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Fulltext Berberine nanoparticles with enhanced in vitro bioavailability: characterization and antimicrobial activity

Sahibzada MUK, Sadiq A, Faidah HS, Khurram M, Amin MU, Haseeb A, et al.

Drug Des Devel Ther, 2018;12:303-312.
PMID: 29491706 DOI: 10.2147/DDDT.S156123

BACKGROUND: Berberine is an isoquinoline alkaloid widely used in Ayurveda and traditional Chinese medicine to treat illnesses such as hypertension and inflammatory conditions, and as an anticancer and hepato-protective agent. Berberine has low oral bioavailability due to poor aqueous solubility and insufficient dissolution rate, which can reduce the efficacy of drugs taken orally. In this study, evaporative precipitation of nanosuspension (EPN) and anti-solvent precipitation with a syringe pump (APSP) were used to address the problems of solubility, dissolution rate and bioavailability of berberine.
METHODS: Semi-crystalline nanoparticles (NPs) of 90-110 nm diameter for APSP and 65-75 nm diameter for EPN were prepared and then characterized using differential scanning calorimetry (DSC) and X-ray powder diffractometry (XRD). Thereafter, drug content solubility and dissolution studies were undertaken. Berberine and its NPs were evaluated for their antibacterial activity.
RESULTS: The results indicate that the NPs have significantly increased solubility and dissolution rate due to conversion of the crystalline structure to a semi-crystalline form.
CONCLUSION: Berberine NPs produced by both APSP and EPN methods have shown promising activities against Gram-positive and Gram-negative bacteria, and yeasts, with NPs prepared through the EPN method showing superior results compared to those made with the APSP method and the unprocessed drug.
Solubilization of beclomethasone dipropionate in sterically stabilized phospholipid nanomicelles (SSMs): physicochemical and in vitro evaluations

Sahib MN, Abdulameer SA, Darwis Y, Peh KK, Tan YT

Drug Des Devel Ther, 2012;6:29-42.
PMID: 22393583

The local treatment of lung disorders such as asthma and chronic obstructive pulmonary disease via pulmonary drug delivery offers many advantages over oral or intravenous routes of administration. This is because direct deposition of a drug at the diseased site increases local drug concentrations, which improves the pulmonary receptor occupancy and reduces the overall dose required, therefore reducing the side effects that result from high drug doses. From a clinical point of view, although jet nebulizers have been used for aerosol delivery of water-soluble compounds and micronized suspensions, their use with hydrophobic drugs has been inadequate.
Fulltext Curcuma purpurascens BI. rhizome accelerates rat excisional wound healing: involvement of Hsp70/Bax proteins, antioxidant defense, and angiogenesis activity

Rouhollahi E, Moghadamtousi SZ, Hajiaghaalipour F, Zahedifard M, Tayeby F, Awang K, et al.

Drug Des Devel Ther, 2015;9:5805-13.
PMID: 26604683 DOI: 10.2147/DDDT.S88196

Curcuma purpurascens BI. is a member of Zingiberaceae family. The purpose of this study is to investigate the wound healing properties of hexane extract of C. purpurascens rhizome (HECP) against excisional wound healing in rats.
Fulltext The chemopreventive potential of Curcuma purpurascens rhizome in reducing azoxymethane-induced aberrant crypt foci in rats

Rouhollahi E, Moghadamtousi SZ, Al-Henhena N, Kunasegaran T, Hasanpourghadi M, Looi CY, et al.

