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PubMed2000

Direct analysis of plasma samples for drug discovery compounds using mixed-function column liquid chromatography tandem mass spectrometry.

A sensitive, efficient, high throughput, direct injection bioanalytical method based on a single column and high-performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS) was developed for pharmacokinetic analysis of early drug discovery compounds in plasma samples. After mixing with a working solution containing an internal standard each plasma sample was directly injected into a polymer-coated mixed-function column for sample cleanup, enrichment and chromatographic separation. The stationary phase incorporates hydrophilic polyoxyethylene groups and hydrophobic groups to the polymer-coated silica. This allows proteins and macromolecules to pass through the column due to restricted access to the surface of the packing while retaining the drug molecules on the bonded hydrophobic phase. The analytes retained in the column with a largely aqueous liquid mobile phase were then chemically separated by switching to a strong organic mobile phase. The column effluent was diverted from waste to the mass spectrometer for analyte detection. Within 200 plasma sample injections the response ratio (analyte vs. internal standard, %CV = 4.6) and the retention times for analyte and internal standard were found consistent and no column deterioration was observed. The recoveries of test compound in various plasma samples were greater than 90%. The total analysis time was </=5 min per sample.

Animals↗
PubMed1986

The effect of training dose on discrimination of compound drug-exteroceptive stimuli.

Rats were trained to discriminate between two compound stimulus arrays that included exteroceptive (ES) and interoceptive (IS) stimulus components. The ES components were illumination and tactile cues, and the IS components were produced by d-amphetamine (A) or Na pentobarbital (P) treatment (drug versus drug discrimination). The relative ES-IS strength was then determined by testing with "mismatched" stimulus arrays consisting of combinations of ES and IS components that had not been presented simultaneously during training. Additional tests were done with ES only (no drug treatments). At training doses of 0.8 mg/kg A versus 10 mg/kg P, the ES were less salient than, but did share stimulus control with, the stronger IS components. In a second group, trained with lower doses (0.5 mg/kg A versus 4 mg/kg P), the ES were much more salient than the IS, although again, both types of stimuli did acquire some control. This dose-related sharing of stimulus control between ES and IS components is similar to relationships among components of compound arrays consisting entirely of ES, and thus further illustrates similarity between drug-produced and exteroceptive stimuli.

Animals↗
PubMed2006

Blind docking of drug-sized compounds to proteins with up to a thousand residues.

Blind docking was introduced for the detection of possible binding sites and modes of peptide ligands by scanning the entire surface of protein targets. In the present study, the method is tested on a group of drug-sized compounds and proteins with up to a thousand amino acid residues. Both proteins from complex structures and ligand-free proteins were used as targets. Robustness, limitations and future perspectives of the method are discussed. It is concluded that blind docking can be used for unbiased mapping of the binding patterns of drug candidates.

Binding Sites↗
PubMed1997

Reverse iontophoresis: monitoring prostaglandin E2 associated with cutaneous inflammation in vivo.

In response to topical application of irritants, increased concentrations of prostaglandin E2 (PGE2) are found in human skin exudate and in cultured dermal fibroblasts. In this study, PGE2 generated in response to transdermal delivery of irritant drug compounds was monitored in hairless guinea pig (HGP) by a non-invasive method, reverse iontophoresis. Reverse iontophoresis is the movement of molecules from the skin under the influence of an applied electric field. Irritant drug compounds were applied with iontophoresis (electrotransport), and reverse iontophoresis of PGE2 from skin was monitored by radioimmunoassay (RIA) after extraction from the delivery system. Chlorpromazine was used as a model drug irritant. When chlorpromazine and saline were applied over a range of current densities from 0 to 200 microA/cm2, visual scores of erythema and edema yielded a correlation with measured skin efflux of PGE2 (r = 0.86). Delivery of chlorpromazine resulted in greater efflux of PGE2 than delivery of non-irritant saline controls under the same delivery conditions. Five drug compounds, chloroquine, promazine, chlorpromazine, tetracaine, metoclopramide, and saline were applied to hairless guinea pig skin. The 6 agents were similarly rank ordered by visual erythema/edema scores and by PGE2 efflux, indicating that the quantity of PGE2 effluxed reflects the intensity of skin irritation. In contrast, vasoconstriction or vasodilation produced by the local delivery of vasoactive agents did not correlate with PGE2 skin efflux, indicating that this measurement is specific for an inflammatory response. In summary, PGE2 generated in response to transdermally applied drug irritants can be monitored non-invasively in vivo by reverse iontophoresis.

