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PubMed1976

Amphotericin B plus 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU-NSC no. 409962) in advanced cancer. Phase I and preliminary phase II results.

Twenty-one patients with advanced metastatic cancer received amphotericin B (AmB) plus BNUC in a Phase I chemotherapy trial. Of 11 patients with measurable metastases from bronchogenic carcinoma, five had partial antitumor responses lasting 1.5 to 12+ months, and one had objective improvement. Only two of six patients with other types of tumors had objective improvement of short duration. No consistent evidence of immunologic stimulation was observed in eight patients studied. These results suggest that amphotericin B may increase the therapeutic ratio of BCNU, and further trials of this new concept in chemotherapy of advanced tumors are in progress. The dose-limiting toxicity was myelosuppression, usually thrombocytopenia. No enhancement of BCNU toxicity by the addition of AmB was observed. The recommended dose for future studies is: AmB, 7.5 mg/m2 on day 1, 15 mg/m2 on day 1, 30 mg/m2 on days 3 and 4; plus BCNU, 250 mg/m3 on day 4. The regimen is repeated every 6 to 8 weeks.

Amphotericin B↗
PubMed2004

Kinetic precipitation of solution-phase polyoxomolybdate followed by transmission electron microscopy: a window to solution-phase nanostructure.

This study aimed to elucidate the structural nature of the polydisperse, nanoscopic components in the solution and the solid states of partially reduced polyoxomolybdate derived from the [Mo132] keplerate, [(Mo)Mo5]12-[Mo2 acetate]30. Designer tripodal hexamine-tris-crown ethers and nanoscopic molybdate coprecipitated from aqueous solution. These microcrystalline solids distributed particle radii between 2-30 nm as assayed by transmission electron microscopy (TEM). The solid materials and their particle size distributions were snap shots of the solution phase. The mother liquor of the preparation of the [Mo132] keplerate after three days revealed large species (r=20-30 nm) in the coprecipitate, whereas [Mo132] keplerate redissolved in water revealed small species (3-7 nm) in the coprecipitate. Nanoparticles of coprecipitate were more stable than solids derived solely from partially reduced molybdate. The TEM features of all material analyzed lacked facets on the nanometer length scale; however, the structures diffracted electrons and appeared to be defect-free as evidenced by Moiré patterns in the TEM images. Moiré patterns and size-invariant optical densities of the features in the micrographs suggested that the molybdate nanoparticles were vesicular.

Journal Article↗
PubMed2007

Investigation of the stability of Chiralpak AD chiral stationary phase under various solvent conditions and development of a method to identify stationary phase-derived polymer contamination.

The stability of Chiralpak AD chiral stationary phase under various solvent conditions was investigated. An analytical method for the detection of the presence of solubilized Chiralpak AD coating was developed using CD spectroscopy (CD signal at 245 nm). In addition, NMR analysis of the solubilized polymer revealed a characteristic signal for the 3,5-dimethylphenyl carbamate methyl protons at around 2.5 ppm. Both of these methods may be helpful in detecting contamination by the Chiralpak AD polymer or in the study of CSP solvent compatibility.

Journal Article↗
PubMed2002

Crossing the phase boundary to study protein dynamics and function: combination of amide hydrogen exchange in solution and ion fragmentation in the gas phase.

Protein dynamics are the key to understanding their behavior. The static protein structure alone in most cases is insufficient to describe the vast array of complex functions they perform in vivo. Until recently there were relatively few techniques available to investigate the dynamic nature of these proteins. Mass spectrometry has recently emerged as a powerful biophysical method, capable of providing both structural and dynamic information. By utilizing the labile nature of amide hydrogens as a marker of the backbone dynamics in solution, combined with gas-phase dissociation techniques, we now have a high-resolution tool to locate these exchanging hydrogens within the sequence of the protein and to probe the functional importance of its structural elements. In this paper we describe several applications of these methodologies to illustrate the importance of dynamics to the biological functions of proteins.

Amides↗
PubMed1993

Determination of benzalkonium chloride in ophthalmic solutions containing tyloxapol by solid-phase extraction and reversed-phase high-performance liquid chromatography.

A procedure using solid-phase extraction (Supelcoclean CN) followed by HPLC [Beckman Ultrasphere CN, acetonitrile:phosphate solution (60:40, v/v)] was developed and validated to quantitate the quaternary ammonium preservative benzalkonium chloride in an experimental ophthalmic formulation containing the polymeric material tyloxapol. This procedure makes routine determinations of benzalkonium chloride at concentrations of 0.0035 to 0.01% simpler than the traditional ion-pairing colorimetric methods. This method is quick, specific, and especially useful for drug product stability studies. In addition, because the method distinguishes each homologue, it can be extended to routinely determine the homologue ratio for quality control purposes.

