Investigating Organ Toxicity Profile of Tenofovir and Tenofovir Nanoparticle on the Liver and Kidney: Experimental Animal Study

Peter, Aniekan Imo,Naidu, Edwin CS,Akang, Edidiong,Ogedengbe, Oluwatosin O,Offor, Ugochukwu,Rambharose, Sanjeev,Kalhapure, Rahul,Chuturgoon, Anil,Govender, Thirumala,Azu, Onyemaechi O Korean Society of ToxicologyKorea Environmental Mu 2018 Toxicological Research Vol.34 No.3

Tenofovir nanoparticles are novel therapeutic intervention in human immunodeficiency virus (HIV) infection reaching the virus in their sanctuary sites. However, there has been no systemic toxicity testing of this formulation despite global concerns on the safety of nano drugs. Therefore, this study was designed to investigate the toxicity of Tenofovir nanoparticle (NTDF) on the liver and kidney using an animal model. Fifteen adult male Sprague-Dawley (SD) rats maintained at the animal house of the biomedical resources unit of the University of KwaZulu-Natal were weighed and divided into three groups. Control animals (A) were administered with normal saline (NS). The therapeutic doses of Tenofovir (TDF) and nanoparticles of Tenofovir (NTDF) were administered to group B and C and observed for signs of stress for four weeks after which animals were weighed and sacrificed. Liver and kidney were removed and fixed in formal saline, processed and stained using H/E, PAS and MT stains for light microscopy. Serum was obtained for renal function test (RFT) and liver function test (LFT). Cellular measurements and capturing were done using ImageJ and Leica software 2.0. Data were analysed using graph pad 6, p values < 0.05 were significant. We observed no signs of behavioural toxicity and no mortality during this study, however, in the kidneys, we reported mild morphological perturbations widening of Bowman's space, and vacuolations in glomerulus and tubules of TDF and NTDF animals. Also, there was a significant elevation of glycogen deposition in NTDF and TDF animals when compared with control. In the liver, there were mild histological changes with widening of sinusoidal spaces, vacuolations in hepatocytes and elevation of glycogen deposition in TDF and NTDF administered animals. In addition to this, there were no significant differences in stereological measurements and cell count, LFT, RFT, weight changes and organo-somatic index between treatment groups and control. In conclusion, NTDF and TDF in therapeutic doses can lead to mild hepatic and renal histological damage. Further studies are needed to understand the precise genetic mechanism.

Serum Neurofilament Light Chain Is Associated with Incident Lacunes in Progressive Cerebral Small Vessel Disease

Nils Peters,Esther van Leijsen,Anil M. Tuladhar,Christian Barro,Marek J. Konieczny,Michael Ewers,Philippe Lyrer,Stefan T. Engelter,Jens Kuhle,Marco Duering,Frank-Erik de Leeuw 대한뇌졸중학회 2020 Journal of stroke Vol.22 No.3

Background and Purpose Serum neurofilament light (NfL)-chain is a circulating marker for neuroaxonal injury and is also associated with severity of cerebral small vessel disease (SVD) crosssectionally. Here we explored the association of serum-NfL with imaging and cognitive measures in SVD longitudinally. Methods From 503 subjects with SVD, baseline and follow-up magnetic resonance imaging (MRI) was available for 264 participants (follow-up 8.7±0.2 years). Baseline serum-NfL was measured by an ultrasensitive single-molecule-assay. SVD-MRI-markers including white matter hyperintensity (WMH)-volume, mean diffusivity (MD), lacunes, and microbleeds were assessed at both timepoints. Cognitive testing was performed in 336 participants, including SVD-related domains as well as global cognition and memory. Associations with NfL were assessed using linear regression analyses and analysis of covariance (ANCOVA). Results Serum-NfL was associated with baseline WMH-volume, MD-values and presence of lacunes and microbleeds. SVD-related MRI- and cognitive measures showed progression during follow-up. NfL-levels were associated with future MRI-markers of SVD, including WMH, MD and lacunes. For the latter, this association was independent of baseline lacunes. Furthermore, NfL was associated with incident lacunes during follow-up (P=0.040). NfL-levels were associated with future SVD-related cognitive impairment (processing speed: β=–0.159; 95% confidence interval [CI], –0.242 to –0.068; P=0.001; executive function β=–0.095; 95% CI, –0.170 to –0.007; P=0.033), adjusted for age, sex, education, and depression. Dementia-risk increased with higher NfL-levels (hazard ratio, 5.0; 95% CI, 2.6 to 9.4; P<0.001), however not after adjusting for age. Conclusions Longitudinally, serum-NfL is associated with markers of SVD, especially with incident lacunes, and future cognitive impairment affecting various domains. NfL may potentially serve as an additional marker for disease monitoring and outcome in SVD, potentially capturing both vascular and neurodegenerative processes in the elderly. Keywords Stroke; Dementia; Small vessel diseases; Neurofilament

