Influence of compounding on sterility and stability of drugs.
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Animals↗
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[Dissolution profiles of powdered inclusion compounds of sulfonamide drugs with beta-cyclodextrin].
The interactions of beta-cyclodextrin (beta-CD) with three sulfonamide drugs were studied. Observations were made on the effects of beta-CD on the solubility and the dissolution rate of these drugs in aqueous solution when comparing two different methods. The solubility of these three drugs was found to increase with the addition of beta-CD. This increase in solubility when using beta-CD was considered to be due to the formation of inclusion compounds. The dissolution rate of drugs increased with beta-CD, and was similar in tendency to the solubility data. These effects on both solubility and dissolution rates were similar regardless of which method was used. The X-ray diffraction pattern of the drug/beta-CD freeze-drying powder showed a clear difference from the physical mixture of intact drugs.
Chemical Phenomena↗
Brain monoamine receptors in a chronic unpredictable stress model in rats.
Antidepressant drugs are devoid of mood-elevating effects in normal (non-depressed) human subjects, thus, it is necessary to evaluate the antidepressant property of compounds (drugs) in animal models of depression. Several animal models of depression have been introduced, however, only a few have been extensively validated. In the present study we report the results of investigations into monoaminergic receptors in the brain of rats subjected to chronic unpredictable stress (CUS) procedure (one of the well validated animal models of depression). We have examined the dopaminergic (D-1, D-2), adrenergic (alpha-1, beta-1) and serotonergic (5HT-1A, 5HT-2A) receptors in different brain regions by a saturation radioligand binding method in rats subjected to CUS paradigm and control animals. CUS procedure resulted in a significant 29% increase in the D-1 receptor density in the limbic system and 52% increase of the density of 5HT-2A receptors in the cerebral cortex. The present data indicate that the increase of the density of brain D-1 and 5HT-2A receptors of rats subjected to CUS might be involved in the pathophysiology of "animal depression" (since chronic antidepressant treatment produced opposite changes i.e. decrease in the density of these receptors) and thus in pathophysiology of human depression.
Adrenergic Agonists↗
Caffeine distribution in acute toxic response among inbred mice.
The median lethal dose (LD50) and the median lethal concentration (LC50) of caffeine administered intravenously (i.v.) and orally (p.o.) were calculated in adult male CD2F1/Crl BR mice. Acute toxic behavioral responses to the drug were observed after administration via the two routes. Deaths followed severe tetanic convulsions: some animals had transient convulsions and survived, and others presented no acute toxicity. In a further study, the LD50 of caffeine was given i.v. and by gavage to animals randomly paired. At the death of one of the two mice the other was killed and caffeine assayed in blood and tissues of both. Different patterns of distribution were observed inter- and intra-route of administration, animals which died always having higher drug levels, although they had received the same dose. These findings suggest that besides the well-known factors affecting acute toxic response to exogenous compounds, drug distribution also has to be taken into account in a multifactorial toxicological investigation.
Animals↗
Clinical implications of in vitro drug-induced interferon gamma release from peripheral blood lymphocytes in cutaneous adverse drug reactions.
BACKGROUND: Drug-specific T cells are involved in the pathogenesis of cutaneous adverse drug reactions (CADRs). OBJECTIVE: We sought to evaluate the diagnostic role of in vitro drug-induced release of interferon gamma in CADRs. METHODS: The study group consisted of 36 patients with CADRs after intake of 106 drugs that were classified into 3 categories of drug suspicion: high, possible, and low. The control group consisted of 22 individuals taking a similar profile of 54 drugs, without CADRs. In vitro drug-induced interferon gamma release was determined by enzyme-linked immunosorbent assay in culture supernatants after incubation of peripheral blood lymphocytes with parent drug compounds. The in vitro tests were conducted after the acute phase of the CADRs. In vitro tests were compared with in vivo withdrawal and/or challenge drug tests. RESULTS: Positive interferon gamma tests were recorded in 77.8% of the patients for 49.0% of the drugs. The proportion of positive interferon gamma tests was directly associated with the degree of drug suspicion (64.4%, 36.4%, and 27.8% for high, possible, and low, respectively). There were significantly more positive tests for high- compared with low-suspicion drugs (P=.001). The degree of agreement between the results of the in vitro interferon gamma release tests and the in vivo tests was intermediate to good (kappa=0.47). CONCLUSION: In vitro drug-induced interferon gamma release may help to identify the responsible drug in CADRs.
Adolescent↗
[Pharmacodynamics and pharmacokinetics of domestic fixed-dose combination of antituberculosis drugs].
