Academic literature on the topic 'Sub-acute toxicity'

Purpose: Most of these studies are conducted to assess the degree to which substances are toxic (poisonous) for humans, animals or the environment, to investigate the mechanism of toxic chemicals, or to develop new or improved tests for specific types of chemically induced effects. The present study was designed to evaluate the acute and 28 days repeated oral toxicity study of Polyherbal formulation according to OECD guidelines. Materials and Methods: In acute oral toxicity study, Herbal mixture was administered at 2000mg/kg orally and animals were observed for toxic signs at 30 min, 1, 2 and 4 hrs and thereafter once a day for the next 14 days. In repeated dose-28-day oral toxicity study, the animals were divided into four groups of 6 animals each. Group-1 animals served as a control. Group II animals received low dose of herbal mixture 50 mg/kg, Group III animals received middle dose 100 mg/kg and Group IV animals received high dose of 200 mg/kg (orally) once daily for 28 days respectively. Results: The assessment study results showed that neither the acute toxicity study of herbal mixture at the dose level of 2000mg/kg nor the 28 days repeated oral toxicity study produced any toxic signs or mortality during study. In 28 days repeated oral toxicity study, no significant changes were observed in the haematological and biochemical parameters, relative organ weight, gross necropsy and histopathological examination with herbal mixture treatment. Conclusion: The results of the present study suggest that LD50 of newly developed Polyherbal formulation was >2000 mg /kg and the mixture is completely safe and non-toxic for therapy.

Roselle leaves are widely used in traditional medicine but have not previously been studied for their safety through standard in vivo toxicity studies. This study aimed to evaluate the safety of roselle leaves extract through acute and sub-acute oral toxicity studies in Sprague Dawley (SD) rats. An acute toxicity study was carried out using a single high dose of roselle leaves extract at 3000 mg/kg and toxic signs were observed within 14 days. While sub-acute toxicological study was carried out using 28-days repeated doses of 0 mg/kg (control), 1000 mg/kg, 2000 mg/kg, and 5000 mg/kg of roselle leaves extract. Bodyweight changes were recorded throughout the experimental period. On day 29, blood was withdrawn and analysed for haematology and clinical biochemistry values. During the 14-day acute toxicity study, there were no significant changes in body weight increment, adverse clinical signs and mortality. In the sub-acute toxicity study, there were also no toxicology significant changes in haematology and clinical biochemistry except a slight decrease in triglyceride (TG) and glucose level (p < 0.05) which is attributed to roselle leaves aqueous extract administration. However, the results were within the normal reference range of SD rats. Therefore, the acute and sub-acute toxicity studies in SD rats showed that roselle leaves aqueous extract is non-toxic and could be classified as a no-observed-adverse-effect level (NOAEL).

Peptic ulcer is described in the siddha system of medicinal classification of 4448 diseases. Information on the use of Sangu Parpam in treating peptic ulcer is known. Therefore, it is of interest to document the acute and sub acute toxicity analysis on Sangu parpam in this regard.

Febrile neutropenia caused by cytostatic therapy in the treatment of oncological diseases is a frequent complication, which results in enforced reduction in chemotherapy doses and lower effectiveness of the treatment. Introduction of the recombinant forms of the natural protein granulocyte colony-stimulating factor into clinical practice has allowed to minimize the negative consequences of myelosuppressive therapies. The main task of repeated dose toxicity studies of drugs is evaluation of damaging effects of the pharmacological substance, revealing the most sensitive organs and systems in the body. Therefore, our work was aimed at studying sub-acute toxicity of PEG-Filstim. Toxicity study of PEG-Filstim was performed in 50 white wild-type rats of both sexes with body weight 170 to 230 g on daily (28 days) subcutaneous administration in the doses of 0.5, 1.0 and 2.0 mg/kg. During the whole observational period, survival, water and food consumption, body weight and symptoms of intoxication were registered. After completion of the experiment, spontaneous diurnal diuresis was evaluated and clinical blood and urine examination performed in all groups of animals. The results have shown that PEG-Filstim on daily subcutaneous administration in the doses of 0.5, 1.0 and 2.0 mg/kg during 28 days does not cause death in the animals, nor general toxic effects on health, behaviour, food and water consumption, body weight growth in laboratory rats. Upon repeated administration in the studied doses, PEG-Filstim does not affect protein, lipid, carbohydrate metabolism, does not impair functions of urinary and hepatobiliary systems, but increases blood serum alkaline phosphatase activity. PEG-Filstim causes development of pronounced neutrophil leucocytosis and increase in monocyte, lymphocyte and eosinophil count. In the maximum dose of 2.0 mg/kg the studied drug decreases blood red cell count and haemoglobin level.

