[Determination of the efficiency of work in serial compounding of drugs in pharmacies].
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Drug Compounding↗
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[3,5-Dinitrobenzoic acid anhydride as reagent for the characterization of drugs and for the activation of polarographically inactive compounds].
Drugs with primary or secondary amino groups react with 3,5-dinitrobenzoic acid anhydride under catalysis of pyridine derivatives almost quantitatively to yield the corresponding amides which are reducible at the dropping mercury electrode (DME). 3,5-Dinitrobenzoic acid will be separated by thin layer chromatography. The limit of detection by DPP is in the range of 10(-8) M. The electrode reaction is irreversible.
Anhydrides↗
Improving the odds in discriminating "drug-like" from "non drug-like" compounds.
We have used a feed-forward neural network technique to classify chemical compounds into potentially "drug-like" and "non drug-like" candidates. The neural network was trained to distinguish between a set of "drug-like" and "non drug-like" chemical compounds taken from the MACCS-II Drug Data Report (MDDR) and the Available Chemicals Directory (ACD). The 2D atom types (of the full atomic representation) were assigned and applied as descriptors to encode numerically each compound. There are four main conclusions: First the method performs well, correctly assigning 88% of the compounds in both MDDR and ACD. Improved discrimination was achieved by a more critical selection of training sets. Second, the method gives much better prediction performance than the widely used "Rule of Five", which accepts as many as 74% of the ACD compounds but only 66% of those in MDDR, resulting in a correlation coefficient which is effectively zero, compared to a value of 0.63 for the neural network prediction. Third, based on a standard Tanimoto similarity search the selection of drug-like compounds in the evaluation set is not biased toward compounds similar to those in the training set. Fourth, the trained neural network was applied to evaluate the drug-likeness of 136 GABA uptake inhibitors with impressive results. The implications of applying a neural network to characterize chemical compounds are discussed.
Algorithms↗
Compliance Policy Guide on Chapter 4 Human Drugs: Section 460.200 Pharmacy Compounding.
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Drug Compounding↗
[Drug vectorization or how to modulate tissular and cellular distribution of biologically active compounds].
Drug vectorization has undergone considerable development over the last few years. This review focuses on the intravenous route of administration. Colloid formulations allow a modulation of drug tissue distribution. Using liposomes and nanoparticles with unmodified surfaces, drugs can be targeted to macrophages of the reticulum endothelium system. When the liposomes or nanoparticles are covered with hydrophilic or flexible polymers, the vascular phase can be favored in order, for example, to facilitate selective extravasation at a tumor site. Therapeutic applications of these systems are presented. The development of "intelligent" vectors capable of modulating intracellular distribution of an active compounds is an equally interesting approach, for example pH-sensitive liposomes or nanoparticles decorated with folic acid capable of targeting intracellular cytoplasm.
Animals↗
In silico approaches to prediction of aqueous and DMSO solubility of drug-like compounds: trends, problems and solutions.
The solubility of drugs and drug-like compounds has been the subject of extensive studies aimed at finding a way to predict solubility from molecular structure. The aqueous solubility of a drug is an important factor that influences its absorption, distribution and elimination in the body. Poor aqueous solubility often causes a drug to appear inactive and may cause other biological problems. Compound solubility in DMSO represents another serious problem in early stages of drug discovery. An appreciation of the factors affecting a compound's DMSO solubility could help in predicting the storage conditions and appropriateness of compounds for primary bioscreening programs. In silico procedures for estimation of water and DMSO solubility represent extremely useful tools for the drug discovery practitioners. In this review, we provide a critical discussion of in silico models for the prediction of DMSO and water solubility of drug-like compounds used for virtual screening. We describe the main tendencies in the field, "booming" approaches and unsolved problems. A critical analysis of the accuracy and applicability of methods is provided.
Biological Availability↗
[Sigma-ligands for new therapeutic drugs].
Compounds that show their pharmacological actions via specific receptors are considered potential candidates for new drugs. Recently, several compounds that have specific binding sites and show certain pharmacological actions have been identified, but neither their binding sites, their endogenous substances, nor the functional role of the binding sites have been clarified. Regardless of the exact role of the binding sites of the compounds, research into the sites has opened up new areas of receptor investigation, and also new strategies for developing drugs. The sigma-ligand is one such kind of compound, and the existence of a binding site for the ligand was first postulated to account for the psychotomimetic effects of N-allylnormetazocine and related racemic benzomorphans. The binding site of the sigma-ligand is widely distributed in the central nervous system and peripheral systems. However, it still remain to be established whether sigma-ligand binding sites are to be referred to as "receptors". The classification of the ligands as agonists or antagonists at the sites and the heterogeneity and the functional role of the binding sites have not yet been clarified. Furthermore, the therapeutic targets have not been clearly determined. However, the sigma-ligands have high potential for developing new drugs. One of the possible targets of the sigma-ligands as new forms of drugs is schizophrenia. Recently, we identified two potent and highly selective sigma-ligands, FH-510 and NE-100. Together with the data on the binding properties and pharmacological actions of these compounds, the possibilities of the sigma-ligand as a new therapeutic drug were discussed.
