Showing papers in "Therapeutic Drug Monitoring in 1993"
TL;DR: It was shown that the citalopram elimination partially depends on the mephenytoin oxygenase, since steady-state serum concentration, half-life, and area under the serum concentration/time curve for cITALopram were significantly higher in poor metabolizers of mephenYtoin than in extensive metabolizer of me Pheny toin.
Abstract: Summary The relationship between the metabolism of the selective serotonin reuptake inhibitor citalopram and the sparteine and mephenytoin oxidation polymorphisms was studied in 24 healthy male volunteers, constituting panels of extensive metabolizers of sparteine and mephenytoin (n = 10), poor metabolizers of sparteine (n = 8), and poor metabolizers of mephenytoin (n = 6). Each subject was given 40 mg/day citalopram for 10 days and citalopram, and its des- and didesmethylmetabolites were assayed in serum and urine. Using a nonenantioselective analytical method (high-performance liquid chromatography), it was shown that the citalopram elimination partially depends on the mephenytoin oxygenase, since steady-state serum concentration, half-life, and area under the serum concentration/time curve for citalopram were significantly higher in poor metabolizers of mephenytoin than in extensive metabolizers of mephenytoin. Both citalopram total clearance and demethylation clearance (formation of desmethylcitalopram) were significantly lower in poor metabolizers of mephenytoin compared to extensive metabolizers (median 15.2 vs. 27.3 and 2.6 vs. 5.9 L/h, respectively). It was further indicated that the demethylation of desmethylcitalopram to didesmethylcitalopram depends on the sparteine oxygenase CYP2D6. Didesmethylcitalopram could virtually not be detected in any poor metabolizers of sparteine, contrasting measurable serum levels in all sparteine/mephenytoin extensive metabolizers. The demethylation clearance of desmethylcitalopram was significantly lower in sparteine poor metabolizers compared to extensive metabolizers (0.3 vs. 2.4 L/h, respectively). During administration of citalopram, there was a modest increase in sparteine metabolic ratio from median 0.31 to 0.80 in extensive metabolizers of sparteine, whereas the mephenytoin S/R ratio was unaltered during citalopram treatment. Both the sparteine and the mephenytoin oxidation polymorphism thus appear to contribute partially to the total pharmacokinetic variability of citalopram.
215 citations
TL;DR: The role of population pharmacokinetic modeling is to store experience with drug behavior to select a specific serum level therapeutic goal based on each individual patient's need for the drug and on the risk of adverse reactions.
Abstract: The role of population pharmacokinetic modeling is to store experience with drug behavior. The behavior of the model is then correlated with the clinical behavior of the patients studied, permitting selection of a specific serum level therapeutic goal that is based on each individual patient's need for the drug and on the risk of adverse reactions, both of which must be considered. A dosage regimen is then computed to achieve that goal with maximum precision. The patient should not run a greater risk of toxicity than is justified, and should obtain the maximum possible benefit within the acceptable risk. The regimen is given and the patient monitored.
160 citations
TL;DR: Findings indicate that, at the dosage tested, fluvoxamine markedly inhibits the demethylation of imipramine without affecting significantly the CYP2D6-mediated hydroxylation of desipramines.
Abstract: SummaryThe effect of the selective serotonin reuptake inhibitor fluvoxamine (100 mg/day for 10 consecutive days) on the kinetics of a single oral dose of imipramine (50 mg) and desipramine (100 mg) was investigated in 12 healthy subjects. Compared with a control session, treatment with fluvoxamine c
129 citations
TL;DR: It is suggested that the presence of tobacco smoke constituents in seminal plasma could provide a warning of the adverse effects of cigarette smoke on the physiology of reproduction.
Abstract: Sperm samples from 44 cigarette smokers and 50 nonsmokers attending an infertility clinic were examined by high-performance liquid chromatography (HPLC) assay and HPLC-mass spectrometry for the presence of nicotine (NIC), cotinine (COT), and trans-3'-hydroxycotinine (THOC) in seminal plasma. Smokers were found to have levels of COT and THOC in seminal plasma that were similar to those found in serum. The level of NIC was significantly increased in seminal plasma compared to serum. Total motility of spermatozoa was significantly and negatively correlated to COT and THOC levels in seminal plasma. Forward motility of spermatozoa was correlated only with cotinine semen levels. On the basis of these results, we suggest that the presence of tobacco smoke constituents in seminal plasma could provide a warning of the adverse effects of cigarette smoke on the physiology of reproduction.
