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PubMed1995

Duration of opioid antagonism by nalmefene and naloxone in the dog. A nonparametric pharmacodynamic comparison based on generalized cross-validated spline estimation.

The opioid antagonist nalmefene was compared in its pharmacodynamic properties to the structurally similar antagonist naloxone in a 2 x 2 cross-over study with 8 dogs. Opioid-induced respiratory depression was produced for ca. 7 hours with a constant rate intravenous infusion of 30 micrograms/kg/hr fentanyl and quantified using noninvasive transcutaneous pCO2 recordings. Upon reaching a pseudo-steady state of respiratory depression at 2 hours post fentanyl infusion initiation, the animals then received either nalmefene (12 micrograms/kg/hr) or naloxone (48 micrograms/kg/hr) for 30 minutes. The pharmacodynamic pCO2 responses produced by the combined agonist/antagonist regimen were fitted with a cubic spline function using a generalized cross-validation technique. Various quantities that describe the onset, duration and relative potency of each antagonist were determined directly from the estimated response curves in a model-independent, nonparametric way. The 2 antagonists were compared in terms of these quantities using a statistical model that considers carry-over effects typically arising from a possible development of tolerance. The results indicate that nalmefene: 1. is approximately 4-fold more potent than naloxone, 2. has an onset of reversal as rapid as naloxone, and 3. has a significantly longer (2-fold) pharmacodynamic duration of action than does naloxone. The mean time required for the agonist to regain 30% or 50% of its effect present at the start of the antagonist infusion was 66 and 112 minutes and 37 and 55 minutes for nalmefene and naloxone, respectively. Early, effective pharmacodynamic screening of new drug compounds is a valuable way of accelerating the drug discovery process and reducing escalating drug development costs. This study exemplifies a novel, endpoint oriented pharmacodynamic comparison procedure that can be done expeditiously before starting the time consuming development and validation of a drug level assay, and before engaging in considerably more involved integrated PK/PD studies.

Analysis of Variance↗

PubMedDate not supplied

[Photosensitization and photoprotection by some drugs, metabolites and other compounds].

Photosensitizing and photoprotecting efficiency of about a hundred of compounds, mainly drugs, was studied. The method based on chemiluminescence occurred along with photooxidation of glycyltryptophan under irradiation in UVB range in solution was used for testing. As a measure of photosensitizing efficiency the concentration of photosensitizer which induced two-fold increase of chemiluminescence intensity was chosen. The most effective photosensitizers are riboflavin, FAD, furagin, psoralene, vicasol, benzobarbital, mydocalm, angelicyn, furadonin, ethacridin, diazolin, folic acid. With regard to pharmacological doses of drugs in organism more dangerous sensitizers (in descending order) are p-aminosalicylic acid, furagin, riboflavin, benzobarbital, thiopental, chloramphenicol, nicodin, mydocalm, furadonin, oxolonic acid, furazolidone, psoralene, nicotinamide and diazolin. Photoprotecting effect was described by the concentration at which chemiluminescence intensity decreased twice. The most effective photoprotectors are etamsilat, quercetin, ftivazid, chlorpromazine, diprazine, thioridazine, aminophenazone, oxaphenamide. Concentration dependence for some of these drugs (etamsilat, chlorpromazine, diprazine, thioridazine) is non-monotonous: they inhibit photooxidation in low concentration (about 10(-7)-10(-6) M), but at higher concentrations (10(-5)-10(-4) M) photosensitization dominates over photoprotection.

Animals↗

PubMed2003

Application of comprehensive two-dimensional gas chromatography to drugs analysis in doping control.

