Microneedles Coated with Tramadol Exhibit Antinociceptive Effect in a Rat Model of Temporomandibular Hypernociception.

Coated microneedles have emerged as a promising drug delivery system for inflammatory pain treatment. We have previously shown that tramadol injection into the rat temporomandibular joint (TMJ) induces an antinociceptive and anti-inflammatory effect. In this study, microneedles coated with tramadol were investigated as a platform to treat TMJ pain. Male Wistar rats were administered tramadol using an intra-TMJ injection or with microneedles coated with tramadol, followed by 1.5% formalin nociceptive challenge administered 15 minutes later. The nociceptive behavior of rats was evaluated, and their periarticular tissues were removed after euthanasia for analysis. The duration of antinociceptive effect was determined by performing the formalin challenge at different time points extending up to 6 days post tramadol administration. Microneedles coated with tramadol produced an antinociceptive effect similar to injection of tramadol into the rat TMJ. Surprisingly, tramadol delivery using coated microneedles produced a more durable antinociceptive effect lasting as much as 2 days post tramadol delivery as compared with an antinociceptive effect lasting under 2 hours from intra-TMJ injection of tramadol. The proinflammatory cytokines tumor necrosis factor-α and interleukin-1ß (IL-1ß) were found to be reduced, whereas the anti-inflammatory cytokine IL-10 was found to be elevated in tramadol-treated groups. In conclusion, microneedles coated with tramadol can offer a therapeutic option for pain control of inflammatory disorders in the TMJ.

Solidified self-nanoemulsifying formulation for oral delivery of combinatorial therapeutic regimen: part II in vivo pharmacokinetics, antitumor efficacy and hepatotoxicity.

PURPOSE: The present work focuses on the in vivo evaluation of tamoxifen and quercetin combination loaded into solid self-nanoemulsifying drug delivery system (s-Tmx-QT-SNEDDS). METHODS: Lyophilization was employed to prepare s-Tmx-QT-SNEDDS using Aerosil 200 as carrier. The developed formulation was evaluated for in vitro cell cytotoxicity, in vivo pharmacokinetics, antitumor efficacy and toxicity studies. RESULTS: In vivo pharmacokinetics revealed ~8-fold and ~4-fold increase in oral bioavailability of tamoxifen and quercetin, respectively as compared to free counterparts. s-Tmx-QT-SNEDDS exhibited significantly higher cell cytotoxicity, as compared to free drug combination revealing ~32-fold and ~22-fold higher dose reduction index for tamoxifen and quercetin, respectively estimated using median effect dose analysis. s-Tmx-QT-SNEDDS could suppress tumor growth in DMBA induced tumor bearing animals by ~80% in contrast to ~35% observed with tamoxifen citrate. The significant appreciation in antitumor efficacy was further supported by normalized levels of tumor angiogenesis markers (MMP-2 and MMP-9). Finally, complete obliteration in tamoxifen induced hepatotoxicity was observed upon administration of developed formulation in contrast to that of clinically available tamoxifen citrate when measured as function of hepatotoxicity markers and histopathological changes. CONCLUSIONS: In nutshell, co-encapsulation of quercetin with tamoxifen in solid SNEDDS poses great potential in improving the therapeutic efficacy and safety of tamoxifen.

Solidified self-nanoemulsifying formulation for oral delivery of combinatorial therapeutic regimen: part I. Formulation development, statistical optimization, and in vitro characterization.