111 citations
TL;DR: The data indicate that the ECMO is associated with lowering of the concentrations of commonly used medications and that this process may depend partially on how new the membrane is, and more experiments with new and used systems are warranted, as well as with different types of ECMO.
Abstract: There is an increased use of extracorporeal membrane oxygenation (ECMO) in the last 15 years for critically ill neonates. While receiving ECMO therapy, the critically ill infant needs various medications. We performed an in vitro study to evaluate the potential effect of the membrane oxygenator on drug extraction. Two closed ECMO circuits were set up at rates of 320 ml/min. One circuit was new and the other was used clinically for 5 days. Morphine at 8 ng/ml, gentamicin 10 micrograms/ml, vancomycin 40 micrograms/ml, phenobarbital 20 micrograms/ml, and phenytoin 20 micrograms/ml were injected into the circuit at 1-h intervals. Blood samples were drawn from the circuit at 10, 30, 60, and 240 minutes after injection. In the new circuit, drugs were eliminated as follows: vancomycin 36%, gentamicin 10%, phenobarbital 17%, phenytoin 43%, morphine 36%. In the used system, levels fell to a much smaller extent: vancomycin 11%, phenobarbital 6%, gentamicin 0%, phenytoin 0%, and morphine 16%. In a child receiving 20 micrograms/kg/h infusion of morphine, steady-state concentrations of 68.2 ng/ml fell to 11.6 ng/ml after changing the membrane. Our data indicate that the ECMO is associated with lowering of the concentrations of commonly used medications and that this process may depend partially on how new the membrane is. Before these changes may lead to new dosing guidelines for small children receiving ECMO, more experiments with new and used systems are warranted, as well as with different types of ECMO.
97 citations
TL;DR: Pharmacokinetic and pharmacodynamic analyses of marijuana data have provided new insights into the relationship of blood concentrations of tetrahydrocannabinol (THC) and metabolites to drug-induced effects and may be beneficial to forensic scientists in their interpretation of cannabinoid blood data associated with accidents, criminal investigations, and traffic violations.
Abstract: Pharmacokinetic and pharmacodynamic analyses of marijuana data have provided new insights into the relationship of blood concentrations of tetrahydrocannabinol (THC) and metabolites to drug-induced effects. THC is rapidly absorbed and distributed to tissues; initial changes in blood concentrations are out of phase (hysteresis) with physiological and behavioral changes. Once blood/tissue equilibrium is established, a direct correlation of THC blood concentration and effect is observed. Various pharmacodynamic models provide concentration estimates in the range of 7-29 ng/ml for amount of THC in blood necessary for production of 50% of maximal subjective high effect. Also, models have been proposed for predicting the time of marijuana exposure from plasma concentrations of THC and THC-carboxy acid metabolite (THCCOOH). These models were based on data from a controlled clinical study of marijuana smoking. Such models allow prediction of the elapsed time since marijuana use based on analysis for cannabinoids from a single plasma sample and provide accompanying 95% confidence intervals around the prediction. These models may be beneficial to forensic scientists in their interpretation of cannabinoid blood data associated with accidents, criminal investigations, and traffic violations.
95 citations
TL;DR: The data indicate that a correlation exists between geographical location and blood lead concentration in young children and government health agencies at all levels should prioritize their limited resources for those areas that are most at risk for lead poisoning.
Abstract: The Centers for Disease Control (CDC) have recently lowered the acceptable blood lead concentration in young children from or = 10 micrograms/dl (0.48 mumol/L), of which only 71 (1.6%) had lead values > or = 25 micrograms/dl (1.21 mumol/L). Only 5 of the 212 studied children (2.4%) from suburbia and 7 of the 120 children (5.8%) from rural communities had blood lead concentrations > or = 10 micrograms/dl (0.48 mumol/L). None of these children, however, had a lead concentration > or = 15 micrograms/dl (0.73 mumol/L). In contrast, 276 inner-city subjects (6.6%) had lead values > or = 15 micrograms/dl (0.73 mumol/L). Our data indicate that a correlation exists between geographical location and blood lead concentration in young children. Government health agencies at all levels should prioritize their limited resources for those areas that are most at risk for lead poisoning.
92 citations
TL;DR: Findings are in agreement with the recent observations that the demethylation of desmethylcitalopram is partly mediated via the sparteine/debrisoquine oxygenase (CYP2D6) and that levomepromazine is a potent inhibitor of CYP2D 6.
