Iridoid Derivatives as Anticancer Agents: An Updated Review from 1970-2022.

The rise of cancer cases has coincided with the urgent need for the development of potent chemical entities and/or modification of existing commodities to improve their efficacy. Increasing evidence suggests that cancer remains one of the leading causes of death globally, with colon cancer cases alone likely to rise exponentially by 2030. The exponential rise in cancer prevalence is largely attributable to the growing change toward a sedentary lifestyle and modern diets, which include genetically modified foods. At present, the prominent treatments for cancer are chemotherapy, surgery, and radiation. Despite slowing cancer progression, these treatments are known to have devastating side effects that may deteriorate the health of the patient, thus, have a low risk-benefit ratio. In addition, many cancer drugs have low bioavailability, thereby limiting their therapeutic effects in cancer patients. Moreover, the drastic rise in the resistance of neoplastic cells to chemotherapeutic agents is rendering the use of some drugs ineffective, thereby signaling the need for more anticancer chemical entities. As a result, the use of natural derivatives as anticancer agents is gaining considerable attention. Iridoids have the potential to form conjugates with other anticancer, antidiabetic, antileishmanial, and antimalarial drugs, which synergistically have the potential to increase their effects. Published studies have identified the role of iridoids, which, if fully explored, may result in cheaper and less toxic alternative/adjuvant cancer drugs. The subject of this article is natural and synthetic iridoid derivatives and their potential therapeutic roles as anticancer agents.

Challenges faced by blind patients using chronic medication at a tertiary hospital in South Africa.

Background: Difficulties faced by blind patients in using medicines are largely unknown and underexplored. This limits the ability of health providers and health policy makers to plan and provide for medicine related needs of this special group. Objectives: To describe the challenges faced by blind patients around Mankweng Hospital when taking chronic medications and to identify methods used to overcome the challenges. Methods: Quantitative cross-sectional descriptive study, where questionnaires were administered to 82 blind patients, 18 years and older, and who were on chronic medications. Data was analysed using the Statistical Package for the Social Sciences (SPSS) software. Results: Majority of participants were elderly (59%) and had partial blindness (78%). Challenges faced by participants included inability to locate and identify medication (60%), missing doses (64%), inaccurate dosing and spilling medicines (33%). A staggering 68.3% of the participants did not have specific methods to overcome challenges. Conclusions: Challenges faced by the blind and visually impaired are similar across the world. However, participants are unaware of other simple, feasible methods available in the market. Current methods used by the participants to overcome the challenges encountered are minimal or caregiver dependent. Programs may be set up at clinics, hospitals and health care centers to teach the visually impaired simple and inexpensive methods to help administer medications. Contribution: Results obtained may be used to raise awareness in health care policy makers of the under-explored challenges faced by the partially blind or completely blind patients in the use of medicines.

De novo design of anti-variant COVID vaccine with T-cell memory

Recent studies have shown the efficacy of hybrid COVID-19 vaccines using wild-type nucleocapsid (N) and Spike (S) protein. We upgrade this strategy by one step further using clinically proven spike protein (but with delta and post-delta omicron mutations) and nucleocapsid peptides conferring T-cell immunity. As per the latest research nucleocapsid peptides are perfect immunological replacement of nucleocapsid protein. Therefore, peptide linking strategy is pursued (economic for cellular biosynthesis than whole protein). One envelope peptide with potent T-cell response is also chosen. This peptide is also functionally indispensable for the virus. All these peptides were clustered in our designed cytoplasmic domain separated by non-immunogenic helical linkers. We also propose the idea of introduction of any T-cell peptide similar to other Human Corona Viruses (HuCoV) in these linker regions whenever required. In addition to COVID, the same approach can be applied for any emergency or even long-term unsolved outbreaks of Influenza, Dengue and West Nile Virus etc. In this era of novelty as presented by subunit and nucleic acid vaccines, multiepitope strategies like this can help to combat multiple diseases successfully in real time to give hope for better future.

Current Advances in Specialised Niosomal Drug Delivery: Manufacture, Characterization and Drug Delivery Applications.

