Aggression, agitation, and mania with olanzapine.
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Adult↗
Biomedical subjects
M Rapp
Publications and source records attributed to M Rapp.
Enhancement by O6-benzyl-N2-acetylguanosine of N'-[2-chloroethyl]-N-[2-(methylsulphonyl)ethyl]-N'-nitrosourea therapeutic index on nude mice bearing resistant human melanoma.
The exposure of cells to O6-benzyl-N2-acetylguanosine (BNAG) and several guanine derivatives is known to reduce the activity of O6-alkylguanine-DNA alkyltransferase (MGMT) and to enhance the sensitivity of Mer+ (methyl enzyme repair positive) tumour cells to chloroethylnitrosoureas (CENUs) in vitro and in vivo. High water solubility and the pharmacokinetic properties of BNAG make it a candidate for simultaneous administration with CENUs by the i.v. route in human clinical use. In vivo we have shown previously that BNAG significantly increases the efficiency of N'-[2-chloroethyl]-N-[2-(methylsulphonyl)ethyl]-N'-nitrosourea (cystemustine) against M4Beu melanoma cells (Mer+) through its cytostatic activity by the i.p. route, but also increases its toxicity. To investigate the toxicity of BNAG and cystemustine when administered simultaneously in mice, we compared the maximum tolerated dose and LD50 doses of cystemustine alone or in combination with 40 mg kg(-1) BNAG by the i.p. route. The toxicity of cystemustine was enhanced by a factor of almost 1.44 when combined with BNAG. To compare the therapeutic index of cystemustine alone and the cystemustine/BNAG combination, pharmacological tests were carried out in nude mice bearing Mer+ M4Beu human melanoma cells. Isotoxic doses were calculated using the 1.44 ratio. The treatments were administered three times by the i.v. route on days 1, 5 and 9 after s.c. inoculation of tumour cells. Although the toxicities of the treatments were equal, BNAG strongly enhanced tumour growth inhibition. These results demonstrate the increase of the therapeutic index of cystemustine by BNAG and justify the use of BNAG to enhance nitrosourea efficiency in vivo by i.v. co-injection.
Animals↗
Tissue distribution and metabolism in rat of an ethynesulphonamide with filaricidal activity.
1. The tissue distribution and metabolism of a new filaricidal agent P903 (N-[(2-phenylethynyl)sulfonyl]morpholine) were studied in rat. 2. After s.c. administration of 14C and 13C P903, the Tmax in the blood was observed on day 2. Elimination was slow and > 95% was bound to protein. Radioactivity was distributed in the whole organism but particularly in erythrocytes and the lymphatic channel. Four days later, > 60% of the radioactivity was excreted in urine and faeces at equal amounts and 15% remained at the injection point. 3. In all biological fluids tested no P903 was found but only its metabolites. 4. One principal metabolite, the N-[(2-phenyloxo-2-ethane) sulphonyl] morpholine or oxosulphonamide was identified in blood, urine and faeces as compared with the reference compound by GC/MS and NMR. This latter molecule was detected following hydrolysis by hydrochloric acid but not with beta glucuronidase/sulphatase. 5. Unconjugated and conjugated oxosulphonamide represented > 85% of the radioactivity at all times tested in blood but only 38 and 35% respectively of urinary and faecal radioactivity on day 1 after the administration of the labelled drug. 6. Thus, P903 is rapidly converted to a reactive metabolite, probably an oxirene, which is then conjugated with endogenous components to form conjugated oxosulphonamide and an unknown metabolite. The role of this reactive metabolite in antifilarial activity seems to be very important in understanding the mechanism of action of P903.
Animals↗
Disposition and metabolism of 2,6-dimethylbenzamide N-(5-methyl-3-isoxazolyl) (D2916) in male and female rats.
