bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kinetic Characterization and Identification of the Enzymes Responsible for the Hepatic Biotransformation of Adinazolam and N-Desmethyladinazolam in Man
Authors: Venkatakrishnan Karthik , Von Moltke Lisa L , Duan Su Xiang , Fleishaker Joseph C , Shader Richard I , Greenblatt David J 
Published: April 2011

Abstract
The kinetics of the N-demethylation of adinazolam to N-desmethyladinazolam (NDMAD), and of NDMAD to didesmethyladinazolam (DDMAD), were studied with human liver microsomes using substrate concentrations in the range 10–1000 μm. The specific cytochrome P450 (CYP) isoforms mediating the biotransformations were identified using microsomes containing specific recombinant CYP isozymes expressed in human lympho-blastoid cells, and by the use of CYP isoform-selective chemical inhibitors.
Adinazolam was demethylated by human liver microsomes to NDMAD, and NDMAD was demethylated to DDMAD; the substrate concentrations, Km, at which the reaction velocities were 50% of the maximum were 92 and 259 μm, respectively. Another metabolite of yet undetermined identity (U) was also formed from NDMAD (Km 498 μm). Adinazolam was demethylated by cDNA-expressed CYP 2C19 (Km 39 μm) and CYP 3A4 (Km 83 μm); no detectable activity was observed for CYPs 1A2, 2C9, 2D6 and 2E1. Ketoconazole, a relatively specific CYP 3A4 inhibitor, inhibited the reaction; the concentration resulting in 50% of maximum inhibition, IC50, was 0·15 μm and the inhibition constant, Ki, was &lt; 0·04 μm in five of six livers tested. Troleandomycin, a specific inhibitor of CYP 3A4, inhibited adinazolam N-demethylation with an IC50 of 1·96 μm. The CYP 2C19-inhibitor omeprazole resulted in only partial inhibition (IC50 21 μm) and sulphaphenazole, α-naphthoflavone, quinidine and diethyldithiocarbamate did not inhibit the reaction. NDMAD was demethylated by cDNA-expressed CYP 3A4 (Km 220 μm, Hill number A 1·21), CYP 2C19 (Km 187 μm, Hill number A 1·29) and CYP 2C9 (Km 1068 μm). Formation of U was catalysed by CYP 3A4 alone. Ketoconazole strongly inhibited NDMAD demethylation (IC50 0·14 μm) and formation of U (IC50 &lt; 0·1 μm) whereas omeprazole and sulphaphenazole had no effect on reaction rates.
These results show that CYP 3A4 is the primary hepatic CYP isoform mediating the N-demethylation of adinazolam and NDMAD. Co-administration of adinazolam with CYP 3A4 inhibitors such as ketoconazole or erythromycin might lead to reduced efficacy, since adinazolam by itself has relatively weak benzodiazepine agonist activity, with much of the pharmacological activity of adinazolam being attributable to its active metabolite NDMAD.
Distribution of Bismuth in the Rat after Oral Dosing with Ranitidine Bismuth Citrate and Bismuth Subcitrate
Authors: Canena J , Reis J , Pinto A S , Santos A M , Leitão J , Pinheiro T , Quina M G 
Published: April 2011

Abstract
Bismuth preparations are used world-wide for the management of peptic ulcer disease, for eradication of Helicobacter pylori, and in the prevention and treatment of diarrhoea. However neurological toxicity of bismuth has always been a major concern and evidence has been found of the absorption of bismuth. Recent studies have suggested that the absorption of bismuth increases when bismuth salts are used with ranitidine hydrochloride. The absorption and deposition of bismuth as a result of the use of the new drug ranitidine bismuth citrate have not been yet clarified.
After 15 days of twice daily oral gavage with bismuth subcitrate, 13·7 mg kg−1 day−1 to eight rats, deposition of bismuth was found in all the tissues studied, especially the kidney (30·81 ± 8·59 μg g−1 dry weight). A similar pattern of distribution and tissue concentrations was found when bismuth subcitrate was given with ranitidine hydrochloride 8·6 mg kg−1 day−1 to another eight rats, although this combination resulted in lower brain levels (3·12 + 1·31 μg g−1 dry weight) than after administration of bismuth subcitrate alone (4·77 ± 0·97 μg g−1 dry weight). When six rats were given ranitidine bismuth citrate by gavage at 22·8 mg kg−1 day−1 for 15 days, kidney levels were lower (4·24 ± 1·75 μg g−1 dry weight) and brain levels were below detection limits; the bismuth concentrations in the faeces from this group were also significantly lower (1603 ± 104·0 μg g−1 dry weight) than for the two other groups. After dosing with bismuth alone or in association with ranitidine hydrochloride, bismuth was detected in several organs and deposition was not influenced by gastric pH. Blood levels correlate poorly with organ deposition and brain deposition was not always associated with encephalopathy. After administration of ranitidine bismuth citrate, significantly lower concentrations of bismuth were found in the kidney and bismuth was not detectable in the brain, suggesting lower bismuth absorption. This was confirmed by higher levels in the faeces after dosing with ranitidine bismuth citrate. Thirty days after dosing with ranitidine bismuth citrate or bismuth subcitrate, bismuth could not be detected in any of the organs examined but could be found in the urine.
In conclusion, bismuth was deposited in the kidney, brain, lung and liver of rats after oral dosing with bismuth subcitrate. After oral dosing with an equivalent amount of bismuth in the form of ranitidine bismuth citrate, significantly lower concentrations of bismuth were deposited in the kidney; in the brain bismuth was not detectable.
Influence of New Fenpropimorph Fungicides on the Growth and Sterol Composition in Saccharomyces cerevisiae: Relationship Between Structure and Activity
Authors: Šajbidor Jan , Lamačka Martin , Baláž Štefan , Huong Lai Mai , Ciesarová Zuzana 
Published: April 2011

