Pharmacokinetics and tissue distribution of spray-dried carboplatin microspheres: lung targeting via intravenous route

Harsha, Sree,Al-Khars, Mohammed,Al-Hassan, Mohammed,Kumar, N. Prem,Nair, Anroop B.,Attimarad, Mahesh,Al-Dhubiab, Bandar E. 대한약학회 2014 Archives of Pharmacal Research Vol.37 No.3

For cancer therapy, microspheres can be used to increase effectiveness while decreasing side effects of treatments. We prepared gelatin microspheres containing carboplatin (GCPtM) for treating lung cancer. We prepared gelatin microspheres of carboplatin (GCPtM) for use in treating lung cancer. Microspheres were prepared using a Buchi B-90 nano spray-drier. Surface morphology was found to be shriveled to nearly spherical, with an average size of $14.7{\mu}m$. Drug loading and percentage yield were found to be $72{\pm}0.4$ and $88{\pm}0.2%$, respectively. In vitro release studies indicated that diffusion followed the Peppas model, with 99.3 % of total carboplatin released from GCPtM after 12 h, while for the pure drug this value was 92.4 % in 0.5 h. Liquification was observed during stability studies at $37^{\circ}C$ with an relative humidity of 75 %. Plasma concentration profile was described using a two-compartment model after intravenous injection of GCPtM. Carboplatin containing microspheres distributed in the lung, spleen, liver, and blood were found to be primarily distributed in the lungs. We used a powder technology (spray-dryer) method in this study to significantly reduce the overall production time and desired particle size, without using organic solvents; additionally, this method is economically feasible. Thus, microsphere may be an effective method for successfully delivering carboplatin to the lungs.

Chronic Rhinosinusitis: Therapeutic Efficacy of Anti-Inflammatory and Antibiotic Approaches

Harsha H Kariyawasam,Glenis K Scadding 대한천식알레르기학회 2011 Allergy, Asthma & Immunology Research Vol.3 No.4

Despite the high prevalence of chronic rhinosinusitis (CRS) worldwide, the exact pathogenesis of the disease remains unknown. Even with therapeutic intervention, treatment response is often only partial and frequently ineffective. The inability to define exact disease phenotypes in relation to specific disease mechanisms has led to a broad based approach with both anti-inflammatory and anti-microbial intervention. The clinical efficacy of such current therapeutic strategies is highlighted and the urgent need for further robust therapeutic intervention studies in CRS is discussed in this article.

Machine Learning Models Identify Novel Histologic Features Predictive of Clinical Disease Progression in Patients with Advanced Fibrosis due to NASH

( Harsha Pokkalla ),( Kishalve Pethia ),( Benjamin Glass ),( Jennifer Kaplan Kerner ),( Ling Han ),( Catherine Jia ),( Ryan Huss ),( Mar-ianne Camargo ),( Kathryn Kersey ),( Chuhan Chung ),( G. Mani S 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: Fibrosis is the primary determinant of disease progression in patients with nonalcoholic steatohepatitis (NASH), but the prognostic impact of other histological features is unclear. We used a machine learning(ML) approach to identify novel morphologic features and associations with disease progression in NASH patients with F3/4 fibrosis. Methods: Biopsies from 644 patients screened in phase3 trial of selonsertib (STELLAR-4) were scored by a central pathologist( CP) according to the NASH CRN and Ishak staging systems. The PathAI research platform(PathAI, Boston, MA) was trained a convolutional neural network(CNN) with >68,000 annotations (e.g. steatosis, ballooning, lobular/portal inflammation) collected from 75 board-certified pathologists on images of H&E and trichrome(TC) stained slides. For staging fibrosis, CNN models were trained using slide-level pathologist scores to recognize unique patterns associated with each stage within fibrotic regions of TC images. 202 features were extracted from biopsy images from patients (F3-F4) enrolled in the STELLAR trials. Cox regression was used to identify associations between these features with progression to cirrhosis in F3 patients, and liver-related events (e.g. decompensation, transplantation, death) in F4 patients. Results: 1526 NASH patients with F3-F4 fibrosis (median age 59 yrs, 73% diabetic, 52% F4) were included. During a median follow-up of 16.5 mos, 14.5% (105/726) of F3 patients progressed to cirrhosis, and over 15.9 mos, 2.8% (22/800) of F4 patients had liver-related events. Progression to cirrhosis was associated with greater area of Ishak 6 fibrosis and portal inflammation (Figure). Similar associations were observed in F4 patients, with hepatocellular ballooning and clinical events. In F3, a greater proportion of area of Ishak 1 fibrosis and steatosis were associated with a reduced risk of progression. In F4, area of steatosis was similarly protective, while proportion of Ishak Stage 1 Fibrosis over Ishak scored area trended towards protective. Conclusions: Liver histological evaluation using ML approach identified novel features associated with progression in NASH patients with advanced fibrosis. These data support the utility of ML approaches to evaluation of liver histology as endpoints in NASH clinical trials.

