Dipivefrine

Dipivefrine is a member of a class of pharmaceutical agents known as prodrugs. Dipivefrine is not active itself but is biotransformed in the body to epinephrine. It is used in the treatment of open-angle and secondary glaucoma

Isoflurophate

Isoflurophate is a long acting cholinesterase inhibitor and potent miotic. It works as an indirect acting parasympathomimetic agent to reduce intraocular pressure. Also known as diisopropyl phosphofluoridate (Dyflos), it is an irreversible organophosphate cholinesterase inhibitor. It and its analogues were studied extensively during the Second World War as substances that could be employed as war gases because of their volatility and rapid absorption from the lungs. Due to its toxicity it is only used in the treatment of patients with open angle glaucoma or other chronic glaucomas which are not controlled with other less toxic short acting agents

Biotransformation of Ethanol to Ethyl Glucuronide in a Rat Model After a Single High Oral Dosage

Ethyl glucuronide (EtG) is a minor ethanol metabolite that confirms the absorption and metabolism of ethanol after oral or dermal exposure. Human data suggest that maximum blood EtG (BEtG) concentrations are reached between 3.5 and 5.5. h after ethanol administration. This study was undertaken to determine if the Sprague-Dawley (SD) rat biotransforms ethanol to EtG after a single high oral dose of ethanol. SD rats (male, n=6) were gavaged with a single ethanol dose (4g/kg), and urine was collected for 3. h in metabolic cages, followed by euthanization and collection of heart blood. Blood and urine were analyzed for ethanol and EtG by gas chromatography and enzyme immunoassay. Blood and urine ethanol concentrations were 195 ± 23 and 218 ± 19. mg/dL, whereas BEtG and urine EtG (UEtG) concentrations were 1,363 ± 98. ng equivalents/mL and 210 ± 0.29. mg equivalents/dL (X̄±standarderrorofthemean[S.E.M.]).Sixty-six male SD rats were gavaged ethanol (4. g/kg) and placed in metabolic cages to determine the extent and duration of ethanol to EtG biotransformation and urinary excretion. Blood and urine were collected up to 24. h after administration for ethanol and EtG analysis. Maximum blood ethanol, urine ethanol, and UEtG were reached within 4. h, whereas maximum BEtG was reached 6. h after administration. Maximum concentrations were blood ethanol, 213 ± 20. mg/dL; urine ethanol, 308 ± 34. mg/dL; BEtG, 2,683 ± 145. ng equivalents/mL; UEtG, 1.2 ± 0.06. mg equivalents/mL (X̄±S.E.M.). Areas under the concentration-time curve were blood ethanol, 1,578. h*mg/dL; urine ethanol, 3,096. h*mg/dL; BEtG, 18,284. h*ng equivalents/mL; and UEtG, 850. h*mg equivalents/dL. Blood ethanol and BEtG levels were reduced to below limits of detection (LODs) within 12 and 18. h after ethanol administration. Urine ethanols were below LOD at 18. h, but UEtG was still detectable at 24. h after administration. Our data prove that the SD rat biotransforms ethanol to EtG and excretes both in the urine and suggest that it is similar to that of the human

Bioequivalence Study of Nabumetone: Tablet Versus Suspension

The orally administered tablet and suspension of the analgesic drug nabumetone (Relafen), a novel naphthylalkanone, were tested for bioequivalence. Nabumetone is rapidly metabolized to an active metabolite, 6-methoxy-2-naphthylacetic acid (BRL 10720). The pharmacokinetics of the metabolite were studied in 24 healthy adult male volunteers. Each received a 1-g dose of the nabumetone formulations in a balanced, randomized, two-way crossover investigation. Serum metabolite concentrations were determined over a 120-hour interval by high-performance liquid chromatography. The values of the pharmacokinetic parameters computed for tablet and suspension are presented in that order: area under the curve = 1,269:1,338 mg · hour/ml; absorption half-life = 1.04:0.83 hour; elimination half-life = 27.16:25.15 hours; lag time = 0.19:0.07 hour; peak concentration = 27.56:31.91 μg/ml, and time to peak concentration = 4.99:4.17 hours. The mean concentration of BRL 10720 was found to be higher during the first eight hours for the suspension than for the tablet. Using criteria for statistical significance, the values for peak concentration, time to peak concentration, elimination half-life, and lag time were found significant (p \u3c0.05). These results may well be reflecting the increased absorption characteristics of the suspension due to the pharmaceutical characteristics of the preparation. The formulations were found to be bioequivalent when compared on the premise that no significant difference was detected when area under the curve and all other parameters were compared, based upon the 75 75 rule analysis