OBJECTIVE To study the pharmacodynamics and pharmacokinetics of domestic fixed-dose of antituberculosis drugs and to evaluate its quality and activity against Mycobacterium tuberculosis both in vitro and in vivo. METHODS The MIC was determined by the tube doubling dilution method, and the effect of the drugs was assessed by half survival time of the mice. A single oral dose of domestic and imported fixed-dose combination of antituberculosis drugs was given to healthy volunteers, and the drug concentration in serum was determined by HPLC. The pharmacokinetic parameters and the relative bioavailability were calculated. RESULTS The MIC of each composition in the compound (INH, RFP, PZA) against Mycobacterium tuberculosis was lower than that of each composition used by single-dose. In a murine tuberculosis model, the antituberculosis activity of this compound drug was superior to that of each agent used alone with the same dose. No significant difference was found as compared to the imported drug, Refater; The major pharmacokinetic parameters of the domestic and the imported drugs, t (1/2), C (max), AUC, and t(max), were not significantly different. Statistical analysis showed the two formulations were bioequivalent. CONCLUSION The three compositions in the combination had synergistic effect, and the domestic and the imported drugs were bioequivalent.
Animals↗
Cloned enzyme donor immunoassay (CEDIA) for drugs-of-abuse screening.
Large numbers of specimens (5000-18,000) were screened for amphetamines, barbiturates, cocaine, marijuana, opiates, and phencyclidine by RIA (Roche), Emit II (Syva), and a new immunoassay, CEDIA (cloned enzyme donor immunoassay, Microgenics). All immunoassays performed equivalently for cocaine, opiates, and phencyclidine. All immunoassays detected the same amphetamine/methamphetamine-positive specimens, but all also detected numerous specimens containing cross-reacting sympathomimetic amines. CEDIA detected 100%, Emit II 93%, and RIA 82% of the barbiturate-positive specimens. Emit II and CEDIA detected 86-88% of the specimens found by RIA to be marijuana positive. A subset of specimens was additionally screened by OnLine (Roche) and TDx (Abbott) for amphetamines, cocaine, and marijuana. OnLine and TDx also detected all of the amphetamine-positive specimens and numerous specimens containing cross-reacting sympathomimetic amines. All immunoassays performed equivalently for cocaine, and the four nonisotopic tests detected 86-89% of the marijuana positives found by RIA. Interfering sympathomimetic amine drug compounds can be eliminated by using an oxidizing agent, thus decreasing the number of unconfirmable amphetamine presumptive positives. The CEDIAs for all of the major drugs of abuse are reliable and effective for large-volume urine screening programs.
Amphetamines↗
Emerging chemotherapeutic strategies for Huntington's disease.
Huntington's disease (HD) is a progressive and fatal neurological disorder caused by an expanded CAG repeat in the gene coding for the protein, huntingtin. There is no clinically proven treatment for HD. Although the exact cause of neuronal death in HD remains unknown, it has been postulated that the abnormal aggregation of the mutant huntingtin protein may cause toxic effects in neurons, leading to a cascade of pathogenic mechanisms associated with transcriptional dysfunction, oxidative stress, mitochondrial alterations, apoptosis, bioenergetic defects and subsequent excitotoxicity. Understanding how these processes interrelate has become important in identifying a pharmacotherapy in HD and in the design of clinical trials. A number of drug compounds that separately target these mechanisms have significantly improved the clinical and neuropathological phenotype of HD transgenic mice and, as such, are immediate candidates for human clinical trials in HD patients. These compounds are discussed herein.
Animals↗
Ulcerogenic drugs and antiulcer compounds: effects on gastroduodenal mucosa.
Nonsteroidal antiinflammatory drugs (NSAID) and steroids are ulcerogenic to the gastroduodenal mucosa in man although the exact incidence of drug-induced lesions is unknown. It is assumed that NSAID are ulcerogenic because they block the biosynthesis of prostaglandins, thereby reducing the mucosal resistance to acid peptic digestion. NSAID inhibit recognized mucosal defense factors, such as bicarbonate transport and mucus glycoprotein production and release; they reduce the thickness of the pH-mucus barrier, interfere with cytoprotection and have antitrophic actions. Prostaglandins reverse the inhibition of defense factors by NSAID and prevent their ulcerogenic actions; they stimulate secretion of bicarbonate and glycoproteins and have trophic and cytoprotective properties. Challenge of the mucosa stimulates defense factors and prostaglandin formation in parallell; pretreatment with NSAID impairs the defensive response and reduces local prostaglandin formation. Mucosal lesions, produced by NSAID may be prevented by agents that neutralize or inhibit gastric acid, such as H2-receptor blockers, antacids and acid antisecretory prostaglandins. Compounds, which stimulate--or simulate--mucosal defense factors are also effective such as sucralfate, colloidal bismuth and prostaglandins devoid of acid antisecretory properties. Of these, several may work by increasing local prostaglandin concentration.
Animals↗
Surface ionization organic mass spectrometry of imipramine, desipramine, clomipramine, and lidocaine.
