 10% of T's and Blues medical examiner's cases, respectively (n = 70). Addicts are usually black males, 20 - 30 years old, from impoverished areas of the city. The drugs are available to the illicit trade through theft or diversion from legitimate sources.

Drug findings in 'Driving Under the Influence of Drugs' cases: a problem of illicit drug use.

Drug findings in 137 drug positive cases of Driving Under the Influence of Drugs (DUID) occurring in St. Louis, Missouri, U.S.A. from June 1983 through May 1986 are presented. Thirty-two different drugs were detected. A single agent was detected in only 34% (47/137) of cases. The most frequently encountered drugs, expressed as percent of positive cases, were: phencyclidine, 47%; marijuana, 47%; benzodiazepines, 22%; barbiturates, 15%; opiates, 11%; and cocaine, 9%. Most multiple drug cases involved popular illicit drug mixtures, such as cocaine and morphine (speedballs) or phencyclidine on marijuana (whack). All the drivers in this survey had displayed inappropriate or impaired operation of a motor vehicle to the extent that a law enforcement officer had stopped and charged them for DUID. In at least 81% of the drug positive cases, persons impaired in the operation of a motor vehicle from a drug or drugs other than alcohol, were impaired not as the result of side effects of therapeutic drug use, but as the result of deliberate self intoxication with illicit or controlled substances.

Acetylcodeine, an impurity of illicitly manufactured heroin, elicits convulsions, antinociception, and locomotor stimulation in mice.

Acetylcodeine is one of the major impurities present in illicitly manufactured heroin (diacetylmorphine). Data on its pharmacology and toxicology are limited and its ability to alter the toxic effects of diacetylmorphine is not known. The first objective of the present study was to compare the acute pharmacological and toxicological effects of acetylcodeine to those of codeine and diacetylmorphine in mice by assessing nociception in the tail-flick test, locomotor stimulation, and convulsive behavior. The second goal of this study was to determine whether acetylcodeine would alter the convulsant effects of diacetylmorphine. The antinociceptive potencies of acetylcodeine and codeine were similar, as reflected by their ED50 (95% confidence limits) values of 35 (29-44) and 51 (40-65) micromol/kg, respectively. Acetylcodeine was somewhat less potent than codeine in stimulating locomotor behavior, with ED50 values of 28 (22-37) and 12 (6-24) micromol/kg, respectively. Diacetylmorphine was considerably more potent than the other two drugs, producing antinociception and locomotor stimulation at ED50 values of 2.4 (1.4-4.1) and 0.65 (0.36-1.2) micromol/kg, respectively. On the other hand, the convulsant effects of acetylcodeine (ED50=138 (121-157) micromol/kg) and diacetylmorphine (ED50=115 (81-163) micromol/kg) were similar in potency and both were more potent than codeine (ED50=231 (188-283) micromol/kg). Finally, a subthreshold dose of acetylcodeine (72 micromol/kg) decreased the convulsant ED50 dose of diacetylmorphine to 40 (32-49). These findings suggest that the convulsant effects of acetylcodeine are more potent than predicted by its effects on locomotor activity and antinociception. The observation that acetylcodeine potentiated the convulsant effects of diacetylmorphine suggests a mechanism for some of the heroin-related deaths reported in human addicts.

alpha-Benzyl-N-methylphenethylamine (BNMPA), an impurity of illicit methamphetamine synthesis: pharmacological evaluation and interaction with methamphetamine.

Methamphetamine is a popular drug of abuse, readily synthesized in clandestine laboratories. Illicitly obtained methamphetamine is frequently impure, containing various purposefully added diluents and adulterants, as well as impurities of manufacture and origin. Few impurities have been studied in vivo and limited information exists concerning their pharmacology/toxicology. One such impurity of manufacture is alpha-benzyl-N-methylphenethylamine (BNMPA). Acute toxicity and spontaneous activity (locomotor) studies were conducted with this compound alone and in combination with S(+)-methamphetamine (METH) in male, ICR mice. In the acute toxicity studies, BNMPA was evaluated for convulsant activity. While BNMPA also produced some behavioral disturbances similar to those seen with methamphetamine (e.g., stereotopy) at doses greater than 30 mg/kg, no tonic-clonic convulsions were noted until pre-terminal convulsion at 50 mg/kg. METH alone produced tonic-clonic convulsions at terminal doses of 70 mg/kg. When BNMPA was given in combination with METH, there was no readily apparent change in the convulsion profile from that of METH given alone. In spontaneous activity studies, doses of BNMPA ranging from 1 mg/kg to 50mg/kg failed to alter locomotor activity significantly from controls though 5 mg/kg METH alone significantly increased spontaneous activity. In addition, increases in spontaneous activity elicited by 5 mg/kg METH were not affected when METH was given with 5 mg/kg BNMPA. While BNMPA appears to have toxic effects in the central nervous system (CNS), the failure to affect locomotor activity or alter either METH-induced increases in spontaneous activity or METH-induced convulsions suggests that the two agents are producing their effects through distinct mechanisms.