Benzalkonium Compounds↗
PubMed2005

Behaviour of carbamate pesticides in gas chromatography and their determination with solid-phase extraction and solid-phase microextraction as preconcentration steps.

This work reports a study of the chromatographic behaviour of seven carbamate pesticides (aldicarb, carbetamide, propoxur, carbofuran, carbaryl, methiocarb, and pirimicarb) by gas chromatography-mass spectrometry (GC-MS). Variables such as injector temperature, solvent, injection mode, and the degree of ageing of the chromatographic column were studied. One of the aims of this work was to achieve a controlled decomposition of carbamates by a solid-phase microextraction (SPME) preconcentration step with a polyacrylate fibre in order to obtain reproducible chromatographic signals of the degradation products. Optimisation of the SPME process was accomplished by means of experimental design. Several methods using ultrapure water were developed with different preconcentration configurations: SPME-GC-MS, SPE followed by SPME-GC-MS, and SPE plus GC-MS. For all the pesticides studied, method detection limit (MDL) values below 0.1 microg L-1 were reached in at least one of the proposed configurations.

Carbamates↗
PubMed2002

Liver phase I and phase II enzymatic induction and genotoxic responses of beta-naphthoflavone water-exposed sea bass.

Sea bass were exposed to 0 (control), 0.1, 0.3, 0.9, and 2.7 microM beta-naphthoflavone (BNF) for 0, 2, 8, and 16 h in order to assess the chronological and concentration relationships between BNF phase I and II biotransformation responses, such as liver cytochrome P450 (P450) content, ethoxyresorufin-O-deethylase (EROD), uridine diphosphate-glucuronosyl transferase (UDP-GT), and the genotoxic effects, measured either by erythrocytic micronuclei (EMN) or erythrocytic nuclear abnormalities (ENA) tests. Liver alanine aminotransferase (ALT) activity and liver somatic index (LSI) were also measured. A significant liver EROD activity was found at 8 h exposure, respectively, to 0.1, 0.3, 0.9, and 2.7 microM BNF. Maximal liver EROD activity increase was observed at 16 h exposure to 0.9 microM BNF, whereas the highest liver P450 was reached at 8 h exposure to 2.7 microM BNF. Liver UDP-GT activity was significantly increased at 2 h exposure to 0.1 and 0.3 microM BNF and at 8 h exposure to 0.1, 0.3, and 0.9 microM BNF, decreasing at 16 h, for every exposure concentration. Significant ENA increase was observed at 2h exposure, respectively, to 0.3, 0.9, and 2.7 microM BNF. Maximal ENA increase was observed at 16 h exposure to 0.9 microM BNF. The MN was significantly increased at 8 and 16 h exposure, respectively, to 2.7 and 0.9 microM BNF. Liver ALT activity significantly increases at 8 h exposure to 0.1 and 0.3 microM BNF, whereas liver somatic index was significantly increased from 2 to 16 h exposure for every BNF concentration. A slight liver EROD activity increase with a concomitant lack of liver UDP-GT activity is able to induce significant erythrocytic genotoxic effects. Liver UDP-GT high levels are important in sea bass BNF detoxification. However, high liver UDP-GT activity is not enough to prevent the BNF metabolite genotoxic effects on sea bass erythrocytes when liver EROD activity is induced at 2 and 8 h exposure to 0.3 and 0.9 microM BNF. The genotoxic effects measured as EMN and ENA suggest that the balance between the rates of liver BNF reactive and conjugated metabolites seems to be critical.

Animals↗
PubMed2000

Enhancement of acute phase and inhibition of chronic phase of experimental autoimmune neuritis in Lewis rats by intranasal administration of recombinant mouse interleukin 17: potential immunoregulatory role.

