Development of matrix controlled transdermal delivery systems of pentazocine: In vitro/in vivo performance.

The present study aimed to develop hydroxypropyl methylcellulose based transdermal delivery of pentazocine. In formulations containing lower proportions of polymer, the drug released followed the Higuchi kinetics while, with an increase in polymer content, it followed the zero-order release kinetics. Release exponent (n) values imply that the release of pentazocine from matrices was non-Fickian. FT-IR, DSC and XRD studies indicated no interaction between drug and polymer.The in vitro dissolution rate constant, dissolution half-life and pharmacokinetic parameters (C(max), t(max), AUC(s), t(1/2), Kel, and MRT) were evaluated statistically by two-way ANOVA. A significant difference was observed between but not within the tested products. Statistically, a good correlation was found between per cent of drug absorbed from patches vs. C(max) and AUC(s). A good correlation was also observed when per cent drug released was correlated with the blood drug concentration obtained at the same time point. The results of this study indicate that the polymeric matrix films of pentazocine hold potential for transdermal drug delivery.

The pharmacokinetics of pentazocine and tripelennamine.

The pharmacokinetics of single and combined doses of pentazocine HCl (40 and 80 mg) and tripelennamine HCl (50 and 100 mg) were studied in six healthy drug abusers. After intramuscular administration of 40 or 80 mg pentazocine alone, mean peak plasma concentrations at 15 minutes were 102 and 227 ng/ml, respectively, and mean plasma t1/2 values were 4.6 and 5.3 hours, respectively. After intramuscular administration of 50 or 100 mg tripelennamine, mean plasma concentrations at 30 minutes were 105 and 194 ng/ml, respectively, and mean plasma t1/2 values were 2.9 and 4.4 hours, respectively. After concurrent administration of pentazocine with tripelennamine, plasma pentazocine and tripelennamine concentrations at all time points were not significantly different from those when pentazocine or tripelennamine was administered alone. Coadministration of pentazocine and tripelennamine had no effect on the distribution, elimination, and clearance of either pentazocine or tripelennamine. In conclusion, there did not appear to be a clinically significant metabolic interaction between pentazocine and tripelennamine.

Distribution of pentazocine in blood and brain of the baboon following intravenous injection.

1 In the baboon the blood levels of pentazocine between 1 and 60 min after intravenous injection of 0.5 mg/kg were measured by a gas chromatographic technique. From cerebral arteriovenous differences it was shown that the peak of the brain concentration occurred within 15 min and probably within 10 min of intravenous injection. At the time of peak concentration about 10% of the injected dose was in the brain, while the corresponding value at 60 min was 2%.2 The concentration of pentazocine in the brain was an order of magnitude greater than the concentration in cerebral venous blood both at 5 min and 60 min after injection. No major brain interregional differences were demonstrated. Cerebrospinal fluid from the cisterna magna did not yield values from which the cerebral concentration of pentazocine could be predicted.

Determination of pentazocine in human whole blood and urine by gas chromatography/surface ionization organic mass spectrometry.

Pentazocine has been found to be measurable with much higher sensitivity by gas chromatography (GC)/surface ionization (SI) organic mass spectrometry (OMS) than by the conventional GC/electron ionization (EI) mass spectrometry. The compound was extracted from human whole blood and urine with Sep-Pak C(18) cartridges before analysis by GC/SIOMS; recoveries were > 96.6% for both samples. The calibration curves were linear in the range 6.25-100 ng ml(-1) and the detection limits were 500 pg ml(-1) of a sample by selected ion monitoring (SIM) with GC/SIOMS. The intra- and inter-day relative standard deviations for the determination of pentazocine in whole blood and urine were not greater than 9.6%. The sensitivity for pentazocine obtained by SI-SIM was about 60 times higher than that obtained by EI-SIM. To validate the present GC/SIOMS method for pentazocine, whole blood and urine samples collected from two volunteers 1-6 h after intramuscular injection of 15 mg of pentazocine were analyzed. The concentrations were 13.5-59.3 ng ml(-1) for whole blood and 0.39-4.00 microg ml(-1) for urine.

Plasma pentazocine radioimmunoassay.