Investigating Organ Toxicity Profile of Tenofovir and Tenofovir Nanoparticle on the Liver and Kidney

Aniekan Imo Peter,Edwin CS Naidu,Edidiong Akang,Oluwatosin O Ogedengbe,Ugochukwu Offor,Sanjeev Rambharose,Rahul Kalhapure,Anil Chuturgoon,Thirumala Govender,Onyemaechi O Azu 한국독성학회 2018 Toxicological Research Vol.34 No.3

Tenofovir nanoparticles are novel therapeutic intervention in human immunodeficiency virus (HIV) infection reaching the virus in their sanctuary sites. However, there has been no systemic toxicity testing of this formulation despite global concerns on the safety of nano drugs. Therefore, this study was designed to investigate the toxicity of Tenofovir nanoparticle (NTDF) on the liver and kidney using an animal model. Fifteen adult male Sprague-Dawley (SD) rats maintained at the animal house of the biomedical resources unit of the University of KwaZulu-Natal were weighed and divided into three groups. Control animals (A) were administered with normal saline (NS). The therapeutic doses of Tenofovir (TDF) and nanoparticles of Tenofovir (NTDF) were administered to group B and C and observed for signs of stress for four weeks after which animals were weighed and sacrificed. Liver and kidney were removed and fixed in formal saline, processed and stained using H/E, PAS and MT stains for light microscopy. Serum was obtained for renal function test (RFT) and liver function test (LFT). Cellular measurements and capturing were done using ImageJ and Leica software 2.0. Data were analysed using graph pad 6, p values < 0.05 were significant. We observed no signs of behavioural toxicity and no mortality during this study, however, in the kidneys, we reported mild morphological perturbations widening of Bowman’s space, and vacuolations in glomerulus and tubules of TDF and NTDF animals. Also, there was a significant elevation of glycogen deposition in NTDF and TDF animals when compared with control. In the liver, there were mild histological changes with widening of sinusoidal spaces, vacuolations in hepatocytes and elevation of glycogen deposition in TDF and NTDF administered animals. In addition to this, there were no significant differences in stereological measurements and cell count, LFT, RFT, weight changes and organo-somatic index between treatment groups and control. In conclusion, NTDF and TDF in therapeutic doses can lead to mild hepatic and renal histological damage. Further studies are needed to understand the precise genetic mechanism.

Increased Neurofilament Light Chain Is Associated with Increased Risk of Long-Term Mortality in Cerebral Small Vessel Disease

Mina A. Jacob,Nils Peters,Mengfei Cai,Marco Duering,Stefan T. Engelter,Jens Kuhle,Frank-Erik de Leeuw,Anil M. Tuladhar 대한뇌졸중학회 2022 Journal of stroke Vol.24 No.2

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Exploring the Potential of Flunarizine for Cisplatin-Induced Painful Uremic Neuropathy in Rats

Arunachalam Muthuraman,Sumeet Kumar Singla,Anil Peters 대한배뇨장애요실금학회 2011 International Neurourology Journal Vol.15 No.3