Abstract
The toxicity of fenpropimorph and seven newly synthesized analogues against Saccharomyces cerevisiae has been determined in liquid media.
The inhibitory effect of the most efficient derivative is 120 times more than that of standard fenpropimorph. The non-linear relationship between hydrophobicity and toxicity indicates that the binding of the compounds to the receptors does not differ and so the differences in toxicity reflect changes in the rate of metabolism. The presence of inhibitors in the fermentation medium resulted in a reduction in harvested biomass and lipid yield, and changes in sterol composition - the amount of ergosterol decreased whereas the amounts of lanosterol, dihydroergosterol and squalene increased.
The toxicity of the compounds was most influenced by their lipophilicity. Use of this information could lead to development of more potent ergosterol inhibitors.
In-vitro Negative Chronotropic and Inotropic Effects of a Novel Dihydropyridine Derivative, CD-832, in the Guinea-pig: - - Comparison with Calcium-channel Antagonists
Authors: Noguchi Kazuo , Takahashi Kenzo , Higuchi Shohei 
Published: April 2011

Abstract
The effects of CD-832 (4R-(-)-2-(nicotinoylamino)ethyl-3-nitroxypropyl-1,4-dihydro-2,6-dimethyl-4,3-nitrophenyl, 3,5-pyridine dicarboxylate), a novel dihydropyridine derivative, on guinea-pig isolated myocardial preparations have been compared with those of Ca2+-channel antagonists.
All ten compounds induced concentration-dependent negative chronotropic effects on preparations of isolated right atria and negative inotropic effects on isolated right ventricular papillary muscles. The order of potency for the negative chronotropic effect was CD-832 &gt; nicardipine = gallopamil &gt; clentiazem &gt; nifedipine = efonidipine &gt; amlodipine = semotiadil &gt; verapamil &gt; diltiazem; that for the negative inotropic effect was nicardipine = gallopamil &gt; nifedipine &gt; verapamil &gt; CD-832 &gt; diltiazem &gt; clentiazem &gt; efonidipine = semotiadil &gt; amlodipine. The ratio of the EC50 (the concentration of Ca2+ antagonist having 50% of the maximum effect) for the negative inotropic effect divided by the EC50 for the negative chronotropic effect, considered to be an index of selectivity for negative chronotropic effect, was higher for CD-832, amlodipine, efonidipine and semotiadil than for the other Ca2+ antagonists. The ratio for CD-832, nifedipine, nicardipine, efonidipine, amlodipine, verapamil, gallopamil, diltiazem, clentiazem and semotiadil was 11·4, 0·29, 0·87, 35·4, 37·1, 0·65, 0·87, 0·92, 7·11 and 30·0, respectively.
These findings indicate that CD-832 and the newly developed Ca2+ antagonists including amlodipine, efonidipine, semotiadil and clentiazem were selective for a negative chronotropic effect rather than for a negative inotropic effect. This ‘chrono-selective’ effect of these drugs might be of benefit in the treatment of cardiovascular disorders.
Why Do We Need New Treatments for Rheumatoid Arthritis?
Authors: Chikanza I C , Jawed S , Naughton D , Blake D R 
Published: April 2011