PURPOSE: The present work reports rationalized development and characterization of solidified self-nanoemulsifying drug delivery system for oral delivery of combinatorial (tamoxifen and quercetin) therapeutic regimen. METHODS: Suitable oil for the preparation of liquid SNEDDS was selected based on the maximum saturation solubility of both the drugs while surfactant and co-surfactant were selected based on their emulsification ability. Extreme vertices mixture design and 3(2) full factorial design were implemented for optimization of liquid SNEDDS and concentration of solid carrier in lyophilization mixture. Finally, extensive characterization of the developed formulation was performed and in vitro cellular uptake was evaluated in Caco-2 cell culture model. RESULTS: Extreme vertices mixture design indicated the desirability of 0.663, corresponded to 40:30:30 w/w as optimum ratio of oil (Capmul® MCM), surfactant (Cremophor RH 40) and co-surfactant (Labrafil 1944CS) in liquid SNEDDS, which solubilized high amount of tamoxifen (10 mg/g) and quercetin (19.44 mg/g). A, 3(2) full factorial design revealed the optimum concentration of the selected solid carrier (Aerosil 200) of 5.24% w/w and 1.61, when measured in terms of total solid content and liquid SNEDDS: Aerosil 200 ratio, respectively. The developed formulation revealed instantaneous emulsification (in < 2 min), while maintaning all the quality attributes even after storage at accelerated stability condition for 6 months. Finally, the developed formulation revealed 9.63-fold and 8.44-fold higher Caco-2 uptake of tamoxifen and quercetin, respectively in comparison with free drug counterparts. CONCLUSIONS: The developed formulation strategy revealed a great potential for oral delivery of combination drugs having utmost clinical relevance.

Novel self-nanoemulsifying formulation of quercetin: Implications of pro-oxidant activity on the anticancer efficacy.

The present work focuses on the anticancer potential of quercetin (QT) loaded self-nanoemulsifying drug delivery system (QT-SNEDDS) composed of Capmul MCM, Tween 20 and ethanol. In vitro cell culture studies revealed potential cell cytotoxicity of developed formulation mediated by its ability to induce DNA damage and apoptosis in MCF-7 cells. QT-SNEDDS at a dose of 50mg/kg demonstrated the antioxidant activity measured as function of prophylactic antitumor efficacy against DMBA induced breast tumors which revealed higher latency to the tumor growth as compared to free QT. This appreciation was further supported by normalized levels of tumor angiogenesis markers (MMP-2, MMP-9, TNF-α and IL-6). At higher doses (100mg/kg) the pro-oxidant activity was noted and exhibited significantly higher therapeutic anticancer efficacy (~65% tumor suppression) in the same model as compared to that of free QT (~20%). Finally, safety profile of developed formulation was established assessing various hepatotoxicity markers. FROM THE CLINICAL EDITOR: This basic science study focuses on the anticancer potential of a specific quercetin loaded self-nanoemulsifying drug delivery system. At higher doses significantly higher therapeutic anticancer efficacy (~65% tumor suppression) was noted in the same model as compared to that of free quercetin (~20%).

ROSE-AHF and lessons learned.

Nesiritide and dopamine have been recognized for some time as potential renal adjunct therapies in the management of patients with acute heart failure (AHF). Several studies have yielded conflicting evidence of the efficacy of both medications in enhancing the renal function of patients with AHF. The Renal Optimization Strategies Evaluation (ROSE) study was a multicenter double-blind placebo controlled trial designed to assess the potential renoprotective effects of low-dose nesiritide and dopamine in AHF patients with renal dysfunction. This article will focus on previous research, summary of results, and lessons learned from the ROSE-AHF trial as well as future directions for clinical research and applications.

Co-encapsulation of tamoxifen and quercetin in polymeric nanoparticles: implications on oral bioavailability, antitumor efficacy, and drug-induced toxicity.

The present investigation reports the preparation, optimization, and characterization of orally administrable PLGA-NPs co-encapsulated with tamoxifen (Tmx) and quercetin (QT). The developed formulation was found to have particle size 185.3 ± 1.20 nm, PDI 0.184 ± 0.004, entrapment efficiency 67.16 ± 1.24% Tmx, 68.60 ± 1.58% QT at a Tmx/QT ratio of 1:2 w/w. The stability of the freeze-dried formulation was established in simulated gastrointestinal fluids for 8 h and at accelerated stability condition for 3 months. DPPH free radical scavenging assay confirmed that the functional architecture of QT was retained in freeze-dried NPs. Higher cellular uptake, cytotoxicity, and nuclear co-localization of Tmx-QT-NPs in MCF-7 cells revealed higher efficiency of the formulation. At the same time, higher Caco-2 cell uptake revealed its potential for oral delivery, which was well corroborated with in vivo pharmacokinetics, which suggested ∼ 5-fold and ∼ 3-fold increase in oral bioavailability as compared to the free Tmx citrate and free QT, respectively. Concomitantly, significantly higher tumor suppression was observed in the case of the developed formulation in contrast to respective free drug(s) and their combination when tested against a DMBA-induced breast cancer model in female SD rats. Multiple oral administrations of Tmx-QT-NPs efficiently controlled the tumor angiogenesis as revealed by normalized levels of respective markers (MMP-2 and MMP-9). The safety profile of Tmx-QT-NPs was also established, and no measurable hepatotoxicity or oxidative stress was observed when measured as a function of respective biochemical markers in contrast to free drug(s) and their combinations. In a nutshell, the co-encapsulation strategy with PLGA-NPs could be a promising approach in improving oral delivery of Tmx and QT for cancer therapy.

