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Biomedical subjects

W R Anderson

Publications and source records attributed to W R Anderson.

At least 19 recordsLinked to original sources
PubMed2002

Intravesical pH: a potentially important variable affecting efficacy and the further development of anthracycline chemotherapy for superficial bladder cancer.

OBJECTIVE: To assess, using epirubicin-sensitive and multidrug resistant (MDR) derivatives of human bladder cancer cell lines in vitro, the probable effect of intravesical pH changes, with and without the MDR antagonist verapamil, on the uptake, intracellular distribution and cytotoxicity of epirubicin during intravesical chemotherapy. MATERIALS AND METHODS: Incubations for cytotoxicity testing were carried out in buffered medium containing epirubicin, at pH values of 6.0-8.5, with verapamil where appropriate. The cytotoxicity of epirubicin, with and without verapamil, was determined using the tetrazolium cytotoxicity assay. Intracellular epirubicin fluorescence was assessed using flow cytometry and confocal microscopy. Flow cytometric total intracellular epirubicin fluorescence was measured at pH 6.0, 6.4, 6.8, 7.2, and 7.6, and confocal microscopy was carried out at pH 6.0 and 8.0. The MDR-reversing agent verapamil was added at 100 micro g/mL to some incubations. RESULTS: Epirubicin cytotoxicity in resistant cell lines appears considerably enhanced by adding verapamil and further improved, especially in MDR cells, by alkalinization of the drug solution to pH 8.0. Flow cytometry results showed striking and consistent differences in epirubicin handling with pH. Sensitive cells can be induced to absorb considerably more drug at alkaline pH, whilst resistant cells show no such behaviour. Nuclear drug fluorescence was greater in sensitive cells at alkaline pH, but cytoplasmic drug fluorescence in the resistant cells was little changed by pH. Adding verapamil to resistant cells restored the sensitive phenotype of drug handling. CONCLUSION: Buffering epirubicin to an alkaline pH before intravesical application should increase its intrinsic cytotoxicity. The potential for synergy at certain drug combinations will be enhanced by applying these findings. MDR reversal and fatty acid augmentation of drug uptake are discussed as examples.

Administration, Intravesical↗
PubMed2001

Atypical hyperplasia, proliferative fibrocystic change, and exogenous hormone use.

BACKGROUND: The association between breast cancer development and exogenous hormone use (EHU) is suggested by indirect clinical evidence. We undertook this study to better define the relationship that EHU has with proliferative fibrocystic change (PFC) and atypical hyperplasia (AH). METHODS: Women diagnosed with AH without associated carcinoma from January 1990 to December 1999 were compared with control subjects who underwent breast biopsy procedures during the same interval and who were diagnosed with either a proliferative fibrocystic change (PFC) or a nonproliferative fibrocystic change (NPFC). EHU was defined as the use of estrogen or progesterone taken together or separately within 3 months of biopsy. RESULTS: EHU was significantly higher in patients with AH compared with women with NPFC (P =.01). This observation was also significant if all proliferative change (both AH and PFC) was compared with NPFC (P =.03); it was not significant when PFC alone was compared with NPFC. No significant difference in EHU was demonstrated between women with AH and those with PFC. CONCLUSIONS: There is strong association between AH and EHU. These results support the theory that a continuum exists between hyperplasia and carcinoma and that EHU may influence the transition from one to the other in an undefined subset of women. We encourage our patients with AH to discontinue EHU.

Adult↗
PubMed2000

Sleep disturbance and nonmalignant chronic pain: a comprehensive review of the literature.

Sleep disturbance is an important clinical complaint for individuals with nonmalignant pain conditions. This review is a broad introduction to the literature on sleep disturbance and chronic pain conditions. The article critically reviews studies of sleep disturbance in musculoskeletal pain, arthritis, headache, and fibromyalgia. Current neurobiological hypotheses regarding the pathogenesis of sleep disturbance and chronic pain, common comorbid disorders, and pharmacologic and non-pharmacologic treatments for sleep disturbance are reviewed.