Mathematical Modeling of the Osmotic Fragility of Rabbit Red Blood Cells

The osmotic fragility (OF) test is used to determine the extent of red blood cell hemolysis (RBCH) produced by osmotic stress. RBCH is dependent upon cell volume, surface area, and functional integrity of cell membranes. The variation of cell lysis with stress reflects underlying cell subpopulations and their membranes\u27 cytoskeletal functionality. OF was determined on blood from New Zealand white rabbits. The dependence of RBCH on NaCl concentration ([NaCl]) was determined spectrophotometrically by measuring absorbance (Abs) from hemoglobin release at 545 nm. Abs data were fitted to the equation Abs = p3 erfc( ([NaCl] - p1) p2) where p3 reflects maximum RBCH, p1 measures the [NaCl] at 50% RBCH, and p2 shows the dispersion in [NaCl] producing the RBCH. Parameter values for control blood were p1 = 0.4489 ± 0.0016; p2 = 0.0486 ± 0.0016; and p3 = 0.4366 ± 0.0022. Addition of indomethacin (9.6 μg/mL) produced an increased fragility in the RBC\u27s characterized by increased values of p1 and p2. Normalization of the data to p3 did not change the values of p1 or p2. Our equation satisfactorily describes the variation in RBCH as a function of [NaCl]. The parameters of the equation can be used to quantitatively characterize Abs/[NaCl]. The compare pharmacological, Toxicological, and pathological effects on the OF of RBC\u27s

Tissue Extraction and High-Performance Liquid Chromatographic Determination of Ketoprofen Enantiomers

Local transcutaneous delivery of non-steroidal anti-inflammatory drugs avoids gastrointestinal side effects and concentrates drugs in the intended tissues. An extraction and HPLC method was developed for ketoprofen in skin, fascia and muscle. Tissue samples were homogenized in NaHCO3. After methylene chloride removal of lipids, the aqueous layer was acidified with HCl and back extracted into isooctane/isopropanol. Ketoprofen was derivatized with ethylchloroformate/S-(-)-α-phenylethylamine in triethylamine, then detected by HPLC. Ketoprofen recovery was linear (1-33 μg/g) and was detected in these tissues following in vivo cathodic iontophoresis (160 mA*min). This represents the first non-radioactive method for determination of ketoprofen in tissues following transcutaneous iontophoresis

Determination of Chromate Adulteration of Human Urine by Automated Colorimetric and Capillary Ion Electrophoretic Analyses

Various chemicals can be added to urine specimens collected for drug analysis to abnormally elevate ionic concentrations and/or interfere with either immunoassay urine drug-screening procedures or gas chromatographic-mass spectrometric confirmation techniques. One such adulterant, Urine Luck (formula 5.3), has been identified in our previous research to contain potassium dichromate. Screening of suspected adulterated specimens and confirmation of the adulterant are important for forensic drug screening. The application and comparison of automated colorimetric and capillary ion electrophoretic techniques for the detection, confirmation, and quantitation of chromate adulteration of urine specimens were the purpose of this investigation. Thirty-six urine specimens suspected of adulteration were analyzed for chromate by colorimetric analysis with diphenylcarbazide. Duplicate aliquots were analyzed for chromate by capillary ion electrophoresis. Results of the colorimetric chromate analyses revealed a mean chromate concentration of 929 μg/mL with a standard error of 177 μg/mL and a range of 30 to 5634 μg/mL. Results of the capillary ion electrophoresis chromate analyses revealed a mean chromate concentration of 1009 μg/mL with a standard error of 218 μg/mL and a range of 20 to 7501 μg/mL. The correlation coefficient between the capillary ion electrophoretic and colorimetric chromate results was r = 0.9669. Application of the automated diphenylcarbazide colorimetric technique provides rapid determination of chromate adulteration of a urine specimen. Capillary ion electrophoresis offers a separation technique to confirm the presence of chromate in suspected adulterated specimens. The excellent correlation between these methods substantiates their application to forensic testing as screening and/or confirmation techniques

Sevoflurane Analysis in Serum by Headspace Gas Chromatography With Application to Various Biological Matrices

