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Mervyn Mer,1 Jacques Rene Snyman,2 Constance Elizabeth Jansen van Rensburg,2 Jacob John van Tonder,3 Ilze Laurens2 1Department of Medicine, Divisions of Critical Care and Pulmonology, University of the Witwatersrand, Johannesburg, South Africa; 2Office of the Dean, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa; 3Scientific Affairs Department, Triclinium Clinical Development (Pty) Ltd, Centurion, South Africa Introduction: Clinicians’ skepticism, fueled by evidence of inferiority of some multisource generic antimicrobial products, results in the underutilization of more cost-effective generics, especially in critically ill patients. The aim of this observational study was to demonstrate equivalence between the generic or comparator brand of meropenem (Mercide®) and the leading innovator brand (Meronem®) by means of an ex vivo technique whereby antimicrobial activity is used to estimate plasma concentration of the active moiety. Methods: Patients from different high care and intensive care units were recruited for observation when prescribed either of the meropenem brands under investigation. Blood samples were collected over 6 hours after a 30 minute infusion of the different brands. Meropenem concentration curves were established against United States Pharmacopeia standard meropenem (Sigma-Aldrich) by using standard laboratory techniques for culture of Klebsiella pneumoniae. Patients’ plasma samples were tested ex vivo, using a disc diffusion assay, to confirm antimicrobial activity and estimate plasma concentrations of the two brands. Results: Both brands of meropenem demonstrated similar curves in donor plasma when concentrations in vials were confirmed. Patient-specific serum concentrations were determined from zones of inhibition against a standard laboratory Klebsiella strain ex vivo, confirming at least similar in vivo concentrations as the concentration curves (90% confidence interval) overlapped; however, the upper limit of the area under the curve for the ratio comparator/innovator exceeded the 1.25-point estimate, i.e., 4% higher for comparator meropenem. Conclusion: This observational, in-practice study demonstrates similar ex vivo activity and in vivo plasma concentration time curves for the products under observation. Assay sensitivity is also confirmed. Current registration status of generic small molecules is in place. The products are therefore clinically interchangeable based on registration status as well as bioassay results, demonstrating sufficient overlap for clinical comfort. The slightly higher observed comparator meropenem concentration (4%) is still clinically acceptable due to the large therapeutic index and should ally fears of inferiority. Keywords: bioequivalence, antimicrobial, multisource products, Meropenem, ­pharmacokinetics, pharmacodynamics

Justin J Gandy, Jacques R Snyman, Constance EJ van RensburgDepartment of Pharmacology, Faculty of Health Sciences, University of Pretoria, Pretoria, South AfricaBackground: The purpose of this study was to evaluate the efficacy and safety of carbohydrate-derived fulvic acid (CHD-FA) in the treatment of eczema in patients two years and older.Methods: In this single-center, double-blind, placebo-controlled, parallel-group comparative study, 36 volunteers with predetermined eczema were randomly assigned to receive either the study drug or placebo twice daily for four weeks.Results: All safety parameters remained within normal limits, with no significant differences in either group. Significant differences were observed for both severity and erythema in the placebo and CHD-FA treated groups, and a significant difference was observed for scaling in the placebo-treated group. With regard to the investigator assessment of global response to treatment, a significant improvement was observed in the CHD-FA group when compared with the placebo group. A statistically significant decrease in visual analog scale score was observed in both groups, when comparing the baseline with the final results.Conclusion: CHD-FA was well tolerated, with no difference in reported side effects other than a short-lived burning sensation on application. CHD-FA significantly improved some aspects of eczema. Investigator assessment of global response to treatment with CHD-FA was significantly better than that with emollient therapy alone. The results of this small exploratory study suggest that CHD-FA warrants further investigation in the treatment of eczema.Keywords: fulvic acid, eczema, anti-inflammatory, efficacy, safety

Introduction: Clinicians' skepticism, fueled by evidence of inferiority of some multisource generic antimicrobial products, results in the underutilization of more cost-effective generics, especially in critically ill patients. The aim of this observational study was to demonstrate equivalence between the generic or comparator brand of meropenem (Mercide ® ) and the leading innovator brand (Meronem ® ) by means of an ex vivo technique whereby antimicrobial activity is used to estimate plasma concentration of the active moiety., Methods: Patients from different high care and intensive care units were recruited for observation when prescribed either of the meropenem brands under investigation. Blood samples were collected over 6 hours after a 30 minute infusion of the different brands. Meropenem concentration curves were established against United States Pharmacopeia standard meropenem (Sigma-Aldrich) by using standard laboratory techniques for culture of Klebsiella pneumoniae. Patients' plasma samples were tested ex vivo, using a disc diffusion assay, to confirm antimicrobial activity and estimate plasma concentrations of the two brands., Results: Both brands of meropenem demonstrated similar curves in donor plasma when concentrations in vials were confirmed. Patient-specific serum concentrations were determined from zones of inhibition against a standard laboratory Klebsiella strain ex vivo, confirming at least similar in vivo concentrations as the concentration curves (90% confidence interval) overlapped; however, the upper limit of the area under the curve for the ratio comparator/innovator exceeded the 1.25-point estimate, i.e., 4% higher for comparator meropenem., Conclusion: This observational, in-practice study demonstrates similar ex vivo activity and in vivo plasma concentration time curves for the products under observation. Assay sensitivity is also confirmed. Current registration status of generic small molecules is in place. The products are therefore clinically interchangeable based on registration status as well as bioassay results, demonstrating sufficient overlap for clinical comfort. The slightly higher observed comparator meropenem concentration (4%) is still clinically acceptable due to the large therapeutic index and should ally fears of inferiority., Competing Interests: The authors report no conflicts of interest in this work.

Aloe vera gel is widely used in the treatment of an array of disturbances, especially skin disorders. The wound-healing effects have been attributed to its moisturizing and anti-inflammatory effects as well as its beneficial effect on the maturation of collagen. The aim of the present study is to compare the effects of topically applied extracts of Aloe ferox with that of Aloe vera on the symptoms as well as IgE levels of a mouse model of atopic dermatitis (AD). Mice were sensitized and challenged with 2,4-dinitrochlorobenzene and treated afterwards for 10 consecutive days with the gels of either A. ferox or A. vera applied topically to the affected areas. A placebo gel was used for the control mice. Blood was collected at the beginning and end of the treatment period to measure serum IgE levels. Although the gels of both the Aloe species inhibited the cutaneous inflammatory response as well as serum IgE levels in the rats, the extracts of A. ferox were superior to that of A. vera in reducing IgE levels. The gels of A. ferox and A. vera, applied topically, may be a safe and useful alternative to antihistamines and topical corticosteroids, for the treatment of patients suffering from recurring chronic AD.

