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P D Brown

Publications and source records attributed to P D Brown.

At least 19 recordsLinked to original sources
PubMed1998

Differing effects of endogenous and synthetic inhibitors of metalloproteinases on intestinal tumorigenesis.

Matrix metalloproteinase (MMP) activity has been associated with tumor invasion and metastasis in many different tumor types, but recent studies also support a role for these enzymes in earlier stages of the tumor progression continuum. Specifically, the expression pattern of MMPs in benign human and mouse gastrointestinal tumors suggests that they may function in the development or growth of non-invasive tumors. To address the contribution of MMP activity to the development of intestinal adenomas, we administered the synthetic MMP inhibitor batimastat and expressed the tissue inhibitor of metalloproteinases-1 (TIMP-1) in the gastrointestinal tract of Min mice, which spontaneously develop pre-malignant small and large intestinal tumors. Batimastat administration resulted in a 48% decrease in the number of Min tumors. This reduction in tumor number is similar to that observed in mice lacking the metalloproteinase matrilysin, and demonstrates the therapeutic and chemopreventive potential of MMP inhibitors for pre-malignant intestinal tumors. In contrast, forced TIMP-1 expression in transgenic mice had no effect or, in one line, unexpectedly augmented Min tumor multiplicity by 32%. This observation supports an in vivo tumor-promoting activity of TIMP-1 that could be related to the growth stimulatory effects of TIMP that have been documented in vitro. Taken together, these 2 approaches of modulating MMP activity in Min mice support a critical function of MMPs in Min tumorigenesis, underscore the importance of an MMP/inhibitor balance in maintaining tissue homeostasis and demonstrate that endogenous MMP inhibitors can have complex effects in particular cellular contexts.

Animals↗
PubMed1998

Community-acquired pneumonia.

This seminar reviews the aetiology, clinical presentation, approach to diagnosis, and management of immunocompetent adults with community-acquired pneumonia (CAP). Pneumonia is a common clinical entity, particularly among the elderly. A thorough understanding of the epidemiology and microbiology of CAP is essential for appropriate diagnosis and management. Although the microbiology of CAP has remained relatively stable over the last decade, there is new information on the incidence of atypical pathogens, particularly in patients not admitted to hospital, and new information on the incidence of pathogens in cases of severe CAP and in CAP in the elderly. Recent studies have provided new data on risk factors for mortality in CAP, which can assist the clinician in decisions about the need for hospital admission. The emergence of antimicrobial resistance in Streptococcus pneumoniae, the organism responsible for most cases of CAP, has greatly affected the approach to therapy, especially in those patients who are treated empirically. Guidelines for the therapy of CAP have been published by the American Thoracic Society, the British Thoracic Society, and, most recently, the Infectious Diseases Society of America. These guidelines differ in their emphasis on empirical versus pathogenic-specific management.

Community-Acquired Infections↗
PubMed1998

The role of calcium in the volume regulation of rat lacrimal acinar cells.

Earlier studies have suggested a role for Ca2+ in regulatory volume decrease (RVD) in response to hypotonic stress through the activation of Ca2+-dependent ion channels (Kotera & Brown, 1993; Park et al., 1994). The involvement of Ca2+ in regulating cell volume in rat lacrimal acinar cells was therefore examined using a video-imaging technique to measure cell volume. The trivalent cation Gd3+ inhibited RVD, suggesting that Ca2+ entry is important and may be via stretch-activated cation channels. However, Fura-2 loaded cells did not show an increase in [Ca2+]i during exposure to hypotonic solutions. The absence of any changes in [Ca2+]i resulted from the buffering of cytosolic Ca2+ by Fura-2 during hypotonic shock and therefore inhibition of RVD. The intracellular Ca2+ chelator, BAPTA, also inhibited the RVD response to hypotonic shock. An increase in [Ca2+]i induced by either acetylcholine or ionomycin, was found to decrease cell volume under isotonic conditions in lacrimal acinar cells. Cell shrinkage was inhibited by tetraethylammonium ion, an inhibitor of Ca2+-activated K+ channels. On the basis of the presented data, we suggest an involvement of intracellular Ca2+ in controlling cell volume in lacrimal acinar cells.

Animals↗
PubMed1998

Regulatory volume increase in rat pancreatic beta-cells.

