Semi-Synthetic Analogues of Cryptolepine as a Potential Source of Sustainable Drugs for the Treatment of Malaria, Human African Trypanosomiasis, and Cancer.

The prospect of eradicating malaria continues to be challenging in the face of increasing parasite resistance to antimalarial drugs so that novel antimalarials active against asexual, sexual, and liver-stage malaria parasites are urgently needed. In addition, new antimalarials need to be affordable and available to those most in need and, bearing in mind climate change, should ideally be sustainable. The West African climbing shrub Cryptolepis sanguinolenta is used traditionally for the treatment of malaria; its principal alkaloid, cryptolepine (1), has been shown to have antimalarial properties, and the synthetic analogue 2,7-dibromocryptolepine (2) is of interest as a lead toward new antimalarial agents. Cryptolepine (1) was isolated using a two-step Soxhlet extraction of C. sanguinolenta roots, followed by crystallization (yield 0.8% calculated as a base with respect to the dried roots). Semi-synthetic 7-bromo- (3), 7, 9-dibromo- (4), 7-iodo- (5), and 7, 9-dibromocryptolepine (6) were obtained in excellent yields by reaction of 1 with N-bromo- or N-iodosuccinimide in trifluoroacetic acid as a solvent. All compounds were active against Plasmodia in vitro, but 6 showed the most selective profile with respect to Hep G2 cells: P. falciparum (chloroquine-resistant strain K1), IC50 = 0.25 µM, SI = 113; late stage, gametocytes, IC50 = 2.2 µM, SI = 13; liver stage, P. berghei sporozoites IC50 = 6.13 µM, SI = 4.6. Compounds 3-6 were also active against the emerging zoonotic species P. knowlesi with 5 being the most potent (IC50 = 0.11 µM). In addition, 3-6 potently inhibited T. brucei in vitro at nM concentrations and good selectivity with 6 again being the most selective (IC50 = 59 nM, SI = 478). These compounds were also cytotoxic to wild-type ovarian cancer cells as well as adriamycin-resistant and, except for 5, cisplatin-resistant ovarian cancer cells. In an acute oral toxicity test in mice, 3-6 did not exhibit toxic effects at doses of up to 100 mg/kg/dose × 3 consecutive days. This study demonstrates that C. sanguinolenta may be utilized as a sustainable source of novel compounds that may lead to the development of novel agents for the treatment of malaria, African trypanosomiasis, and cancer.

Oral thin films as a remedy for noncompliance in pediatric and geriatric patients.

Pediatric and geriatric patients experience swallowing difficulties for traditional oral dosage forms, such as tablets. Further, microbial contamination, chemical stability, unpleasant taste and swallowing large volumes of fluids have led to low therapeutic efficacy and patient noncompliance. The emergence of oral thin films has resulted in dramatic improvements in compliance and drug therapy outcomes in pediatric and geriatric patients. Oral thin films do not require water for administration, are readily hydrated upon contact with saliva, adhere to the mucosa and disintegrate ideally under 1 min. This article provides an overview of oral thin films, modern trends in their formulation and characterization, available commercial products, information to fill knowledge gaps and future potential and economic prospects of oral thin film technology, with emphasis on their use in the pediatric and geriatric patient groups.

The prevalence of malaria among HIV seropositive individuals and the impact of the co- infection on their hemoglobin levels.

BACKGROUND: Malaria and HIV/AIDS are the two most common infections in sub-Sahara Africa. There are hypotheses and study reports on the possible association between these two infections, hence the prevalence and outcome of their co-infection in an endemic population will be important in defining healthcare strategies. A cross sectional study was carried out at the Holy Family Hospital in Techiman, Ghana, between November 2011 and January 2012, to determine the prevalence of malaria among HIV sero-positive patients and its impact on hemoglobin levels. METHOD: A total of 400 HIV sero-positive participants (292 females and 108 males) aged between 1 and 73 years were randomly sampled for the study. A questionnaire was administered and 2 ml of venous blood samples were drawn for malaria parasites detection, CD4 count and haemoglobin level estimations. RESULTS: Malaria parasites were detected in 47 (11.75%) of the participants. There was no statistically significant difference between the malaria prevalence rate of females (12.1%) and males (10.2%) P = 0.6047. An overall anaemia prevalence of 67% was observed. Among participants with malaria the anaemia prevalence was 93.6%. The CD4 cell count of all the participants ranged between 3 and 1604 cells/µl with a mean of 386.2 (±274.3) cells/µl. Participants with malaria had CD4 cell count ranged 3 and 512 Cells/µl with the mean being 186.33 (±133.49) Cells/µl. Out of 377 participants (all above 15 years) interviewed on knowledge of malaria transmission and prevention, 87.0% had knowledge on transmission but only 8.5% use in bed nets. CONCLUSION: It was revealed that almost all the patients with malaria infection were anemic.

Clerodane diterpenes from Polyalthia longifolia (Sonn) Thw. var. pendula: Potential antimalarial agents for drug resistant Plasmodium falciparum infection.