Disposition and metabolism of the new anticonvulsant 2,6-dimethylbenzamide N-(5-methyl-3-isoxazolyl) (D2916) was studied in male and female rats after oral administration of 14C-labeled material. D2916 was well absorbed in both sexes and distributed to all tissues, with maximal drug concentrations found in elimination and metabolization organs, as well as in fatty tissues. Striking differences in pharmacokinetic parameters of total radioactivity were observed between males and females; females had higher brain concentrations and longer blood and tissue half-lives. The study of blood, bile, urine, and brain metabolites showed that D2916 follows two degradation pathways related to hydroxylation of methyl groups. Males prefer to hydroxylate one of the methyl groups of the phenyl ring, and females prefer to hydroxylate the methyl of the isoxazolyl ring forming the active metabolite D3187. These findings suggest a sex difference in the location of the hydroxylation of the D2916 molecule and can explain the longer anticonvulsant effect observed in the female rat that is related both to an orientation of the metabolism toward the formation of the active metabolite and to a better ability to this metabolite to cross the blood-brain barrier, compared with the unchanged drug.
Animals↗
Structure-activity relationships in a series of substituted indolocarbazoles: topoisomerase I and protein kinase C inhibition and antitumoral and antimicrobial properties.
A series of compounds structurally related to staurosporine, rebeccamycin, and corresponding aglycones was synthesized, and their activities toward protein kinase C and topoisomerases I and II were tested together with their in vitro antitumor efficiency against murine B16 melanoma and P388 leukemia cells. Their antimicrobial activities were also examined against a Gram-negative bacterium (Escherichia coli), a yeast (Candida albicans), and three Gram-positive bacteria (Bacillus cereus, Streptomyces chartreusis, and Streptomyces griseus). To avoid side effects expected with protein kinase C inhibitors, we introduced substitution on the maleimide nitrogen and/or a sugar moiety linked to one of the indole nitrogens to obtain specific inhibitors of topoisomerase I with minimal activities on protein kinase C. As expected, these structures were inefficient on topoisomerase II, and some of them exhibited a strong activity against topoisomerase I. Generally, dechlorinated compounds were found to be more active than chlorinated analogues against both purified topoisomerase I and protein kinase C. On the other hand, opposite results were obtained in the cell antiproliferative assays. These results suggest lack of cell membrane permeability in the absence of the chlorine residue or cleavage of carbon-chlorine bonds inside the cell.
Animals↗
Modeling back propagating action potential in weakly excitable dendrites of neocortical pyramidal cells.
Simultaneous recordings from the soma and apical dendrite of layer V neocortical pyramidal cells of young rats show that, for any location of current input, an evoked action potential (AP) always starts at the axon and then propagates actively, but decrementally, backward into the dendrites. This back-propagating AP is supported by a low density (-gNa = approximately 4 mS/cm2) of rapidly inactivating voltage-dependent Na+ channels in the soma and the apical dendrite. Investigation of detailed, biophysically constrained, models of reconstructed pyramidal cells shows the following. (i) The initiation of the AP first in the axon cannot be explained solely by morphological considerations; the axon must be more excitable than the soma and dendrites. (ii) The minimal Na+ channel density in the axon that fully accounts for the experimental results is about 20-times that of the soma. If -gNa in the axon hillock and initial segment is the same as in the soma [as recently suggested by Colbert and Johnston [Colbert, C. M. & Johnston, D. (1995) Soc. Neurosci. Abstr. 21, 684.2]], then -gNa in the more distal axonal regions is required to be about 40-times that of the soma. (iii) A backward propagating AP in weakly excitable dendrites can be modulated in a graded manner by background synaptic activity. The functional role of weakly excitable dendrites and a more excitable axon for forward synaptic integration and for backward, global, communication between the axon and the dendrites is discussed.
Animals↗
c-Axis Conductivity and Intrinsic Josephson Effects in YBa2Cu3O7- delta.
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Journal Article↗
Effects of fluoxetine and olfactory bulbectomy on mouse circadian activity rhythms.
Olfactory bulbectomy (OBX) in SWR outbred male mice lengthened the free-running period and delayed the phase of a circadian rhythm for wheel-running activity. OBX also increased mean levels of activity. Two weeks of daily intraperitoneal injections of Fluoxetine (8 mg/kg), a serotonin re-uptake inhibitor, reversed the effects of bulbectomy on the mean level of activity and significantly shortened the free-running period of the activity rhythm. The phase of the activity rhythm was not significantly affected by the Fluoxetine treatment. These results are consistent with a hyposerotonergic mediation of the effects of OBX on circadian period and activity level.