This study investigated regulatory volume increase (RVI) in rat pancreatic beta-cells. Volume changes in isolated beta-cells were measured by a video-imaging method. Cell shrinkage was induced by exposure to solutions made hypertonic by the addition of 100 mM mannitol. In HEPES-buffered solutions, beta-cells exhibited an RVI which was almost completely abolished by 10 microM bumetanide. These data indicate that Na+-2Cl--K+ cotransporters make a major contribution to RVI in beta-cells. In HCO3--buffered solutions, however, an RVI was observed in the presence of 10 microM bumetanide. This bumetanide-insensitive component of RVI was inhibited by 100 microM amiloride or 100 microM 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS). These data suggest that, in addition to the Na+-2Cl--K+ cotransporter, functionally coupled Na+-H+ exchangers and Cl--HCO3- exchangers may also contribute to RVI in pancreatic beta-cells.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1998

Results of single and repeat dose studies of the oral matrix metalloproteinase inhibitor marimastat in healthy male volunteers.

AIMS: To assess the tolerability and pharmacokinetic profile of single and repeat doses of the oral matrix metalloproteinase inhibitor marimastat in healthy male volunteers. METHODS: A total of 31 subjects participated in two placebo-controlled, rising-dose studies. The first study assessed the pharmacokinetics and tolerability of single doses of marimastat of 25, 50, 100, 200, 400 and 800 mg. In the second study, continuous dosing over 6.5 days with three incremental dose levels of 50, 100 and 200 mg twice daily was assessed. Full pharmacokinetic profiles were obtained on days 0 and 6, and trough concentrations were measured on all days. For each pharmacokinetic profile in the studies, summary measures including Cmax, tmax, elimination half-life and AUC were calculated. Urinary drug weights were also measured. All adverse events were documented, and haematological and biochemical variables, vital signs and ECGs were monitored throughout the study. RESULTS: Peak plasma concentrations were observed at 1.5-3 h for all subjects at all doses. Peak levels were approximately proportional to dose, as was drug exposure as calculated by AUC. Data from both studies indicate that the terminal elimination half-life is of the order of 8-10 h, and that there is no unexpected drug accumulation. Marimastat was well-tolerated, with adverse effects being mild and occurring with similar frequency to placebo. Small but reversible elevations in liver transaminases were noted with repeat dosing of marimastat, the most significant of these occurring at a dose of 200 mg twice daily. CONCLUSION: Single and repeat oral doses of marimastat in healthy male subjects appear to be well-tolerated. The drug is rapidly absorbed with high peak levels achieved. It has a terminal elimination half-life of 8-10 h which would support twice daily dosing in further clinical trials.

Administration, Oral↗
PubMed1998

Batimastat, a synthetic inhibitor of matrix metalloproteinases, potentiates the antitumor activity of cisplatin in ovarian carcinoma xenografts.

Batimastat (also known as BB-94) is a synthetic matrix metalloproteinase inhibitor that has shown antineoplastic and antiangiogenic activity in various tumor models. In this study, two human ovarian carcinoma (HOC) xenografts (HOC22 and HOC8) were used to investigate the effect of batimastat on the antineoplastic activity of cisplatin. Both xenografts produced ascites and solid lesions in the peritoneal cavity of nude mice. HOC cells were inoculated i.p. in nude mice, and treatment was started at different stages of the disease. Batimastat was administered alone or concurrently with or subsequent to cisplatin therapy. In all of the protocols, the response of HOC xenografts was confirmed by cytological analysis of ascites and histological examination of the organs in the peritoneal cavity. Treatment of nude mice bearing early-stage (3 days after tumor implantation) HOC22 or HOC8 with cisplatin or batimastat alone delayed tumor growth and increased the survival time of the mice, although all animals eventually died. In contrast, treatment with batimastat (60 mg/kg i.p. every other day, for a total of eight injections) concomitantly with cisplatin (4 mg/kg i.v., every 7 days for a total of three injections) completely prevented growth and spread of both xenografts, and all animals were alive and healthy on day 200. The potentiation of cisplatin's activity by batimastat was dose dependent and was observed in the treatment of both advanced (7 days after tumor inoculation) and late-stage (20 days after inoculation) tumor. The administration of batimastat following cisplatin therapy also led to significant improvement in the survival of mice compared to treatment with cisplatin alone. These results suggest a potentiation of the antineoplastic activity of cisplatin by batimastat and support the use of the two agents in combination in the treatment of ovarian cancer patients.

Animals↗
PubMed1997

Glucose-induced swelling in rat pancreatic beta-cells.