BACKGROUND: Plasmodium falciparum drug resistance is a major public health challenge in sub-Sahara Africa. Many people are now resorting to the use of herbs in managing malaria due to the increasing treatment failures with the conventional drugs. In this study the ethanolic extract of Polyalthia longifolia (Sonn) Thw. var. pendula, a variety fondly used in folklore medicine in Ghana was investigated for potential antimalarial drug development. METHOD: The ethanolic extract of P. longifolia (Sonn) Thw. var. pendula stem bark was screened against the multidrug resistant, K1 strain of P. falciparum by the parasite lactate dehydrogenase (pLDH) assay and a good antiplasmodial activity (IC50 22.04± 4.23µg/ml) was observed which led to further chromatographic analysis in search for actives. RESULTS: Bioassay guided fractionation of the extract yielded; three clerodane diterpenes [16-hydroxycleroda-3,13-dien-16,15-olide (1), 16-oxocleroda-3,13E-dien-15-oic acid (2) and 3,16-dihydroxycleroda-4(18),13(14)Z-dien-15,16-olide (3)], a steroid [beta-stigmasterol (4)] and two alkaloids [darienine (5) and stepholidine (6)]. While compounds 4, 5 and 6 exhibited weak antiplasmodial activity (IC50 22-105µg/ml), the clerodane diterpenes exhibited significantly potent (p<0.005) blood schizonticidal activity (IC50: 3-6µg/ml). This is the first report of the antiplasmodial activity of compounds 2 and 3. In combination assay with chloroquine, compounds 1, 2, 3 and 5 antagonized the antiplasmodial activity of chloroquine while 4 and 6 demonstrated a synergistic action. CONCLUSION: The potent antiplasmodial activity of the extract of P. longifolia (Sonn) Thw. var. pendula and compounds therein strongly suggests its usefulness as an antimalarial agent and supports its inclusion or exploitation in formulations of herbal remedies for malaria in Ghana.

Synthesis, biological profiling and mechanistic studies of 4-aminoquinoline-based heterodimeric compounds with dual trypanocidal-antiplasmodial activity.

Dual submicromolar trypanocidal-antiplasmodial compounds have been identified by screening and chemical synthesis of 4-aminoquinoline-based heterodimeric compounds of three different structural classes. In Trypanosoma brucei, inhibition of the enzyme trypanothione reductase seems to be involved in the potent trypanocidal activity of these heterodimers, although it is probably not the main biological target. Regarding antiplasmodial activity, the heterodimers seem to share the mode of action of the antimalarial drug chloroquine, which involves inhibition of the haem detoxification process. Interestingly, all of these heterodimers display good brain permeabilities, thereby being potentially useful for late stage human African trypanosomiasis. Future optimization of these compounds should focus mainly on decreasing cytotoxicity and acetylcholinesterase inhibitory activity.

Synthesis and antiprotozoal activity of oligomethylene- and p-phenylene-bis(methylene)-linked bis(+)-huprines.

We have synthesized a series of dimers of (+)-(7R,11R)-huprine Y and evaluated their activity against Trypanosoma brucei, Plasmodium falciparum, rat myoblast L6 cells and human acetylcholinesterase (hAChE), and their brain permeability. Most dimers have more potent and selective trypanocidal activity than huprine Y and are brain permeable, but they are devoid of antimalarial activity and remain active against hAChE. Lead optimization will focus on identifying compounds with a more favourable trypanocidal/anticholinesterase activity ratio.

Antibiotic producing microorganisms from River Wiwi, Lake Bosomtwe and the Gulf of Guinea at Doakor Sea Beach, Ghana.

BACKGROUND: Microorganisms have provided a wealth of metabolites with interesting activities such as antimicrobial, antiviral and anticancer. In this study, a total of 119 aquatic microbial isolates from 30 samples (taken from water bodies in Ghana) were screened by the agar-well diffusion method for ability to produce antibacterial-metabolites. RESULTS: Antibacterial activity was exhibited by 27 of the isolates (14 bacteria, 9 actinomycetes and 4 fungi) against at least one of the indicator microorganisms: Enterococcus faecalis (ATCC 29212), Bacillus thuringiensis (ATCC 13838), Pseudomonas aeruginosa (ATCC 27853), Staphylococcus aureus (ATCC 25923), Proteus vulgaris (NCTC 4635) and Bacillus Subtilis (NCTC 10073). A sea isolate MAI2 (identified as a strain of Pseudomonas aeruginosa) exhibited the highest antibacterial activity (lowest zone of inhibition = 22 mm). The metabolites of MAI2 extracted with chloroform were stable to heat and gave minimum inhibitory concentrations ranging between 250 and 2000 µg/ml. Bioautography of the extract revealed seven active components. CONCLUSION: This study has therefore uncovered the potential of water bodies in the West African sub-region as reservoirs of potent bioactive metabolite producing microorganisms.

Wound healing properties and kill kinetics of Clerodendron splendens G. Don, a Ghanaian wound healing plant.

As part of our general objective of investigating indigenous plants used in wound healing in Ghana, we hereby report our findings from some in vitro and in vivo studies related to wound healing activities of Clerodendron splendens G. Don (Verbanaceae). Methanolic extract of the aerial parts of the plant was tested for antimicrobial activity against Gram positive bacteria (Bacillus subtilis, Staphylococcus aureus, Streptococcus faecalis, Micrococcus flavus, as well as resistant strains of Staph. aureus SA1199B, RN4220 and XU212), Gram negative bacteria (Escherichia coli, Pseudomonas aeruginosa, Proteous mirabilis, Klebsiella pneumoniae) and Candida albicans using the micro-well dilution method. Survivor-time studies of the microorganisms, radical scavenging activity using 2,2'-diphenylpicrylhydrazyl (DPPH) and various in vivo wound healing activity studies were also conducted on the extract. The extract exhibited biostatic action against all the test microorganisms with a Minimum Inhibition Concentration (MIC) ranging between 64 and 512 µg/ml and a free radical scavenging property with an IC(50) value of 103.2 µg/ml. The results of the in vivo wound healing tests showed that upon application of C. splendens ointment, there was a reduction in the epithelization period from 26.7 days (control) to 13.6 days along with a marked decrease in the scar area from 54.2 mm(2) (control) to 25.2 mm(2). Significant increase in the tensile strength and hydroxyproline content were also observed as compared to the control and was comparable to nitrofurazone. The above results appear to justify the traditional use of C. splendens in wound healing and treatment of skin infections in Ghana.