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A similar buy genuine cialis sublingual on-line impotence of organic origin, rapid distribution half-time of about 2 min was observed for both drugs generic 20 mg cialis sublingual with visa erectile dysfunction young age causes. Studies of cellular uptake suggested that the passage of teniposide into leukaemic cells in culture was linear up to 5 min and reached a steady state by 20 min, the intra- cellular concentrations being about 20 times higher than the extracellular concen- trations. Other authors have reported greater cellular accumulation of teniposide than etoposide at the same extracellular concentration of the two drugs in Lewis lung carci- noma cells in vitro, with intracellular concentrations of 1. Although few published data are available on the metabolism of teniposide in experimental systems, it appears to be similar to that of etoposide (see section 4. In isolated human liver preparations, cytochrome P450 mixed-function isozymes catalysed metabolism of the (pendant) E-ring to O-deme- thylated and catechol metabolites (Relling et al. Peroxidase-mediated O-demethylation of teniposide has also been reported (Haim et al. With the more commonly used five-day regime (30–60 mg/m2 per day), bone-marrow suppression was the dose-limiting toxic effect, with leukopenia reported in 28–38% of patients and thrombocytopenia in 7–30%. The lowest blood counts typically occurred around day 10, with recovery by day 21. Nausea and vomiting were reported as mild, occurring in up to 20% of patients, with occasional reports of diarrhoea. Less common toxic effects in this group included increased liver enzyme activity (11 patients), acute hypotension (10 patients), fever (six patients) and anaphylaxis (five patients). More recent studies of patients given 50–80 mg/m2 per day for five days confirmed these findings, haematological effects occurring most commonly. Episodes of nausea, vomiting and diarrhoea occurred occasionally but were generally mild, and some degree of alopecia was observed in most patients. Less common effects in these studies included transient increases in liver enzyme activity, anaphylaxis, hypotension and hypertension, which in one study was attributed to the vegetable oil base used in the formulation (Oishi et al. Single doses of 100 mg/m2 given once weekly are gener- ally less toxic (Tirelli et al. Because of the reports of hypotension and anaphylaxis in the early studies, reports of 82 hypersensitivity reactions in 2250 patients (3. Of these reactions, 45% occurred in patients with neuroblastoma or brain tumour, a much higher incidence than in patients with other tumour types. These reactions are manifest as respiratory difficulty, changes in blood pressure, urticaria and flushing. These patients also developed an intensely pruritic erythematous rash with purpura four to seven days after the start of chemotherapy, which involved the upper part of the chest and the upper part of the legs. The rash cleared spontaneously within one week and, in two patients who were treated again at 500 mg/m2, no rash occurred. In the one patient who received a second dose of 1000 mg/m2, paraesthesia and an abnormal electromyography were seen (de Vries et al. In one study, the intravenous formulation was tested orally after dilution in 100 mL of syrup or orange juice (Smit et al. Several patients retched during administration, 12 received antiemetics, and vomiting persisted in five patients. The dose-limiting toxic effect was myelosuppression, and gastrointestinal toxicity was also common. At equitoxic doses, the two drugs had equivalent anti-tumour activity in a murine tumour model in vivo (Jensen et al. The infant was fully developed and normal in all respects, the examinations including electrocardiography and blood counts. Injection on day 8 caused no embryo- toxicity or effect on fetal body weight at the low and intermediate doses, but the frequencies of embryolethality and fetal malformations were increased at 1. Teniposide was considerably more embryotoxic and teratogenic than etoposide, which was also included in this investigation (see the monograph on eto- poside). The commonest malformations observed at the highest dose were dextro- cardia, seen in 9. A second case of treatment-related acute lymphoblastic leukaemia with t(4;11) was reported after primary treatment for acute lymphoblastic leukaemia with a teniposide-containing regimen (Brizard et al. Teniposide has been used most often in the treatment of childhood acute lymphoblastic leukaemia, sometimes in com- bination with etoposide; the observations of specific leukaemia-associated chromo- somal translocations in this situation, most of which involve chromosome band 11q23, are described in the monograph on etoposide (see also Pui et al. Cytogenetic studies were performed in six cases, and translocations of chromosome band 11q23 were observed in two of these. In one case, the treatment-related leukaemia was acute lymphoblastic leukaemia with t(4;11)(q21;q23). In one patient who received teniposide and eto- poside, the karyotype showed t(9;11)(p22;q23), +der(9)t(9;11)(p22q23). In one case of leukaemia, there was homology to seven of eight bases of a χ-like sequence element. The presence of these sequences near the translocation break-points may facilitate recombination. Teniposide gave mainly negative responses in a range of assays in prokaryotes and lower eukaryotes. Teniposide caused about a twofold increase in the frequency of revertant colonies in S. In several of these bacterial tests, toxicity but not mutagenicity occurred at a dose of 250 μg/plate, which is higher than those studied in mammalian cells. Teniposide induced the formation of quadriradial chromosomes and affected accurate chromosomal segregation in Chinese hamster ovary cells. Fluorescence in- situ hybridization techniques revealed that about 40% of the rearrangement sites in teniposide-induced quadriradial and triradial chromosomal configurations in Chinese hamster Don cells involved a telomere-like block of base sequences (Fernández et al. Teniposide induced micronuclei and chromosomal aberrations in the bone marrow of mice. The drug induced sister chromatid exchange in V79 Chinese hamster cells and mutation and somatic recombination in Drosophila melanogaster in the wing spot test. It did not induce mutations at the Hprt locus in mouse lymphoma L5178Y cells, although it had weak effects at the same locus in Chinese hamster ovary cells. It induced primarily small colony mutants at the Tk locus in L5178Y cells; these mutants are usually caused by chromosomal mutations, and teniposide induced a series of deletions and duplications in the Aprt gene of Chinese hamster ovary cells. Cytogenetic changes were measured in bone marrow and embryonic tissue from pregnant mice given a single intraperitoneal injection of 1. Treatment on day 7 or 8 increased the frequency of embryonic cells with structural aberrations, one-fourth or more of which were stable, consisting of chromosomes with metacentric or submetacentric markers. Teniposide increased the percentage of embryonic cells with numerical aberrations, but this was statistically significant only on day 8. Most of the aberrations were hypo- ploidy (usually monosomy) and hyperploidy (usually trisomy) (Sieber et al.