Humic substances are effective in the suppression of delayed type hypersensitivity, rat paw oedema, a graft-versus-host reaction and contact hypersensitivity in rats. They reduce the C-reactive protein levels of patients suffering from osteoarthritis of the knee and the wheel and flare reaction of patients suffering from hay fever. They have also been described as cardioprotective and pro-angiogenic. Toxicity studies have indicated that potassium humate is safe in humans up to a daily dosage of 1 g/kg, whereas fulvic acid is safe in humans up to a daily dosage of 1.8 g per adult. The antiinflammatory action of potassium humate can be contributed to the inhibition of the release of inflammatory-related cytokines, an adhesion molecule, oxidants and components of the complement system., (Copyright © 2015 John Wiley & Sons, Ltd.)

Background: Ferrocene-containing β-diketones and cisplatin, [(NH(3))(2)PtCl(2)], possess strong antineoplastic activity. No information is available regarding the anticancer activity of the corresponding ruthenocene complexes. This study examined the cytotoxicity of stable ruthenocene-containing β-diketones. The results were related to the cytotoxicity of cisplatin and the ease of ruthenium electrochemical oxidation., Materials and Methods: The ruthenocene-containing β-diketones RcCOCH(2)COR where Rc=Ru(II)(C(5)H(5))(C(5)H(4)) and R=CF(3) (1), CH(3) (2), Ph=C(6)H(5) (3) and Fc=Fe(II)(C(5)H(5))(C(5)H(4)) (4) were tested for cytotoxicity against HeLa (human cervix epithelioid) cancer, COR L23 (human large cell lung carcinoma) and the platinum-resistant CoLo 320DM (human colorectal) and COR L23/CPR cancer cell lines. Cell survival was measured by means of the colourimetric 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT) assay., Results: The 50% cell growth inhibition (IC(50)) values of 1-4 towards the cells ranged between 8.2 and 84.6 μmol dm(-3), with 1 being the most cytotoxic complex. Drug activity was directly proportional to the electron density on the ruthenium centre as well as the oxidation potential of the ruthenium core but inversely proportional to the pK(a) of the β-diketones. The strongest activity was observed against the COR L23 cell line, and the weakest activity against COR L23 CPR., Conclusion: A drug activity-structural relationship exists for ruthenocene-containing β-diketones in that drugs with the lowest electron density on the ruthenium centre are more cytotoxic. Compounds with larger ruthenium oxidation potentials and stronger acid strength (i.e. smaller pK(a) values) are more cytotoxic.

Background: The water-soluble ionic gold(I) complex [Au(PPh(2)CH(2)CH(2)PPh(2))(2)]Cl possesses at least ten times stronger antineoplastic activity than the water-soluble neutral silver(I) carboxylates [AgO(2)C(CH(2)OCH(2))(n)H], 1, (n=1), 2 (n=2), or 3 (n=3) even though Au(I) and Ag(I) are isoelectronic d(10) metals lying one above the other in the periodic table of the elements. In this study we determined the cytotoxicity of the stable water-soluble gold(I) carboxylates [(Ph(3)P)AuO(2)C(CH(2)OCH(2))(n)H], 4 (n=1), 5 (n=2) and 6 (n=3) to compare the intrinsic antineoplastic activity of gold(I) and silver(I) under conditions where different complex charges do not influence the result., Materials and Methods: The cytotoxicity of carboxylato gold complexes 4-6 towards the HeLa (human cervix epithelioid) cancer cell line ATCC CCL-2, resting lymphocytes and phytohaemagglutinin(PHA)-stimulated lymphocytes were determined. Cell survival was measured by means of the colorimetric 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT) assay., Results: The IC(50) values of 4-6 from six experiments causing 50% cell growth inhibition were essentially constant; values ranged between 0.50 and 0.82 μmol dm(-3). Drug activity was thus independent of the carboxylato ligand chain length. Metal complexes 4-6 were at least one order of magnitude more cytotoxic towards the HeLa cancer cell line than the silver carboxylates 1-3 and were almost as cytotoxic as [Au(PPh(2)CH(2)CH(2)PPh(2))(2)]Cl and cisplatin [(H(3)N)(2)PtCl(2)]. Complexes 4-6 were also 2-5 times more toxic against PHA-stimulated lymphocyte cultures than to HeLa cancer cell., Conclusion: Unlike for the silver complexes 1-3, no meaningful drug activity-structural relationship exists for the gold(I) d(10) carboxylates 4-6. Gold(I) complexes in neutral and charged form are intrinsically more cytotoxic than silver(I) against the HeLa cancer cell line.

A series of new neutral mononuclear or dinuclear gold(I) complexes and a cyclic cationic tetranuclear amidogold(I) complex comprising of the phosphines 1,2-bis(dimethylphosphino)ethane (dmpe), μ-1,2-bis(diphenylphosphino)ethane (dppe), μ-1,3-bis(diphenylphosphino)propane (dppp), μ-1,5-bis(diphenylphosphino)pentane (dpppe), μ-1,6-bis(diphenylphosphino)hexane (dpph) or trimethylphosphine, and several N-heterocyclic ring systems (imidazolate, pyrazolate, 1,2,3-triazolate, 1,2,4-triazolate, pyrrolate, 9H-purine-9-ate or 9H-purine-6-amine-9-ate) as ligands, reveal intermolecular aurophilic interactions and 2D channels available for solvent molecules in some of their crystal structures. The antitumour activity of the acyclic gold(I) compounds is highly dependent on the substituents on the phosphorus atoms being highest for phenyl groups and lower for methyl groups. The activity of these compounds against selected cell lines is linked to the length of the carbon bridge between the two phosphorus atoms being highest with a bridge consisting of 5 or 6 carbons. Two compounds with the highest tumour specifities that contain dpppe and pyrazolate (a lipophilic compound) or 1,2,4-triazolate (a hydrophilic compound) induce an apoptotic cell death pathway and a maximum dose to Balb/C mice is tolerated., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Gold(I) and platinum(II) d(10) and d(8) electronic complexes such as (Au(PPh(2)CH(2)CH(2)PPh(2))(2))Cl and cisplatin, ((H(3)N)(2)PtCl(2)), possess strong antineoplastic activities. Almost no information is available regarding the anticancer activity of isoelectronic silver(I) d(10) complexes. This study examined the cytotoxicity of stable water-soluble silver(I) carboxylates. The results were related to the cytotoxicity of cisplatin and (Au(PPh(2)CH(2)CH(2)PPh(2))(2))Cl., Materials and Methods: The silver carboxylates (AgO(2)CCH(2)OCH(3)), 1, (AgO(2)C-CH(2)OCH(2)CH(2)OCH(3)), 2, and (AgO(2)CCH(2)OCH(2)CH(2)OCH(2)CH(2)OCH(3)), 3, were investigated. Cytotoxicity tests were performed on the HeLa (human cervix epitheloid) cancer cell line, resting lymphocytes and PHA (phytohaemagglutinin)-stimulated lymphocyte cultures. Cell survival was measured by means of the colorometric 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT) assay., Results: The IC(50) (50% cell growth inhibition) values of 1-3 in the HeLa cells varied between 2.6 and 6.1 μmol dm(-3) with being 1 the most cytotoxic silver complex. Drug activity was inversely proportional to the length of the carboxylato chain length. Complexes 1-3 were 3-5 times more cytotoxic against the HeLa cancer cells than against the PHA stimulated lymphocyte cultures., Conclusion: A drug activity-structure relationship exists in that short-chain silver carboxylates are more cytotoxic than long-chain silver carboxylates, but silver d(10) complexes are one order of magnitude less cytotoxic than platinum(II) d(8) or gold(I) d(10) complexes.