Comprehensive two-dimensional gas chromatography (GC x GC) now occupies a niche within the GC technology regime. The technique is undeniably unique in the manner in which the experiment is conducted, the way results are presented and the interpretive opportunities offered. For the 1000th volume of this journal it is appropriate to expand upon these features, and review the progress made in GC x GC to date. Firstly, brief general comment is made on multidimensional procedures, and to review key aspects of GC x GC. The use of the targeted multidimensional GC method allows absolute retentions in the second dimension of a GC x GC experiment to be estimated, and also offers a novel way to obtain enhanced response for resolved solutes. Then, to illustrate the utility of the technique, the application of GC x GC to the screening of drugs and their metabolites in biological fluids is described using prolintane metabolites in canine urine as an example, with samples taken at four time intervals after administration. This example illustrates the first application of GC x GC in the field of forensic toxicology, an area traditionally dominated by GC-MS. Most drug compounds were found to be retained on the 0.8-m second column for a greater time than the modulation period (3 s) used for initial analysis, under the conditions described. Hence a 0.4-m D2 BPX50 (50% phenyl methyl polysilphenylene) column was then used throughout, with most compounds retained less than 4 s. For the standard drug mixture, three overlapping drugs on the first dimension column (BPX5) were subsequently baseline resolved on the BPX50 column. For prolintane administration samples, the parent drug and metabolites could be effectively resolved from background matrix peaks. Likewise a 23-drug spike standard in horse urine blank gave acceptable resolution of the drugs from matrix peaks.

Calibration↗

PubMedDate not supplied

Facile synthesis of fused pyrazolo[1,5-a]pyrimidinepyrazolo [1,5-a]triazines and N-sulphonamidopyrazoles as antiinflammatory.

Interaction of hydrazine hydrate with methyl (2-E)-2-cyano-3-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]-3-(methylsulphanyl)-2-propenoate 2 which was obtained by the reaction of methyl-2-cyano-3,3-bis(methylsulphanyl) acrylate 1 with 4-amino-1-phenyl-2,3-dimethyl pyrazoline-5-one afforded methyl-5-amino-3-[(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino]-1H-pyrazole-4-carboxylate 3a. The pyrazolin derivative 3a is a good precursor for the synthesis of pyrazolo[1,5-a]pyrimidines which is based on the interaction of 3a with alpha,beta-unsaturated nitrile derivatives. The biological effects of some of the newly synthesized compounds were also investigated as antiinflammatory, analgesic and antipyretic drugs. Compounds 2b, 4a, 3a, 3b, 2a and 4b were found to have significant antiinflammatory activity in descending order in comparison to control groups phenylbutazone. Compounds 3a, 2a, 4b, 4a, 2b and 3b have analgesic activity in decreasing order. Compound 3a was the most potent and had 82.6% potency of Novalgin. Compounds 2b, 2a, 3b, 4b, 3a and 4a were found to have significant antipyretic activity in descending order. Compounds 2a, 4b induced no ulcerogenic activity, while compounds 3b, 2b, 4a and 3a showed only slight ulcerogenic activity.

Analgesics↗

PubMed1994

Antipsychotic drug use in older adults.

The pharmacology, pharmacokinetics, drug interactions, adverse effects, indications for use, efficacy, dosage, and pattern of use of antipsychotics in adults older than 65 years are reviewed. Most available antipsychotic agents block dopamine type 2 postsynaptic receptors. Antipsychotics also bind to cholinergic, alpha-adrenergic, histamine type 1, and serotonin receptors. The affinities of a given agent for receptors determine its adverse effects and probably its efficacy. There are many obstacles to therapeutic drug monitoring. Many antipsychotics are metabolized into multiple active compounds. Drug clearance from brain tissue may be slower than from plasma. Therapeutic steady-state concentrations are difficult to define. Age-related physiological changes alter the pharmacokinetic and pharmacodynamic characteristics of antipsychotics, placing the elderly adult at heightened risk for adverse effects. Agents that may interact with the antipsychotics include carbamazepine, phenytoin, phenobarbital, tricyclic antidepressants, and lithium. Adverse effects frequently observed in the elderly are orthostatic hypotension, anticholinergic effects, pseudoparkinsonism, and tardive dyskinesia. Neuroleptic malignant syndrome is a rare but potentially fatal reaction. The antipsychotics carry approved labeling for use in treating psychotic disorders; many antipsychotics are approved for use in treating other conditions as well, such as behavioral problems. The Omnibus Budget Reconciliation Act of 1987 established dosage and documentation guidelines for antipsychotic drug use in residents of nursing homes. The guidelines specify that antipsychotics should not be used in this population if the only indication is a problem behavior like wandering. Although antipsychotics are often prescribed for behavioral control in older adults, most studies show only modest efficacy, while some show worsening of symptoms. As-needed orders for antipsychotics are controversial. Antipsychotics can relieve symptoms in the older adult, but lower dosages and more frequent assessments are necessary than for younger adults.