Abstract: The pharmacokinetic interactions between the selective serotonin reuptake inhibitor citalopram, given as an oral dose of 40 mg/day for 10 days, and (1) levomepromazine (50 mg single oral dose), (2) imipramine (100 mg single oral dose), and (3) lithium (30 mmol/day orally for 5 days) were examined in three panels each of 8 healthy young male volunteers (age 20-31). All volunteers were classified as extensive metabolizers of sparteine and mephenytoin. Each subject completed three study phases--one with citalopram alone, one with one of the three other drugs, alone, and one with citalopram combined with the corresponding other drug. For citalopram and its metabolites, a non-enantioselective analytical method (high-performance liquid chromatography) was used. Only two statistically significant interactions were indicated. First, levomepromazine caused a 10-20% increase from the initial steady-state levels of the primary citalopram metabolite, desmethylcitalopram. Second, citalopram caused approximately 50% increase in the single-dose area under the serum concentration/time curve of desipramine (primary metabolite or imipramine) and a corresponding reduction in the level of the subsequently formed metabolite 2-hydroxydesipramine. These findings are in agreement with the recent observations that (1) the demethylation of desmethylcitalopram (to didesmethylcytalopram) is partly mediated via the sparteine/debrisoquine oxygenase (CYP2D6) and that levomepromazine is a potent inhibitor of CYP2D6, and (2) that desmethylcitalopram has a somewhat stronger affinity for CYP2D6 than desipramine, and therefore may inhibit the hydroxylation of desipramine, which is also a substrate of CYP2D6.
79 citations
TL;DR: Aluminum toxicity should represent a rare and unusual side effect in dialyzed uremic patients in the future by eliminating aluminum from the water used to prepare the dialysate, substituting calcium-containing phosphate-binding agents for those containing aluminum, and strict avoidance of the concomitant use of citrate- and aluminum-containing compounds.
Abstract: During the past two decades, in association with the commencement of chronic dialysis therapy and prolongation of the uremic state, aluminum toxicity has represented a major cause of morbidity and mortality in uremic patients. The uremic patient has been found to be at higher risk of aluminum loading and toxicity from various sources of parenteral exposure, enhanced gastrointestinal absorption, and compromised ability to eliminate any systemically administered aluminum due to renal impairment. However, the potential sources of aluminum exposure and loading resulting in toxicity in uremic patients have recently been identified. As a result, this toxicity can largely be prevented by eliminating aluminum from the water used to prepare the dialysate, substituting calcium-containing phosphate-binding agents for those containing aluminum, and strict avoidance of the concomitant use of citrate- and aluminum-containing compounds. Thus, in the future, aluminum toxicity should represent a rare and unusual side effect in dialyzed uremic patients.
76 citations
TL;DR: Analysis of nicotine along the hair shafts may serve as a useful way of assessing individual cigarette-smoking behavior over a period from several months to a number of years.
Abstract: The concentration of nicotine in hair was measured by a capillary gas chromatograph with a nitrogen-phosphorus detector after hair was dissolved in 2.5 N sodium hydroxide and nicotine was extracted using diethyl ether. In hair samples obtained from 36 smokers, who had smoked ≥3 years, there was a significant positive correlation between the concentration of nicotine and the number of cigarettes consumed daily (r=0.685; p<0.001). The nicotine content of white hair was much less than that of black hair collected from the same subjects with grizzled hair. The above findings were confirmed by an animal experiment, in which nicotine (0.2, 0.6, and 2 mg/kg/day for 2 weeks) was administered intraperitoneally to pigmented rats whose hair had been removed beforehand by plucking from an area of the back of each rat
74 citations
TL;DR: A videotaped home behavior (VHB) assessment instrument with high construct validity and reliability and a strong relationship to criterion references was employed to test the hypothesis that aluminum is an important pathogenic factor in AD.
Abstract: Drug trials designed to modify the progression of Alzheimer's disease (AD) have required the development of mental state and behavior evaluation instruments that are sensitive to cognitive decline and measure skills useful in everyday living. We describe a videotaped home behavior (VHB) assessment instrument with high construct validity and reliability and a strong relationship to criterion references. The VHB was employed to test the hypothesis that aluminum is an important pathogenic factor in AD. The trivalent chelating agent desferrioxamine (DFO), 125 mg i.m. twice daily five days per week, was used in a randomized single-blind, oral lecithin, placebo-controlled clinical trial in 48 patients with AD. Analysis showed that the treatment and no-treatment groups were closely matched at entry into the trial but that the rate of decline, as measured by the VHB over 2 years of observation, was twice as rapid in the no-treatment group compared with the DFO-treated group. Furthermore, trace-metal analysis of autopsied brain confirmed that extended treatment with DFO lowered neocortical brain aluminum concentrations to near control concentrations. Aluminum ion-specific chelation may be a useful palliative treatment for AD, and further clinical trials are indicated.
