Malignancies in Immunoglobulin G4-related ophthalmic disease.

PURPOSE: Clinical phenotypes in Immunoglobulin G4-related disease (IgG4-RD) according to the patterns of affecting organs have different risks of malignancies. We attempt to determine the association of malignancies with IgG4-related ophthalmic disease (IgG4-ROD). DESIGN: Retrospective cohort study. METHODS: Review of medical records, orbital images and histopathology reports in a territory-wide cohort of biopsy proven IgG4-ROD patients from 2005-2019. FINDINGS: Among 122 patients who had biopsies taken from adnexal lesions including lacrimal glands (n = 108), orbital mass (n = 30), infiltrated orbital fat (n = 10), conjunctiva (n = 2) or extraocular muscles (n = 3), 13% (16/122) developed malignancies over 73 ± 48months' follow-up. There were 9 cases of ocular adnexal lymphoma (OAL) and 7 extra-orbital malignancies. Compared with the general population, the incidence of OAL was significantly higher (standardized incidence ratios, SIRs = 10.0, 95%CI = 4.5-17.6) while that of extra-orbital malignancies was similar. The SIRs was highest within the first year (SIR = 46.7, 95%CI = 18.5-87.6) when 7 OAL were concomitantly diagnosed. Patients who developed OAL or extra-orbital malignancies were older than other patients at IgG4-ROD diagnosis (64.9 ± 7.1, 68.3 ± 8.5 versus 55.2 ± 15.0 years, P < 0.05). Asymmetric lacrimal gland enlargement (78% versus 13%), lack of frontal (0% versus 12%) or infraorbital nerve enlargement (0% versus 36%) were associated with OAL (all P < 0.05). Pre-treatment serum IgG4 level or extra-orbital IgG4-RD involvement was similar among patients with or without malignancies. CONCLUSION: In this biopsy-proven IgG4-ROD cohort, 7% developed OAL which was 10 times higher than the general population. Patients with asymmetric lacrimal gland enlargement or without trigeminal nerves involvement radiologically were associated with OAL.

New antimitotic agents with activity in multi-drug-resistant cell lines and in vivo efficacy in murine tumor models.

During a screen for compounds that could inhibit cell proliferation, a series of new tubulin-binding compounds was identified with the discovery of oxadiazoline 1 (A-105972). This compound showed good cytotoxic activity against non-multi-drug-resistant and multi-drug-resistant cancer cell lines, but its utility in vivo was limited by a short half-life. Medicinal chemistry efforts led to the discovery of indolyloxazoline 22g (A-259745), which maintained all of the in vitro activity seen with oxadiazoline 1, but also demonstrated a better pharmacokinetic profile, and dose-dependent in vivo activity. Over a 28 day study, indolyloxazoline 22g increased the life span of tumor-implanted mice by up to a factor of 3 upon oral dosing. This compound, and others of its structural class, may prove to be useful in the development of new chemotherapeutic agents to treat human cancers.

Efficacy of AZT therapy in reducing p24 antigen burden in a modified SCID mouse model of HIV infection.

A modified severe combined immunodeficient (SCID) mouse model of HIV infection which utilized multiple reconstitutions with human lymphocytes and a large inoculum of HIV was investigated. This mouse model yielded splenic HIV p24 antigen concentrations detectable by standard clinical means. The concentration of p24 exceeded 600 pg/g of spleen through 4 weeks postinfection. A 1-week course of AZT therapy initiated after infection produced a dose responsive reduction in p24 antigen burden. Up to a 95% reduction in p24 antigen burden was observed following AZT therapy at 50 mg/kg/day, while AZT therapy at 5 and 0.5 mg/kg/day produced 52 and 18% reductions. In vitro and pharmacokinetic evaluations correlated potency and tissue concentrations of AZT with treatment efficacy. Active HIV replication in the SCID mice was suggested by both the recovery of viable virus from SCID spleens, and by the efficacy of a brief course of AZT therapy. This SCID mouse model of HIV infection was more quantitative than previous mouse models that utilize PCR-based techniques for detection of HIV. The high HIV burden in this SCID mouse model allowed reductions in p24 concentration to be monitored in response to AZT therapy. A dose response to AZT therapy was demonstrated, even when the first dose was administered after infection. This result suggests greater sensitivity than in previous models in which pretreatment with AZT was required to produce a protective response. This SCID mouse model may be useful for determining efficacy of experimental HIV therapeutics prior to clinical use. An effective animal model could result in a reduction in cost and more rapid development of effective HIV therapeutics.

Biologically active acetogenins from stem bark of Asimina triloba.

