Receptor-Assisted Nanotherapeutics for Overcoming the Blood-Brain Barrier.

Blood-brain barrier (BBB) is a distinguishing checkpoint that segregates peripheral organs from neural compartment. It protects the central nervous system from harmful ambush of antigens and pathogens. Owing to such explicit selectivity, the BBB hinders passage of various neuroprotective drug molecules that escalates into poor attainability of neuroprotective agents towards the brain. However, few molecules can surpass the BBB and gain access in the brain parenchyma by exploiting surface transporters and receptors. For successful development of brain-targeted therapy, understanding of BBB transporters and receptors is crucial. This review focuses on the transporter and receptor-based mechanistic pathway that can be manoeuvred for better comprehension of reciprocity of receptors and nanotechnological vehicle delivery. Nanotechnology has emerged as one of the expedient noninvasive approaches for brain targeting via manipulating the hurdle of the BBB. Various nanovehicles are being reported for brain-targeted delivery such as nanoparticles, nanocrystals, nanoemulsion, nanolipid carriers, liposomes and other nanovesicles. Nanotechnology-aided brain targeting can be a strategic approach to circumvent the BBB without altering the inherent nature of the BBB.

Biomolecular interactions between Plasmodium and human host: A basis of targeted antimalarial therapy.

Malaria is one of the serious health concerns worldwide as it remains a clinical challenge due to the complex life cycle of the malaria parasite and the morphological changes it undergoes during infection. The malaria parasite multiplies rapidly and spreads in the population by changing its alternative hosts. These various morphological stages of the parasite in the human host cause clinical symptoms (anemia, fever, and coma). These symptoms arise due to the preprogrammed biology of the parasite in response to the human pathophysiological response. Thus, complete elimination becomes one of the major health challenges. Although malaria vaccine(s) are available in the market, they still contain to cause high morbidity and mortality. Therefore, an approach for eradication is needed through the exploration of novel molecular targets by tracking the epidemiological changes the parasite adopts. This review focuses on the various novel molecular targets.

Vincristine-based nanoformulations: a preclinical and clinical studies overview.

Vincristine (VCR) is a chemotherapeutic agent obtained from natural alkaloid plant source Catharanthus roseus. VCR has been significantly useful in treatments of lung cancer, lymphocyte-based leukaemia, glioblastomas and acute myeloid leukaemia. VCR attaches to tubulin fibrils and prevents filament polymerization that permanently led to mitosis inhibition in cancer cells. Clinically, VCR is administered to patients in multidrug combination to reduce adverse drug effects and potential blockage of bone marrow inhibition due to prescribed monotherapy. However, VCR possesses low cancer tissue affinity and at higher dose often led to irreversible neurotoxicity. Conventional VCR injectables are successfully used in clinics, but lack of controlled release, non-specific biodistribution and consequent off-target side effects are still major challenges. Currently, nanotechnological drug delivery systems are being explored for improvement of VCR pharmacokinetic profile and tumour-specific targeting. Various nanomedicine formulations such as liposomes, lipid nanoparticles, and polymeric nanocarriers of VCR have been studied under various in vitro and in vivo models. In this review, we have summarised the chemotherapeutic role of VCR, evaluated the mechanism of action, pharmacokinetics and challenges associated with VCR delivery. Moreover, application of VCR in nanomedicine and effect on anticancer efficacy in preclinical and clinical setting are also being discussed.

Overcoming biological barriers BBB/BBTB by designing PUFA functionalised lipid-based nanocarriers for glioblastoma targeted therapy.

A major obstacle for chemotherapeutics in Glioblastoma (GB) is to reach the tumour cells due to the presence of the blood-brain barrier (BBB) and chemoresistance of anticancer drugs. The present study reports two polyunsaturated fatty acids, gamma-linolenic acid (GLA) and alpha-linolenic acid (ALA) appended nanostructured lipid carriers (NLCs) of a CNS negative chemotherapeutic drug docetaxel (DTX) for targeted delivery to GB. The ligand appended DTX-NLCs demonstrated particle size < 160 nm, PDI < 0.29 and a negative surface charge. The successful linkage of GLA (41 %) and ALA (30 %) ligand conjugation to DTX- NLCs was confirmed by diminished surface amino groups on the NLCs, lower surface charge and FTIR profiling. Fluorophore labelled GLA-DTX-NLCs and ALA-DTX-NLCs permeated the in-vitro 3D BBB model with Papp values of 1.8 × 10-3 and 1.9 × 10-3 cm/s respectively. Following permeation, both formulations showed enhanced uptake by GB immortalised cells while ALA-DTX-NLCs showed higher uptake in patient-derived GB cells as evidenced in an in-vitro 3D blood brain tumour barrier (BBTB) model. Both surface functionalised formulations showed higher internalisation in GB cells as compared to bare DTX-NLCs. ALA-DTX-NLCs and GLA-DTX-NLCs showed 13.9-fold and 6.8-fold higher DTX activity respectively at 24 h as indicated by IC50 values when tested in patient-derived GB cells. ALA-DTX-NLCs displayed better efficacy than GLA-DTX-NLCs when tested against 3D tumour spheroids and patient-derived cells. These novel formulations will contribute widely to overcoming biological barriers for treating glioblastoma.