TL;DR: Pharmacokinetic parameters obtained in cycle 10 indicate significant differences for total plasma clearance, mean residence time, and distribution half-life when compared to those in cycles 1–9.
Abstract: A case report of toxicity following concurrent administration of high-dose methotrexate and amoxycillin is presented. A 16-year-old male patient was administered 10 high-dose methotrexate cycles for treatment of a fully malignant osteogenic sarcoma. Methotrexate was administered at a dosage of 8 g/m2 and infused intravenously over a 6-h period. The patient received pre- and posttreatment hydration and sodium bicarbonate for alkalinization of urine. Calcium folinate rescue was performed when appropriate. During the 10th cycle, coadministration of amoxycillin (1 g/6 h, p.o.) resulted in prolonged and marked enhancement of methotrexate serum levels. Pharmacokinetic parameters obtained in cycle 10 indicate significant differences for total plasma clearance, mean residence time, and distribution half-life when compared to those in cycles 1-9. Amoxycillin decreased the renal clearance of methotrexate, probably by competition at the common tubular secretion system and by secondary methotrexate-induced renal impairment. The patient experienced acute and subacute toxicity with renal failure, myelosuppression, mucositis, nausea, vomiting, fever, and dermatologic abnormalities. Patients receiving amoxycillin during methotrexate therapy should be closely monitored to avoid severe toxicity.
TL;DR: A sensitive high-performance liquid chromatographic (HPLC) method for the measurement of doxorubicin and its metabolites in plasma is described and is readily adaptable to automated analysis of large series of samples.
Abstract: A sensitive high-performance liquid chromatographic (HPLC) method for the measurement of doxorubicin and its metabolites in plasma is described. After precipitation with zinc sulphate and methanol, samples are resolved by isocratic elution from a C18 reverse phase support within 20 min and quantified by endogenous fluorescence. Recoveries over a concentration range from 5 to 1,000 nM of doxorubicin, doxorubicinol, doxorubicinone, doxorubicinolone, and 7-deoxydoxorubicinolone were 80-110%, while recovery for 7-deoxydoxorubicinone was approximately 60%. At concentrations of 5 nM, within-run and between-day coefficients of variation for each compound were < 8 and < 16%, respectively. Limits of detection for the compounds were 1-2 nM and standard curves were linear up to at least 1,000 nM. The drug and its metabolites are stable in deproteinized plasma samples at room temperature and in the dark for at least 24 h. The method requires few manipulations and is readily adaptable to automated analysis of large series of samples.
TL;DR: This assay is more sensitive than earlier methods; it is simple and rapid, and it enables the quantification of midazolam and its α-hydroxy metabolite with very good precision and accuracy in human plasma and urine.
Abstract: We describe a new high-performance liquid chromatography (HPLC) method for measurement of midazolam and its major metabolite, alpha-hydroxymidazolam, in clinical samples. Plasma or urine was mixed with 100 ng internal standard Ro 05-6669 and borate buffer, 0.1 M, pH 9. Midazolam and its related compounds were extracted into diethylether. The organic phase was evaporated to dryness. The residue was dissolved in HPLC mobile phase [methanol-isopropyl alcohol-perchloric acid, 0.5 microM (57:25:18)] and injected into the chromatograph. The separation of substances was performed on an Spherisorb S5CN 250 x 4.6 mm HPLC column maintained at 45 degrees C. The detection was performed by absorption measurement at 245 nm. At a flow rate of 1.7 ml/min, the retention times of Ro 05-6669, 1,4 dihydroxymidazolam, alpha-hydroxymidazolam, 4-hydroxymidazolam and midazolam were 4.0, 6.7, 7.8, 9.6, and 10.8 min, respectively. In the concentration range of 5-1,000 ng/ml, the calibration graphs for both compounds were linear. The coefficients of variation of the between-day and within-day assay were < 14% for the concentration range 5-10 and < 7% for the range 10-600 ng/ml. The limits of detection for midazolam and alpha-hydroxymidazolam were 2 and 4 ng/ml, respectively. This assay is more sensitive than earlier methods; it is simple and rapid, and it enables the quantification of midazolam and its alpha-hydroxy metabolite with very good precision and accuracy in human plasma and urine.
TL;DR: The serum protein binding of both oxycodone and morphine was independent of drug concentration in the therapeutic range (5–100 ng/ml), but was dependent on protein concentration, which increased with increasing concentrations of both albumin and A AG.