Group 2 This category includes agents cheap cialis sublingual 20 mg free shipping erectile dysfunction normal testosterone, mixtures and exposure circumstances for which cheap 20 mg cialis sublingual with visa impotence from steroids, at one extreme, the degree of evidence of carcinogenicity in humans is almost sufficient, as well as those for which, at the other extreme, there are no human data but for which there is evidence of carcinogenicity in experimental animals. Agents, mixtures and exposure circumstances are assigned to either group 2A (probably carcinogenic to humans) or group 2B (possibly carcinogenic to humans) on the basis of epidemiological and experi- mental evidence of carcinogenicity and other relevant data. The exposure circumstance entails exposures that are probably carcinogenic to humans. This category is used when there is limited evidence of carcinogenicity in humans and sufficient evidence of carcinogenicity in experimental animals. In some cases, an agent (mixture) may be classified in this category when there is inadequate evidence of carcinogenicity in humans, sufficient evidence of carcinogenicity in experimental animals and strong evidence that the carcinogenesis is mediated by a mechanism that also operates in humans. Exceptionally, an agent, mixture or exposure circumstance may be classified in this category solely on the basis of limited evidence of carcinogenicity in humans. This category is used for agents, mixtures and exposure circumstances for which there is limited evidence of carcinogenicity in humans and less than sufficient evidence of carcinogenicity in experimental animals. It may also be used when there is inadequate evidence of carcinogenicity in humans but there is sufficient evidence of carcinogenicity in experimental animals. In some instances, an agent, mixture or exposure circumstance for which there is inadequate evidence of carcinogenicity in humans but limited evidence of carcinogenicity in experimental animals together with supporting evidence from other relevant data may be placed in this group. Group 3—The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circums- tances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is ina- dequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category. This category is used for agents or mixtures for which there is evidence suggesting lack of carcinogenicity in humans and in experimental animals. In some instances, agents or mixtures for which there is inadequate evidence of carcinogenicity in humans but evidence suggesting lack of carcinogenicity in experimental animals, consistently and strongly supported by a broad range of other relevant data, may be classified in this group. For several compounds evaluated in this volume, no data were available on carcino- genicity in experimental animals, and this limited the possibility of a comprehensive evaluation of their carcinogenic risks to humans. Although they may not have been tested for carcinogenicity, the Working Group suspected that studies might have been conducted by pharmaceutical companies but never published. The Working Group encourages pharmaceutical companies and cognizant governmental agencies to make available all studies of carcinogenesis that have been, or will be, carried out on pharma- ceutical agents in the form of publications or technical reports. Two chemicals were tested for carcinogenicity in genetically engineered mice which are particularly susceptible to induction of tumours at certain sites through specific mechanisms. The use of such animals for evaluation of the carcinogenicity of chemicals has been reviewed (McGregor et al. Some, but not all, of these transgenic (‘knockout’) models can be considered the laboratory counterparts of certain rare human genetic syndromes, and the models may be particularly useful for testing drugs to be administered to individuals with such syndromes. Also, genetically engineered mice that lack one copy of an essential tumour suppressor gene, such as p53, model the situation in which a functioning copy of the suppressor gene has been lost in the somatic cells of a normal individual through a stochastic process. The transgenic models may therefore also be useful for studying the mechanism or mode of action of chemicals and, in parti- cular, to test genetic targets of carcinogenicity. Because of the limited database on the responses of particular genetically engineered mice to chemical carcinogens, however, the results of bioassays with these animals must be interpreted with caution. In two large, well-conducted trials, initial therapy with multiple drugs followed by simplification of the regimen in a maintenance phase has been shown to be less effective than continued multi-agent therapy (Havlir et al. Centers for Disease Control and Prevention, 1998; Gazzard & Moyle, 1998) on the goals of combination therapy, monitoring and recommended combinations. These beneficial results may, however, mask potential carcinogenic effects of the antiviral agents. Much of the evidence on the possible carcinogenic effects of antiretroviral agents in humans is derived from trials designed to evaluate the efficacy of these agents in the treatment of patients with immunosuppression of varying severity. In consequence, the survival of infected patients was relatively poor and the opportunity for long-term follow-up to assess cancer risk was limited. In addition, the occurrence of cancer may have been underascertained, and in many of the studies, no formal, appropriate analyses of cancer rates were presented. While the situation is similar in other developed countries, most developing countries are currently unable to offer these therapies because of their cost. The topological changes mediated by these enzymes are important for chromosomal replication and conden- sation, and disruption of their function may prevent accurate chromosomal segregation and increase recombination. Such combinations may confound analysis of the association of specific agents with leukaemia. Furthermore, in some studies in which patients were treated with etoposide and/or teniposide, the authors used various empi- rical conversion factors to derive an ‘equivalent dose’ of etoposide from that of teni- poside. The conversions were based, however, on the therapeutic effects rather than on metabolic considerations or on possible leukaemogenic potency at a given dose. Such studies do not allow evaluation of the carcinogenicity of either compound as a single agent. Additional chromosomal and genetic changes may occur in secondary leukaemias (Corral et al. The suspension may also contain carboxymethylcellulose sodium, flavours (banana, orange), glycerol, methyl 4-hydroxybenzoate, microcrystalline cellulose, propyl 4-hydroxybenzoate, sorbitol and vanillin. The cream may also contain cetostearyl alcohol, glycerol monostearate, liquid paraffin, macrogol stearate, petroleum