Development of nanomaterials for drug delivery has received considerable attention due to their potential for achieving on-target delivery to the diseased area while the surrounding healthy tissue is spared. Safe and efficiently delivered payloads have always been a challenge in pharmaceutics. Niosomes are self-assembled vesicular nanocarriers formed by hydration of a non-ionic surfactant, cholesterol or other molecules that combine to form a versatile drug delivery system with a variety of applications ranging from topical delivery to targeted delivery. Niosomes have advantages similar to those of liposomes with regards to their ability to incorporate both hydrophilic and hydrophobic payloads. Moreover, niosomes have simple manufacturing methods, low production cost and exhibit extended stability, consequently overcoming the major drawbacks associated with liposomes. This review provides a comprehensive summary of niosomal research to date, including the types of niosomes and critical material attributes (CMA) and critical process parameters (CPP) of niosomes and their effects on the critical quality attributes (CQA) of the technology. Furthermore, physical characterisation techniques of niosomes are provided. The review then highlights recent applications of specialised niosomes in drug delivery. Finally, limitations and prospects for this technology are discussed.

A Comprehensive Review of Cross-Linked Gels as Vehicles for Drug Delivery to Treat Central Nervous System Disorders.

Gels are attractive candidates for drug delivery because they are easily producible while offering sustained and/or controlled drug release through various mechanisms by releasing the therapeutic agent at the site of action or absorption. Gels can be classified based on various characteristics including the nature of solvents used during preparation and the method of cross-linking. The development of novel gel systems for local or systemic drug delivery in a sustained, controlled, and targetable manner has been at the epitome of recent advances in drug delivery systems. Cross-linked gels can be modified by altering their polymer composition and content for pharmaceutical and biomedical applications. These modifications have resulted in the development of stimuli-responsive and functionalized dosage forms that offer many advantages for effective dosing of drugs for Central Nervous System (CNS) conditions. In this review, the literature concerning recent advances in cross-linked gels for drug delivery to the CNS are explored. Injectable and non-injectable formulations intended for the treatment of diseases of the CNS together with the impact of recent advances in cross-linked gels on studies involving CNS drug delivery are discussed.

Fabrication and Characterisation of a Photo-Responsive, Injectable Nanosystem for Sustained Delivery of Macromolecules.

The demand for biodegradable sustained release carriers with minimally invasive and less frequent administration properties for therapeutic proteins and peptides has increased over the years. The purpose of achieving sustained minimally invasive and site-specific delivery of macromolecules led to the investigation of a photo-responsive delivery system. This research explored a biodegradable prolamin, zein, modified with an azo dye (DHAB) to synthesize photo-responsive azoprolamin (AZP) nanospheres loaded with Immunoglobulin G (IgG). AZP nanospheres were incorporated in a hyaluronic acid (HA) hydrogel to develop a novel injectable photo-responsive nanosystem (HA-NSP) as a potential approach for the treatment of chorio-retinal diseases such as age-related macular degeneration (AMD) and diabetic retinopathy. AZP nanospheres were prepared via coacervation technique, dispersed in HA hydrogel and characterised via infrared spectroscopy (FTIR), X-ray diffraction (XRD) and thermogravimetric analysis (TGA). Size and morphology were studied via scanning electron microscopy (SEM) and dynamic light scattering (DLS), UV spectroscopy for photo-responsiveness. Rheological properties and injectability were investigated, as well as cytotoxicity effect on HRPE cell lines. Particle size obtained was <200 nm and photo-responsiveness to UV = 365 nm by decreasing particle diameter to 94 nm was confirmed by DLS. Encapsulation efficiency of the optimised nanospheres was 85% and IgG was released over 32 days up to 60%. Injectability of HA-NSP was confirmed with maximum force 10 N required and shear-thinning behaviour observed in rheology studies. In vitro cell cytotoxicity effect of both NSPs and HA-NSP showed non-cytotoxicity with relative cell viability of ≥80%. A biocompatible, biodegradable injectable photo-responsive nanosystem for sustained release of macromolecular IgG was successfully developed.

Empty electron states in cobalt-intercalated graphene.