Role of Mitochondrial Oxidative Stress in Sepsis

Harsha Nagar,Shuyu Piao,Cuk-Seong Kim 대한중환자의학회 2018 Acute and Critical Care Vol.33 No.2

Mitochondria are considered the power house of the cell and are an essential part of the cellular infrastructure, serving as the primary site for adenosine triphosphate production via oxidative phosphorylation. These organelles also release reactive oxygen species (ROS), which are normal byproducts of metabolism at physiological levels; however, overproduction of ROS under pathophysiological conditions is considered part of a disease process, as in sepsis. The inflammatory response inherent in sepsis initiates changes in normal mitochondrial functions that may result in organ damage. There is a complex system of interacting antioxidant defenses that normally function to combat oxidative stress and prevent damage to the mitochondria. It is widely accepted that oxidative stress-mediated injury plays an important role in the development of organ failure; however, conclusive evidence of any beneficial effect of systemic antioxidant supplementation in patients with sepsis and organ dysfunction is lacking. Nevertheless, it has been suggested that antioxidant therapy delivered specifically to the mitochondria may be useful.

Drug Targeting to Lungs by Way of Microspheres

Harsha, N. Sree,Rani, R.H. Shobha The Pharmaceutical Society of Korea 2006 Archives of Pharmacal Research Vol.29 No.7

In many conventional drug delivery systems in vogue, failure to deliver efficient drug delivery at the target site/organs; is evident as a result, less efficacious pharmacological response is elicited. Microspheres can be derived a remedial measure which can improve site-specific drug delivery to a considerable extent. As an application, Lung-targeting Ofloxacin-loaded gelatin microspheres (GLOME) were prepared by water in oil emulsion method. The Central Composite Design (CCD) was used to optimize the process of preparation, the appearance and size distribution were examined by scanning electron microscopy, the aspects such as in vitro release characteristics, stability, drug loading, loading efficiency, pharmacokinetics and tissue distribution in albino mice were studied. The experimental results showed that the microspheres in the range of $0.32-22\;{\mu}m$. The drug loading and loading efficiency were 61.05 and 91.55% respectively. The in vitro release profile of the microspheres matched the korsmeyer’s peppas release pattern, and release at 1h was 42%, while for the original drug, ofloxacin under the same conditions 90.02% released in the first half an hour. After i.v. administration (15 min), the drug concentration of microspheres group in lung in albino mice was $1048\;{\mu}g/g$, while that of controlled group was $6.77\;{\mu}g/g$. GLOME found to release the drug to a maximum extent in the target tissue, lungs.

mTOR signalling pathway - A root cause for idiopathic autism?

( Harsha Ganesan ),( Venkatesh Balasubramanian ),( Mahalaxmi Iyer ),( Anila Venugopal ),( Mohana Devi Subramaniam ),( Ssang-goo Cho ),( Balachandar Vellingiri ) 생화학분자생물학회(구 한국생화학분자생물학회) 2019 BMB Reports Vol.52 No.7

Autism spectrum disorder (ASD) is a complex neurodevelopmental monogenic disorder with a strong genetic influence. Idiopathic autism could be defined as a type of autism that does not have a specific causative agent. Among signalling cascades, mTOR signalling pathway plays a pivotal role not only in cell cycle, but also in protein synthesis and regulation of brain homeostasis in ASD patients. The present review highlights, underlying mechanism of mTOR and its role in altered signalling cascades as a triggering factor in the onset of idiopathic autism. Further, this review discusses how distorted mTOR signalling pathway stimulates truncated translation in neuronal cells and leads to downregulation of protein synthesis at dendritic spines of the brain. This review concludes by suggesting downstream regulators such as p70S6K, eIF4B, eIF4E of mTOR signalling pathway as promising therapeutic targets for idiopathic autistic individuals. [BMB Reports 2019; 52(7): 424-433]

Sensitivity analysis and optimization of thin-film thermoelectric coolers

Harsha Choday, Sri,Roy, Kaushik American Institute of Physics 2013 JOURNAL OF APPLIED PHYSICS - Vol.113 No.21

