By G. Grompel. University of Massachusetts at Boston. 2018.

Magnehelic manometers to indicate the pressure differential were found in all strategic places zudena 100mg without a prescription. Separate return air ducts were found provided in each room at a height of 30 cm from the floor and were fitted with 10 micron filters in the return grills zudena 100 mg visa. Dust extraction systems with proper hoods were found provided in granulation and compression areas buy 100mg zudena visa. Water System It was observed that the firm maintained a pre specified water system for the whole plant. Training record of some of the employees were checked by the inspecting team and found satisfactory. All the technical personnel were found possessing proper academic background and competent enough to perform the duty assigned to them. Two sets of aprons, caps and foot wares were found provided to the employees authorized to enter into the general areas. Non fiber shedding garments with full covering were found provided (two sets) to all employees authorized to enter in to the manufacturing area. The documents reviewed during the inspection revealed satisfactory level of implementation and compliance with current requirements. Additionally, Quality audits were also found performed by the Corporate Quality Assurance team once in a year, which involves audit of facilities, systems, procedure and documentation. Vendor Development All starting and primary packaging materials were found procured from the approved vendors who were pre qualified through regular audits and review of satisfactory vendor assessment questionnaire. Training It was observed that the firm meticulously follows a structured training program, which covers all employees. Managers were also found exposed to different training programs conducted by various professional bodies. Manufacturing Operation and Control It was observed that all the critical parameters of the manufacturing operations were found carried out under the active supervision of competent technical personnel following the Standard Master Formula (properly validated). Records All necessary records starting from receipt of material to the distribution of finished goods were found maintained by the firm. Some of the records were verified by the inspecting team at the time of inspection and found satisfactory. List of instruments as submitted with the application were verified by the inspecting team at the time of inspection and found all are operational. The competency of the microbiologist was examined by the inspecting team at the time of inspection and found satisfactory. The chemical laboratory was found provided with proper fuming chamber with adequate space for storage of tests samples, retained samples, reference standards, reagents and records. The data of stability studies of the following products were verified at the time of inspection by the inspecting team and found satisfactory. All the critical parameters of the manufacturing process were found validated by prospective as well as concurrent validation method. Constitution Details Product(s) 268 Technical staff Name Qualification Experience (Attach sheet, if reqd. Noradrenaline, Mephentin, Betamethasone ( or dexamethasone),Metochlorpropamide injections M Accessories a Blankets, emesis basins, haemostats, set clamps, sponge forceps, gauze, dressing jars, waste cans etc. Production department(s) Typho-Vi Oral Polio Vaccine Rabies Filling [ ] Labeling/Packaging [ ] Quality Control [ ] Engineering/Maintenance [ ] Quality Assurance [ ] Receiving/Warehousing [ ] Shipping/Distribution [ ] Purchasing [ ] Animal Procurement/Care [ ] 2 Are there job descriptions for key personnel? Production Filling Labeling/Packaging Quality Control Engineering Maintenance Quality Assurance Marketing & Supply General Administration & Account Procurement & Stores 2 Are they skilled/trained in fields such as biology, microbiology, chemistry veterinary medicine, chemical or industrial engineering, etc.? Engineering Production Department(s) Filling Quality Control Quality Assurance Animal Care 298 1. Are they designed with an atmospheric break to prevent back- siphonage from sewer? Are they maintained in a manner that permits identification of the product with the 319 particular manufacturing and sterilization process? Observations to be noted by Remark Location and surroundings: the inspecting team at the time of inspection 1. What