Evaluation of the antineoplastic activities of the riminophenazine agents clofazimine and b669 in tumor-bearing rats and mice

The riminophenazine agents clofazimine and its analogue B669 displayed anti-tumor activity at 30 mg/kg/day in benzo[a]pyrene (BP) induced sarcomas of mice as well as dimethylbenz-anthracene (DMBA)-induced rat mammary tumors. No hematological toxicity of these drugs at doses up to 60 mg/kg/day for one month was observed. This is the first study to document in vivo anti-neoplastic activities of clofazimine and B669.     

Quadriceps and hamstrings peak torque ratio changes in persons with chronic anterior cruciate ligament deficiency

STUDY DESIGN: Cross-sectional analytical study in which subjects served as their own controls. OBJECTIVE: To assess the concentric and eccentric peak torque in the hamstrings and quadriceps muscles, hamstrings/quadriceps amplitude ratios, and lean thigh volume differences in the involved and uninvolved limb of subjects with anterior cruciate ligament (ACL) deficiency. BACKGOUND: Although the hamstrings/quadriceps ratios for concentric and eccentric activity have been studied, the more functional eccentric hamstings/concentric quadriceps ratio has not been previously described in chronic ACL deficient individuals. METHODS AND MEASURES: Eighteen subjects (36 +/- 11 years; 12 men, 6 women) with unilateral chronic ACL deficiency were recruited. Changes in activities of daily living, lean thigh volume (LTV) and isokinetic peak torque and total work capacity of both the quadriceps and hamstring muscles were investigated. The uninvolved limb served as control. RESULTS: Eccentric quadriceps peak torque in the ACL deficient limb was reduced by 38% compared with the 16% reduction of concentric quadriceps peak torque. Eccentric hamstrings peak torque was reduced by 15% compared with an 8% reduction in concentric hamstrings peak torque. LTV in the ACL deficient limb was 11% smaller than the uninvolved limb (3,541 +/- 899 vs 3,161 +/- 742 cc, uninvolved versus ACL deficient limb). The relation between LTV and eccentric peak torque was stronger in the uninvolved (r = 0.82) compared with the ACL deficient limb (r = 0.66). The eccentric hamstrings/quadriceps ratio was significantly higher in the ACL deficient (0.80 +/- 0.26) compared with the uninvolved limb (0.55 +/- 0.13). However, the eccentric hamstrings/concentric quadriceps ratio was similar between ACL deficient (0.75 +/- 0.17) and uninvolved (0.77 +/- 0.20) limbs, while the concentric hamstrings/eccentric quadriceps ratio was significantly higher in the ACL deficient (0.79 +/- 0.26) compared with the uninvolved (0.50 +/- 0.14) limb. CONCLUSIONS: Quadriceps and hamstrings peak torque values were significantly decreased in ACL deficient compared with the uninvolved limb. Eccentric muscle activity was affected to a greater degree than concentric muscle activity in the quadriceps muscle after ACL injury. The eccentric hamstrings/concentric quadriceps ratios were similar in ACL deficient and normal limbs, indicating that muscular co-ordination strategies may have been altered to maintain normal limb activity despite the strength losses particularly evident in quadriceps muscle function.     

Recent developments in our understanding of the implications of traditional African medicine on drug metabolism

Introduction: The use of traditional herbal medicines has become increasingly popular globally, but in some countries, it is the main or sometimes even the only healthcare service available in the most rural areas. This is especially true for Africa where herbal medicines form a key component of traditional medicinal practices and there is access to a diversity of medicinal plants. Although many benefits have been derived from the use of traditional herbal medicines, many concerns are associated with their use of which herb-drug interactions have been identified to have a rising impact on patient treatment outcome. One type of pharmacokinetic interaction involves the modulation of drug metabolizing enzymes, which may result in enhanced or reduced bioavailability of co-administered drugs.

Areas covered: This review highlights the current information available on drug metabolism-associated information with regards to traditional African medicines related to some of the most prevalent diseases burdening the African continent.

Expert opinion: It is clear from previous studies that enzyme modulation by traditional African medicines plays a significant role in the pharmacokinetics of some co-administered drugs, but more research is needed to provide detailed information on these interactions, specifically for treatment of prevalent diseases such as tuberculosis and hypertension.     

Effects of tetramethylpiperidine (TMP)-substituted phenazines on membrane stability and P-glycoprotein function

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.     

Efflux as a mechanism of antimicrobial drug resistance in clinical relevant microorganisms: the role of efflux inhibitors

Introduction: Microbial resistance against antibiotics is a serious threat to the effective treatment of infectious diseases. Several mechanisms exist through which microorganisms can develop resistance against antimicrobial drugs, of which the overexpression of genes to produce efflux pumps is a major concern. Several efflux transporters have been identified in microorganisms, which infer resistance against specific antibiotics and even multidrug resistance.

Areas covered: This paper focuses on microbial resistance against antibiotics by means of the mechanism of efflux and gives a critical overview of studies conducted to overcome this problem by combining efflux pump inhibitors with antibiotics. Information was obtained from a literature search done with MEDLINE, Pubmed, Scopus, ScienceDirect, OneSearch and EBSCO host.

Expert opinion: Efflux as a mechanism of multidrug resistance has presented a platform for improved efficacy against resistant microorganisms by co-administration of efflux pump inhibitors with antimicrobial agents. Although proof of concept has been shown for this approach with in vitro experiments, further research is needed to develop more potent inhibitors with low toxicity which is clinically effective.     

Combination therapy of Western drugs and herbal medicines: recent advances in understanding interactions involving metabolism and efflux

INTRODUCTION: While complementary and alternative medicine markets prosper with an increasing number of consumers of herbal medicines, there is an associated likelihood for herb-drug interactions to occur. Modulation of the activity of metabolic enzymes and/or active transporters by chemical constituents of herbal medicines may influence the therapeutic outcomes of coadministered allopathic medicines due to changes in their pharmacokinetic profiles. Although valuable information on herb-drug interactions is obtained by in vitro studies, such as the mechanisms of interaction, clinical significance of interactions is ultimately demonstrated by in vivo data. AREAS COVERED: The authors outline the mechanisms of herb-drug pharmacokinetic interactions briefly and discuss pharmacokinetic interactions between different therapeutic classes of Western drugs and herbal medicines. Furthermore, the authors also discuss herb-drug interactions from both in vitro and in vivo studies with specific focus on recent findings. EXPERT OPINION: Basic and clinical researches have contributed to the comprehension of the underlying mechanisms involved as well as the practical implications of herb-drug interactions. This provides a foundation for development of guidelines to inform patients about herb-drug interactions that can affect their health.