Optimal dosage regimen calculation program based on the remaining drug concentrations in plasma

A program is presented to calculate the optimal drug doses to make the plasma drug concentration at a constant level throughout the therapy. The package requires data input of experimentally determined pharmacokinetic parameters such as As and ramdas, and provides the optimal intravenous drug doses at every minute. This program is applicable to any drug in a given individual, provided that the single-dose plasma concentration curve equation of the first dose of the therapy in this inidividual is known.     

Factorial analysis of the influence of dissolution medium on drug release from carrageenan-diltiazem complexes

This research studied the influence of buffer composition, pH, and ionic strength on the release of diltiazem hydrochloride from a complex of the drug with lambda carrageenan. Two viscosity grades of carrageenan were also compared. A factorial analysis was used to evaluate the influence of individual variables and their interactions. Both the complex solubility, measured as the drug concentration in equilibrium with the solid complex, and the drug release rate from constant surface area were considered. The increase of ionic strength significantly increased complex solubility in all the buffer systems. A significant effect of polymer grade on complex solubility was evidenced only in phosphate buffer with a pH of 6.8, indicating lower solubility of the complex when higher polymer molecular weight was involved. In most cases, drug release rate decreased when high polymer grade was involved in the complex. Ionic strength did not always have a significant effect on drug release rate and was quantitatively less important than for solubility lonic strength especially affected the drug release profiles. At higher ionic strength drug release was no longer constant, but decreased with time, probably because of lower polymer solubility.     

An Oral-Controlled Release Drug Delivery System for Liquid and Semisolid Drug Formulations

A novel oral drug delivery system for the controlled release of liquid drugs, drug solutions, and semisolid drug preparations is presented that is utilizing the constant vapor pressure of liquefied gas. The system is equipped with a capillary as an element determining the drug delivery rate and contains a liquefied propellant with a suitable boiling point below human body temperature. In the dissolution studies, polyacrylate gels of different viscosities containing paracetamol as model drug were used. Zero-order release kinetics was obtained. The release rates were dependent on the gel viscosity. Besides, by gel viscosity, the drug release rates could also be modified by changing the propellant type and the capillary parameters such as length or diameter. Accordingly, the new system enables a wide range of drug delivery kinetics which can be modified in a case-by-case basis in order to match the desired drug delivery characteristics.     

Modeling the influence of cyclodextrins on oral absorption of low‐solubility drugs: I. Model development

The ability to quantitatively predict the influence of a solubilization technology on oral absorption would be highly beneficial in rational selection of drug delivery technology and formulation design. Cyclodextrins (CDs) are cyclic oligosaccharides which form inclusion complexes with a large variety of compounds including drugs. There are many studies in the literature showing that complexation between CD and drug enhances oral bioavailability and some demonstrating failure of CD in bioavailability enhancement, but relatively little guidance regarding when CD can be used to enhance bioavailability. A model was developed based upon mass transport expressions for drug dissolution and absorption and a pseudo‐equilibrium assumption for the complexation reaction with CD. The model considers neutral compound delivered as a physical mixture with CD in both immediate release (IR) and controlled release (CR) formulations. Simulation results demonstrated that cyclodextrins can enhance, have no effect, or hurt drug absorption when delivered as a physical mixture with drug. The predicted influence depends on interacting parameter values, including solubility, drug absorption constant, binding constant, CD:drug molar ratio, dose, and assumed volume of the intestinal lumen. In general, the predicted positive influence of dosing as a physical mixture with CD was minimal, alluding to the significance of dosing as a preformed complex. The model developed enabled examination of which physical and chemical properties result in oral absorption enhancement for neutral drug administered as a physical mixture with CD, demonstrating the utility of modeling the influence of a drug delivery agent (e.g., CD) on absorption for rational dosage form design. Biotechnol. Bioeng. 2010; 105: 409–420. © 2009 Wiley Periodicals, Inc.     