The dispersion of the electronic states of epitaxial graphene (Gr) depends significantly on the strength of the bonding with the underlying substrate. We report on empty electron states in cobalt-intercalated Gr grown on Ir(111), studied by angle-resolved inverse photoemission spectroscopy and x-ray absorption spectroscopy, complemented with density functional theory calculations. The weakly bonded Gr on Ir preserves the peculiar spectroscopic features of the Gr band structure, and the empty spectral densities are almost unperturbed. Upon intercalation of a Co layer, the electronic response of the interface changes, with an intermixing of the Gr π* bands and Co d states, which breaks the symmetry of π/σ states, and a downshift of the upper part of the Gr Dirac cone. Similarly, the image potential of Ir(111) is unaltered by the Gr layer, while a downward shift is induced upon Co intercalation, as unveiled by the image state energy dispersion mapped in a large region of the surface Brillouin zone.

Graphene as an Ideal Buffer Layer for the Growth of High-Quality Ultrathin Cr2O3 Layers on Ni(111).

Metal-oxide nanostructures play a fundamental role in a large number of technological applications, ranging from chemical sensors to data storage devices. As the size of the devices shrinks down to the nanoscale, it is mandatory to obtain sharp and good quality interfaces. Here, it is shown that a two-dimensional material, namely, graphene, can be exploited as an ideal buffer layer to tailor the properties of the interface between a metallic substrate and an ultrathin oxide. This is proven at the interface between an ultrathin film of the magnetoelectric antiferromagnetic oxide Cr2O3 and a Ni(111) single crystal substrate. The chemical composition of the samples has been studied by means of X-ray photoemission spectroscopy, showing that the insertion of graphene, which remains buried at the interface, is able to prevent the oxidation of the substrate. This protective action leads to an ordered and layer-by-layer growth, as revealed by scanning tunneling microscopy data. The structural analysis performed by low-energy electron diffraction indicates that the oxide layer grown on graphene experiences a significant compressive strain, which strongly influences the surface electronic structure observed by scanning tunneling spectroscopy.

Drastic Improvement of Air Stability in an n-Type Doped Naphthalene-Diimide Polymer by Thionation.

Organic thermoelectrics are attractive for the fabrication of flexible and cost-effective thermoelectric generators (TEGs) for waste heat recovery, in particular by exploiting large-area printing of polymer conductors. Efficient TEGs require both p- and n-type conductors: so far, the air instability of polymer n-type conductors, which typically lose orders of magnitude in electrical conductivity (σ) even for short exposure time to air, has impeded processing under ambient conditions. Here we tackle this problem in a relevant class of electron transporting, naphthalene-diimide copolymers, by substituting the imide oxygen with sulfur. n-type doping of the thionated copolymer gives rise to a higher σ with respect to the non-thionated one, and most importantly, owing to a reduced energy level of the lowest-unoccupied molecular orbital, σ is substantially stable over 16 h of air exposure. This result highlights the effectiveness of chemical tuning to improve air stability of n-type solution-processable polymer conductors and shows a path toward ambient large-area manufacturing of efficient polymer TEGs.

Magnetic behavior of metastable Fe films grown on Ir(1 1 1).

We investigated the growth of ultra-thin Fe films on Ir(1 1 1) by means of in situ low energy electron diffraction and spin-resolved photoemission techniques. We observe a (1 × 1) diffraction pattern, characteristic of the fcc substrate, below four monolayers (ML). Then, a complex superstructure starts to develop, compatible with the formation of bcc-like Fe domains aligned with the substrate according to the Kourdjumov-Sachs orientation relationships. The analysis of the diffraction patterns reveals a progressive evolution towards a fully relaxed bcc lattice, characteristic of bulk Fe. Both photoemission (filled states) and inverse photoemission (empty states) results show characteristic features related to the contribution of the Fe layer, evolving towards those observed on the Fe (1 1 0) bcc surface. Spin resolution allows to detect a spectral polarization above 4 ML, corresponding to the formation of bcc Fe, which gradually increases indicating the formation of an in-plane magnetized ferromagnetic layer in thick films. No in-plane net magnetization is detected in thinner films, independent of the sample temperature down to 30 K. Following recent investigations on the Fe/Ir(1 1 1) system with microscopy techniques, we link this observation to the stabilization of a non collinear spin structure yielding an overall nil magnetization.

Spectroscopic, single crystal X-ray, Hirshfeld, in vitro and in silico biological evaluation of a new series of potent thiazole nucleus integrated with pyrazoline scaffolds.