Experimental autoimmune neuritis (EAN) is a CD4(+) T-cell-mediated demyelinating disease of the peripheral nervous system (PNS). We examined the effect of recombinant mouse interleukin 17 (rmIL-17) on chronic EAN induced in Lewis rats by inoculation of P2 57-81 peptide in Freund's complete adjuvant. Animals were treated nasally for 6 days with either 0.1 or 0.9 microg/rat/day rmIL-17 from the onset of neurological signs, i.e., days 9 to 14 postimmunization (p.i.). Prolonged follow-up demonstrated a chronic course in control and rmIL-17-treated rats. Treated rats had more severe disease initially (days 18-36 p.i.) with a stronger enhancing effect observed with the higher rmIL-17 dose. At day 19 rmIL-17-treated rats showed increased infiltration of inflammatory cells into the sciatic nerve, more severe demyelination, augmented proliferation of regional lymph node cells, and increased serum levels of tumor necrosis factor-alpha. After the initial phase of disease enhancement the IL-17-treated EAN rats improved gradually and ultimately recovered completely, whereas the control EAN rats remained affected until the end of the observation (day 120 p.i.). The lower dose of rmIL-17 induced an earlier recovery from clinical deficits than the higher one. The results indicate that IL-17 plays an immunoregulatory role in chronic EAN which could have implications for immunomodulatory treatments of chronic autoimmune disease of the PNS.

Acute Disease↗
PubMed1988

Phase I--preliminary phase II trial of iproplatin, a cisplatin analogue.

Iproplatin was administered intravenously over 30 min daily for 5 consecutive days every 3 weeks to 80 evaluable patients with a variety of refractory solid tumor malignancies. Thrombocytopenia was the dose-limiting toxicity. Reversible drug-induced renal dysfunction was observed in 3 patients. One patient sustained mild ototoxicity but neurotoxicity was not encountered. Transient neutropenia, anemia, nausea, vomiting, diarrhea, elevations of liver enzymes, alopecia, and skin rash also occurred. The spectrum and severity of toxicity of iproplatin were found to differ from those of cisplatin. The maximally tolerated dose (MTD) was 45 mg/m2/day in patients who received prior chemotherapy and 65 mg/m2/day in those who did not. No complete responses occurred. Partial responses were obtained in 2/15 patients with colon cancer, 3/18 with breast cancer, 2/4 with carcinoma of unknown primary site and 1/2 with pancreatic cancer. Thirteen patients with lung (5), breast (4), colon (2), head and neck (1) and cervical (1) cancers had stable disease. Based on the different toxicity profiles between iproplatin and cisplatin and the possible antitumor efficacy of the former, phase II investigation of iproplatin has been initiated.

Adult↗
PubMed1991

Influence of affinity of antibodies upon their detection by liquid phase radiobinding assay and solid phase enzyme linked immunosorbent assay. Demonstration using monoclonal antibodies raised against rDNA human proinsulin.

Hybridomas producing proinsulin antibodies were cloned by limiting dilution of cell cultures obtained by fusion of splenocytes of immunized mice with immortal myeloma cells. Some proinsulin monoclonal antibodies crossreacted with labelled insulin but none did with labelled C-peptide indicating that the involved epitopes were at one of the insulin/C-peptide junctions or included in the insulin moiety. Hybridoma supernatants were assayed for IgG concentration by a solid phase assay and for ligand binding by a radiobinding assay and an enzyme linked immunosorbent assay. The half-life of immune complexes formed with radioligand was measured and, as expected, correlated with affinity as measured by the method of Scatchard. Antibody titres determined by enzyme linked immunosorbent assay did not correlate to those measured by radiobinding assay. IgG concentration correlated to enzyme linked immunosorbent assay titres but not to radiobinding assay titres. Finally, a significant correlation was found between radiobinding assay titre and the product of enzyme linked immunosorbent assay titre by the period of immune complexes. It is concluded that, except for very low affinity antibodies, enzyme linked immunosorbent assay is a capacity assay whereas radiobinding assay is influenced by both antibody concentration and affinity. The former assay is thus best suited to detecting low affinity antibodies whereas the latter is more efficient in the presence of low levels of high affinity antibodies.

Animals↗
PubMed2001

Solid-phase reactors in sequential injection analysis. Determination of manganese (II) in tap water and effluent streams using a solid-phase lead(IV) dioxide reactor in a sequential injection system.

The determination of manganese(II) in tap water and effluent streams, using a solid-phase reactor incorporated into a sequential injection system was investigated. Mn2+-ions in samples injected into a carrier stream, were oxidised by solid lead(IV) dioxide suspended on silica gel beads to form MnO4- -ions which were detected spectrophotometrically at 526 nm. The linear range of the system is from 1 to 7 mg L(-1) with a detection limit of 0.62 mg L(-1). The proposed system is suitable for the determination of manganese(II) in tap and effluent streams at a rate of approximately 50 samples per hour with a relative standard deviation of better than 3%. Statistical comparison between the proposed sequential injection system and a standard ICP method revealed that there is no significant difference between the two methods at the 95% confidence level for effluent streams and at 99.9% for tap water.