Gas chromatography: elution temperature, speed of analysis, and separation, efficiency as influenced by rate of temperature programming and carrier gas velocity in open tubular glass capillary columns.

The elution temperatures and degree of separation of a model system series of hydrocarbons were followed as functions of the rate of temperature programming and carrier gas velocity. Graphs are presented that permit individual assessment of these variables. Lower elution temperatures can be achieved by raising the carrier gas velocity or lowering the rate of temperature programming. In glass capillary columns of normal dimensions (0.25-mm i.d. × 50 m), the former is much less effective and results in lower column efficiency. The elution temperature of n-pentadecane varied from 139 to 309°C and the separation efficiency of the column decreased by 50% as the program rate varied from 1 to 32°C/min at constant pressure drop. A simplified glass inlet splitter and constant pressure-drop device is also described.     

A program for least squares analysis of reassociation and hybridization data.

A computer program is described for the rapid calculation of least squares solutions for data fitted to different functions normally used in reassociation and hybridization kinetic measurements. The equations for the fraction not reacted as a function of Cot follow: First order, exp(-kCot); second order, (1+kCot)-1; variable order, (1+kCot)-n; approximate fraction of DNA sequence remaining single stranded, (1+kCot)-.44; and a function describing the pairing of tracer when the rate constant for the tracer (k) is distinct from the driver rate constant (kd): (formula: see text). Several components may be used for most of these functional forms. The standard deviations of the individual parameters at the solutions are calculated.     

Stochastic modeling of controlled-drug release

A drug release process by the oral route is random in nature and thus is subject to constant fluctuations. Moreover, individuals have varied tolerances to such fluctuations. The objective of this work is to characterize these fluctuations by a stochastic formalism. The system under consideration, i.e., the gastrointestinal tract consists of four consecutive compartments, i.e., stomach, duodenum, jejunum, and ileum. The master equation of the system as well as the governing equations for the means, variances, and covariances of the random variables, each representing the number of microspheres in an individual compartment, have been derived through the probabilistic population balance. These equations have been numerically solved to predict the total release fraction of drug and its internal fluctuations, and the dynamic statistics (means, variances, and covariances) of the amount of drug in each compartment at any time after administration. The dissolution-intensity functions in the model have been recovered from the available in vitro dissolution data from controlled-release pellets of isosorbide-5-nitrate (IS-5-N) by assuming that the rate of release is of the first order. The residence times and transition-intensity functions of drug in the individual compartments have been estimated from the available data generated by the gamma scintigraphies of IS-5-N pellets labeled by ¹¹¹In. Based on these parameters, the total numbers of dissolved drug microspheres and their fluctuations at any instance have been calculated. The model is in accord with the existing in vivo dissolution data of the same drug independently obtained through plasma analysis. More important, the model predicts that fluctuations in terms of the standard deviations of the numbers of particles in the duodenum, jejunum, and ileum can be of the same orders of magnitude as the corresponding mean numbers when 100 microspheres are simultaneously administered orally; in practice, such fluctuations characterized by these deviations could result in an undesirable release profile. Discussion is given of the potential direct clinical application of the results obtained as well as the plausible indirect application of these results and the model derived to the analyses of chemical and biochemical reactors.     

Sterile filtration of a multi-serotype glycoconjugate vaccine drug product

Glycoconjugate vaccines consisting of multiple serotypes of the bacterial capsular polysaccharide can provide strong protection against infection by significant pathogens. Previous studies of the sterile filtration behavior of these glycoconjugates have been limited to experiments with individual serotypes even though the formulated vaccines contain several different serotypes to provide broad immunization. The objective of this study was to explore the fouling behavior of a glycoconjugate vaccine drug product consisting of four different polysaccharide serotypes. Sterile filtration data were obtained with 0.22 µm Durapore® membranes at both constant flux and constant pressure for both the individual serotypes and the drug product containing multiple serotypes. Fouled membranes were examined by confocal microscopy, demonstrating that all four serotypes deposit in a narrow band near the filter inlet. The different ionic composition of the formulation buffer (compared to the buffers used with the drug substance) had a large effect on the fouling behavior. In addition, the fouling resistance associated with the drug product was greater than the sum of the resistances of the individual serotypes. These results provide important insights into the sterile filtration behavior of these multivalent glycoconjugate vaccines.     

