Absorption kinetics of local anesthetics from rat subcutaneous tissue. II. Effects of vasodilators

The effects of acetylcholine at two concentrations (10^–4 g/ml, solution A, and 5.0×10 ^–5 g/ml, solution B) and methacholine (10^–4 g/ml) on the subcutaneous absorption kinetics of lidocaine, diethylaminoacetanilide (I), and 5-methyl-diethylaminoacetanilide (II) were investigated using the rat model of Ballard and Menczel (8) under uncontrolled pH conditions (isotonic saline). The absorption half-life measurements were made before and after the addition of each vasodilator solution to the subcutaneous absorption cell containing the three local anesthetics. Equivalent concentrations of acetylcholine (solution A) and methacholine significantly decreased the absorption half-lives of lidocaine, I, and II, whereas solution B of acetylcholine significantly decreased the absorption half-lives of lidocaine and I only. Lidocaine and I were affected to the same extent (percent decrease in absorption half-life) by each vasodilator solution. The percent decrease in absorption half-life of II was significantly lower than that of lidocaine and I in the case of all three vasodilator solutions. Solution A and solution B of acetylcholine did not produce a significantly different percent decrease in absorption half-life of either lidocaine, I, or II. Likewise, no significant difference in the effects of acetylcholine (solution A) and methacholine was observed. The role of blood flow at the absorption site is discussed.Supported by General Research Support Grant RR-05635-05 from the U.S. Public Health Service.This paper was submitted to a Consulting Editor who served as the Journal Editor during its review process. Direct all inquiries to R.H.L.     

Planning Future Strategies for Domestic and International NeuroAIDS Research, July 24–25, 2008

The National Institute of Mental Health in cooperation with the National Institute on Drug Abuse and the National Institute of Neurological Disorders and Stroke organized a meeting on July 24–25, 2008 to develop novel research directions for neuroAIDS research. The deliberations of this meeting are outlined in this brief report. Several critical research areas in neuroAIDS were identified as areas of emphasis. Opportunities for collaborations between large NIH-funded projects were also discussed. NeuroAIDS Research Participants. Cristian Achim, University of California, San Diego, San Diego, CA; Sunil Ahuja, University of Texas Health Science Center at San Antonio, San Antonio, TX; James Becker, University of Pittsburgh Medical School, Pittsburgh, PA; Bruce Brew, University of New South Wales, Sydney, Australia; Janice Clements, Johns Hopkins University, Baltimore, MD; Ronald Ellis, University of California, San Diego, San Diego, CA; Leon Epstein, Northwestern University Feinberg School of Medicine, Chicago, IL; Lynda Erinoff, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD; Dana Gabuzda, Dana Farber Cancer Institute, Harvard Medical School Boston, MA; Harris Gelbard, University of Rochester Medical Center School of Medicine, Rochester, NY; Benjamin Gelman, University of Texas Galveston, TX; David Goldstein, Duke University, Durham, NC; Colin Hall, University of North Carolina, Chapel Hill, NC; Rohan Hazra, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD; Robert Heaton, University of California, San Diego, San Diego, CA; Robin Huebner, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institute of Health, Bethesda, MD; Kamel Khalili, Temple University, Philadelphia, PA; Dennis Kolson, University of Pennsylvania, Philadelphia PA; Diane Lawrence, National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD; Scott Letendre, University of California, San Diego, San Diego, CA; Thomas Marcotte, University of California, San Diego, San Diego, CA; Michael McGrath, University of California, San Francisco, San Francisco, CA; Susan Morgello, Mount Sinai Medical Center, New York, NY; Avindra Nath, Johns Hopkins University, Baltimore, MD; Vinayaka Prasad, Albert Einstein School of Medicine, Bronx, NY; Richard Price, University of California, San Francisco, San Francisco, CA; Lynn Pulliam, University of California, San Francisco, San Francisco, CA; Dianne Rausch, HIV Pathogenesis, Neuropsychiatry and Treatment Branch, Center for Mental Health Research on AIDS, National Institute of Mental Health, National Institutes of Health Bethesda, MD; Kevin Robertson, University of North Carolina at Chapel Hill, Chapel Hill, NC; Ned Sacktor, The Johns Hopkins University, Baltimore, MD; Gerald Sharp Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD; Elyse Singer, University of California, Los Angeles, Los Angeles, CA; Stephen Spector, University of California, San Diego, LaJolla, CA; Beth Stevens, Harvard Medical School, Children’s Hospital, Kirby Neurobiology Center, Boston, MA; Mario Stevenson, University of Massachusetts Medical Center, Worcester, MA; Ellen Stover, National Institute of Mental Health, National Institutes of Health, Bethesda, MD; Ronald Swanstrom, University of North Carolina at Chapel Hill-Chapel Hill, NC; Victor Valcour, University of California, San Francisco, San Francisco, CA; David Volsky, Columbia University Medical Center, New York, NY; Brian Wigdahl, Drexel University College of Medicine, Philadelphia, PA; May Wong, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Constantin Yiannoutsos, Indiana University, Indianapolis, IN; Christine Zink, The Johns Hopkins University, Baltimore, MD     

