PubMed Health⌕ Search

Biomedical subjects

S W Johnson

Publications and source records attributed to S W Johnson.

At least 55 records · Page 3Linked to original sources
PubMed1996

Cross-resistance, cisplatin accumulation, and platinum-DNA adduct formation and removal in cisplatin-sensitive and -resistant human hepatoma cell lines.

The BEL7404 human hepatoma cell line was selected in vitro for primary cisplatin resistance. A panel of four cisplatin-resistant sublines were generated which exhibited resistance to cisplatin (up to 34-fold) but were not cross-resistant to adriamycin, taxol, etoposide, or mitomycin C. Further characterization of this panel of cell lines revealed that increased cisplatin resistance was associated with decreased cisplatin accumulation in the selected sublines (up to 14-fold) relative to the parental BEL7404 cell line. A significant reduction in platinum-DNA adduct formation (9-fold) and ribosomal RNA gene-specific interstrand crosslink formation (12-fold) were also observed in the 7404-CP20 cell line. No differences in the rate of platinum efflux from the BEL7404 and 7404-CP20 cell lines were detected following a 4-h loading period, and total platinum-DNA adduct and gene-specific interstrand crosslink removal rates were similar in both cell lines. There were approximately 3-fold more total platinum-DNA adducts present in the BEL7404 cells relative to the 7404-CP20 cells at equitoxic concentrations of cisplatin, suggesting that DNA damage tolerance also contributes to the cisplatin resistance phenotype. Overall, these results indicate that decreased cisplatin accumulation is the major cisplatin resistance mechanism present in the in vitro-selected cell lines. This model system of acquired cisplatin resistance may be valuable in determining the molecular basis for decreased cisplatin uptake and be useful for the study of potential resistance modulators.

Carcinoma, Hepatocellular↗
PubMed1996

Identification of zinc finger mRNAs using domain-specific differential display.

An oligonucleotide primer specific for a conserved amino acid region of the Cys2/His2 zinc finger proteins was used in conjunction with mRNA differential display to amplify related mRNAs from a human ovarian cancer cell line. Six of the 12 cDNAs analyzed from the differential display polyacrylamide gel exhibited zinc finger homology at the nucleotide and predicted amino acid sequence level. None of these cDNA fragments, however, shared complete homology with genes encoding any known zinc finger proteins. All 6 cDNA fragments with zinc finger homology had a poly-A tail and 3 of these fragments contained a putative polyadenylation signal. Northern blot analysis was performed using radiolabeled probes prepared from the 12 cDNA fragments. Two of the 6 cDNA fragments with zinc finger homology hybridized to 3.6- and 6.0-kb mRNAs. In addition, 2 of the fragments which did not contain significant homology to zinc finger or any other known sequences hybridized to 4.1- and 5.8-kb mRNAs. These results suggest that domain-specific differential display may be a useful approach for the identification of novel gene family members as well as for the analysis of changes in gene expression of family members between related cell lines or tissue samples.

Amino Acid Sequence↗
PubMed1996

Analysis of HMG protein binding to DNA modified with the anticancer drug cisplatin.

Cisplatin (CDDP) is an effective and widely used cancer chemotherapy drug. High mobility group (HMG) proteins 1 and 2 have been shown to bind with high affinity to CDDP-DNA. In this study we analyzed the interaction of HMG proteins with CDDP-DNA. We demonstrate that after binding, HMG proteins can be removed from CDDP-DNA leaving the Pt adducts intact and capable of rebinding HMG proteins. Furthermore, the very HMG proteins that have been removed remain functionally viable and capable of rebinding CDDP-DNA. We also investigated the role that Cys residues play in protein binding. Replacement of Cys 45 or Cys 106 with a Ser residue reduced HMG2 protein binding to CDDP-DNA. These results indicate that Cys residues play a critical role in the high affinity binding of this protein to CDDP-DNA. From these findings, we speculate that the intracellular oxidative environment could affect the redox state of protein thiols in HMG1 and HMG2 and in addition, regulate the ability of these proteins to recognize cis-Pt-DNA adduct formation in tumor cells.