jelly, poloxamer 407, poly- oxyethylene fatty acid, propylene glycol, sodium lauryl sulfate and soft white paraffin. Aciclovir sodium is available as a powder for injection or intravenous infusion in dosages of 25 and 50 mg/mL. After reconstitution with sterile water for injection, aci- clovir sodium solutions containing 50 mg/mL aciclovir, have a pH of approximately 11 (10. The following impurities are limited by the requirements of the British and Euro- pean pharmacopoeias: 2-amino-9-{[2-(acetyloxy)ethoxy]methyl]}-1,9-dihydro-6H- purin-6-one; 2-amino-1,7-dihydro-6H-purin-6-one; 2-amino-7-{[2-hydroxyethoxy]- methyl}-1,7-dihydro-6H-purin-6-one; 2-amino-9-{[2-(benzoyloxy)ethoxy]methyl}- 1,9-dihydro-6H-purin-6-one; 6-amino-9-{[2-hydroxyethoxy]methyl}-1,3-dihydro-2H- purin-2-one; 2-acetamido-9-{[2-hydroxyethoxy]methyl}-1,9-dihydro-6H-purin-6-one; 2-acetamido-9-{[2-(acetyloxy)ethoxy]methyl}-1,9-dihydro-6H-purin-6-one; and 2-ace- tamido-9-{[2-(benzoyloxy)ethoxy]methyl}-1,9-dihydro-6H-purin-6-one (British Phar- macopoeial Commission, 1996; Council of Europe, 1998). Those that have been dis- continued include Acicloftal, Aciviran, Clovix, Viclocir, Vipral and Zovir. Trade names for aciclovir sodium include Acic, Aciclovir Alonga, Aciclovir- Austropharm, Aciclovir Biochemie, Aciclovir Brahms i. By 1988, aciclovir had been licensed in more than 40 countries, and it was estimated that intravenous and oral preparations had already been used in over 10 million courses of treatment (Tilson, 1988). It is also the drug of choice for treatment of herpes simplex encephalitis (American Hospital Formulary Service, 1997; Medical Economics Data Production, 1999). Aciclovir is frequently given orally in the management of first and recurrent epi- sodes of mucocutaneous herpes in selected patients, for the acute treatment of herpes zoster (shingles) and for the treatment of chickenpox in adults and children. The oral doses of aciclovir for adults range from 200 mg every 4 h (while awake) to 800 mg three times a day for 5–10 days. The oral dose for treatment of chickenpox and herpes zoster is 800 mg aciclovir every 4 h for 5–10 days.

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Multinational pharmaceutical companies are obliged to provide two-dimensional barcodes for all products bound for Turkey order cialis sublingual 20 mg with visa youth erectile dysfunction treatment, though some may print serial labels separately and attach them to pack- ages in-country (Taylor cheap cialis sublingual 20mg overnight delivery impotence of organic origin 60784, 2010). Brazil has a similar re- quirement, rolled out over 3 years starting in 2009 and allowing a 1-year grace period to sell all warehoused products that predated the requirement (Taylor, 2010). The use of matrix barcodes for tracking and tracing is not foolproof; barcodes can be forged. They are also not helpful when a patient does not receive the manufacturer’s packaging. The system also demands ac- tive participation from every intermediary on the distribution chain. If a pharmacist fails to scan the barcode, the information it carries is of no use. Nevertheless, electronic track-and-trace can do much to thwart criminals and protect the drug supply. The systems in Brazil and Turkey give vendors and motivated consumers a way to verify the safety of their products, and they allow regulators to better understand where and how frequently prod- ucts leave the distribution chain. The chip holds the product’s unique serial number, expiry date, batch code, and information about its previous transactions; the antenna, when activated by the tag reader, conducts radio energy to the chip to send and receive data (Lefebvre et al. The technician reading the chip does not need to position the reader within sight of the tag to read it; the signal is sent by radio waves, not sight. The amount of information encoded in electronic product codes and the ease of accessing this information make the system attractive for drug pedigrees (Lefebvre et al. The technology clearly has innovative potential, but a critical mass of intermediaries on the drug distribution chain need to upgrade their systems for it to be useful (Lefebvre et al. Consumer electronics and other expensive products are commonly labeled with radio frequency tags, but using the technology for medicines presents obstacles. After marking each primary package (the smallest unit of packaging) with a radio frequency tag, access to the electronic product code database neces- sary to decipher the information in the chip costs about $50,000 in the frst year (Wunder and Roach, 2008). Generics companies in many parts of the world share this sentiment, although the generics industry is not at consensus on the question (Barlas, 2005; Jagdale, 2010; Wolinsky, 2006). Even if the technology were cheaper, it is unclear that it would be practical in the markets most hurt by falsi- fed drugs. Chapter 3 explains that the burden of falsifed medicines is borne mostly by the poor, especially the poor in low- and middle-income countries, who buy drugs at unlicensed drug stores and unregulated street markets. Mobile phone verifcation, an ingenious form of mass serialization, can fll in for an electronic pedigree at a drug’s last step to the consumer. Mobile verifcation companies such as Sproxil take subscriptions from drug companies and wholesalers. Sproxil provides labels to their clients; each label is marked with a visible serial number and secret code hidden under the scratch-off surface. When the label is attached to the fnal package, the manufacturer enters the visible serial number in the Sproxil database through a secure web portal. The visible serial number links the product manufacturer, batch number, manufacture, and expiry dates to the secret scratch-off code. At the point of purchase, the consumer sends a text message or, in some systems, an e-mail to the verifcation company, the company that makes the scratch-off labels and manages the linked database. An immediate text message response confrms if the secret code number is registered with the manufacturer, or if it is from a shipment reported to have left the legitimate supply chain. Mobile verifcation of pharmaceuticals is gaining users in 17 sub-Saharan African countries and India (Mukherjee, 2012; Sproxil, 2012; Versel, 2012). An elegant system for assigning unique product numbers, mobile verifcation empowers consumers to act for their own safety. Mobile verifcation cannot prevent fraud, nor is it a substitute for phar- macovigilance and postmarket surveillance. A product could be substan- dard at the factory but still gain a valid mobile verifcation label. Mobile verifcation, however, appeals to good-quality manufacturers, who see the service as an investment in their brand or as a way for consumers to have Sproxil standard labels with visible serial number and scratch-of covering the secret