Challenges of current treatment and exploring the future prospects of nanoformulations for treatment of atopic dermatitis.

Atopic dermatitis (AD) is a predominant and deteriorating chronic inflammation of the skin, categorized by a burning sensation and eczematous lesions in diverse portions of the body. The treatment of AD is exclusively focused to limit the itching, reduce inflammation, and repair the breached barrier of the skin. Several therapeutic agents for the treatment and management of AD have been reported and are in use in clinics. However, the topical treatment of AD has been an unswerving challenge for the medical fraternity owing to the impaired skin barrier function in this chronic skin condition. To surmount the problems of conventional drug delivery systems, numerous nanotechnology-based formulations are emerging as alternative new modalities for AD. Latter enhances the bioavailability and delivery to the target disease site, improves drug permeation and therapeutic efficacy with reduced systemic and off-target side effects, and thus improves patient health and promotes compliance. This review aims to describe the various pathophysiological events involved in the occurrence of AD, current challenges in treatment, evidence of molecular markers of AD and its management, combinatorial treatment options, and the intervention of nanotechnology-based formulations for AD therapeutics.

In Vitro Effect on Plasmodium falciparum and In Vivo Effect on Plasmodium berghei of Annomaal, an Oily Fraction Obtained from the Seeds of Annona squamosa.

Malaria remains a life-threatening health problem and is responsible for the high rates of mortality and morbidity in the tropical and subtropical regions of the world. The increasing threat of drug resistance to available artemisinin-based therapy warrants an urgent need to develop new antimalarial drugs that are safer, more effective, and have a novel mode of action. Natural plants are an excellent source of inspiration in searching for a new antimalarial agent. This research reports a systematic investigation for determining the antimalarial potential of the seeds of A. squamosa. The study shows that the crude seed extract (CSE), protein, saponin, and the oily fractions of the seeds were nontoxic at a 2000 mg/kg body weight dose when tested in Wistar rats, thus revealing high safety is classified as class 5. The oily fraction, Annomaal, demonstrated pronounced antimalarial activity with low IC50 (1.25 ± 0.183 µg/mL) against P. falciparum in vitro. The CSE and Annomaal significantly inhibited the growth of P. berghei parasites in vivo with 58.47% and 61.11% chemo suppression, respectively, while the standard drug artemether showed chemo suppression of 66.75%. Furthermore, the study demonstrated that oral administration of Annomaal at a daily dose of 250 mg/kg/day for 3 days was adequate to provide a complete cure to the P. berghei-infected mice. Annomaal thus holds promise as being patient-compliant due to the shorter treatment schedule, eliminating the need for frequent dosing for extended time periods as required by several synthetic antimalarial drugs. Further studies are needed to determine the active compounds in the oily fraction responsible for antimalarial activity.

Potential of Phytomolecules in Alliance with Nanotechnology to Surmount the Limitations of Current Treatment Options in the Management of Osteoarthritis.