Age Factors↗

PubMed2004

4-sulphamoylphenyl semicarbazones with anticonvulsant activity.

A series of 4-sulphamoylphenyl semicarbazone derivatives were prepared starting from sulphanilamide and screened for anticonvulsant activity. The results indicated that greater protection was obtained in the maximal electroshock screen (MES) and subcutaneous strychnine (scSTY) than the subcutaneous pentylenetetrazole (scPTZ) tests. All the compounds showed low neurotoxicity when compared to the clinically used drugs. Compounds with substituted acetophenone (8-11) showed good activity in the rat oral MES screen. Seven compounds (6, 8-10, 12, 14 and 15) exhibited anticonvulsant activity greater than sodium valproate. Among the new derivatives evaluated, compound 10 emerged as the most active compound as indicated by its protection in the MES and scSTY screens and with low neurotoxicity. Seven compounds possessed sedative-hypnotic activity.

Animals↗

PubMed1998

Permeability of articular cartilage to matrix metalloprotease inhibitors.

PURPOSE: To develop an in vitro cartilage permeation model for cartilage permeability study and to evaluate the effects of molecular hydrophilicity and cartilage location on the permeability of articular cartilage to matrix metalloprotease inhibitors. METHODS: An in vitro cartilage permeation model was developed and utilized to determine the permeability of articular cartilage to the matrix metalloprotease inhibitors of different hydrophilicity. Permeability coefficients were obtained by measuring the steady-state flux of the inhibitor compounds. HPLC methods were also developed and employed for the analysis of drug levels in assay media. RESULTS: The relationship between permeability and hydrophilicity of drug molecules was examined. Results indicated that the permeability coefficient increased with increasing hydrophilicity of the molecule. Additionally, the relationship between the permeability and the location of the cartilage section within the animal joint was investigated. Our results showed that the drug molecules penetrated faster in the surface layer cartilage than in the deep layer cartilage. CONCLUSIONS: Increasing the hydrophilicity of a molecule would increase its permeability across articular cartilage. The in vitro cartilage permeation model developed could be used to rank order drug compounds according to their cartilage permeability profiles and to aid in drug selection and development.

Animals↗

PubMed2004

Bioavailability prediction based on molecular structure for a diverse series of drugs.

PURPOSE: Radial basis function artificial neural networks and theoretical descriptors were used to develop a quantitative structure-pharmacokinetic relationship for structurally diverse drug compounds. METHODS: Human bioavailability values were taken from the literature and descriptors were generated from the drug structures. All models were trained with 137 compounds and tested with a further 15, after which they were evaluated for predictive ability with an additional 15 compounds. RESULTS: The final model possessed a 10-31-1 topology and training and testing correlation coefficients were 0.736 and 0.897, respectively. Predictions for independent compounds agreed well with experimental literature values, especially for compounds that were well absorbed and/or had high observed bioavailability. Important theoretical descriptors included solubility parameters, electronic descriptors, and topological indices. CONCLUSIONS: Useful information regarding drug bioavailability was gained from drug structure alone, reducing the need for experimental methods in drug development.

Analysis of Variance↗

PubMedDate not supplied

[The forensic chemical analysis of cadaveric material for the presence of drug and narcotic compounds].

The authors consider that the list of drugs and narcotics which can be reliably identified in a general forensic chemical analysis of cadaveric material (not a purposeful screening) should be changed. Isolation by acidified water, hydrochloric acid hydrolysis, and by acetonitrile should be used for isolation of drugs and narcotic compounds in forensic chemical analysis of cadaveric material.

Cadaver↗

PubMed2004

Metabonomics: its potential as a tool in toxicology for safety assessment and data integration.