Animals↗
Liquid chromatographic methods for the determination of albuterol (salbutamol), albuterol sulphate and related compounds in drug raw materials, tablets and inhalers.
Liquid chromatographic methods for the determination of albuterol (salbutamol), albuterol sulphate and related compounds in drug raw materials, tablets and inhalers are described. The methods resolve five known related compounds from the drug and, in the case of inhalers, several compounds not related to the drug. Two of these were identified as 2,6-di-t-butyl-4-methylphenol, a common antioxidant, and 2,2'-methylene bis(6-t-butyl-4-methylphenol). Related compounds are detectable at levels of about 0.03%. Eleven albuterol and 12 albuterol sulphate raw materials and eight tablet formulations were found to contain related compounds ranging from 0.03 to 0.54%, 0.09 to 0.50% and 0.32 to 0.95%, respectively. Non-drug compounds in three inhaler samples ranged from 4.6 to 12% of the drug delivered through the valve. Some of the non-drug compounds may be excipients.
Albuterol↗
Selection criteria for drug-like compounds.
The fast identification of quality lead compounds in the pharmaceutical industry through a combination of high throughput synthesis and screening has become more challenging in recent years. Although the number of available compounds for high throughput screening (HTS) has dramatically increased, large-scale random combinatorial libraries have contributed proportionally less to identify novel leads for drug discovery projects. Therefore, the concept of 'drug-likeness' of compound selections has become a focus in recent years. In parallel, the low success rate of converting lead compounds into drugs often due to unfavorable pharmacokinetic parameters has sparked a renewed interest in understanding more clearly what makes a compound drug-like. Various approaches have been devised to address the drug-likeness of molecules employing retrospective analyses of known drug collections as well as attempting to capture 'chemical wisdom' in algorithms. For example, simple property counting schemes, machine learning methods, regression models, and clustering methods have been employed to distinguish between drugs and non-drugs. Here we review computational techniques to address the drug-likeness of compound selections and offer an outlook for the further development of the field.
Algorithms↗
Membrane-assisted liquid-liquid extraction coupled with gas chromatography-mass spectrometry for determination of selected polycyclic musk compounds and drugs in water samples.
Selected polycyclic musk compounds and drugs were extracted from water samples by membrane-assisted micro liquid-liquid extraction. The two-phase extraction system consisted of polyethylene membrane bags filled with an organic solvent. Chloroform proved to be most suited as acceptor phase to extract caffeine, Galaxolide, Tonalide, phenazone and carbamazepine from aqueous samples. The compounds were enriched from 50 mL sample into a volume of 500 microL of chloroform. Gas chromatography-mass spectrometry (GC-MS) was applied for analysis. The extraction procedure was optimised in regard to membrane material, extraction time and temperature. The evaluation of the entire analysis protocol found limits of detection that ranged from 20 to 200 ng/L. The linear range of calibration covered one magnitude with standard deviations between 4 and 12%. Method comparison with standard analysis techniques such as solid-phase extraction (SPE) combined with GC-MS as well as LC-MS-MS confirmed this method as an easy and reliable protocol, even for the monitoring of matrix-loaded wastewater. The analysis of real samples established the feasibility of the technique.
Calibration↗
[Naphthalenesulfonate compounds of alkylaminoalkyl drugs].
New compounds of alkylaminoalkyl with some naphthalenosulphonate (Na) were obtained and some of their physicochemical properties have been determined. Ability to formation of these compounds was utilised in qualitative and quantitative analysis of the above drugs.
Alkanes↗
[Deterioration of drugs in compounding studied by thin-layer chromatography. 2].
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Chromatography, Thin Layer↗
Computer-aided prediction of receptor profile for drug-like compounds.
Computer program SIMEST (Similarity Estimating) for prompt estimation of drug-like compounds' interaction with various receptors has been developed. More than 200 kinds of receptor activities (agonists and antagonists) can be predicted analysing new compound's similarity with known ligands. SIMEST consists of two components: (a) database of low-molecular weight ligands (agonists and antagonists) for 106 receptors and (b) similarity estimation module based on original MNA descriptors. The predictive abilities of SIMEST were evaluated on two data sets: (a) about 24,000 biologically active compounds from MDDR-99.2 database; (b) seven well-studied antipsychotic drugs. Average accuracy of prediction was 85.2% for compounds from MDDR and 78.7% for antipsychotic drugs. SIMEST can be effectively applied for predicting possible mechanisms of action and side effects for drug-like substances on the basis of their structural formulae.
Databases, Factual↗
A novel liquid chromatography/tandem mass spectrometry based depletion method for measuring red blood cell partitioning of pharmaceutical compounds in drug discovery.