Drug Des Devel Ther, 2015;9:3911-22.
PMID: 26251570 DOI: 10.2147/DDDT.S84560

Curcuma purpurascens BI. rhizome, a member of the Zingiberaceae family, is a popular spice in Indonesia that is traditionally used in assorted remedies. Dichloromethane extract of C. purpurascens BI. rhizome (DECPR) has previously been shown to have an apoptosis-inducing effect on colon cancer cells. In the present study, we examined the potential of DECPR to prevent colon cancer development in rats treated with azoxymethane (AOM) (15 mg/kg) by determining the percentage inhibition in incidence of aberrant crypt foci (ACF). Starting from the day immediately after AOM treatment, three groups of rats were orally administered once a day for 2 months either 10% Tween 20 (5 mL/kg, cancer control), DECPR (250 mg/kg, low dose), or DECPR (500 mg/kg, high dose). Meanwhile, the control group was intraperitoneally injected with 5-fluorouracil (35 mg/kg) for 5 consecutive days. After euthanizing the rats, the number of ACF was enumerated in colon tissues. Bax, Bcl-2, and proliferating cell nuclear antigen (PCNA) protein expressions were examined using immunohistochemical and Western blot analyses. Antioxidant enzymatic activity was measured in colon tissue homogenates and associated with malondialdehyde level. The percentage inhibition of ACF was 56.04% and 68.68% in the low- and high-dose DECPR-treated groups, respectively. The ACF inhibition in the treatment control group was 74.17%. Results revealed that DECPR exposure at both doses significantly decreased AOM-induced ACF formation, which was accompanied by reduced expression of PCNA. Upregulation of Bax and downregulation of Bcl-2 suggested the involvement of apoptosis in the chemopreventive effect of DECPR. In addition, the oxidative stress resulting from AOM treatment was significantly attenuated after administration of DECPR, which was shown by the elevated antioxidant enzymatic activity and reduced malondialdehyde level. Taken together, the present data clearly indicate that DECPR significantly inhibits ACF formation in AOM-treated rats and may offer protection against colon cancer development.
Fulltext Novel swellable polymer of orchidaceae family for gastroretentive drug delivery of famotidine

Razavi M, Nyamathulla S, Karimian H, Noordin MI

Drug Des Devel Ther, 2014;8:1315-29.
PMID: 25246773 DOI: 10.2147/DDDT.S68517

This study aimed to develop hydrophilic, gastroretentive matrix tablets of famotidine with good floating and swelling properties. A novel gastroretentive drug delivery formulation was designed using salep, also known as salepi, a flour obtained from grinding dried palmate tubers of Orchis morio var mascula (Orchidaceae family). The main polysaccharide content of salep is glucomannan, highly soluble in cold and hot water, which forms a viscous solution. Salep was characterized for physicochemical properties, thermal stability, chemical interaction, and surface morphology using X-ray diffraction analysis, differential scanning calorimetry, Fourier transform infrared spectroscopy, and scanning electron microscopy. Ten different formulations (S1-S10) were prepared using famotidine to salep ratios from 1:0.5 to 1:5. Results demonstrated that all formulations were able to sustain the drug release for more than 24 hours. The S5 formulation, with a famotidine to salep ratio of 1:2.5, had the shortest floating lag time of 35 seconds and 100% drug release within 24 hours. The dissolution data were fitted into popular mathematical models to assess the mechanism of drug release. S5 showed Zero order release (R=0.9746) with Higuchi diffusion (R=0.9428). We conclude that salep, a novel polymer, can be used in controlled release formulations to sustain release for 24 hours, due to inherent swelling and gelling properties.
Fulltext Gamma scintigraphic evaluation of floating gastroretentive tablets of metformin HCl using a combination of three natural polymers in rabbits

Razavi M, Karimian H, Yeong CH, Chung LY, Nyamathulla S, Noordin MI

Drug Des Devel Ther, 2015;9:4373-86.
PMID: 26273196 DOI: 10.2147/DDDT.S86263

The present research was aimed at formulating a metformin HCl sustained-release formulation from a combination of polymers, using the wet granulation technique. A total of 16 formulations (F1-F16) were produced using different combinations of the gel-forming polymers: tamarind kernel powder, salep (palmate tubers of Orchis morio), and xanthan. Post-compression studies showed that there were no interactions between the active drug and the polymers. Results of in vitro drug-release studies indicated that the F10 formulation which contained 5 mg of tamarind kernel powder, 33.33 mg of xanthan, and 61.67 mg of salep could sustain a 95% release in 12 hours. The results also showed that F2 had a 55% similarity factor with the commercial formulation (C-ER), and the release kinetics were explained with zero order and Higuchi models. The in vivo study was performed in New Zealand White rabbits by gamma scintigraphy; the F10 formulation was radiolabeled using samarium (III) oxide ((153)Sm2O3) to trace transit of the tablets in the gastrointestinal tract. The in vivo data supported the retention of F10 formulation in the gastric region for 12 hours. In conclusion, the use of a combination of polymers in this study helped to develop an optimal gastroretentive drug-delivery system with improved bioavailability, swelling, and floating characteristics.
Fulltext Gamma scintigraphic study of the hydrodynamically balanced matrix tablets of Metformin HCl in rabbits

Razavi M, Karimian H, Yeong CH, Sarji SA, Chung LY, Nyamathulla S, et al.

