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PubMed1997

Exponential heating in drug stability experiment and statistical evaluation of nonisothermal and isothermal prediction.

A new nonisothermal heating model (exponential heating model) for drug stability experiments, based on a theoretical study of simulated nonisothermal data, is presented. In the model, the heating rate dT/dt is increased by 2-4 times at every increase of 10 degrees C in temperature: dT/dt = a(T-T0)/10.(dT/dt)0 where a is the times by which the heating rate is increased at every increase of 10 degrees C. A computation method with optimization and Simpson integration for the experiment was also introduced. The estimates for the shelf-life and activation energy obtained by the exponential and other nonisothermal heating models were statistically evaluated and were compared with those obtained by the isothermal method under various conditions. The results indicated that under the same experimental conditions, the estimates obtained by the exponential heating model were significantly more accurate and precise than those obtained by the linear, reciprocal, and logarithmic heating models. The accuracy and precision of the estimates were independent of the shelf-life of drugs and experimental period. The estimates obtained by the isothermal method were somewhat more accurate and precise than those obtained by the exponential heating model. However, the experimental period needed by the isothermal method was about five times longer than that needed by the exponential heating model. The results also showed that in each of the heating models, the estimates are more accurate and precise by increasing the extent of drug degradation, changing temperature range or sampling frequency, or by having the mean temperature closer to room temperature. To demonstrate its applicability, the exponential heating model was used to study the stability of vitamin C tablets and predict their shelf-life.

Drug Stability↗
PubMed2002

Imidazoline drugs stabilize lysosomes and inhibit oxidative cytotoxicity in astrocytes.

Oxidative stress is a primary pathogenesis in the brain, which is particularly vulnerable to oxidative stress. Maintenance of astrocyte functions under oxidative stress is essential to prevent neuronal injuries and to recover neuronal functions in various pathologic conditions. Imidazoline drugs have affinities for imidazoline receptors, which are highly distributed in the brain, and have been shown to be neuroprotective. This study presented the protective effects of several imidazoline drugs against oxidative cytotoxicity, in primary cultures of astrocytes. Imidazoline drugs, such as idazoxan, guanabenz, guanfacine, BU224, and RS-45041-190, showed protective effects against naphthazarin-induced oxidative cytotoxicity, as evidenced by LDH release and Hoechst 33342/propidium iodide staining. The imidazoline drugs stabilized lysosomes and inhibited naphthazarin-induced lysosomal destabilization, as evidenced by acridine orange relocation. Guanabenz inhibited, the leakage of lysosomal cathepsin D to cytosol, the decreased mitochondrial potential, and the release of mitochondrial cytochrome c, which were induced by naphthazarin. The lysosomal destabilization by oxidative stress and other apoptotic signals and subsequent cathepsin D leakage to the cytosol can induce apoptotic changes of mitochondria and eventually cell death. Therefore, lysosomal stabilization by imidazoline drugs may be ascribed to their protective effects against oxidative cytotoxicity.

Acridine Orange↗
PubMed2003

Differences in the longevity of topo IIalpha and topo IIbeta drug-stabilized cleavable complexes and the relationship to drug sensitivity.

PURPOSE: DNA topoisomerase II (topo II) is an important cellular target for chemotherapeutic agents. Human cells have two isoforms of topo II (alpha and beta), and both are inhibited by the chemotherapeutic agents etoposide, amsacrine (mAMSA) and mitoxantrone. It is known that the cytotoxic importance of topo IIalpha or topo IIbeta drug-induced complexes differs depending on which drug is present. This study was designed to (a) assess isoform-specific formation and reversal of topo IIalpha and beta cleavable complexes, and (b) determine whether the cytotoxic importance of either isoform was related to differences in the longevity of the complexes. METHODS: Mouse embryonic fibroblasts (MEFs) were used to study the cellular response to the topo II poisons etoposide, mitoxantrone and mAMSA. The longevity of topo IIalpha and beta complexes was determined using the TARDIS assay. This immunofluorescence assay can differentiate between the topo II isoforms and thus allowed us to investigate the persistence and importance of topo IIalpha and beta complexes for the first time. RESULTS: In MEFs treated with etoposide, 50% of topo IIalpha complexes dissociated within 40 min whereas dissociation of topo IIbeta complexes took only 20 min. Disappearance of complexes was a slower process for mitoxantrone-treated cells. The time taken to reduce topo IIalpha and topo IIbeta cleavable complexes by 50% was 10 and 6 h, respectively. In contrast, mAMSA-stabilized topo IIalpha and topo IIbeta cleavable complexes were equally stable (dissociation within 15 min for both isoforms). These stability data were confirmed using an in vitro assay. CONCLUSIONS: We previously demonstrated that topo IIalpha is the major target for etoposide and mitoxantrone but that both topo IIalpha and topo IIbeta are important for mAMSA cytotoxicity. The longevity of the topo IIalpha and beta cleavable complexes shown here is therefore an important factor in determining the cytotoxic sensitivity of either isoform to these drugs.