Background: The purpose of this research was to determine the acute and subacute safety and proof-of-concept efficacy of carbohydrate-derived fulvic acid (CHD-FA)., Methods: In this double-blind study, 30 male volunteers with predetermined atopy were randomly assigned to either Group A or Group B, each consisting of 15 participants. In part 1 of the study, the groups were administered increasing amounts of CHD-FA, ranging from 5 mL to 40 mL, provided that no adverse events had occurred at the previous dosage. In part 2, Group A participants received 20 mL of 3.8% CHD-FA twice daily for 3 days and were monitored for a week. Because no adverse events occurred, Group B received 40 mL of 3.8% CHD-FA twice daily for a period of 3 days. In part 3, both groups received either 40 mL of 3.8% CHD-FA or placebo twice daily for a period of one week, followed by a one-week washout period before crossover to the alternative treatment schedule. Parameters used to establish safety were electrocardiography, a physical examination, a health questionnaire, and hematology and biochemistry, determined at baseline, during regular calculated intervals, and at the end of each part of the study. A skin prick test was done as part of the screening process and, from the result, the allergen the participant was most allergic to was then selected, along with the positive histamine and negative control to be repeated at the start and end of each respective stage., Results: Safety parameters remained constant throughout the trial. A significant decrease in skin prick test results was observed., Conclusion: No severe adverse events occurred, establishing that CHD-FA to be safe at doses up to 40 mL twice daily for a week and that at this dosage CHD-FA acts as an anti-inflammatory agent. These findings confirm earlier animal data.

4-Aminoquinolines were hybridized with artemisinin and 1,4-naphthoquinone derivatives via the Ugi-four-component condensation reaction, and their biological activities investigated. The artemisinin-containing compounds 6a-c and its salt 6c-citrate were the most active target compounds in the antiplasmodial assays. However, despite the potent in vitro activities, they also displayed cytotoxicity against a mammalian cell-line, and had lower therapeutic indices than chloroquine. Morphological changes in parasites treated with these artemisinin-containing hybrid compounds were similar to those observed after addition of artemisinin. These hybrid compounds appeared to share mechanism(s) of action with both chloroquine and artemisinin: they exhibited potent β-hematin inhibitory activities; they caused an increase in accumulation of hemoglobin within the parasites that was intermediate between the increase observed with artesunate and chloroquine; and they also appeared to inhibit endocytosis as suggested by the decrease in the number of transport vesicles in the parasites. No cross-resistance with chloroquine was observed for these hybrid compounds, despite the fact that they contained the chloroquinoline moiety. The hybridization strategy therefore appeared to be borrowing the best from both classes of antimalarials., (Copyright © 2011 Elsevier Inc. All rights reserved.)

A series of dihydroartemisinin derivatives were synthesized via an aza-Michael addition reaction to a dihydroartemisinin-based acrylate and were evaluated for antiplasmodial and antitumor activity. The target compounds showed excellent antiplasmodial activity, with dihydroartemisinin derivatives 5, 7, 9 and 13 exhibiting IC(50) values of ≤10 nM against both D10 and Dd2 strains of Plasmodium falciparum. Derivative 4d was the most active against the HeLa cancer cell line, with an IC(50) of 0.37 μM and the highest tumor specificity., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Ferrocene derivatives may possess antineoplastic activity. Those with low ferrocenyl reduction potentials often have the highest anticancer activity, as cell components have to oxidise them to the active ferrocenium species before cytotoxicity can be recorded. Some gold(I) complexes also possess anticancer activity. This study examined the cytotoxicity of ferrocenyl-ethynyl and ruthenocenyl-ethynyl complexes of gold and platinum. The results were related to the ease of iron oxidation in the ferrocenyl fragment and compared with the cytotoxicity of cisplatin, [(H(3)N)(2)PtCl(2)] and [Au(PPh(2)CH(2)CH(2)PPh(2))(2)]Cl., Materials and Methods: Ferrocene-containing gold and platinum complexes of the type Fc-C≡C-PPh(2), 1, and Fc-C≡C-PPh(2)→M with Fc=ferrocenyl (Fe(II)(η(5)-C(5)H(5)) (η(5)-C(5)H(4))), Ph=phenyl (C(6)H(5)) and M=Au-Cl, 2, Au-C≡C-Fc, 3, or Au-C≡C-Rc, 4 (Rc=ruthenocenyl, (Ru(II)(η(5)-C(5)H(5)) (η(5)-C(5)H(4))) and the complex [(Fc-C≡C-PPh(2))(2)PtCl(2)], 5, were investigated. Cytotoxicity tests were determined on the HeLa (human cervix epitheloid) cancer cell line, ATCC CCL-2. Cell survival was measured by means of the colorometric 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide assay., Results: The IC(50) values of compounds 1-4 from four experiments causing 50% cell growth inhibition, ranged between 4.6 and 27 μmol dm(-3). Drug activity was inversely proportional to the sum of all formal reduction potentials, E(o'), of the ferrocenyl groups of the Fc-C≡C-PPh(2) and Fc-C≡C-ligands coordinated to the gold centre. The Fc-C≡C-PPh(2)→Au-Cl complex, compound 2, was most cytotoxic with IC(50)=4.6 μmol dm(-3) , demonstrating the beneficial effect the Cl(-) ion has on the cytotoxicity of these neutral gold complexes. The platinum complex [(Fc-C≡C-PPh(2))(2)PtCl(2)], compound 5, resembling the structure of cisplatin, in principle should exhibit good cytotoxicity, but was not tested due to its total insolubility in any biocompatible medium.