An insight on topically applied formulations for management of various skin disorders.

Various types of skin disorders across each age group and in each part of geographical world are very dreadful. Despite not being fatal each time they are always of social and mental concern for suffering individuals, causing complications in millions of patients every day and require comparatively longer duration of treatment. Off late, various topical/transdermal formulations have been widely explored for the treatment of various skin ailments. The efficiency of topical therapy depends on various physiochemical properties of drugs like particle size, particle size distribution, partition coefficient, viscosity of dosage form, skin permeability, skin condition and the site of application. Therefore, in plenty of examples, long-acting topical formulations have shown to be markedly excellent in comparison to conventional dosage forms. The major advantages of topical formulations accrue from their demonstrated ability: (i) Reduced serious side effects that may occur due to undesirably higher systemic absorption of drug. (ii) Enhancement of drug accumulation at the desired site. (iii) Easy incorporation of enormous range of hydrophilic and hydrophobic drugs and (iv) Reduced risk of dose dumping and comparatively easy termination of drug release. The prospective applications of topically applied formulations and the deposition of pharmaceuticals into the skin are examined.

COVID-19 Pandemic Lockdown: A Cloud with a Silver Lining for the Road Traffic Accidents Pandemic.

Context: Effects of coronavirus disease 2019 (COVID-19) pandemic lockdown on road traffic accidents (RTAs) in Chhattisgarh, India. Background: Most neurosurgical emergencies are from brain and spine trauma. RTA is the leading cause of such injuries. While the nationwide lockdown was an extreme measure to control the COVID pandemic, it influenced the overall road traffic dynamics and neurotrauma. Objective: This study aims to assess the impact of the lockdown on neurotrauma. Methods and Materials: This retrospective study included all patients with brain and spine injuries who were admitted between January 17th and May 31st, 2020. The study population was divided into prelockdown (PL) and lockdown (L) groups. Results: Of the 668 patients, 436 were placed in the PL and 232 in the L group. The mean ages were 36.34 (SD = 17.96) and 35.98 (SD = 16.93), respectively. Male to female ratios were 82.3:17.7 in the PL group and 79.7:20.3 for the L group. RTA-related injuries were significantly lower during the lockdown period (n = 335 PL vs. 162 L [P = 0.048]). During the lockdown, there were more mild injuries (25.91% PL vs. 36.63% L) and less severe injuries (33.25% PL vs. 18.96% L [P = 0.0002]). Mortality was significantly less (P = 0.029) during the lockdown (n = 48 L vs. 124 PL). The proportion of RTA-related neurotrauma cases increased (33.33% L1, 57.14% L2, 73.13% L3, and 80.39% L4) with each phase of lockdown (L1-L4). Conclusions: During the lockdown period, the number of trauma cases had decreased, with a significant decrease in RTA-related admissions, along with their severity and mortality. The number of trauma cases and their severity increased gradually with each phase of lockdown.

Toxicity of multiwalled carbon nanotubes with end defects critically depends on their functionalization density.