Amsacrine↗
PubMed1998

Formation of F-actin aggregates in cells treated with actin stabilizing drugs.

We have electroporated Dictyostelium amoebae with fluorescent phalloidin in order to visualize the localization and behavior of F-actin filaments in living cells. Immediately after electroporation with phalloidin, cells became round and showed bright staining in the cortical region. Over time, the cortical staining disappeared and was replaced by a large aggregate of actin filaments. The aggregates were predominantly localized to the apical posterior of actively moving cells and in the middle of dividing cells or stationary AX4 cells. Mutants lacking myosin II or ABP-120 also formed actin aggregates; however, the rate of formation of aggregates was slower in myosin II mutant cells. In order to investigate this phenomenon further, we have used jasplakinolide, a membrane-permeable drug that also stabilizes F-actin filaments. Cells treated with jasplakinolide formed actin aggregates in a concentration-dependent manner. Drug treatment led to an increase in the proportion of actin associated with the cytoskeleton. Jasplakinolide-treated cells were still motile; however, their rate of movement was less than that of untreated cells. Cytochalasin B and nocodazole had inhibitory effects on aggregate formation, while azide blocked the process completely. We hypothesize that aggregates are formed from the cortical flow of F-actin filaments. These filaments would normally be depolymerized but are artificially stabilized by phalloidin or jasplakinolide binding. The localization of the aggregate is likely to be an indication of the direction of cortical flow.

Actins↗
PubMed1996

[Effect of biological membrane stabilizing drugs (coenzyme Q10, dextran sulfate and reduced glutathione) on adriamycin (doxorubicin)-induced toxicity and microsomal lipid peroxidation in mice].

The protective effects of the biological membrane stabilizing drugs, coenzyme Q10 (CoQ), dextran sulfate (DS) and reduced glutathione (GSH), on doxorubicin (adriamycin, ADM)-induced toxicity and microsomal lipid peroxidation were studied in mice. The mice administered ADM with combined treatment of CoQ, DS or GSH showed a significantly longer survival time than the ADM control group (which were injected with 15 mg/kg of ADM twice). The optimum protective doses of these drugs against ADM-induced toxicity were 10 mg/kg/day (p.o.) for CoQ, 100 mg/kg/day (s.c.) for DS and 100 mg/kg/day (i.p.) for GSH. The survival times of the mice (expressed as a percent of the treated group per control group) were 224.1% for CoQ, 220.7% for DS and 213.7% for GSH. The groups treated with these drugs showed a significant decrease in mouse liver and heart microsomal lipid peroxidation in comparison to that of the ADM control group. These results suggest that the heart microsomal lipid peroxidation levels may be one of the indications of ADM-induced cardiac toxicity. These drugs tested in the present study may stabilize the heart microsomal membrane lipid or may improve the myocardiac mitochondrial functions over those in ADM-treated mouse.

Animals↗
PubMedDate not supplied

[Prediction of the effects of energy-stabilizing drugs in diabetes mellitus].

The authors describe a method for the prediction of the therapeutic effect of energy-stabilizing drugs, that helps rapidly select the optimal individual therapeutic policy. The method is based on measurement of the red cell ATP concentration in the course of in vitro incubation of cells in polyionic medium with the drug, and may be used in various diseases associated with energy metabolism disorders on the cellular level. The authors have used this method for the selection of a thiamine drug to be included in therapy of a diabetic in the period of the disease compensation.

Adenine↗
PubMed1990

Micellar modification of drug stability: analysis of the effect of hexadecyltrimethylammonium halides on the rate of degradation of cephaclor.

The intra- and intermolecular rates of degradation of cephaclor were determined with and without hexadecyltrimethylammonium bromide (CTABr). Micellar-derived spectral shifts were used to measure the association of the ionic forms as well as to determine the effect of CTABr on the apparent acid dissociation constant of the antibiotic. The rate of degradation of cephaclor increased with detergent and was salt sensitive. Micellar effects were analyzed quantitatively within the framework of the pseudophase ion exchange model. All experimental data were fitted to this model which was used to predict the combined effects of pH and detergent concentration. Micelles increased the rate of OH- attack on cephaclor; most of the effect was due to the concentration of reagents in the micellar pseudophase. The intramolecular degradation was catalyzed 25-fold by micelles, and a working hypothesis to rationalize this effect is proposed. The results demonstrate that quantitative analysis can be utilized to assess and predict effects of detergents on drug stability.