Abstract: Protein binding of oxycodone and morphine in human serum was determined in vitro using ultrafiltration. Binding studies were also performed using both purified human serum albumin and human alpha 1-acid glycoprotein (AAG). Albumin was found to be the major binding protein for both oxycodone and morphine. The serum protein binding of both oxycodone and morphine was independent of drug concentration in the therapeutic range (5-100 ng/ml), but was dependent on protein concentration. In addition, bound fractions of oxycodone and morphine increased with increasing concentrations of both albumin and AAG. At physiological pH and temperature, the mean (+/- SD) serum protein binding of oxycodone was 45.1% (+/- 0.4%) and that of morphine was 35.3% (+/- 0.2%) A decrease in temperature from 37 to 23 degrees C significantly increased the serum protein binding of oxycodone and morphine by 8-9% (p < 0.0001) and 7-10% (p < 0.0001), respectively, indicating the importance of maintaining the temperature at 37 degrees C during protein binding experiments. A reduction in pH from 7.75-8.85 to 7.4 significantly reduced serum protein binding of both oxycodone and morphine by 4-5% (p < 0.0001) and 4-7% (p < 0.0001), respectively. Serum samples, to which known concentrations of oxycodone had been added and which were stored at -20 degrees C, showing a gradual but significant decline (p < 0.0001) in serum protein binding of oxycodone from approximately 45 to 39% during the 4-week storage period.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: The data suggest that both enantiomers of methadone should be measured if correlations between pharmacodynamics and kinetics are made due to the stereoselective differences in half-life, total volume of distribution, and clearance.
Abstract: Ten patients with chronic pain were randomized to an open, balanced, crossover study. Each patients received two different preparations of racemic methadone, i.e., tablets and intravenous infusion. The pharmacokinetic parameters of the R- and S-enantiomers of the racemate are reported. The analgesically active R-methadone has a significantly longer mean elimination half-life than the optical antipode S-methadone (t1/2 = 37.5 and 28.6 h, respectively). The mean total volume of distribution is 496.6 L for R-methadone and 289.1 L for S-methadone. Significant differences in the mean clearance between R- and S-methadone are seen (0.158 and 0.129 L/min, respectively). However, the lagtime after oral administration and the bioavailability did not show differences between the isomers. The data suggest that both enantiomers of methadone should be measured if correlations between pharmacodynamics and kinetics are made due to the stereoselective differences in half-life, total volume of distribution, and clearance.
TL;DR: Information obtained from animal and human studies of the neurochemical and behavioral properties of cocaethylene and of cocaine-ethanol interactions is reviewed, and the possible implications with respect to the mechanisms and consequences of combined cocaine and ethanol abuse are described.
Abstract: Consumption of ethanol during the course of cocaine binges is common, with an estimated prevalence well in excess of 50%. Cocaine abusers indicate that coingestion of ethanol may enhance and/or prolong the euphoria and reduce unpleasant side effects that may follow. Cocaethylene, an active homologue/metabolite that arises through transesterification of cocaine following coconsumption of cocaine and alcohol, shares many neurochemical and behavioral properties with cocaine and reaches significant blood concentrations. However, cocaine and cocaethylene also appear to differ in some respects, including the relative potency of their actions on the dopamine and serotonin transporters. Information obtained from animal and human studies of the neurochemical and behavioral properties of cocaethylene and of cocaine-ethanol interactions is reviewed, and the possible implications with respect to the mechanisms and consequences of combined cocaine and ethanol abuse are described.
TL;DR: Repeated coadministration of OXC significantly reduced the area under the concentration-time curve (AUC0–24) of FEL by 28% and the FEL maximum plasma concentration (Cmax) by 34%.
Abstract: Eight healthy male volunteers (age 25-41 years) entered an open-label, within-subject study. They were treated for 13 consecutive days with felodipine (FEL) extended-release tablets, 10 mg daily. On day 6, oxcarbazepine (OXC) 600 mg was given in the morning, and from day 7 to 13, the daily dose was increased to 450 mg b.i.d. Blood samples for measurement of FEL and its pyridine metabolite (determined by gas-chromatography) were drawn just before dosing and at 2, 4, 6, 8, 10, 12, and 24 h after dosing on days 5, 6, and 13. Steady-state pharmacokinetic parameters of FEL and its pyridine metabolite were not influenced by the single dose of OXC. Repeated coadministration of OXC significantly reduced the area under the concentration-time curve (AUC0-24) of FEL by 28% and the FEL maximum plasma concentration (Cmax) by 34%. This reduction in FEL bioavailability is much smaller than that observed after co-administration of carbamazepine (CBZ) (i.e., 94%).