Carboxylated carbon nanotubes stand as the most promising nanovectors for biomedical and pharmaceutical applications due to their ease of covalent conjugation with eclectic functional molecules including therapeutic drugs, proteins, and oligonucleotides. In the present study, we attempt to investigate how the toxicity of acid-oxidized multiwalled carbon nanotubes (MWCNTs) can be tweaked by altering their degree of functionalization and correlate the toxicity trend with their biodistribution profile. In line with that rationale, mice were exposed to 10 mg/kg of pristine (p) and acid-oxidized (f) MWCNTs with varying degrees of carboxylation through a single dose of intravenous injection. Thereafter, extensive toxicity studies were carried out to comprehend the short-term (7 day) and long-term (28 day) impact of p- and various f-MWCNT preparations on the physiology of healthy mice. Pristine MWCNTs with a high aspect ratio, surface hydrophobicity, and metallic impurities were found to induce significant hepatotoxicity and oxidative damage in mice, albeit the damage was recovered after 28 days of treatment. Conversely, acid-oxidized carboxylated CNTs with shorter lengths, hydrophilic surfaces, and high aqueous dispersibility proved to be less toxic and more biocompatible than their pristine counterparts. A thorough scrutiny of various biochemical parameters, inflammation indexes, and histopathological examination of liver indicated that toxicity of MWCNTs systematically decreased with the increased functionalization density. The degree of shortening and functionalization achieved by refluxing p-MWCNTs with strong mineral acids for 4 h were sufficient to render the CNTs completely hydrophilic and biocompatible, while inducing minimal hepatic accumulation and inflammation. Quantitative biodistribution studies in mice, intravenously injected with Tc-99m labeled MWCNTs, clearly designated that clearance of CNTs from reticuloendothelial system (RES) organs such as liver, spleen, and lungs was critically functionalization density dependent. Well-individualized MWCNTs with shorter lengths (<500 nm) and higher degrees of oxidation (surface carboxyl density >3 µmol/mg) were not retained in any of the RES organs and rapidly cleared out from the systematic circulation through renal excretion route without inducing any obvious nephrotoxicity. As both p- and f-MWCNT-treated groups were devoid of any obvious nephrotoxicity, CNTs with larger dimensions and lower degrees of functionalization, which fail to clear out from the body via renal excretion route, were thought to be excreted via biliary pathway in faeces.

Augmented anticancer efficacy of doxorubicin-loaded polymeric nanoparticles after oral administration in a breast cancer induced animal model.

The present investigation reports an extensive evaluation of in vitro and in vivo anticancer efficacy of orally administered doxorubicin-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Dox-NPs) in a breast cancer induced animal model. Spherically shaped Dox-NPs were prepared with an entrapment efficiency and particle size of 55.40 ± 2.30% and 160.20 ± 0.99 nm, respectively, and freeze-dried with 5% trehalose using stepwise freeze-drying. Cytotoxicity, as investigated on C127I cell line, revealed insignificant differences between the IC(50) of free Dox and Dox-NPs treated cells in the first 24 h, while higher cytotoxicity was demonstrated by Dox-NPs, following 72 h of incubation. Confocal laser scanning microscopy (CLSM) imaging corroborated that nanoparticles were efficiently localized into the nuclear region of C127I cells. The cellular uptake profile of Dox-NPs revealed both time and concentration dependent increases in the Caco-2 cell uptake as compared to the free Dox solution. Further, Dox-NPs significantly suppressed the growth of breast tumor in female Sprague-Dawley (SD) rats upon oral administration. Finally, orally administered Dox-NPs showed a marked reduction in cardiotoxicity when compared with intravenously injected free Dox as also evident by the increased level of malondialdehyde (MDA), lactate dehydrogenase (LDH), and creatine phosphokinase (CK-MB) and reduced levels of glutathione (GSH) and superoxide dismutase (SOD). The reduced cardiotoxicity of orally administered Dox-NPs was also confirmed by the major histopathological changes in the heart tissue after the treatments of intravenously injected free Dox and orally delivered Dox-NPs.

Mucormycosis: A deadly black fungus infection among COVID-19 patients in India.

After first phase of Covid-19, the second wave affects a lot to the Indians with mysterious fungal infection known as Mucormycosis. Here, we reviewed clinical pathogenesis, signs, symptoms and treatment against black fungus. The conclusion revealed that use of immunosuppressant to combat Covid-19 also increases the risk to get infected with mucormycosis. Patients with hyperglycemia, ketoacidosis, solid organ or bone marrow transplantion, liver cirrhosis, neutropenia are more susceptible to get attacked by Mucormycosis moulds. Early diagnosis, removal of predisposing factors, timely antifungal therapy with surgical removal of all infected tissues and adjunctive therapies are four major factors to eradicate Mucormycosis.