Hepatic clearance of drugs. II. Experimental evidence for acceptance of the “well-stirred” model over the “parallel tube” model using lidocaine in the perfused rat liverin situ preparation

Theoretical analysis of two models of hepatic drug clearance revealed that one powerful discriminator between them is the effect of changes of hepatic blood flow on either the emergent drug concentration or the availability of a highly extracted compound when operating under linear conditions. Lidocaine (extraction ratio 0.997) was employed in the discriminatory studies. The behavior of this drug under linear conditions (input lidocaine concentrations < 5 mg/ liter) to changes in hepatic blood flow rate (10–16 ml/min per liver) was examined in the perfused rat liver in situpreparation. The steady-state output lidocaine concentration in the blood leaving the liver was predicted better by a well-stirred model than by a parallel tube model. As anticipated, the clearance of a poorly extracted compound, antipyrine (extraction ratio 0.08),was unaltered by changes in hepatic blood flow. These experimental findings, and the data from the literature, point to the acceptance of the well-stirred model, which describes the liver as a well-stirred compartment with the drug in the hepatic venous blood being in equilibrium with that in the liver.Supported in part by National Institutes of Health Grant GM 16496 and the Patent Fund, Graduate Division, University of California, San Francisco.Abstracted in part from a dissertation submitted by K. Sandy Pang to the Graduate Division, University of California, San Francisco, California, in partial fulfillment of the Doctor of Philosophy degree requirements.     

Hepatic clearance of drugs. III. Additional experimental evidence supporting the “wellstirred” model,using metabolite (MEGX) generated from lidocaine under varying hepatic blood flow rates and linear conditions in the perfused rat liverin situ preparation

The disposition of monoethylglycine xylidide (MEGX), a metabolite of lidocaine, was studied in the perfused rat liver in situpreparation in an attempt to further discriminate between two models of hepatic drug clearance. In the well-stirred model, the liver is regarded as a well-stirred compartment with the emergent drug concentration in equilibrium with that in the liver. In the parallel tube model, the liver is viewed as a series of indentical paralllel units with enzymes distributed evenly around the units. Using a single-passage perfusate system, we found in a previous study that the extraction ratio of lidocaine was maximal and constant (0.997) below 7 mg/liter. The steady-state output MEGX concentration appearing in the emergent blood upon a constant and low-input concentration of lidocaine (4 mg/liter) was determined under varying hepatic blood flow rates (10–16 ml/min per liver). The data suggest that operationally the well-stirred model adequately describes the appearance of MEGX from lidocaine.Supported in part by National Institutes of Health Grant GM 16496 and the Patent Fund, Graduate Division, University of California, San Francisco.Abstracted in part from a dissertation by K. Sandy Pang to the Graduate Division, University of California, San Francisco, California, in partial fulfillment of the Doctor of Philosophy degree requirement.     