Suryashekhara Rasa is unique mercurial preparation, which contains Parada, Gandhaka, Hingula and Vatsanabha. The quantity of Vatsanabha is equal to the sum of other ingredients, and also its antidote (Tankana) is not mentioned in this formulation. To ensure that the drug is devoid of toxicity and harmful effects, assessing the level of toxicity is important. So, this research work is an attempt to perform acute and sub-acute toxicity evaluation of Suryashekhara Rasa. Acute toxicity study of test drug was carried at a limit dose of 2000mg/kg orally in albino mice. For sub-acute toxicity Suryashekhara rasa was adminis-tered at therapeutic equivalent dose (TED) (0.35mg/kg bw po), TED x 2 (0.70mg/kg bw po) TED x 5 (1.75 mg/kg bw po) for 28 days. Acute toxicity result showed that drug did not produce any signs and symptoms of toxicity or mortality up to an oral dose of 2000 mg/kg in albino mice. The data generated during sub-acute toxicity study are indicated that it is mild toxic substance for sub-acute administration at TED dose level, may be because of alkanes which are found in functional group of aconitum ferox.

The use of herbal medicines has tremendously grown over the past few years. Owing to their safety, they are more preferred over conventional allopathic medicine. Plant-based therapies have significantly improved and protected human health. Additionally, dry powdered herbal medications are more effective than liquid extracts. The numerous claims are not backed up by any data that can be verified. It is the first time that the activity of Tribulus Terrestris spray-dried extract has been linked to acute and suba-cute oral toxicity. The objective of the current work was to investigate the acute and sub-acute toxicity of spray-dried extract (SDE) of Tribulus terrestris. For acute toxicity, two different doses, i.e., 2000 and 5000 mg/kg, were given to the female Wistar rats. Only one dose was administered and each animal was observed for any signs of mortality along with behavioral changes and physical symptoms for 2 weeks. Multiple doses of the SDE were given to the Wistar (both genders) rats for 28 days in the sub-acute toxicity. Animals of both the genders received 500, 1000, and 1500 mg/kg/day SDE doses for 28 days consecutively. Blood samples were obtained for biochemical and hematological analysis on the 29th day of the experiment, following which subjects were sacrificed for the histopathological examination. The results of acute toxicity revealed no signs of morbidity and mortality in rats. Similar results were recorded in the sub-acute toxicity. Mild variations were observed at 1000 and 1500 mg/kg/day, however results were non-significant. The SDE of Tribulus terrestris did not show any significant harmful effects in the treated animals after 14 and 28 days of treatment. Therefore, SDE of Tribulus terrestris can be safely employed in pharmaceutical formulations for therapeutic use, addressing further safety in chronic and sub-chronic study.