The functional genomic techniques of transcriptomics and proteomics promise unparalleled global information during the drug development process. However, if these technologies are used in isolation the large multivariate data sets produced are often difficult to interpret, and have the potential of missing key metabolic events (e.g. as a result of experimental noise in the system). To better understand the significance of these megavariate data the temporal changes in phenotype must be described. High resolution 1H NMR spectroscopy used in conjunction with pattern recognition provides one such tool for defining the dynamic phenotype of a cell, organ or organism in terms of a metabolic phenotype. In this review the benefits of this metabonomics/metabolomics approach to problems in toxicology will be discussed. One of the major benefits of this approach is its high throughput nature and cost effectiveness on a per sample basis. Using such a method the consortium for metabonomic toxicology (COMET) are currently investigating approximately 150 model liver and kidney toxins. This investigation will allow the generation of expert systems where liver and kidney toxicity can be predicted for model drug compounds, providing a new research tool in the field of drug metabolism. The review will also include how metabonomics may be used to investigate co-responses with transcripts and proteins involved in metabolism and stress responses, such as during drug induced fatty liver disease. By using data integration to combine metabolite analysis and gene expression profiling key perturbed metabolic pathways can be identified and used as a tool to investigate drug function.

Animals↗

PubMed1998

[Translation of the prologue to the Libro de medicamentos simples by Abû-l-Salt of Denia].

This article offers the Spanish translation of the theoretical introduction that Abu-l-Salt of Denia (1068-1134) placed at the beginning of his treatise on simple drugs. In his introduction he explained the reasons for preparing compound drugs, and how to prepare them. Although the rest of the book was translated from Arabic into Latin by Arnau de Vilanova (c. 1283) this introduction is not found in any of the extant Latin manuscripts and therefore does not appear in the critical edition of the works of Arnau.

Arab World↗

PubMed1989

Afloqualone phototoxicity--photosensitized lipid peroxidative potency and its biological significance.

Photosensitivity due to afloqualone (AQ), a muscle relaxant acting on the central nervous system, has tended to increase with increasing clinical use of this drug by orthopedists. The initial step leading to drug photosensitivity is a photochemical reaction between photo excited phototoxic compounds (drugs) or their metabolites and target molecules in skin. The present study was an attempt to determine whether unsaturated lipids are one of the target molecules of AQ-photosensitivity. Squalene, an unsatulated model lipid, was subjected to UVA irradiation in the presence of AQ and production of squalene hydroperoxides was confirmed. AQ-photosensitized peroxidation of squalene was repressed in the presence of 2.5-dimethylfuran, a singlet oxygen acceptor. Production of singlet oxygen by UVA irradiation of AQ was also observed in aqueous solution. These findings suggested participation of singlet oxygen in the AQ photosensitized peroxidation of squalene. Although photohemolysis was not observed by UVA irradiation in the presence of AQ, We propose that lipids can be a target molecule of AQ-phototoxicity, and lipid peroxidation might be one of the important factors responsible for induction of the AQ phototoxic reaction.

Hemolysis↗

PubMed1993

Clinical reversal of drug resistance in ovarian cancer.

Human ovarian cancer cell lines and relevant in vivo model systems have been used to identify mechanisms of resistance associated with alkylating agents and platinum compounds. Drug resistance in ovarian cancer is multifactorial and it is probable that additional mechanisms than those already identified may be responsible for clinical drug resistance. Presently drug transport, increased inactivation in the cytosol, increased repair of damaged DNA, and alterations in signal transduction pathways have been shown to account for resistance of alkylating agents and platinum compounds. Clinical trials have been initiated with agents such as buthionine-sulfoximine, an inhibitor of glutathione biosynthesis which decreases the ability of resistant cells to inactivate platinum compounds prior to their interaction with DNA. In a phase I trial, it has been demonstrated that glutathione levels can be depleted both in normal tissues and tumor biopsies from drug-resistant ovarian cancer patients. Additional clinical trials are needed to determine the effect that glutathione reduction has upon response rate to alkylating agents and platinum compounds. Ultimately, successful modulation of drug resistance may require a combination of agents which inhibit multiple critical biochemical sites. In addition, an understanding of the mechanisms associated with antineoplastic drug resistance may lead to novel therapeutic strategies aimed at preventing the emergence of clinically relevant resistance.