Drug Des Devel Ther, 2015;9:3125-39.
PMID: 26124637 DOI: 10.2147/DDDT.S82935

The purpose of this study is to evaluate the in vitro and in vivo performance of gastro-retentive matrix tablets having Metformin HCl as model drug and combination of natural polymers. A total of 16 formulations were prepared by a wet granulation method using xanthan, tamarind seed powder, tamarind kernel powder and salep as the gel-forming agents and sodium bicarbonate as a gas-forming agent. All the formulations were evaluated for compendial and non-compendial tests and in vitro study was carried out on a USP-II dissolution apparatus at a paddle speed of 50 rpm. MOX2 formulation, composed of salep and xanthan in the ratio of 4:1 with 96.9% release, was considered as the optimum formulation with more than 90% release in 12 hours and short floating lag time. In vivo study was carried out using gamma scintigraphy in New Zealand White rabbits, optimized formulation was incorporated with 10 mg of (153)Sm for labeling MOX2 formulation. The radioactive samarium oxide was used as the marker to trace transit of the tablets in the gastrointestinal tract. The in vivo data also supported retention of MOX2 formulation in the gastric region for 12 hours and were different from the control formulation without a gas and gel forming agent. It was concluded that the prepared floating gastro-retentive matrix tablets had a sustained-release effect in vitro and in vivo, gamma scintigraphy played an important role in locating the oral transit and the drug-release pattern.
Fulltext Gastroretentive behavior of orally administered radiolabeled tamarind seed formulations in rabbits validated by gamma scintigraphy

Razavi M, Karimian H, Yeong CH, Fadaeinasab M, Khaing SL, Chung LY, et al.

Drug Des Devel Ther, 2017;11:1-15.
PMID: 28031701 DOI: 10.2147/DDDT.S115466

This study aimed to formulate floating gastroretentive tablets containing metformin hydrochloric acid (HCl), using various grades of hydrogel such as tamarind powders and xanthan to overcome short gastric residence time of the conventional dosage forms. Different concentrations of the hydrogels were tested to determine the formulation that could provide a sustained release of 12 h. Eleven formulations with different ratios of tamarind seed powder/tamarind kernel powder (TKP):xanthan were prepared. The physical parameters were observed, and in vitro drug-release studies of the prepared formulations were carried out. Optimal formulation was assessed for physicochemical properties, thermal stability, and chemical interaction followed by in vivo gamma scintigraphy study. MKP3 formulation with a TKP:xanthan ratio of 3:2 was found to have 99.87% release over 12 h. Furthermore, in vivo gamma scintigraphy study was carried out for the optimized formulation in healthy New Zealand White rabbits, and the pharmacokinetic parameters of developed formulations were obtained. 153Sm2O3 was used to trace the profile of release in the gastrointestinal tract of the rabbits, and the drug release was analyzed. The time (Tmax) at which the maximum concentration of metformin HCl in the blood (Cmax) was observed, and it was extended four times for the gastroretentive formulation in comparison with the formulation without polymers. Cmax and the half-life were found to be within an acceptable range. It is therefore concluded that MKP3 is the optimal formulation for sustained release of metformin HCl over a period of 12 h as a result of its floating properties in the gastric region.
Fulltext Aceclofenac nanocrystals with enhanced in vitro, in vivo performance: formulation optimization, characterization, analgesic and acute toxicity studies

Rahim H, Sadiq A, Khan S, Khan MA, Shah SMH, Hussain Z, et al.