Osteoarthritis (OA), a chronic degenerative musculoskeletal disorder, progressively increases with age. It is characterized by progressive loss of hyaline cartilage followed by subchondral bone remodeling and inflammaging. To counteract the inflammation, synovium releases various inflammatory and immune mediators along with metabolic intermediates, which further worsens the condition. However, even after recognizing the key molecular and cellular factors involved in the progression of OA, only disease-modifying therapies are available such as oral and topical NSAIDs, opioids, SNRIs, etc., providing symptomatic treatment and functional improvement instead of suppressing OA progression. Long-term use of these therapies leads to various life-threatening complications. Interestingly, mother nature has numerous medicinal plants containing active phytochemicals that can act on various targets involved in the development and progression of OA. Phytochemicals have been used for millennia in traditional medicine and are promising alternatives to conventional drugs with a lower rate of adverse events and efficiency frequently comparable to synthetic molecules. Nevertheless, their mechanism of action in many cases is elusive and uncertain. Even though many in vitro and in vivo studies show promising results, clinical evidence is scarce. Studies suggest that the presence of carbonyl group in the 2nd position, chloro in the 6th and an electron- withdrawing group at the 7th position exhibit enhanced COX-2 inhibition activity in OA. On the other hand, the presence of a double bond at the C2-C3 position of C ring in flavonoids plays an important role in Nrf2 activation. Moreover, with the advancements in the understanding of OA progression, SARs (structure-activity relationships) of phytochemicals and integration with nanotechnology have provided great opportunities for developing phytopharmaceuticals. Therefore, in the present review, we have discussed various promising phytomolecules, SAR as well as their nano-based delivery systems for the treatment of OA to motivate the future investigation of phytochemical-based drug therapy.

Recent nanoengineered diagnostic and therapeutic advancements in management of Sepsis.

COVID-19 acquired symptoms have affected the worldwide population and increased the load of Intensive care unit (ICU) patient admissions. A large number of patients admitted to ICU end with a deadly fate of mortality. A high mortality rate of patients was reported with hospital-acquired septic shock that leads to multiple organ failures and ultimately ends with death. The patients who overcome this septic shock suffer from morbidity that also affects their caretakers. To overcome these situations, scientists are exploring progressive theragnostic techniques with advanced techniques based on biosensors, biomarkers, biozymes, vesicles, and others. These advanced techniques pave the novel way for early detection of sepsis-associated symptoms and timely treatment with appropriate antibiotics and immunomodulators and prevent the undue effect on other parts of the body. There are other techniques like externally modulated electric-based devices working on the principle of piezoelectric mechanism that not only sense the endotoxin levels but also target them with a loaded antibiotic to neutralize the onset of inflammatory response. Recently researchers have developed a lipopolysaccharide (LPS) neutralizing cartridge that not only senses the LPS but also appropriately neutralizes with dual mechanistic insights of antibiotic and anti-inflammatory effects. This review will highlight recent developments in the new nanotechnology-based approaches for the diagnosis and therapeutics of sepsis that is responsible for the high number of deaths of patients suffering from this critical disease.

Chemometrics-assisted development of a validated LC method for simultaneous estimation of temozolomide and γ-linolenic acid: Greenness assessment and application to lipidic nanoparticles.

The described work entails the development of a simple, sensitive, green, and robust high-performance liquid chromatographic (HPLC) method for simultaneous estimation of temozolomide (TMZ) and γ-linolenic acid (GLA). The chemometric factor screening study helped identify the critical method parameters optimized using Box-Behnken design for improved understanding and enhancing the method performance. Chromatographic separation was performed on a Kinetex® C18 column (150 × 4.6 mm, 5 µm particle size) using methanol: water (pH adjusted to 3.5 using 0.5% v/v O-phosphoric acid) as the mobile phase at 0.5 mL/min flow rate and diode array detection between 210 and 360 nm. The linearity of the method was observed for concentrations of TMZ and GLA ranging between 1 and 100 µg.mL-1 (R2 = 0.999, p < 0.05). Accuracy evaluation showed good percent recovery within 97.9-100%, while intra- and inter-day precision showed RSD values within 0.37%-1.01%. The limit of detection and quantification for TMZ was found to be 0.75 and 1.0 µg.mL-1, respectively, while the values 0.55 and 1.0 µg.mL-1, respectively, were observed for GLA. System suitability (96.9-102.8%), its limits, and robustness evaluation indicated good percent recovery within, while RSD values were found to be within the acceptable limit of less than 2%. The method was specific for its ability to detect the analytes and their degradation products during forced degradation studies, which also indicated that TMZ was highly prone to alkaline conditions while GLA showed mild degradation in all the studied conditions. The estimation of both the analytes from lipid nanoparticles formulation showed good values for total drug content (82.6-85.3%), entrapment efficiency (95.4 to 98.7%), and drug loading (25.2 to 38.4%). Overall, the results indicated that the developed method was reliable for its accuracy, precision, sensitivity, and specificity for simultaneous estimation of the analytes. The method was found to be stability-indicating in nature and suitable for simultaneous estimation of TMZ and GLA from the developed nanoparticles formulation. Further, employing a greenness assessment approach established the method greenness.