are the measures employed to prevent the entry of insects, rodents, flies, etc. Specify the nature of construction used in the facility in respect of its maintenance and hygienic conditions. What measures have been taken to make Interior surface of (walls, floors, and ceilings) be smooth, even and washable, water-proof and capable of being kept clean and shall be such as not to permit retention or accumulation of dust. Specify material of construction and finish for walls, ceiling, floor, coving etc. Pls attach equipment lay out, men and material movement, waste movement if applicable. Attach copy of pest / rodent control schedule along with contract agreement if any. Pls specify source of raw water and give details of treatment processes, sampling points, distribution and storage system for raw and purified water. Health, clothing and sanitation of workers: - Whether all personnel prior to employment have undergone medical 4. Pls specify nature and type of dress used by the personnel in various areas of operation. Whether arrangements provided for cleaning of outside dust and dirt from foot Please specify whether hands are disinfected before entering the production area Whether for sterile garments in house clean laundry has been provided. Are they clean and dry and maintained within acceptable temperature limits where ever required. If not what provision has been made for sampling so as to prevent mix-ups at a time of sampling. Whether All such raw materials shall be identified and assigned control reference number. What is the air class of this areas and whether pressure difference is maintained in these areas? Specify the nature of floor, ceiling, fixtures and service lines to meet the clean room requirements as per design qualification. Specify the nature of work benches whether the top of which are smooth impervious & capable of being washed. Specify the arrangement for in and out of materials including device parts, primary packaging materials and primary packed device from this area, any material transfer pass box provided? Please specify the provision of air conditioned and ventilation system for the animal house. Whether the products sterilized in this manner shall be monitored to assure acceptable levels of residual 352 gas and its degradation products. Specify the total area provided for basic installation of such facility:- Whether adequate space provided for quarantine & sterilized items. Whether the Sterilization cycle validated with the use of physic- chemical parameters and biological indicators. In case of contractual testing what are the responsibilities of contract giver and contract acceptor. Please specify detailed account of sanitation program specific to various areas, equipment.

Srisurapanont M cheap 100mg zudena with mastercard, Ali R generic zudena 100mg with mastercard, Marsden J et al (2003) Psychotic symptoms in methamphetamine psychotic in- patients buy generic zudena 100mg on-line. Aldington S, Harwood M, Cox B et al (2008) Cannabis use and risk of lung cancer: a case-control study. Hall W (2009) The adverse health effects of cannabis use: what are they, and what are their implications for policy? Kuepper R, Van Os J, Lieb R et al (2011) Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study. Advisory Council on the Misuse of Drugs (2008) Cannabis: classification and public health. Arseneault L, Cannon M, Witton J et al (2004) Causal association between cannabis and psychosis: examination of the evidence. Rubino T, Zamberletti E & Parolaro D (2012) Adolescent exposure to cannabis as a risk factor for psychiatric disorders. Macleod J, Oakes R, Copello A et al (2004) Psychological and social sequelae of cannabis and other illicit drug use by young people: a systematic review of longitudinal, general population studies. A scientific statement from the American Heart Association Acute Cardiac Care Committee of the Council on Clinical Cardiology. Darke S, Kaye S & Duflou J (2006) Comparative cardiac pathology among deaths due to cocaine toxicity, opioid toxicity and non-drug-related causes. Kaye S & Darke S (2004) Non-fatal cocaine overdose among injecting and non-injecting cocaine users in Sydney, Australia. Alaraj A, Wallace A, Mander N et al (2010) Effect of acute cocaine use on vasospasm and outcome in aneurysmal subarachnoid hemorrhage. Kaye S & Darke S (2004) Injecting and non-injecting cocaine use in Sydney, Australia: physical and