Alkylating Agents↗

PubMed2006

Towards an understanding of the structurally based potential for mechanically activated disordering of small molecule organic crystals.

The potential for various small molecule organic crystals to undergo complete mechanically induced disordering is investigated. A model is proposed, which considers changes in free energy required for lattice incorporation of a critical dislocation density. Application requires knowledge of a few physical properties, namely the elastic shear modulus, Burgers vector magnitude, molar volume, melting temperature, and heat of fusion. The model was tested using seven compounds; acetaminophen, aspirin, gamma-indomethacin, salicylamide, sucrose, and two proprietary drug compounds, PFZ1 and PFZ2. Crystalline solids were subjected to high shear, controlled temperature comminution for various durations, after which the samples were examined using powder X-ray diffraction (PXRD) and differential scanning calorimetry (DSC). The results verified that acetaminophen, aspirin, and salicylamide, which were suggested by the model to be resistant to complete mechanical disordering, remained fully crystalline, even after 5 h of milling. Sucrose and gamma-indomethacin were both predicted to be susceptible to amorphization, which was confirmed by physical characterization. Single, 3-h grinding experiments were performed on two proprietary compounds, PFZ1 and PFZ2. The model indicated that each should be resistant to complete disordering, a trend held by PFZ1. Evidence of partial disordering of PFZ2 was unexpected and is discussed with respect to possible temperature effects.

Acetaminophen↗

PubMed2004

Microsphere size, precipitation kinetics and drug distribution control drug release from biodegradable polyanhydride microspheres.

A thorough understanding of the factors affecting drug release mechanisms from surface-erodible polymer devices is critical to the design of optimal delivery systems. Poly(sebacic anhydride) (PSA) microspheres were loaded with three model drug compounds (rhodamine B, p-nitroaniline and piroxicam) with a range of polarities (water solubilities). The drug release profiles from monodisperse particles of three different sizes were compared to release from polydisperse microspheres. Each of the model drugs exhibited different release mechanisms. Drug distribution within the polymer was investigated by laser scanning confocal microscopy and scanning electron microscopy. Rhodamine, the most hydrophilic compound investigated, was localized strongly toward the microsphere surface, while the much more hydrophobic compound, piroxicam, distributed more evenly. Furthermore, all three compounds were most uniformly distributed in the smallest microspheres, most likely due to the competing effects of drug diffusion out of the nascent polymer droplets and the precipitation of polymer upon solvent extraction, which effectively "traps" the drug in the polymer matrix. The differing drug distributions were manifested in the drug release profiles. Rhodamine was released very quickly independent of microsphere size. Thus, extended release profiles may not be obtainable if the drug strongly redistributes in the microspheres. The release of p-nitroaniline was more prolonged, but still showed little dependence on microsphere size. Hence, when water-soluble drugs are encapsulated with hydrophobic polymers, it may be difficult to tailor release profiles by controlling microsphere size. The piroxicam-loaded microspheres exhibit the most interesting release profiles, showing that release duration can be increased by decreasing microsphere size, resulting in a more uniform drug distribution.

Anhydrides↗

PubMed2006

[Clinicopharmacological study of gastrointestinal drugs from the viewpoint of postmarketing development].

