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Doses of 1–10 mg given subcutaneously twice daily for two days to female Wistar rats weighing 35–40 g induced a dose-related increase in uterine weight purchase grifulvin v 125 mg otc fungus gnats tomato plants, but the maximum increase was only about half of that induced by oestradiol discount 125mg grifulvin v with amex antifungal acne cream. Phenolphthalein was shown to bind to the oestrogen receptor and was a competitive antagonist to oestradiol (Nieto et al buy grifulvin v 250 mg amex fungus underarm. In a study reported in an abstract buy 125 mg grifulvin v free shipping antifungal otc oral, exposure of female B6C3F1 mice to 1895 mg/kg bw phenolphthalein orally [method not stated] daily for 30 or 60 days caused no changes in weight gain, oestrous cycles or the numbers of oocyte-containing follicles of any class (primordial, primary, growing or antral), or any detectable pathological change in ovarian cells (Hoyer et al. Pairs of 40 control and 20 treated mice were housed together and allowed to produce up to five litters, the last of which was reared and their reproductive performance measured. Significant reproductive toxicity was observed at the intermediate and high doses. At the intermediate dose, the proportions of pairs producing one to five litters were 100, 89, 84, 68 and 36%, the percentages producing second to fifth litters being significantly smaller than in controls. The decrease at the high dose was more severe, only 5% of pairs producing a fifth litter. Overall, the mean number of litters per pair was reduced by 24 and 50% at the inter- mediate and high doses, and the number of pups per litter decreased by 58–59%. Cross-over breeding of animals at the inter- mediate dose with controls showed that the fertility of the females was affected, the litter sizes being reduced to half. Breeding of the F1 offspring at the intermediate dose with controls showed that treatment halved the number of litters and the litter size. Examination of F0 males at the intermediate dose showed a reduction in testis weight by 36% and in the epididymal sperm count by 30%, and seminiferous tubular degeneration was seen in 9 of 10 treated males. The oestrous cycles and ovarian histology of females at this dose were not affected. After 13 weeks of exposure to the same doses as used in the studies of toxicity, there was no evidence of reproductive toxicity in female B6C3F1 mice or male or female Fischer 344/N rats. Lower epididymal weights and lower sperm density (number of sperm/g of crude epididymal tissue) were observed in male mice at 12 000, 25 000 and 50 000 mg/kg (National Toxicology Program, 1996). Phenolphthalein did not induce sister chromatid exchange in Chinese hamster ovary cells in the presence or absence of exogenous metabolic activation, but it induced a dose-related response in chromosomal aberrations in these cells only in the presence of exogenous metabolic activation. In experiments in which a number of end-points were studied in Syrian hamster embryo cells (a mixed population of cell types that retain some endogenous metabo- lizing enzymic activity, including oxidation and peroxidation), phenolphthalein induced chromosomal aberrations and Hprt mutations, but not ouabain mutations or aneuploidy. Phenolphthalein caused cellular transformation in the same cell line, indicating that it is metabolized appropriately in this system. They found significant increases in the frequency of micronucleated ery- throcytes, most of which appeared to arise from whole chromosomes rather than chromosomal damage; these were observed at doses comparable to those to which humans are exposed. In phenolphthalein-induced thymic lymphomas in B6C3F1 mice, p53 protein accumulated in most tumour cell nuclei, but detectable p53 protein was not seen in control thymuses in this model (Dunnick et al. Other studies have shown that accumulation of p53 protein results from p53 gene alterations (Hegi et al. In p53+/– heterozygous mice, phenolphthalein induced atypical hyperplasia and malignant lymphomas of thymic origin within six months in 0% of controls, 5% of animals at 200 mg/kg, 5% at 375 mg/kg, 25% at 750 mg/kg, 100% at 3000 mg/kg and Table 5. Two of two thymic lymphomas examined from animals at 750 mg/kg, 13/13 from those at 3000 mg/kg and 6/6 from those at 12 000 mg/kg had lost the remaining p53 wild-type allele (Dunnick et al. No spontaneous thymic lymphomas were found in control mice in these studies, but in other studies in p53+/– mice of spontaneous tumours (which may occur in mice after one year of age), only 55% showed loss of the remaining functional p53 allele (Harvey et al. When this protein is absent, as is the case in phenolphthalein-induced thymic lym- phomas, regulation of cell cycle electrophoresis is lost and malignant progression may be enhanced. Generally available without prescription, it is now being withdrawn from the market in many countries because of recent toxicological concern. Phenolphthalein has also long been used in the laboratory as an indicator in acid–base titrations. In one experiment in mice, it induced histiocytic sarcomas and lymphomas in both males and females and benign ovarian tumours in females. In an experiment in mice lacking one allele of the p53 tumour suppressor