Amebicides↗
PubMed1993

Food and drug regulatory issues.

The Federal Food, Drug, and Cosmetic Act does not purport to interfere with the practice of veterinary medicine; however, it does regulate the drugs that veterinarians use in their practice. According to federal law, it is illegal for a veterinarian to use animal drugs in a manner other than that stated on the approved label, to use human-labeled drugs products to treat animals, or to compound drugs for their patients. Because the Act fails to meet the needs of the veterinary profession, the Food And Drug Administration (FDA) has adopted a policy of discretionary enforcement to "allow" veterinarians to use approved animal drugs in an extralabel fashion or to use human drugs to treat animals in certain situations. FDA will not enforce the law against practitioners treating companion, exotic, or sporting animals. Instead, enforcement effort will be directed to treating food-producing animals under conditions most likely to result in illegal drug residues. This is current effort to amend the Act in a way that will make it legal for the FDA to permit extralabel drug use rather than doing so only as a matter of enforcement discretion. Even so, practicing veterinarians will still be limited in how they can use drugs in everyday practice.

Animals↗
PubMed2004

Influence of serum collected from rat perfused with compound Biejiaruangan drug on hepatic stellate cells.

AIM: To observe the effect of compound Biejiaruangan decoction (CBJRGC) (composite prescription of Carapax trionycis for softening the liver) on proliferation, activation, excretion of collagen and cytokine of hepatic stellate cells (HSCs) and to find the mechanism of prevention and treatment of hepatic fibrosis by CBJRGC. METHODS: Using MTT, immunohistochemistry and image analysis technology, the related indexes for proliferation, activation, excretion of collagen and cytokine of hepatic stellate cells were detected in 24 h, 48 h, and 72 h after administration of different dosages of CBJRGC. RESULTS: Statistical analysis showed that serum collected from rat perfused with CBJRGC could restrain the proliferation of HSC in 48 h and 72 h especially in high and medium dosage groups, markedly decrease the expression of desmin, synapsin and platelet derived growth factor (PDGF) in HSC in 24 h, 48 h and 72 h, as well as the expression of alpha-SMA, collagen III, TIMP and TGFbeta1 in 48 h and 72 h, decrease the excretion of collagen I in 72 h. CBJRGC serum had no significant effect on collagens I, III and TIMP in 24 h. CONCLUSION: CBJRGC serum has a good curative effect on hepatic fibrosis. Its main mechanism may be related to the following factors. The drug serum can restrain the proliferation and activation of HSC, decrease the number of activated HSC and the total number of HSC, the excretion of collagens I, III, enhance the degradation of collagen and restore the balance of synthesis and degradation of collagen, inhibit the expression of transforming growth factor beta1 (TGFalpha1) and platelet derived growth factor (PDGF) in HSC, block and delay the process of hepatic fibrosis. Synapsin is a new marker of activation of HSC, which provides a theoretical and testing basis for neural regulation in the developing process of hepatic fibrosis.

Actins↗
PubMed2005

[Cloning, expression, purification of protein kinase Cdelta and its preliminary application in drug lead compounds screening].