2010/2011
The present thesis was developed for the characterization of the risk associated to palytoxins as seafood contaminants. To this aim, an integrated approach between in vitro and in vivo studies was chosen. Palytoxin and its analogues are known seafood contaminants that can accumulate in several edible species of shellfish, fish, crustaceans and echinoderms. Generally, primary symptoms associated to the ingestion of contaminated food involve the gastro-intestinal apparatus and later develop with the involvement of the muscular tissue. For a better comprehension of the mechanism of action of this family of biotoxins, the effects of PLTX have been studied on primary culture of mouse skeletal muscle cells. The myotoxic insult triggered by PLTX was described in detail with the definition of the cytotoxicity together with the description of the morphologic alterations and functional impairment caused by the toxin. Moreover, the influence of the ionic composition of the extracellular medium on the effects of the toxin was elucidated. Primary cultures of skeletal muscle cells, that presents in vitro many of the peculiarities of the adult muscle fiber, allowed the investigation of the membrane mechanisms that regulate the intracellular calcium increase triggered by the toxin. It was possible to discriminate the difference between calcium release from intracellular stores and the calcium entrance from extracellular compartment both elicited by the toxin, and to understand the importance of the latter in relation to the toxic event. Moreover, the involvement of the main membrane channels and transporters that may be related to the entrance of calcium was investigated and the crucial role of stretch-activated channels in the mechanism of toxicity was demonstrated. Once defined the crucial molecular mechanisms of action of PLTX, experiments were also performed with two of its analogue: the 42-hydroxyl-palytoxin and the ostreocin-D. In parallel to in vitro studies, the effects of repeated oral administration of PLTX in mice were also investigated. In fact, in vitro studies are not sufficient for the complete comprehension of the real hazard associated to a food contaminant, since molecules once in contact with the body may undergo adsorption, distribution and metabolism before reaching the target tissue. Short-term (7 days) administration of the toxin revealed toxicity at all the doses tested and lethality was recorded in the treated animals already from the dose of 30 µg/kg. Histological analysis highlighted alterations in several tissues: severe inflammatory processes and even foci of necrosis were observed in lungs. Alteration of the muscular tissues was visible as fiber separation and degeneration in the heart and increased cellularity between fibers in skeletal muscle. Moreover, depletion of glycogen content of hepatocytes and moderate alterations of the spleen were also observed. Data collected in the present project revealed, for the first time, toxicity of PLTX at doses much lower than that currently used by European Food Safety Authority (EFSA) for the estimation of limit values for presence of these compounds in seafood. For this reason, these results are likely to have a considerable impact at regulatory level and to have crucial importance for the protection of the consumers.
Il presente lavoro di tesi è stato sviluppato con lo scopo di caratterizzare il rischio associato alla presenza delle palitossine quali contaminanti dei prodotti ittici destinati ad uso alimentare. A tal fine, è stato scelto un approccio integrato tra studi in vitro e in vivo. La palitossina e i suoi analoghi sono noti contaminanti dei prodotti ittici e possono accumularsi in diverse specie edibili di molluschi, pesci, crostacei ed echinodermi. Generalmente, i primi sintomi associati all’ingestione di cibo contaminato coinvolgono l’apparato gastro-intestinale e poi si sviluppano con l’interessamento del tessuto muscolare. Per una migliore comprensione del meccanismo d’azione di questa famiglia di biotossine, gli effetti della PLTX sono stati studiati mediante colture primarie murine di cellule muscolari scheletriche. L’insulto miotossico indotto dalla PLTX è stato descritto nel dettaglio con la definizione della citotossicità assieme alla descrizione delle modifiche morfologiche e delle alterazioni funzionali causate dalla tossina. Inoltre, è stata caratterizzata l’influenza della composizione ionica dell’ambiente extracellulare negli effetti della tossina. Le colture primarie di cellule muscolari scheletriche, che presentano molte delle caratteristiche peculiari della fibra muscolare adulta, hanno permesso l’indagine dei meccanismi che regolano l’aumento intracellulare di calcio indotto dalla tossina. E’ stato possibile discriminare la differenza tra il rilascio di calcio dai depositi intracellulari e l’entrata di calcio dai compartimenti extracellulari, entrambi effetti indotti dalla tossina, e comprendere l’importanza del secondo meccanismo in relazione agli eventi tossici. E’ stato indagato il coinvolgimento dei canali e trasportatori di membrana in relazione all’ingresso di calcio ed è stato dimostrato il ruolo cruciale dei canali attivati da stiramento nel meccanismo di tossicità. Una volta definiti i meccanismi d’azione cruciali per la PLTX, esperimenti sono stati condotti anche con due dei suoi analoghi, la 42-idrossi-palitossina e l’ostreocina-D. Parallelamente agli studi in vitro, sono stati studiati gli effetti della somministrazione orale ripetuta della PLTX nel topo. Infatti, gli studi in vitro non sono sufficienti alla comprensione del reale pericolo associato ad un contaminate alimentare, dal momento che, le molecole, una volta a contatto con l’organismo, possono subire assorbimento, distribuzione e metabolismo prima di raggiungere il tessuto bersaglio. La somministrazione a breve termine della tossina (7 giorni) ha rivelato tossicità a tutte le dosi somministrate, e letalità è stata registrata negli animali trattati già alla dose di 30 µg/kg. Le analisi istologiche hanno evidenziato alterazioni a carico di diversi tessuti: a livello polmonare sono stati osservati severi processi infiammatori associati anche a focolai di necrosi. Le alterazioni del tessuto muscolare erano visibili come degenerazione e separazione delle fibre nel cuore e aumento degli elementi cellulari tra le fibre del muscolo scheletrico. Inoltre sono stai osservati, deplezione del contenuto di glicogeno negli epatociti e moderate alterazioni della milza. I dati raccolti nel presente elaborato hanno rivelato, per la prima volta, la tossicità della palitossina a dosi molto inferiori rispetto a quelle correntemente utilizzate della European Food Safety Authority (EFSA) per la stima di valori limite per la presenza di questi composti nei prodotti ittici destinati ad uso alimentare. Per questo motivo, i risultati avranno probabilmente un considerevole impatto a livello legislativo e un’importanza cruciale per la protezione dei consumatori.
XXIV Ciclo
1984