Pharmaceutical strategies for the treatment of bacterial biofilms in chronic wounds.

Biofilms are sessile communities of microorganisms, mainly bacteria, that grow on biotic and abiotic surfaces. These microorganisms are embedded within an extracellular polymeric substance that provides enhanced protection from antimicrobials. Chronic wounds provide an ideal habitat for biofilm formation. Bacteria can easily attach to wound debris and can infect the wound due to an impaired host immune response. This review highlights the mechanism of biofilm formation and the role of biofilms in the pathophysiology of chronic wounds. Our major focus is on various formulation strategies and delivery systems that are employed to eradicate or disperse biofilms, thereby effectively managing acute and chronic wounds. We also discuss clinical research that has studied or is studying the treatment of biofilm-infected chronic wounds.

Tetrahydrocurcumin Lipid Nanoparticle Based Gel Promotes Penetration into Deeper Skin Layers and Alleviates Atopic Dermatitis in 2,4-Dinitrochlorobenzene (DNCB) Mouse Model.

Treatment of atopic dermatitis (AD) is challenging due to its complex pathophysiology. Tetrahydrocurcumin (THC) a polyphenolic, colorless compound that is more polar than curcumin. It possesses superior anti-inflammatory properties and has a clinical advantage over curcumin. The present study investigated the therapeutic effectiveness of THC solid lipid nanoparticle (THC-SLN)-based gels in AD. THC-SLNs prepared using microemulsification resulted in a particle size of 109.2 nm as determined by nanoparticle tracking, and FTIR confirmed the entrapment of drug within the lipid matrix. THC-SLNs greatly enhanced skin hydration when tested both ex vivo and in vivo in Lacca mice. Deeper skin penetration was clearly established using dermatokinetics and CLSM. The in vivo pharmacodynamics of THC-SLNs gel in 2,4-dinitrochlorobenzene (DNCB)-induced AD mice showed enhanced bioactivity; reduced levels of TNF-α and IL-6; and complete healing, as evident from histopathological studies. Thus, the novel topical THC-SLN gel has potential to emerge as a safe alternative to conventional corticosteroids for AD and other skin disorders with overbearing inflammation.

Nanostructured Lipid Carriers Deliver Resveratrol, Restoring Attenuated Dilation in Small Coronary Arteries, via the AMPK Pathway.

Nanostructured lipid carriers (NLCs) are an emerging drug delivery platform for improved drug stability and the bioavailability of antihypertensive drugs and vasoprotective nutraceutical compounds, such as resveratrol (RV). The objective of this study was to ascertain NLCs' potential to deliver RV and restore attenuated dilator function, using an ex vivo model of acute hypertension. Trimyristin-triolein NLCs were synthesized and loaded with RV. The uptake of RV-NLCs by human coronary artery endothelial cells (HCAECs) maintained their viability and reduced both mitochondrial and cytosolic superoxide levels. Acute pressure elevation in isolated coronary arteries significantly attenuated endothelial-dependent dilator responses, which were reversed following incubation in RV-NLCs, superoxide dismutase or apocynin (p < 0.0001). RV-NLCs demonstrated a five-fold increase in potency in comparison to RV solution. At elevated pressure, in the presence of RV-NLCs, incubation with Nω-nitro-l-arginine (L-NNA) or indomethacin resulted in a significant reduction in the restored dilator component (p < 0.0001), whereas apamin and TRAM-34 had no overall effect. Incubation with the adenosine monophosphate-activated protein kinase (AMPK) inhibitor dorsomorphin significantly attenuated dilator responses (p < 0.001), whereas the SIRT-1 inhibitor EX-527 had no effect. RV-NLCs improved the impaired endothelial-dependent dilation of small coronary arteries, following acute pressure elevation, via NO and downstream COX elements, mediated by AMPK. We suggest that RV-NLCs are an effective delivery modality for improved potency and sustained drug release into the vasculature. Our findings have important implications for the future design and implementation of antihypertensive treatment strategies.

Recent advances in lipid-engineered multifunctional nanophytomedicines for cancer targeting.