Animals↗
Circadian variation in O6-methylguanine-DNA methyltransferase activity in mouse liver.
Bifunctional chloroethylating cytostatic agents produce lethal DNA lesions, as a result of the formation of O6-alkylguanines. These lesions can be repaired by O6-methylguanine-DNA methyltransferase (MGMT). This ubiquitous nuclear and cytosolic enzyme removes the alkyl group by accepting it to the cysteine residue of its active site, thus preventing the formation of DNA interstrand cross-links. The role of the circadian organization in cellular protection against such DNA insults was examined in male B6D2F1 mice, synchronized with an alternation of 12 h of light and 12 h of darkness (LD12:12). MGMT activity was determined in liver of mice obtained at eight different circadian times, located 3 h apart. MGMT activity varied 5-fold along the 24 h time-scale, from 7 +/- 1 pmol/g of tissue at 7 h after light onset (HALO), during the rest span, up to 32 +/- 9 pmol/g at 19 HALO (second mid to late activity span). This large amplitude circadian rhythm in MGMT activity may be an important determinant of the susceptibility rhythms to alkylating agents. The greatest DNA repair activity occurred at night when mice were active, eat and drink, and thus are at a higher risk of being exposed to chemical insults.
Animals↗
Syntheses and antimicrobial activities of five-membered ring heterocycles coupled to indole moieties.
Indole-substituted oxazolidinones, oxazolones, pyrrolidinone, imidazolidinone and imidazolones were synthesized. Their inhibitory potencies towards protein kinase C and protein kinase A were determined and their in vitro activities against Streptomyces chartreusis, Streptomyces griseus, Bacillus cereus, Candida albicans and Escherichia coli were examined. The inhibition of Streptomyces sporulation observed for some of them could not be linked to in vitro protein kinase C inhibition. All proved inactive against C. albicans but three of them exhibited a marked activity towards E. coli. This effect extends to other Gram-negative bacteria.
Alkaloids↗
Characterization of a conserved gene block in the murine cytomegalovirus genome.
The nucleotide sequence between the lytic origin and the gH gene of the murine cytomegalovirus genome (map units 0.416-0.455) was determined. Five of the 15 open reading frames identified encode polypeptides, which exhibit significant homology to polypeptides of human cytomegalovirus (HCMV) (UL69, UL71, and UL73) and to polypeptides of several other herpesviruses (dUTPase and helicase/primase). The location in the genome of the five open reading frames and their direction of transcription is perfectly conserved between murine cytomegalovirus (MCMV) and HCMV. These data suggest that MCMV and HCMV have a highly related genome organization. Thus, MCMV offers a good model for molecular and functional analysis of cytomegalovirus genes in vitro and in vivo.
Amino Acid Sequence↗
Antimicrobial activities of indolocarbazole and bis-indole protein kinase C inhibitors. II. Substitution on maleimide nitrogen with functional groups bearing a labile hydrogen.
New compounds, structurally related to the potent protein kinase C inhibitor staurosporine, and substituted on the imide nitrogen with a functional group bearing a labile hydrogen (hydroxymethyl, amino, hydroxy), were synthesized. Their in vitro inhibitory potencies towards protein kinase C and protein kinase A showed that N-hydroxymethyl and N-hydroxy substitution, unlike alkyl substitution, can provide efficient protein kinase C inhibitors. The antimicrobial activities of these new compounds against Streptomyces chartreusis and Streptomyces griseus, Bacillus cereus, Escherichia coli, Candida albicans and Botrytis cinerea were examined. They proved to be inactive against E. coli and two fungi. The results suggest that there is no link between in vitro inhibition of protein kinase C and inhibition of growth and sporulation of the two Streptomyces tested. Unlike indolocarbazole maleimides, bis-indole maleimides are active against the two Streptomyces species.
Carbazoles↗
The conditions of primary infection define the load of latent viral genome in organs and the risk of recurrent cytomegalovirus disease.