code number. A more likely problem would be a wholesaler assigning a legitimate label to a falsifed drug. Also, the verifcation service only confrms a product’s identity at the end of the distribution chain, at purchase. These systems cannot track the chain of custody or monitor if the product has been stored and transported properly. A reliable system for tracking and tracing drugs through the distribu- tion chain would greatly reduce the likelihood of falsifed and substandard medicines reaching patients. Recent technological advances, such as the use of radio frequency identifcation and the expansion of mobile phones in de- veloping countries, hold promise for supply chain security. The committee believes that manufacturers and governments should use these technologies to integrate all records of a drug’s chain of custody. A mandatory track-and-trace system for drugs is the best way to moni- tor the chain of custody and protect patients from unsafe drugs. A full track-and-trace system would allow all parties in the drug distribution chain to see a complete record of the product’s path from the manufacturer to the patient (Rappeport and Jack, 2012). Track-and-trace systems place unique demands on drug manufacturers, retailers, and wholesalers. Some may see the imposition of a drug pedigree system as a matter of pharmacy practice, and therefore under the jurisdiction of state boards of pharmacy, the state health department, or another state authority. This authority should accompany an increase in funding to allow the agency, which has received many unfunded mandates in recent years, the staffng and technical upgrades necessary to monitor compliance (McCain, 2011; Palmer, 2010). A track-and-trace system would allow pharmacists to identify suspi- cious drugs before dispensing them and would facilitate more effcient product recalls (Buynak, 2011; DeCardenas, 2007). Companies tag drug pallets or other bulk packages with radio frequency tags, for example, but use barcodes or other identifers on smaller units (Lefebvre et al. Nevertheless, consumers and governments have demanded a stronger chain of custody (DeCardenas, 2007). This problem has been lingering for years and should be addressed promptly (Palmer, 2012). Without a clear federal mandate on the problem, companies and state governments work in a state of uncertainty, not knowing where and how to make the neces- sary investments that track-and-trace will require. If Congress does not set a mandatory requirement, then the competing demands of state track- and-trace systems will create an unmanageable burden for manufacturers, wholesalers, and retailers. Stakeholder comments on the workshop mentioned the importance of track-and-trace and “the need for one standard, without variations imposed, for example, by individual states” (Ducca, 2011). Any track-and-trace system will be an expense to manufacturers and industry, but the expense can be contained by making one national requirement. An increased track-and-trace requirement will put a fnancial burden on these companies, even if the added cost is low. This can help control the burden an inevitable shift to drug tracking will put on these businesses. Tracking primary packages through the drug distribution chain with unique serial numbers is a good defense against criminal infltration (Ludwig, 2012; Pellek, 2009; Power, 2008).

The chemical laboratory was found provided with proper fuming chamber with adequate space for storage of tests samples cialis sublingual 20mg without a prescription erectile dysfunction drugs that cause, retained samples order 20 mg cialis sublingual visa erectile dysfunction treatment fruits, 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. If by electronic data processing system then how access is controlled to enter, modify etc. How the finished medical Devices evaluated whether the device is manufactured as per pre established specification, specify the standard 18. How promptly recall operation at the level of each distribution channel up- to the retail level can be carried out. Whether reports of serious reaction with comments and documents immediately sent to Licensing Authority Is there any criterion for action to be taken on the basis of nature of complaint / adverse reaction? Whether approval has been granted for carrying out testing on the following Categories of Drugs Items and Cosmetics 2. Other Drugs (Indicate Category) (a) Medicinal Gases (b) Diagnostics (c) Medical Devices 2. Sera, Vaccines, Antigens, Toxins, Antitoxins, Toxoids, Bacteriophages & similar Immunological products 2. Whether workbenches are constructed with acid, alkali and 367 solvent resistant material and are smooth and free from crevices 6. Whether any Standard Operating Procedure are available for breeding and care of animals, maintenance, cleaning or sanitation with suitable 368 schedule for cleaning of animal Cages, racks, floor and other equipments. Cabinet ii) Soxhlet extractor 370 iii) Oven iv) Scale v) Absorbency Tester vi) Balance (Analytical) vii) All equipment required for Sterility testing 8. Whether in case of other substances such records are being maintained for six years. The detailed observations about the infrastructure, technical personnel and other set up of the testing facility applied for instrumental, chemical and microbiological analysis of Drugs and pharmaceuticals or raw materials used in the manufacture there of on behalf of licensees for manufacture for sale of Drugs were noted and summarized in aforesaid checklist. Following observations were made by the joint inspection team during the course of inspection. Observations Conclusion & Recommendation :- On the basis aforesaid inspection checklist and summarized observations it may be concluded that M/s. In the view of above the inspecting team is of the opinion that the application furnished by the subject firm as per Form 36, for approval to carry out test on Drugs & pharmaceuticals or raw materials used in the manufacture thereof on behalf of 382 licensees for manufacture for sale of Drugs or raw material on Form-37 for following categories of Drugs by Chemical, Instrumental & Microbiological testing may be granted for the followings category of the drugs & Cosmetics: Drugs other than those specified in schedule C & C(1) excluding Homeopathic Drugs  Drugs requiring the use of ultraviolet spectroscopy or chromatography  Disinfectants  Cosmetics b. Procedure Under the provision of Rule – 89 it is mentioned that “in the case of a drug, the composition of which is such that the drug is not generally recognized among experts qualified by scientific training and experience to evaluate the safety of drugs as safe for use, no licence in Form – 29 shall be granted unless the applicant produces a certificate from the “Licensing Authority” mentioned in Rule 21, to the effect that there would be No Objection to such license being granted”.