Biliary excretion of diethylstilbestrol in the rhesus monkey

The biliary excretion of diethylstilbestrol in the bile fistula rhesus monkey was investigated during exogenous taurocholate- and taurodehydrocholate-induced choleresis. Following intravenous administration, 36% of the dose was excreted into the bile (as diethylstilbestrol monoglucuronide) and 53% in the urine (as diethylstilbestrol monoglucuronide plus more polar unidentified metabolites). During the steady-state infusion of diethylstilbestrol, with taurocholateinduced choleresis, a bile flow dependent transport for the biliary excretion of diethylstilbestrol monoglucuronide was observed. Evidence for carrier-mediated transport of this metabolite was a bile-to-blood concentration ratio which ranged from 228 to 279 during steady-state experiments. In vitroexperiments indicated that diethylstilbestrol monoglucuronide forms an association with taurocholate, as well as the micellar structures of bile, resulting in a severalfold enhancement of solubility above that in aqueous buffer alone. Taurodehydrocholate, a nonmicelle -forming bile salt, did not interact with this metabolite and had no effect on its solubility. Substitution of taurodehydrocholate for taurocholate during the steady-state infusion of diethylstilbestrol produced no significant changes in the transport of diethylstilbestrol monoglucuronide from blood to bile.Abstracted in part from a dissertation submitted by Edward J. Mroszczak to the Graduate Division, University of California, San Francisco Medical Center, San Francisco, California 94122, in partial fulfillment of the Doctor of Philosophy degree requirements. This investigation was supported in part by a Training Grant in Pharmaceutical Chemistry GM-00728 and by General Research Support Grant FR-05435 from the NIH, USPHS.     

Recent advances in occupational cancer

The contribution of occupational and environmental exposures to the etiology of cancer is a topic of considerable scientific and public interest. If an occupational environmental exposure is associated with cancer in man, then both the exposure and the disease are preventable by appropriate protection. In order to enhance the awareness and timeliness of new information concerning occupational cancer, the University of California, San Francisco, School of Medicine in conjunction with the Northern California Occupational Health Center and the National Institutes of Occupational Safety and Health, the American Cancer Society sponsored a two day meeting in San Francisco at the end of 1983. Five of the presentations are highlighted in this review. In addition, twenty special questions of clinical relevance concerning occupational and environmental cancers are reviewed with the consensus answers given.     

Incidence and Predictors of Onset of Injection Drug Use in a San Francisco Cohort of Homeless Youth

Few studies document incidence of injection drug use among homeless youth. We followed a cohort of 70 street-recruited homeless youth in San Francisco, California who had never injected drugs for six months in 2004-5. We examined initiation of injection drug use and its predictors, informed by prior ethnographic findings. Data were analyzed using exact logistic regression. 11.4% of youth initiated injection drug use. Having no high school education, being over 21 years old, and being in disequilibrium predicted initiation. Limitations, implications and suggestions for future research are noted. Funding was provided by the National Institute for Child Health and Development.     

The influence of bacterial gut hydrolysis on the fate of orally administered isonicotinuric acid in man

Following oral administration to human subjects, isonicotinuric acid was hydrolyzed within the gastrointestinal tract to isonicotinic acid. This metabolism did not occur following intravenous administration. Evidence is presented indicating that most of the ingested isonicotinuric acid escaped absorption from the small intestine and passed into the large intestine, where gastrointestinal bacteria hydrolyzed it to isonicotinic acid. The latter compound was subsequently absorbed into the systemic circulation, where some was reconjugated with glycine, forming the originally administered compound, isonicotinuric acid.This work was supported in part by National Science Foundation Grant GY 10651 and National Institutes of Health Training Grant GM 00728, U.S. Public Health Service, Bethesda, Maryland.This paper was submitted to a Consulting Editor who served as the Journal Editor during its review process.National Science Foundation Undergraduate Research Participant, Summer 1973, under Grant GY 10651.     