A novel liquid chromatography/tandem mass spectrometry (LC/MS/MS)-based depletion method for measuring compound partitioning between human plasma and red blood cells (RBC) in a drug discovery environment is presented. Conventionally, RBC partitioning is determined by separate measurements of drug concentrations in equilibrating plasma and whole blood or RBC using separate standards prepared in their respective matrices, i.e., in plasma and whole blood or RBC lysates. The process is very tedious, labor-intensive, and difficult to automate. In addition, interferences from the heme and other highly abundant cellular composites make the measurement of the drug concentration in whole blood or RBC inevitably variable even with a highly specific LC/MS/MS method. Therefore, there is an imminent need to develop a straightforward and fast method to assess the partitioning of drug-like compounds in RBC. This work describes an LC/MS/MS-based depletion assay that measures the compound concentration in plasma that has been equilibrating with RBC. Compounds were spiked into fresh human whole blood and plasma respectively to a final concentration of 500 nM. Both the spiked whole blood and plasma control were incubated at 37 degrees C for up to 60 min. During the time course, aliquots of plasma and whole blood from both incubation mixtures were sampled at 10 and 60 min. The whole blood samples were centrifuged to yield the plasma. The plasma samples from both incubations were extracted using a protein precipitation method, and analyzed using LC/MS/MS under the multiple-reaction monitoring (MRM) mode. The RBC partitioning ratio was calculated using the analyte peak area responses of the plasma samples through an equation deduced in this work. The method was first tested using two commercial compounds, phenoprobamate and acetazolamide, to determine the optimal incubation conditions and the concentration dependency of the assay. The assay reproducibility was also assessed by three inter-day assays for phenoprobamate. This method was further evaluated using 20 commercial compounds of different classes with a wide range of RBC partitioning coefficients and the results were compared with those reported in the literature. Excellent correlation (R2=0.9396) was found between the measured and literature values. In addition, several proprietary compounds were assayed using both the new and traditional methods and the measured partitioning ratios from the two methods are equivalent. The experiments in this work demonstrate that the LC/MS/MS-based depletion method can provide direct and accurate measurement of RBC partitioning for compounds in drug discovery.
Acetazolamide↗
FDA/CVM's Compliance Policy Guide on compounding of drugs.
As a veterinary practitioner, do you combine drug agents for anesthesia? Create antidotes? Dilute liquids for administration to small, young, or exotic species? Such efforts are examples of compounding. The FDA/CVM's new Compliance Policy Guide (CPG), which regulates the compounding of drugs by veterinarians and pharmacists for use in animals appears here, as originally published in the Compliance Policy Guide Manual. The CPG provides guidance to FDA's field and headquarters staff and serves as a source of useful information to veterinarians. The CPG for Compounding of Drugs for Use in Animals reflects the efforts of a task force made up of a diverse group of veterinarians, pharmacists, and regulators whose conclusions were published in the Symposium of Compounding in JAVMA, July 15, 1994, pp 189-303.
Animals↗
Extemporaneous (magistral) preparation of oral medicines for children in European hospitals.
UNLABELLED: The lack of availability of licensed paediatric medicines forces pharmacists to compound drugs into a form that children can tolerate. There is a lack of information to support much of this practice and standards tend to vary. Suitable licensed alternatives are often available in other countries but importing restrictions complicate obtaining them. CONCLUSION: Regulatory action is needed to simplify licensing and importation processes to facilitate universal access to suitable paediatric medicines.
Administration, Oral↗
DMSO-related effects in protein characterization.
DMSO is the standard solvent for preparing stock solutions of compounds for drug discovery. The assay concentration of DMSO is normally 0.1% to 5% (v/v) or 14 to 715 mM. Thus, DMSO is often one of the principal additives in assay buffers. This standardization of stock solutions does not eliminate possible pitfalls associated with the effects of the DMSO-containing solutions on individual proteins. In this article, the authors want to emphasize the importance of detailed studies of these effects in the early stages of drug discovery. Two protein systems, the extracellular soluble domain of the human growth hormone receptor (hGHbp) and the phosphatase domain of PFKFB1 (BPase), were used for the study on effects of DMSO on protein stability, protein aggregation, and binding of drug compounds. The study revealed significant differences in the proteins' behavior in the presence and absence of low amounts of DMSO. The addition of DMSO resulted in destabilization of the proteins investigated and also changed the apparent binding property of 1 protein. The authors have also shown that low DMSO concentrations influence the ionization process in electrospray ionization mass spectrometry (ESI-MS).
Calorimetry, Differential Scanning↗
[Simultaneous determination of four components in the compound child phenobarbital tablet using ultraviolet spectrophotometry].
OBJECTIVE: To establish a method to determine four components in the child phenobarbital tablet. METHODS: Ultraviolet spectrophotometry was used to determine four components without separation. RESULTS: The contents of aspirin, phenacetin, caffeine and phenobarbital could be measured simultaneously. The average recoveries of four components in simulated samples and the compound child phenobarbital tablet samples were 99.0%, 98.9%, 99.8%, and 101%, respectively, and relative standard deviations of those were 2.0%, 2.0%, 2.9%, and 2.2%, respectively. CONCLUSION: The method is simple, fast, reliable, and can be used to monitor the quality of compound drugs.
Aspirin↗