Naphthylisoquinoline alkaloids: novel agents against the causative pathogens of eumycetoma and actinomycetoma-en route to broad-spectrum antimycetomal drugs.

Mycetoma is a devastating neglected tropical infection of the subcutaneous tissues. It is caused by fungal and bacterial pathogens recognized as eumycetoma and actinomycetoma, respectively. Mycetoma treatment involves diagnosing the causative microorganism as a prerequisite to prescribing a proper medication. Current therapy of fungal eumycetoma causative agents, such as Madurella mycetomatis, consists of long-term antifungal medication with itraconazole followed by surgery, yet with usually unsatisfactory clinical outcomes. Actinomycetoma, on the contrary, usually responds to treatment with co-trimoxazole and amikacin. Therefore, there is a pressing need to discover novel broad-spectrum antimicrobial agents to circumvent the time-consuming and costly diagnosis. Using the resazurin assay, a series of 23 naphthylisoquinoline (NIQ) alkaloids and related naphthoquinones were subjected to in vitro screening against two fungal strains of M. mycetomatis and three bacterial strains of Actinomadura madurae and A. syzygii. Seven NIQs, mostly dimers, showed promising in vitro activities against at least one strain of the mycetoma-causative pathogens, while the naphthoquinones did not show any activity. A synthetic NIQ dimer, 8,8'''-O,O-dimethylmichellamine A (18), inhibited all tested fungal and bacterial strains (IC50 = 2.81-12.07 µg/mL). One of the dimeric NIQs, michellamine B (14), inhibited a strain of M. mycetomatis and significantly enhanced the survival rate of Galleria mellonella larvae infected with M. mycetomatis at concentrations of 1 and 4 µg/mL, without being toxic to the uninfected larvae. As a result, broad-spectrum dimeric NIQs like 14 and 18 with antimicrobial activity are considered hit compounds that could be worth further optimization to develop novel lead antimycetomal agents.

Gum Arabic (Acacia Senegal) Augmented Total Antioxidant Capacity and Reduced C-Reactive Protein among Haemodialysis Patients in Phase II Trial.

BACKGROUND: Oxidative processes might increase in patients with end-stage renal disease (ESRD) according to the current literature. Oxidative stress (OS) is a risk factor of atherosclerosis and cardiovascular complications, which are major causes of mortality among ESRD patients. Haemodialysis (HD) is life-saving procedure, nevertheless it is an active chronic inflammatory status that could augment cardiovascular disease and increase mortality. Gum Arabic (GA) has been claimed to act as an antioxidant and anti-inflammatory agent in experimental studies and clinical trials. Therefore, we assumed GA supplementation among haemodialysis patients would reduce oxidative stress and consequently reduce the state of chronic inflammatory activation associated with haemodialysis. METHODS: Forty end-stage renal failure (ESRF) patients aged 18-80 years who were on regular haemodialysis in Arif Renal Center, Omdurman, Sudan, were recruited. All recruited patients met the inclusion criteria and signed informed consent prior to enrolment. The patients received 30 g/day of GA for 12 weeks. C-reactive protein (CRP) and complete blood count (CBC) were measured as baseline and monthly. Total antioxidant capacity (TAC) and oxidative stress marker malondialdehyde (MDA) levels were measured before and after GA intake. Ethical approval from the National Medicines and Poisons Board was obtained. RESULTS: Gum Arabic significantly augmented total antioxidant capacity level (P < 0.001) (95% CI, 0.408-0.625) and also attenuated oxidative marker MDA and C-reactive protein (P < 0.001). CONCLUSIONS: GA has revealed potent antioxidative and anti-inflammatory properties in haemodialysis patients. Oral digestion of GA (30 g/day) decreased oxidative stress and inflammatory markers among haemodialysis patients. Trial registration. ClinicalTrials.gov Identifier: NCT03214692, registered 11 July 2017 (prospective registration).