1. Changes in relative cell volume in response to hypotonic solutions and glucose were studied in single isolated rat pancreatic beta-cells using a video-imaging technique. beta-cell electrical activity was recorded under similar conditions using the perforated patch technique. 2. Exposure of beta-cells to hypotonic solutions (10 and 33% hypotonicity) caused an immediate increase in cell volume to relative values of 1.09 and 1.33, respectively. This was followed by a gradual regulatory volume decrease. 3. Raising the concentration of glucose from 4 to 20 mM or 12 mM (with substitution of mannitol) increased beta-cell volume by 12 and 10%, respectively. This effect of glucose persisted when CO2+ was added to inhibit insulin release. Glucose-induced volume increases were sustained for the duration of exposure to elevated hexose concentration. The addition of 16 mM 3-O-methylglucose, which is transported into the beta-cell but not metabolized, produced only a transient 5% increase in beta-cell volume. 4. Exposure of beta-cells to a 15% hypotonic solution resulted in a transient depolarization and electrical activity. Raising the glucose concentration to 20 or 12 mM caused a sustained depolarization and generation of electrical activity. However, the addition of 16 mM 3-O-methylglucose had no effect on beta-cell membrane potential. The glucose-induced increase in volume and induction of electrical activity, when measured in single beta-cells simultaneously, showed comparable kinetics. 5. The secretion of insulin from intact pancreatic islets was stimulated by exposure to hypotonic solutions (10-33% hypotonicity). A 15% hypotonic solution stimulated insulin release to a peak value comparable to that elicited by raising the glucose concentration from 4 to 20 mM. Whereas hypotonic solutions caused a transient stimulation of insulin release, the effect of glucose was sustained. 6. It is suggested that glucose increases the volume in rat pancreatic beta-cells by a mechanism dependent upon metabolism of the sugar. The extent of cell swelling evoked by raised glucose concentrations is sufficient to depolarize the cells and induce electrical and secretory activity and may involve activation of a volume-sensitive anion conductance.

Animals↗
PubMed1997

Inhibition of the inward-rectifying Cl- channel in rat choroid plexus by a decrease in extracellular pH.

1. The sensitivity of the inward-rectifying Cl- channel in choroid plexus to changes in external pH (pHo) was examined. 2. Cl- currents were recorded using whole-cell patch-clamp methods. The inward-rectifying channel was activated by 375 nM of the catalytic subunit of protein kinase A which was added to the electrode solution. 3. Reducing pHo from 7.3 to 6.5 inhibited the inward-rectifying Cl- currents, whereas an increase in current was observed when pHo was elevated to 8.5. The inhibition of the conductance exhibited a sigmoidal relationship with decreasing pH over a range of 8.5 to 5.5. A half-maximal inhibition of the current was observed at pH 7.3. 4. The inhibition of the whole-cell current by reducing pHo suggests that it is carried by channels which are distinct from other inward-rectifier Cl- channels, e.g. ClC-2, phospholemman and the channel in Xenopus oocytes.

Animals↗
PubMed1997

Matrix metalloproteinase inhibitors in the treatment of cancer.

Matrix metalloproteinases are a family of zinc-containing proteolytic enzymes that break down extracellular matrix proteins in normal physiological processes such as embryogenesis, tissue growth, and wound healing. The family includes collagenases, gelatinases, stromelysins and metalloelastase. Observational and experimental data from studies of human malignancy indicate that these proteinases are induced by the tumour in order to reconstruct adjacent normal tissue to allow neovascularisation, tumour growth and spread. Tumours have been shown to overexpress certain matrix metalloproteinases relative to normal tissue and recent studies have shown an association between high levels of expression and poor prognosis. A large series of synthetic inhibitors have been developed using the structure of a principal substrate, collagen. The inhibitors contain a chemical group that binds the zinc atom in the active site of the metalloenzyme. Inhibition is specific for the known matrix metalloproteinase family and is reversible. Studies with these inhibitors and native tissue inhibitors of matrix metalloproteinases have shown that they can prevent the growth and spread of experimental tumours. In other studies, the inhibitors have been shown to be directly anti-angiogenic. Synthetic matrix metalloproteinase inhibitors have now reached the stage of clinical testing and preliminary results indicate that the compounds may be effective in slowing tumour growth. Trials currently underway should reveal whether this approach will become a standard part of anti-neoplastic therapy in the future.

Clinical Trials as Topic↗
PubMed1997

Differentiation of Leptospira species and serovars by PCR-restriction endonuclease analysis, arbitrarily primed PCR and low-stringency PCR.