Surface ionization organic mass spectrometry (SIOMS) has been performed on some clinically important drugs (imipramine, desipramine, clomipramine, lidocaine) by using quadrupole mass spectroscopy in which the thermal ion source has a rhenium oxide emitter. The mass spectra were presented, interpreted in a purely empirical way, by means of evidence from previous investigations, and then compared to conventional EI techniques. Sensitivity and selectivity have also been studied, demonstrating that (a) these drug compounds are efficiently surface-ionized, (b) experimental results rationalize the high sensitivity of the surface ionization detector (SID) of gas chromatography (GC) for the examined drugs, and (c) the GC/SIOMS coupling can be used for sensitive and selective detection of the drugs in the serum. An approach to detection of these drugs in serum by GC/SIOMS and GC with SID is described. The characteristics of both methods provide a reliable, sensitive, and selective method, which is needed for low concentration level measurements in complex mixtures.
Clomipramine↗
Network-based de-noising improves prediction from microarray data.
BACKGROUND: Prediction of human cell response to anti-cancer drugs (compounds) from microarray data is a challenging problem, due to the noise properties of microarrays as well as the high variance of living cell responses to drugs. Hence there is a strong need for more practical and robust methods than standard methods for real-value prediction. RESULTS: We devised an extended version of the off-subspace noise-reduction (de-noising) method to incorporate heterogeneous network data such as sequence similarity or protein-protein interactions into a single framework. Using that method, we first de-noise the gene expression data for training and test data and also the drug-response data for training data. Then we predict the unknown responses of each drug from the de-noised input data. For ascertaining whether de-noising improves prediction or not, we carry out 12-fold cross-validation for assessment of the prediction performance. We use the Pearson's correlation coefficient between the true and predicted response values as the prediction performance. De-noising improves the prediction performance for 65% of drugs. Furthermore, we found that this noise reduction method is robust and effective even when a large amount of artificial noise is added to the input data. CONCLUSION: We found that our extended off-subspace noise-reduction method combining heterogeneous biological data is successful and quite useful to improve prediction of human cell cancer drug responses from microarray data.
Algorithms↗
Crystal structure of the transcription activator BmrR bound to DNA and a drug.
The efflux of chemically diverse drugs by multidrug transporters that span the membrane is one mechanism of multidrug resistance in bacteria. The concentrations of many of these transporters are controlled by transcription regulators, such as BmrR in Bacillus subtilis, EmrR in Escherichia coli and QacR in Staphylococcus aureus. These proteins promote transporter gene expression when they bind toxic compounds. BmrR activates transcription of the multidrug transporter gene, bmr, in response to cellular invasion by certain lipophilic cationic compounds (drugs). BmrR belongs to the MerR family, which regulates response to stress such as exposure to toxic compounds or oxygen radicals in bacteria. MerR proteins have homologous amino-terminal DNA-binding domains but different carboxy-terminal domains, which enable them to bind specific 'coactivator' molecules. When bound to coactivator, MerR proteins upregulate transcription by reconfiguring the 19-base-pair spacer found between the -35 and -10 promoter elements to allow productive interaction with RNA polymerase. Here we report the 3.0 A resolution structure of BmrR in complex with the drug tetraphenylphosphonium (TPP) and a 22-base-pair oligodeoxynucleotide encompassing the bmr promoter. The structure reveals an unexpected mechanism for transcription activation that involves localized base-pair breaking, and base sliding and realignment of the -35 and -10 operator elements.
Antineoplastic Agents↗
[Alcohol-xenobiotic interactions. Role of cytochrome P450 2E1].
Alcohol and xenobiotics share the same oxidative microsomal pathway, which is mainly located in the endoplasmic reticulum of hepatocytes. This pathway involves enzymes that belong to the super family of cytochrome P450 and allows to explain a lot of pharmacokinetic or toxic interactions between alcohol and xenobiotics. Cytochrome P450 2E1 (CYP2E1) is the key enzyme of the microsomal pathway of ethanol oxidation. It is inducible by chronic ethanol consumption and its activity is increased by three to five fold in liver from alcoholics subjects. This induction involves to a lesser extent cytochromes P450 3A4 and 1A2 and contributes to the metabolic tolerance of alcohol and drugs observed in alcoholics. The metabolic tolerance persits several days after ethanol withdrawal. Furthermore, CYP2E1 has a high capacity to activate numerous xenobiotics into toxic or carcinogenic compounds. Drugs currently used such as paracetamol, anesthetics (enflurane, halothane), industrial solvents (benzene or its derivatives), halogenated solvents (CCl4, trichlorethylene) and nitrosamines which are present in food or tobacco smoke are included. Therefore, heavy consumption of alcohol, which results in CYP2E1 induction, increases individual susceptibility to the toxic or carcinogenic effects of these xenobiotics.