Abstract
Rheumatoid arthritis is a chronic systemic autoimmune inflammatory disease characterized by progressive joint damage. The classical treatments of the disease such as myocrisin and sulphasalazine, are not always effective at controlling the disease. This has necessitated the development of novel agents for treating rheumatoid arthritis. Most of these drugs are biological in nature and are targeted at specific sites of the inflammatory cascade of reactions. A number of clinical trials have been conducted.
The clinical effects that have been observed are transient, necessitating repeated treatments and the risk of vaccination effects. Many of these agents have to be administered parenterally, production costs are very high. Consequently, chemical entities which can be taken orally need to be developed. Since the immune system is very complex with pleiotropic cytokines and redundancy in some of the regulatory networks, it may therefore be necessary to use multiple agents targeted at different specific sites of the inflammatory cascade or that different agents could be given at different stages of the disease, to induce disease remission and maintain the response to therapy. Cytokines such as tumour necrosis factor (TNF) and interleukin 1 (IL-1) play important physiological roles in the host’s defence systems against infections and malignancy. The chronic inhibition of these cytokines by targeted therapies may therefore lead to the development of side effects. Thus, carefully controlled long-term studies will be required to assess the safety of selective targeting of processes involved in inflammation.
A more recent novel approach is to target hypoxic tissues with bioreductive agents. Thus, some of the established rheumatoid arthritis treatments could be linked to bioreductive agents and released in hypoxic tissues where inflammation is occurring. This review summarizes the important developments in the therapy of rheumatoid arthritis. There is no doubt that despite these developments we need to develop new and advanced treatment modalities for rheumatoid arthritis.
In-vivo Monitoring of Dosage Forms
Authors: Wilson Clive G 
Published: April 2011

Abstract
The use of imaging techniques including gamma scintigraphy to follow the behaviour of drug formulations has revolutionized our knowledge of absorption and distribution in drug delivery. The development of gamma camera techniques as physiological tools to explore organ function became routine by the mid-seventies. Several research groups started to explore the applications of technique in drug delivery. Within 5 years, the utility of the technique became obvious and scintigraphy is now widely accepted as an important investigation tool in formulation research.
Gamma scintigraphy is especially useful in exploring sources of inter-subject variation, especially in examining food effects in pharmacokinetic estimations and establishing windows of absorption for oral delivery. As a tool to examine drug delivery to the lung and to the eye, scintigraphy is the method of choice.
Magnetic Resonance Imaging (MRI) became more generally employed in medicine two decades after the gamma camera. The superior soft-tissue contrast and resolution compared to computed X-ray tomography rapidly established MRI in clinical investigation. Recent applications in oral drug research has allowed the pharmaceutical scientist to explore new facets of delivery and ultimately combine MRI and scintigraphy in human clinical trials.
The Design of Selectively-activated Anti-cancer Prodrugs for use in Antibody-directed and Gene-directed Enzyme-Prodrug Therapies
Authors: Denny William A , Wilson William R 
Published: April 2011

Abstract
Systemic anti-proliferative agents (cytotoxins) have been the most successful single design concept for anti-cancer drugs. However, they have inherent limitations (they target dividing cells rather than cancer cells) which limit their clinical efficacy, especially toward the more slowly-growing solid tumours. New concepts are required to improve the selectivity of their killing of tumour cells.
One possibility is the use of prodrugs which can be activated selectively in tumour tissue. Several potential mechanisms for this are being explored, including tumour hypoxia, low extracellular pH, therapeutic radiation and tumour-specific endogenous or exogenous enzymes. In the last approach the exogenous enzyme can be delivered by attachment to monoclonal antibodies (ADEPT) or as DNA constructs containing the corresponding gene (GDEPT). A limitation of both approaches is that only a small proportion of the tumour cells become activation-competent, but this can be substantially overcome by the design of appropriate prodrugs capable of killing activation-incompetent cells via a bystander effect.
We have proposed a modular approach to prodrug design in which a trigger unit determines tumour selectivity and an effector unit achieves the desired level of killing of cells when the trigger is activated. For ADEPT and GDEPT prodrugs the primary requirement of the trigger is efficient and selective activation by the appropriate enzyme; the released effector must be a potent, diffusible cytotoxin which fully exploits the small proportion of cells capable of activating the prodrug. A wide variety of chemistries has been used, but many of the existing effectors do not have all of these properties. We report work on two types of cytotoxin derived from very potent anti-tumour antibiotics (enediynes and amino-seco-cyclopropylindolines) as effectors in prodrugs for ADEPT and GDEPT applications.
Genetic Toxicology
Authors: Kramer P J 
Published: April 2011