In the present study, the spectroscopic characterization of a new series of substituted thiazole linked pyrazoline scaffolds 4a-l was performed. The formation of 4a-l from the intermediate 3-(4-chlorophenyl)-5-[4-(propan-2-yl)phenyl]-4,5-dihydro-1H-pyrazole-1-carbothioamide 2 and substituted 2-bromo-1-phenylethanone 3a-l was evidenced through the changes in FTIR, 1H NMR, 13C NMR, LCMS data. The X-ray diffraction studies revealed that compound 2 and 4g crystallized in monoclinic crystal system with P21/n space group. Compound 4j crystallized in triclinic system, P1̄ space group with Z=4. The percentage of intermolecular contacts and distribution of electrostatic potential of molecular crystal structures was resolved by Hirshfeld surface analysis with 2D finger plots and electrostatic potential map. The newly synthesized derivatives were screened for their in vitro antioxidant and antimicrobial activity. The single crystal studies revealed that, for compounds 2, 4g and 4j the isopropyl phenyl ring is positioned at near right angle with the other rings. Due to the lack of planarity of bulkier group substituted to phenyl ring (ring B), all the synthesized molecules showed weak to moderate radical scavenging capacity owing to the destabilization of the radical formed during oxidation. Also, on performing molecular docking studies to explore the interactions of ligand with the target pyrimidine nucleoside hydrolase YbeK with bound ribose complex (PNH, PDB ID-3GHW), disclosed that active compounds emerged for in vitro studies also bound to PNH more efficiently. The compounds with polar group substitution interacted through hydrogen bonding while other molecules with non-covalent interactions.

Arthroscopic treatment of femoroacetabular impingement following slipped capital femoral epiphysis.

UNLABELLED: Slipped capital femoral epiphysis (SCFE) may lead to symptomatic femoroacetabular impingement (FAI). We report our experience of arthroscopic treatment, including osteochondroplasty, for the sequelae of SCFE. Data were prospectively collected on patients undergoing arthroscopy of the hip for the sequelae of SCFE between March 2007 and February 2013, including demographic data, radiological assessment of the deformity and other factors that may influence outcome, such as the presence of established avascular necrosis. Patients completed the modified Harris hip score (mHHS) and the non-arthritic hip score (NAHS) before and after surgery. In total, 18 patients with a mean age of 19 years (13 to 42), were included in the study. All patients presented with pain in the hip and mechanical symptoms, and had evidence of FAI (cam or mixed impingement) on plain radiographs. The patients underwent arthroscopic osteoplasty of the femoral neck. The mean follow-up was 29 months (23 to 56). The mean mHHS and NAHS scores improved from 56.2 (27.5 to 100.1) and 52.1 (12.5 to 97.5) pre-operatively to 75.1 (33.8 to 96.8, p = 0.01) and 73.6 (18.8 to 100, p = 0.02) at final follow-up, respectively. Linear regression analysis demonstrated a significant association between poorer outcome scores and increased time to surgery following SCFE (p < 0.05 for all parameters except baseline MHHS). Symptomatic FAI following (SCFE) may be addressed using arthroscopic techniques, and should be treated promptly to minimise progressive functional impairment and chondrolabral degeneration. TAKE HOME MESSAGE: Arthroscopy of the hip can be used to treat femoroacetabular impingement successfully following SCFE. However, this should be performed promptly after presentation in order to prevent irreversible progression and poorer clinical outcomes.

Two peg spade plate for distal radius fractures: A novel technique.

BACKGROUND: The management of distal radius fractures raises considerable debate among orthopedic surgeons. The amount of axial shortening of the radius correlates with the functional disability after the fracture. Furthermore, articular incongruity has been correlated with the development of arthritis at the radiocarpal joint. We used two peg volar spade plate to provide a fixed angle subchondral support in comminuted distal radius fractures with early mobilization of the joint. MATERIALS AND METHODS: Forty patients (26 males and 14 females) from a period between January 2009 and December 2011 were treated with two peg volar spade plate fixation for distal radius fracture after obtaining reduction using a mini external fixator. Patients were evaluated using the demerit point system of Gartland and Werley and Sarmiento modification of Lindstrom criteria at final followup of 24 months. RESULTS: The average age was 43.55 years (range 23-57 years). Excellent to good results were seen in 85% (n = 34) and in all patients when rated according to the demerit point system of Gartland and Werley and Sarmiento modification of Lindstrom criteria, respectively. Complications observed were wrist stiffness in 5% (n = 2) and reflex sympathetic dystrophy in 2.5% (n = 1). CONCLUSIONS: The two peg volar spade plate provides a stable subchondral support in comminuted intraarticular fractures and maintains reduction in osteoporotic fractures of the distal radius. Early mobilization with this implant helps in restoring wrist motion and to prevent development of wrist stiffness.