The pharmacological activity of inhalation exposure to marijuana smoke in mice.

Although the majority of cannabinoid users smoke marijuana, the preponderance of laboratory animal research is based on administration of Delta9-tetrahydrocannabinol (Delta9-THC) or other cannabinoid agents via injection. The aim of the present study was to evaluate the impact of inhaling marijuana, or ethanol-extracted placebo smoke in the mouse model of cannabinoid activity by assessing inhibition of spontaneous activity, antinociception, catalepsy, and body temperature. In order to determine dosimetry, blood levels of Delta9-THC were obtained following either marijuana exposure or intravenous injection of Delta(9)-THC. Inhalation exposure to marijuana produced dose-related increases in antinociception and catalepsy, with estimated ED50 doses of Delta9-THC of 2.4 and 3.8 mg/kg, respectively. However, hypothermia and locomotor depression occurred in both the placebo- and marijuana-exposed mice. The CB1 receptor antagonist, SR 141716A antagonized the antinociceptive effects of marijuana (AD50 = 0.6 mg/kg), but only slightly decreased marijuana-induced catalepsy, and failed to alter either the hypothermic or locomotor depressive effects. In contrast, SR 141716A antagonized the antinociceptive, cataleptic, and hypothermic effects of intravenously administered Delta9-THC in mice that were exposed to air alone, though all subjects exhibited locomotor depression, possibly related to the restraint. In accordance with reports of others, these data suggest that exposure to smoke alone has pharmacological consequences. Our findings also indicate that marijuana-induced antinociception is mediated through a CB1-receptor mechanism of action and are consistent with the notion that Delta9-THC is mainly responsible for this effect.

Thioridazine-5-sulfoxide cardiotoxicity in the isolated, perfused rat heart.

The potential cardiotoxicity of a racemic mixture of thioridazine-5-sulfoxide, an oxidative metabolite of thioridazine, was studied in the isolated, perfused rat heart. Thioridazine-5-sulfoxide (ring sulfoxide) was prepared by a new method in which a racemic mixture of the two diastereoisomeric forms of the compound was formed. Hearts from male Sprague-Dawley rats were perfused using a modified Langendorff preparation. Quinidine (31 microM) served as a positive control for the measurements of the electrocardiogram (ECG) and the heart rate. Thioridazine (13 microM) perfusion resulted in a variable heart rate and elevated S-T segment. Perfusate concentrations of the ring sulfoxide as low as 12 microM increased P-R and Q-T intervals, produced delays in A-V and ventricular conduction, premature ventricular contractions and ultimately A-V block. These findings suggest that thioridazine cardiotoxicity may be due in part to the actions of thioridazine ring sulfoxide.

The effect of inorganic lead on heptic biochemical and ultrastructural changes produced by phenobarbital.

Lead acetate (105 mumol/kg, i.p.) decreased rat hepatic cytochrome P-450 to 57% and 63% of control values when measured 24 and 48 h after lead administration, respectively. A large increase in urinary delta-aminolevulinic acid (U-ALA) was observed after lead treatment, indicating a depression of heme synthesis. In addition, lead treatment produced dilated cisternae of the smooth endoplasmic reticulum (SER). Phenobarbital (100 mg/kg, i.p.) produced an induction of cytochrome P-450, proliferation of the SER, and did not alter U-ALA content. Simultaneous lead and phenobarbital treatment produced a delayed but robust induction of cytochrome P-450, only a moderate rise in U-ALA, and a reduced proliferation of the SER of hepatocytes. Therefore, phenobarbital, an inducer of heme synthetic enzymes, is apparently capable of reversing lead-induced inhibition of heme synthesis as measured by hepatic cytochrome P-450 induction and U-ALA content.