It has been shown in a previous study that brown coal-derived potassium humate is safe and effective in suppressing contact hypersensitivity in rats. In this study the efficacy of potassium humate on other types of inflammation was determined. Preparative TLC followed by mass spectroscopy was used in an attempt to fingerprint the product. The effects of potassium humate, at an oral dose of 60 mg/kg bodyweight, on a delayed type hypersensitivity reaction, a carrageenan-induced inflammation model and an allogeneic graft-versus-host reaction (GVHR) in rats were investigated. Paw oedema was used as a measure of inflammation. It was found that potassium humate had no effect on the delayed type hypersensitivity reaction but significantly inhibited the increase in paw volume of the carrageenan-induced oedema in rats which compared favourably with indomethacin treatment. Furthermore, potassium humate inhibited the GVHR induced in normal and cyclophosphamide-treated immune-incompetent rats. The identification of a naturally occurring compound that is safe and effective in reducing different types of inflammation merits further evaluation in clinical trials.

The effects of brown coal derived potassium humate on lymphocyte proliferation, cytokine production and complement activation were investigated in vitro. Potassium humate increased lymphocyte proliferation of phytohaemaglutinin A (PHA) and pokeweed mitogen (PWM) stimulated mononuclear lymphocytes (MNL) in vitro from concentrations of 20 to 80 microg/ml, in a dose dependant manner. On the other hand potassium humate, at 40 microg/ml, significantly inhibited the release of TNF-alpha, IL-1beta, IL-6 and IL-10 by PHA stimulated MNL. Regarding complement activation it was found that potassium humate inhibits the activation of both the alternative and classical pathways without affecting the stability of the red blood cell membranes. These results indicate that the anti-inflammatory potential of potassium humate could be partially due to the inhibition of pro-inflammatory cytokines responsible for the initiation of these reactions as well as inhibition of complement activation. The increased lymphocyte proliferation observed, might be due to increased IL-2 production as previously been documented.

The anti-tumour activity of the Au (I) phosphine complex [Au(dppe(2)]Cl was first discovered in the mid 1980s although promising results were obtained it did not pass clinical studies because of its toxicity to organs such as the liver and heart. The aim of this study was to determine whether the two novel gold compounds (MM5 and MM6), selected for this study, have higher selectivity for cancer cells with less toxicity towards normal cells than [Au(dppe)(2)]Cl, and also to determine whether they have improved bio distribution compared to [Au(dppe)(2)]Cl. The Au-compounds as potential chemotherapeutic drugs were evaluated by using radioactive tracers in the in vitro and in vivo studies. Results obtained from these experiments showed that the uptake of these experimental compounds was dependent on their octanol/water partition coefficient. However; the inhibition of cell growth did not correlate with the uptake of these compounds by the cells that were tested. In terms of the total uptake it was found that the compounds that were less lipophilic (MM5, MM6) were taken up less efficiently in cells than those that are more lipophilic. Therefore hydrophilic drugs are expected to have a limited biodistribution compared to lipophilic drugs. This might imply a more selective tumour uptake.

Background: Oxidised ferrocenium compounds often possess antineoplastic activity. In contrast, reduced ferrocene derivatives frequently only show activity if cell components can oxidise them inside cells to the ferrocenium species. Ferrocene compounds having the lowest formal reduction potential are normally expected to be the most cytotoxic. Here we demonstrate this is not always the case. Some of the structure-related and physical properties that enhance ferrocenyl antineoplastic activity have been investigated., Materials and Methods: Ferrocene-containing beta-diketones of the type FcCOCH2COR with Fc=ferrocenyl and R=CF3, CCl3, CH3, Ph(=C6H5, phenyl) and Fc, were tested for cytotoxicity against HeLa (human cervix epitheloid), COR L23 (human large cell lung carcinoma) and platinum resistant CoLo320DM (human colorectal) and COR L23/CPR cancer cell lines. Cell survival was measured by means of the colorometric 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide (MTT) assay., Results: The mean drug concentration from 3 experiments causing 50% cell growth inhibition, (IC50) values, varied between 4.5 and 85.0 micromol dm(-3'), with the CF3(-) containing beta-diketone being the most active. Drug activity was inversely proportional to the formal reduction potential, Eo', of the ferrocenyl group, and dependent on the R group in the general beta-diketone structure. The CF3 complex was more cytotocic than cisplatin inter alia against platinum-resistant cell lines, and at least eight times more reactive against cancer cell lines than against PHA (phytohaemagglutinin)-stimulated lymphocyte cultures., Conclusion: A drug activity-structural relationship exists in that ferrocenyl drugs with halogen substituents chains are more cytotoxic. Compounds with higher ferrocenyl group formal reduction potential and stronger acid strength (i.e. smaller pKa value) are more cytotoxic.

In this study we compared the effects of two previously described antimitochondrial gold complexes, that is, [A] [Au(dppe)(2)]Cl and [B] [Au(d4pype)(2)]Cl with two novel lipophilic cations, that is, [C] [Au(dpmaaH(2))(dpmaaSnMe(2))]Cl and [D] [Au(dpmaaSnMe(2))(2)]Cl as antimitochondrial agents. The results of this study indicate that [C] and [D] have intermediate partition coefficients and exhibited a selective uptake by cells. They exhibited a higher selectivity for the various cell lines than [A] but were more cytotoxic than [B]. There is a significant correlation between the cytotoxic potential of [A], [B], [C], and [D] and their octanol/water partition coefficients in both MCF-7 (breast cancer) and MCF-12A (nonmalignant breast) cells, whereas their cytotoxic potential and ability to induce the release of cytochrome c correlated only in the case of the MCF-12A cells. Complexes [C] and [D] are promising new chemotherapeutic drugs. These compounds target the mitochondrial membranes of certain cancer cells exploiting the differences between the mitochondrial membrane potential of these cells and normal cells. Although the concentrations of these compounds necessary to eradicate cancer cells are very high, the results provide a basis for the synthesis of a new family of compounds with intermediate partition coefficients compared to [A] and [B] but with increased activity against cancer cells.

