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Biomedical subjects

J F O'Sullivan

Publications and source records attributed to J F O'Sullivan.

At least 19 recordsLinked to original sources
PubMed2001

Tetramethylpiperidine-substituted phenazines inhibit the proliferation of intrinsically multidrug resistant carcinoma cell lines.

The effects of nine new tetramethylpiperidine (TMP)-substituted phenazines on the growth of a human esophageal cancer cell line (WHCO3), two human hepatocellular carcinoma cell lines (PLC and HepG2) and three human colon cancer cell lines (CaCo2, COLO 320DM and HT29) were compared to those of clofazimine, B669 and five standard chemotherapeutic agents. The three most active TMP-substituted phenazines against these cell lines were B3962, B4126 and B4125 with mean IC50 values for all the cancer cell lines tested of 0.36, 0.47 and 0.48 microg/ml respectively. B3962 and B4126, but not B4125 were also the most active against a semi-continuous human fibroblast culture (MRC5). The compound with the highest tumor specificity relative to the fibroblast culture, was B4125. Importantly, there was minimal variation in sensitivity of the different cell lines, including a multidrug resistant cell line (COLO 320DM) expressing high levels of P-glycoprotein, to the TMP-substituted phenazines. This was not the case with the standard chemotherapeutic agents. The efficacy of compounds such as B4125 against a broad spectrum of multidrug resistant cancer cell lines, together with their relatively high tumor specificity, suggests that these agents may be useful in the treatment of intrinsically resistant cancers such as colon and liver cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

The history of obstetrics in Northern Ireland 1921-1992.

In 1921 there was little provision for the care of the pregnant woman in Northern Ireland where there were only two hospitals staffed by specialist obstetricians. The mortality statistics reflected this, the province having the highest maternal mortality and the second highest infant mortality rates in the United Kingdom. There was little progress until the establishment of the National Health Service in 1948. Within a short time, excellent hospital specialist and domiciliary midwifery services were developed. Scientific advances, mainly during the 1970's, led to further expansion of the specialist service and the disappearance of the general practitioner service. These advances have again been reflected in the statistics. The maternal mortality is now zero and the perinatal mortality 8 per 1,000 births.

Female↗
PubMed2000

Tetramethylpiperidine-substitution increases the antitumor activity of the riminophenazines for an acquired multidrug-resistant cell line.

The multidrug resistance (MDR)-neutralizing and cytotoxic properties of five tetramethylpiperidine (TMP)-substituted phenazines were compared with those of their corresponding isopropyl-substituted analogues using a P-glycoprotein (P-gp)-expressing small cell lung cancer cell line (H69/LX4). All of the TMP-substituted phenazines tested outperformed their isopropyl analogues with respect to both cytotoxic and chemosensitizing properties, indicating the importance of TMP-substitution when designing novel riminophenazines with increased activity against MDR cancer cell lines. Of the TMP-substituted phenazines tested, B4112, chlorinated at position 3 of the phenyl- and anilino-rings, had the most potent anti-cancer activity in vitro, making this agent a potential candidate for evaluation in experimental and clinical oncology.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1999

Antimycobacterial activities of riminophenazines.

Riminophenazines were specifically developed as drugs active against Mycobacterium tuberculosis but extensive research over several decades has shown that these compounds are also active against many other mycobacterial infections, particularly those caused by Mycobacterium leprae and the Mycobacterium avium complex (MAC). Clofazimine, the lead compound in this series, is included in the regimens that are approved by the WHO for the treatment of leprosy and has contributed significantly to the control of that disease, particularly that caused by dapsone-resistant bacteria. Despite early problems, clofazimine has shown clinical efficacy in tuberculosis, in particular that caused by multiple drug resistant strains. Clofazimine does not induce resistance and also inhibits emergence of resistance to isoniazid in M. tuberculosis. The efficacy of clofazimine against MAC is more varied and the availability of better drugs has limited its use. Newer riminophenazines, such as B746 and B4157, not only showed increased anti-mycobacterial activity but also produced less skin pigmentation, which is the main drawback of this group of compounds. The most important virtues of riminophenazines, such as intracellular accumulation in mononuclear phagocytic cells, anti-inflammatory activity, a low incidence of drug resistance and slow metabolic elimination, make them attractive candidates for the treatment of mycobacterial infections. It is essential, however, to investigate the newer analogues clinically, while continuing the pursuit of alternate candidates that demonstrate higher anti-mycobacterial activity and lower rates of skin pigmentation.

Animals↗
PubMed1998

Midwifery in the Belfast City Hospital.

The process of improving midwifery services for poor women in Belfast was a slow one. Traditional midwives were gradually supplanted by midwives who were trained and controlled by the medical profession, but it was many years before the problems of puerperal infection were brought under control in the new institutions.

Education, Nursing↗
PubMed1997

Novel tetramethylpiperidine-substituted phenazines are potent inhibitors of P-glycoprotein activity in a multidrug resistant cancer cell line.