psychological morbidity. European Monitoring Centre for Drugs and Drug Addiction (2007) Cocaine and crack cocaine: a growing public health issue. Darke S, Kaye S & Duflou J (2005) Cocaine related fatalities in New South Wales, Australia 1993-2002. Rogers G, Elston J, Garside R et al (2009) The harmful health effects of recreational ecstasy: a systematic review of observational evidence. Miotto K, Darakjian J, Basch J et al (2001) Gamma-hydroxybutyric acid: patterns of use, effects and withdrawal. Hickman M, Carnwath Z, Madden P et al (2003) Drug-related mortality and fatal overdose risk: pilot cohort study of heroin users recruited from specialist drug treatment sites in London. Smyth B, Hoffman V, Fan J et al (2007) Years of potential life lost among heroin addicts 33 years after treatment. Shahani R, Streutker C, Dickson B et al (2007) Ketamine-associated ulcerative cystitis: a new clinical entity. European Monitoring Centre for Drugs and Drug Addiction (2009) Polydrug use: patterns and responses. Cruts G, Buster M, Vicente J et al (2008) Estimating the total mortality among problem drug users. British Medical Association (2007) Fetal alcohol spectrum disorders – a guide for healthcare professionals. British Medical Association (2004) Smoking and reproductive life – the impact of smoking on sexual, reproductive and child health. Cole C, Jones L, McVeigh J et al (2011) Adulterants in illicit drugs: a review of empirical evidence. Department of Health (2002) Getting ahead of the curve: a strategy for combating infectious diseases (including other aspects of health protection). Aldington S, Williams M, Nowitz M et al (2007) Effects of cannabis on pulmonary structure, function and symptoms. Bancroft A, Wilson S, Cunningham-Burley S et al (2004) Parental drug and alcohol misuse. Kübler D & Wälti S (2001) Metropolitan governance and democracy: how to evaluate new tendencies? In: Mclaverty P (ed) Public participation and developments in community governance. Officer J (2009) Trends in drug use of Scottish drivers arrested under Section 4 of the Road Traffic Act – a 10 year review. European Monitoring Centre for Drugs and Drug Addiction (2008) Drug use, impaired driving and traffic accidents. Proceedings of 11th World Congress of the International Association for Accident and Traffic Medicine, 24-28 May, Dubrovnik. Proceedings of the 16th International Conference on Alcohol, Drugs and Traffic Safety, 4-9 August, Montreal. Singleton N, Murray R & Tinsley L (2006) Measuring different aspects of problem drug use: methodological developments. The Health and Social Care Information Centre (2011) Statistics on drug misuse: England, 2011. Scottish Government (2008) The road to recovery: a new approach to tackling Scotland’s drug problem. World Health Organization (2004) Neuroscience of psychoactive substance use and dependence. Yokoyama A, Muramatsu T, Ohmori T et al (1998) Alcohol-related cancers and aldehyde dehydrogenase-2 in Japanese alcoholics. Kuepper R, Van Os J, Lieb R et al (2011) Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study. Advisory Council on the Misuse of Drugs (2008) Cannabis: classification and public health. Arseneault L, Cannon M, Witton J et al (2004) Causal association between cannabis and psychosis: examination of the evidence. Zuckerman M (1994) Behavioural expressions and biosocial bases of sensation seeking. Schulteis G & Koob G (1996) Reinforcement processes in opiate addiction: a homeostatic model. Rende R & Slomkowski C (2009) Incorporating the family as a critical context in genetic studies of children: implications for understanding pathways to risky behavior and substance use. McArdle P, Wiegersma A, Gilvarry E et al (2002) European adolescent substance use: the roles of family structure, function and gender. A 4-year prospective examination of risk factors in a community sample of adolescents and young adults. Kokkevi A, Richardson C, Florescu S et al (2007) Psychosocial correlates of substance use in adolescence: a cross-national study in six European countries. Ledoux S, Miller P, Choquet M et al (2002) Family structure, parent–child relationships, and alcohol and other drug use among teenagers in France and the United Kingdom. Best D, Gross S, Manning V et al (2005) Cannabis use in adolescents: the impact of risk and protective factors and social functioning. McKeganey N, McIntosh J, MacDonald F et al (2004) Preteen children and illegal drugs.