Pharmaceutical development starts with the discovery of a new compound. Drugs become commercially available after non-clinical and clinical studies, but processes that take place after marketing are also important for pharmaceutical development. In recent years, use of the phrase "Ikuyaku" meaning postmarketing development has become more common. Sometimes, the proper usage, indications and harmful effects of a drug are discovered only after it becomes commercially available and is administered to many patients. Hence, pharmacists need to actively perform postmarketing studies to reveal the true nature of drugs. In the present clinicopharmacological study, we investigated the effects of histamine H(2) receptor antagonists (H(2)-RAs) on the plasma concentrations of gastrointestinal peptides from the viewpoint of postmarketing development. First we established an enzyme immunoassay for secretin, which is involved in gastrointestinal motility. Then we used this and existing peptide assays to investigate the above-mentioned issues. Ranitidine and nizatidine increased the plasma concentration of motilin. It is believed that the plasma concentration of Ach is elevated by ranitidine and nizatidine, which possesses an anti-AchE activity, and that the increased the plasma concentration of Ach facilitated release of motilin, elevating the plasma concentration of motilin. When compared to the placebo, lafutidine significantly increased the plasma concentration of CGRP (calcitonin gene-related peptide) and substance P. Furthermore, released CGRP stimulated CGRP1 receptors to facilitate secretion of somatostatin. Therefore, lafutidine appears to protect the gastric mucosa and regulate gastrointestinal motility. The same results were obtained with ranitidine and nizatidine. While H(2)-RAs have a common function in suppressing the secretion of gastric acid, they do not exhibit the same effects on factors related to recurrence of peptic ulcer, such as gastrointestinal motility and blood flow in the gastrointestinal mucosa. Hence, measuring the plasma concentration of gastrointestinal peptides can be used to estimate the effects of drugs on gastrointestinal motility. From the viewpoint of postmarketing development, we are in the process of establishing indicators for the proper usage of pharmaceutical drugs. Pharmacists need to closely follow and monitor adverse reactions. In order to further improve monitoring of drug therapy, it will be necessary to assess not only the blood concentrations of drugs, but also biological reactions to the drugs. Since the levels of peptides reflect the clinical efficacy of gastrointestinal drugs, measuring peptide levels appears to be useful for selecting appropriate drugs.

Adult↗

PubMed1997

Distribution of antihistamines into the CSF following intranasal delivery.

The preferential absorption of certain drug compounds from the nasal cavity into the cerebrospinal fluid (CSF) raises questions regarding the transport processes controlling drug disposition following intranasal delivery. The disposition characteristics of several structurally similar antihistamine compounds, hydroxyzine, chlorpheniramine, triprolidine, and chlorcyclizine, into the CSF following nasal administration were studied using the rat as an animal model. The antihistamines were administered either intranasally or intra-arterially, and serial CSF and plasma samples were collected from the cisterna magna and the femoral artery, respectively. The drug levels in CSF and plasma were assayed by HPLC. Hydroxyzine concentrations in plasma and CSF were found to be significantly greater than most of the other compounds tested. In addition, hydroxyzine also showed the most rapid systemic absorption following nasal administration. Interestingly, the hydroxyzine levels in CSF following intranasal administration were significantly higher than those following intra-arterial administration. The AUC ratios between CSF and plasma for hydroxyzine after intranasal and intra-arterial administration were 4.0 and 0.4, respectively. The AUC ratios for triprolidine, the other antihistamine with measurable CSF concentrations, were 0.5 and 0.7, respectively. The distribution of antihistamines from the nasal membrane into the CSF appears to be controlled by a combination of their molecular properties. It also appears that the intranasal delivery of drugs with optimal physicochemical characteristics can result in an improved CNS bioavailability compared to those achieved from an equivalent parenteral dose.

Administration, Intranasal↗

PubMed2004

Investigation of microenvironmental factors influencing the longitudinal relaxation times of drugs and other compounds.

The aim of this study was to investigate the microenvironmental factors likely to influence the longitudinal relaxation time of MR visible drugs or compounds in vivo at 1.5 T. The relative influence that viscosity, albumin and paramagnetic contrast agent concentrations have on the observed longitudinal relaxation times of three 19F MR detectable drugs and compounds have been investigated. Our data show that for 5-fluorouracil, flucloxacillin and tetrafluorosuccinic acid-containing phantoms, the presence of albumin at normal physiological concentrations will have relaxation effects of the same order of magnitude as that of a commonly clinically administered contrast agent, gadolinium diethylenetriamine pentaacetic acid. The contribution of viscosity is shown, in the examples studied here, to be of minor importance, contributing less than 6.5% to the observed relaxation effects. It is also demonstrated that in the presence of competitive binding of other ligands for common binding sites on albumin, the 19F longitudinal relaxation time of 5-fluorouracil can increase by up to 340% from its value in the absence of the competing ligand. The relevance of the findings to in vivo studies is discussed.

Albumins↗