Crude methanol and water extracts of 36 plants, employed in the treatment of diseases of probable bacterial etiology by the Venda people, were screened for antibacterial activity. Combretum molle, Peltophorum africanum, Piper capense, Terminalia sericea and Zanthoxylum davyi were the most active and presented MIC values < or =1.00 mg/ml.

New 7-chloroquinolinyl thiourea derivatives derived from the corresponding 4,7-dichloroquinoline isothiocyanate were synthesized and evaluated for in vitro antimalarial and anticancer activity. The most active compound from the series displayed an inhibitory IC(50) value of 1.2 microM against the D10 strain of Plasmodium falciparum. Lack of cytotoxicity towards HeLa cells indicates selectivity towards parasites.

Objectives: The effects of two humate products were compared to that of prednisolone on a contact hypersensitivity rat model., Methods: Rats, sensitized with dinitrofluorobenzene (DNFB), were placed on a daily oral treatment of 61 mg/kg BW of humate derived from either leonardite or bituminous coal or on prednisolone at one mg/kg BW and challenged 6 days later with a topical application of DNFB to the right ear. The inflamed ears were measured daily. In a toxicity study rats were exposed to daily oral treatment of leonardite humate at 1,000 mg/kg BW for 1 month. A teratogenicity study was done where pregnant rats were treated with 500 mg/kg BW on days 5 to 17 of pregnancy., Results: Only the leonardite humate compared favourably with prednisolone in suppressing contact hypersensitivity. No signs of toxicity were observed and weight gain was normal during the 6-day and 1 month treatments and during the teratogenicity study with the leonardite humate. However, the rats on the other two products experienced slower weight gain., Conclusion: The identification of a naturally occurring nontoxic compound with anti-inflammatory activity is exciting and merits further evaluation in the treatment of patients suffering from inflammatory conditions.

Background: Often potentially good chemotherapeutic drugs find limited clinical use due to the many negative medical and physical side-effects they may exhibit. To combat these negative side-effects, new antineoplastic materials are continuously being synthesised and evaluated. Ferrocene-containing compounds under certain conditions may show appreciable anticancer activity. Some of the factors that determine this activity have been investigated., Materials and Methods: Ferrocene-containing alcohols were tested for cytotoxicity against the HeLa cancer cell line. Cell survival was measured by means of the colorometric 3-(4,5-dimethylthiazol-2-yl)-diphenyltetrazolium bromide assay., Results: The 50% lethal dosage of 4-ferrocenylbutanol was 5.72 micromol. dm(-3) and for 2-ferrocenylethanol and 3-ferrocenylpropanol it was 35.0 and 17 micromol. dm(-3) respectively while for ferrocenylmethanol IC50 was >100 micromol. dm(-3)., Conclusion: A drug activity-structural relationship exists in that ferrocenyl drugs with longer side chains are more cytotoxic. Compounds with lower ferrocenyl group formal reduction potential are also more cytotoxic.

The recent increase in the incidence of tuberculosis with the emergence of multidrug-resistant (MDR) cases has lead to the search for new drugs that are effective against MDR strains of Mycobacterium tuberculosis and can augment the potential of existing drugs against tuberculosis. In the present study, we investigated the activities of a naphthoquinone, 7-methyljuglone, isolated from the roots of Euclea natalensis alone and in combination with other antituberculous drugs against extracellular and intracellular M. tuberculosis. Combinations of 7-methyljuglone with isoniazid or rifampicin resulted in a four to six-fold reduction in the minimum inhibitory concentration of each compound. Fractional inhibitory concentration (FIC) indexes obtained were 0.2 and 0.5, respectively, for rifampicin and isoniazid, suggesting a synergistic interaction between 7-methyljuglone and these anti-TB drugs. The ability of 7-methyljuglone to enhance the activity of isoniazid and rifampicin against both extracellular and intracellular organisms suggests that 7-methyljuglone may serve as a promising compound for development as an anti-tuberculous agent.

The in vitro affinity and adsorption capacity of a humic acid, oxihumate, for aflatoxin B1 (AFB1) was evaluated, utilizing Langmuir and Freundlich adsorption isotherms. Oxihumate showed a high in vitro affinity for AFB1. The Freundlich isotherm fitted the data better than the Langmuir isotherm, and binding capacities of 10.3, 7.4, and 11.9 mg of AFB1/g of oxihumate at pH 3, 5, and 7, respectively, were calculated. The in vivo efficacy of oxihumate as an aflatoxin binder in male broiler chickens exposed to aflatoxin-contaminated feed from 7 to 42 d of age was also assessed. The efficacy of oxihumate was compared with a commercially available product with a brewers dried yeast (BDY) and brewers fermentation solubles as main active ingredients. A total of 420 birds were assigned to 28 pens, with 15 birds per pen. The following treatments were applied: 1) 0 mg of AFB1 + 0 additives, 2) 1 mg of AFB1/kg of feed + 0 additives, 3) 1 mg of AFB1/kg of feed + 3.5 g of oxihumate/kg of feed, 4) 1 mg of AFB1/kg of feed + 3.5 g of BDY/kg of feed, 5) 2 mg of AFB1/kg of feed + 0 additives, 6) 2 mg of AFB1/kg of feed + 3.5 g of oxihumate/kg of feed, and 7) 2 mg of AFB1/kg of feed + 3.5 g of BDY/kg of feed. Each treatment consisted of 4 replicates. Oxihumate was effective in diminishing the adverse effects caused by aflatoxin on BW of broilers (P < 0.05). Oxihumate also showed protective effects against liver damage, stomach and heart enlargement, as well as some of the hematological and serum biochemical changes associated with aflatoxin toxicity (P < 0.05). Results indicated that oxihumate, but not BDY, could alleviate some of the toxic effects of aflatoxin in growing broilers. Oxihumate might, therefore, prove to be beneficial in the management of aflatoxin-contaminated feedstuffs for poultry when used in combination with other mycotoxin management practices. Additional studies are warranted to assess its efficacy under a wide variety of circumstances.