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Macromolecules can cross the endothelial barrier: • through the cytoplasm of endothelial cells themselves; • across the endothelial cell membrane vesicles; • through inter-endothelial cell junctions; • through endothelial cell fenestrae buy zudena 100 mg. Based on the morphology and continuity of the endothelial layer cheap 100 mg zudena with mastercard, capillary endothelium can be divided into three categories: continuous discount zudena 100 mg with mastercard, fenestrated, and discontinuous endothelium (see Section 5. The continuous capillaries are found in skeletal, cardiac, and smooth muscles, as well as in lung, skin, subcutaneous and mucous membranes. The endothelial layer of brain microvasculature is the tightest endothelium, with no fenestrations. Capillaries with fenestrated endothelia and a continuous basement membrane are generally found in the kidney, small intestine and salivary glands. Most of these capillaries have diaphragmed fenestrae, which are circular openings of 40–60 nm in diameter. The discontinuous capillaries, also known as sinusoidal capillaries, are common in the liver, spleen, and bone marrow. These capillaries show large interendothelial junctions (fenestrations up to 150 nm). Highly phagocytic Kupffer cells line the sinusoids of the liver, and those of the bone marrow by flattened, phagocytic reticuloendothelial cells. In the spleen, the endothelial cells contain a large number of pinocytic vesicles (up to 100 nm in diameter). Due to their large molecular weight (> 1,000 kDa) and hydrodynamic diameter in aqueous suspension of 100 nm, plasmids extravasate poorly via continuous capillaries because of tight junctions between the cells. However, plasmids can easily extravasate to sinusoidal capillaries of liver and spleen. Formulating plasmids into unimeric particles of 20–40 nm in diameter may enhance extravasation of plasmids across continuous and fenestrated capillaries. The (patho)physiology and microanatomy of tumors is significantly different from normal tissues (see Section 5. A tumor contains vessels recruited from the pre-existing network and vessels resulting from angiogenic response induced by cancer cells. There is a considerable variation in the cellular composition, basement membranes and in the size of the interendothelial cell fenestrations. Tumor interstitium is characterized by large interstitial volume and high diffusion rate. Sven Frøkjaer, Lona Christrup and Povl Krogsgaard-Larsen; Munksgaard, Copenhagen, 1998, pp. Tumor accumulation of plasmid could result from the enhanced permeability of the tumor vasculature, combined with their reduced clearance from the tumor due to the absence of the lymphatic system. Pharmacokinetic analysis of in vivo disposition profiles of radiolabeled plasmid provides useful information on the overall distribution characteristics of systemically administered plasmids, with one critical limitation. The plasma half-life of plasmid is less than 10 min, and hence tissue distribution and pharmacokinetic parameters of plasmid calculated on the basis of total radioactivity are not valid at longer time points. Thus, polymerase chain reaction and Southern-blot analysis are required to establish the time at which the radiolabel is no longer an index of plasmid distribution. The deposition of plasmids after systemic administration is restricted to the intravascular space due to its low microvascular permeability in most organs with continuous capillary bed. Some organs with fenestrated capillaries, such as liver, spleen, and bone marrow, provide some opportunities for extravasation of plasmids. Intravenously injected plasmids initially perfuse the pulmonary vascular beds, maximizing the 347 Figure 14. Reproduced with permission from: Biodistribution and gene expression of plasmid/lipid complexes after systemic administeration, Mahato R. Southern-blot analysis of blood showed the rapid degradation of plasmid, with a half-life of less than 5 min for intact plasmid, and was no longer detectable at 1 hr postinjection. By Southern-blot analysis, there was no detectable plasmid in the brain, large intestine, small intestine, or gonads at the 1-hr timepoint. Southern blot analysis also demonstrated that plasmid remained in the liver, spleen, lung, marrow, and muscle, although at diminished levels, up to 24 hr postinjection. The plasma membrane is the next obstacle to be overcome in delivering genes into a cell. Gene delivery systems rely on binding to cell surface molecules, either specific, non- specific or both, prior to cellular internalization. The surface bound material usually gains entry into the cell either by endocytosis or membrane fusion. The schematic representation of the process of gene delivery and expression is shown in Figure 14. Gene delivery systems can distribute plasmids to the desired target cells, after which the plasmid is internalized into the cell by a number of mechanisms, such as adsorptive endocytosis, receptor-mediated endocytosis, micropinocytosis, caveolae-mediated endocytosis and phagocytosis (see Section 1. The intracellular fate of plasmids depends on the means by which they are internalized and translocated to the cytoplasms and then to the nucleus. Extacellular environment → tissue targetability → cellular uptake → intracellular trafficking → nuclear entry → gene expression The transition from coated vesicle to early endosome is accompanied by acidification of the vesicular lumen that continues into the late endosomal and lysosomal compartments, reaching a final pH in the perinuclear lysosome of approximately 4. Such acidification associated with endosome maturation provides the means by which certain viruses gain access to the cytosol. Acid-induced conformational changes in the viral proteins trigger translocation across the endosomal membrane via a fusion process. By taking advantage of the endosomal acidification, pH-sensitive liposomes, adenovirus and endosomolytic peptides have been used to facilitate the release of plasmids into the cytoplasm prior to lysosomal degradation. Non-clathrin-coated pit internalization can occur through smooth imagination of 150–300 nm vesicles or via potocytosis. This pathway has been shown to be involved in the transport of folate and other small molecules into the cytoplasm. Plasmids are taken up by muscles through the T-tubules system and caveolae via potocytosis. Muscle cells appear to take up plasmids through the T-tubule system and caveolae via potocytosis. Apart from coated or uncoated pit pathways, cells may also take up plasmid/cationic carrier complexes via plasma membrane destabilization. Particles greater than 200 nm in diameter are not 350 efficiently taken up by endocytosis, but cells may also take up some larger plasmid/cationic carrier complexes via phagocytosis. Plasmid/cationic carrier complexes have been proposed to internalize into the endosome and initiate the destabilization of endosomal membranes. This destabilization would induce diffusion of anionic lipids from the external layer of the endosomal membrane into the complexes and form charge neutralized ion pairs with the cationic lipids. Destabilization and/or fusion of the complex with the plasma membrane would permit the same anionic lipids to diffuse to the surface, as would fusion with the endosomal membrane. Transfection efficiency is dependent on mitotic activity, as cells prevented from going into mitosis after transfection express transgenes much less efficiently than proliferating cells.