Sevoflurane is a nonflammable general anesthetic administered by inhalation of vaporized liquid that rapidly partitions out of aqueous biological matrices into a gaseous phase because of its volatility and hydrophobicity. We describe a headspace analysis of sevoflurane that can be performed without the use of an expensive automated headspace analyzer. Sevoflurane standards (0-109 mg/L) and quality control specimens (12.2 and 72.9 mg/L) were prepared and quantitated on an intraday and interday basis. Headspace gas was manually injected (150°C) with a 2.5-mL gas-tight syringe into a Perkin-Elmer model 8500 gas Chromatograph equipped with a 6-ft × 2-mm i.d. glass column (100°C) containing 0.2% Carbowax 1500 on Carbopak C packing with a flame-ionization detector (200°C), which allowed for elution of the internal standard, 1 -propanol (1.56 min), and sevoflurane (2.92 min). Linear regression of the peak-area ratios of sevoflurane to 1-propanol (6.38 g/L), versus the sevoflurane concentrations yielded an average intraday correlation coefficient of 0.989 (S.D. = 0.003, n = 5) and mean quality control specimen values of 14.19 mg/L (C.V. = 5.1 %, n = 5) and 66.72 mg/L (C.V. = 3.3%, n = 5). The average interday standard curve correlation coefficient was 0.987 (S.D. = 0.01, n = 5), and the mean quality control specimen values were 12.22 mg/L (C.V. = 13.7%, n = 5) and 74.27 mg/L (C.V. = 8.7%, n = 5). The Chromatographic method described produced accurate and reproducible results with a simple on-column headspace gas injection. This method allows for quantitation of sevoflurane in various biological matrices by Chromatographic separation of the headspace gas in a sealed specimen container

A Fatal Drug Interaction Between Clozapine and Fluoxetine

A case is presented of a fatal drug interaction caused by ingestion of clozapine (Clozaril(TM)) and fluoxetine (Prozac(TM)). Clozapine is a tricyclic dibenzodiazepine derivative used as an \u27atypical antipsychotic\u27 in the treatment of severe paranoid schizophrenia. Fluoxetine is a selective serotonin reuptake inhibitor used for the treatment of major depression. Clinical studies have proven that concomitant administration of fluoxetine and clozapine produces increased plasma concentrations of clozapine and enhances clozapine\u27s pharmacological effects due to suspected inhibition of clozapine metabolism by fluoxetine. Blood, gastric, and urine specimens were analyzed for fluoxetine by gas chromatography/mass spectrometry (GC/MS) and for clozapine by gas-liquid chromatography (GLC). Clozapine concentrations were: plasma, 4.9 μg/mL; gastric contents, 265 mg; and urine, 51.5 μg/mL. Fluoxetine concentrations were: blood, 0.7 μg/mL; gastric contents, 3.7 mg; and urine 1.6 μg/mL. Norfluoxetine concentrations were: blood, 0.6 μg/mL, and none detected in the gastric contents or urine. Analysis of the biological specimens for other drugs revealed the presence of ethanol (blood, 35 mg/dL; vitreous, 56 mg/dL; and urine 153 mg/dL) and caffeine (present in all specimens). The combination of these drugs produced lethal concentrations of clozapine and high therapeutic to toxic concentrations of fluoxetine. The deceased had pulmonary edema, visceral vascular congestion, paralytic ileus, gastroenteritis and eosinophilia. These conditions are associated with clozapine toxicity. The combined central nervous system, respiratory and cardiovascular depression of these drugs was sufficient to cause death. The death was determined to be a clozapine overdose due to a fatal drug interaction

The Distribution of Sevoflurane in a Sevoflurane Induced Death

The distribution of sevoflurane (fluoromethyl 2,2,2,-trifluoro-1-(trifluoromethyl) ethyl ether) in blood, urine, liver, kidney, vitreous humor, and tracheal aspirate is presented from a subject with a sevoflurane induced death. Sevoflurane is a nonflammable general anesthetic administered by inhalation of vaporized liquid. Although general inhalation anesthetics have the potential to be fatal if not properly administered, the incidence of abuse is minute in comparison to other illicit drugs (1). Currently, there are no citations in the literature defining the body distribution of sevoflurane in a sevoflurane induced death. The decedent was found lying in a bed with an oxygen mask containing a gauze pad secured to his face. Three empty bottles and one partially full bottle of Ultane™ (sevoflurane) were found with the body in addition to two pill boxes containing a variety of prescription and non-prescription drugs. Serum, urine and gastric contents from the deceased were screened for numerous drugs and metabolites using a combination of thin layer chromatographic, colorimetric and immunoassay techniques. Analysis of biological specimens from the deceased revealed the presence of: amphetamine, caffeine, pseudoephedrine, nicotine, nicotine metabolite, and valproic acid. Sevoflurane concentrations were determined by headspace gas chromatography with flame ionization detection and revealed concentrations of 26.2 μg/mL in the blood, 105 μg/mL in the urine, 31.9 μg/mL in the tracheal aspirate, 86.7 μg/mL in the vitreous humor, 30.8 mg/kg in the liver, and 12.8 mg/kg in the kidney. The decedent had pathologies consistent with respiratory suppression including pulmonary atelectasis, pulmonary edema, and neck vein distention. The official cause of death was respiratory suppression by sevoflurane and the manner of death was unclear