Protein kinase Cdelta (PKCdelta) is a member of protein kinase C family, which possess phospholipid-dependent serine and threonine kinase activity. PKCdelta is a potential drug target of diabetes and some cancers. The abnormal activation of PKCdelta can arouse diabetes and some cancers. Therefore the specific inhibitors of PKCdelta can be applied in the research and development of the drug candidate of these diseases. The present aim is to obtain active recombinant PKCdelta from COS1 cells. For cloning of mouse PKCdelta a pair of specific primers were designed based on the published sequence of this gene. The cDNA of full coding region was obtained by RT-PCR. The amplified cDNA was subsequently cloned into FLAG-tagged pcDNA3.0 and its sequence was confirmed by DNA sequencing analysis. FLAG-tagged pcDNA3.0-PKCdelta was transfected into COS1 cells. A cell strain which can stably express PKCdelta was obtained by G418 screening. FLAG-tagged PKCdelta in the supernant of COS1 cells extracts was absorbed by anti-FLAG resin and eluted by FLAG peptide. The purified protein appeared as a single band on both SDS-PAGE and western blotting, indicating that it was chemical and antigenic pure. By kinase assay, the recombinant PKCdelta was active. Positive inhibitor, staurosporine, was used to prove the enzyme could be greatly inhibited. Several compounds have been found to inhibit the enzyme, which indicates the preliminary application in drug lead compounds screening.

Animals↗
PubMed1985

[Formation of volatile carcinogenic N-nitroso compounds from drugs under simulated human gastric conditions].

41 commercial drugs approved for peroral application in the GDR, whose active agents contain N,N-dialkylamino groups in their chemical structures, have been investigated under simulated conditions of the human stomach. With the drugs containing aminophenazone, amitriptyline, doxycycline and oxytetracycline as active agents N-nitrosodimethylamine is formed as a result of nitrosation reactions. With the drugs containing clomiphene++, disulfiram, probenecid and a diethylamine-containing liquid hypnoticum, there occurred N-nitrosodiethylamine. In no case N-nitrosodi-n-propylamine or N-nitrosopiperidine were detectable. The isolated active agents amitriptyline, clomiphene++ and probenecid themselves proved not to be nitrosatable. The positive findings with these drugs were caused by not yet identified nitrosatable contaminants of these drugs. The quantitative determination of volatile N-nitroso compounds was done upon steam distillation by means of gas chromatograph and chemiluminescence detector.

Aminopyrine↗
PubMedDate not supplied

Effects of excipients on the crystallization of pharmaceutical compounds during lyophilization.

Many drug compounds fail to crystallize during lyophilization, producing the less stable amorphous form. During a study to screen various excipient materials for their effect on crystallinity, the addition of certain excipients (glycine, alanine, serine, methionine, urea, and niacinamide) to aqueous solutions of atropine sulfate, cefoxitin sodium, cefotaxime sodium, cefazolin sodium, doxycycline hyclate, procainamide hydrochloride, lactose, and polyvinylpyrrolidone induced these compounds to crystallize during the freeze drying process. Crystallinity was determined by microscopic examination under polarized light. This method of producing a crystalline freeze dried solid could prove useful in the production of stable, cost-effective freeze dried pharmaceuticals.

Crystallization↗
PubMed1996

Erythrocytes and the transport of drugs and endogenous compounds.

This review considers the significance and measurement of endogenous compounds and drugs on erythrocytes. Part I examines literature examples where a direct measurement of hydrocortisone, phenytoin and valproate was performed on unwashed red cells in vitro and in vivo, showing a consistent contribution of the erythrocyte fraction to the transport of these compounds. In vitro partition experiments using systems composed of plasma water, plasma proteins and erythrocytes are discussed. When spiked blood is diluted with blank autologous plasma water, erythrocytes always discharge the compound over-proportionally compared to plasma proteins. In vivo, during the distribution phase, the elimination half-life from the erythrocyte is the same as or shorter than that from plasma water, and substantial amounts of drug leaving the circulation originate from erythrocytes. In Part II, the transfer of compounds is considered and evidence for the facilitated exchange of red cell associated substances between the erythrocyte and capillary endothelium presented. Situations where a failure to analyse the erythrocyte compartment leads to the loss of vital information are identified. Part III explores methods for analysing erythrocyte associated substances, most commonly indirect calculation, or analysis of washed erythrocytes. A direct determination is rarely performed, but one such method, allowing concurrent plasma analysis, is discussed. An instrument collects a fixed and known quantity of a maximally compressed cell mass, without disturbing the equilibrium between cells and plasma. To isolate compounds associated with the mass of erythrocytes, the red cell sediment can often be extracted quantitatively into a blank protein solution.

