Experimental analyses of synergistic combinations of antibiotics with a recently recognised antibacterial agent, lacidipine.

The cardiovascular drug lacidipine (Lc) is known to possess antibacterial activity. Further potentiation of action is possible by synergism between Lc and an antibiotic or a non-antibiotic. The minimum inhibitory concentration (MIC) of antibiotics, Lc and other non-antibiotics were detected by the agar dilution technique in different bacteria. Synergism was determined by disc diffusion assay, the fractional inhibitory concentration (FIC) index through checkerboard assessment and, also, the protective capacity of the combination by administering the drugs along with 50 x LD(50) challenge dose of virulent Salmonella typhimurium in animal experiments. Synergism between Lc and penicillin was found to be statistically significant (P

In vitro and in vivo efficacies of amlodipine against Listeria monocytogenes.

Listeria monocytogenes causes suppurative gastritis in BALB/c mice. We investigated the effect of the antihypertensive drug amlodipine (Aml) on the growth of L. monocytogenes in vitro and in vivo. Aml showed noteworthy inhibitory action (minimum inhibitory concentration, MIC(90) 32 microg/ml) against Listeria strains and demonstrated cidal (minimum bactericidal concentration, MBC 64 microg/ml) activity. Aml administered orally at 2.5 microg/g in female BALB/c mice for 7 days, commencing 4 days before oral challenge (1 x 10(8) CFU/ml with L. monocytogenes ATCC 51774), significantly reduced bacterial counts in the stomach (P < 0.01), liver (P < 0.01), and spleen (P < 0.05), and decreased (P < 0.05) gastric lesions, neutrophilic infiltration, edema, vascular degeneration, and necrosis of gastric tissues. It caused the down-regulation of expression of inflammatory cytokines (IFN-gamma, IL-1 beta, and TNF-alpha) compared to drug-free control. Aml may be used in the presence of an antibiotic as adjunct therapy that boosts the host immunity against Listeria. Further, QSAR studies might contribute in manipulating it as a lead compound for the synthesis of new, more effective non-antibiotics (helper compounds), perhaps devoid of side-effects, that could be recommended as compassionate therapy for listeriosis.

The anti-inflammatory non-antibiotic helper compound diclofenac: an antibacterial drug target.

Diclofenac sodium (Dc) was found to possess antibacterial activity against both drug-sensitive and drug-resistant clinical isolates of Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, and Mycobacterium spp., in addition to its potent anti-inflammatory activity. The time-kill curve study indicates that this non-steroidal drug exhibits bactericidal activity against Listeria, E. coli, and M. tuberculosis. The antibacterial activity of Dc comes, in part, from its ability to inhibit the DNA synthesis of E. coli and L. monocytogenes. Dc could protect murine listeriosis, salmonellosis, and tuberculosis at doses ranged within its maximum recommended human or non-toxic ex-vivo dose. Dc possesses anti-plasmid activity and acts as a 'helper compound' in synergistic combination with streptomycin against E. coli and Mycobacterium or gentamicin against Listeria. This review focuses on the possible use of Dc, a non-antibiotic helper compound, in infections and inflammatory conditions, rationalized on the basis of the activities of the compounds.

In vitro synergistic effect of gentamicin with the anti-inflammatory agent diclofenac against Listeria monocytogenes.

AIMS: A total of nine Listeria monocytogenes strains (seven serotypes) were studied to ascertain whether the non-steroidal anti-inflammatory drug diclofenac (Dc) used in combination with the conventional antilisterial antibiotic gentamicin (Gm) or ampicillin (Am) synergistically augments the efficacy of the antibiotic in vitro. METHODS AND RESULTS: The effect of combination was evaluated by the checkerboard method to obtain a fractional inhibitory concentration (FIC) index followed by kill curves. Dc was synergistic with Gm (FIC 0.37) and there was indifference with Am (FIC 1) against L. monocytogenes ATCC 51774. The magnitude of the differences between killing by a single agent and the combination observed at 24 h was significant (P < 0.05) for Dc plus Gm but not Dc plus Am. CONCLUSIONS: Thus, the ability of extended antibiotic therapy may be improved with the help of this synergistic drug pair in listeriosis. SIGNIFICANCE AND IMPACT OF THE STUDY: Such findings may indicate parallel administration of anti-inflammatory and anti listeriosis drugs.

The anti-inflammatory drug Diclofenac retains anti-listerial activity in vivo.

AIMS: The interactions between nonsteroidal anti-inflammatory drugs (NSAID) and Listeria monocytogenes have not been sufficiently documented to date. The aim of this study was to investigate the possible effects of Diclofenac (Dc) in a murine listerial infection model. METHODS AND RESULTS: Dc was administered orally at 2.5 mug g(-1) to female albino strain of laboratory mouse (BALB/c) thrice postinfection (1 x 10(8) CFU ml(-1) oral challenge with L. monocytogenes ATCC 51774), which resulted in significantly (P < 0.01) reduced bacterial counts in liver and spleen, decreased (10-fold, P < 0.05) hepatic colonization and necrosis, and caused up-regulation of the expression of inflammatory cytokines (interferon-gamma, interleukin-1beta, tumour necrosis factor-alpha), compared with drug-free control. CONCLUSIONS: Dc may be useful as a promising adjuvant to the existing therapies in controlling systemic listerial infection. Further, quantitative structure-activity relationship studies might contribute in manipulating it as a lead compound for the synthesis of new, more effective nonantibiotics, perhaps, devoid of side-effects that could be recommended as a compassionate therapy for listeriosis. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first in vivo study designed to evaluate the antilisterial effect of the NSAID Dc with special emphasis on the immunological mechanism of action of the drug.

