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Biomedical subjects

R Duncan

Publications and source records attributed to R Duncan.

263 records · Page 15Linked to original sources
PubMedDate not supplied

N-(2-hydroxypropyl)methacrylamide copolymer-6-(3-aminopropyl)-ellipticine conjugates. Synthesis, in vitro, and preliminary in vivo evaluation.

Ellipticine derivatives have potential as anticancer drugs. Their clinical use has been limited, however, by poor solubility and host toxicity. As N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-anticancer conjugates are showing promise in early clinical trials, a series of novel HPMA copolymer conjugates have been prepared containing the 6-(3-aminopropyl)-ellipticine derivative (APE, NSC176328). Drug was linked to the polymer via GFLG or GG peptide side chains. To optimize biological behavior, HPMA copolymer-GFLG-APE conjugates with different drug loading (total APE: 2.3-7% w/w; free APE: <0.1% w/w) were synthesized. Conjugation of APE to HPMA copolymers considerably increased its aqueous solubility (>10-fold). HPMA copolymer-GG-APE did not liberate drug in the presence of isolated lysosomal enzymes (tritosomes), but HPMA copolymer-GFLG-APE released APE to a maximum of 60% after 5 h. The rate of drug release was influenced by drug loading; lower loading led to greater release. Whereas free APE (35 microg/mL) caused significant hemolysis (50% after 1 h), HPMA copolymer-APE conjugates were not hemolytic up to 300 microg/mL (APE-equiv). As would be expected from its cellular pharmacokinetics, HPMA copolymer-GFLG-APE was >75 times less cytotoxic than free drug (IC(50) approximately 0.4 microg/mL) against B16F10 melanoma in vitro. However, in vivo when tested in mice bearing s.c. B16F10 melanoma, HPMA copolymer-GFLG-APE (1-10 mg/kg single dose, APE-equiv) given i.p. was somewhat more active (highest T/C value of 143%) than free APE (1 mg/kg) (T/C =127%). HPMA copolymer-APE conjugates warrant further evaluation as potential anticancer agents.

Acrylamides↗
PubMedDate not supplied

Understanding the mechanism of action of poly(amidoamine)s as endosomolytic polymers: correlation of physicochemical and biological properties.

Bioresponsive poly(amidoamine)s (PAA)s are currently under development as endosomolytic polymers for intracellular delivery of proteins and genes. Here for the first time, small-angle neutron scattering (SANS) is used to systematically investigate the pH-dependent conformational change of an endosomolytic polymer, the PAA ISA 23. The radius of gyration of the ISA23 was determined as a function of pH and counterion, the aim being to correlate changes in polymer conformation with membrane activity assessed using a rat red blood cell haemolysis assay. With decreasing pH, the ISA23 radius of gyration increased to a maximum (R(g) approximately 80 A) around pH = 3, before subsequently decreasing once more. At high pH and therefore high ionic strengths, the polymer is negatively charged and adopts a rather compact structure (R(g) approximately 20 A), presumably with the dissociated carboxylic groups on the exterior of the polymer coil. At low pH, the coil again collapses (R(g) < 20 A), presumably due to the effects of the high ionic strength. It is concluded that the nature of the salt form has no direct bearing on the size of the polymer coil, but it does indirectly determine the prevailing pH and, hence, polymer conformation. Pulsed-gradient spin-echo NMR measurements were in good agreement with the SANS estimates of the radius of gyration, although ISA23 polydispersity does complicate the data interpretation/comparison. These results support the proposed mode of action of PAAs, namely a coil expansion on passing from a neutral pH (extracellular) to an acidic pH (endosomal and lysosomal) environments. The results do, however, suggest that the charge on the polymer shows a closer correlation with the haemolysis activity rather than the polymer conformation.

Animals↗
PubMedDate not supplied

Everted rat intestinal sacs: a new model for the quantitation of P-glycoprotein mediated-efflux of anticancer agents.

P-Glycoprotein (p-gp) situated in the epithelium of the gastrointestinal tract is a recognised barrier limiting oral absorption of antitumour agents. Here we describe the rat everted gut sac as a new in vitro model for quantitation of p-gp-mediated efflux of anti-cancer agents using [3H]vinblastine, [14C] doxorubicin and verapamil as reference compounds. Tissue and serosal uptake of [3H]vinblastine was linear over 90 min (0.031 +/- 0.001 and 0.003 +/- 0.001 ng/mg protein/h respectively). [14C]Doxorubicin tissue accumulation was significantly lower; 0.006 +/- 0.001 ng/mg protein/h (p < 0.05) whereas serosal transfer was significantly higher 0.017 +/- 0.001 ng/mg protein/h (p < 0.05) than [3H]vinblastine. Addition of verapamil (40 ng/mL) increased significantly both tissue accumulation of [3H] vinblastine and [14C]doxorubicin (to 0.060 +/- 0.024 and 0.034 +/- 0.012 ng/mg protein/h respectively) and serosal transfer (to 0.006 +/- 0.002 and 0.023 +/- 0.001 ng/mg protein/h) (p < 0.05 in all cases). The reproducibility of this in vitro model suggests that the rat everted gut sac is a useful screening tool for studying transport of p-gp substrates and potential p-gp modifiers.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Sequential cranial MR findings of asymptomatic and neurologically symptomatic HIV+ subjects.

