The mixed dissociation constants of five drugs—clotrimazole, terbinafine HCl, acetylsalicylic acid, salicylic acid, and galanthamine—at various ionic strengths I and at temperatures of <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msup><mml:mrow><mml:mn>25</mml:mn></mml:mrow><mml:mrow><mml:mo>°</mml:mo></mml:mrow></mml:msup></mml:math>C and <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msup><mml:mrow><mml:mn>37</mml:mn></mml:mrow><mml:mrow><mml:mo>°</mml:mo></mml:mrow></mml:msup></mml:math>C were determined with the use of multiwavelength and multivariate treatments of spectral data SPECFIT/32 nonlinear regression analysis and INDICES factor analysis. The factor analysis in the INDICES program predicts the number of components, when the data quality is high and the instrumental error is known. The thermodynamic dissociation constant <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mtext>p</mml:mtext><mml:msubsup><mml:mi>K</mml:mi><mml:mtext>a</mml:mtext><mml:mtext>T</mml:mtext></mml:msubsup></mml:mrow></mml:math> was estimated by nonlinear regression of <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mrow><mml:mo>{</mml:mo><mml:mrow><mml:mtext>p</mml:mtext><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mtext>a</mml:mtext><mml:mo>,</mml:mo></mml:mrow></mml:msub><mml:mi>I</mml:mi></mml:mrow><mml:mo>}</mml:mo></mml:mrow></mml:mrow></mml:math> data at <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msup><mml:mrow><mml:mn>25</mml:mn></mml:mrow><mml:mrow><mml:mo>°</mml:mo></mml:mrow></mml:msup></mml:math>C and <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msup><mml:mrow><mml:mn>37</mml:mn></mml:mrow><mml:mrow><mml:mo>°</mml:mo></mml:mrow></mml:msup></mml:math>C: for clotrimazole <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mtext>p</mml:mtext><mml:msubsup><mml:mi>K</mml:mi><mml:mrow><mml:mtext>a</mml:mtext><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mtext>T</mml:mtext></mml:msubsup></mml:mrow></mml:math> = 4.38(1) and 4.16(3); for terbinafine HCl <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mtext>p</mml:mtext><mml:msubsup><mml:mi>K</mml:mi><mml:mrow><mml:mtext>a</mml:mtext><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mtext>T</mml:mtext></mml:msubsup></mml:mrow></mml:math> = 4.19(3) and 4.12(5); for acetylsalicylic acid <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mtext>p</mml:mtext><mml:msubsup><mml:mi>K</mml:mi><mml:mrow><mml:mtext>a</mml:mtext><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mtext>T</mml:mtext></mml:msubsup></mml:mrow></mml:math> = 3.49(25) and 3.41(15); for salicylic acid <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mtext>p</mml:mtext><mml:msubsup><mml:mi>K</mml:mi><mml:mrow><mml:mtext>a</mml:mtext><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mtext>T</mml:mtext></mml:msubsup></mml:mrow></mml:math> = 3.01(1) and 3.00(1) and for galanthamine <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mtext>p</mml:mtext><mml:msubsup><mml:mi>K</mml:mi><mml:mrow><mml:mtext>a</mml:mtext><mml:mo>,</mml:mo><mml:mn>1</mml:mn></mml:mrow><mml:mtext>T</mml:mtext></mml:msubsup></mml:mrow></mml:math> = 8.21(1) and 7.99(2) where in brackets the standard deviation is in the last significant digits. Goodness-of-fit tests for various regression diagnostics enabled the reliability of the parameter estimates found to be proven. Pharma Algorithms predicts <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mtext>p</mml:mtext><mml:msub><mml:mi>K</mml:mi><mml:mtext>a</mml:mtext></mml:msub></mml:mrow></mml:math> being based on the structural formulae of drug compounds.