Animals↗
PubMed2006

Investigation of a 2-step agglomeration process performed in a rotary processor using polyethylene glycol solutions as the primary binder liquid.

The purpose of this research was to investigate the use of polyethylene glycol (PEG) solutions as the primary binder liquid in a 2-step agglomeration process performed in a rotary processor and characterize the resulting granules and their tableting characteristics. This was done by granulation of binary mixtures of microcrystalline cellulose (MCC) and either lactose, calcium phosphate, acetaminophen, or theophylline, in a 1:3 ratio, using a 50% (wt/wt) aqueous solution of PEG and water as the binder liquid. Formulations containing lactose were agglomerated using 5 different amounts of the PEG binder solution, giving rise to a PEG content in the range of 6% to 43% (wt/wt). The process outcome was characterized according to adhesion, yield, and water requirement, and the prepared granules were characterized according to size, size distribution, and flow properties as well as tableting properties. The agglomeration of all mixtures resulted in high yields of free-flowing agglomerates and gave rise to good reproducibility of the investigated agglomerate characteristics. The process allowed for the incorporation of 42.5% (wt/wt) PEG, which is higher than the percentage of PEG reported for other equipment. Tablets of sufficient strength could be prepared with all investigated excipients using 20% wt/wt PEG; higher PEG contents gave rise to adhesion and prolonged disintegration. In conclusion, agglomeration in a torque-controlled rotary processor using solutions of PEG as the primary binder liquid was found to be a robust process, suitable for the incorporation of high contents of PEG and/or drug compounds.

Drug Carriers↗
PubMed1967

Biliary excretion in foreign compounds. Sulphonamide drugs in the rat.

1. The extent of biliary excretion in the rat of 15 sulphonamide compounds was studied. 2. Most of the sulphonamides studied, with molecular weights from 172 (sulphanilamide) to 352 (N(4)-acetylsulphadimethoxine) are poorly excreted in the bile (0-4% of the dose), except sulphapyridine, sulphamethoxypyridazine and sulphadimethoxine. The last three are partly metabolized to glucuronides, whose molecular weights and polarities are such as to allow them to be excreted in the bile in appreciable amounts. 3. Succinylsulphathiazole and phthalylsulphathiazole are polar and have molecular weights (355 and 403) of an appropriate order, and are excreted unchanged in the bile in appreciable amounts. 4. Sulphadimethoxine N(1)-glucuronide (mol.wt. 487) is extensively excreted in the bile unchanged. 5. The results are examined in the light of the hypotheses put forward in the preceding paper (Millburn, Smith & Williams, 1967).

Journal Article↗
PubMed2006

Air to muscle and blood/plasma to muscle distribution of volatile organic compounds and drugs: linear free energy analyses.

Distribution coefficients, K(mus), from the gas phase to the muscle have been collected for volatile organic compounds (VOCs). For 114 VOCs, a linear free energy relationship (LFER) yields an equation for log K(mus) with R(2) = 0.944 and SD = 0.267; construction of a training and test set shows that the LFER can predict further values to around 0.30 log units. The combination of the log K(mus) values with values for air to blood yields distribution coefficients from blood to muscle, log P(mus), for 110 VOCs; the corresponding LFER has R(2) = 0.537 and SD = 0.207 and a predictive capability of 0.22 log units. We also collected data on the distribution of drugs from blood or plasma to muscle and showed that the two sets of data can be combined. A LFER for blood/plasma to muscle for 59 drugs has R(2) = 0.745 and SD = 0.253 and a predictive capability of 0.25 log units. Finally, we show that the in vitro data on VOCs and the in vivo data on drugs can be combined; a LFER on the total data for 163 compounds has R(2) = 0.595, SD = 0.220, and a predictive capability of about 0.25 log units.

Air↗
PubMed2002

Semi-automated determination of plasma stability of drug discovery compounds using liquid chromatography-tandem mass spectrometry.