Drug Des Devel Ther, 2017;11:2443-2452.
PMID: 28860715 DOI: 10.2147/DDDT.S140626

This study was aimed to enhance the dissolution rate, oral bioavailability and analgesic potential of the aceclofenac (AC) in the form of nanosuspension using cost-effective simple precipitation-ultrasonication approach. The nanocrystals were produced using the optimum conditions investigated for AC. The minimum particle size (PS) and polydispersity index was found to be 112±2.01 nm and 0.165, respectively, using hydroxypropyl methylcellulose (1%, w/w), polyvinylpyrrolidone K30 (1%, w/w) and sodium lauryl sulfate (0.12%, w/w). The characterization of AC was performed using zeta sizer, scanning electron microscopy, transmission electron microscopy, powder X-ray diffraction and differential scanning calorimetry. The saturation solubility of the AC nanocrystals was substantially increased 2.6- and 4.5-fold compared to its unprocessed active pharmaceutical ingredient in stabilizer solution and unprocessed drug. Similarly, the dissolution rate of the AC nanocrystals was substantially enhanced compared to its other counterpart. The results showed that >88% of AC nanocrystals were dissolved in first 10 min compared to unprocessed AC (8.38%), microsuspension (66.65%) and its marketed tablets (17.65%). The in vivo studies of the produced stabilized nanosuspension demonstrated that the Cmax were 4.98- and 2.80-fold while area under curve from time of administration to 24 h (AUC0→24 h) were found 3.88- and 2.10-fold greater when compared with unprocessed drug and its marketed formulation, respectively. The improved antinociceptive activity of AC nanocrystals was shown at much lower doses as compared to unprocessed drug, which is purely because of nanonization which may be attributed to improved solubility and dissolution rate of AC, ultimately resulting in its faster rate of absorption.
Fulltext Mechanism involved in insulin resistance via accumulation of β-amyloid and neurofibrillary tangles: link between type 2 diabetes and Alzheimer's disease

Rad SK, Arya A, Karimian H, Madhavan P, Rizwan F, Koshy S, et al.

Drug Des Devel Ther, 2018;12:3999-4021.
PMID: 30538427 DOI: 10.2147/DDDT.S173970

The pathophysiological link between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) has been suggested in several reports. Few findings suggest that T2DM has strong link in the development process of AD, and the complete mechanism is yet to be revealed. Formation of amyloid plaques (APs) and neurofibrillary tangles (NFTs) are two central hallmarks in the AD. APs are the dense composites of β-amyloid protein (Aβ) which accumulates around the nerve cells. Moreover, NFTs are the twisted fibers containing hyperphosphorylated tau proteins present in certain residues of Aβ that build up inside the brain cells. Certain factors contribute to the aetiogenesis of AD by regulating insulin signaling pathway in the brain and accelerating the formation of neurotoxic Aβ and NFTs via various mechanisms, including GSK3β, JNK, CamKII, CDK5, CK1, MARK4, PLK2, Syk, DYRK1A, PPP, and P70S6K. Progression to AD could be influenced by insulin signaling pathway that is affected due to T2DM. Interestingly, NFTs and APs lead to the impairment of several crucial cascades, such as synaptogenesis, neurotrophy, and apoptosis, which are regulated by insulin, cholesterol, and glucose metabolism. The investigation of the molecular cascades through insulin functions in brain contributes to probe and perceive progressions of diabetes to AD. This review elaborates the molecular insights that would help to further understand the potential mechanisms linking T2DM and AD.
Fulltext Evaluation of cytotoxic and chemotherapeutic properties of boldine in breast cancer using in vitro and in vivo models

Paydar M, Kamalidehghan B, Wong YL, Wong WF, Looi CY, Mustafa MR

Drug Des Devel Ther, 2014;8:719-33.
PMID: 24944509 DOI: 10.2147/DDDT.S58178

To date, plants have been the major source of anticancer drugs. Boldine is a natural alkaloid commonly found in the leaves and bark of Peumus boldus. In this study, we found that boldine potently inhibited the viability of the human invasive breast cancer cell lines, MDA-MB-231 (48-hour IC₅₀ 46.5±3.1 μg/mL) and MDA-MB-468 (48-hour IC₅₀ 50.8±2.7 μg/mL). Boldine had a cytotoxic effect and induced apoptosis in breast cancer cells as indicated by a higher amount of lactate dehydrogenase released, membrane permeability, and DNA fragmentation. In addition, we demonstrated that boldine induced cell cycle arrest at G2/M phase. The anticancer mechanism is associated with disruption of the mitochondrial membrane potential and release of cytochrome c in MDA-MB-231. Boldine selectively induced activation of caspase-9 and caspase-3/7, but not caspase-8. We also found that boldine could inhibit nuclear factor kappa B activation, a key molecule in tumor progression and metastasis. In addition, protein array and Western blotting analysis showed that treatment with boldine resulted in downregulation of Bcl-2 and heat shock protein 70 and upregulation of Bax in the MDA-MB-231 cell line. An acute toxicity study in rats revealed that boldine at a dose of 100 mg/kg body weight was well tolerated. Moreover, intraperitoneal injection of boldine (50 or 100 mg/kg) significantly reduced tumor size in an animal model of breast cancer. Our results suggest that boldine is a potentially useful agent for the treatment of breast cancer.
Fulltext A Review on the Role of Denosumab in Fracture Prevention