Cancer is a leading cause of death in many countries around the world. However, the efficacy of current treatments available for variety of cancers is considered to be suboptimal due to the pathophysiological challenges associated with the disease which limits the efficacy of the anticancer drugs. Moreover, the vulnerability towards off-target effects and high toxicity also limits the use of drugs for the treatment of cancers. Besides, the biopharmaceutical challenges like poor water solubility and permeability of the drugs, along with the absence of active targeting capability further decreases the utility of drugs in cancer therapy. As a result of these deficiencies, the current therapeutic strategies face noncompliance to patients for providing meaningful benefits after administration. With the advancements in nanotechnology, there has been a paradigm shift in the modalities for cancer treatment with the help of phytomedicine-based nanosized drug delivery systems coupled with variegated surface-engineering strategies for targeted drug delivery. Among these delivery systems, lipid-based nanoparticles are considered as one of the highly biocompatible, efficient and effective systems extensively explored for anticancer drug delivery. These include diverse range of systems including liposomes, nanoemulsions, solid lipid nanoparticles, nanostructured lipidic carriers and supramolecular carriers, which alters pharmacokinetic and biodistribution of the drugs for active targeting to the desired site of action by overcoming the biopharmaceutical challenges associated with anticancer drug delivery. The present review endeavours to provide a comprehensive account on the recent advances in the application of lipid-based nanostructured systems for improving the pharmacotherapeutic performance of phytomedicines for cancer targeting application.

Tailoring functional nanostructured lipid carriers for glioblastoma treatment with enhanced permeability through in-vitro 3D BBB/BBTB models.

The blood-brain barrier (BBB) and blood-brain tumour barrier (BBTB) pose a significant challenge to drug delivery to brain tumours, including aggressive glioblastoma (GB). The present study rationally designed functional nanostructured lipid carriers (NLC) to tailor their BBB penetrating properties with high encapsulation of CNS negative chemotherapeutic drug docetaxel (DTX). We investigated the effect of four liquid lipids, propylene glycol monolaurate (Lauroglycol® 90), Capryol® propylene glycol monocaprylate, caprylocaproylmacrogol-8-glycerides (Labrasol®) and polyoxyl-15-hydroxystearate (Kolliphor® HS15) individually and in combination to develop NLCs with effective permeation across in-vitro 3D BBB model without alteration in the integrity of the barrier. With desirable spherical shape as revealed by TEM and an average particle size of 123.3 ± 0.642 nm and zeta potential of -32 mV, DTX-NLCs demonstrated excellent stability for six months in its freeze-dried form. The confocal microscopy along with flow cytometry data revealed higher internalisation of DTX-NLCs in U87MG over SVG P12 cells. Micropinocytosis was observed to be one of the dominant pathways for internalisation in U87MG cells while clathrin-mediated pathway was more predominat in patient-derived glioblastoma cells. The NLCs readily penetrated the actively proliferating peripheral cells on the surface of the 3D tumour spheroids as compared to the necrotic core. The DTX-NLCs induced cell arrest through G2/M phase with a significant decrease in the mitochondrial reserve capacity of cells. The NLCs circumvented BBTB with high permeability followed by accumulation in glioblastoma cells with patient-derived cells displaying ~2.4-fold higher uptake in comparison to U87MG when studied in a 3D in-vitro model of BBTB/GB. We envisage this simple and industrially feasible technology as a potential candidate to be developed as GB nanomedicine.

Nebulised surface-active hybrid nanoparticles of voriconazole for pulmonary Aspergillosis demonstrate clathrin-mediated cellular uptake, improved antifungal efficacy and lung retention.

BACKGROUND: Incidence of pulmonary aspergillosis is rising worldwide, owing to an increased population of immunocompromised patients. Notable potential of the pulmonary route has been witnessed in antifungal delivery due to distinct advantages of direct lung targeting and first-pass evasion. The current research reports biomimetic surface-active lipid-polymer hybrid (LPH) nanoparticles (NPs) of voriconazole, employing lung-specific lipid, i.e., dipalmitoylphosphatidylcholine and natural biodegradable polymer, i.e., chitosan, to augment its pulmonary deposition and retention, following nebulization. RESULTS: The developed nanosystem exhibited a particle size in the range of 228-255 nm and drug entrapment of 45-54.8%. Nebulized microdroplet characterization of NPs dispersion revealed a mean diameter of ≤ 5 µm, corroborating its deep lung deposition potential as determined by next-generation impactor studies. Biophysical interaction of LPH NPs with lipid-monolayers indicated their surface-active potential and ease of intercalation into the pulmonary surfactant membrane at the air-lung interface. Cellular viability and uptake studies demonstrated their cytocompatibility and time-and concentration-dependent uptake in lung-epithelial A549 and Calu-3 cells with clathrin-mediated internalization. Transepithelial electrical resistance experiments established their ability to penetrate tight airway Calu-3 monolayers. Antifungal studies on laboratory strains and clinical isolates depicted their superior efficacy against Aspergillus species. Pharmacokinetic studies revealed nearly 5-, 4- and threefolds enhancement in lung AUC, Tmax, and MRT values, construing significant drug access and retention in lungs. CONCLUSIONS: Nebulized LPH NPs were observed as a promising solution to provide effective and safe therapy for the management of pulmonary aspergillosis infection with improved patient compliance and avoidance of systemic side-effects.