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Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq
The present research aimed to investigate the acute toxicity of glyphosate (Nphosphomethyl-glycine), the active ingredient of Roundup®, as well as of aminomethylphosphonic acid (AMPA), its main degradation product, in the teleost fish Poecilia reticulata, commonly known as guppies. Thus, were performed tests Lethal Concentration mean (LC50) and behavioral, histopathology and proteomics analysis. Male and female P. reticulata presented median lethal concentration (LC50) at 96h the values of 68.78 and 70.87 mg/L for glyphosate and 180.00 and 164.32 mg/L for AMPA, respectively, characterizing them as practically non toxic compounds to guppies. However, the results of behavioral analyses showed that both products generate stressing situations to the fish, causing behavioral changes such shock against the tank walls, hypoactivity, irregular swimming, swimming on the surface of water, darkening of the body, aggressiveness, and lethargy. Histopathological and morphometric analyses of liver and gill of guppies exposed to sublethal concentrations of glyphosate (35mg/L) and AMPA (82 mg/L) indicated that both organs were affected . The gills of fish exposed to the tested products presented higher reaction rates to progressive changes, such as proliferation of the interlamellar epithelium and partial and total fusion of secondary lamellae. Liver presented higher reaction rates to regressive changes, such as steatosis, pyknotic nuclei, and necrosis. The proteomic analysis showed that Glyphosate induces differential liver proteins in P. reticulata. The image analysis allowed measuring 225 spots in the control group and 180 spots in the group exposed to Glyphosate. Of this total, 88 spots were exclusive to the control group and 43 spots were exclusive of the treated group. Of the 137 spots matched between control and treated groups 13 were down regulated and 8 were up regulated due to sublethal exposure to Glyphosate. The behavioral, histopathological and proteomic changes observed indicated that, although considered to have low toxicity to animals in the guides that evaluate toxicity of chemicals, both glyphosate and AMPA promote that are deleterious to animal health, indicating the need to establish new parameters or modify concepts indicating the need to use several biomarkers, beyond assessing the mortality rate, to establish a more reliable criteria for toxicity parameters.
A presente pesquisa teve como objetivo investigar a toxicidade aguda do Glifosato (Nfosfometil-glicina), princípio ativo dos herbicidas Roundup, e do AMPA (ácido aminometil-fosfônico), seu principal produto de degradação. O sistema-modelo eleito para a investigação foi o teleósteo Poecilia reticulata. Realizaram-se testes de Concentração Letal média (CL50), análises comportamentais, histopatológicas e proteômicas. Os dados de mortalidade coletados durante o teste de Concentração Letal média (CL50) permitiram determinar os valores de 68,78 e 70,87 mg/L como CL50 do Glifosato e os valores de 180 e 164,32 mg/L como a CL50 do AMPA para machos e fêmeas de P. reticulata respectivamente. Tais valores caracterizam o Glifosato e o AMPA como praticamente não tóxico aos guarus em testes de toxicidade aguda. No entanto, os resultados das análises comportamentais também realizadas durante a CL50 mostraram que ambos os produtos testes são capazes de gerar situações de estresse aos peixes, causando alterações de comportamento como choques contra as paredes do aquário, hipoatividade, natação irregular, nado na superfície da água, escurecimento corporal, agressividade e letargia. As análises histopatológicas e morfométricas das brânquias e do fígado de guarus expostos a concentrações subletais de Glifosato (35µg/L) e de AMPA (82µg/L) indicaram que ambos os órgãos são alterados morfologicamente. As brânquias de peixes expostos aos produtos testes apresentaram maiores índices de reação para as alterações progressivas tais como aumento do epitélio interlamelar e fusão parcial e total das lamelas secundárias. O fígado por sua vez apresentou maiores índices de reação para as alterações regressivas como esteatose, núcleos picnóticos e necrose. As análises proteômicas mostraram que o Glifosato induz a expressão diferencial de proteínas hepáticas em P. reticulata. As análises das imagens dos géis permitiram mensurar 225 spots no grupo controle e 180 spots no grupo exposto a Glifosato. Desse total, 88 spots foram exclusivos do grupo controle e 43 spots foram exclusivos do grupo tratado. Dos 137 spots pareados entre os grupos controle e tratado 13 foram regulados negativamente e 8 foram regulados positivamente devido a exposição subletal ao Glifosato. As alterações encontradas indicam que o Glifosato e o AMPA, apesar de serem considerados poucos tóxicos por guias que avaliam a toxicidade de produtos químicos, são promotores de alterações deletérias para a saúde animal, indicando que há necessidade de estabelecimento de novos parâmetros ou mudança de conceitos, indicando a necessidade de utilizar vários biomarcadores, além da avaliação da taxa de mortalidade, para estabelecer um critério mais confiável para parâmetros de toxicidade.