Cefaclor↗
PubMed2004

Glutathione S-transferase is a novel target for mood stabilizing drugs in primary cultured neurons.

Oligonucleotide microarray technology was used to analyze gene expression profiles after chronic treatment with the mood stabilizing drug valproate at a therapeutically relevant concentration in primary cultured rat cerebral cortical cells. We discovered that valproate regulates expression of 28 genes, including three isoenzymes (M1, A3 and A4) of glutathione S-transferase (GST), an important protective factor against oxidative stress. Because previous studies in our laboratory found that chronic valproate treatment protected cultured neurons against oxidative stress, further experiments on the regulation of GST were performed. Regulation of GST M1, GST A3 and GST A4 was verified using northern blotting hybridization. Chronic valproate treatment increased mRNA levels of M1 and A4, but decreased the A3 mRNA level dose-dependently, indicating further complexities in the regulation of GST by valproate. The level of GST M1 protein and GST activity were also increased by chronic valproate treatment. In addition, chronic treatment with lithium, another commonly prescribed mood stabilizer, also increased levels of GST M1 mRNA and protein. The present findings suggest that regulation of GST M1, and possibly GST A4, may mediate the anti-oxidative effects of valproate treatment, and regulation of GST may be involved in the mood stabilizing effect of valproate and lithium.

Animals↗
PubMed1999

Differential display PCR reveals novel targets for the mood-stabilizing drug valproate including the molecular chaperone GRP78.

Differential display polymerase chain reaction was used to identify genes regulated by the mood-stabilizing drug valproate (VPA). Four differentially displayed valproate-regulated gene fragments were isolated in rat cerebral cortex after i.p. injection of sodium VPA (300 mg/kg) for 3 weeks, and their expression was confirmed by Northern and slot blot analysis in rat cerebral cortex and C6 glioma cells. Sequencing analysis revealed three previously unidentified cDNA fragments in addition to a sequence with 100% homology with a molecular chaperone, 78-kDa glucose-regulated protein (GRP78). VPA treatment did not increase mRNA expression of 70-kDa heat shock protein, which is a related stress-induced molecular chaperone protein. All four candidate genes, including GRP78, showed similar VPA concentration-dependent increases in mRNA abundance. Another commonly prescribed mood-stabilizing anticonvulsant, carbamazepine, also increased GRP78 mRNA expression in C6 glioma cells, whereas lithium had no effect at doses up to 2 mM. Immunoblotting revealed that GRP78 protein levels were also increased in C6 glioma cells treated with VPA under the same conditions. Nuclear runoff analysis showed that VPA increased GRP78 gene transcription. Because GRP78 possesses molecular chaperone activity, binds Ca2+ in the endoplasmic reticulum, and protects cells from the deleterious effects of damaged proteins, the present findings suggest that VPA (and possibly carbamazepine) treatment may target one or more of these processes.

Animals↗
PubMed2006

Data analysis of kinetic modelling used in drug stability studies: isothermal versus nonisothermal assays.

PURPOSE: Kinetic modelling was applied to predict the stability of cholecystokinin fragment CCK-4 in aqueous solution, which was analyzed by isothermal and nonisothermal methods using a validated stability indicating HPLC method. METHODS: The isothermal studies were performed in the temperature range 40 to 80 degrees C at pH 12 and ionic strength 0.01 M as constants, whereas nonisothermal stability studies were performed using a linear increasing temperature program, heating rate 0.25 degrees C/h and a temperature interval 40-82 degrees C. The isothermal studies require two-step linear regression to estimate the parameters, resulting in a well-defined confidence interval. Nonisothermal kinetic studies require nonlinear or linear regression by previous transformation of data to estimate the parameters. In this case, the two most popular approaches, derivative and integral, were used and compared. RESULTS: Under isothermal conditions, an apparent first-order degradation process was observed at all temperatures. The linear Arrhenius plot suggested that the CCK-4 degradation mechanism was the same within the studied temperature range, with quite large uncertainties due to the small number of degrees of freedom based only on the scatter in the plot, and giving an estimated shelf life at 25 degrees C of 35.2 days. The derivative approach yields high variability in the Arrhenius parameters, since they are dependent on the number of polynomial terms chosen, so several statistical criteria were applied to select the best model. The integral approach allows activation parameters to be calculated directly from experimental data, and provides results in good agreement with those of the traditional method, but have the advantage that the uncertainty in the final result directly reflects the goodness of fit of the experimental data to the chosen kinetic model. The application of the bootstrap technique to estimating confidence limits for the Arrhenius parameters and shelf life is also illustrated, and shows there is no difference between the asymptotic and bootstrap confidence intervals. CONCLUSIONS: Nonisothermal studies give us fast and valuable information about drug stability, although their potential for predicting isothermal behaviour is conditioned by the data analysis method applied.