Pharmacokinetic profile of (+/-)-gossypol in male Sprague-Dawley rats following single intravenous and oral and subchronic oral administration

The pharmacokinetic profile of (+/-)-gossypol was determined in male Sprague-Dawley rats following a single intravenous or oral 10 mg/kg dose and after receiving a daily oral 10 mg/kg dose for 14 days. The intravenous plasma (+/-)-gossypol level data were fitted with a three-compartment, open-model system. The apparent half-life of elimination of (+/-)-gossypol following intravenous administration was 11.44 hr, corresponding to an elimination rate constant of 0.05 hr-1. The total plasma clearance (Cl), volume of distribution (Vd), and AUCplasma following a single intravenous administration were 0.16 liter/hr/kg, 0.05 liter/kg, and 63.09 mg.hr/liter, respectively. The bioavailability of a single oral dose of (+/-)-gossypol in rats was 60%. The change in plasma (+/-)-gossypol concentration after a single or after multiple doses showed a biphasic pattern. A single oral dose of (+/-)-gossypol, however, was eliminated five times faster than the daily administered chemical. Thus, a single oral dose of (+/-)-gossypol was eliminated at a rate constant of 0.01 hr-1, corresponding to half-life of 64.76 hr. Subchronic oral administration of (+/-)-gossypol showed an apparent half-life of 101.91 hr-1, corresponding to a rate constant of 0.007 hr-1. The results indicate that multiple oral dosing of (+/-)-gossypol resulted in its longer retention in body tissue than a single oral dose. This study suggests that pharmacokinetics of (+/-)-gossypol may play, at least in part, a role in the reproductive toxicity of subchronic but not single oral dosing.     

Opportunity lost: a frontline view of reference-based pricing.

The introduction in October 1995 of reference-based pricing as a cost-saving measure for British Columbia''s drug benefit program represented an opportunity for collaboration between frontline practitioners and the bureaucracy that supports some of their work. If well-established principles of continuing education, quality improvement and modern management had been followed, practitioners in the field could have focused their individual and collective talents effectively and constructively on the task of improving cost-effectiveness in drug prescribing. Although the reference-based pricing program may well achieve its purpose of saving money, it is sad that it was not used to build bridges of common interest and mutual trust between two camps that are often in conflict.     

The effect of the lysosomotropic drug chloroquine on the binding of N-acetyl-beta-D-glucosaminidase to mannose-6-phosphate recognizing receptors of rat liver

The binding of N-acetyl-beta-D-glucosaminidase to rat liver receptors was studied in the presence of chloroquine. The association rate constant was not affected in the presence of the drug, while the dissociation rate constant and consequently the equilibrium dissociation binding constant significatively decreased. This results may explain effects of chloroquine on lysosomal enzyme transport found in cultured cells by other authors.     

Theoretical Comparison of Grab and Composite Sampling Programs

A mathematical formula for determining the sampling frequency on the basis of the coefficients of variation of the various parameters of interest of water quality is developed. The uncertainty or the variability of each sampling program is expressed as a function of the sampling design variable in order to construct a performance index which will enable one to select the best sampling program. The notion of information content is used as a basis for the performance index. Under certain circumstances, the information content of a single composite is more than that of a single grab sample. However, the average of a series of grab samples provides more information than the average of a series of composite samples. This happens because the individual information content (entropy) of discrete portions of the composite sample are confounded in the average. It is shown that if the variability of the proportions is greater than the upper limit (provided in Table 2), the information content of the composite, where the volume of each discrete portion is collected in proportion to the rate of flow (or discharge) at the time it is collected, is much smaller than that of the same number of grab samples or composite samples collected at constant volume-constant time intervals. Time constant, volume proportional-to-flow since last sample composites have the same disadvantages.     