Irinotecan and its metabolite SN38 were evaluated for their cytotoxicity and influence on radiosensitivity in WHO3 human oesophageal cells under hypoxic conditions. The IC50's of Irinotecan and SN-38 were found to be 0.8 and 0.04 microM, repectively, with SN-38 emerging as the more potent drug. The toxicities were similar under anoxic conditions. Given in conjunction with irradiation under hypoxic conditions, the two drugs restored the radiosensitivity of WHO3 cells in a dose-dependent manner by factors of 1.5-2.1 as compared to a control oxygen enhancement ratio (OER) of 2.1 in this cell system. In the subtoxic concentration range of 10(-2) microM SN-38 still generated a marked sensitisation of hypoxic tumour cells by factors of 1.2-1.6. It is concluded that the topoisomerase inhibitor Irinotecan and in particular the metabolite SN-38 may be clinically useful for radiotherapy of notoriously hypoxic tumour pathologies.

Background: Tumour hypoxia severely limits the success of radiotherapy. Radiosensitization of hypoxic tumour cells by drugs is thus an important clinical issue., Materials and Methods: Two novel ferrocene-containing beta-diketonato complexes of the transition metals rhodium and iridium were examined for their cytotoxic activity against Chinese hamster ovary (CHO) cells by MTT and clonogenic assays. The same complexes were also tested for their capacity to sensitize hypoxic CHO cells against 8 MeV photons., Results: The IC50 for [Rh(fcta)(cod)] (I) and [Rh (fctca)(cod)] (II), where (fctfa) = ferrocenoylacetonato-4,4,4-trifluoro and (fctca) = ferrocenoyl-4,4,4-trichloro- and (cod) = 1,5-cyclooctadiene, were found to be 1.38 microM and 4.18 microM, respectively, closely resembling that of cisplatin which was found to be 1.21 microM. The rhodium (I) complex was identified as an effective anoxic radiosensitizer showing a dose-modifying factor (DMF) of 1.93 +/- 0.02, resembling cisplatin where the DMF was found to be 1.99 +/- 0.02. Small DMF's in the range of 1.10 were also found for cisplatin and the rhodium (I) complex under aerobic conditions, but these were not statistically significant. The DMF for the iridium complex was small and found to be 1.06 +/- 0.04., Conclusion: The cytotoxicity and radiosensitizing properties of the rhodium (I) complex are very similar to cisplatin and show considerable potential for clinical application.

Background: A dramatic increase in multiple-drug-resistant (MDR) Gram-positive pathogens has occurred in recent times, leading to increased rates or morbidity and mortality and also associated with high costs for the treatment of these infections. It is clear that there is an urgent need for the development of effective antimicrobial agents. The anti-bacterial activity of seven 2,2,6,6-tetramethylpiperidine (TMP)-substituted phenazines, compared to clofazimine (B663), were tested against 70 clinical isolates of methicillin-resistant Staphylococcus aureus, MDR Streptococcus pneumoniae and resistant Enterococcus sp., Methods: Standard minimum inhibitory concentration agar dilution susceptibility tests were done on all isolates, including ATCC control strains., Results: All the TMP-substituted phenazines were more active than clofazimine against all isolates tested. Compound B4125 was the most active by inhibiting all growth of the organisms tested, including vancomycin-resistant Enterococcus faecium., Conclusion: Clofazimine has been shown to have anti-staphylococcal activity. We demonstrate enhanced anti-bacterial activity of TMP-substituted phenazines against drug-resistant Gram-positive organisms compared to clofazimine.

The toxicity and distribution of cisplatin and two novel platinum (Pt) polymer conjugates (Pt-6 and Pt-7) were determined in serum and tissue of BALB/c mice at specific time points after i.p. administration of a drug bolus containing identical Pt concentrations. Pt concentrations were determined in serum, liver and kidney at 5 and 15 min, respectively, after drug administration by inductively coupled plasma mass spectrometry. It was found that the Pt polymer Pt-7 gave rise to a considerably lower Pt concentration in serum and considerably higher concentration in liver and kidney than cisplatin. LD25 measurements indicated that the Pt-7 polymer is considerably less toxic than cisplatin. In vitro experiments and determination of IC50 values in a variety of human tumor cell lines, normal lymphocytes and fibroblasts confirmed that Pt-6 and Pt-7 polymers are 40-500 times more toxic for tumor cells than for normal cells, perhaps reflecting preferential uptake. The toxicity of cisplatin was found to be only 1.6-40 times more effective in tumor cells. These inter-relationships are supported by the observation that the tumor enrichment factor (TEF) for cisplatin is only in the region of 6, and much lower than for Pt-6 and Pt-7, where TEFs are in the region of 40 and 150, respectively. These results demonstrate that the Pt polymer conjugates exhibit greater tumor specificity than cisplatin, killing tumor cells more effectively while being considerably less toxic for normal cells. It is concluded that the Pt polymer conjugates may be superior for cancer therapy and warrant further testing to assess their full clinical potential.

Aqueous and methanol extracts of Urtica urens, Capparis tomentosa, Dicoma anomala, Leonotis leonorus, Xysmalobium undulatum, Helichrysum foetidum, Pterocarpus angolensis, Terminalia sericea and Gunnera perpensa, plants documented as being used for topical wound healing in the literature, were tested for antibacterial activity against Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli and Pseudomonas aeruginosa. Methanol and water extracts of two of these plants, Terminalia sericea and Gunnera perpensa, were more active compared to the other extracts against Streptococcus pyogenes and Staphylococcus aureus. The effects of the latter plants on fibroblast growth as well as oxidant production by N-formyl-methionyl-leucyl-phenylalanine were also studied. The water and methanol extracts of Terminalia sericea and Gunnera perpensa significantly decreased luciginin enhanced chemiluminescence at concentrations of 100 microg/ml and higher. However, the extracts had no effect on the growth of primary human fibroblasts.

One of the best-known multi-purpose medicinal plants in Southern Africa, Sutherlandia frutescens subsp. microphylla (family: Fabaceae/Leguminosa), is used for a wide range of conditions, including cancer, viral diseases and inflammatory conditions. Little scientific data has been documented on the mechanism by which Sutherlandia frutescens acts on the immune system. Phagocyte derived reactive oxygen species, such as hydrogen peroxide and superoxide radicals, are responsible for the pathogenesis of various inflammatory conditions. Anti-inflammatory properties of various medicinal-plant extracts have been explained, at least in part, by their antioxidant activities. We investigated the effects of a hot water extract of Sutherlandia frutescens on both luminol and lucigenin enhanced chemiluminescence of neutrophils stimulated with L-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP) as well as its superoxide and hydrogen peroxide scavenging properties in a cell free system. The results indicate that Sutherlandia frutescens extract possesses superoxide as well as hydrogen peroxide scavenging activities at concentrations as low as 10 microg/ml, which could account for some of the anti-inflammatory properties that have been described.