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Treatment at full therapeutc dose should be contnued for at least 4-6 months afer resolu- ton of symptoms (about 12 months in the elderly) 20mg cialis sublingual for sale erectile dysfunction medications otc. Treatment should not be withdrawn prematurely otherwise symptoms are likely to recur buy cialis sublingual on line amex erectile dysfunction treatment malaysia. Patents with a history of recurrent depres- sion should contnue to receive maintenance treatment (for at least 5 years and possibly indefnitely). Reducton in dose should be gradually carried out over a period of about 4 weeks or longer if withdrawal symptoms emerge (6 months in patents who have been on long-term maintenance treatment). Tricyclic and related antdepressants can be divided into those with more or less sedatve efect. Those with sedatve propertes include amitriptyline and those with less sedatve efects include imipramine. These drugs are most efectve in the treatment of depression associated with psychomotor and physiological disturbances. Adverse efects include ant- cholinergic (more correctly antmuscarinic) symptoms of dry mouth, blurred vision, constpaton and urinary retenton. Minimal quanttes of tricyclic antdepressants should be prescribed at any one tme because they are dangerous in overdose. Amitriptyline* Pregnancy Category-C Schedule H Indicatons Moderate to severe depression, migraine prophylaxis; tension, headache, enuresis. Dose Oral Adult- Initally 75 mg (adolescents 30 to 75 mg) daily in divided doses or as a single dose at bed tme increased gradually as necessary to 150 to 200 mg daily. Contraindicatons Recent myocardial infarcton, arrhythmias (especially heart block); manic phase in bipo- lar disorders; severe liver disease; children; porphyria; glaucoma, prostatc hypertrophy. Precautons Cardiac disease (see Contraindicatons above); history of epilepsy; lactaton (Appendix 7b); elderly; hepatc impairment (Appendix 7a); thyroid disease; pheochromocytoma; history of mania, psychoses (may aggravate psychotc symptoms); angle-closure glaucoma; history of urinary retenton; concurrent electroconvulsive therapy; avoid abrupt withdrawal; anaesthesia (increased risk of arrhythmias and hypotension); interactons (Appendix 6a, 6b, 6c); pregnancy (Appendix 7c); pre-existng haematological disorder, abrupt disorientaton. May impair ability to perform skilled tasks, for example operatng machinery, driving. Escitalopram Pregnancy Category-C Indicatons Depression, obsessive compulsive disorder, anxiety disorder, panic disorder. Fluoxetne* Pregnancy Category-C Schedule H Indicatons Major depression (including pediatric de- pression); obsessive-compulsive disorder (in both adult and pediatric populatons); bulimia nervosa; anorexia nervosa; panic disorder and premenstrual dysphoric disor- der; depression illness, Parkinson’s disease. Contraindicatons Should not be used if the patent enters a manic phase; renal failure, hypersensitvity. Precautons Should be used with cauton in patents with epilepsy (avoid if poorly controlled, discontnue if convulsions develop), cardiac disease, diabetes mellitus, susceptbility to angle-closure glaucoma, a history of mania or bleeding disorders (especially gastro- intestnal bleeding), and if used with other drugs that increase the risk of bleeding, hepatc impairment (Appendix 7a), renal impairment, pregnancy (Appendix 7c), and lactaton. They should also be used with cauton in those receiving concurrent electroconvulsive therapy (prolonged seizures reported with fuoxetne). Adverse Efects Gastro-intestnal efects (dose-related and fairly common-include nausea, vomitng, dyspepsia, abdominal pain, diarrhoea, const- paton), anorexia with weight loss (increased appette and weight gain also reported) and hypersensitvity reactons including rash (consider discontnuaton-may be sign of impending serious systemic reacton, pos- sibly associated with vasculits), urtcaria, angioedema, anaphylaxis, arthralgia, myal- gia and photosensitvity; other side-efects include dry mouth, nervousness,anxiety, headache, insomnia, tremor, asthenia, hallu- cinatons, drowsiness, convulsions, galactor- rhoea, sexual dysfuncton, urinary retenton, sweatng, hypomania or mania, movement disorders and dyskinesias, visual disturbanc- es, hyponatraemia; serum sickness, eleva- ton of liver enzymes. Imipramine* Pregnancy Category-D Schedule H Indicatons Panic atacks; chronic pain; nocturnal enuresis; Kleine-Levin syndrome; depression, hyperactvity, atenton defcit disorder. Child- <6 years: not recommended, 6-12 years: 25 mg at bed tme, >12 years: 50 mg at bed tme. Contraindicatons Recent myocardial infarcton, arrhythmias (partcularly heart block), not indicated in manic phase, severe liver disease; epilepsy, mania, narrow angle glaucoma, hypersensitvity. Precautons Cardiac disease (partcularly with arrhythmias), history of epilepsy, pregnancy (Appendix 7c), lactaton, elderly, hepatc impairment, interactons (Appendix 6a), thyroid disease, pheochromocytoma, history of mania, psychoses (may aggravate psychotc symptoms), susceptbility