Needle exchange programs: an economic evaluation of a local experience

OBJECTIVE: To determine whether providing a needle exchange program to prevent HIV transmission among injection drug users would cost less than the health care consequences of not having such a program. DESIGN: Incidence outcome model to estimate the number of cases of HIV infection that this program would prevent over 5 years, assuming that the HIV incidence rate would be 2% with the program and 4% without it, and that an estimated 275 injection drug users would use the service over this time. SETTING: Hamilton, Ont. OUTCOME MEASURES: Estimated number of cases of HIV infection expected to be prevented with and without the program over 5 years; estimated lifetime health care costs of treating an AIDS patient. The indirect costs of AIDS to society (e.g., lost productivity and informal caregiving) were not included. Projected costs were adjusted (discounted) to reflect their present value. In a sensitivity analysis, 3 parameters were varied: the estimate of the HIV transmission rate if no needle exchange program were provided, the number of injection drug users participating in the program, and the discount rate. RESULTS: With very conservative estimates, it was predicted that the Hamilton needle exchange program will prevent 24 cases of HIV infection over 5 years, thereby providing cost savings of $1.3 million after the program costs are taken into account. This translates into a ratio of cost savings to costs of 4:1. The sensitivity analysis confirmed that these findings are robust. CONCLUSION: Needle exchange programs are an efficient use of financial resources.     

Constant Pharmacologic Effect and Chronopharmacology: Theoretical Aspects

The theoretical drug infusion rates requisite to obtain a constant pharmacologic effect are determined taking into account chronopharmacologic phenomena. The introduction of chronopharmacology into pharmacokinetic theory leads to a clocktime-dependent infusion rate. The infusion modulation depends both on type of chronophenomenon, chronopharmacokinetics or chronestesy, and plasma clearance rate of the drug. In the presence of chronestesy of a biosystem the pharmacologic effect can be maintained constant only when plasma drug clearance is fast enough to allow an adequate modulation of the plasma drug concentration. Although the established equations proceed from theoretical concept they could be useful for programming drug delivery systems.     

Design and optimization of a series of 4-(3-azabicyclo[3.1.0]hexan-3-yl)pyrimidin-2-amines: Dual inhibitors of TYK2 and JAK1

Herein, we disclose a new series of TYK2/ JAK1 inhibitors based upon a 3.1.0 azabicyclic substituted pyrimidine scaffold. We illustrate the use of structure-based drug design for the initial design and subsequent optimization of this series of compounds. One advanced example 19 met program objectives for potency, selectivity and ADME, and demonstrated oral activity in the adjuvant-induced arthritis rat model.     

Constant Pharmacologic Effect and Chronopharmacology: Theoretical Aspects

The theoretical drug infusion rates requisite to obtain a constant pharmacologic effect are determined taking into account chronopharmacologic phenomena. The introduction of chronopharmacology into pharmacokinetic theory leads to a clocktime-dependent infusion rate. The infusion modulation depends both on type of chronophenomenon, chronopharmacokinetics or chronestesy, and plasma clearance rate of the drug. In the presence of chronestesy of a biosystem the pharmacologic effect can be maintained constant only when plasma drug clearance is fast enough to allow an adequate modulation of the plasma drug concentration. Although the established equations proceed from theoretical concept they could be useful for programming drug delivery systems.     