Abstract
Systems for testing genetic toxicology are components of carcinogenic and genetic risk assessment. Present routine genotoxicity-testing is based on at least 20 years of development during which many different test systems have been introduced and used. Today, it is clear that no single test is capable of detecting all genotoxic agents. Therefore, the usual approach is to perform a standard battery of in-vitro and in-vivo tests for genotoxicity. Work-groups of the European Union (EU), the Organization for Economic Co-operation and Development (OECD), and, very recently, the work-group of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) have defined such standard battery tests. These and some currently used supplementary or confirmatory tests are briefly discussed here.
Additional test systems for the assessment of genotoxic and carcinogenic hazard and risk are seriously needed. These tests must be more relevant to man than are current assays and less demanding in respect of cost, time and number of animals. Another aspect for reassessment derives from the actual situation in the pharmaceutical industry. Companies have to prepare for the world economy of the 21st century. Therefore, pharmaceutical research is speeding up tremendously by use of tools such as genomics, combinatorial chemistry, high throughput screening and proteomics. Toxicology and genotoxicology need to re-evaluate their changing environment and must find ways to respond to these needs.
In conclusion, genetic toxicology needs to answer questions coming from two major directions: hazard and risk identification and high throughput testing.
A Study on the In-vitro Percutaneous Absorption of Propranolol from Disperse Systems
Authors: Ktistis G , Niopas I 
Published: April 2011

Abstract
Transdermal administration of propranolol can be used to avoid hepatic first-pass metabolism of the drug. The effect of polysorbate 80 concentration on the permeation of propranolol incorporated into micelles of polysorbate 80 in water, oil-in-water microemulsions of isopropyl myristate-polysorbate 80-sorbitol-water and oil-in-water emulsions of isopropyl myristate-polysorbate 80-sorbitan monooleate-water has been investigated by use of an artificial double-layer membrane, composed of a barrier foil and a lipid barrier, in Franz-type diffusion cells. Reversed-phase high-performance liquid chromatography, with celiprolol as internal standard, was used to determine the concentration of propranolol in the receptor compartment and a logarithmic equation was used to estimate the apparent permeability coefficient of propranolol from disperse systems.
For each disperse system the apparent permeability coefficient of propranolol decreased with increasing polysorbate 80 concentration. Moreover, for a given polysorbate 80 concentration the apparent permeability coefficient of propranolol increased when the disperse system was changed from emulsion to microemulsion and then to solubilized system, because of the increasing interfacial area of total disperse phase.
The results show that transdermal permeation of propranolol is greater when it is diffused from solubilized systems rather than from microemulsions or emulsions.
Hepatic Clearance of ONO-5046, a Novel Neutrophil Elastase Inhibitor, in Rats and in the Rat Perfused Liver
Authors: Murakami Teruo , Sato Masahiko , Higashikawa Fumiko , Okochi Atsuko , Higashi Yutaka , Yata Noboru , Takano Mikihisa 
Published: April 2011

Abstract
The hepatic clearance of ONO-5046 (N-[2-[4-(2,2-dimethylpropionyloxy)phenylsulphonyl-amino]benzoyl]aminoacetic acid), a low-molecular-weight neutrophil elastase inhibitor, has been investigated in rats and in the rat perfused liver.
This ester was easily hydrolysed to its inactive metabolite EI-601 (N-[2-[(4-hydroxy-phenyl)sulphonylamino]benzoyl]aminoacetic acid) in liver homogenate and in erythrocytes suspension in-vitro. On the other hand, it was stable in biological media such as plasma and whole blood, which contain plasma proteins. Scatchard plot analysis of ONO-5046 binding to bovine serum albumin (BSA) in-vitro indicated that the association constant (K) and number of binding sites (n) were 6.91 times 104 (M−1) and 4.33, respectively. Thus, ONO-5046 (100 μM) would bind to plasma proteins to an extent &gt;99% at physiological plasma-protein concentrations. The total plasma clearance of ONO-5046 in rats was constant (approximately 9 mL min−1 kg−1) under different steady-state plasma concentrations (5–50 μM) a value equivalent to the hepatic clearance. In the rat perfused liver, the hepatic extraction ratio of ONO-5046 was significantly reduced by adding BSA to the dosing solution. Thus, the relatively low hepatic clearance of ONO-5046, which has an ester linkage in its structure and is naturally susceptible to enzymatic hydrolysis, was found to be because of the extremely high protein-binding of the compound.
Effect of Thioridazine or Chlorpromazine on Increased Hepatic NAD+ Level in Rats Fed Clofibrate, a Hypolipidaemic Drug
Authors: Shin Mariko , Asada Sumiyo , Mizumori Nanae , Sano Keiji , Umezawa Chisae 
Published: April 2011