Journal Article↗
PubMed1997

Phagocytosis of nonopsonized Cryptococcus neoformans by swine microglia involves CD14 receptors.

The interaction of the opportunistic fungus Cryptococcus neoformans with swine microglia was studied in vitro in the presence and absence of anti-CD14 monoclonal antibodies. In the absence of anti-CD14 antibodies, 36% of microglia had phagocytized nonopsonized, encapsulated cryptococci after 2 hr incubation (effector-to-target ratio, 1:50). Preincubation of microglia with anti-CD14 antibodies resulted in a 63% reduction of phagocytosis. These findings suggest that CD14 receptors facilitate uptake of nonopsonized C, neoformans by resident macrophages within the brain.

Animals↗
PubMed1997

Effect of sustained estradiol release in the intact male rat: correlation of estradiol serum levels with actions on body weight, serum testosterone, and peripheral androgen-dependent tissues.

The differential effect of increasing serum estradiol on various parameters in the intact male rat was assessed through the use of subcutaneously implanted, hormone-laden pellets. The delivery systems were designed to release drug through bioerosion at a zero-order rate over a 12-day time-course. Male Sprague-Dawley rats (190 to 220 g) were given estrogen pellets at increasing labeled strenghts (0, 0.001, 0.01, 0.1, 1.0, 10, 50, and 100 mg). Animals were weighed at various intervals before and after implantation. At Day 6, 12, and 26 after drug administration, rats were examined for 4 additional parameters, including serum estradiol and testoterone concentrations and accessory organ weights (i.e., ventral prostate and seminal vesicles). Serum estradiol levels were consistent with pellet potency and lifetime. Increases in body weight were suppressed 50% by circulating estradiol levels of approximately 200 pg/mL at Day 6,250 pg/mL at Day 12, and 285 pg/mL at Day 26. On the other hand, suppression of serum testosterone was more sensitive and was decreased 50% by peripheral estrogen levels of 36, 43, and 51 pg/mL at Days 6, 12, and 26, respectively. Accessory organ weights essentially reflected serum testosterone levels as indicated by their similar ED50 values: 50.5, 50.5, and 44.3 pg/mL for the ventral prostate at Day 6, 12, and 26, respectively, and 48, 56, and 51.5 pg/mL for the seminal vesicle regression at Day 6, 12, and 26, respectively. The data indicate the pellet used provided sustained plasma levels of hormone and these constant peripheral levels exerted potent pharmacological action. Initial body weight changes seemed to be less sensitive to the action of estradiol than serum testosterone or derivative properties, such as accessory organ weight.

Animals↗
PubMed1997

Alpha 2 mRNA of Na+K+ ATPase is increased in astroctyes of rat hippocampus after treatment with kainic acid.

The Na+K+ ATPase (Na+ pump) plays a central role in regulating cation homeostasis and is thought to have an important role in cell proliferation. The multitude of subunit isoforms comprising the functional Na+K+ ATPase has raised the possibility that specific subunit isoform combinations may be involved in different cellular processes. We have investigated the involvement of the specific isoforms in neurons and glia at the site of a CNS lesion. Intracerebroventricular injection of kainic acid was used to induce neuronal cell loss and reactive gliosis in rat hippocampus and levels of Na+K+ ATPase subunit isoform mRNA levels were determined in cells of rat hippocampus using in situ hybridization. alpha 2 mRNA levels increased 35-40% in CA1 and CA3 astrocytes between 1-3 weeks after KA injection with no significant change in other subunit isoform mRNA levels. In addition alpha 3 mRNA levels in CA1 pyramidal neurons were decreased by approx. 35%. Small neurons in the CA1 and CA3 region showed no changes in mRNA levels for any of the Na+K+ ATPase subunit isoforms. These results may indicate a possible role for alpha 2 subunit isoform in the conversion of glial cells from a normal phenotype to the reactive phenotype characteristic in this model of CNS injury.

Animals↗
PubMed1997

Macrognathia of renal osteodystrophy in dialysis patients.