Purpose: The present study was designed to explore the potential of flunarizine for cisplatin induced painful uremic neuropathy in rats. Methods: Cisplatin (2 mg/kg; i.p., for 5 consecutive days) was administered and renal uremic markers i.e., serum creatinine were estimated on days 4 and 25. Behavioral changes were assessed in terms of thermal hyperalgesia (hot plate, plantar, tail immersion,and tail flick tests at different time intervals). Biochemical analysis of total calcium, superoxide anion, DNA, and transketolase,and myeloperoxidase activity in tissue samples was also performed. Furthermore, flunarizine (100, 200, and 300 μM/kg; p.o., for 21 consecutive days) was administered to evaluate its potency on uremic neuropathy, and the results were compared with those for the carbamazepine-treated (30 mg/kg; p.o., for 21 consecutive days) groups. Results: Flunarizine attenuated the cisplatin-induced uremic neuropathy, and the degree of behavioral and biochemical changes in serum and tissue samples in a dose dependent manner. The medium and high doses of flunarizine were shown to produce a significant effect on cisplatin induced painful uremic neuropathy. Conclusions: Our results indicate the potential of flunarizine for anti-oxidative, anti-inflammatory, and neuroprotective actions. Therefore, it may have use as a novel therapeutic agent for the management of painful uremic neuropathy.

Final report on CCM.M-K4: Key comparison of 1 kg stainless steel mass standards

Becerra, Luis Omar,orys, Michael,Chung, Jin Wan,Davidson, Stuart,Fuchs, Peter,Jacques, Claude,Jian, Wang,Kubarych, Zeina J,Kumar, Anil,Malengo, Andrea,Fen, Kitty,Medina, Nieves,Meury, Paul-André BUREAU INTERNATIONAL DES POIDS ET MESURES 2014 METROLOGIA -BERLIN- Vol.51 No.-

<P>This report describes a key comparison of 1 kg stainless steel mass standards, CCM.M-K4, undertaken by the Consultative Committee for Mass and Related Quantities (CCM) Working Group on the Dissemination of the kilogram (WGD-kg). The CCM.M-K4 comparison was launched during the 12th meeting of the CCM (2010). The aim of the present comparison is to verify the consistency of 1 kg stainless steel mass standards among members of the CCM.</P><P>The previous CCM 1 kg stainless steel mass standards comparison was carried out in 1995–1997 as the CCM.M-K1 comparison. The Bureau International des Poids et Mesures (BIPM) was the pilot laboratory for this key comparison. There were sixteen participants in the CCM.M-K4 comparison, all are CCM members. The comparison was structured into four petals with two stainless steel travelling mass standards per petal. The measurements and the reported results were completed in between one month and five months depending on the participants. One laboratory's results were found to be inconsistent with the other laboratories' results and one other laboratory gave a significant deviation from the key comparison reference value (KCRV). Both laboratories were contacted before preparation of the draft A report, without disclosing the details of the deviations, to allow them to check and revise their values. The fourteen other participants were in agreement with each other and degrees of equivalence have been established.</P><P>Finally, the mass values of the eight stainless steel travelling standards were determined in air by the NMIs with claimed standard uncertainties ranging from 0.007 mg to 0.021 mg. Degrees of equivalence have been established by using the generalized linear least-squares estimation (GLS) method. The result demonstrates the high quality of this comparison and that some participants are able to provide, for their mass calibration services, standard uncertainties of around ten micrograms. The good uniformity of worldwide mass dissemination since the last periodic mass verification carried out in 1992 is demonstrated by the agreement among the NMIs' results. In addition, the observed weighted mean of the NMI deviations against the BIPM is −0.0098 mg (σ = 0.0036 mg). Despite the good result obtained in this particular comparison we should, in order to have a more accurate calibration system, improve the knowledge of the ageing effects of the mass references and increase the BIPM calibration frequency of the national prototypes.</P><P>Main text.To reach the main text of this paper, click on Final Report. Note that this text is that which appears in Appendix B of the BIPM key comparison database kcdb.bipm.org/.</P><P>The final report has been peer-reviewed and approved for publication by the CCM, according to the provisions of the CIPM Mutual Recognition Arrangement (CIPM MRA).</P>