Animals↗
PubMed1996

Sulfonylurea-sensitive potassium current evoked by sodium-loading in rat midbrain dopamine neurons.

In Parkinson's disease, there is evidence of impaired mitochondrial function which reduces the capacity to synthesize ATP in dopamine neurons. This would be expected to reduce the activity of the sodium pump (Na+/K+ ATPase), causing increased intracellular levels of Na+. Patch pipettes were used to introduce Na+ (40 mM in pipette solutions) into dopamine neurons in the rat midbrain slice in order to study the electrophysiological effects of increased intracellular Na+. We found that intracellular Na+ loading evoked 100-300 pA of outward current (at -60 mV) and increased whole-cell conductance; these effects developed gradually during the first 10 min after rupture of the membrane patch. Extracellular Ba2+ reduced most of the outward current evoked by Na+ loading; this Ba(2+)-sensitive current reversed direction at the expected reversal potential for K+ (EK), and was also blocked by extracellular tetraethylammonium (30 mM) and intracellular Cs+ (which replaced K+ in pipette solutions). The sulfonylurea drugs glipizide (IC50 = 4.9 nM), tolbutamide (IC50 = 23 microM) and glibenclamide (1 microM) were as effective as 300 microM Ba2+ in reducing the K+ current evoked by Na+ loading. When recording with "control" pipettes containing 15 mM Na+, diazoxide (300 microM) increased chord conductance and evoked outward current at -60 mV, which also reversed direction near EK. Effects of diazoxide were blocked by glibenclamide (1 microM) or glipizide (300 nM). Diazoxide (300 microM) and baclofen (3 microM), which also evoked K(+)-mediated outward currents recorded with control pipettes, caused little additional increases in outward currents during Na+ loading. Raising ATP concentrations to 10 mM in pipette solutions failed to significantly reduce currents evoked by diazoxide or Na+ loading, suggesting that these currents may not be mediated by ATP-sensitive K+ channels. Finally, Na+ loading using pipettes containing Cs+ in place of K+ evoked a relatively small outward current (50-150 pA at -60 mV), which developed gradually over the first 10 min after rupturing the membrane patch. This current was reduced by dihydro-ouabain (3 microM) and a low extracellular concentration of K+ (0.5 mM instead of 2.5 mM), but was not affected by Ba2+. We conclude that intracellular Na+ loading evokes a current generated by Na+/K+ ATPase in addition to sulfonylurea-sensitive K+ current. This Na(+)-dependent K+ current is unusual in its sensitivity to sulfonylureas, and could protect dopamine neurons against toxic effects of intracellular Na+ accumulation.

Animals↗
PubMed1996

Carboplatin and paclitaxel in ovarian carcinoma: a phase I study of the Gynecologic Oncology Group.