Acetaminophen↗
Prediction of partition coefficient based on atom-type electrotopological state indices.
The aim of this study was to determine the efficacy of atom-type electrotopological state indices for estimation of the octanol-water partition coefficient (log P) values in a set of 345 drug compounds or related complex chemical structures. Multilinear regression analysis and artificial neural networks were used to construct models based on molecular weights and atom-type electrotopological state indices. Both multilinear regression and artificial neural networks provide reliable log P estimations. For the same set of parameters, application of neural networks provided better prediction ability for training and test sets. The present study indicates that atom-type electrotopological state indices offer valuable parameters for fast evaluation of octanol-water partition coefficients that can be applied to screen large databases of chemical compounds, such as combinatorial libraries.
Chemical Phenomena↗
Peptides targeting protein kinases: strategies and implications.
Protein kinases are important key regulators in most, if not all, biological processes and are linked with many human diseases. Protein kinases thus became attractive targets for drug design. Intracellularly active peptides that selectively interfere with kinase function and or kinase-mediated signaling pathways are potential drug compounds with therapeutic implications.
Amino Acid Sequence↗
[Beta-adrenoblocking activity and other pharmacological properties of 2-(3-amino-2-hydroxypropoxy)phenyoxymethyl isoxazole derivatives].
Some derivatives of 2-(3-amino-2-hydroxypropoxy)phenoxymethyl isoxazole possess beta- and alpha-adrenoblocking activity. 3-Methyl-4-chlor-5-(3-isopropylamino-2-hydroxypropoxy)phenoxymethyl isoxazole hydrochloride (compound OF-4452) is the most active of the compounds studied. As to the beta-adrenoblocking activity, this compound given in vivo and in vitro compares very favourably with propranolol, oxprenolol and labetalol, in particular; as regards the alpha-adrenoblocking action, it is not inferior to the latter drug. Compound OF-4452 has a partial agonist activity and nonspecific membrane-stabilizing action. It displays antifibrillatory and antiarrhythmic activity as well.
Adrenergic alpha-Antagonists↗
The occurrence and removal of selected pharmaceutical compounds in a sewage treatment works utilising activated sludge treatment.
Pharmaceutical substances have been detected in sewage effluents as well as receiving waters in many parts of the world. In this study, the occurrence and removal of a number of drug compounds were studied within a large sewage treatment plant in the south of England. Samples were processed using solid phase extraction and analysed using gas chromatography-mass spectrometry (GC-MS). The results demonstrate that ibuprofen, paracetamol, salbutamol and mefenamic acid were present in both the influent and effluent of the works while propranolol-HCl was not found above the limit of quantification in any sample. Elimination rates were circa 90% for each compound but several hundred nanograms per litre were still present in the final effluent.
Acetaminophen↗
[Drug prescription in internal medicine: an analysis of the influencing factors].
BACKGROUND: The amount and quality of drugs prescribed after hospitalization in Internal Medicine and the factors which influence them have been rarely evaluated in Spain. MATERIAL AND METHODS: We study prospectively drugs prescribed in patients hospitalized in Internal Medicine analyzing amount of drugs before admission (BAD), on discharge (DD), end drugs after temporal drugs were removed (ED), drugs prescribed as chronic treatment (CTD), symptomatic drugs (SD), acute-use drugs (AUD) and low therapeutic utility drugs (LTUD). We also evaluated the sort of drugs and the factors implicated in increase or decrease of prescription volume. RESULTS: Two hundred and eighty-five patients were evaluated [164 males, 121 females, mean age 68.08 (SD 15.27)]. They had mean BAD 3.42(SD 2.67)7 DD 3.92 (SD 2.36) (p < 0.001) and ED 3.65 (SD 2.30) (No differences with BAD). The amount of drugs were higher in patients 65 years old and elder (p < 0.001). LTUD were decreased from 62(22%) patients on admission to 21 (7%) on discharge (p < 0.001). Compounded drugs were reduced from 36 (13%) patients to 17 (6%) (p < 0.05). Age older 65, length of stay greater 7 days, need for intravenous administration of drugs, comorbidities and complications during hospitalization all caused increase in prescription volume on discharge. Logistic-regression analysis showed that CTD and AUD were the main causes of increase of drugs while BAD and LTUD were protective. Drugs reduced in higher proportion were mucolytics (p < 0.005) drugs to treat plant-based hyperplasia benign of prostate (p < 0.05), brain vasodilators (p < 0.001) and peripheral vasodilators (p < 0.01). CONCLUSIONS: Hospitalization in Internal Medicine results in an increase of prescription volume though it is short-term. The higher number of drugs is accumulated in elderly. Factors implicated in increasing are length of stay, need for intravascular access, complications during inpatient, drugs to treat acute diseases and chronic use drugs. Low therapeutic utility drugs are used before admission in outpatients.
Aged↗