Milan Meloun

Sylva Bordovská

Lubomír Galla

The Thermodynamic Dissociation Constants of Clotrimazole, Terbinafine HCL, Acetylsalicylic Acid, Salicylic Acid, and Galanthamine by the Nonlinear Regression of Multiwavelength Spectrophotometric pH-Titration Data

Early treatment of bloodstream infections with appropriate, definitive antimicrobial therapy has proven to reduce mortality, length of hospital stay, and healthcare costs. Culture-based testing methods require up to five days for final pathogen identification and susceptibility reporting, forcing use of broad spectrum empiric therapy. Recently, multiple rapid microbiological and molecular testing methods have been developed that reduce the time to identify the pathogen and susceptibility, allowing optimal antimicrobial therapy to be prescribed earlier.  Real-time polymerase chain reaction and gene microarray have been described in literature, yet only peptide nucleic acid fluorescent in-situ hybridization has published data justifying its use based on clinical outcomes and cost savings. Target enriched multiplex polymerase chain reaction was developed to identify both the pathogen and multiple genes associated with resistance from blood within 6 hours and this methodology was studied in our hospital to assess effectiveness at optimizing antimicrobials in staphylococcal bloodstream infections.

Edward H. Eiland

Nicholas Beyda

Jian Han

William Lindgren

Randy Ward

Thomas MacAndrew English

Ali Hassoun

Kathi Hathcock

The Utility of Rapid Microbiological and Molecular Techniques in Optimizing Antimicrobial Therapy

Recent developments in the computational diagnostic tools for the <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mtext>p</mml:mtext><mml:msub><mml:mi>K</mml:mi><mml:mi>a</mml:mi></mml:msub></mml:mrow></mml:math> estimation of druglike molecules carried out by the nonlinear regression of multiwavelength spectrophotometric pH-titration data are demonstrated on the protonation equilibria of silybin. The factor analysis of spectra predict the correct number of components when the signal-to-error ratio SER is higher than 10. The mixed dissociation constants of the drug silybin at ionic strength I = 0.03 and a temperature of <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msup><mml:mn>25</mml:mn><mml:mo>&#x2218;</mml:mo></mml:msup><mml:mtext>C</mml:mtext></mml:math> were determined using two different programs, SPECFIT32 and SQUAD(84). A proposed experimental and computational strategy for the determination of the dissociation constants is presented. The dissociation constant <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mtext>p</mml:mtext><mml:msub><mml:mi>K</mml:mi><mml:mi>a</mml:mi></mml:msub></mml:mrow></mml:math> was estimated by nonlinear regression of the <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mo>{</mml:mo><mml:mrow><mml:mtext>p</mml:mtext><mml:msub><mml:mi>K</mml:mi><mml:mi>a</mml:mi></mml:msub><mml:mo>,</mml:mo><mml:mi>I</mml:mi></mml:mrow><mml:mo>}</mml:mo></mml:mrow></mml:math> data at <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:msup><mml:mn>25</mml:mn><mml:mo>&#x2218;</mml:mo></mml:msup><mml:mtext>C</mml:mtext></mml:math> with SQUAD (and SPECFIT); that is, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mtext>p</mml:mtext><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi>a</mml:mi><mml:mn>1</mml:mn></mml:mrow></mml:msub></mml:math>
 = 6.898(0.022) and 6.897(0.002); <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mtext>p</mml:mtext><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi>a</mml:mi><mml:mn>2</mml:mn></mml:mrow></mml:msub></mml:math>
 = 8.666(0.021) and 8.667(0.012); <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mtext>p</mml:mtext><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi>a</mml:mi><mml:mn>3</mml:mn></mml:mrow></mml:msub></mml:math> = 9.611(0.010) and 9.611(0.004); <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mtext>p</mml:mtext><mml:msub><mml:mi>K</mml:mi><mml:mrow><mml:mi>a</mml:mi><mml:mn>4</mml:mn></mml:mrow></mml:msub></mml:math>
 = 11.501(0.008) and 11.501(0.007). While great progress has been achieved in terms of the reliability of the protonation model estimation, among the most efficient diagnostics of the nonlinear regression of multiwavelength pH-spectra are the goodness-of-fit test, Cattel&#39;s scree plot of the factor analysis, spectra deconvolution, the signal-to-error SER ratio analysis, and other tools of efficient spectra analysis.