Aerosolizable Lipid-Nanovesicles Encapsulating Voriconazole Effectively Permeate Pulmonary Barriers and Target Lung Cells.

The entire world has recently been witnessing an unprecedented upsurge in microbial lung infections. The major challenge encountered in treating the same is to ensure the optimum drug availability at the infected site. Aerosolization of antimicrobials, in this regard, has shown immense potential owing to their localized and targeted effect. Efforts, therefore, have been undertaken to systematically develop lung-phosphatidylcholine-based lipid nanovesicles of voriconazole for potential management of the superinfections like aspergillosis. LNVs, prepared by thin-film hydration method, exhibited a globule size of 145.4 ± 19.5 nm, polydispersity index of 0.154 ± 0.104 and entrapment efficiency of 71.4 ± 2.2% with improved in vitro antifungal activity. Aerodynamic studies revealed a microdroplet size of ≤5 µm, thereby unraveling its promise to target the physical barrier of lungs effectively. The surface-active potential of LNVs, demonstrated through Langmuir-Blodgett troughs, indicated their ability to overcome the biochemical pulmonary surfactant monolayer barrier, while the safety and uptake studies on airway-epithelial cells signified their immense potential to permeate the cellular barrier of lungs. The pharmacokinetic studies showed marked improvement in the retention profile of voriconazole in lungs following LNVs nebulization compared to pristine voriconazole. Overall, LNVs proved to be safe and effective delivery systems, delineating their distinct potential to efficiently target the respiratory fungal infections.

Engineered Site-specific Vesicular Systems for Colonic Delivery: Trends and Implications.

Steering drug-loaded, site-specific, coated lipid vesicles to the target receptor sites have the potential of plummeting adverse effects and improving the pharmacological response in diverse pathologies of the large bowel, especially the colon. Colonic delivery via oral route has its own challenges, often governed by several glitches such as drug degradation or absorption in the upper GIT, instability of proteins/peptides due to high molecular weight, and peptidase activity in the stomach. Consequently, colon-specific coated liposomal systems (CSLS) offer a potential alternate for not only site-specificity, but protection from proteolytic activity, and prolonged residence time for greater systemic bioavailability. On the other hand, liposomal delivery via the oral route is also cumbersome owing to several barriers such as instability in GIT, difficulty in crossing membranes, and issues related to production at the pilot scale. New advancements in the field of CSLS have successfully improved the stability and permeability of liposomes for oral delivery via modulating the compositions of lipid bilayers, adding polymers or ligands. Despite this ostensible propitiousness, no commercial oral CSLS has advanced from bench to bedside for targeted delivery to the colon as yet. Nevertheless, CSLS has quite fascinated the manufacturers owing to its potential industrial viability, simplistic and low-cost design. Hence, this review aims to decipher the convolutions involved in the engineering process of industrially viable CSLS for colonic delivery.

In vitro anti-HIV activity of some Indian medicinal plant extracts.