Binding of gold to bovine serum albumin using flameless atomic absorption.

A graphite furnace atomic absorption spectrophotometric assay capable of accurately determining nanogram amounts of gold in biological fluids was developed. The presence of bovine serum albumin and/or phosphate in the sample reduced the method sensitivity without affecting the linear response. Binding of gold was studied by ultrafiltration using cones with a molecular weihght cutoff of 25,000. The binding of gold at various concentrations to 2 and 4% bovine serum albumin in 0.1 M phosphate buffer, pH 7.4, was independent of the gold and protein concentrations. In the 2-10 microgram/ml range, the overall binding values (mean +/- SD) of gold to 2 and 4% bovine serum albumin were 98 +/- 1.6 (n = 35) and 99 +/- 1.0% (n = 15), respectively. When ultrafiltration cones with a molecular weight cutoff of 50,000 were used, the extent of binding to 2% bovine serum albumin was 85.4 +/- 1.6% (n=11). This statistically significant difference (p less than 0.001) was due to variations in the protein retention of the two cone types. Interaction studies showed that gold was not displaced from the binding sites by salicylic acid (200 microgram/ml) or vice versa.

Convenient oxidation of phenothiazine salts to their sulfoxides with aqueous nitrous acid.

A simple method is reported for the preparation of gram quantities of phenothiazine sulfoxides by aqueous nitrous acid oxidation of phenothiazines at room temperature. The chiral levomepromazine gave rise to diastereoisomeric products analogous to those reported for thioridazine sulfoxidation.

Toxicological findings in deaths due to ingestion of pentazocine: a report of two cases.

Two cases of fatal suicidal ingestion of pentazocine are presented. Toxicological findings in these deaths are compared to those of twelve similar pentazocine fatalities gleaned from various compilation of toxicology data. Pentazocine blood and liver concentrations in the presented cases were 3.3 and 9.2 mg/l, and 34 and 43 mg/kg, respectively. Blood and liver concentrations in references cases ranged from 0.8 - 38 mg/l and 3 - 197 mg/kg, respectively. The interpretation of toxicology findings following the ingestion of pentazocine is discussed.

The detection of acetylcodeine and 6-acetylmorphine in opiate positive urines.

Acetylcodeine (AC), an impurity of illicit heroin synthesis, was investigated as a urinary biomarker for detection of illicit heroin use. One hundred criminal justice urine specimens that had been confirmed positive by GC/MS for morphine at concentrations > 5000 ng/ml were analyzed for AC, 6-acetylmorphine (6AM), codeine, norcodeine and morphine. The GC/MS analysis was performed by solid phase extraction and derivatization with propionic anhydride. Total codeine and morphine concentrations were determined by acid hydrolysis and liquid/liquid extraction. AC was detected in 37 samples at concentrations ranging from 2 to 290 ng/ml (median, 11 ng/ml). 6AM was also present in these samples at concentrations ranging from 49 to 12 600 ng/ml (median, 740 ng/ml). Of the 63 specimens negative for AC, 36 were positive for 6AM at concentrations ranging from 12 to 4600 ng/ml (median, 124 ng/ml). When detected, the AC concentrations were an average of 2.2% (0.25 to 10.2%) of the 6AM concentrations. There was a positive relationship between AC concentrations and 6AM concentrations (r = 0.878). Due to its very low concentration in urine, AC was found to be a much less reliable biomarker for illicit heroin use than 6AM in workplace or criminal justice urine screening programs. However, AC detection could play an important role in determining if addicts in heroin maintenance programs are supplementing their supervised diacetylmorphine doses with illicit heroin.

Disposition of fluoride in a fatal case of unsuspected sodium fluoride poisoning.

A case of suicidal ingestion of sodium fluoride roach powder by a 33-year-old black woman is presented. Disposition of fluoride (mg/l or mg/kg) was: bile, 3.4; gastric content, 225; kidney, 16; liver, 8.6 and urine, 295. No history of roach powder ingestion was available at autopsy. This case illustrates the need for extensive toxicological screening to determine if fatal poisoning has occurred when histopathological findings are unremarkable.