A sensitive and specific radioimmunoassay of dog and human plasma pentazocine is described. Rabbit antiserum and the second antibody method separated bound from free pentazocine. The radioimmunoassay employed an 125I-labeled radioligand and required extraction from the sample prior to quantitation. The method had a detection limit of approximately 200 pg/assay tube (1 ng/ml). The assay was used successfully to measure pentazocine in the plasma of beagle hounds given 0.3 mg of pentazocine/kg iv. The decline in plasma levels fitted a two-compartment body model with a 100-min mean overall half-life and a 3.2-liters/hr mean plasma clearance rate.

Pentazocine and tripelennamine (T's and Blues) abuse: toxicological findings in 39 cases.

The post mortem findings of pentazocine and tripelennamine ("T's and Blues") in abusers dying in the City of St. Louis between July 1, 1979 and July 30, 1981 are presented. Thirty-three deaths were homicides; 30 black males, ages 21-38; one white male, age 26, died from gunshot wounds; and two black females, age 18 and 32, died of stab wounds. Blood concentrations of pentazocine and tripelennamine in these cases ranged from 0.20 to 3.3 mg/L, (mean +/- SD 0.72 +/- 0.64 mg/L) and 0.02 to 1.8 mg/L (mean +/- SD 0.29 +/- 0.40 mg/L), respectively. The six deaths attributed to T's and Blues abuse involved three black males, ages 20, 28 and 49, and three black females, ages 21, 25, and 45 years. Blood concentrations of pentazocine and tripelennamine ranged from 0.44 to 2.5 mg/L and 0.09 to 4.1 mg/L, respectively. Ethanol and diazepam were also detected in 49% and 13% of all deaths, respectively. Foreign body or talc granulomas in lung were the most common pathological finding relevant to the abuse of T's and Blues.

Analysis of zopiclone (Imovane) in postmortem specimens by GC-MS and HPLC with diode-array detection.

A 26-year-old black female was found dead at home. Her mouth was covered with a fluid containing chalky particles. Empty strips of Imovane (zopiclone) and an empty bottle of Fortal (pentazocine) were also found. No urine was available at autopsy. Screening of postmortem blood and stomach contents with enzyme-multiplied immunoassay technique (EMIT) detected only caffeine. Further screening using routine high-performance liquid chromatography (HPLC) with diode-array detection and gas chromatography (GC) with mass spectrometric detection revealed the presence of large amounts of pentazocine in the blood and stomach contents. In the HPLC chromatogram, a second peak that was only partially resolved from the solvent front was observed. Thin-layer chromatography demonstrated the presence of zopiclone, but optimized HPLC and GC conditions had to be used for proper identification and quantitation. This case illustrates the fact that zopiclone can be easily overlooked during routine forensic screening.

Euthanasia: a challenge for the forensic toxicologist.

People die daily in the hospital. Mostly, they die because their illnesses were no longer treatable (natural death). Unfortunately, some people die an unnatural death, in particular, as the result of euthanasia. In contrast to the situation in most countries, in the Netherlands euthanasia is accepted by the courts under strict conditions. It can be very difficult for the legal authorities to establish whether a person has died from natural causes or from suicide, euthanasia, or murder. In addition to the pathologist and the lawyer, the toxicologist also has a number of problems in showing whether euthanasia has been carried out. These can consist of the following analytical problems: (a) interactions--the patients involved have frequently been receiving a large number of toxic and nontoxic drugs simultaneously; (b) identification--not all drugs administered are included in general screening procedures; (c) metabolites--a large number of metabolites may have accumulated toward the end of a long therapeutic regimen; and (d) determination--determination of quaternary muscle relaxants and their various metabolites, as well as other drugs, can be problematic. There are also toxicokinetic problems; because of poor kidney and liver function, low serum albumen, general malaise, and interactions between these factors and other drugs, the kinetics of a given drug can differ from normal. This makes it all the more difficult to determine whether the patient died from an accumulation of medication or from a so-called "euthanetic" drug mixture.(ABSTRACT TRUNCATED AT 250 WORDS)

Analytical problems with putrefaction in a fatal case involving ergotamine and pentazocine.