Pharmacokinetics and tissue distribution of spray-dried carboplatin microspheres: lung targeting via intravenous route

Sree Harsha,Mohammed Al-Khars,Mohammed Al-Hassan,N. Prem Kumar,Anroop B. Nair,Mahesh Attimarad,Bandar E. Al-Dhubiab 대한약학회 2014 Archives of Pharmacal Research Vol.37 No.3

For cancer therapy, microspheres can be usedto increase effectiveness while decreasing side effects oftreatments. We prepared gelatin microspheres containingcarboplatin (GCPtM) for treating lung cancer. We preparedgelatin microspheres of carboplatin (GCPtM) for use intreating lung cancer. Microspheres were prepared using aBuchi B-90 nano spray-drier. Surface morphology wasfound to be shriveled to nearly spherical, with an averagesize of 14.7 lm. Drug loading and percentage yield werefound to be 72 ± 0.4 and 88 ± 0.2 %, respectively. In vitro release studies indicated that diffusion followed thePeppas model, with 99.3 % of total carboplatin releasedfrom GCPtM after 12 h, while for the pure drug this valuewas 92.4 % in 0.5 h. Liquification was observed duringstability studies at 37 C with an relative humidity of75 %. Plasma concentration profile was described using atwo-compartment model after intravenous injection ofGCPtM. Carboplatin containing microspheres distributedin the lung, spleen, liver, and blood were found to be primarilydistributed in the lungs. We used a powder technology(spray-dryer) method in this study to significantlyreduce the overall production time and desired particlesize, without using organic solvents; additionally, thismethod is economically feasible. Thus, microsphere maybe an effective method for successfully delivering carboplatinto the lungs.

Update on Gastrointestinal Stromal Tumors for Radiologists

Sree Harsha Tirumani,Akshay D. Baheti,Harika Tirumani,Ailbhe O’Neill,Jyothi P. Jagannathan 대한영상의학회 2017 Korean Journal of Radiology Vol.18 No.1

The management of gastrointestinal stromal tumors (GISTs) has evolved significantly in the last two decades due to better understanding of their biologic behavior as well as development of molecular targeted therapies. GISTs with exon 11 mutation respond to imatinib whereas GISTs with exon 9 or succinate dehydrogenase subunit mutations do not. Risk stratification models have enabled stratifying GISTs according to risk of recurrence and choosing patients who may benefit from adjuvant therapy. Assessing response to targeted therapies in GIST using conventional response criteria has several potential pitfalls leading to search for alternate response criteria based on changes in tumor attenuation, volume, metabolic and functional parameters. Surveillance of patients with GIST in the adjuvant setting is important for timely detection of recurrences.

Physico-chemical properties of green leaf volatiles (GLV) for ascertaining atmospheric fate and transport in fog

Vempati, Harsha,Vaitilingom, Mickael,Zhang, Zenghui,Liyana-Arachchi, Thilanga P.,Stevens, Christopher S.,Hung, Francisco R.,Valsaraj, Kalliat T. Techno-Press 2018 Advances in environmental research Vol.7 No.2

Green Leaf Volatiles (GLVs) is a class of biogenically emitted oxygenated hydrocarbons that have been identified as a potential source of Secondary Organic Aerosols (SOA) via aqueous oxidation. The physico-chemical properties of GLVs are vital to understanding their fate and transport in the atmosphere via fog processing, but few experimental data are available. We studied the aqueous solubility, 1-octanol/water partition coefficient, and Henry's law constant ($K_H$) of five GLVs at $25^{\circ}C$: methyl jasmonate, methyl salicylate, 2-methyl-3-buten-2-ol, cis-3-hexen-1-ol, and cis-3-hexenyl acetate. Henry's law constant was also measured at temperatures and ionic strengths typical of fog. Experimental values are compared to scarcely-available literature values, as well as estimations using group and bond contribution methods, property-specific correlations and molecular dynamics simulations. From these values, the partition coefficients to the air-water interface were also calculated. The large Henry's law constant of methyl jasmonate ($8091{\pm}1121M{\cdot}atm^{-1}$) made it the most significant GLV for aqueous phase photochemistry. The HENRYWIN program's bond contribution method from the Estimation Programs Interface Suite (EPI Suite) produced the best estimate of the Henry's constant for GLVs. Estimations of 1-octanol/water partition coefficient and solubility are best when correlating an experimental value of one to find the other. Finally, the scavenging efficiency was calculated for each GLV indicating aqueous phase processing will be most important for methyl jasmonate.