Journal Article↗
PubMed1990

Suppression and contrasuppression in athymic nude mice: nude mice produce the antigen-specific component of a T suppressor factor that inhibits the late 24-hr phase of DTH but do not generate suppression nor contrasuppression of the early initiating phase of DTH.

Previous studies demonstrated that the initiation of murine delayed-type hypersensitivity (DTH), as exemplified by contact sensitivity induced by picryl chloride (PCI) or oxazolone (OX), is due to antigen-specific, T cell-derived, DTH-initiating factors called, respectively, PCl-F and OX-F. These factors participate in the extravascular recruitment of CD4+, Th-1, DTH effector T cells in the elicitation of DTH. Related factors also participate, together with nonantigen binding factors derived from CD8+ T cells, to constitute an antigen-specific T cell-derived suppressor factor (TsF) that can down regulate the ability of Th-1 effector T cells to mediate DTH. Since it was shown recently that athymic nude mice can make antigen-specific, DTH-initiating T cell factors, the current study tested whether nude mice also could produce the antigen-specific component of the TsF that suppresses DTH effector T cells. We found that antigen-specific factors from nu/nu mice could complement the nonantigen-binding subfactor produced in normal mice to constitute the whole antigen-specific TsF. Additional studies showed that the successful adoptive cell transfer of DTH-initiating T cell activity from nude mice into normal mice required cyclophosphamide treatment of the recipient. In contrast, transfer of DTH-initiating cell activity from nu/+ mice did not require cyclophosphamide treatment of the recipients. We hypothesized that nude mice lacked contrasuppressor cells. Although nude mice were able to manifest the early, initiating phase of DTH, we found that there was no suppression of early DTH-initiating T cells in nude mice, compared to nu/+. Therefore the production of DTH-initiating T cell factor could be boosted in nude mice. The ability to boost DTH-initiating cells in nude mice should facilitate the development of cell lines and clones with the ability to initiate DTH.

Animals↗
PubMed1981

Metabolic study of 7-methylbenzo[a]pyrene with rat liver microsomes: separation by reversed-phase and normal-phase high performance liquid chromatography and characterization of metabolites.

The 7-methylbenzo[a]pyrene (7-MBaP) was incubated with liver microsomes of rats pretreated with polychlorinated biphenyls (Aroclor 1254) (PCBs). Metabolites of 7-MBaP were isolated by both reversed-phase and normal-phage high performance liquid chromatography (HPLC) and were characterized by nuclear magnetic resonance, UV-visible and mass spectral analyses. The predominant metabolite of 7-MBaP was found to be 3-hydroxy-7-methylbenzo[a]pyrene (3-hydroxy-7-MBaP). Other identified metabolites include 7-MBaP 4,5-, 7,8-, and 9,10-trans-dihydrodiols, 7-hydroxymethyl-BaP, 7-hydroxymethyl-BaP trans-9,10-dihydrodiol, 9-hydroxy-7-MBaP, 3-hydroxy-7-hydroxymethyl-BaP, 7-MBaP 1,6- and 3,6- quinones, and a hydroquinone which is also formed by further metabolism of the 3-hydroxy-7-MBaP. Comparative metabolic studies of 7-MBaP and BaP indicated that, relative to that of BaP, the methyl substituent of 7-MBaP slightly increases the formation of 3-hydroxy-7-MBaP and decreases the metabolism at other regions of the 7-MBaP molecule. The finding that a 7,8-dihydrodiol is a metabolite indicates that, like BaP, 7-MBaP may also be activated to the potentially reactive 7,8-dihydrodiol 9,10-epoxides although their formations are significantly reduced.

Animals↗
PubMed1990

Controlling the retention of clopenthixol and other basic drug substances by reversed-phase ion-pair chromatography on bonded-phase materials using two counter-ions of opposite charge.

In the reversed-phase chromatography of nitrogen-containing bases on chemically bonded ODS-silica, peak tailing and prolonged retention are often considerable problems. These effects are due to residual silanols on the surface of the column material and may be remedied by adding suitable amines or quaternary ammonium ions to the eluent as anti-tailing agents. However, further addition of an anionic compound is often needed to achieve a suitable retention. The retention mechanism in such systems is complex as interaction takes place between the anionic compound and the solute molecules, anti-tailing agent and column packing material. The influence of the nature of the anti-tailing agent and anionic counter-ion on the retention of cis- and trans-clopenthixol and of other basic drug substances was investigated and it was found that both the retention and the selectivity were greatly affected.