Abstract
The effect of the phenothiazines, thioridazine and chlorpromazine, on the increased hepatic NAD+ level of rats fed clofibrate, a hypolipidaemic drug, has been investigated.
Short-term (6 days) addition of phenothiazines to the diet negatively affected diet intake and body-weight gain, but increased liver weight and hepatic NAD+ levels, which was synergistic to clofibrate. The phenothiazines were shown to inhibit hepatic peroxisomal fatty acid oxidation in-vivo, as determined by the increased residual catalase activity. In hepatocytes prepared from clofibrate-fed rats, phenothiazines inhibited not only peroxisomal but also mitochondrial fatty acid oxidation to the same extent. In the hepatocytes, NAD+ was maintained at the high level until the phenothiazine concentration was increased to 0–2 mM.
The result suggests that the increase of hepatic NAD+ in rats fed Clofibrate is not related to peroxisomal fatty acid oxidation.
Synthesis of Novel Derivatives of Aroylaminoalcohols and 3-Amino-substituted 1-Phenylpropanols with Potential Anti-inflammatory and Immunomodulating Activities
Authors: Gavalas Antonis M , Hadjipetrou Lygeri , Kourounakis Panos N 
Published: April 2011

Abstract
The synthesis of aroylaminoalcohols and 3-amino-substituted 1-phenylpropanols is described. These novel basic compounds have potent anti-inflammatory activity, significantly inhibiting rat paw oedema induced by a variety of phlogistic agents as a result of the release of inflammatory mediators such as histamine, 5-hydroxytryptamine, kinins, prostaglandins or leukotrienes.
The biological activity of a selected, representative number of these compounds was examined on adjuvant-induced arthritis, a good animal model for rheumatoid arthritis in man. The results show that 3-(1-hydroxymethylpropylamino)-1-phenylpropan-1-one hydrochloride (2) and 3-(3-hydroxypiperidin-1-yl)-1-phenylpropan-1-one hydrochloride (4) effectively suppress the secondary lesions of adjuvant arthritis. 2-(3-Hydroxy-3-phenylpropylamino)-butan-1-ol hydrochloride (6) had no preventive activity in this animal model. In addition, several of the compounds suppressed the mitogenic responses of T-lymphocytes to concanavalin A, suggesting direct or indirect action on lymphocytes and therefore possible immunosuppressive properties. Finally, we investigated the in-vitro effects of compounds 2 and 4 on production of interleukins 1 and 2 (IL-1 and IL-2). We found that compound 4 suppressed the in-vitro production or action of IL-2 and IL-1. In contrast, compound 2 significantly increased the IL-1 activity of arthritic macrophages while reducing the ability of normal and arthritic splenocytes to produce or release IL-2.
Our data suggest that compounds 2 and 4 have immunomodulatory properties that influence T lymphocyte functions.
Mathematical Modelling of Drug Transport in Emulsion Systems
Authors: Yoon Kyung Ae , Burgess Diane J 
Published: April 2011

Abstract
Two mathematical models for the prediction of drug transport in triphasic (oil, water and micellar) emulsion systems as a function of micellar concentration have been developed and these models were evaluated by comparing experimental and simulated data. Fick’s first law was used to derive a transport model for hydrophilic drugs, assuming that the oil/water (o/w) partitioning process was fast compared with membrane transport and therefore drug transport was limited by the membrane. Consequetive rate equations were used to model transport of hydrophobic drugs in emulsion systems assuming that the o/w interface acts as a barrier to drug transport.
Benzoic acid and phenol were selected as hydrophilic model drugs. Phenylazoaniline and benzocaine were selected as hydrophobic model drugs. Transport studies at pH 3.0 and 7.0 were conducted using side-by-side diffusion cells. According to the hydrophilic model, an increase in micellar concentration is expected to decrease drug transport rates. The effective permeability coefficients (Peff) of drugs were calculated using an equation relating Peff and the total apparent volume of drug distribution (determined experimentally using drug/membrane permeability and partition coefficient values). The hydrophobic model was fitted to the experimental data for the cumulative amount of model drug in the receiver cells using a weighted least-squares estimation program (PCNONLIN). The oil/continuous phase partitioning rates (k1) and the membrane transport rates (k2) were estimated.
The goodness of fit was assessed from the correlation coefficients of plots of predicted versus experimental data. The predicted data were consistent with the experimental data for both the hydrophilic and hydrophobic models.