Numerous metabolic approaches have been employed clinically for seizure suppression, including the ketogenic diet (KD). Inhibiting or bypassing glycolysis may be one way by which the KD suppresses seizures. 2-Deoxy-d-glucose (2DG) is a glucose analog that partially inhibits glycolysis and has antiseizure effects in seizure models. Acutely, 2DG diminishes the frequency of interictal bursts in hippocampal area CA3 induced by high K_o ⁺, bicuculline, 4-aminopyridine, or Mg²⁺-free/4-aminopyridine. 2DG exerts an anticonvulsant effect in vivo in mice. 2DG also has acute anticonvulsant actions against status epilepticus evoked by pilocarpine in adult mice and in neonatal rats, and status epilepticus evoked by kainic acid in rats. Chronically, 2DG exerts disease-modifying antiepileptic effects in three kindling models and the posttraumatic epilepsy model, attenuates progression of the 6-Hz corneal kindling, and prevents traumatic brain injury-induced hyperexcitability. The mechanisms underlying the acute and chronic effects of 2DG are being investigated. Preliminary studies provide evidence that the acute anticonvulsant actions of 2DG involve activity-dependent presynaptic suppression of excitatory synaptic transmission during network synchronization. The chronic effects of 2DG entail reduction of the expression of brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase B (trkB). BDNF and trkB gene expression are required for kindling progression; by reducing glycolysis, 2DG modulates transcriptional repression of BDNF and trkB by neuron-restrictive silencing factor (NRSF) at the promoter regions of BDNF and trkB. Currently available preclinical efficacy and toxicity studies support 2DG as a novel first-in-class metabolic treatment for epilepsy with an antiglycolytic mechanism that is distinct from other anticonvulsants.