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Three of the leukaemias had monoblastic features; in one case there was a t(9;11)(p22;q23) trans- location; in another there was t(9;11;18)(p22;q23;q12) cheap 100mg zudena otc. The fourth case had a complex karyotype generic zudena 100 mg with amex, with -5 and -7 abnormalities typical of alkylating agent-induced cases zudena 100 mg. Several additional case reports and cohort studies have indicated that, while the 9p22 locus is commonly involved in translocations with band 11q23 (Pedersen- Bjergaard et al. Observations of cases of undifferentiated leukaemia and acute lymphoblastic leukaemia with t(4;11)(q21;q23) suggested additional heterogeneity in the partner chromosomes involved in translocations with band 11q23 (Hunger et al. The translocation at band 11q23 was usually the only abnor- mality, but in five cases additional structural or numerical changes were detected. Trans- location of chromosome band 11q23 occurred in eight of the 10 cases, with fusions to band 9p21 or 9p22 in three cases and fusions to band 17q25, 19p13. Heterogeneous translocations involving band 11q23 were also observed in cases of leukaemia after epipodophyllotoxin-containing treatment for paediatric solid tumours. A translocation t(9;11)(p21;q23) was seen in two cases, one of which also contained t(4;11)(q26;p13). The treatment regimens were not described completely, but epipodophyllotoxins were used in two patients with translocations involving band 11q23. Karyotypic features in leukaemias were evaluated after more dose-intensive, repetitive adminis- tration of high-dose alkylating agents, anthracycline and etoposide for paediatric non- lymphoid solid tumours (Kushner et al. One case that occurred 24 months after the start of neuroblastoma treatment showed del(7)(q22) and del(11)(q13q23), possibly reflecting the combined effects of an alkyl- ating agent and an epipodophyllotoxin (Kushner et al. Two cases of acute myeloid leukaemia with t(8;21) were observed among 212 patients who received etoposide, cisplatin and bleomycin for germ-cell tumours (Pedersen-Bjergaard et al. Translocations t(3;21)(q26;q22) are uncommon variants in treatment-related acute myeloid leukaemia and treatment-related myelo- dysplastic syndrome (Nucifora & Rowley, 1995). Of five cases of leukaemia with t(3;21) after heterogeneous chemotherapy, one had been treated with etoposide (Rubin et al. Individual case reports indicate that t(15;17) is also a recurrent chromosomal alteration after etoposide-containing treatment for a variety of tumours (Raiker et al. Etoposide has rarely been used as a single agent, except in some cases for the treatment of Langerhans cell histiocytosis (Haupt et al. Although t(15;17) is present in the vast majority of cases of acute pro- myelocytic leukaemia, the karyotypes in cases where etoposide was used a single agent revealed -6, -10, +mar, +ring in one case and del(20)(q11q13) in another. Cyto- genetic analysis in one case in which etoposide was used with vinblastine and high- dose methylprednisolone did reveal the t(15;17), but in another case in which eto- poside was used the t(15;17) was detectable only by molecular analysis. At the cytogenetic level, abnormalities including add(11)(p15), inv(11)(p15q22), t(11;20)(p15;q11. Cytogenetic studies revealed that translocations, especially those involving chromosome band 11q23, are hallmark features of leukaemias related to etoposide. Later, detailed mapping by Southern blot analysis suggested a biased distribution of the translocation break-points in treatment-related leukaemias in the 3′ break-point cluster region (Strissel Broeker et al. This line of investigation yields insights about regions of the genome affected by the drugs and provides some clues about the mechanism. The break-point deviated from the predilection for 3′ distribution in the break-point cluster region that was suggested in the adult cases (Strissel