A multiinstitutional study of macrognathia secondary to renal osteodystrophy in dialysis patients is presented. The nine cases reviewed reveal a variety of radiographic and histopathologic features, some of which resemble fibrous dysplasia and others suggestive of Paget's disease of bone. This article contains diagnostic criteria for differentiating renal osteodystrophy from similar fibro-osseous proliferations along with a discussion of the underlying cause and appropriate therapeutic interventions.

Adult↗
PubMed1997

Intravenous and oral pharmacokinetic evaluation of a 2-hydroxypropyl-beta-cyclodextrin-based formulation of carbamazepine in the dog: comparison with commercially available tablets and suspensions.

Complexation of carbamazepine with 2-hydroxypropyl-beta-cyclodextrin was performed to provide improved formulations of this widely used antiepileptic drug. Based on this approach, liquid dosage forms were configured for both parenteral and oral use. Intravenous administration of an aqueous carbamazepine x 2-hydroxypropyl-beta-cyclodextrin (CBZ x HPbetaCD) complex at a CBZ dose of 20 mg/kg was well tolerated and generated high initial drug levels that fell monoexponentially as a function of time, yielding a plasma elimination half-life of 38 min. Oral studies were completed with three preparations: a commercially available tablet and suspension, as well as a CBZ x HPbetaCD oral solution. Oral administration of tablets gave erratic and slow absorption, leading to maximum CBZ concentrations (C(max)) of <2 microg/mL, which were manifested only at 2.5 h after drug dosing. The absolute bioavailability of CBZ from the tablets was approximately 25%. Both the suspension and CBZ x HPbetaCD solution gave a significantly improved profile. Thus, the liquid oral dosage forms approximately doubled the oral bioavailability of CBZ compared with the tablets.

2-Hydroxypropyl-beta-cyclodextrin↗
PubMed1997

Evaluation of a brain-targeting zidovudine chemical delivery system in dogs.

AIDS encephalopathy is an insidious complication of human immunodeficiency virus infection which is difficult to treat because of the poor uptake of many potentially useful antiretroviral drugs through the blood-brain barrier. A chemical delivery system (CDS) for zidovudine (AZT) based on redox trapping within the brain has been prepared and tested in several animal models to circumvent this limitation. The behavior of the AZT-CDS in the dog was considered. Parenteral administration of AZT resulted in rapid systemic elimination and poor uptake by the central nervous system. Ratios of the area under the concentration-time curve of AZT for cerebrospinal fluid to that for blood were 0.32, and ratios of the area under the concentration-time curve of AZT for brain to that for blood were approximately 0.25. Administration of an aqueous formulation of the AZT-CDS resulted in rapid tissue uptake and conversion of the CDS to the corresponding quaternary salt with the subsequent production of AZT. Delivered in this way, the levels of AZT in brain were 1.75- to 3.3-fold higher than those associated with conventional AZT administration. In addition, the levels of AZT in blood were 46% lower than those associated with AZT administration. The higher concentrations in brain and lower concentration in blood combined to significantly increase the ratio of the concentration of AZT in the brain to that in blood after AZT-CDS administration compared to that after AZT dosing.

Animals↗
PubMed1996

Striatal dopamine, dopamine transporter, and vesicular monoamine transporter in chronic cocaine users.

Depletion of striatal dopamine (DA) has been hypothesized to explain some of the neurological and psychiatric complications of chronic use of cocaine, including increased risk for neuroleptic-precipitated movement disorders. We measured levels of DA, as well as two DA nerve terminal indices, namely, the DA transporter (DAT) and the vesicular monoamine transporter (VMAT2) in autopsied brain of 12 chronic cocaine users. Mean DA levels were normal in the putamen, the motor component of the striatum; however 4 of the 12 subjects had DA values below the lower limit of the control range. DA concentrations were significantly reduced in the caudate head (head, -33%; tail, -39%) with a trend for reduction in nucleus accumbens (-27%). Striatal DAT protein (-25 to -46%) and VMAT2 (-17 to -22%) were reduced, whereas DAT determined by [3H]WIN 35,428 binding was normal. In conclusion, our data suggest that chronic cocaine use is associated with modestly reduced levels of striatal DA and the DA transporter in some subjects and that these changes might contribute to the neurological and psychiatric effects of the drug.