A 29-year-old male drug addict was found dead at the bottom of a staircase. Analysis of the acid-hydrolized blood showed the presence of pentazocine and two characteristic compounds that contained L-phenylalanine and D-proline, linked together by peptide bounds. It was shown that the latter two components could emanate from the peptide part of ergotamine under the conditions used. It seemed likely that, at the time of analysis, pentazocine and ergotamine were present at concentrations far above therapeutic values. A third component in the blood could not be identified.

[Identification of pentazocine, piritramide and methadone in blood using thin layer chromatography]. / Identyfikacja pentazocyny, pirytramidu i metadonu we krwi metoda chromatografii cienkowarstwowej.

Pentazocine, piritramide and methadone, when extracted from blood or plasma with ether at pH ca. 12, were separated by TLC method on alumina or silica gel by ascending technique on 5 x 20 cm and 2.5 x 7.5 cm plates and also by horizontal development, using suitable mobile phases. The substances were identified by reaction with potassium iodoplatinate or 20% Na2CO3 solution (up to the amount 2 micrograms pentazocine, 0.5 microgram piritramide and 1.5 micrograms methadone.

[Pharmacokinetics of ketamine and pentazocine during total intravenous anesthesia with droperidol, pentazocine and ketamine].

Pharmacokinetics was studied in ten surgical patients who underwent various operative procedures of about 4 hours under total intravenous anesthesia with droperidol, pentazocine and ketamine (DPK). Plasma levels of ketamine, its metabolites and pentazocine were determined thirteen times during and after DPK. During anesthesia, ketamine (KO) and norketamine (KMI) levels ranged from 0.7 to 1.0 micrograms.ml-1 and from 0.09 to 0.74 micrograms.ml-1, respectively. A small amount of dehydronorketamine (KM II) was detected only 90 min after the start of DPK anesthesia. Plasma half-lives of ketamine were calculated to be 33 min for distribution phase (alpha phase) and 60 min for elimination phase (beta phase), respectively. Pentazocine levels decreased 300 min after the induction of DPK to 10% of the control level measured 5 min after its injection. Plasma half-lives of pentazocine were 60 min for alpha phase and 140 min for beta phase, respectively. The data obtained in this clinical study show that pharmacokinetics of ketamine during DPK is almost similar to that of DFK.

[Halothane-pentazocine interaction in dogs (author's transl)].

It is known that narcotics reduce the alveolar concentration of inhalation anesthetics in man and animals. However the magnitude and duration of narcotic effect on inhalation anesthesia is not known. Accordingly, I determined in dogs the temporal effect of various doses of pentazocine, a commonly used anesthetic adjuvant, on the minimum alveolar concentration (MAC) of halothane. In addition, I compared plasma pentazocine concentrations in dogs both awake and during halothane anesthesia using an identical intramuscular dose of pentazocine. Intramuscular injection of pentazocine, group II (2.5 mg/kg), group III (5 mg/kg), group IV (10 mg/kg) reduced MAC of halothane required for anesthesia. The magnitude of MAC depression were 19.3% of control halothane MAC in group II, 36.4% of control in group III and 41.7% of control in group IV. Postinjection plasma concentration was fitted by computer with a 2-compartment open pharmacokinetic model. Plasma pentazocine concentration for awake (group I) and anesthetized (group II) dogs given the same dose (2.5 mg/kg) did not differ significantly on biological half-life, total apparent volume of distribution and body clearance. Halothane minimum alveolar concentration (MAC) was correlated to plasma pentazocine concentration (r= -0.60) and cerebrospinal fluid pentazocine concentration (r= -0.74).

Hollow fiber-based liquid-liquid-liquid microextraction combined with electrospray ionization-ion mobility spectrometry for the determination of pentazocine in biological samples.

A new method based on liquid-liquid-liquid microextraction combined with electrospray ionization-ion mobility spectrometry (LLLME-ESI-IMS) was used for the determination of pentazocine in urine and plasma samples. Experimental parameters which control the performance of LLLME, such as selection of composition of donor and acceptor phase, type of organic solvent, ionic strength of the sample, extraction temperature and extraction time were studied. The limit of detection and relative standard deviation of the method were 2 ng/mL and 5.3%, respectively. The linear calibration ranged from 10 to 500 ng/mL with r(2)=0.998. Pentazocine was successfully determined in urine and plasma samples without any significant matrix effect.