In continuing our research with cytotoxic and pesticidal components from the stem bark of the North American paw paw, Asimina triloba, the novel cytotoxic monotetrahydrofuran Annonaceous acetogenins, cis- and trans-annonacin-A-one, cis- and trans-gigantetrocinone and cis-isoannonacin, in addition to the known compounds, trans-isoannonacin and squamolone, have been identified. Brine shrimp lethality testing was used to direct the fractionation. The structures were elucidated by spectral analysis and/or chemical synthesis. These acetogenins have potent cytotoxicities against the human tumour cell lines of A-549 (lung carcinoma), MCF-7 (breast carcinoma) and HT-29 (colon adenocarcinoma).

Mode of action of bullatacin: a potent antitumor and pesticidal annonaceous acetogenin.

Bullatacin, a compound isolated from plants of the Annonaceae, and its analogues show in vivo potential as antitumor agents based on their efficacy in normal mice bearing L1210 murine leukemia and athymic mice bearing A2780 conventional ovarian cancer xenografts. These compounds also have interesting potential as insecticides and inhibit respiration in insect-derived Sf9 cells with high potency. Their toxicity in both cases probably arises from their strong inhibition of mitochondrial electron transport with a specific action at complex I.

Analytical method development for the simultaneous quantitation of dexmedetomidine and three potential metabolites in plasma.

Dexmedetomidine, a novel alpha 2-adrenergic receptor agonist, is being developed as an anesthetic adjunct for perioperative use. An assay method has been developed for the sensitive quantitation of dexmedetomidine and three metabolites in plasma: MPV-1305, MPV-1306 and MPV-1709. The method involves solid-phase extraction (C18 cartridge) of dexmedetomidine and metabolites followed by a two-step derivatization. The first step utilized BF3-MeOH to simultaneously mask a primary alcohol in MPV-1305 and a carboxylic acid in MPV-1306. The second step applied PFB-Cl to derivatize the imidazole ring for sensitive detection of these compounds by GC-negative chemical ionization MS at pg/ml concentrations. MPV-1709 was not derivatized in the process and was detected by GC-positive chemical ionization MS. Optimization of extraction and derivatization is discussed. The method is suitable for quantitation of dexmedetomidine, MPV-1305, MPV-1306 and MPV-1709 over concentration ranges of 0.1, 40, 0.5-100, 0.5-100 and 1.0-500 ng/ml, respectively. The method showed excellent specificity, linearity and sensitivity and is useful for profiling the pharmacokinetic disposition of these compounds.

Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo.

(2.4)-Dimethoxybenzylidene anabaseine dihydrochloride (GTS-21), a compound that interacts with rat neuronal nicotinic acetylcholine receptors (nAChRs), was evaluated using human recombinant nAChRs in vitro and various pharmacokinetic and behavioral models in rodents, dogs and monkeys. GTS-21 bound to human alpha 4 beta 2 nAChR (K1-20 nM) 100-fold more potently than to human alpha 7 nAChR, and was 18- and 2-fold less potent than (-)-nicotine at human alpha 4 beta 2 and alpha 7 nAChR, respectively. Functionally. GTS-21 stimulated [5H]dopamine release from rat striatal slices with an EC50 of 10 +/- 2 microM (250-fold less potent and 70% as efficacious as (-)-nicotine), an effect blocked by the nAChR antagonist dihydro-beta-erythroidine. However, GTS-21 did not stimulate human alpha 4 beta 2 nor human ganglionic nAChRs significantly. In vivo, GTS-21 had no adverse effect on dog blood pressure (< or = 2.5 micromol/kg i.v. bolus infusion), in marked contrast with (-)-nicotine, GTS-21 (-62 micromol/kg.s.e.) also did not cross-discriminate significantly with (-)-nicotine in rats and did not reduce temperature or locomotion in mice. Neither was it active in the elevated plus maze anxiety model (0.19-6.2 micromol/kg.IP) in normal mice. However, GTS-21 did improve learning performance of monkeys in the delayed matching-to-sample task (32-130 nmol/kg.i.m.).

Enhanced accuracy of needle placement in horizontal stereotactic core biopsy by a plastic slot.

Horizontal stereotactic core biopsy can be used in the investigation of clinically occult mammographic abnormalities especially when breast thickness is less than 3 cm. We designed a 6-mm plastic slot that can be inserted between the bushing and the biopsy gun to enhance the accuracy of needle placement within the lesion. With this device, the centre of the lesion can be targeted at the centre of the biopsy trough. We advocate the use of this piece of small, simple and inexpensive instrument in every case of horizontal stereotactic core biopsy.

Ethanol with small doses of morphine establishes a conditioned place preference.