Controlled Release of Lidocaine from Injectable Gels and Efficacy in Rat Sciatic Nerve Block

Purpose. Methods of delaying the action of local anesthetics are important, since short duration of action limits their use in the treatment of postoperative and chronic pain. The present study evaluated the use of low-viscosity gels in prolonging the release of lidocaine. Methods. Release of lidocaine from 2% lidocaine-HC1 containing methylcellulose (MC), hydroxypropylmethylcellulose (HPMC), sodiumcarboxymethyl cellulose (CMC), and poloxamer 407 (PO) gels was studied in phosphate buffer, pH 7.4, at 37°C. Commercial metylcellulose gel (MC_com) served as control. The in vivo efficacy of the respective gel formulations were evaluated in rats. The gel was injected into the vicinity of the sciatic nerve and nociception and motor function were tested. Results. The cumulative amount of lidocaine released during 8 hr was slowest from the PO gel, followed by the CMC, HPMC and MC gels. The antinociceptive effect was not prevented by the motor block and lasted longest with the PO gel. Good linear and rank order correlation was obtained between in vitro and in vivoresults. The microscopic examination of the tissue samples revealed only mild or no irritation of the skeletal muscle tissue by the PO, HPMC, and CMC gels. Conclusions. Based on these results poloxamer gel proved to be the most promising carrier for lidocaine.     

Buccal absorption as a parameter of analgesic activity of some p-substituted acetanilides

The extent of buccal absorption of 16 p-substituted acetanilides is related parabolically to analgesic activity. The correlation is slightly better than that between log (partition coefficient) and analgesic activity. Thus, for this series of compounds at least, an in vivo partition test provides a slightly better parameter of biological response than does an in vitro test.     

Absorption and tissue distribution of various polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs and PCDFs) in the rat

A defined mixture of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs and PCDFs) was parenterally administered to rats and absorption and tissue distribution were measured: 1) Toluene/DMSO (1+2; v/v) proved to be a convenient vehicle for the subcutaneous administration of the various PCDDs and PCDFs. Seven days after application the rate of absorption was 90% of the administered dose or even higher for almost all of the PCDDs/PCDFs in the mixture. In a few cases only (e.g. OCDD) the rate was found to be 84–89%; 2) Seven days after subcutaneous administration all 2378-substituted congeners were found in the liver, whereas only a few non-2378-substituted congeners could be measured in minor quantities. The 2378-substituted congeners also predominated in adipose tissue; however, most of the non-2378-substituted congeners were also detected; 3) The amount deposited within the liver as percentage of the administered dose differed for the various 2378-substituted PCDDs and PCDFs, ranging from <10% for OCDD or 2378-T4CDF, and between 60 and close to 100% for 12378-P5CDD or the H6CDDs. Therefore, the concentration ratio (liver/adipose tissue) was also found to be very different, ranging from <3 in the case of 2378-T4CDD or 2378-T4CDF to >40 in the case of 1234678-H7CDD, 23478-P5CDF, 123678-H6CDF, or 1234678-H7CDF; 4) Studies performed at the time period of ongoing absorption (13–14 h after injection) provided the first evidence that some of the non-2378-substituted congeners do reach substantial concentrations in hepatic tissue shortly after administration; 5) Subsequent to intraperitoneàl injection of the same PCDD/PCDF mixture the concentrations within the liver were found to be almost identical with that found after subcutaneous injection. In contrast, much higher concentrations of the congeners were found in (abdominal) adipose tissue; 6) In the liver of untreated rats of the same strain no T4CDDs/T4CDFsAbbreviations Used PCDDs, PCDFs polychlorinated dibenzo-p-dioxins, and dibenzofurans - T4CDDs, T4CDFs tetra-chlorinated dibenzo-p-dioxins, and dibenzofurans - P5CDDs, P5CDFs penta-chlorinated dibenzo-p-dioxins, and dibenzofurans - H6CDDs, H6CDFs hexa-chlorinated dibenzo-p-dioxins, and dibenzofurans - H7CDDs, H7CDFs hepta-chlorinated dibenzo-p-dioxins, and dibenzofurans - OCDD, OCDF octa-chlorinated dibenzo-p-dioxin, and dibenzofuran - DMSO dimethylsulfoxide     