Pang KL, Low NY, Chin KY

Drug Des Devel Ther, 2020;14:4029-4051.
PMID: 33061307 DOI: 10.2147/DDDT.S270829

Denosumab is a receptor activator of nuclear factor kappa-Β ligand inhibitor, which suppresses the bone resorption process to preserve bone mass. It is usually recommended to postmenopausal women and men with high fracture risk. With the recent publication of the results from FREEDOM study and its extension, the long-term effect of denosumab in preventing fragility fractures has been put forward. This review aims at summarising the evidence of denosumab in reducing fracture risk and its safety derived from clinical studies. Most of the evidence are derived from FREEDOM trials up to 10 years of exposure. Denosumab is reported to prevent vertebral and non-vertebral fractures. It is also proven effective in Japanese women, patients with chronic kidney diseases and breast cancer patients receiving antineoplastic therapy. Denosumab discontinuation leads to high remodeling, loss of bone mineral density and increased fracture risk. These negative effects might be preventable by bisphosphonate treatment. The safety profile of denosumab is consistent with increased years of exposure. In conclusion, denosumab is a safe and effective option for reducing fracture risk among patients with osteoporosis.
Fulltext Gallic acid attenuates dextran sulfate sodium-induced experimental colitis in BALB/c mice

Pandurangan AK, Mohebali N, Norhaizan ME, Looi CY

Drug Des Devel Ther, 2015;9:3923-34.
PMID: 26251571 DOI: 10.2147/DDDT.S86345

Gallic acid (GA) is a polyhydroxy phenolic compound that has been detected in various natural products, such as green tea, strawberries, grapes, bananas, and many other fruits. In inflammatory bowel disease, inflammation is promoted by oxidative stress. GA is a strong antioxidant; thus, we evaluated the cytoprotective and anti-inflammatory role of GA in a dextran sulfate sodium (DSS)-induced mouse colitis model. Experimental acute colitis was induced in male BALB/c mice by administering 2.5% DSS in the drinking water for 7 days. The disease activity index; colon weight/length ratio; histopathological analysis; mRNA expressions of IL-21 and IL-23; and protein expression of nuclear erythroid 2-related factor 2 (Nrf2) were compared between the control and experimental mice. The colonic content of malondialdehyde and the activities of superoxide dismutase, catalase, glutathione peroxidase, and glutathione reductase activity were examined as parameters of the redox state. We determined that GA significantly attenuated the disease activity index and colon shortening, and reduced the histopathological evidence of injury. GA also significantly (P<0.05) reduced the expressions of IL-21 and IL-23. Furthermore, GA activates/upregulates the expression of Nrf2 and its downstream targets, including UDP-GT and NQO1, in DSS-induced mice. The findings of this study demonstrate the protective effect of GA on experimental colitis, which is probably due to an antioxidant nature of GA.
Fulltext Methanol leaf extract ofActinodaphne sesquipedalis(Lauraceae) enhances gastric defense against ethanol-induced ulcer in rats

Omar H, Nordin N, Hassandarvish P, Hajrezaie M, Azizan AHS, Fadaeinasab M, et al.