to angle-closure glaucoma, history of urinary retenton, concurrent electroconvulsive therapy; if possible avoid abrupt withdrawal; anaesthesia (increased risk of arrhythmias and hypotension), see surgery; porphyria; for additonal nocturnal enuresis warnings; acetylsalicylic acid hypersensitvity. Individual and community programmes for relearning old skills and developing new ones and for learning to cope with the illness should be initated. Classes of antpsychotc drugs include phenothiazines (for example chlorpromazine), butyrophenones (for example haloperidol), thioxanthenes (for example fupentxol) and newer ‘atypical’ neuroleptcs including clozapine and risperidone. The various antpsychotc drugs do not, in general, difer in their antp- sychotc actvity, but difer in range and quality of adverse efects (see below). Acute Phase Treatment: The administraton of chlorpromazine or haloperidol will relieve symptoms such as thought disorder, hallucinatons and delusions and prevent relapse. However, haloperidol may restore an acutely ill schizophrenic, who was previously withdrawn, or even mute and akinetc, to normal actvity and social behaviour. In the acute phase chlorpromazine may be administered by intramuscular injecton in a dose of 25-50 mg which can be repeated every 6-8 h while observing the patent for possible hypotension. In most cases, however, the intramuscular injecton is not needed and patents can be treated with an oral dose. Maintenance Therapy: Long-term treatment in patents with a defnite diagnosis of schizophrenia may be necessary afer the frst episode to prevent the manifest illness from becoming chronic. The lowest possible dose of antpsychotc drug that will prevent major exacerbatons of forid symptoms is used for long-term management. Intramuscular depot preparatons such as fuphenazine may be used as an alternatve to oral mainte- nance therapy especially when compliance with oral treat- ment is unreliable. Exacerbatons of illness in patents on maintenance drug therapy can be precipitated by stress. Withdrawal of maintenance drug treatment requires careful surveillance since it is not possible to predict the course of the disease and the patent may sufer a relapse if treatment is withdrawn inappropriately. Further, the need for contnuaton of treatment may not be evident on withdrawal of treatment because relapse may be delayed for several weeks. Hypotension and interference with tempera- ture regulaton, neuroleptc malignant syndrome and bone- marrow depression are the most life-threatening. They can result in dangerous falls and hypothermia in the elderly and this must be considered before prescribing these drugs for patents over 70 years of age. Extrapyramidal symptoms are the most troublesome and are caused most frequently by the piperazine phenothiazines such as fuphenazine, the butyrophenones such as haloperidol and the depot preparatons. Although easily recognized, they are not so easy to predict because they depend in part on the dose and patent susceptbility as well as the type of drug. However, there is a general tendency for low-potency drugs to have less extrapyramidal adverse efects, while high-potency drugs such as haloperidol have more extrapyramidal efects but less seda- ton and antcholinergic (more correctly antmuscarinic) efects. Extrapyramidal symptoms consist of parkin- sonian-type symptoms including tremor which may occur gradually; dystonia (abnormal face and body movements) and dyskinesia, which may appear afer only a few doses; akathisia (restlessness), which may occur afer large inital doses and may resemble an exacerbaton of the conditon being treated; and tardive dyskinesia (an orofacial dyskinesia), which usually takes longer to develop but may develop on short-term treat- ment with low doses; short-lived tardive dyskinesia may occur afer withdrawal of the drug. Parkinsonian symptoms are usually reversible on withdrawal of the drug and may be suppressed by antcholinergic (antmuscarinic) drugs but they may unmask or worsen tardive dyskinesia. Tardive dyskinesia is usually associated with long-term treatment and high dosage of an antpsychotc, partcularly in elderly patents. There is no established treatment for tardive dyskinesias, which may be irreversible on withdrawing therapy. However, withdrawal at the earliest signs of tardive dyskinesia may halt its full devel- opment. Treatment of all patents on antpsychotcs must be carefully and regularly reviewed. Neuroleptc malignant syndrome (hypothermia, fuctuatng levels of consciousness, muscular rigidity, and autonomic dysfuncton with pallor, tachycardia, labile blood pressure, sweatng and urinary incontnence) is a rare adverse efect of haloperidol and chlorpromazine. It is managed by discontn- uing the antpsychotc, correctng fuid and electrolyte defects, and giving bromocriptne and sometmes dantrolene. Dose Oral Adult- Schizophrenia and other psychoses, mania, psychomotor agitaton, violent behaviour and severe anxiety (adjuvant): initally 25 mg 3 tmes daily (or 75 mg at night) adjusted to response to usual maintenance dose of 100-300 mg daily (but up to 1.