Reference strains from 30 serovars representing seven species of Leptospira and 48 recent isolates from human patients, dogs and rats, were characterised by polymerase chain reaction-restriction endonuclease analysis (PCR-REA), arbitrarily primed PCR (AP-PCR) and low stringency PCR (LS-PCR). PCR-REA analysis yielded seven groups among 29 serovars of pathogenic Leptospira; the non-pathogenic L. biflexa serovar patoc was not amplified with the primer pairs studied. AP-PCR and LS-PCR fingerprinting resulted in 25 and 21 distinct profiles, respectively, among the 30 reference strains. The results of the three PCR-based techniques were highly concordant and were in general agreement with those from previous DNA studies, confirming the high level of polymorphism among Leptospira species and serovars, and supported the concept of the serovar as the basic taxonomic unit of leptospiral classification. Results of the PCR-based typing methods for 11 randomised leptospiral strains, 36 clinical isolates from human patients and dogs and 12 survey isolates from trapped rats agreed with those from serological identification. With one exception, isolates of the same serovar gave identical profiles irrespective of the source. AP-PCR and LS-PCR are simple to perform and interpret, and appear to be useful for characterising isolates of Leptospira spp. for diagnostic and epidemiological purposes.

Animals↗
PubMed1997

Whole cell Cl- conductances in mouse choroid plexus epithelial cells do not require CFTR expression.

Whole cell patch-clamp studies were performed with tissue isolated from the cystic fibrosis (CF) transgenic Cftrm1cam mouse, to determine whether anion currents in choroid plexus epithelial cells require the expression of cystic fibrosis transmembrane conductance regulator (CFTR). Inclusion of 0.25 mM adenosine 3',5'-cyclic monophosphate (cAMP) and 375 nM protein kinase A (PKA) in the pipette solution caused a significant activation of a Cl(-)-selective, inward-rectifying conductance in cells from wild-type and CF mice. The small, outward currents observed in wild-type and CF animals, however, were not activated by cAMP-PKA. There were no significant differences in the size of currents between wild-type, heterozygote, and CF cells in the presence or absence of cAMP-PKA. A second whole cell conductance was activated when cells from wild-type mice were swollen. These volume-activated currents were Cl- selective and exhibited outward rectification. They were Ca2+ independent and ATP dependent and blocked by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid and 5-nitro-2-(3-phenylpropylamino)benzoic acid. The volume-activated channels were also activated in CF mutant cells, and there was no significant difference in the size of the volume-activated currents between wild-type, heterozygote, and CF cells. It is concluded that CFTR neither contributes to the whole cell conductance nor regulates the other anion conductances in choroid plexus epithelial cells.

Animals↗
PubMed1997

Matrix metalloproteinases.

BACKGROUND: The matrix metalloproteinases (MMPs) have a role in gastrointestinal malignancy. This role is reviewed, with particular reference to the gelatinase subgroup of enzymes. METHODS: All relevant papers derived from the Medline and Enbase databases between 1984 and early 1996 were reviewed. RESULT AND CONCLUSION: There is now strong evidence that MMPs play a major role in tumour invasion and metastasis. The development of MMP inhibitors may lead to important new treatment for the control of malignant disease.

Clinical Trials as Topic↗
PubMed1996

Properties of the cAMP-activated C1- current in choroid plexus epithelial cells isolated from the rat.

1. This study used whole-cell patch clamp and RNA in situ hybridization experiments to determine whether the cAMP-activated C1- current expressed in choroid plexus epithelial cells was carried by the cystic fibrosis transmembrane conductance regulator (CFTR) channel. 2. In patch clamp experiments, inclusion of 0.25 mM cAMP and 375 protein kinase A catalytic subunit (PKA) in the electrode solution caused activation of an inwardly rectifying current (21/23 cells). This current was C1- selective, since the current reversal potential (Erev) was -31 +/- 3 mV with equilibrium potential values for C1- (EC1) and Na+ (ENa) of -44 and 0 mV, respectively. 3. In anion substitution experiments, the relative anion permeability sequence for the inward rectifier was: I- (3.5) > HCO3-(1.5) = C1-(1.0) > Br-(0.6) > aspartate (0.2). 4. The inward rectifier was sensitive to inhibition by a range of known channel inhibitors, including: glibenclamide (100 microns), DIDS (100 and 500 microns), NPPB (100 microns) and Ba2+ (1 mM). 5. In RNA in situ hybridization experiments, using two independent rat CFTR cRNA probes, expression of CFTR could not be detected in epithelial cells from the rat choroid plexus. 6. In conclusion, the cAMP-dependent whole-cell C1- current present in choroid plexus epithelial cells from the rat has properties which are distinctly different from those of CFTR.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1996

Control of lymphatic and hematogenous metastasis of a rat mammary carcinoma by the matrix metalloproteinase inhibitor batimastat (BB-94).