PURPOSE: To compare results of a prospective MR and clinical reevaluation of HIV+ asymptomatic and neurologically symptomatic subjects who had had initially abnormal cranial studies to determine what cranial MR changes occur and how these changes correlate with serial neurologic and neuropsychologic findings. PATIENTS AND METHODS: Thirty-one asymptomatic (n = 20) and neurologically symptomatic (n = 11) subjects seropositive for the human immunodeficiency virus (HIV+) were prospectively reevaluated by cranial magnetic resonance (MR) one to two years following an initially abnormal MR of the brain. RESULTS: All 31 HIV+ subjects with initial abnormal MR had abnormal follow-up scans (showing atrophy and/or white matter lesions). Twenty-seven showed no progression of MR abnormalities (among whom were 18 with minimally abnormal scans who remained asymptomatic with improved or static neuropsychologic performance). Of the four subjects with scan changes (all with clinically suspected HIV encephalopathy), one showed MR, clinical, and neuropsychologic test improvement; the remaining three showed MR (n = 3), neurologic (n = 3), neuropsychologic (n = 1) worsening and autopsy (n = 1) confirmed the presence of HIV-1 containing multinucleated giant cells in the brain. CONCLUSIONS: This study suggests that: 1) Progression of intracranial MR abnormalities due to HIV-1 is seen only in a minority of HIV+ subjects over a 1- to 2-year time period, only in those neurologically symptomatic, and correlates with clinical deterioration. 2) Minor cerebral MR abnormalities seen in HIV+ subjects who remain neurologically asymptomatic do not change over a 1- to 2-year period. 3) Although HIV is known to infect the brain early, it may, nevertheless, not routinely do significant anatomical damage early on in the disease, as based on MR criteria.

Acquired Immunodeficiency Syndrome↗
PubMedDate not supplied

Histamine tachyphylaxis in young dog airway--compared with adult dog.

The phenomenon of histamine tachyphylaxis in vitro previously observed in the airway smooth muscle from adult dogs was investigated in airway smooth muscle from young dogs (age 72-96 days; mean: 91 days). Tachyphylaxis was demonstrated by repetitive exposure to 10(-4) M histamine (4th contractile response was 53.0 +/- 4.9% of the initial histamine contraction; n = 6, P less than 0.01). This result was similar to that previously reported (Anderson et al., 1979) in adult canine tracheal smooth muscle. Tachyphylaxis to histamine was demonstrated also by repetitive exposure to histamine (10(-4) M) in the small airway smooth muscle (2 mm diameter), (4th contractile response was 59.6 +/- 7.2% of the initial histamine contraction; n = 6, P less than 0.01). This tachyphylaxic response is not present in the small airways from adult animals. The development of histamine tachyphylaxis in both tracheal and small airway smooth muscle could be prevented or reversed by preincubation of the tissue with indomethacin (2.8 x 10(-6) M). The composite information thus implicates prostaglandins as the most probable mediators of the process. These results suggest that the variable phenomenon of histamine tachyphylaxis is dependent on the maturity of the animal and on the size of the airway.

Aging↗
PubMedDate not supplied

Diagnostic findings in the 1992 epornitic of neurotropic velogenic Newcastle disease in double-crested cormorants from the upper midwestern United States.

Neurotropic velogenic Newcastle disease (NVND) occurred in juvenile double-crested cormorants, Phalacrocorax auritus, simultaneously in nesting colonies in Minnesota, North Dakota, South Dakota, and Nebraska and in Lakes Michigan, Superior, Huron, and Ontario during the summer of 1992. Mortality as high as 80%-90% was estimated in some of the nesting colonies. Clinical signs observed in 4- to 6-wk-old cormorants included torticollis, tremors, ataxia, curled toes, and paresis or weakness of legs, wings or both, which was sometimes unilateral. No significant mortality or unusual clinical signs were seen in adult cormorants. Necropsy of 88 cormorants yielded no consistent gross observations. Microscopic lesions in the brain and spinal cord were consistently present in all cormorants from which Newcastle disease virus (NDV) was isolated. Characteristic brain lesions provided rapid identification of new suspect sites of NVND. Lesions were also present in the heart, kidney, proventriculus, spleen, and pancreas but were less consistent or nonspecific. NDV was isolated at the National Wildlife Health Center from 27 of 93 cormorants tested. Virus was most frequently isolated from intestine or brain tissue of cormorants submitted within the first 4 wk of the epornitic. Sera collected from cormorants with neurologic signs were consistently positive for NDV antibody. The NDV isolate from cormorants was characterized as NVND virus at the National Veterinary Services Laboratories, Ames, Iowa. The NVND virus was also identified as the cause of neurologic disease in a North Dakota turkey flock during the summer of 1992. Although no virus was isolated from cormorants tested after the first month of submission, brain and spinal cord lesions characteristic of NVND were observed in cormorants from affected sites for 2 mo, at which time nesting colonies dispersed and no more submissions were received. Risk to susceptible populations of both wild avian species and domestic poultry makes early recognition and confirmation of NVND in wild birds a priority.

Animals↗
PubMedDate not supplied

Necrotizing enteritis as a cause of mortality in Laysan albatross, Diomedea immutabilis, chicks on Midway Atoll, Hawaii.

A necropsy survey of Laysan albatross, Diomedea immutabilis, chicks on Midway Atoll in June 1993, 1994, and 1995 revealed 54% (21/39), 67% (49/71), and 93% (15/16), respectively, to have enteritis as the most severe pathologic finding. The lesion was limited to the ileum, ceca, and large intestine. We were unable to attribute a single infectious etiology to this lesion. Many birds with enteritis also exhibited renal lesions similar to those encountered in chickens experimentally deprived of water. We propose that enteritis is a significant cause of mortality in Laysan albatross chicks on Midway and that it may be a sequela to dehydration. It is likely that the pathology of dehydration in Laysan albatross differs from that in chickens largely because of diet.

Animals↗