Recurrence of cytomegalovirus (CMV) from latency is a frequent cause of disease in immunocompromised patients. To date, there is no explanation for the diversity in the clinical manifestations. Primary infection can occur perinatally or later in life, and inevitably results in latent infection. Seropositivity for antibodies against CMV is indicative of latent infection, but is insufficient as a predictor for the risk of recurrence. As a model for this important medical problem, we compared the risks of murine CMV recurrence from latency established after neonatal primary infection and after infection at adult age. The risk of CMV recurrence was high only after neonatal infection. The copy number of latent viral genome in tissues was identified as the key parameter that determines the overall and organ-specific risks of recurrence. Latent CMV burden and risk of recurrence were related to the extent of virus multiplication during primary infection. The presence of latent CMV in multiple organs provides the molecular basis for stochastic events of recurrence in single organs or in any combination thereof. These findings are discussed as a concept of multifocal CMV latency and recurrence. It provides a rationale for the diversity in the clinical outcome of CMV disease.
Animals↗
Physiology, morphology and detailed passive models of guinea-pig cerebellar Purkinje cells.
1. Purkinje cells (PCs) from guinea-pig cerebellar slices were physiologically characterized using intracellular techniques. Extracellular caesium ions were used to linearize the membrane properties of PCs near the resting potential. Under these conditions the average input resistance, RN, was 29 M omega, the average system time constant, tau 0, was 82 ms and the average cable length, LN, was 0.59. 2. Three PCs were fully reconstructed following physiological measurements and staining with horseradish peroxidase. Assuming that each spine has an area of 1 micron 2 and that the spine density over the spiny dendrites is ten spines per micrometre length, the total membrane area of each PC is approximately 150,000 microns 2, of which approximately 100,000 microns 2 is in the spines. 3. Detailed passive cable and compartmental models were built for each of the three reconstructed PCs. Computational methods were devised to incorporate globally the huge number of spines into these models. In all three cells the models predict that the specific membrane resistivity, Rm, of the soma is much lower than the dendritic Rm (approximately 500 and approximately 100,000 omega cm2 respectively). The specific membrane capacitance, Cm, is estimated to be 1.5-2 muF cm-2 and the specific cytoplasm resistivity, Ri, is 250 omega cm. 4. The average cable length of the dendrites according to the model is 0.13 lambda, suggesting that under caesium conditions PCs are electrically very compact. Brief somatic spikes, however, are expected to attenuate 30-fold when spreading passively into the dendritic terminals. A simulated 200 Hz train of fast, 90 mV somatic spikes produced a smooth 12 mV steady depolarization at the dendritic terminals. 5. A transient synaptic conductance increase, with a 1 nS peak at 0.5 ms and a driving force of 60 mV, is expected to produce approximately 20 mV peak depolarization at the spine head membrane. This EPSP then attenuates between 200- and 900-fold into the soma. Approximately 800 randomly distributed and synchronously activated spiny inputs are required to fire the soma. 6. The passive model of the PC predicts a poor resolution of the spatio-temporal pattern of the parallel fibre input. An equally sized, randomly distributed group of approximately 1% of the parallel fibres, activated within a time window of a few milliseconds, would result in approximately the same composite EPSP at the soma.
Animals↗
Indolocarbazole protein kinase C inhibitors from rebeccamycin.
Structural modifications were carried out on rebeccamycin, an antitumour antibiotic, to obtain analogues. The inhibitory potencies of these analogues against protein kinase C are compared. The method described represents an alternative route to the staurosporine aglycone, a potent protein kinase C inhibitor.
Aminoglycosides↗
Expression of the murine cytomegalovirus glycoprotein H by recombinant vaccinia virus.