Limb reconstruction in Ollier's disease.

We present our experience of lengthening and correction of complex deformities in the management of patients with Ollier's dysplasia (multiple enchondromatosis) from 1985 and 2002. All patients were under 18 years with a minimum follow-up time of 2 years (mean 9.6 years, range 2-15 years). There were a total of ten patients of which seven were male and three female. The mean age at presentation was 10.7 years (range 5-17 years; SD 3.7 years). The total length gain was 42.3 mm (range 30-110 mm; SD 28.9 mm). The number of days in external fixation was 164.8 days (range 76-244 days; SD 42.9 days). The bone healing index was 32.5 days/cm (18-50 days/cm; SD 10.3 days/cm). Patients with Ollier's disease have limb length inequality and angular deformities and require multiple reconstructive procedures owing to a high incidence of recurrence. We identified a tendency for the osteotomy to prematurely consolidate and advise the latency period after surgery to be 4-5 days and for distraction to proceed at a faster rate.

Multimodal and time-lapse skin registration.

BACKGROUND/PURPOSE: Computational skin analysis is revolutionizing modern dermatology. Patterns extracted from image sequences enable algorithmic evaluation. Stacking multiple images to analyze pattern variation implicitly assumes that the images are aligned per-pixel. However, breathing and involuntary motion of the patient causes significant misalignment. Alignment algorithms designed for multimodal and time-lapse skin images can solve this problem. Sequences from multi-modal imaging capture unique appearance features in each modality. Time-lapse image sequences capture skin appearance change over time. METHODS: Multimodal skin images have been acquired under five different modalities: three in reflectance (visible, parallel-polarized, and cross-polarized) and two in fluorescence mode (UVA and blue light excitation). For time-lapse imagery, 39 images of acne lesions over a 3-month period have been collected. The method detects micro-level features like pores, wrinkles, and other skin texture markings in the acquired images. Images are automatically registered to subpixel accuracy. RESULTS: The proposed registration approach precisely aligns multimodal and time-lapse images. Subsurface recovery from multimodal images has misregistration artefacts that can be eliminated using this approach. Registered time-lapse imaging captures the evolution of appearance of skin regions with time. CONCLUSION: Misalignment in skin imaging has significant impact on any quantitative or qualitative image evaluation. Micro-level features can be used to obtain highly accurate registration. Multimodal images can be organized with maximal overlap for successful registration. The resulting point-to-point alignment improves the quality of skin image analysis.

The treatment of severe slipped capital femoral epiphysis via the Ganz surgical dislocation and anatomical reduction: a prospective study.

We present our experience of the modified Dunn procedure in combination with a Ganz surgical dislocation of the hip to treat patients with severe slipped capital femoral epiphysis (SCFE). The aim was to prospectively investigate whether this technique is safe and reproducible. We assessed the degree of reduction, functional outcome, rate of complications, radiological changes and range of movement in the hip. There were 28 patients with a mean follow-up of 38.6 months (24 to 84). The lateral slip angle was corrected by a mean of 50.9° (95% confidence interval 44.3 to 57.5). The mean modified Harris hip score at the final follow-up was 89.1 (sd 9.0) and the mean Non-Arthritic Hip score was 91.3 (sd 9.0). Two patients had proven pre-existing avascular necrosis and two developed the condition post-operatively. There were no cases of nonunion, implant failure, infection, deep-vein thrombosis or heterotopic ossification. The range of movement at final follow-up was nearly normal. This study adds to the evidence that the technique of surgical dislocation and anatomical reduction is safe and reliable in patients with SCFE.

A pharmacokinetic and bioequivalence study of Contiflo ICON 400 µg tablets in healthy Indian subjects.