Drug Des Devel Ther, 2017;11:1353-1365.
PMID: 28496305 DOI: 10.2147/DDDT.S120564

Actinodaphne sesquipedalis
Hook. F. Var. Glabra (Kochummen), also known as "Medang payung" by the Malay people, belongs to the Lauraceae family. In this study, methanol leaf extract ofA. sesquipedaliswas investigated for their acute toxicity and gastroprotective effects to reduce ulcers in rat stomachs induced by ethanol. The rats were assigned to one of five groups: normal group (group 1), ulcer group (group 2), control positive drug group (group 3) and two experimental groups treated with 150 mg/kg (group 4) and 300 mg/kg (group 5) of leaf extract. The rats were sacrificed an hour after pretreatment with extracts, and their stomach homogenates and tissues were collected for further evaluation. Macroscopic and histological analyses showed that gastric ulcers in rats pretreated with the extract were significantly reduced to an extent that it allowed leukocytes penetration of the gastric walls compared with the ulcer group. In addition, an ulcer inhibition rate of >70% was detected in rats treated with both doses ofA. sesquipedalisextract, showing a notable protection of gastric layer. Severe destruction of gastric mucosa was prevented with a high production of mucus and pH gastric contents in both omeprazole-treated and extract-treated groups. Meanwhile, an increase in glycoprotein uptake was observed in pretreated rats through accumulation of magenta color in Periodic Acid Schiff staining assay. Analysis of gastric homogenate from pretreated rats showed a reduction of malondialdehyde and elevation of nitric oxide, glutathione, prostaglandin E2, superoxide dismutase and protein concentration levels in comparison with group 2. Suppression of apoptosis in gastric tissues by upregulation of Hsp70 protein and downregulation of Bax protein was also observed in rats pretreated with extract. Consistent results of a reduction of gastric ulcer and the protection of gastric wall were obtained for rats pretreated withA. sesquipedalisextract, which showed its prominent gastroprotective potential in rats' stomach against ethanol-induced ulcer.
Fulltext Liriodenine, an aporphine alkaloid from Enicosanthellum pulchrum, inhibits proliferation of human ovarian cancer cells through induction of apoptosis via the mitochondrial signaling pathway and blocking cell cycle progression

Nordin N, Majid NA, Hashim NM, Rahman MA, Hassan Z, Ali HM

Drug Des Devel Ther, 2015;9:1437-48.
PMID: 25792804 DOI: 10.2147/DDDT.S77727

Enicosanthellum pulchrum is a tropical plant from Malaysia and belongs to the Annonaceae family. This plant is rich in isoquinoline alkaloids. In the present study, liriodenine, an isoquinoline alkaloid, was examined as a potential anticancer agent, particularly in ovarian cancer. Liriodenine was isolated by preparative high-performance liquid chromatography. Cell viability was performed to determine the cytotoxicity, whilst the detection of morphological changes was carried out by acridine orange/propidium iodide assay. Initial and late apoptosis was examined by Annexin V-fluorescein isothiocyanate and DNA laddering assays, respectively. The involvement of pathways was detected via caspase-3, caspase-8, and caspase-9 analyses. Confirmation of pathways was further performed in mitochondria using a cytotoxicity 3 assay. Apoptosis was confirmed at the protein level, including Bax, Bcl-2, and survivin, while interruption of the cell cycle was used for final validation of apoptosis. The result showed that liriodenine inhibits proliferation of CAOV-3 cells at 37.3 μM after 24 hours of exposure. Changes in cell morphology were detected by the presence of cell membrane blebbing, chromatin condensation, and formation of apoptotic bodies. Early apoptosis was observed by Annexin V-fluorescein isothiocyanate bound to the cell membrane as early as 24 hours. Liriodenine activated the intrinsic pathway by induction of caspase-3 and caspase-9. Involvement of the intrinsic pathway in the mitochondria could be seen, with a significant increase in mitochondrial permeability and cytochrome c release, whereas the mitochondrial membrane potential was decreased. DNA fragmentation occurred at 72 hours upon exposure to liriodenine. The presence of DNA fragmentation indicates the CAOV-3 cells undergo late apoptosis or final stage of apoptosis. Confirmation of apoptosis at the protein level showed overexpression of Bax and suppression of Bcl-2 and survivin. Liriodenine inhibits progression of the CAOV-3 cell cycle in S phase. These findings indicate that liriodenine could be considered as a promising anticancer agent.
Fulltext Chemistry, Biosynthesis and Pharmacology of Streptonigrin: An Old Molecule with Future Prospects for New Drug Design, Development and Therapy

Nabihah Nasir N, Sekar M, Ravi S, Wong LS, Sisinthy SP, Gan SH, et al.