PURPOSE: To develop a tolerable, dose-intense regimen of carboplatin and paclitaxel for the treatment of primary epithelial ovarian carcinoma. PATIENTS AND METHODS: Patients underwent initial surgical assessment and tumor debulking. Patients with stage III/IV disease received six cycles of chemotherapy on a planned 21-day cycle. Carboplatin dose was calculated based on projected area under the curve (AUC) for concentration over time (mg. mL-1.min) and escalated to determine the maximum-tolerated dose (MTD). Paclitaxel dose was also escalated as a 3-, 24-, or 96-hour infusion. Granulocyte colony-stimulating factors (G-CSFs) were required at selected dose levels or could be added based on hematologic toxicity. RESULTS: Thirty-nine patients were enrolled and assessable for toxicity and response. Dose-limiting toxicity (DLT) was hematologic, primarily neutropenia. Less than 2% of all cycles with paclitaxel as a 3- or 24-hour infusion were associated with either grade 4 thrombocytopenia or febrile neutropenia. The carboplatin MTD was AUC 7.5 (equivalent to a median dose of 471 mg/m2). The MTD for paclitaxel was 135 mg/m2 over 24 hours and 175 mg/m2 over 3 hours without initial G-CSF. A 96-hour infusion of paclitaxel at a dose of 120 mg/m2 was associated with excessive single-cycle and cumulative myelosuppression, and was not further evaluated. Measured carboplatin AUC agreed well with the calculated AUC. The overall complete (n = 16) and partial (n = 2) response rate among 24 patients with measurable disease was 75%, with a median progression-free survival time of 15 months. CONCLUSION: Carboplatin could be safely combined with paclitaxel using a dose formula based on projected renal clearance. The recommended outpatient regimen is carboplatin AUC 7.5 and paclitaxel 175 mg/m2 over 3 hours without initial G-CSF. This treatment safely achieved a greater dose-intensity of carboplatin than would have been achieved with conventional dosing based on body-surface area.

Adult↗
PubMed1996

Pharmacological characterization of inward current evoked by N-methyl-D-aspartate in dopamine neurons in the rat brain slice.

In midbrain dopamine neurons in vitro, N-methyl-D-aspartate (NMDA) evokes oscillation of membrane potential and burst firing which are dependent on a ouabain-sensitive sodium pump. In the present study, we investigated the ionic dependence and pharmacological modulation of NMDA-mediated currents which might be important in burst firing. By use of patch pipettes to record membrane currents in whole-cell voltage clamps, we found that NMDA (10 microM) evoked inward currents that were significantly reduced in a low extracellular concentration of Na+ (25 mM), but not when extracellular Ca+2 was decreased from 2.5 to 0.5 mM. The current-voltage relationship for subtracted NMDA currents showed a prominent region of negative slope conductance which was absent when the slice was perfused with solution containing zero Mg++. 7-Chlorokynurenic acid, an antagonist at the nonstrychnine-sensitive glycine binding site, produced a concentration-dependent reduction in amplitude of excitatory postsynaptic currents mediated by NMDA receptors (IC50 = 15 +/- 3 microM). NMDA-activated currents were blocked by phencyclidine (IC50 = 130 +/- 65 nM), dizocilpine maleate (MK-801) (1 microM) and ketamine (100 microM), but not by amantadine (1 mM). Spermine (100 microM), a polyamine which reportedly modulates NMDA currents in other neurons, presynaptically inhibited excitatory postsynaptic currents mediated by NMDA receptors but had no effect on the currents mediated by NMDA. We conclude that the most important factors for NMDA-induced burst firing are the relatively large Na+ influx through NMDA-gated channels and the strong voltage-dependent block of conductance by Mg++.

Animals↗
PubMed1996

Evaluation of carboplatin pharmacokinetics in the absence and presence of paclitaxel.

In a clinical trial of paclitaxel (Taxol) and carboplatin in combination, the severity of thrombocytopenia was less than would be expected with an equivalent dose of carboplatin alone. To determine whether a pharmacokinetic interaction was responsible for this observation, the effect of pretreatment with Taxol on the pharmacokinetics of carboplatin was examined in 11 patients. Each patient was randomized to one of two treatment groups that determined the order of drug treatments. The treatments were carboplatin as a 30-min infusion alone or immediately following 175 mg/m2 Taxol administered as a 3-h i.v. infusion. The treatments were separated by 1 week. The carboplatin dose was chosen to produce a target area under the concentration-time curve (AUC) of 3.75 mg-min/ml according to a previously published formula (A. H. Calvert et al., J. Clin Oncol., 7: 1748-1756, 1989). The mean administered dose of carboplatin was 338 mg. Serial blood samples were collected over 24 h and analyzed for total and free platinum, and, in some patients, Taxol. The pharmacokinetics of carboplatin (i.e., total clearance and volume of distribution at steady state), was not significantly affected by pretreatment with Taxol. Total clearances of carboplatin were 67.2 +/- 28.8 ml/min and 64.6 +/- 27.9 ml/min in the absence and presence of Taxol, respectively (P = 0.56). The AUC of free carboplatin (3.45 mg-min/ml) obtained in the absence of Taxol was not significantly different from that measured in the presence of Taxol (3.27 mg-min/ml). The AUC of carboplatin in both the absence and presence of Taxol agreed with the projected target AUC of 3.75 mg-min/ml. In conclusion, the application of an individualized dosing strategy is valid for the calculation of the carboplatin dose in this combination. The pharmacokinetics of carboplatin is not altered by pretreatment with Taxol at a standard dose, and a pharmacokinetic interaction is not responsible for the altered toxicity of the combination.