TL;DR: Phenobarbital, ethosuximide, and primidone are shown to elute in front of the solubilized proteins, thus permitting quantitation of these drugs without any sample pretreatment, and MECC data obtained using the external standard method and peak areas as the basis for quantitation are shows to be in excellent agreement with those of nonisotopic immunoassays.
Abstract: The determination of antiepileptic drugs in human serum by micellar electrokinetic capillary chromatography (MECC) with direct sample injection is discussed. Nanoliter quantities of patient sera are applied to the beginning of a fused silica capillary filled with a phosphate/borate buffer (pH 9.2) containing 75 mM sodium dodecylsulfate. Upon application of an electric field along the capillary, endogenous and drug substances are transported toward the cathode and separate into distinct zones which are detected by on-column UV absorption. Phenobarbital, ethosuximide, and primidone are shown to elute in front of the solubilized proteins, thus permitting quantitation of these drugs without any sample pretreatment. For phenobarbital and ethosuximide, MECC data obtained using the external standard method and peak areas as the basis for quantitation are shown to be in excellent agreement with those of nonisotopic immunoassays and, for ethosuximide, also with those of high-performance liquid chromatography. The correlation coefficients (n = 50) are between 0.972 and 0.986. Intraday and interday reproducibility data are 2.0-4.5% and 4.5-8.0%, respectively. For primidone, insufficient samples have been available for a comprehensive comparison of MECC data with those of other analytic techniques.
TL;DR: No significant changes in steady-state plasma concentrations of CBZ and its active metabolite, carbamazepine-10,11-epoxide (CBZ-E) occurred, suggesting that CBZ metabolism is probably not affected by fluoxetine or fluvoxamine administration.
Abstract: To study the potential interaction between carbamazepine (CBZ) and selective serotonin reuptake inhibitors, fluoxetine (20 mg/day) and fluvoxamine (100 mg/day) were administered for 3 weeks to eight and seven epileptic patients, respectively, on chronic CBZ treatment. No significant changes in steady-state plasma concentrations of CBZ and its active metabolite, carbamazepine-10,11-epoxide (CBZ-E) occurred, suggesting that CBZ metabolism is probably not affected by fluoxetine or fluvoxamine administration.
TL;DR: The percentage of CsA in each type of lipoproteins was shown to vary with the lipid levels among individuals, and a significant negative correlation was found between apparent distribution volume at steady state in plasma and TC, PL, and LDLc.
Abstract: The present study attempted to characterize the distribution of cyclosporin A (CsA) among the lipoprotein fractions, very-low-, intermediate-, low-, and high-density (VLDL, IDL, LDL, and HDL, respectively) in the plasma of patients awaiting heart transplantation and the influence of plasma lipid constituents on the pharmacokinetics of CsA. Major fractions of a therapeutic concentration of CsA were found in HDL and in LDL. In addition, plasma lipid concentrations (total cholesterol, triglycerides, phospholipids, VLDL-cholesterol--TC, TG, PL, VLDLc, respectively) are positively correlated with the CsA distribution within the LDL fraction, and negatively correlated with the CsA distribution within the HDL fraction. Thus, the percentage of CsA in each type of lipoproteins was shown to vary with the lipid levels among individuals. A significant negative correlation was found between apparent distribution volume at steady state (Vss) in plasma and TC, PL, and LDLc and between the area under the curve measured in blood (AUCB) for whole blood and PL.
TL;DR: Besides its role in producing neurofibrillary pathology, Al appears to modify the blood-brain barrier and exert cholinergic and noradrenergic effects and possible mechanisms could be related to cell damage via free radical production, impairment of glucose metabolism, and effects on signal transduction.
Abstract: Neurotoxic effects of aluminum (AI) were recognized >100 years ago, but have only recently been studied in detail. By far, the most dramatic effect of Al is that of producing intraneuronal perikaryal neurofilamentous aggregates, which consist of phosphorylated neurofilaments. Several species have been used to demonstrate this effect, rabbit being most common; the effect also is seen in in vitro systems. Besides its role in producing neurofibrillary pathology, Al appears to modify the blood-brain barrier and exert cholinergic and noradrenergic effects. Possible mechanisms of Al neurotoxicity could be related to cell damage via free radical production, impairment of glucose metabolism, and effects on signal transduction
TL;DR: Understanding the cellular pharmacology of MTX and other antifolates has provided a strong rationale for the use of high-dose MTX with leucovorin (LV) rescue, and the combination ofMTX and LV prevents severe toxicity without diminishing the antitumor activity of the drugs.