In this study the anti-inflammatory potential of potassium humate, derived from bituminous coal, has been investigated in vitro. Exposure of resting and phorbol-12-myristate-13-acetate (PMA) stimulated human neutrophils to potassium humate resulted in a decreased expression of CR3 by activated, but not resting cells, in a dose-related way. Humate also inhibited the adhesion of PMA-stimulated neutrophils to a baby hamster kidney cell line expressing ICAM1 (the CR3 ligand) (BHK331-7). Similar results were obtained using normal BHK cells indicating that this inhibition does not only target specific adhesion molecules on the neutrophil and eosinophil membrane by activated phagocytes, but also affects other mechanisms involved in cell adhesion. Opsonised Sephadex or FMLP/Cyto B-induced degranulation of neutrophils and eosinophils were also decreased by humate treatment. Inhibition of the adhesion of activated phagocytes, as well as inhibition of the release of granule polypeptides, both of which are responsible for tissue damage during inflammatory processes, are attractive targets for anti-inflammatory drugs. Because humate is well tolerated with an excellent safety profile it merits further evaluation in patients suffering from inflammatory conditions.

Background: Determination of the drug concentration required to kill 50% of the tumour cells (EC50) does not take into account the propensity of cells to undergo apoptosis and necrosis. These 2 parameters and the viable cells are here assessed by a flow cytometric (FC) approach using propidium iodide (PI) and FITC-Annexin V staining., Materials and Methods: A number of carcinoma cell lines of defined p53 status were exposed to cis-PtII for 24 hours, stained with PI and FITC-Annexin V and analyzed by FC. Unstained viable cells, early apoptotic cells and necrotic cells were scored separately in dual parameter plots of green fluorescence (FITC) against red fluorescence (PI) to generate dose response curves., Results: EC50 values for cell viability were found to be 1-4 times higher than survival data from colony assays resembling data obtained by MTT or Crystal Violet vital dye staining. Percentage apoptosis measured by Annexin V binding was in agreement with microscopic scoring of apoptotic cells after Acridine Orange staining., Conclusion: The FC assay described gives a good estimate of cell viability resembling data from vital dye staining assays and provides additional information on apoptosis and necrosis. FC data from Annexin V binding and microscopic scoring after Acridine Orange staining were in excellent agreement.

A unique process has been developed to convert bituminous coal by controlled wet oxidation followed by base treatment to a water-soluble humate called oxihumate. The effects of oxihumate on the proliferative response of lymphocytes has been studied in vitro and ex vivo. Oxihumate increased the proliferative response of phytohaemagglutinin-stimulated human lymphocytes, from a concentration of 20 microg/ml and upwards. This response was even more striking in the case of lymphocytes from HIV-infected patients and was not limited to the in vitro setting since similar effects were observed ex vivo following administration of a non-toxic dosage of 4 g oxihumate per day to HIV-positive individuals for two weeks. Mechanistic studies revealed that stimulation of the proliferative response of lymphocytes by oxihumate is associated with an increased production of IL-2, as well as expression of the IL-2 receptor in the setting of decreased production of IL-10. Oxihumate therefore holds promise for the treatment of immunocompromized patients.

A unique process has been developed to convert bituminous coal by controlled wet oxidation followed by base treatment to a water-soluble humate called oxihumate. Oxihumate inhibited HIV-1 infection of MT-2 cells with an IC(50) of 12.5 microg/ml. Treatment of free and cell-attached HIV with oxihumate irreversibly reduced infectivity, while the susceptibility of target cells to the virus was not impaired by treatment prior to infection. The infectivity of the HIV particles was inhibited by interference with CD4 binding and the V3 loop-mediated step of virus entry. No viral resistance to oxihumate developed over a 12-week period in vitro. Oxihumate therefore holds promise for the treatment of HIV-infected patients., (Copyright 2002 S. Karger AG, Basel)

Background: Mixed-valent diruthenium tetracarboxylate complexes were shown to have slight antineoplastic activity against P388 leukemia cell lines. However these complexes suffered from poor water-solubility, which may have detrimentally affected their activity., Materials and Methods: Mixed-valent diruthenium tetracarboxylates of the type [Ru2(O2CR)4(L)2] (PF6) with L = imidazole, 1-methylimidazole and H2O when R = CH3, L = ethanol when R = Fc (ferrocenyl) or Fc-CH=CH- and of the type M3[Ru2(O2CR)4(H2O)2]4H2O, M = Na+ when R = m-C6H4SO3- and M = K+ when R = p-C6H4SO3-, were tested for cytotoxicity against HeLa and multidrug resistant CoLo 320DM human cancer cell lines. Cell survival was measured by means of the colorometric 3-(4,5dimethylthiazol-2-yl)-diphenyltetrazodium bromide assay., Results: The mean drug concentration from 3 experiments causing 50% cell killing, ie, IC50 values, varied between 120 and 950 micromol dm(-3)., Conclusion: The antineoplastic activity of the highly water-soluble m-sulpho derivative was the highest, while the poorly water-soluble imidazole derivatives did not exhibit any cytotoxic properties. The CoLo 320DM cancer cells were 5 times more prone to drug-induced cell death than the HeLa cells.

The lipophilicity and membrane-destabilizing activities of clofazimine and three tetramethyl-piperidine (TMP)-substituted phenazines were compared with the anti-tumor and multiple drug resistance (MDR) neutralizing potential of these agents using a P-glycoprotein (P-gp)-expressing small cell lung cancer cell line (H69/LX4). Partition coefficients were measured as an index of lipophilicity, while membrane-destabilizing potential was measured using a conventional hemolytic assay. The membrane-destabilizing potential of the TMP-substituted phenazines was found to correlate positively with the degree of lipophilicity, as well as with MDR reversal activity. The presence of a TMP group, as well as chlorine atoms on the phenyl and anilino rings of these agents contributed to the enhancement of anti-tumor activity by potentiating membrane-destabilizing activity. TMP-substituted phenazines may be useful in the design of novel anti-cancer and MDR reversal agents.