Clearance concepts in pharmacokinetics

The kinetics of a drug eliminated by first-order processes in a perfusion-limited isolated perfused organ system are examined. In this model, the mean clearance, determined by dividing the dose by the area under the blood concentration profile, and the steady-state clearance are shown to be equal. The perfusion model and the compartmental model are compared and contrasted. Effects of blood flow and reservoir size on drug clearance are examined. Similarities and differences between the isolated and the in vivoorgan system are explored. The virtue of using clearance, instead of half-life, as a correlative parameter between these systems is stressed.Supported by Grant NIGMS 16496 from the National Institutes of Health, U.S. Public Health Service, Bethesda, Maryland.This paper was submitted to a Consulting Editor who served as the Journal Editor during its review process.     

Interview: Interview with Professor Malcolm Rowland

Malcolm Rowland is Professor Emeritus and former Dean of the School of Pharmacy and Pharmaceutical Sciences and a member and former director (1996-2000), of the Centre for Applied Pharmacokinetic Research, University of Manchester. He holds the positions of Adjunct Professor, School of Pharmacy, University of California, San Francisco; Member, Governing Board, EU Network of Excellence in Biosimulation; Founder member of NDA Partners; academic advisor to a Pharmaceutical initiative in prediction of human pharmacokinetics and Scientific Advisor to the EU Microdose AMS Partnership Program. He was President of the EU Federation for Pharmaceutical Sciences (1996-2000); Vice-President of the International Pharmaceutical Federation (2001-2009) and a Board Member of the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs, 2004-2008). He received his degree in Pharmacy and PhD at the University of London and was on faculty (School of Pharmacy, University of California San Francisco [1967-1975]) before taking up a professorship at Manchester. His main research interest is physiologically based pharmacokinetics and its application to drug discovery, development and use. He is author of over 300 scientific articles and co-author, with TN Tozer, of the textbooks Clinical Pharmacokinetics and Pharmacodynamics: Concepts and Applications and Introduction to Pharmacokinetics and Pharmacodynamics. He was editor of the Journal of Pharmacokinetics and Pharmacodynamics (formerly Journal of Pharmacokinetics and Biopharmaceutics, 1973-2007) and, since 1977, has organized regular residential workshops in pharmacokinetics.     

Post-translational modification of betaH-crystallin of bovine lens with aging

This study investigates post-translational modification of proteins of bovine lens with aging (3 year old vs. 6 month old cows). After water-soluble proteins were submitted to gel and ion exchange chromatography, betaH-crystallin, a subunit of beta-crystallin, and modified materials were isolated. These materials were then submitted to two dimensional polyacrylamide gel electrophoresis (2D-SDS PAGE) to detect and isolate the new spots. Results for lens proteins from 3 year old animals were compared to those from 6 month old animals. All spots were digested in gel with trypsin and the molecular masses of tryptic digests were measured by matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOFMS). Peptides peaks obtained from mass mapping were identified using the protein database of the MS-Fit program in the Protein prospector program of the University of California, San Francisco. We found that two post translational modifications of betaH-crystallin, acetylation and phosphorylation occurred with aging.     