Abstract: Antifolates have demonstrated effective antineoplastic activity in the treatment of disorders of cell proliferation, e.g., acute lymphocytic leukemia, breast cancer, and mycosis fungoides. The enzymatic pathways involved in DNA biosynthesis, specifically dihydrofolate reductase and thymidylate synthetase, are the biochemical targets of antifolates. Methotrexate (MTX) and its analogs, 10-ethyl-10-deazaaminopterin (edatrexate), and trimetrexate (TMT) are paradigms for cytotoxicity at the biochemical level. Understanding the cellular pharmacology of MTX and other antifolates has provided a strong rationale for the use of high-dose MTX with leucovorin (LV) rescue
TL;DR: Increased sensitivity with fluorescence detection enabled detection of lower dextromethorphan and dextrorphan concentrations when compared with UV detection, which may be helpful in phenotyping individuals with extremely rapid metabolism of dextramethorphans.
Abstract: Summary To establish the usefulness of fluorescence detection to quantify urinary concentrations of dextromethorphan and dextrorphan for oxidation phenotyping, we determined the molar concentration ratio of dextromethorphan to dextrorphan in 38 subjects by UV and fluorescence detection. Dextromethorphan and dextrorphan concentrations were quantified after overnight hydrolysis of urine samples and organic solvent extraction with heptane and butanol. The compounds were separated by high-performance liquid chromatography using a phenyl column and a mobile phase consisting of acetonitrile and an aqueous mixture of 0.01 M heptane sulfonic acid and 0.01 M phosphate buffer. The eluents were detected in series by a UV detector (280 nm) and fluorescence detector (excitation 280 nm and emission 310 nm). The dextromethorphan to dextrorphan molar concentration ratio by UV and fluorescence detection was highly correlated (r = 0.997) and not statistically different (p = 0.1036). However, increased sensitivity with fluorescence detection enabled detection of lower dextromethorphan and dextrorphan concentrations when compared with UV detection. Fluorescence detection was able to detect dextromethorphan as low as 0.02 μg/ml, which may be helpful in phenotyping individuals with extremely rapid metabolism of dextromethorphan. Fluorescence detection also produced chromatograms with significantly less interference and allows a more accurate quantitation of dextromethorphan and dextrorphan concentrations.
TL;DR: Examples of the application of GC/MS andGC/MS/MS methods for the detection of Δ9-tetrahydrocannabinol, naltrexone, and their active metabolites are described and compared in terms of sensitivity, specificity, and unique features.
Abstract: The combination of gas chromatography and mass spectrometry (GC/MS) is generally recognized as offering the best sensitivity and specificity for the detection and measurement of drugs and their metabolites in biological specimens. This finding has resulted in the widespread use of GC/MS in many areas of pharmacology and toxicology. However, a GC/MS assay can be performed in many ways, depending upon the specific requirements of the analytical tasks. For example, pharmacokinetic studies generally employ chemical ionization and single-ion monitoring to obtain optimum sensitivity, whereas GC/MS methods for confirmation of the presence of drugs of abuse in urine most often use electron ionization and multiple-ion monitoring to obtain conclusive results. Another example is the increasing use of the combination of gas chromatography and tandem mass spectrometry (GC/MS/MS) for analyses requiring sensitivities better than nanograms per milliliter. Examples of the application of GC/MS and GC/MS/MS methods for the detection of delta 9-tetrahydrocannabinol, naltrexone, and their active metabolites are described and compared in terms of sensitivity, specificity, and unique features.
TL;DR: Saliva collection may be advantageous under conditions in which blood collection is impractical and may provide greater sensitivity because of the high concentration of nicotine in saliva relative to that in blood, replicating results of previous studies.
Abstract: This study examined whether salivary nicotine concentrations would provide a useful index of plasma concentrations in studies of the effects of transdermal nicotine administration. Twenty-four subject smokers abstained from smoking for 12 h prior to admission to a clinical research unit ward and for 36 h while remaining confined to the ward. Three doses of nicotine skin patches were applied to different groups of subjects, and blood and saliva samples were collected at several time points. Saliva flow was stimulated by three different methods: (a) sucking on a lemon candy, (b) dissolving a sugar cube in the mouth, and (c) chewing on parafilm. Nicotine and cotinine concentrations were measured in both saliva and blood using gas chromatography. There was a high correlation between blood and saliva values of nicotine (r = 0.82). Overall, saliva nicotine concentrations were approximately 8.1 times higher than those of plasma. Saliva and blood cotinine concentrations were also highly correlated (r = 0.94), replicating results of previous studies. Results suggest that saliva nicotine may be a useful marker of nicotine intake during nicotine skin patch treatment. Saliva collection may be advantageous under conditions in which blood collection is impractical and may provide greater sensitivity because of the high concentration of nicotine in saliva relative to that in blood.