Conditioned place preference (CPP) testing is a way of indexing the reinforcing efficacy of drugs among rats. CPP testing involves using an alley with two distinctive sides. Typically, rats have drug experiences on one side and placebo experiences on the other. At testing, without drugs, their preference for side is tabulated. Rats' (6 groups of 12 each) place preferences were assessed before and after they were placed, once a day for 9 days, in the putative side of conditioning, and on 3 interspersed days, in the other side. During putative conditioning, one group received saline prior to being placed in both sides (a control group). Two groups had either morphine (2.0 mg/kg) or ethanol (0.5 g/kg) with the putative side of conditioning and saline with the other side. Three groups received morphine plus ethanol before being placed in the putative side of conditioning and either saline, morphine, or ethanol in the other side. At testing, rats that received morphine plus ethanol on side of putative conditioning showed a strong CPP whereas others did not. Results are compatible with the idea that ethanol's reinforcing effect is enhanced when there is a surfeit of opioidergic activity.

Annonaceous acetogenins: a review.

The Annonaceous acetogenins are a series of apparently polyketide-derived fatty acid derivatives that possess tetrahydrofuran rings and a methylated gamma-lactone (sometimes rearranged to a methyl ketolactone) with various hydroxyl, acetoxyl, and/or ketoxyl groups along the hydrocarbon chain. They exhibit a broad range of potent biological activities (cytotoxicity, antitumor, antimalarial, antimicrobial, immunosuppressant, antifeedant, and pesticidal). The sources, isolation, chemistry, biogenesis, and biological actions of these compounds, published to date, are tabulated and discussed. Strategies for structural elucidation are reviewed, and structural revisions and refinements are suggested for some of the previously published compounds.

Development of a sensitive method for quantitation of ABT-089 in plasma using fluorescence labeling with 7-fluoro-4-nitrobenzo-2-oxa-1,3-diazole.

A high-performance liquid chromatography method for the quantitation of ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine] (I), a new structural type of cholinergic channel modulators (ChCM), is described in this paper using 7-fluoro-4-nitrobenzo-2-oxa-1,3-diazole (NBD-F) as a fluorescent-labeling reagent. The method combined an optimized liquid-liquid extraction from plasma followed by pre-column derivatization to yield a fluorescence product. The selectivity, sensitivity, and reproducibility of this method were found to be excellent. This method was applied to the determination of ng/ml plasma and tissue levels of ABT-089 and similar compounds in biological samples.

Bullatencin, 4-deoxyasimicin, and the uvariamicins: additional bioactive Annonaceous acetogenins from Annona bullata Rich. (Annonaceae).

Additional bioactive Annonaceous acetogenins have been isolated from the EtOH extract of the bark of Annona bullata Rich. by bioactivity-directed fractionation using lethality to brine shrimp. These acetogenins include bullatencin, a new single tetrahydrofuran acetogenin having a double bond in the hydrocarbon chain; 4-deoxyasimicin, a new adjacent bis-tetrahydrofuran acetogenin; and the uvariamicins, an isomeric mixture of four single tetrahydrofuran acetogenins showed selective cytotoxicities for certain human solid tumor cell lines comparable to or better than adriamycin.

10-, 12-, and 29-hydroxybullatacinones: new cytotoxic Annonaceous acetogenins from Annona bullata Rich (Annonaceae).

In our continuing activity-directed search for new antitumor compounds, using brine shrimp lethality (BST), mixtures of three additional pairs (1-6) of bis-THF ketolactone acetogenins were isolated from the ethanol extract of the bark of Annona bullata Rich. (Annonaceae). Compared with (2,4-cis and trans)-bullatacinone (7 and 8), these new compounds each have one more aliphatic OH group at a different position on the hydrocarbon chain, and, thus, were named (2,4-cis and trans)-10-hydroxybullatacinone (1 and 2), (2,4-cis and trans)-12-hydroxybullatacinone (3 and 4), and (2,4-cis and trans)-29-hydroxybullatacinone (5 and 6). These mixtures all showed potent activities in the brine shrimp lethality test (BST) and exhibited cytotoxicities comparable to those of adriamycin against human solid tumor cells in culture with selectivities exhibited especially toward the breast cancer cell line (MCF-7).

16 alpha-hydroxy-(-)-kauranoic acid: a selectively cytotoxic diterpene from Annona bullata.

Using brine shrimp lethality to direct fractionation, extracts of the bark of Annona bullata Rich. (Annonaceae) have yielded 16 alpha-hydroxy-(-)-kauranoic acid as a bioactive plant constituent. This previously known diterpene showed significant (ED50 8.25 x 10(-2) micrograms/ml) and selective cytotoxicity against A-549 (lung) cells in our panel of human tumor cells.