Phosphatidylserine as a Determinant for the Tissue Distribution of Weakly Basic Drugs in Rats

Interorgan variation in tissue distribution of weakly basic drugs such as quinidine, propranolol, and imipramine was investigated as a function of binding to phosphatidylserine (PhS) in tissues. Tissue distributions of these drugs were determined using 10 different tissues at a steady-state plasma concentration and were expressed as tissue-to-plasma partition coefficients (K _p values). The concentration of PhS in the tissue was determined by two-dimensional thin-layer chromatography. Plotting of K _p values, except for brain, against the tissue PhS concentrations showed a linear relationship, indicating that PhS is a determinant in the interorgan variation of these tissue distributions. Further, differences in tissue distribution among the drugs was considered to be due to the difference in binding potency to PhS. Drug binding parameters to individual standard phospholipid were determined using a hexane-pH 4.0 buffer partition system. Binding was highest to PhS, and a linear relationship was found between the log nK [product of the number of binding sites (n) and the association constant (K) for PhS binding] obtained in vitro and K _p values of drugs in tissues in vivo. The empirically derived equation, K _p = 14.3 × (log nK) × (PhS cone.) – 8.09, was found to predict K _p values in vivo of weakly basic drugs. Thus, a determinant of interorgan variation in the tissue distribution of the weakly basic drugs studied was the tissue concentration of PhS and the drug binding affinity to PhS.     

借鉴美国经验促进我国临床药师的培养

临床药学人才的培养已成为国际药学教育发展的趋势.以加利福尼亚大学旧金山分校为例,介绍其临床药学专业的培养标准、特点及其课程设置,并以此为借鉴对我国高等药学教育的发展提出建议.     

The effect of strychnine administration during development on adult maze learning in the rat II: Drug administration from day 51 to 70

Strychnine sulphate administered to rats during development from day 51 to day 70 affected the rate of maze learning in adulthood. Rats given the drug in a rich environment learned the maze at a faster rate and with fewer errors than rats treated with the same drug but raised in small laboratory cages. The performance of rats given no drug was intermediate to that of the drug-rich and drug-caged groups.This research was supported in part by General Research Support Grant FR 05550 from N. I. M. H. to Langley Porter Neuropsychiatric Institute, and in part by Mental Health Training Grant 5-TI-MH-7082-07 to the University of California at San Francisco.     

Use of the unanesthetized rhesus monkey as a model for studying the gastrointestinal absorption of drugs

A model has been developed to study the gastrointestinal absorption of drugs and dosage forms in the unanesthetized rhesus monkey. Chronic vascular catheters were implanted in the iliac vein and the artery to enable the investigator to withdraw blood samples without disturbing the monkey. The vascular catheters also allow intravenous studies to be carried out so that the kinetic parameters of any drug can be determined. Plastic cannulae were implanted surgically in the stomach and in the duodenum very close to the pylorus. These cannulae provide a means of instilling a drug solution or a dosage form directly into the stomach or the duodenum. A technique was developed using Foley catheters to block the pylorus so that a drug solution or drug particles can be maintained in the stomach. With this setup, absorption of a drug specifically from the stomach can be studied. Sample data for salicylic acid absorption from the stomach and the intestine and for carbamazepine absorption following gastric administration of a solution or a broken tablet are presented.Supported in part by Grant GM 16496 from the National Institutes of Health.Presented, in part, at the APhA Academy of Pharmaceutical Sciences Symposium on Pharmacokinetics, Chicago, Illinois, November 1972.This paper was submitted to a Consulting Editor who served as the Journal Editor during its review process.     

Serum lidocaine concentrations following subcutaneous administration

Serum lidocaine concentrations were determined following subcutaneous administration for local anesthesia in the management of lacerations in the emergency room setting. Thirty patients received doses of lidocaine hydrochloride 1% solution ranging from 10 to 300 mg. Venous blood samples were drawn 15, 30, 45, and 60 minutes after lidocaine administration. Serum lidocaine determinations were made using an immunoassay system and verified by gas chromatography. There was no evidence of lidocaine absorption from the subcutaneous injection sites. There were no detectable concentrations of lidocaine in any of the patient blood samples. The absorption characteristics of subcutaneously administered lidocaine appear to be altered in traumatized tissue.