转化医学真菌学实例——直接提取DNA鉴定菌种及体外药敏试验指导诊治面部难辨认癣

目的报道1例由万博节皮菌(趾间毛癣菌有性期)所致面部难辨认癣,取皮损鳞屑直接提取真菌DNA做菌种鉴定,并与真菌培养鉴定结果比较,对培养的菌落直接用抗真菌乳膏做药敏实验指导治疗。方法病变部鳞屑经KOH涂片真菌镜检阳性后,取鳞屑直接提取DNA,以真菌通用引物ITS1/4做PCR扩增后测序;同时从培养生长的菌提取DNA做分子生物学鉴定;并将抗真菌乳膏加入含菌平板孔中观察抑菌圈大小。结果鳞屑直接提取的DNA与培养获得菌落提取的DNA经PCR-测序均鉴定为万博节皮菌,诊断万博节皮菌感染所致面部难辨认癣。镜检阳性后即给予特比萘芬口服(250mg/d)及1%萘替芬-0.25%酮康唑乳膏外用,每周复诊并取鳞屑镜检和培养,基于药物抑菌实验结果指导治疗5周,至临床治愈和真菌培养转阴。结论鳞屑直接提取DNA做PCR-测序能及早明确菌种,待培养菌落长出后做PCR-测序验证,直接用成品抗真菌乳膏做体外药敏实验指导临床选药,动态培养鳞屑以确定疗程。此个体化诊治方案为从临床到实验室、从实验室到临床转化医学真菌学的成功实例。     

Evaluation of alginate compressed matrices as prolonged drug delivery systems

This research investigated the use of sodium alginate for the preparation of hydrophylic matrix tablets intended for prolonged drug release using ketoprofen as a model drug. The matrix tablets were prepared by direct compression using sodium alginate, calcium gluconate, and hydroxypropylmethylcellulose (HPMC) in different combinations and ratios. In vitro release tests and erosion studies of the matrix tablets were carried out in USP phosphate buffer (pH 7.4). Matrices consisting of sodium alginate alone or in combination with 10% and 20% of HPMC give a prolonged drug release at a fairly constant rate. Incorporation of different ratios of calcium gluconate leads to an enhancement of the release rate from the matrices and to the loss of the constant release rate of the drug. Only the matrices containing the highest quantity of HPMC (20%) maintained their capacity to release ketoprofen for a prolonged time.     

Pharmacokinetic monitoring of aminoglycoside therapy: an optimal method of administration of individualized doses of gentamicin and sisomicin]

One of the most promising approaches to design the optimal schedule for TDM provides a single determination of a drug content in the blood specimen being collected at the "ideal" sampling time equaled to the inverse value of the elimination rate constant. Three versions of the one-point method when the specimen was collected at the "ideal" time point (3 h after a single i.m. drug administration), as well as at the times of "maximum" (1 h after injection) and "minimum" (6 h after injection) concentrations were compared by the retrospective analysis of the routine TDM data obtained with HPLC-techniques in 47 patients treated with gentamicin or sisomicin. As optimal individualized doses were considered ones calculated on the base of three subsequent determinations of the aminoglycoside concentrations, i.e. 1, 3 and 6 h after injection, and the estimation of individual clearance values (Cli). The optimal doses (DCl) were calculated according to equation DCl = Dp.Cli/Clp, where Dp and Clp are population values of the dose (1 mg/kg) and Cl 72.4 ml/(h.kg), respectively. The approximate values of the individual doses (D) were calculated according to equation D = Dp.Cp/Ci, where Ci is the individual drug serum concentration 1, 3 or 6 h after administration and Cp is the corresponded population value (4.8, 1.9 and 0.8 mg/l, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

The pattern of replication of cortical units in Tetrahymena

The patterns of increase in numbers of argentophilic elements (kinetosomes) are studied during the cell cycle of Tetrahymena pyriformis, syngen 1. The patterns suggest that new ciliary units are added uniformly to all ciliary rows during the early part of the cell cycle. After the start of the formation of the new oral apparatus, the rate of increase of the row to the right of the oral apparatus is increased and the rate of growth of the row to the left is decreased. The increase in total ciliary units, both somatic and oral, may well be constant for the entire cell cycle.