Alkanesulfonates↗
PubMed1994

Reversed-phase high-performance liquid chromatography of the stereoisomers of some sweetener peptides with a helical nickel(II) chelate in the mobile phase.

The use of a chiral mobile phase additive in the form of the helically distorted, square-planar, chiral nickel(II) chelate dl-[4,4'-(1-methyl-2-propylethane-1,2-diyldiimino)bis(pent-3 -en-2- onato)]nickel(II) was investigated for the resolution of optical isomers of dipeptide-type sweeteners, viz., aspartame, alitame and antiaspartame, and some of their decomposition products, e.g., diketopiperazines. The chiral discrimination mechanism for the solutes was elucidated. The proposed chiral RP-HPLC system was applied to the stereoselective determination of aspartame impurities in samples of its commercial dietetic and pharmaceutical formulations.

Aspartame↗
PubMed1983

ELISA solid phase: partial denaturation of coating antibody yields a more efficient solid phase.

We have examined conditions which will improve the solid phase in ELISAs for HBsAg and ferritin in human serum. Sheep and rabbit antibodies were used. It was found that pre-exposure of antibody to low pH, 3 M urea and temperatures as high as 82 degrees C will enhance ELISA colour in these assays. Further experiments indicate that these conditions perturb the structure of the antibody molecules and results in the exposure of new hydrophobic regions. It is speculated that these more hydrophobic molecules can bind to regions on the plastic surface normally not coated by non-perturbed molecules.

Alkylation↗
PubMed1996

Development and standardization of solid phase assays for the detection of anti-neutrophil cytoplasmic antibodies (ANCA). A report on the second phase of an international cooperative study on the standardization of ANCA assays.

Anti-neutrophil cytoplasmic antibodies (ANCA) are diagnostic markers for systemic vasculitis. They are classically detected by an indirect immunofluorescence test using normal donor neutrophils as substrate. This assay lacks antigenic specificity and is not quantitative. The 'EC/BCR Project for ANCA Assay Standardization' is an international collaboration study with the aim to develop and standardize solid phase assays for ANCA detection. In this part of the study the isolation and characterization of proteinase-3 and myeloperoxidase, the two main target molecules for ANCA, and the development and standardization of ELISAs with these antigens are described. Six laboratories successfully isolated purified proteinase-3 preparations that could be used. Three of these preparations, together with one myeloperoxidase preparation, were subsequently used for ANCA testing by ELISA. The ELISA technique was standardized in two rounds of testing in the 14 participating laboratories. The coefficient of variation of these new assays decreased from values of approx. 50% in the first round to approx. 20% in the second round. We conclude that purified proteinase-3 and myeloperoxidase can be used in standardized ELISAs for ANCA detection. Whether such procedures offer advantages over the IIF test will be determined in a prospective clinical study.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1989

Early treatment with intravenous metoprolol for suspected acute myocardial infarction: a phase IV United States trial. Phase IV Metoprolol in Myocardial Infarction Study Group.

Recent randomized clinical trials have shown that total mortality and cardiovascular mortality are reduced by the early intravenous administration of beta-blockers to patients suspected of suffering from acute myocardial infarction. These trials were conducted on patients meeting strict entry criteria. In order to assess this therapy when applied to a broader range of myocardial infarction patients, we performed a Phase IV study of metoprolol in acute myocardial infarction. The study was designed to test whether early (less than 8 hours from onset of chest pain) intervention by practicing physicians with open label intravenous metoprolol for cases of suspected acute myocardial infarction achieved mortality results similar to those obtained in large randomized clinical trials. We studied 3824 patients treated by 741 physicians representing a broad spectrum of clinical practice in the United States. Seventy-two percent of the patients entered into the study had confirmed myocardial infarction (39% anterior, 39% inferior, 22% other locations) and 85% of all individuals treated tolerated the full intravenous dose of 15 mg of metoprolol. The 15 day total mortality and cardiovascular mortality rates were 4.9% and 4.5%; 90 day mortality rates were 6.9 and 5.9%. Patients with anterior infarctions had a significantly greater cumulative mortality rate than patients with other types of infarctions. Marked bradycardia (heart rate less than 45 beats per minute) in the first 8 hours post treatment occurred in 4.7% cases and hypotension (systolic blood pressure less than 90 mm Hg) occurred in 9.8% of cases. When compared with the results of the Göteborg and MIAMI trials of metoprolol, it appears that there is no appreciable increase in mortality or morbidity when metoprolol is used in the community practice of acute coronary care.

Adult↗