Adult↗
PubMed1995

Efficacy of a 3-substituted versus 17-substituted chemical delivery system for estradiol brain targeting.

Brain-targeted delivery of estrogens has been achieved by a chemical delivery system (CDS) in which a molecular targetor (1-methyl-1,4-dihydronicotinate) was attached to the 17-alcohol of estradiol. Optimization of this effect was attempted with the isomeric 3-phenol ester. Estradiol 3-nicotinate was prepared with nicotinic anhydride, which selectively acylated the phenol position. Methylation and reduction gave estradiol 3-(1-methyl-1,4-dihydronicotinate) of the 3-E2-CDS. Theoretical and electrochemical investigation indicated that the 3-E2-CDS was more stable to oxidation than was the prototype 17-ester (17-E2-CDS). Systemic administration of the 17-E2-CDS produced high levels of the corresponding quaternary salt in the brain of rats, which disappeared with an estimated half-life of > 2 days, but 3-E2-CDS dosing resulted in no significant quaternary salt trapping. Pharmacological activity was potent and sustained after 17-E2-CDS dosing but transient after 3-E2-CDS administration. Thus, the 3-E2-CDS reduced the rate of weight gain in male rats but to a lesser extent and for a shorter duration than did the 17-E2-CDS. Similar effects were seen on pituitary hypertrophy, reduction in serum androgen concentrations, and involution of prostate and seminal vesicles. The results of these studies suggest that placement of the targeting ester at the phenol position increases dihydropyridine stability but, at the same time, reduces brain sequestration.

Animals↗
PubMed1995

Tissue distribution of LY231617, an antioxidant with neuroprotectant activity, in the rat.

The tissue distribution of a butylated phenol antioxidant, LY231617, which has been shown to exert potent neuroprotection action was examined. Preliminary pharmacokinetic examination suggests that LY231617 was eliminated in a biphasic fashion after iv administration to the rat with a distribution half-life of 5 min and an elimination half-life of close to 2.5 h. The volume of distribution of the compound was large (7.4 L), consistent with its lipophilic structure. Dosing paradigms that have historically resulted in pharmacologically relevant activity were examined and were found to generate brain tissue levels of LY231617 of approximately 45 micrograms/g.

Animals↗
PubMed1995

Preparation, characterization, and anesthetic properties of 2-hydroxypropyl-beta-cyclodextrin complexes of pregnanolone and pregnenolone in rat and mouse.

Prototype formulations of the progesterone derivatives pregnanolone and pregnenolone were prepared by solubilizing the steroids in 2-hydroxypropyl-beta-cyclodextrin (HP beta CD). The aqueous solubility of the steroids was increased as a function of HP beta CD concentration generating linear (AL) or curvilinear (AP) phase-solubility profiles. While the solubility of pregnanolone could not be increased with the addition of water-soluble pharmaceutical polymers, the concentration of pregnenolone in HP beta CD was increased more than 60% by the addition of small amounts (0.10%) of (hydroxypropyl)methylcellulose. Mice studies found that while pregnanolone was highly potent in an HP beta CD vehicle, pregnenolone was devoid of activity. Since pregnenolone and pregnanolone differ marginally in structure and physicochemical profile, the data suggest that these derivatives interact via a specific receptor and not via nonspecific membrane perturbations. Sex differences in the action of the pregnanolone complex was observed in that parenteral (i.v. and i.p.) drug administration was more effective in males than females. These data are in contrast to observations made in the case of alfaxalone, a related steroid anesthetic, in which the sex difference favored female animals. On the other hand, females appeared to be more sensitive to the effects of the pregnanolone complex when administered orally. Finally, parenteral pregnanolone was more toxic to males than females with LD50 (i.v.) values of 355 and 548 micromol/kg, respectively.

2-Hydroxypropyl-beta-cyclodextrin↗