Drug Stability↗
PubMedDate not supplied

Amyloid peptide toxicity and microtubule-stabilizing drugs.

Based on microtubule (MT) disruption observed in primary neurons exposed to fibrillar amyloid peptides (A beta), we tested the potential protective effect of MT-stabilizing drugs such as Taxol against A beta-induced disruption of the cytoskeleton. Although Taxol was strongly protective, the fact that it does not cross the blood brain barrier (BBB) led us to synthesize and test other agents with MT-stabilizing properties and possible penetration into the brain. Our studies have thus far demonstrated that several MT-stabilizing agents, including some with structures quite different from that of Taxol, showed significant protective effects. However, not all agents that promoted MT-assembly were protective, suggesting additional mechanisms are involved in the actions of the drugs. A small number of neuroprotective compounds appear to have potential to enter the brain and thus might be tested to see if they slow progression of neurodegeneration in an appropriate animal model of Alzheimer's disease.

Alzheimer Disease↗
PubMed2001

Effects of antimanic mood-stabilizing drugs on fetuses, neonates, and nursing infants.

Pregnancy presents a special problem to the clinician treating bipolar disorders in women. Since the first episode of mania typically occurs before the age of 30, many women in their prime childbearing years may be exposed to potentially teratogenic mood-stabilizing agents. This exposure may also continue for the nursing infant during lactation. Pregnancy itself can exacerbate bipolar symptoms and also alter the pharmacokinetics of mood-stabilizing drugs. Risks to mother and fetus can be reduced with a number of simple strategies, including monotherapy with the lowest effective dose of a drug for the shortest period necessary, periconceptional use of multivitamins with folate, prescription of drugs with established safety records, and avoidance of exposure to antimanic agents during the first trimester of pregnancy. In this article, we review existing evidence on the risks to fetuses and nursing infants of mothers taking specific mood-stabilizing agents, and we present appropriate management guidelines designed to minimize these risks.

Abnormalities, Drug-Induced↗
PubMed2001

Effects of the actin-stabilizing drug, jasplakinolide, on pigment granule motility in isolated retinal pigment epithelial (RPE) cells of green sunfish, Lepomis cyanellus.

The retinal pigment epithelium (RPE) of teleosts contains pigment granules that migrate in response to changes in light condition. Dissociated, cultured RPE cells in vitro can be triggered to aggregate or disperse pigment granules by the application of cAMP or dopamine, respectively. Previous research using the actin-disrupting drug, cytochalasin D, suggested that pigment granule motility is actin dependent. To further examine the role of actin in pigment granule motility, we tested the effects of the actin-stabilizing drug, jasplakinolide, on pigment granule motility. Pigment granules in previously dispersed RPE cells remained dispersed after jasplakinolide exposure (0.1-1 microM), but the drug halted movement of most pigment granules and stimulated rapid bi-directional movements in a small subset of granules. Jasplakinolide also blocked net pigment granule aggregation and interfered with the maintenance of full aggregation. Although jasplakinolide did not block pigment granule dispersion, it did alter the motility of dispersing granules compared to control cells; rather than the normal saltatory, primarily centrifugal movements, granules of jasplakinolide-treated cells demonstrated slow, creeping centrifugal movements and more rapid bi-directional movements. Jasplakinolide also altered cell morphology; the length and thickness of apical projections increased, and enlarged, paddle-like structures, which contained F-actin appeared at the tips of projections. Actin antibody labeling of jasplakinolide-treated cells revealed a more reticulated network of actin compared to antibody-labeled control cells. These results indicate that jasplakinolide-induced disruption of the actin network compromises normal pigment granule dispersion and aggregation in isolated RPE cells, thus providing further evidence that these movements are actin dependent.

Actins↗
PubMedDate not supplied

[Criteria of pharmacologic effectiveness of antioxidant and membrane-stabilizing drugs in various disorders of cerebral circulation].

The criteria of the effectiveness of preparations possessing the antioxidative and membrane reparative properties in 135 patients with different clinical forms of disorders of the cerebral circulation were developed. It was found that the effectiveness of antioxidative and membrane stabilizing drugs in relieving consequences of free radical aggression as compared with traditional means varied and manifested itself in such an order: essenciale----alpha-tocopherol----unithiol. The presented methods of therapy and appropriate drugs may be recommended for the introduction in the complex of therapeutic and rehabilitative measures.

Cerebrovascular Disorders↗