Adult↗
PubMed1995

Evidence for altered regulation of gamma-glutamylcysteine synthetase gene expression among cisplatin-sensitive and cisplatin-resistant human ovarian cancer cell lines.

We have shown previously that tumor cell resistance to cisplatin is associated with elevated intracellular levels of glutathione, which is accomplished at least in part by increased expression of the heavy subunit of gamma-glutamylcysteine synthetase (gamma-GCS). To investigate the mechanism by which gamma-GCS expression is elevated, we have examined four related human ovarian cancer cell lines with increasing cisplatin resistance. Relative amounts of steady-state gamma-GCS mRNA in CP70, C30, and C200 were 4.8, 6.0, and 10.6, respectively, compared to the parental A2780 cell line, and a proportional increase in the transcriptional rate but not RNA stability was demonstrated. In contrast, no increase in mRNA for the gamma-GCS light subunit was found. To determine the mechanism of upregulation of this mRNA, we have cloned the promoter of the gene that encodes the heavy subunit of gamma-GCS. This region contains AP-1, NF-kappa B, XRE, AP-2, EpRE, CAAT, and TATA box elements upstream of the transcription initiation site and two MREs between this site and the start codon for the protein. Using gel mobility shift assays, we have found nuclear extract binding activity to the AP-1 response element to be closely associated with the level of gamma-GCS gene expression. A supershift assay showed that the AP-1 DNA-binding complexes are predominantly formed by dimers of JUN family members. Consistent with this finding, the expression of c-JUN was found to be elevated in the resistant cells. In contrast to AP-1 binding, AP-2 and NF-kappa B binding were inversely related to resistance. Furthermore, we have examined a partial revertant of the C200-resistant cells, which shows lower glutathione levels, and found decreased gamma-GCS expression associated with decreased AP-1 binding activity.

Antineoplastic Agents↗
PubMed1995

Alpha 1-adrenergic effects on dopamine neurons recorded intracellularly in the rat midbrain slice.

Previous studies have indicated excitatory adrenergic effects on midbrain dopamine systems. To investigate the cellular mechanisms, intracellular recordings were made from neurons in perfused, oxygenated slices of male rat midbrain. Electrophysiological and pharmacological parameters were used to identify cells as principal (presumably dopaminergic) neurons as opposed to secondary (presumably GABAergic) neurons in the substantia nigra zona compacta and the ventral tegmental area. Noradrenalin (10-100 microM) hyperpolarized 57% of all principal cells and depolarized 36%. Sulpiride (100-1000 nM), a dopamine D2 receptor antagonist, completely blocked noradrenalin-induced hyperpolarizations (six of six cells). In sulpiride, noradrenalin depolarized 58% of all principal neurons and had no effect in 42%; this effect was mimicked by the alpha-adrenergic agonist phenylephrine (10-30 microM) which depolarized 43 of 72 cells. The alpha 1 receptor antagonist prazosin (30-100 nM) completely blocked the membrane depolarization produced by either noradrenalin or phenylephrine in all cells tested, whereas alpha 2- and beta-adrenergic agents had no effect. In voltage clamp, phenylephrine evoked an inward current (at -60 mV) and reduced cord conductance by 0.81 +/- 0.14 nS (n = 4). Inward current evoked by phenylephrine became outward at -96 +/- 8 mV, which is near the membrane reversal potential for potassium as predicted by the Nernst equation. Phenylephrine also depolarized secondary cells and increased the frequency of spontaneous GABAA receptor-mediated postsynaptic potentials recorded in both principal and secondary cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Determinants of cisplatin sensitivity in normal versus spontaneously transformed rat ovarian surface epithelial cells.