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However order on line cialis sublingual erectile dysfunction research, in actual gravimetric analysis order genuine cialis sublingual online erectile dysfunction causes agent orange, the final weight of the product is usually accomplished by adopting anyone of the following standard methods, namely : (a) Solvent extraction, (b) Ignition or volatalization, and (c) Precipitation from solution. Gravimetric techniques are broadly based upon the quantitative precipitation of the respective cation or anion from a given solution in two different ways : (i) as an insoluble compound that yields a residue having a specific composition after ignition, and (ii) as an insoluble compound having a known composition. There are four vital steps that are essentially required for a successful gravimetric method, namely : (a) Identify an insoluble form with a definite composition, (b) Separate the analyte exclusively from another constituents which may cause interference, (c) Wash the precipitate free of coprecipitants and impurities as far as possible, and (d) Convert the precipitate ultimately to a reasonably measurable form. All the above three aspects shall be described briefly vis-a-vis their direct impact on the gravimetric analysis. These reactions under certain prevailing experimental param- eters are made to proceed to completion, whereas in certain other conditions they may even attain equilibrium before completion. In the latter instance, erroneous results may creep in with regard to the pharmaceutical substance under estimation. Hence, it has become absolutely necessary first to establish the appropriate con- ditions whereby the reactions must move forward to attain completion so as to achieve the ultimate objective in all quantitative assays. In general, there are three cardinal experimental parameters that must be observed rigidly in order to check the reversal processes and help the completion of a reaction, namely : (a) formation of very slightly ionized molecules, (b) formation of an insoluble gas, and (c) formation of a sparingly soluble solid. The ‘law of mass action’ advocates that the rate of a reaction is directly proportional to the product of the molecular concentrations of the reacting substances. At equilibrium the rates of the forward reaction (a) and opposing reaction (b) are equal. Evidently, in most quantitative analysis one entity is added invariably to allow the reaction to proceed as closely to completion as possible. The principle of solubility product is applicable to : (i) difficultly soluble salts in their saturated solutions, (ii) occurrence of precipitation, (iii) prevention of precipitation, and (iv) dissolution of a substance. For instance, a difficultly soluble salt ApBq on dissociation provides a relative number of p cations and q anions. Thus, we have : ApBq pA+ + qB– Hence, solubility product ApBq = [A+]p × [B–]q where, [ ] are generally used to express the molar concentrations. On exceeding this concentra- tion, the AgCl gets precipitated which remains in equilibrium with the dissolved AgCl. Therefore, at equilib- rium, the clear supernatant liquid is a saturated solution, and at this critical juncture the rate at which the dissolved salt gets precipitated is almost equal to the rate at which the solid undergoes dissolution. This establishes the following equilibria : AgCl AgCl Ag+ + Cl– Solid Dissolved Dissolved precipitate unionized ionized Hence, the ionization equilibrium may be expressed as follows : + [Ag ] × [Cl ] ionized = K AgCl unionized where, K = ionization constant. Therefore, it may be inferred that—‘in a saturated solution of a difficultly soluble salt, the product of the molecular concentration of its ions is constant’. Now, if to the resulting supernatant liquid, which is nothing but a saturated solution of barium sul- phate, an additional small quantity of either a soluble barium salt or a soluble sulphate is provided, a slight further precipitation may occur. Evidently, this decrease in the concentration of the ions in either instance may be achieved by the combination of barium and sulphate ions to give rise to the insoluble barium sulphate thereby forcing the reaction towards completion. In short, the common-ion effect is employed invariably in carrying out the gravimetric analysis of pharmaceutical substances so as to drive reactions toward completion. The gravimetric meth- ods adopted vary according to the nature of the substance under determination. However, most of the sub- stances being estimated gravimetrically fall into one or the other categories stated below, which would be discussed briefly with suitable examples : (a) Substances assayed gravimetrically, (b) Substances assayed after conversion : (i) Substances assayed after conversion to Free Acid, (ii) Substances assayed after conversion to Free Base, (iii) Substances assayed after conversion to Free Compound, and (iv) Substances assayed after conversion to Derivatives or Substitution Products. A few typical examples are cited below so as to expatiate the procedure as well as the theoretical aspects. Theory : The following reaction forms the basis for the calculation of the theoretical amount of silver nitrate solution required as well as the purity of the given sample of NaCl. From above, the percentage purity of the given sample of NaCl may be found as shown below : 58 44. Consequently, the percentage purity of the sample is determined by the formula : W E 100 = % S where, W = Wt. By incorporating the data given above, the amount of sodium chloride present in 100 g of the sample i. Check and confirm that the resulting solution is acidic with the help of blue litmus paper. The requisite quantity of silver nitrate solution must be added in small lots at intervals with constant stirring with a glass rod. Cover the beaker with a watch-glass and boil the contents very gently with occasional stirring (to avoid bumping of the liquid and loss of volume). Stop heating and digest the mixture for 10 minutes so as to agglomerate the precipitate and enhance settling thereby leaving a clear supernatant liquid. Add 2 drops of silver nitrate solution to the hot supernatant liquid in order to confirm whether precipitation is completed. Take a properly prepared Gooch crucible, heat to constant weight and fit it into the suction flask. Decant most of the supernatant liquid first into the Gooch crucible by applying gentle suction to hasten filtration. Wash the precipitate on the Gooch crucible at least thrice with 15 ml portions of 0. Now, apply vigorous suction to drain out the liquid from the precipitate to the maximum extent. Dry the crucible to a constant weight between 110-120°C in an electric oven until two concurrent weighings are achieved. Thus, the weight of the crucible (tare) must be deducted from the weight of the crucible plus the precipitate to arrive at the weight of silver chloride duly obtained from the sample. Add the requisite quantity of the oxine reagent and then add a 2 N solution of ammonium acetate gradually from a pipette till precipitation just commences. Add a further portion (50 ml) of ammonium acetate solution with vigorous stirring. Filter the precipitate through No : 3 or 4 sintered glass crucible that has been previously dried to a constant weight at 130—150°C. Cognate Assays A good deal of pharmaceutical substances are officially assayed gravimetrically as appears in Table 10. All these typical cases shall be discussed briefly with their appropriate examples in the following sections. Substances Assayed after Conversion to Free Acid A few official pharmaceutical substances may be assayed gravimetrically by affecting separation, purification, and weighing an organic medicinal compound without causing any permanent change in composition. It is an usual practice that before extraction of the organic medicinal compound, the sample of the crushed tablets is carefully washed with petroleum benzene to get rid of undesirable components, for instance : lubricants and binders that would be extracted along with the organic medicinal compound by such solvents as ether or chloroform which is employed subsequently. The resulting aqueous solution of the salt of the respective organic medicinal compound is subsequently made acidic and the liberated organic acid (amobarbital) is finally extracted with ether or chloroform. Add to it 5 ml of 2 M hydrochloric acid and extract with 50 ml of ether and then with successive 25 ml quantities of ether until complete extraction is affected.