Bioactive phospholipids (PL), particularly lysophosphatidylcholine (LPC), are being increasingly implicated in the pathogenesis of various acute and chronic inflammatory disorders, particularly those of the airways, while there is emerging evidence that vitamin E may function as a natural antagonist of these lipid mediators of inflammation. The aims of this study were to document the effects of vitamin E on the inhibition of ciliary beating and damage to structural integrity of human ciliated epithelium induced by the PL, platelet-activating factor (PAF), lyso-PAF and LPC in vitro in relation to the anti-oxidative and membrane-stabilizing properties of the vitamin. Ciliary beat frequency was measured by a phototransistor technique, and damage to structural integrity assessed by a visual-scoring index, while superoxide production by polymorphonuclear leukocytes and membrane-stabilizing potential were measured using lucigenin-enhanced chemiluminescence and haemolytic procedures, respectively. All three PL caused inhibition of ciliary beating and structural damage to human ciliated epithelium by membrane-directed cytotoxic mechanisms, which were potentiated by human polymorphonuclear leukocytes due to induction of oxidant-mediated injury. Both direct and phagocyte-inflicted epithelial injury was attenuated by vitamin E. In haemolytic and chemiluminescence assays, vitamin E neutralized both the membrane-destabilizing and pro-oxidative actions of all three PL, while spectrophotometric analysis of mixtures of vitamin E with PAF, lyso-PAF and LPC revealed alterations in peak intensity, as well as peak shifts, indicative of physicochemical interactions between the vitamin and the PL. Vitamin E status may be a determinant of susceptibility to phospholipid-mediated airway inflammation and damage.

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.

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.

The potential of B4121 to sensitize three intrinsically resistant human colon cancer cell lines (CaCo2, ATCC HTB 37; COLO 32 DM, ATCC CCL 220; HT-29, ATCC HTB 38) to vinblastine, doxorubicin, daunorubicin, paclitaxel, taxotere and cisplatin at a non-toxic, therapeutically relevant concentration of 0.25 microg/ml was compared with that of clofazimine at a similar concentration. The cell line expressing high levels of P-glycoprotein (P-gp), COLO 320 DM, was susceptible to chemosensitization by the experimental agents for the P-gp substrates (paclitaxel, taxotere, daunorubicin, vinblastine and doxorubicin) but not for cisplatin. CaCo2 cells expressed lower levels of P-gp and were only marginally susceptible to sensitization by any one of these drugs, except in the case of sensitization by B4121 for doxorubicin and taxotere, whereas the HT-29, a P-gp negative cell line, was unaffected. The riminophenazines, especially B4121, might prove useful as combination treatment in circumventing P-gp mediated resistance of colon cancers.

The intra- and extracellular activities of 5 novel tetramethylpiperidine (TMP)-substituted phenazines against Mycobacterium tuberculosis H37Rv (ATCC 27294) were determined and compared with those of clofazimine and rifampicin. Two of these agents, together with clofazimine, were also tested for their activities against drug-resistant strains of M. tuberculosis. Three of the TMP-substituted phenazine compounds were significantly more active than clofazimine against M. tuberculosis, including multidrug-resistant clinical strains of this microbial pathogen, demonstrating a lack of cross-resistance between the riminophenazines and standard anti-tuberculous drugs. Using M. tuberculosis-infected monocyte-derived macrophages, all of the TMP-substituted phenazines were found to possess intracellular activity which was superior to that of both clofazimine and rifampicin. In this model of intracellular bioactivity, the experimental compounds inhibited bacterial growth at concentrations which were approximately 10-fold lower than the corresponding minimal inhibitory concentration values obtained using conventional in vitro sensitivity testing procedures. These results demonstrate that the novel TMP phenazines are active against multidrug-resistant M. tuberculosis strains, and particularly effective intracellularly., (Copyright 2000 S. Karger AG, Basel)

GF120918, at 250 ng/ml, increased the sensitivity of a P-glycoprotein (P-gp)-mediated multidrug resistant (MDR) small cell lung cancer cell line (H69/LX4) to the P-gp substrates, paclitaxel, taxotere, vinblastine, vinorelbine, daunorubicin and etoposide to levels which were either greater (in the case of etoposide) or close to that of the parent cell line (H69/P). This was achieved in spite of the great variation in the levels of resistance of the MDR cell line for the various anti-cancer drugs tested. These data suggest that GF120918 is a potent antagonist of P-gp mediated multidrug resistance, even in the case of high levels of resistance, as was the case with paclitaxel and taxotere (2560 and 2215 fold more than the sensitive parent cell line respectively).

Setting: Inflammation-related oxidative stress has been implicated in the pathogenesis of lung fibrosis and dysfunction in patients with pulmonary tuberculosis., Objective: To investigate the effects of antimicrobial chemotherapy and smoking status on the plasma concentrations of the anti-oxidative nutrients vitamin C, vitamin E and beta-carotene, as well as those of iron, lipid peroxides and the acute phase reactants C-reactive protein (CRP) and ferritin., Design: A total of 41 patients with active pulmonary tuberculosis were studied at the outset and after 6 months of antimicrobial chemotherapy., Results: Initial plasma concentrations of vitamin C and beta-carotene were low, returning to normal values after chemotherapy in the non-smokers, but not in the smokers, while those of vitamin E remained low throughout in both groups. Ferritin and CRP concentrations decreased significantly following chemotherapy, with the former higher in smokers than in non-smokers. Serum lipid peroxides were elevated in patients with pulmonary tuberculosis and were unaffected by chemotherapy or smoking habits, while iron levels were not significantly affected by chemotherapy. Although residual dysfunction and infiltration were evident, pulmonary function (FEV1) and radiographic score improved equally in both smokers and non-smokers following antimicrobial chemotherapy., Conclusions: Even after 6 months of apparently successful antimicrobial chemotherapy, pulmonary tuberculosis is associated with increased oxidative stress, which is unrelated to cigarette smoking and characterized by increased levels of circulating lipid peroxides and low concentrations of plasma vitamin E.

The effects of the membrane-stabilizing agent, alpha-tocopherol (25 microg/ml), on the chemosensitizing interactions of cyclosporin A (5 microg/ml), verapamil (2 microg/ml), clofazimine (1 microg/ml), B669 (0.5 microg/ml) and GF120918 (0.015 microg/ml) with a P-glycoprotein-expressing human lung cancer cell line (H69/LX4) have been investigated in vitro. In an assay of cell proliferation, all the chemosensitizing agents restored the sensitivity of H69/LX4 cells to doxorubicin and vinblastine. The inclusion of alpha-tocopherol (25 microg/ml) antagonized the multidrug-resistance (MDR)-modifying activity of all five chemosensitizing agents, effectively preventing restoration of sensitivity to both doxorubicin and vinblastine in H69/LX4 cells.