The chemosensitivity of spontaneously transformed rat ovarian surface epithelial (ROSE) cell lines was compared to that of the parental cells from which they were derived. Cisplatin cytotoxicity was determined in three nontransformed (early passage) and three transformed (late passage) ROSE cell lines. Transformed cells were uniformly more sensitive to cisplatin than parental cells (1.5- to 2.6-fold) and grew more rapidly (doubling time range 15-22 hr) than parental cells (28-37 hr). Increased doubling time correlated with decreased cisplatin sensitivity (rho = 0.771). Cisplatin accumulation did not correlate with cisplatin sensitivity. Glutathione (GSH) levels were higher in two of three early passage cell lines, but the correlation between GSH and decreased cisplatin sensitivity in the overall panel of cell lines was modest (rho = 0.549). No statistically significant differences in DNA-platinum binding were observed between early and late passage cell lines. However, initial levels of DNA-bound platinum correlated with cisplatin sensitivity (rho = 0.812) in the six-cell-line panel. GSH levels were inversely correlated with cisplatin accumulation (rho = -0.829) and DNA platination (rho = -0.786). Increased cisplatin sensitivity in spontaneously transformed ROSE cell lines showed a weak, inverse relationship with GSH levels, but more strongly correlated with their increased growth kinetics and to DNA platination.

Animals↗
PubMed1995

Client counseling in orthopedic emergencies.

Important client communication issues associated with most orthopedic emergencies are addressed. Information on client communication and support, providing a prognosis, discussing economic concerns, discharge planning, euthanasia, and client grief is presented. The issue of animal abuse as a cause of orthopedic emergencies also is examined.

Animal Welfare↗
PubMed1995

Presynaptic inhibition of gamma-aminobutyric acidB-mediated synaptic current by adenosine recorded in vitro in midbrain dopamine neurons.

Adenosine receptor antagonists such as caffeine cause dopamine-dependent behavioral arousal and hyperlocomotion in rodents. In the present study, we used the whole-cell recording technique in the rat brain slice to investigate effects of adenosine on dopamine neurons and their synaptic inputs in the substantia nigra zona compacta and ventral tegmental area. Adenosine was most potent for inhibiting the amplitude of the inhibitory postsynaptic current (IPSC) mediated by gamma-aminobutyric acid (GABA)B receptors (EC50 = 47 +/- 3 microM) compared with inhibition of the GABAA-mediated IPSC (117 +/- 51 microM) and the excitatory amino acid-mediated excitatory postsynaptic current (119 +/- 36 microM). Adenosine failed to inhibit current evoked by exogenous GABA or baclofen, suggesting that adenosine acted presynaptically to reduce GABA release from nerve terminals. Adenosine inhibited the GABAB-mediated IPSC by acting at the adenosine A1 receptor, because its effect was blocked by the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (100 nM), as well as by the methylxanthines caffeine (1 mM) and theophylline (300 microM). The rank-order of potency of adenosine agonists [N6-cyclohexyladenosine > R-(-)-N6-(2-phenylisopropyl)-adenosine = N6- cyclohexyladenosine > 5'-N-ethylcarboxamidoadenosine > 2-chloroadenosine] also was consistent with activation of the adenosine A1 receptor, whereas the selective adenosine A2A agonist CGS 21680 [2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamido adenosine] had no effect on the GABAB IPSC. None of the adenosine agonists or antagonists affected holding current or membrane conductance.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1994

Relationship between platinum-DNA adduct formation and removal and cisplatin cytotoxicity in cisplatin-sensitive and -resistant human ovarian cancer cells.