INTRODUCTION: Tamsulosin, an alpha1 adrenoceptor blocking agent, exhibits selectivity for alpha1 receptors in human prostate. Blockade of these adrenoceptors can cause smooth muscles in the bladder neck and prostate to relax, resulting in an improvement in urine flow rate and a reduction in symptoms of benign prostatic hypertrophy. A new formulation Contiflo ICON 400 µg has been developed by Ranbaxy Laboratories Limited, India similar to Flomaxtra XL 400 µg of Astellas Pharma Limited, United Kingdom. This product is specifically designed to achieve a more consistent plasma concentration over a period of 24-h, a lower maximum plasma concentration (Cmax) and an independence of pharmacokinetics (PKs) on food intake. METHODS: The objective of the present study was to evaluate the pharmacokinetics and bioequivalence of the new formulation Contiflo ICON 400 µg of Ranbaxy Laboratories Limited, India and Flomaxtra XL 400 µg prolonged release tablets (containing tamsulosin hydrochloride prolonged release 400 µg) of Astellas Pharma Limited, United Kingdom. Study was conducted as an open label, balanced, randomized, two-treatment, two-period, two-sequence, cross over, single-dose bioequivalence study in 32 adult male human subjects under fed conditions. The mean (range) age, weight and height of the study subjects were 27.03 years (19 - 40 years), 57.19 kg (48 - 72 kg) and 166.81 cm (154 - 181 cm) respectively. Blood samples were collected at pre-dose and at 0.5, 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 8, 9, 10, 12, 16, 20, 24, 36, 48, 72, and 96 h post dose in each period. Plasma samples were analyzed for tamsulosin by using validated liquid chromatographic mass spectrometry (LC-MS/MS) method. RESULTS: The Mean ± SD of pharmacokinetic parameters tmax, Cmax, AUC24, AUClast and AUCinf for Tamsulosin were 11.741 ± 4.7201 and 12.155 ± 6.3077 h, 10.7614 ± 4.76709 and 10.4954 ± 5.08979 ng/ml, 171.4674 ± 77.39695 and 160.6738 ± 77.98628 ng.h/ml, 262.7771 ± 150.21432 and 250.6854 ± 156.75581 ng.h/ml, 280.0702 ± 152.14253 and 273.5078 ± 156.85910 ng.h/ml for test and reference formulations respectively. The ratios of least square means and the 90% confidence interval of log transformed pharmacokinetic parameter Cmax, AUC24, AUClast and AUCinf were within 80 - 125% acceptance range. CONCLUSION: In conclusion, Contiflo ICON 400 µg tablets developed by Ranbaxy Laboratories Limited is bioequivalent to the reference formulation in healthy adult male volunteers under fed condition.

Tumor necrosis factor-alpha polymorphisms in women with idiopathic recurrent miscarriage.

We investigated the association of tumor necrosis factor-alpha (TNFalpha) gene polymorphisms with idiopathic recurrent miscarriage (RM). TNFalpha -1031T/C, -863C/A, -857C/T, -376G/A, -308G/A, -238G/A, and +488G/A single nucleotide polymorphisms (SNPs) were investigated in 204 RM women and 248 age-matched parous women by PCR-restriction fragment length polymorphism. Significantly higher frequencies of -1031C and -376A alleles were seen in RM patients; significant differences were also noted in the distribution of -1031T/C, -376G/A, and -238G/A genotypes between case and control subjects. Haploview analysis revealed high linkage disequilibrium between -857C/T and +488G/A SNPs, but was lower between the other polymorphisms. Of the possible 52 seven-locus haplotypes constructed, 10 were common, and were included in subsequent analysis. Increased frequency of CCCGGGG and CCCGGAA haplotypes, and reduced frequency of TCCGGGG and TCCGGGA haplotypes were seen in RM patients than in controls. When the Bonferroni correction was applied, differences were significant for the CCCGGAA haplotype, which was higher (OR=4.14; 95% CI=1.84-8.95), and the TCCGGGA haplotype, which were lower among RM cases (OR=0.09; 95% CI=0.02-0.68), thereby conferring RM susceptibility and protection to these haplotypes, respectively. Multivariate analysis confirmed the positive association of only CCCGGAA haplotype with RM (P=0.010; aOR=2.03; 95% CI=1.18-4.47), after controlling for a number of covariates. These results demonstrate that the TNFalpha polymorphisms, in particular the -1031T/C variant, are significantly associated with idiopathic RM. Additional replication studies on other racial groups are needed to confirm our findings.