TL;DR: Routine clinical pharmacokinetic data collected from 90 patients receiving lithium have been analyzed to evaluate the role of patient characteristics for estimating dosing regimens and indicated that lithium clearance was influenced by the demographic variables of age, total body weight, and serum creatinine.
Abstract: Routine clinical pharmacokinetic data (n = 303) collected from 90 patients receiving lithium have been analyzed to evaluate the role of patient characteristics for estimating dosing regimens The data were analyzed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data The pharmacokinetic model of lithium was described using a one-compartment steady-state model The effect of a variety of developmental and demographic factors on clearance was investigated NONMEM estimates indicated that lithium clearance was influenced by the demographic variables of age, total body weight, and serum creatinine The interindividual variability in lithium clearance was modeled with proportional error with an estimated coefficient of variation of 251% The intraindividual variability, or residual error, was 143% The dosing method based on clearance values obtained by NONMEM analysis allowed the prediction of the minimum steady-state lithium concentration as a function of maintenance dose with acceptable error for therapeutic drug monitoring
TL;DR: The quinine concentration was found to be lower in whole blood than in plasma (mean ratio, plasma-whole blood, 1.17) and the concentration in capillary blood was lower than that in venous blood ( mean ratio, capillaryBlood-venous blood, 0.93).
Abstract: Summary The analysis of quinine in whole blood, plasma, urine, and samples dried on filter paper is described. Extraction was made with toluene followed by back-extraction into phosphate buffer. A reversed-phase liquid chromatography system with fluorescence detection was used. The within-day coefficient of variation of the method was 4–10% at the lower limit of determination (2 nM in plasma and 50 nM in whole blood, dried samples, and urine) and 2–4% at 10μM. The quinine concentration was found to be lower in whole blood than in plasma (mean ratio, plasma-whole blood, 1.17). The concentration in capillary blood was lower than that in venous blood (mean ratio, capillary blood-venous blood, 0.93).
TL;DR: A 73-year-old woman with bipolar manic-depressive illness was treated with nortriptyline for more than 2 years, and during concomitant intake of 500-600 mg/day carbamazepine, the SNT decreased to 140 and 134 nM and the depression persisted but the depression disappeared.
Abstract: A 73-year-old woman with bipolar manic-depressive illness was treated with nortriptyline, 75 mg/day, for more than 2 years. At this dose her mean (+/- SD) serum nortriptyline concentration (SNT) was 355 +/- 49 nM (n = 13). Nevertheless, the patient again was depressed and was admitted to initiate prophylactic treatment with carbamazepine. During concomitant intake of 500-600 mg/day carbamazepine, the SNT decreased to 140 and 134 nM and the depression persisted. The nortriptyline dose was therefore increased to 150 mg/day; the mean SNT rose to 402 +/- 69 nM (n = 4) and the depression disappeared. This case shows that carbamazepine induces nortriptyline metabolism.
TL;DR: Primary peaks in the plasma concentration curves strongly indicated an enterohepatic circulation of morphine, including EHC, in a pharmacokinetic-pharmacodynamic model, in which the studied effects were well correlated to the concentrations of morphine.
Abstract: Ten healthy volunteers were given an i.v. infusion of 10 mg morphine HCl, an oral solution of 20 mg morphine HCl, or a new controlled release tablet of 30 mg morphine sulphate on three separate occasions in a complete crossover design. Venous blood samples were collected serially for 14-24 h and analyzed for morphine using high-performance liquid chromatography (HPLC). Continuous reaction times (CRTs) and salivation were measured repeatedly in all subjects. Oxygen saturation remained normal throughout the procedure. Five subjects experienced nausea on at least one occasion. Pharmacokinetic parameters, calculated using a two-compartment model, were in accordance with previous results for i.v. and oral administration of morphine solutions. The absolute bioavailability of morphine in the oral solution was 21.6% (15.4-27.7%; 95% CI) and in the controlled release tablet, 17.1% (12.6-21.6%; CI). Secondary peaks in the plasma concentration curves strongly indicated an enterohepatic circulation (EHC) of morphine. Alternative pharmacokinetic calculations, including EHC, were performed and used in a pharmacokinetic-pharmacodynamic model, in which the studied effects were well correlated to the concentrations of morphine.