We examined several aspects of platinum-DNA adduct formation and repair in cisplatin-sensitive and -resistant human ovarian cancer cell lines. The formation of cisplatin-interstrand crosslinks (ICLs) was measured in five DNA sequences by renaturing agarose gel electrophoresis. There were considerable differences (up to 4-fold) in ICL levels in these DNA sequences following a 4-h incubation with cisplatin; however, the pattern of ICL formation did not depend on whether the region was transcriptionally active or gene encoding. Incubation of purified DNA with cisplatin yielded an ICL pattern with considerably less variability between the regions examined. Cisplatin ICL and total DNA platination levels were significantly higher (up to 20- and 40-fold, respectively) in cisplatin-resistant cell lines as compared to the parental, cisplatin-sensitive cell line at equivalent levels of cisplatin cytotoxicity. Under cisplatin exposure conditions which yielded similar initial levels of sequence-specific ICLs, the cisplatin-resistant cells removed up to 2.5 times more ICLs by 12-h posttreatment than the parental cell line. Increased removal of the individual platinum-deoxyribonucleosides of platinum-DNA adducts was also observed in the highly resistant C200 cell line as determined by high performance liquid chromatography separation and quantitation by atomic absorption spectrometry. These results indicate that DNA repair contributes significantly to cisplatin resistance and that increased DNA-damage tolerance may also be a component of the resistance phenotype in this model system.

Cisplatin↗
PubMed1994

Actions of 5-hydroxytryptamine on ventral tegmental area neurons of the rat in vitro.

Intracellular recordings were made with conventional microelectrodes and with whole-cell patch-clamp electrodes from neurons of the rat ventral tegmental area and substantia nigra zona compacta in vitro. Neurons were distinguished as principal cells and secondary cells; it is known from previous work that most principal cells contain dopamine whereas secondary cells do not. 5-Hydroxytryptamine (5-HT; 3-100 microM) depolarized (or evoked an inward current at -60 mV) 46% of 153 principal cells; a small proportion (11%) of cells were hyperpolarized (or showed outward current at -60 mV). Secondary cells were equally likely to be depolarized (or inward current at -60 mV, 30% of 80 cells) or hyperpolarized (or outward current at -60 mV, 28%). approximately 40% of each type of cell were unaffected by 5-HT. Depolarizing responses of 5-HT were mimicked by (+/-)-1-(2,5-dimethoxy-4-iodophenyl)- 2-aminopropane (DOI) and blocked by ketanserin. Hyperpolarizing responses were mimicked by dipropyl-5-carboxamidotryptamine and reversed polarity at the K+ equilibrium potential. Inhibitory postsynaptic potentials (or currents) mediated at GABAA receptors occurred spontaneously in some principal cells; they were reversibly blocked by tetrodotoxin and bicuculline. 5-HT either increased or decreased the frequency of these synaptic potentials but did not change their mean amplitude or decay time.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamines↗
PubMed1994

Role of platinum-DNA adduct formation and removal in cisplatin resistance in human ovarian cancer cell lines.

A series of cisplatin-resistant cell lines were used to examine the formation and removal of platinum-DNA adducts from the overall genome and the formation and removal of cisplatin-interstrand cross-links from specific genomic regions. Cisplatin accumulation and DNA platination levels, which correlated linearly, were similar in three of the resistant cell lines despite differences in their primary cisplatin resistance. Increased platinum removal from total genomic DNA was found to be associated with increased resistance. Interstrand cross-link levels were found to be 2- to 4-fold lower in the 28S ribosomal RNA gene and a non-coding genomic region of the resistant cell lines as compared with the parental A2780 cell line. In addition, 1.2- to 2.7-fold more cross-links were formed in the non-coding region than in the ribosomal RNA gene in all of the cell lines. Interstrand cross-links were removed more rapidly from both regions of the highly cisplatin-resistant C80 and C200 cells and from the ribosomal RNA gene only in the cell lines of lower resistance. The results support a role for DNA repair and alterations in interstrand cross-link formation in cisplatin resistance and provide evidence for heterogeneous interstrand cross-link formation in the genome.