Note: Repeat in increments of half to complete initial dose to maintain anesthesia buy cialis sublingual online from canada erectile dysfunction and diabetes ppt. Warnings/precautions: Emergent reactions including hallucina- tions buy 20 mg cialis sublingual overnight delivery erectile dysfunction from diabetes treatment for, delerium, and vivid dreams may occur up to 24 hours after administration. Clinically important drug interactions • Drugs that increase effects/toxicity of ketamine: barbiturates, opi- oids, thyroid hormone, halothane, hydroxyzine, muscle relaxants. Editorial comments • Ketamine should be used only under the strict guidance and supervision of physicians who are experienced in the adminis- tration of general anesthetics. Such physicians must be knowledgeable in maintaining an airway and controlling respi- ration. Mechanism of action: Inhibits synthesis of steroids in fungal cell membranes, resulting in leakage of essential cellular compo- nents. Susceptible organisms in vitro: Candida sp, Cryptococcus, Coccidioides, Histoplasma, Blastomyces. Contraindications: Hypersensitivity to ketoconazole or other azole antifungals, concomitant astemizole, triazolam. Warnings/precautions • Treatment of candidiasis requires 1–2 weeks; for other sys- temic mycoses, 6 months. Clinically important drug interactions • Ketoconazole increases effects/toxicity of hepatotoxic drugs, cisapride, oral anticoagulants, astemizole, cyclosporine, astem- izole, corticosteroids, midazolam, triazolam. Mechanism of action: Inhibits cyclooxygenase, resulting in inhi- bition of synthesis of prostaglandins and other inflammatory mediators. Mechanism of Action: Inhibits cyclooxygenase, resulting in inhibition of synthesis of prostaglandins and other inflammatory mediators. Ophthalmic solution: hypersensi- tivity to any ingredient in the formulations of patients wearing soft contact lenses. Clinically important drug interactions • Drugs that increase effects/toxicity of ketorolac: alcohol, cor- ticosteroids, insulin, cimetidine, probenicid. Editorial comments: Ketorolac is recommended only for short- term use (up to 5 days) for management of moderate to severe pain. Mechanism of action: Competitive blocker of β-adrenergic receptors in heart and blood vessels. Editorial comments • Labetolol injection is intended for use only in hospitalized patients. Adjustment of dosage • Kidney disease: Creatinine clearance 30–59 mL/min: mainte- nance 150 mg/d; creatinine clearance 5–14 mL/min: initial 150 mg, maintenance 50 mg/d. Warnings/precautions: Use with caution if there is prior history or risk of developing pancreatitis, particularly in children. Stop drug administration if there are clinical or laboratory abnormal- ities suggestive of pancreatitis, kidney disease, elderly. Adverse reactions • Common: headache, insomnia, fatigue, nausea, diarrhea, vom- iting, cough, fever, chills, musculoskeletal pain. Clinically important drug interactions • The following drugs increase effects/toxicity of lamivudine: trimethoprim–sulfamethoxazole. Warnings/precautions • Use with caution in patients with the following conditions: kidney, liver, cardiac diseases. Advice to patient • Avoid driving and other activities requiring mental alertness or that are potentially dangerous until response to drug is known. Clinically important drug interactions • Drug that increases effects/toxicity of lamotrigine: valproic acid. Editorial comments: Dosage of lamotrigine is complicated by the enhancement of its metabolism by several antiepileptic drugs (phenytoin, phenobarbital, primidone) and its half-life prolongation by valproic acid. Awareness of these interactions is vital to the proper administration of this drug. Mechanism of action: Inhibits dihydroorotate dehydrogenase, resulting in inhibition of pyrimidine synthesis; also has antipro- liferative effect on T cells as well as antinflammatory actions. Contraindications: Pregnancy, significant liver disease, serology positive for hepatitis B or C. Patients with bone marrow sup- pression, severe immunodeficiency, or severe infection. Advice to patient • Use two forms of birth control including hormonal and barrier methods. Adverse reactions • Common: hypertension, diarrhea, nausea, headache, rash, res- piratory infection. Clinically important drug interactions • Drugs that increase effects/toxicity of leflunomide: folic acid, rifampin. The following method has been suggested to promote elimination of leflunomide in the event of severe toxicity: (1) discontinue leflunomide; (2) take 8 g of cholestyramine t. Mechanism of action: Drug acts as a cofactor in the biosynthesis of purines and pyrimidines which is blocked by folic acid antag- onists such as methotrexate, trimethoprim, and pyrimethamine. Leucovorin is an active metabolite of folic acid and should therefore be com- patible. Contraindications: Pernicious anemia, megaloblastic anemia secondary to vitamin B12 deficiency. Clinically important drug interactions • Leucovorin decreases effects/toxicity of trimethoprim–sulfa- methoxazole, barbiturates, phenytoin, primidone. Treatment should con- tinue until methotrexate plasma level is less than 5 × 10–8 M. Editorial comments • Parenteral leucovorin is advised for treatment of megaloblas- tic anemia due to folic acid deficiency when it is not feasible to use oral therapy. Mechanism of action: Inhibits synthesis of estrogen and andro- gens in the ovaries and testicles, thus reducing serum and tissue levels of these hormones. Should not be given to women of childbearing potential who might become pregnant during leuprolide therapy. Advice to patient • Do not stop medication without first consulting with physician. Clinically important drug interactions: Leuprolide increases effects/toxicity of antineoplastic drugs: megestrol, flutamide. Editorial comments • Leuprolide is used as palliative treatment of advanced prostate cancer when alternatives such as orchiectomy and estrogen administration are unacceptable to the patient. Mechanism of action: Relaxes bronchial smooth muscles of the bronchioles by stimulating β2-adrenergic receptors. Properties are similar to those of albuterol, and levalbuterol offers no specific advantages according to The Medical Letter. Mechanism of action: Restores depressed immune function: stimulates antibody formation, activates T cells and macro- phages.