The multidrug resistance (MDR)-neutralizing and cytotoxic properties of 16 novel tetramethylpiperidine (TMP)-substituted phenazines were compared with those of clofazimine and B669 using a P-glycoprotein (P-gp)-expressing undifferentiated, human leukemia cell line (K562/MMB). Unchlorinated TMP-substituted phenazine molecules were more cytotoxic than their chlorinated counterparts, while the halogenated molecules, especially those with chlorine atoms at position 3 on the aniline and phenyl rings, were less cytotoxic but more effective as chemosensitizing, P-gp-neutralizing agents. One of the TMP-substituted phenazines, B4121, increased the sensitivity of K562/MMB cells to vinblastine by 100-fold. TMP-substituted phenazines are a novel class of pharmacologic anti-cancer agents with both direct cytotoxic, as well as MDR-neutralizing anti-tumor properties.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Determination of serum and tissue levels of phenazines including clofazimine.

A rapid and sensitive HPLC method is described for the analysis of synthetic phenazines, including clofazimine, from a variety of biological samples. Phenazines were extracted from serum, tissue and fat using a mixture of dichloromethane and sodium hydroxide. The drugs were then quantified on a reversed-phase C18 column using a mobile phase consisting of 594 ml of water, 400 ml of tetrahydrofuran, 6 ml of concentrated acetic acid and 0.471 g of hexanesulfonic acid. In this mobile phase, each phenazine tested had its own retention time. This allowed one phenazine to be used as an internal standard for the analysis of other phenazines. The method was validated for clofazimine [3-(4-chloroanilino)-10-(4-chlorophenyl)-2,10-dihydro-2-(isopro pylimino) phenazine] and B4090 [7-chloro-3-(4-chloranilino)-10-(4-chlorophenyl)-2, 10-dihydro-2-(2,2,6,6-tetramethylpiperid-4-ylimino)phenazine ] (VI) and shown to be accurate and precise across a broad concentration range from 0.01 to 50 micrograms/g (microgram/ml). Extraction was 100% for each agent across this range. This system was used to measure clofazimine and VI levels following their administration to rats. The pharmacokinetic profile of VI was different to that of clofazimine, with high tissue concentrations but lower fat levels.

Adipose Tissue↗
PubMed1996

Antituberculosis activities of clofazimine and its new analogs B4154 and B4157.

In our efforts to develop new drugs for the treatment of tuberculosis, especially that caused by multidrug-resistant strains, we investigated clofazimine (CFM) and two of its analogs, B4154 and B4157, for their antituberculosis activities. Twenty M. tuberculosis strains were tested, including 16 drug-resistant strains (strains resistant to one or more antituberculosis drugs), for their susceptibilities to these three agents. All of the strains were found to be susceptible to B4154 and B4157, and one strain showed moderate resistance to CFM. The MICs of B4154, B4157, and CFM at which 90% of strains were inhibited were 0.25, 0.12, and < or = 1.0 microgram/ml, respectively. The intracellular activities of CFM and B4157 were superior to that of B4154. The chemotherapeutic activities of the three compounds were evaluated in C57BL/6 mice. At a dose of 20 mg/kg of body weight, the activity of CFM was slightly superior to that of B4157; however, both compounds prevented mortality and caused a significant reduction in the numbers of CFU in the lungs and spleens. The animals treated with B4157 showed less pigmentation than animals treated with CFM. The chemotherapeutic activity of CFM was comparable to those of rifampin and isoniazid. Complete susceptibility of multidrug-resistant strains to CFM and B4157 and the therapeutic efficacies of these compounds against mouse tuberculosis make these drugs attractive agents for the treatment of drug-resistant tuberculosis.

Animals↗
PubMed1995

Autocrine mitogen IgEGF cooperates with c-myc or with the Hcs locus during hepatocarcinogenesis in transgenic mice.

Hepatocarcinogenesis is deterministic in transgenic mice expressing in the liver gene construct Alb-DS4 that encodes autocrine growth factor IgEGF (D Stern et al. (1987), Science 235: 321-324), causing their death within 7.1 months. Hepatic expression of construct AAT-myc encoding murine c-myc causes liver cancer in 44% of the mice at 14.8 months. Cooperation of these genes was evident in CD2F1 transgenics bearing Alb-DS4 plus AAT-myc, in which accelerated hepatocellular carcinoma (HCC) formation caused death of all mice within 4.4 months. Alb-DS4 also cooperates with the Hcs locus, which in C3H/HeJ mice mediates high susceptibility to spontaneous hepatocarcinogenesis, causing accelerated formation of HCC to which mice succumbed at 5.1 months. Thus, genes that predispose to HCC formation cooperate in transgenic mice and their interaction is a key to understand mechanisms that cause liver cancer.

Animals↗
PubMed1995

Chemotherapeutic activity of clofazimine and its analogues against Mycobacterium tuberculosis. In vitro, intracellular, and in vivo studies.