Drug Des Devel Ther, 2023;17:1065-1078.
PMID: 37064433 DOI: 10.2147/DDDT.S388490

Streptonigrin is an aminoquinone alkaloid isolated from Streptomyces flocculus and is gaining attention as a drug molecule owing to its potential antitumor and antibiotic effects. It was previously used as an anticancer drug but has been discontinued because of its toxic effects. However, according to the most recent studies, the toxicity of streptonigrin and its structurally modified derivatives has been reduced while maintaining their potential pharmacological action at lower concentrations. To date, many investigations have been conducted on this molecule and its derivatives to determine the most effective molecule with low toxicity to enable new drug discovery. Therefore, the main objective of this study is to provide a comprehensive review and to discuss the prospects for streptonigrin and its derived compounds, which may boost the molecule as a highly interesting target molecule for new drug design, development and therapy. To complete this review, relevant literature was collected from several scientific databases, including Google Scholar, PubMed, Scopus and ScienceDirect. Following a complete screening, the obtained information is summarized in the present review to provide a good reference and accelerate the development and utilization of streptonigrin and its derivatives as pharmaceuticals.
Fulltext Estrogen receptor modulatory effects of germinated brown rice bioactives in the uterus of rats through the regulation of estrogen-induced genes

Muhammad SI, Maznah I, Mahmud RB, Saeed MI, Imam MU, Ishaka A

Drug Des Devel Ther, 2013;7:1409-20.
PMID: 24324328 DOI: 10.2147/DDDT.S50861

The expression of genes regulated by estrogen in the uterus was studied in ovariectomized (OVX) rats treated with germinated brown rice (GBR) bioactives, and compared to Remifemin or estrogen at different doses to identify the regulation of these genes in the uterus and their molecular mechanisms.
Fulltext Evaluation of wound healing properties of bioactive aqueous fraction from Moringa oleifera Lam on experimentally induced diabetic animal model

Muhammad AA, Arulselvan P, Cheah PS, Abas F, Fakurazi S

Drug Des Devel Ther, 2016;10:1715-30.
PMID: 27307703 DOI: 10.2147/DDDT.S96968

Diabetic foot ulcer is a serious complication of diabetes, which affects a significant percentage (15%) of diabetics and up to 15%-24% of those affected may require amputation. Therefore, the economic burden of diabetic foot ulcers is enormous and is associated with high cost of treatment and prolongs hospitalization. The present study was conducted to evaluate antibacterial and in vivo wound healing activities of an aqueous fraction of Moringa oleifera on a diabetic condition. Antibacterial activity testing was carried out using agar well and tube dilution techniques. The in vivo study was conducted using six groups of animals that comprise of one normal and diabetic control group each, three treatment groups of 0.5%, 1%, and 2% w/w aqueous fraction, and a positive control group (1% w/w silver sulfadiazine). Rats were induced with diabetes using a combination of streptozotocin 65 and 150 mg/kg nicotinamide daily for 2 days, and excision wounds were created and treated with various doses (0.5%, 1%, and 2% w/w aqueous fraction) daily for 21 days. Biophysical, histological, and biochemical parameters were investigated. The results of the study revealed that aqueous fraction possessed antibacterial activity through inhibition of growth of Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli organisms. The topical application of aqueous fraction revealed enhancement of wound healing under sustained hyperglycemic condition for the duration of the experiment. This enhancement was achieved through decreased wound size, improved wound contraction, and tissue regeneration, as well as downregulation of inflammatory mediators, such as tumor necrosis factor-α, interleukin-1β, interleukin-6, inducible nitric oxide synthase, and cyclooxygenase-2, and upregulation of an angiogenic marker vascular endothelial growth factor in wound tissue treated with various doses of aqueous fraction of M. oleifera. The findings suggest that aqueous fraction of M. oleifera containing Vicenin-2 active compound may accelerate wound healing in hyperglycemic condition.
Fulltext Chemistry, Pharmacology and Therapeutic Potential of Swertiamarin - A Promising Natural Lead for New Drug Discovery and Development

Muhamad Fadzil NS, Sekar M, Gan SH, Bonam SR, Wu YS, Vaijanathappa J, et al.