Rapid Spontaneous Resolution of the Acute Subdural Hematoma: Case Series and Review of Literature.

BACKGROUND: Traumatic acute subdural hematoma (ASDH) is an oft encountered entity in neurosurgery. While resolution of such thick SDHs usually takes time, certain cases of rapid spontaneous resolution have also been reported. This article attempts to review the pathophysiology, clinical and radiological features of such cases, as well as provide an insight into decision making for their management. METHODS: Electronic literature search was done to look for similar cases of spontaneous rapid resolution of ASDH. Five of authors cases have been described. Their clinical and radiological features along with those of cases from literature search were tabulated and analyzed. RESULTS: A total of 44 relevant cases were included for analyses. Of these, 39 cases were from 33 articles found in existing literature and 5 cases were from author's collection. The M:F ratio was 25:19 with a mean age was 41.84(SD-4.094) years. Twenty -six patients showed "Rapid" neurological improvement (24 hours) occurred in 10 patients. The mean hematoma resolution time on CT scan was 13.78 hours (SD 16.46) ranging from 1- 72 hours. Twenty-nine patients showed redistribution of hematoma, most commonly to tentorium and falx cerebelli. CT scan findings were classified into 5 types as per the nature of hypodensity around hematoma. The geometric mean time to resolution of hematoma was least for type 2 (7.27 hours) and type 1(7.52 hours) patients. CONCLUSION: Selected patients of ASDH with rapid neurological improvement and specific CT findings may show spontaneous resolution of ASDH. Multicentric studies with larger study population may provide better insight into the nature and outcomes of such entities.

Carbohydrate-conjugated multiwalled carbon nanotubes: development and characterization.

This work presents a novel cascade of chemical functionalization of multiwalled carbon nanotubes (MWCNTs) through chemical modification by a carbohydrate, D-galactose. Galactose-conjugated or galactosylated MWCNTs were synthesized involving the sequential steps of carboxylation, acylation, amine modification, and finally, galactose conjugation. The modification of MWCNTs with galactose was investigated by elemental analysis, x-ray diffraction analysis, Fourier transform-infrared spectroscopy, Raman spectroscopy, and zeta potential measurements, at every sequential step of functionalization. Size and surface characteristics of chemically modified MWCNTs were monitored by transmission electron microscopy and scanning electron microscopy. That galactosylation improved the dispersibility of MWCNTs in aqueous solvents was confirmed by investigation of their dispersion characteristics at different pH values. Thus, the galactosylated MWCNTs as developed could be used for delivery of different bioactive(s) as well as active ligand (galactose)-based targeting to hepatic tissue. FROM THE CLINICAL EDITOR: This work presents a novel cascade of functionalization of multiwalled carbon nanotubes (MWCNTs) through chemical modification by a carbohydrate. Galactosylation improves the dispersibility of MWCNTs in aqueous solvents. The galactosylated MWCNTs could be used for delivery of different bioactive(s) as well as active ligand-based targeting to hepatic tissue.

Clinico-etiological profile of hyponatremia among elderly age group patients in a tertiary care hospital in Sikkim.

BACKGROUND: Hyponatremia is a common condition observed in hospitalized patients. The incidence is much more in the elderly patients owing to impaired ability to maintain water and electrolyte homeostasis. It is important to evaluate and understand the causes and patient characteristics in order to deliver precise management. MATERIALS AND METHODS: Study was conducted at a teaching referral hospital in Sikkim and total of 100 elderly patients, diagnosed with hyponatremia, were enrolled in the study. Detailed medical history, clinical and laboratory examination were performed and data including treatment details were collected. Descriptive analysis was performed and results were correlated with patient characteristics. RESULTS: Mean age of the patients was 73.87 ± 6.54 years with a male to female ratio of 1:0.96. About 81% of patients were symptomatic among which lethargy (50%), drowsiness (40%), and abnormal behavior (39%) were common symptoms. Most patients (51%) had profound hyponatremia and Syndrome of inappropriate antidiuretic hormone secretion (SIADH) (36%) and drugs (26%) were the most common cause of hyponatremia in this study. The common treatment given in this study was 0.9% NaCl (71%). Mortality of patients in this study was 20%. CONCLUSION: Clinicians need to be aware of the common occurrence of hyponatremia in the elderly, especially acutely sick elderly. A systematic approach to its diagnosis with the application of simple standardized diagnostic algorithms can significantly improve the assessment and management of hyponatremia as the outcome in profound hyponatremia is governed by etiology, and not by the serum sodium level.