Broeker et al. Heterogeneous partner genes have been reported to be involved in the translocation. The site-specific cleavage was attributed to the higher-order chromatin fragmentation which occurs during apoptosis. Most recently, the t(11;20)(p15;q11) was identified in two paediatric cases of treatment-related myelodysplastic syndrome after exposure to multi-agent chemo- therapy in which etoposide was included. Etoposide gave mainly negative responses in a range of assays in prokaryotes and lower eukaryotes. Etoposide caused a slight (about twofold) increase in the frequency of revertant colonies in S. Toxicity but not mutagenicity occurred at a dose of about 800 μg/plate, which is higher than those studied in mammalian cells. In Saccharomyces cerevisiae strain D5, etoposide did not induce either mitochondrial ‘petite’ mutations or mitotic recombination. Single- strand breaks typically occur rapidly during exposure to the drug, reaching a maxi- mum by 15 min, whereas double-strand breaks accumulate more slowly, reaching a plateau between 1–2 h after the start of exposure (Long et al. Cells from patients with ataxia telangiectasia show increased sensitivity to etoposide, accompanied by an increased frequency of chromo- somal aberrations (Pandita & Hittelman, 1992). It also induced micronucleus formation in neonatal lymphocytes grown in vitro and in mouse splenocytes in culture. Various human lym- phoblastoid cell lines derived from patients with ataxia telangiectasia were hyperensitive to the induction of chromosomal aberrations by etoposide. The Chinese hamster cell line xrs-1 was also hypersensitive to etoposide, with an elevated frequency of micronucleus induction; however, the two ionizing radiation-sensitive cell lines, irs1 and irs3, appeared to be similar to the parental V79-4 cell line in terms of micronucleus induction. Etoposide caused both clastogenic and aneuploidogenic effects in all these cell lines (Hermine et al. Fluorescence in-situ hybridization techniques revealed that eto- poside caused almost equal numbers of dicentric and stable translocations in human peri- pheral blood lymphocytes in culture (Mosesso et al. It induced micronuclei and/or chromosomal aberrations in the bone marrow of mice and rats. Etoposide induced sister chromatid exchange in Chinese hamster lung cells and in human lymphocytes and other human cell lines in vitro. Sister chromatid exchange induction has also been seen in mouse bone-marrow cells in vivo. Etoposide induced mutation and somatic recombination in Drosophila melanogaster in the wing spot test. It also induced a positive response in the Drosophila white–ivory assay, probably again through recombinogenic events. These mice can therefore be used to detect somatic intrachromo- somal recombination inversion events in vivo in various tissues. When these mice were given a single intraperitoneal injection of etoposide and spleen cells were exam- ined three days later, significant induction of inversion events was found by histo- chemical staining of tissue sections (Sykes et al. It induced primarily small colony mutants at the Tk locus in mouse lymphoma L5178Y cells. Small colony mutants in L5178Y cells are usually caused by chromosomal mutations (DeMarini et al. Whether cellular damage results in mutation or apoptosis depends on a number of factors (Ferguson & Baguley, 1994). Etoposide-induced apoptosis has been demon- strated in cultured retinoblastoma Y79 cells (Lauricella et al. In mice, etoposide caused apoptosis through a p53-dependent pathway in imma- ture thymocytes and also through a p53-independent pathway in a particular sub-popu- lation of these cells. The drug induced apoptosis at significantly lower levels and at later times in p53 null as compared with p53 wild-type mice (MacFarlane et al. Polyploidy was also demon- strated by cytogenetic techniques in Chinese hamster ovary cells.

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