The sequence of the gene encoding glycoprotein H (gH) of murine cytomegalovirus (MCMV) strain Smith was determined and compared with the sequence of the gH of MCMV strain K181. Transcriptional analysis showed that gH is encoded by a large mRNA of 5.0 kb, which is synthesized late in infection. A recombinant vaccinia virus expressing the MCMV gH open reading frame was constructed (Vac-gH). Anti-MCMV serum precipitated a protein of 87K from Vac-gH-infected cells. Reactivity with a monoclonal antibody showed the identity of the MCMV gH with a 87K envelope glycoprotein described previously by Loh and Qualtiere. Immunization of mice with the Vac-gH recombinant gave rise to an anti-gH serum, which neutralized MCMV without complement in vitro.
Amino Acid Sequence↗
Disposition in rat of a new fluorinated, biocompatible, non-ionic telomeric carrier.
1. The disposition of the new fluorinated, biocompatible, non-ionic telomeric carrier trisacryl conjugate (F-TAC) labelled with 13C and 14C on the amide function has been studied in the rat after p.o. and i.v. administration. 2. After i.v. administration, excretion measurements have shown that radioactivity was eliminated mainly in the urine (69% within 24 h), and that faecal excretion was low (8% within 72 h). After p.o. administration, faecal elimination was significantly increased (30% within 72 h). No radioactivity was eliminated as 14CO2, after either route of administration. 3. After i.v. administration, plasma radioactivity exhibited a biphasic decrease, with t1/2 = 20 min for the first phase and 29.5 h for the second phase. The maximal plasma concentration was obtained 40 min after oral dosing, followed by a monoexponential decrease with t1/2 = 38.1 h. The ratio AUC (p.o.)/AUC (i.v.) as an assessment of bioavailability was 0.22. 4. After both i.v. and p.o. administration, a relatively homogeneous concentration of radioactivity was found in most organs, close or below the plasma concentration, indicating that tissues do not exhibit a high affinity for this molecule. In addition, F-TAC did not cross the blood-brain barrier. 5. Analysis of urine and plasma on DOWEX AG1X2 anionic resin showed that < 20% of the radioactivity was bound to this support. 13C- and 19F-nmr analysis of the non-bound radioactivity identified it to unchanged F-TAC, with bound radioactivity being due to polyanionic telomers arising from the hydrolysis of the amide function.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Oral↗
Enhancement by O6-benzyl-N-acetylguanosine derivatives of chloroethylnitrosourea antitumor action in chloroethylnitrosourea-resistant human malignant melanocytes.
The exposure of cells to O6-methylguanine or O6-benzylguanine is known to reduce the enzymatic activity of O6-alkylguanine-DNA alkyltransferase, which leads to a sensitivity enhancement to chloroethylnitrosourea cytotoxic effects. The main disadvantage of the guanine derivatives is their low water solubility, which makes their formulation difficult for clinical use in humans. To overcome this problem, water-soluble O6-alkylguanine-DNA alkyltransferase inhibitors have been synthesized and their ability to increase the chloroethylnitrosourea potency in vitro and in vivo was evaluated. Four water-soluble molecules (O6-methyl-N-acetylguanosine; O6-methyl-N-acetyldeoxyguanosine; O6-benzyl-N-acetylguanosine, BNAG; and O6-benzyl-N-acetyldeoxyguanosine, BNADG) were tested for sensitivity of M4Beu cells to N'-(2-chloroethyl]-N[2-(methylsulfonyl)ethyl]-N'-nitrosourea (cystemustine) based on the colony-forming ability of M4Beu melanoma cells. The cell sensitivity to cystemustine was increased by benzylated derivative pretreatment but not with methylated derivative pretreatment. Furthermore, BNAG or BNADG pretreatment followed by cystemustine was less cytotoxic than BNAG or BNADG given simultaneously and followed 24 hr later by BNAG or BNADG. Comparative studies performed with O6-benzylguanine on the same model showed that this inhibitor was effective at lower concentrations than the corresponding guanosine or deoxyguanosine analogs. Preliminary pharmacological assays were carried out in nude mice bearing the M4Beu tumor to determine whether the BNAG-cystemustine combination has greater antitumor activity than cystemustine alone. Simultaneous i.p. injection of 200 mg/kg of BNAG and 15 mg/kg of cystemustine followed by an i.p. injection 4 hr later of 200 mg/kg of BNAG led to a significant enhancement of inhibition of tumor growth.
Animals↗