Preparation, characterization and evaluation of Marsupsin-phospholipid complex.

The aim of this research was to formulate Marsupsin-phospholipid complex (M-P Complex) in attempt to increase the bioavailability of marsupsin and to characterize this new formulation along with its evaluation. Marsupsin-phospholipid complex was formulated by mechanical dispersion method. In this new formulation, complex formation was confirmed by carrying out transmission electron microscopy (TEM), IR, (1)H-NMR and RP-HPLC analysis. TEM showed M-P Complex diameter range of 0.05-0.5 microm. The entrapment efficiency of M-P Complex was found to be 44%. In vitro release study revealed its first order release profile. Mean blood serum concentration vs time curve of marsupsin was of first order after oral administration of M-P Complex in albino rabbits which clearly showed remarkably increased bioavailability of M-P Complex than standardized marsupsin. The average value of C(max) and T(max) of M-P Complex were found to be 3.02 mg/ml and 10.2 h, respectively. Hence the findings demonstrate that complexing marsupsin with phospholipids results in better oral bioavailability and improved biological response than free form of standardized marsupsin.

Carbon nanomaterials in oncology: an expanding horizon.

Carbon nanomaterials have been attracting attention in oncology for the development of safe and effective cancer nanomedicines in increasing improved patient compliance for generally recognized as safe (GRAS) prominence. Toxicity, safety and efficacy of carbon nanomaterials are the major concerns in cancer theranostics. Various parameters such as particle size and shape or surface morphology, surface charge, composition, oxidation and nonoxidative-stress-related mechanisms are prone to toxicity of the carbon nanomaterials. Currently, few cancer-related products have been available on the market, although some are underway in preclinical and clinical phases. Thus, our main aim is to provide comprehensive details on the carbon nanomaterials in oncology from the past two decades for patient compliance and safety.

Metabolic enzyme considerations in cancer therapy.

The clinical application of new antineoplastic drugs has been limited because of low therapeutic index and lack of efficacy in humans. Thus, improvement in efficacy of old and new anticancer drugs has been attempted by manipulating their pharmacokinetic properties. Four inter-related factors, which determine the pharmacokinetic behavior of a drug include absorption, distribution, metabolism and excretion. The drug-metabolizing enzymes have been classified in two major groups: phase I and phase II enzymes. Phase I enzymes comprise the oxidases, dehydrogenases, deaminases, hydrolases. Phase II enzymes include primarily UDP-glucuronosyltransferases (UGTs), glutathionetransferases (GSTs), sulfotransferases (SULTs), N-acetyl transferases (NATs), methyltransferases and aminoacid transferases that conjugate products of phase I reactions and parent compounds with appropriate functional groups to generate more water soluble compounds which are more readily eliminated. The importance of these enzymes in the metabolism of specific drugs varies according to the chemical nature of the drug, Drug metabolism is modulated by factors that change among species and even among individuals in a population. Such factors can be environmental or genetic in origin, and influence how a drug is metabolized and to what extent. An awareness of these variables is invaluable when the safety and efficacy of new anticancer drugs are evaluated (1).

Microneedles enhance topical delivery of 15-deoxy-Δ12,14-prostaglandin J2 and reduce nociception in temporomandibular joint of rats.