Cisplatin↗
PubMed1994

Phase I and pharmacokinetic study of ormaplatin (tetraplatin, NSC 363812) administered on a day 1 and day 8 schedule.

Ormaplatin (tetraplatin, NSC 363812) is a platinum(IV) analogue that is active against cisplatin-resistant cell lines in preclinical models. A schedule previously shown to be active and well tolerated for cisplatin was evaluated in 26 patients. Ormaplatin was administered over a dose range of 4.4-60.8 mg/m2 i.v. given over 30 min on a day 1 and day 8 schedule every 28 days. Twenty-three patients had received prior chemotherapy, and the median performance status was 1. Nausea/vomiting (> or = grade 2) occurred in 40% of patients but was well controlled with standard antiemetic therapy. One patient had grade 2 renal toxicity and 1 patient had grade 3 hepatotoxicity (grade 2 pretreatment). No toxicity limited the dose given during the first course. With repeated drug administration delayed severe neurotoxicity developed in 4 patients, manifested as a sensory polyneuropathy in 3 patients and a possible autonomic neuropathy in one. Prospective nerve conduction studies did not detect subclinical neuropathy prior to the onset of symptoms. Patients who received cumulative doses above 200 mg/m2 were at increased risk for developing neurotoxicity. Plasma elimination of ultrafilterable platinum (measured by atomic absorption spectrometry) was biphasic with a harmonic mean terminal half-life of 15.8 h. The mean total body clearance and renal clearance of ultrafilterable platinum were 173 and 29.8 ml/min/m2, respectively. Thus, renal clearance accounted for 16% of total clearance suggesting that extensive protein/tissue binding was responsible for the majority of platinum clearance. Approximately 60% of the platinum is protein bound (one-half irreversibly) at the end of the infusion. Pharmacokinetic parameters were not dose dependent. No pharmacokinetic parameters were more predictive of neurotoxicity than the cumulative ormaplatin dose. A phase II dose cannot be recommended on this schedule because severe and unpredictable neurotoxicity precludes the administration of more than three cycles at the three highest doses levels tested.

Adult↗
PubMed1994

Effect of dopamine and baclofen on N-methyl-D-aspartate-induced burst firing in rat ventral tegmental neurons.

Intracellular microelectrode recordings were made from dopamine-containing neurons of the ventral tegmental area or substantia nigra zona compacta in rat brain slices in vitro. The firing pattern of the neurons was switched from a tonic, single-spike pattern to a burst firing mode by adding N-methyl-D-aspartate (20 microM) to the superfusing solution; after adding tetrodotoxin the membrane potential underwent rhythmical oscillations of 20-40 mV at 0.5-2 Hz. Baclofen (1 microM) and dopamine (30 microM) hyperpolarized the neurons; when the potential was restored to its original level, the oscillations of potential and/or burst firing were not observed, but the tonic firing pattern was restored. These effects of baclofen and dopamine were prevented by barium (1 mM), which also prevented the membrane hyperpolarization. Oscillations of membrane current of a similar frequency were observed when the somatic membrane was voltage-clamped at -60 mV; these were also blocked by barium (1 mM). It is concluded that the oscillations in membrane potential observed with N-methyl-D-aspartate are generated predominantly at a dendritic location which is not voltage-clamped with an electrode at the soma. Baclofen and dopamine inhibit the oscillations by increasing the potassium conductance and hyperpolarizing the dendrites.

Action Potentials↗