BACKGROUND: Human Immunodeficiency Virus (HIV) persists to be a significant public health issue worldwide. The current strategy for the treatment of HIV infection, Highly Active Antiretroviral Therapy (HAART), has reduced deaths from AIDS related disease, but it can be an expensive regime for the underdeveloped and developing countries where the supply of drugs is scarce and often not well tolerated, especially in persons undergoing long term treatment. The present therapy also has limitations of development of multidrug resistance, thus there is a need for the discovery of novel anti-HIV compounds from plants as a potential alternative in combating HIV disease. METHODS: Ten Indian medicinal plants were tested for entry and replication inhibition against laboratory adapted strains HIV-1IIIB, HIV-1Ada5 and primary isolates HIV-1UG070, HIV-1VB59 in TZM-bl cell lines and primary isolates HIV-1UG070, HIV-1VB59 in PM1 cell lines. The plant extracts were further evaluated for toxicity in HEC-1A epithelial cell lines by transwell epithelial model. RESULTS: The methanolic extracts of Achyranthes aspera, Rosa centifolia and aqueous extract of Ficus benghalensis inhibited laboratory adapted HIV-1 strains (IC80 3.6-118 µg/ml) and primary isolates (IC80 4.8-156 µg/ml) in TZM-bl cells. Methanolic extract of Strychnos potatorum, aqueous extract of Ficus infectoria and hydroalcoholic extract of Annona squamosa inhibited laboratory adapted HIV-1 strains (IC80 4.24-125 µg/ml) and primary isolates (IC80 18-156 µg/ml) in TZM-bl cells. Methanolic extracts of Achyranthes aspera and Rosa centifolia, (IC801-9 µg/ml) further significantly inhibited HIV-1 primary isolates in PM1cells. Methanolic extracts of Tridax procumbens, Mallotus philippinensis, Annona reticulate, aqueous extract of Ficus benghalensis and hydroalcoholic extract of Albizzia lebbeck did not exhibit anti-HIV activity in all the tested strains. Methanolic extract of Rosa centifolia also demonstrated to be non-toxic to HEC-1A epithelial cells and maintained epithelial integrity (at 500 µg/ml) when tested in transwell dual-chamber. CONCLUSION: These active methanolic extracts of Achyranthes aspera and Rosa centifolia, could be further subjected to chemical analysis to investigate the active moiety responsible for the anti-HIV activity. Methanolic extract of Rosa centifolia was found to be well tolerated maintaining the epithelial integrity of HEC-1A cells in vitro and thus has potential for investigating it further as candidate microbicide.

An Efficient and Cost-Effective Nose-Only Inhalational Chamber for Rodents: Design, Optimization and Validation.

The mainstay treatment of pulmonary disorders lies around the direct drug targeting to the lungs using a nebulizer, metered-dose inhaler, or dry powder inhaler. Only few inhalers are available in the market that could be used for inhalational drug delivery in rodents. However, the available rodent inhalers invariably require high cost and maintenance, which limits their use at laboratory scale. The present work, therefore, was undertaken to develop a simple, reliable, and cost-effective nose-only inhalation chamber with holding capacity of three mice at a time. The nebulized air passes directly and continuously from the central chamber to mouthpiece and maintains an aerosol cloud for rodents to inhale. Laser diffraction analysis indicated volume mean diameter of 4.02 ± 0.30 µm, and the next-generation impactor studies, however, revealed mean mass aerodynamic diameter of 3.40 ± 0.27 µm, respectively. An amount of 2.05 ± 0.20 mg of voriconazole (VRC) was available for inhalation at each delivery port of the inhaler. In vivo studies indicated the deposition of 76.12 ± 19.50 µg of VRC in the mice lungs when nebulized for a period of 20 min. Overall, the developed nose-only inhalation chamber offers a reliable means of generating aerosols and successfully exposing mice to nebulization.

Inhalational Drug Delivery in Pulmonary Aspergillosis.

Pulmonary infections have long represented one of the major threats to humans. These vary from acute to chronic conditions, depending upon the underlying disease of the airways. Pulmonary aspergillosis (PMAP) has raised vital concerns in the immunocompromised patients. The fungal infection is difficult to diagnose in the early stages, often making the disease more complicated. Currently, three classes of antifungal agents are available on the market for the treatment of pulmonary infections. These agents are available in oral and intravenous forms only, which limits the availability of therapeutic concentrations of drug in the lungs for longer durations. Consequently, this leads to therapeutic failure and/or resistance of the organism(s) towards the antifungal agents because the optimum amount of drug does not reach the infection site. To combat the issues associated with the conventional regimens, inhalation of antifungal agents is gaining importance because administration to the lungs offers huge advantages of localized and targeted delivery. A wide range of inhalational devices such as nebulizers, dry powder inhalers, and metered dose inhalers are available on the market to deliver drug molecules to the lungs effectively. However, their clinical utility is limited to conditions such as asthma, chronic obstructive pulmonary disease, and cystic fibrosis only. For a few decades, inhalation therapy has also been gaining importance to treat infectious diseases such as tuberculosis and aspergillosis, though more research efforts are required to make the transition from bench to bedside. The current review provides an explicit account of the potential role of inhalation drug delivery in PMAP.