The pain arising from temporomandibular disorders is often treated with opioids and agents that inhibit the immune response and are associated with substantial adverse effects and long-term risks. Thus, the development of new therapies that are safer and more effective is of great interest to patients and clinicians. 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is naturally produced in the human body and has anti-inflammatory properties. We have previously shown in a rat temporomandibular joint (TMJ) model that injection of 15d-PGJ2 into the rat TMJ can provide antinociceptive relief against a subsequent noxious challenge from formalin injection into the same TMJ. However, intra-TMJ injections are painful. Thus, to make the treatment patient friendly, this study aimed to evaluate whether the antinociceptive property of 15d-PGJ2 cream can be enhanced with microneedles (MNs). We found that topical application of 15d-PGJ2 cream for 15min directly on the rat TMJ skin did not induce any significant antinociceptive effect. However, if MNs were inserted in the skin for 5min, removed, and then 15d-PGJ2 cream was applied, a significant reduction in formalin-induced nociceptive behavior was observed. This reduction in nociception was comparable to an intra-TMJ injection of 15d-PGJ2. A concentration-dependent effect of 15d-PGJ2 was observed, with higher concentrations of 15d-PGJ2 in the cream showing a more durable effect up to 8h. 15d-PGJ2 cream associated with MNs also significantly reduced the release of tumor necrosis factor-α and interleukin-1 beta, which are pro-inflammatory cytokines. Our findings suggest that 15d-PGJ2 cream associated with MNs provides antinociceptive and anti-inflammatory effect, and can offer a potential patient-friendly therapeutic option for pain control related to inflammatory disorders of the TMJ.

Advances in oral delivery of anti-cancer prodrugs.

INTRODUCTION: Most anticancer drugs have poor aqueous solubility and low permeability across the gastrointestinal tract. Furthermore, extensive efflux by P-glycoproteins (P-gp) in the small intestine also limits the efficient delivery of anticancer drugs via oral route. Area covered: This review explores the prodrug strategy for oral delivery of anticancer drugs. Different categories of oral anticancer prodrugs along with recent clinical studies have been comprehensively reviewed here. Furthermore, novel anticancer prodrugs such as polymer-prodrugs and lipid-prodrugs have been discussed in detail. Finally, various nanocarrier-based approaches employed for oral delivery of anticancer prodrugs have also been discussed. Expert opinion: Premature degradation of anticancer prodrugs in the gastrointestinal tract could lead to variable pharmacokinetics and undesired toxicity. Despite their increased aqueous solubility, the oral bioavailability of several anticancer prodrugs are limited by their poor permeability across the gastrointestinal tract. These limitations can be overcome by the use of functional excipients (polymers, lipids, amino acids/dipeptides), which are specifically absorbed via transporters and receptor-mediated endocytosis. Oral delivery of anticancer prodrugs using nanocarrier-based drug delivery system is a recent development; however it should be justified based on the comparative advantages of encapsulating prodrug in a nanocarrier versus the use of anticancer prodrug molecule itself.

5-Aminolevulinic acid coated microneedles for photodynamic therapy of skin tumors.

This study evaluated the potential of coated microneedles for improved dermal delivery of 5-aminolevulinic acid (5-ALA), which naturally gets converted by cells of the tissue in to a photosensitizer called protoporphyrin IX (PPIX). Microneedle patches containing 57 microneedles were coated with 5-ALA using an in-house developed micro-precision dip coater. The coating process was optimized to achieve higher 5-ALA loading on microneedles and a high delivery efficiency into porcine cadaver skin. Using 5 dips with 25% w/v 5-ALA solution, a mass of about 350µg of 5-ALA was coated per patch, which gave a delivery efficiency of about 90% in porcine cadaver skin. Bright-field and scanning electron microscopy established that coatings of 5-ALA on microneedles of the patch were uniform. In vivo dermal pharmacokinetics showed that delivery of just 350µg of 5-ALA using coated microneedles led to about 3.2-fold higher PPIX formation after 4h, as compared to topical application of 20% w/w 5-ALA in a conventional cream formulation (25mg cream). Furthermore, with use of coated microneedles, PPIX was observed in deeper regions of the skin (~480µm) as compared to topical 5-ALA cream formulation (~150µm). The potential of PPIX for photodynamic therapy was tested in vivo. After light exposure (633nm; 118J/cm(2)), PPIX got photosensitized, and due to higher initial amount of PPIX in the coated microneedle group, about twice the amount of PPIX was photobleached compared to topical cream application. Finally, even with a lower dose of just 1.75mg 5-ALA, coated microneedles suppressed the growth of subcutaneous tumors by ~57%, while a topical cream containing 5mg of 5-ALA did not suppress the tumor volume and led to tumor growth comparable to the untreated control group. Overall, the strategy of delivering 5-ALA using coated microneedles could be a promising approach for photodynamic therapy of skin tumors.