Drug Des Devel Ther, 2021;15:2721-2746.
PMID: 34188450 DOI: 10.2147/DDDT.S299753

Swertiamarin, a seco-iridoid glycoside, is mainly found in Enicostemma littorale Blume (E. littorale) and exhibits therapeutic activities for various diseases. The present study aimed to provide a review of swertiamarin in terms of its phytochemistry, physicochemical properties, biosynthesis, pharmacology and therapeutic potential. Relevant literature was collected from several scientific databases, including PubMed, ScienceDirect, Scopus and Google Scholar, between 1990 and the present. This review included the distribution of swertiamarin in medicinal plants and its isolation, characterization, physicochemical properties and possible biosynthetic pathways. A comprehensive summary of the pharmacological activities, therapeutic potential and metabolic pathways of swertiamarin was also included after careful screening and tabulation. Based on the reported evidence, swertiamarin meets all five of Lipinski's rules for drug-like properties. Thereafter, the physicochemical properties of swertiamarin were detailed and analyzed. A simple and rapid method for isolating swertiamarin from E. littorale has been described. The present review proposed that swertiamarin may be biosynthesized by the mevalonate or nonmevalonate pathways, followed by the seco-iridoid pathway. It has also been found that swertiamarin is a potent compound with diverse pharmacological activities, including hepatoprotective, analgesic, anti-inflammatory, antiarthritis, antidiabetic, antioxidant, neuroprotective and gastroprotective activities. The anticancer activity of swertiamarin against different cancer cell lines has been recently reported. The underlying mechanisms of all these pharmacological effects are diverse and seem to involve the regulation of different molecular targets, including growth factors, inflammatory cytokines, protein kinases, apoptosis-related proteins, receptors and enzymes. Swertiamarin also modulates the activity of several transcription factors, and their signaling pathways in various pathological conditions are also discussed. Moreover, we have highlighted the toxicity profile, pharmacokinetics and possible structural modifications of swertiamarin. The pharmacological activities and therapeutic potential of swertiamarin have been extensively investigated. However, more advanced studies are required including clinical trials and studies on the bioavailability, permeability and administration of safe doses to offer swertiamarin as a novel candidate for future drug development.
Fulltext Promising Natural Products in New Drug Design, Development, and Therapy for Skin Disorders: An Overview of Scientific Evidence and Understanding Their Mechanism of Action

Mohd Zaid NA, Sekar M, Bonam SR, Gan SH, Lum PT, Begum MY, et al.

Drug Des Devel Ther, 2022;16:23-66.
PMID: 35027818 DOI: 10.2147/DDDT.S326332

The skin is the largest organ in the human body, composed of the epidermis and the dermis. It provides protection and acts as a barrier against external menaces like allergens, chemicals, systemic toxicity, and infectious organisms. Skin disorders like cancer, dermatitis, psoriasis, wounds, skin aging, acne, and skin infection occur frequently and can impact human life. According to a growing body of evidence, several studies have reported that natural products have the potential for treating skin disorders. Building on this information, this review provides brief information about the action of the most important in vitro and in vivo research on the use of ten selected natural products in inflammatory, neoplastic, and infectious skin disorders and their mechanisms that have been reported to date. The related studies and articles were searched from several databases, including PubMed, Google, Google Scholar, and ScienceDirect. Ten natural products that have been reported widely on skin disorders were reviewed in this study, with most showing anti-inflammatory, antioxidant, anti-microbial, and anti-cancer effects as the main therapeutic actions. Overall, most of the natural products reported in this review can reduce and suppress inflammatory markers, like tumor necrosis factor-alpha (TNF-α), scavenge reactive oxygen species (ROS), induce cancer cell death through apoptosis, and prevent bacteria, fungal, and virus infections indicating their potentials. This review also highlighted the challenges and opportunities of natural products in transdermal/topical delivery systems and their safety considerations for skin disorders. Our findings indicated that natural products might be a low-cost, well-tolerated, and safe treatment for skin diseases. However, a larger number of clinical trials are required to validate these findings. Natural products in combination with modern drugs, as well as the development of novel delivery mechanisms, represent a very promising area for future drug discovery of these natural leads against skin disorders.

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