Tom&#225;&#353; Syrov&#253;

Jahan Ghasemi

Recent Progress in the<svg style="vertical-align:-3.3907pt" height="15.4" version="1.1" viewBox="0 0 28.862499 15.4" width="28.862499" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns="http://www.w3.org/2000/svg"><g transform="matrix(.017,-0,0,-.017,.062,11.112)"><path id="x70" d="M169 380l92 53q26 16 49 16q80 0 128.5 -56t48.5 -133q0 -108 -72.5 -180.5t-176.5 -91.5q-38 1 -69 18v-131q0 -57 13 -70t71 -18v-27h-236v27q49 5 61 17t12 61v452q0 48 -9.5 58.5t-56.5 16.5v24q66 11 145 43v-79zM169 346v-270q37 -39 94 -39q63 0 101.5 50&#xA;t38.5 134q0 78 -38.5 123t-95.5 45q-45 0 -100 -43z" /></g><g transform="matrix(.017,-0,0,-.017,8.97,11.112)"><path id="x1D43E" d="M764 650l-7 -26q-61 -10 -91.5 -22.5t-76.5 -48.5l-235 -184q104 -152 208 -276q31 -37 54.5 -48.5t68.5 -16.5l-7 -28h-156q-138 170 -213 284q-19 29 -33.5 35t-33.5 -7l-29 -173q-15 -75 -5.5 -90.5t74.5 -20.5l-5 -28h-260l7 28q58 5 74 21.5t30 89.5l70 378&#xA;q12 68 2 83t-72 22l6 28h257l-7 -28q-62 -7 -76 -21.5t-27 -83.5l-32 -172q29 11 78 46q112 84 217 179q18 16 23.5 25.5t-1 14.5t-26.5 8l-30 4l5 28h249z" /></g><g transform="matrix(.012,-0,0,-.012,22.162,15.187)"><path id="x1D44E" d="M483 97q-42 -50 -88.5 -79.5t-68.5 -29.5q-37 0 -17 93l22 102h-2q-54 -79 -144 -149q-59 -46 -100 -46q-24 0 -43 29t-19 86q0 78 34.5 153t94.5 120q41 31 94 51.5t98 20.5q29 0 72 -9q26 -6 39 -6l2 -4q-30 -117 -67 -323q-8 -41 2 -41q16 0 79 58zM374 387&#xA;q-32 15 -73 15q-52 0 -83 -23q-48 -36 -78 -108.5t-30 -152.5q0 -33 8.5 -50.5t20.5 -17.5q31 0 107 79t99 132q15 40 29 126z" /></g></svg>Estimation of Druglike Molecules by the Nonlinear Regression of Multiwavelength Spectrophotometric pH-Titration Data

Chemotherapeutic agents are generally characterized by a large inter-individual pharmacokinetic variability.  The balance of efficacy and toxicity is critical and the imbalance can have devastating effects on patients. Standard dosing methods are inadequate in optimizing systemic exposure .Therapeutic drug monitoring (TDM) has the potential to improve the clinical use of chemotherapy agents. TDM has been successfully applied to optimize a few anticancer treatments including carboplatin, methotrexate, and 6-mercaptopurine. 5-Flurouracil (5-FU) is considered the backbone in treatments of advanced CRC. Toxic side effects remain a significant problem despite increased safety of newer regimens. Molecular mechanisms that control DPD-activity are complex and have not been fully elucidated and cannot be used effectively to individualize Fluorouracil dosing as there is no established standard genetic test for DPD deficiency. Current phenotypic methods to measure DPD-activity are cumbersome. A reliable relationship between DPD genotype and 5-FU toxicity phenotype has not been established.  Standard dosing of 5FU is by body surface area (BSA). Low correlation exists  between exposure and BSA. A better predictor of total exposure is the area under the curve (AUC). Toxicity and efficacy have been correlated to AUC with target of 24-30 (mg.h/l). The therapeutic window is very narrow and difficult to attain by clinical follow-up alone.  TDM has been shown effective in adjusting the dose based on AUC.