Skin and soft tissue infections (SSTIs) can be sub-divided based on the anatomical structure(s) affected from superficial to deep. Impetigo affects children more commonly than adults, starting as a macule of erythema and evolving into vesicles that rupture, leaving a golden crusted appearance. Fever and systemic signs are absent. It is highly transmissible and children should be excluded from school until exposed lesions have resolved. Folliculitis is a superficial infection presenting with small papules or pustules on an erythematous base around a hair. Fever and systemic signs are absent. If extension into deeper tissues occurs a dermal abscess (‘boil’ or ‘furuncle’) may occur, and several lesions may coalesce into a ‘carbuncle’. Deeper infection may cause discomfort, fever, and systemic upset. Any hair-bearing area may be affected, but sites most commonly affected include the face, scalp, axilla, inguinal area, thighs, or eyelid (‘stye’), and may be associated with shaved or occluded skin. Cellulitis is rapidly spreading erythema of the skin associated with pain, swelling, fever, and systemic features such as nausea and malaise. It may be seen as a complication of tinea pedis, superficial abrasions, or insect bites, venous insufficiency, lymphoedema, chronic ulcers, and diabetes. It is almost always unilateral and bilateral cellulitis is extremely rare and should prompt consideration of an alternative diagnosis. The Eron grading system can help guide treatment and admission decisions: ● Class I: the patient has no signs of systemic toxicity and no uncontrolled comorbidities. ● Class II: the patient is either systemically unwell or systemically well but with a comorbidity such as peripheral vascular disease, chronic venous insufficiency, diabetes, or obesity, which may complicate or delay resolution of infection. ● Class III: the patient has significant systemic upset such as acute confusion, tachycardia, tachypnoea, hypotension, or unstable comorbidities that may interfere with a response to treatment, or a limb-threatening infection due to vascular compromise. ● Class IV: the patient is septic or has life-threatening infection such as necrotizing fasciitis.

Introduction: Carcinoma cervix is the fourth (GLOBACON 2012) most common cancer among women worldwide, and the main cancer affecting women in Sub-Saharan Africa, Central America and south-central Asia. In India, approx. 1,23,000 (GLOBACON 2012) new cases of carcinoma cervix are diagnosed each year. Brachytherapy is an integral part of treatment of cancer cervix. In the context of a developing country like us where maximum utilization of the resource is of prime importance to provide treatment to the large patient cohort, shortening the treatment duration and number of fractions always increases efficiency. In order to maximize the logistic benefits of HDR-BT while improving patient compliance and resource sparing, various fractionation regimens are used. Fractionation and dose adjustments of the total dose are radiobiologically important factors in lowering the incidence of complications without compromising the treatment results. Aim: To compare patient outcomes and complications using two linear-quadratic model-based fractionation schemes of high-dose-rate intracavitary brachytherapy (HDR-IC) used to treat cervical cancer. Materials and Methods: A prospective randomized study on 318 patients, with histologically proven advanced carcinoma cervix (stages IIB-IIIB) was enrolled in the study. All patients received External Beam Radio Therapy (EBRT) 50 Gy in 25 fractions with concurrent chemotherapy (cisplatin 35 mg/m2) followed by IntraCavitary brachytherapy using high dose rate equipment. Patients were randomised after completion of EBRT into two arms: (1) Arm 1: HDR ICRT 6.5 Gy per fraction for 3 fractions, a week apart. (2) Arm 2: HDR ICRT, 9 Gy per fraction for 2 fractions, 1 week apart. On completion of treatment, patients were assessed monthly for 3 months followed by 3 monthly thereafter. Treatment response was assessed according to WHO criteria after one month of completion of radiotherapy. The RTOG criteria were used for radiation induced toxicities. We analyzed late toxicities in terms of Rectal, Bladder, Small Bowel toxicity and Vaginal Stenosis. Results: Acute reactions in both the groups were comparable. None of the patient developed Grade 4 toxicity in our study and no toxicity related mortality was encountered. A slightly high frequency of late toxicity was observed in 9Gy Arm patients but was not statistically significant. Conclusion: In our setup, HDR brachytherapy at 9 Gy per fraction in two fractions is safe, effective and resource saving method with good local control, survival, and manageable normal tissue toxicity.