A simple procedure for the measurement of stability of drug candidates in plasma was developed to eliminate the traditional labor-intensive and time-consuming sample preparation procedures that are typically used for these studies. The procedure makes use of a thermostatic autosampler as an incubator combined with the direct plasma injection method based on high-performance liquid chromatography (HPLC) coupled to tandem mass spectrometry (MS-MS). Untreated human, monkey, mouse and rat plasma containing the test compound was directly injected into a mixed-function column for on-line protein removal and chromatography. The test compound and its biotransformation product were separated via HPLC and monitored using the tandem mass spectrometer. The need for adequate chromatographic separation of the test compound (M) from its carboxylic acid metabolite (M+1) is demonstrated. Plasma samples from four different species at specified incubation temperatures were sequentially assayed in one analytical procedure. The injection-to-injection time was about 6 min. The peak responses of the test compound in individual plasma samples were repeatedly determined every 24 min. The retention times and peak shape of all analytes were found to be consistent throughout the experiments. The stability of the test compound in plasma was found to be a function of animal species, incubation time and temperature. The test compound was rapidly degraded in rat plasma at 37 degrees C, but it could be stabilized by adding sodium thiosulfate.

Automation↗
PubMed2005

Hepatic, extrahepatic, microsomal, and mitochondrial activation of the N-hydroxylated prodrugs benzamidoxime, guanoxabenz, and Ro 48-3656 ([[1-[(2s)-2-[[4-[(hydroxyamino)iminomethyl]benzoyl]amino]-1-oxopropyl]-4-piperidinyl]oxy]-acetic acid).

In previous studies, it was shown that liver microsomes from rabbit, rat, pig, and human are involved in the reduction of N-hydroxylated amidines, guanidines, and amidinohydrazones of various drugs and model compounds (Drug Metab Rev 34: 565-579). One responsible enzyme system, the microsomal benzamidoxime reductase, consisting of cytochrome b5, its reductase, and a cytochrome P450 isoenzyme, was isolated from pig liver microsomes (J Biol Chem 272:19615-19620). Further investigations followed to establish whether such enzyme systems are also present in microsomes of other organs such as brain, lung, and intestine. In addition, the mitochondrial reduction in human and porcine liver and kidney preparations was studied. The reductase activities were measured by following the reduction of benzamidoxime to benzamidine, guanoxabenz to guanabenz, and Ro 48-3656 ([[1-[(2S)-2-[[4-[(hydroxyamino)iminomethyl]benzoyl]amino]-1-oxopropyl]-4-piperidinyl]oxy]-acetic acid) to Ro 44-3888 ([[1-[(2S)-2-[[4-(aminoiminomethyl)benzoyl]amino]-1-oxopropyl]-4-piperidinyl]oxy]-acetic acid). Interestingly, preparations of all tested organs were capable of reducing the three compounds. The highest specific rates were found in kidney followed by liver, brain, lung, and intestine, and usually the mitochondrial reduction rates were superior. From the determined characteristics, similarities between the enzyme systems in the different organs and organelles were detected. Furthermore, properties of the benzamidoxime reductase located in the outer membrane of pig liver mitochondria were studied. In summary, these results demonstrate that in addition to the microsomal reduction, mitochondria are involved to a great extent in the activation of amidoxime prodrugs. The importance of extrahepatic metabolism in the reduction of N-hydroxylated prodrugs is demonstrated.

Animals↗
PubMed2005

Therapy of systemic fungal infections: a pharmacologic perspective.

An increase in the incidence of severe, invasive, systemic fungal infections has been noted over the last decade in human and veterinary medicine. Reports of drug resistance and therapeutic failure to currently available antifungal agents have also been on the rise. Many factors are likely to be involved in these trends, including immune suppression and the use of broad-spectrum antibiotics. The use of fungistatic drugs, suboptimal doses, compounded drugs, poorly absorbed drug formulations, and inadequate tissue penetrations of antifungals also contribute to the development of acquired resistance. Because of the unique chemical complexities of the antifungal agents, drug/drug and drug/food interactions may also play a significant role in poor therapeutic outcome. This review summarizes the pharmacology and toxicology of the antifungal agents in current use for systemic mycosis and introduces some of the newer antifungal agents that anecdotally show very promising results.

Animals↗