Lamya Alnaim

Individualization of 5-Fluorouracil in the Treatment of Colorectal Cancer

Context. The fenofibrate effect on the subclass size distribution of lipoproteins before and after a high-fat challenge is not well studied. Objective. To characterize the baseline and post-prandial response (PPL) to a high-fat challenge following fenofibrate therapy, on changes in LDL, HDL, and VLDL particle subclasses, number, and size in 271 hypertriglyceridemic participants. Methods. Participants from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) study who conducted PPL studies both before and after three weeks of fenofibrate (160&#x2009;mg/d) treatment were analyzed. Particle size distributions were determined using nuclear magnetic resonance imaging, and lipid determinations were measured at fasting (0&#x2009;hr), 3.5 hours, and 6 hours after ingestion of a standardized high-fat meal. Analyses were stratified by gender. Changes in particle subclass distributions were assessed using repeated measures analysis of variance adjusted for pedigree. Results. Before PPL, fenofibrate in men (adjusted for age, field center, smoking status, diabetes, and weight circumference) lowered fasting and postprandial VLDL primarily due to reductions in postprandial levels of large and medium VLDL particles (9&#x2009;SE <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mrow><mml:mo>+</mml:mo><mml:mo>/</mml:mo><mml:mo>&#x2212;</mml:mo></mml:mrow><mml:mn>0.7</mml:mn></mml:mrow></mml:math> to 4 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mrow><mml:mo>+</mml:mo><mml:mo>/</mml:mo><mml:mo>&#x2212;</mml:mo></mml:mrow><mml:mn>0.4</mml:mn></mml:mrow></mml:math> and 78 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mrow><mml:mo>=</mml:mo><mml:mo>/</mml:mo><mml:mo>&#x2212;</mml:mo></mml:mrow><mml:mn>4</mml:mn></mml:mrow></mml:math> to 36 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mrow><mml:mo>=</mml:mo><mml:mo>/</mml:mo><mml:mo>&#x2212;</mml:mo></mml:mrow><mml:mn>3</mml:mn></mml:mrow></mml:math>&#x2009;nmol/L both <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>P</mml:mi><mml:mo>&#x003C;</mml:mo><mml:mn>.0001</mml:mn></mml:mrow></mml:math>, resp.). Fenofibrate also reduced fasting and postprandial total LDL particles, primarily a result of reduced small LDL particles (1497 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mrow><mml:mo>=</mml:mo><mml:mo>/</mml:mo><mml:mo>&#x2212;</mml:mo></mml:mrow><mml:mn>37</mml:mn></mml:mrow></mml:math> to 1088 <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mrow><mml:mo>=</mml:mo><mml:mo>/</mml:mo><mml:mo>&#x2212;</mml:mo></mml:mrow><mml:mn>36</mml:mn></mml:mrow></mml:math>&#x2009;nmol/L, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mrow><mml:mi>P</mml:mi><mml:mo>&#x003C;</mml:mo><mml:mn>.0001</mml:mn></mml:mrow></mml:math>). Directional changes were similar in men and women but the magnitude of change was different for some parameters. Conclusion. Fenofibrate treatment resulted in a lower triglyceride excursion following a high-fat meal. This investigation provides new knowledge of the magnitude and time course of fenofibrate induced attenuation of Lipoprotein subclass size distribution following a postprandial lipid challenge.

Stephen P. Glasser

Mary K. Wojczynski

A. l. Oberman

Edmond K. Kabagambe

Michael Y. Tsai

Jose M. Ordovas

Robert J. Straka

Donna K. Arnett

Comparison of Postprandial Responses to a High-Fat Meal in Hypertriglyceridemic Men and Women before and after Treatment with Fenofibrate in the Genetics and Lipid Lowering Drugs and Diet Network (GOLDN) Study

Objectives. Tricotillomania (TTM) is more common than expected. SSRI&#39;s are the treatment of choice in TTM. However, response rates are lower with SSRI&#39;s. The aim of our study is to explore other pharmacological interventions. Materials and Methods. Nine female TTM patients with SSRI treatment failure were included. Sample was treated with bupropion SR up to 450&#x2009;mg/day. Results. Six out of nine patients responded well to bupropion SR. Massachusetts General Hospital Hair Pulling Scale (MGH) demonstrated a significant improvement at the twelve week point (f: 32.3, power: 1, lambda: 97.1, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML"><mml:mi>P</mml:mi><mml:mo>&#x003C;</mml:mo><mml:mn>.0001</mml:mn></mml:math>) and the response rates remained stable at sixteen-month follow up visit. Conclusions. Bupropion SR could be an alternative pharmacological treatment for TTM. Larger samples with double blind placebo controlled design are needed to confirm our preliminary report.

Pinhas N. Dannon

Netta Shoenfeld

Oded Rosenberg

Moshe Kotler

Sustain Released Bupropion in the Treatment of Tricotillomania: Outpatient Follow Up Survey

About this journal

Journal profile

Meet the editorial board

Editor spotlight

Find out more

This journal's articles appear in a wide range of abstracting and indexing databases, and are covered by numerous other services that aid discovery and access. Find out more about where and how the content of this journal is available.

Abstracting and Indexing

title

description

https://images.hindawi.com/journals/srx.pharmacology/srx.pharmacology.banner.jpg

SRX Pharmacology