Clofazimine (CFM), a riminophenazine drug, is primarily used in therapy for leprosy and Mycobacterium avium infections. With an objective of identifying drugs active against Mycobacterium tuberculosis, including those with multi-drug resistance, we investigated CFM and nine of its chemical analogues. Among these, B746 and B4101 had better activity than CFM against six drug-susceptible and nine single/multiple drug-resistant M. tuberculosis strains. B746 also showed slightly better activity than CFM against intracellular M. tuberculosis in J774A.1 macrophages and was comparable to CFM in its in vivo activity against experimental tuberculosis in C57BL/6 mice. Interestingly, it caused less pigmentation in internal organs.

Animals↗
PubMed1994

The riminophenazine agents clofazimine and B669 reverse acquired multidrug resistance in a human lung cancer cell line.

The potential of the riminophenazine agents clofazimine and B669, at therapeutically relevant concentrations, to reverse P-glycoprotein-mediated multidrug-resistance (MDR) in a human lung cancer cell line (H69/LX4) has been investigated in vitro. Cyclosporin A, a well-documented MDR-modifying agent, was included for comparison. Clofazimine, B669 and cyclosporin A at minimally cytotoxic concentrations of 1, 0.5 and 5 micrograms/ml, respectively, were equally effective in restoring sensitivity to vinblastine, doxorubicin, daunorubicin and mitomycin C in the H69/LX4 cell line. All three chemosensitizing agents also increased the accumulation of [14C]vinblastine by H69/LX4 cells. Riminophenazines, which are relatively non-toxic, non-carcinogenic and non-myelosuppressive agents, are promising contenders for evaluation in experimental and clinical oncology as modulators of acquired MDR.

Anti-Infective Agents↗
PubMed1993

Effects of clofazimine analogues and tumor necrosis factor-alpha individually and in combination on human polymorphonuclear leukocyte functions in vitro.

In the present study the individual and interactive effects of clofazimine, or three analogues of this agent (selected on the basis of similar or superior pro-oxidative properties: B669, B746 and B4021) and human recombinant TNF-alpha on the generation of antimicrobial oxidants by human polymorphonuclear leukocytes (PMNL), as well as release of granule enzymes from these cells, were investigated in vitro. All four riminophenazines at the concentrations tested (0.5 and 1.0 micrograms/ml) significantly increased myeloperoxidase (MPO)-mediated iodination, superoxide (0(2).-) generation, oxygen (0(2)) consumption and chemiluminescence (CL), as well as the release of both primary and secondary granule contents (measured as the release of MPO, lysozyme and vitamin B12-binding protein) by stimulated PMNL. Similar, but less impressive effects were observed with TNF-alpha (0.4-50.0 ng/ml). When PMNL were preincubated with both TNF-alpha and clofazimine or its analogues, the observed stimulation of cellular oxidative metabolism and granule enzyme release was at least additive in many assays. These data demonstrate that the spectrum of effects of clofazimine and its analogues on PMNL closely resemble those of TNF-alpha. Furthermore, TNF-alpha potentiates the pro-oxidative effects of clofazimine and its analogues on PMNL. Among the riminophenazines tested, clofazimine and B669 appear to be the most potent pro-oxidative agents for PMNL.

Adult↗
PubMed1993

Autoimmune oophoritis. An incidental finding.

A case of autoimmune oophoritis is reported. A 41-year-old woman had a total abdominal hysterectomy and bilateral salpingo-oophorectomy for menorrhagia, polymenorrhoea and cystic ovaries. The diagnosis of autoimmune oophoritis was not suspected clinically, and was an unexpected histological finding in the ovaries. The gross and histological appearances of this rare condition are described, and the lymphoid infiltrate characterised by immunocytochemistry. Recognition of this condition by pathologists is important, as there is an associated risk of developing other autoimmune disease, even some years later, necessitating close patient follow-up. In this case serum auto-antibodies to adrenal cortex were detected, indicating a subsequent risk of Addison's disease.

Adult↗
PubMed1993

Activity of phenazine analogs against Mycobacterium leprae infections in mice.

Twenty-five compounds structurally related to clofazimine were tested for their ability to inhibit the growth of Mycobacterium leprae using the kinetic method of drug evaluation in the mouse foot pad model of leprosy. Seven of the phenazine derivatives displayed anti-M. leprae activity comparable to that of clofazimine when administered at a concentration of 0.01% (w/w) in the diet. Three of the compounds, B746, B4087, and B4101, were active when administered at 0.001% in the diet. At a dietary concentration of 0.0001%, B4087 and B4101 were slightly more active than clofazimine, while B746 was less active. In the kinetic method of drug evaluation, greater anti-M. leprae activity of phenazine derivatives was generally associated with greater pigmentation of abdominal fat. Of the compounds which did not cause pigmentation when fed at a concentration of 0.01% in the diet B4090 was the most active. This compound also inhibits the growth of a clofazimine-resistant M. smegmatis strain.

Abdomen↗