Studies on the protective effects of L-ascorbic acid in chronic chlordane toxicity.

The influence of extraneous supplementation of L-ascorbic acid in chronic chlordane toxicity has been studied in rats. Oral administration of chlordane brings about a marked growth retardative effect, stimulates vitamin C synthesis in the system, elevates the vitamin C status of the liver and kidney tissues and also the urinary excretion. It inhibits the activities of acid and alkaline phosphatases, SDH and Mg2+-ATPase of both hepatic and renal tissues. The activities of serum and mitochondrial GOT, serum alkaline phosphatase, and glucose-6-phosphatase of both hepatic and renal tissues are markedly stimulated. The normal histological patterns of both liver and kidney tissues are grossly altered under chlordane toxicity condition. There occurs marked increase in the hepatic lipid composition. Supplementation of L-ascorbic acid in high doses to the chlordane treated rats can effectively counteract some of these alterations in respect of enzyme activities, morphological characteristics and of hepatic lipid composition.

Patient education programme in bronchial asthma in India: why, how, what and where to communicate?

Judicious and prolonged use of 'protector' metered dose inhalers of steroid aerosol, sodium cromoglycate, both orally and nasally, and 'reliever' drugs like beta 2-agonists etc can induce a state of controlled asthma in many cases. Continued patient education programme (PEP) in a well-staffed asthma clinic is needed to achieve this state. Various aspects of PEP programme should be discussed during each visit. Presence of superstition, misconceptions, ignorance and strong bias against the use of metered-dose inhalers should be removed during PEP. Poor level of literacy, language-barrier, poverty and inadequate contingency fund for prolonged treatment in most families, poor medical infrastructure, inadequate health care facilities, overcrowding in all hospitals, insufficient para-medical staff-pattern (even in private hospitals), high cost of inhalers, tendency for early discontinuation of protector drugs, dislike for prolonged supervision and follow-up investigations, distrust for doctors, fear of social stigma, lure for homeopathy and indigenous branch of medicine for children, etc., are some of the many problems, peculiar to our country, to be faced during PEP. Because of the presence of adequate medical and primary health care services, PEP in developed and affluent Western countries is liable to differ from what is advised here.

Potential role of the cardiovascular non-antibiotic (helper compound) amlodipine in the treatment of microbial infections: scope and hope for the future.

The appearance of multiresistant bacterial strains coupled with the globally ongoing problem of infectious diseases point to the imperative need for novel and affordable antimicrobial drugs. The antibacterial potential of cardiovascular non-antibiotics such as amlodipine (AML), dobutamine, lacidipine, nifedipine and oxyfedrine has been reported previously. Of these drugs, AML proved to have the most significant antibacterial activity against Gram-positive and Gram-negative bacteria. Time-kill curve studies indicate that this Ca(2+) channel blocker exhibits bactericidal activity against Listeria monocytogenes and Staphylococcus aureus. AML could protect against murine listeriosis and salmonellosis at doses ranging within its maximum recommended human or non-toxic ex vivo dose. AML acts as a 'helper compound' in synergistic combination with streptomycin against several Gram-positive and Gram-negative bacterial strains in vitro as well as in the murine salmonellosis model in vivo. The present review focuses on the possible use of cardiovascular non-antibiotics such as AML as auxiliary compound targets for synergistic combinations in infections and hypertension conditions, rationalised on the basis of the activities of the compounds.

In vitro efficacy of diclofenac against Listeria monocytogenes.

Chemotherapy is often futile in systemic listeriosis, translating to being a peril to public health. There is, thus, an imperative need for novel antilisterial compounds, possibly acting through mechanisms dissimilar to those of existing drugs. The present study describes one such agent-the non-steroidal anti-inflammatory drug (NSAID) diclofenac sodium (Dc). The National Committee for Clinical Laboratory Standards (NCCLS) minimum inhibitory concentration (MIC), mode of action, and two mechanisms of action, i.e., on bacterial DNA and membrane, have been characterized with respect to Dc. The drug showed noteworthy inhibitory action (MIC90 = 50 microg/ml) against Listeria strains, demonstrated cidal (minimum bactericidal concentration [MBC]=100 microg/ml) activity, inhibited listerial DNA synthesis (45.48%; incorporation of [methyl-3H] thymidine), and possessed bacterial membrane-damaging activity (37.33%; BacLight assay). Dc could be used as a lead compound for the synthesis of new, more active agents perhaps devoid of side effects. Further, quantitative structure-activity relationship (QSAR) studies will contribute to a new generation of promising adjuvants to existing antilisterial drugs.