We examined the effects of the synthetic matrix metalloproteinase inhibitor batimastat (BB-94) on lung colonization and spontaneous metastasis of a rat mammary carcinoma, HOSP.1P. This tumor expresses both latent and active forms of the matrix metalloproteinases MMP-2 and MMP-9, although the former, as in human breast cancer, is the most prominent. Administration of batimastat (6 x 30 mg/kg i.p.) inhibited by up to 80% both the number and median weights of HOSP.1P lung colonies following i.v. inoculation of cells. This implies an effect both on seeding efficiency and subsequent tumor development. In spontaneous metastasis assays, limited treatment with batimastat (commencing when s.c. tumors were established and continuing until 5 or 14 days after their surgical removal) significantly inhibited lung metastasis but had little effect on lymphatic metastasis. However, when treatment was initiated 2 days prior to surgery and continued until day 70, 100% of animals survived to day 120 when there was no evidence of metastatic disease. All control animals (n = 25) in two separate experiments died before day 100 with lymphatic, lung, and extrapulmonary metastases. Taken together, these data suggest that lymphatic dissemination by HOSP.1P tumor cells is less susceptible to inhibition by batimastat than vascular invasion, but that long-term treatment can effectively prevent the outgrowth of putative micrometastases in both lymph nodes and lungs, allowing sustained tumor-free survival.

Animals↗
PubMed1996

[Survival after childhood cancer in Denmark 1943-1987. A population-based study].

Survival from cancer in childhood and adolescence was studied in 8312 children aged 0-19 years notified to the Danish Cancer Registry during 1947-1987. During the first period (1943-1972), five-year survival rates from all malignant neoplasms increased from 23% (1943-1952) to 33% (1963-1972). The greatest improvement was seen during the period 1973-87 when five-year survival rates reached 64% (1983-1987). Between 1973-1977 and 1983-1987, five-year survival rates increased from 32% to 62% for leukaemia, from 40 to 70% for acute lymphoblastic leukaemia, from 35 to 54% for non-Hodgkin's lymphoma, from 50 to 66% for central nervous system neoplasms and from 25 to 49% for bone tumours. An improvement in five-year survival rates for Wilms' tumour was seen between 1960 (19%) and 1980 (81%). Up to 1972, the five-year survival rate from germ-cell neoplasms was approximately 40%; among patients diagnosed in 1973-1987, 76% survived for five years. Survival was similar for boys and girls during the early period, but was significantly higher for girls subsequently. A marked effect of age at diagnosis was seen in the early registration period where survival rates for the age group 0-9 years was substantially lower compared to the age group 10-19 years. This inequality persisted only for children less than two years of age in the later period.

Adolescent↗
PubMed1996

A volume-activated anion conductance in insulin-secreting cells.

The whole-cell patch-clamp recording technique was used to measure volume-activated currents in K+-free solutions in RINm5F and HIT-T15 insulinoma cells and in dispersed rat islet cells. Cell swelling, induced by intracellular hypertonicity or extracellular hypotonicity, caused activation of an outwardly rectifying conductance which could be subsequently inactivated by hypertonic extracellular solutions. The conductance required adenosine 5'-triphosphate (ATP) in the pipette solution but was Ca2+ independent. Na+ and Cl- substitution studies suggested that the swelling-activated current is Cl- selective with a halide permeability sequence of Br > Cl > I. The conductance was reversibly inhibited by the anion channel inhibitors 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS) and by 5-nitro-2-(3-phenylpropylamino) benzoic acid (NPPB). Further evidence for a volume-activated anion conductance was provided by studies of volume regulation in insulin-secreting cells. When RINm5F cells were exposed to a hypotonic medium, the initial cell swelling was followed by a regulatory volume decrease (RVD). This RVD response was also inhibited by DIDS and by NPPB. These data therefore provide evidence for a volume-activated anion conductance in insulin-secreting cells which could be involved in the RVD following osmotic stress. A possible role for the conductance in hypotonically induced insulin release is also discussed.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