gene, it increased the incidence of lymphomas. It induced benign renal tumours in male rats and benign phaeochromocytomas in males and females. As it passes through the small intestine, it is partially deconjugated and reabsorbed. Phenolphthalein and its glucuronide enhance oxygen radical production and cause oxidative damage in vitro. Phenolphthalein has also been shown to have low oestrogenic activity in some model systems. Phenolphthalein induced micronucleated erythrocytes in mice given multiple but not single treatments by gavage or in feed. Abnormal spermatozoa were induced in male mice but not male rats treated with phenolphthalein in the feed for 13 weeks. The malignant thymic lymphomas induced by phenolphthalein in female heterozygous p53-deficient mice showed loss of the normal p53 allele. Phenolphthalein induced chromosomal aberrations, Hprt gene mutations and morphological transformation but not aneuploidy or ouabain-resistant mutations or sister chromatid exchange in cultured mammalian cells. There is sufficient evidence in experimental animals for the carcinogenicity of phenolphthalein. Biphenyl, stilboestrol and phenolphthalein in the rat: Molecular weight, polarity and meta- bolism as factors in biliary excretion. The Metabolism and Detoxication of Drugs, Toxic Substances and Other Organic Compounds, 2nd Ed. The K vitamins all contain the 2-methyl-1,4-naphthoquinone (menadione) moiety, and the various naturally occurring forms differ in the alkyl substituent at the 3-position. Phylloquinone (vitamin K1) is 2-methyl-3-phytyl-1,4-naphthoquinone and is widely found in higher plants, including green leafy vegetables, and in green and blue algae. The menaquinones (formerly vitamin K2) have polyisoprenyl substituents at the 3-position and are produced by bacteria. The compound menadione (formerly vitamin K3) lacks an alkyl group at the 3-position but can be alkylated in vivo in some species. Several synthetic water-soluble derivatives, such as the sodium diphosphate ester of menadiol and the addition product of menadione with sodium bisulfite, also have commercial applications (National Research Council, 1989; Gennaro, 1995; Weber & Rüttimann, 1996). The United States Pharmaco- peia uses the name ‘phytonadione’; The European Pharmacopoeia uses the name ‘phytomenadione’, which is a synonym occasionally found in the pharmaceutical and pharmacological literature. In the biolo- gical literature, vitamin K2 is frequently referred to as menaquinone and is further designated by the number of isoprene units in the side-chain. For example, vitamin K2(20) is also called menaquinone-4 for the four isoprene units in the side-chain. The compound originally isolated from rotting fish meal and named vitamin K2 was later identified as menaquinone-7 (2-methyl-3-farnesylgeranyl-geranyl-1,4-naphthoquinone). In the older literature, the designation vitamin K2(35) is used for menaquinone-7, but this is no longer used. Menaquinones found in nature have side-chains of 4–13 isoprenoid residues and are usually in the all-trans configuration; however, menaquinones with the cis confi- guration and partially saturated side-chains also exist (Suttie, 1985, 1991; Weber & Rüttimann, 1996; Van Arnum, 1998). Phylloquinone occurs in nature only as the 2′,3′-trans-phylloquinone stereoisomer (Weber & Rüttimann, 1996; American Hospital Formulary Service, 1997; Council of Europe, 1997).
Because this type of antagonist binds reversibly to the re- ceptor site buy cheap grifulvin v 125 mg on-line anti fungal die off, administering larger doses of an agonist can overcome the antagonist’s effects order grifulvin v 250 mg amex fungus gnats flowering. Administering larger doses of the ago- Stimulate nist can’t reverse the antagonist’s action buy grifulvin v 250 mg low cost antifungal washing detergent. If a drug acts on a variety of receptors purchase 250 mg grifulvin v fungus gnats wood, it’s said to be nonselective and can cause multiple and widespread effects. For exam- ple, beta receptors typically produce increased heart rate and bronchial relaxation as well as other systemic effects. Beta receptors, however, can be further divided into beta1 re- ceptors (which act primarily on the heart) and beta2 receptors (which act primarily on smooth muscles and gland cells). Potent power Drug potency refers to the relative amount of a drug required to produce a desired response. If drug X produces the same response as drug Y but at a lower dose, then drug X is more potent than drug Y. As its name implies, a dose-response curve is used to graphi- cally represent the relationship between the dose of a drug and the response it produces. The relationship between a drug’s desired therapeutic effects and its adverse effects is called the drug’s therapeutic index. The therapeutic index usually measures the differ- ence between: • an effective dose for 50% of the patients treated • the minimal dose at which adverse reactions occur. Narrow index = potential danger Drugs with a narrow, or low, therapeutic index have a narrow margin of safety. This means that there’s a nar- row range of safety between an effective dose and a lethal one. On the other hand, a drug with a high thera- peutic index has a wide margin of safety and poses less risk of toxic effects. Dose-response curve This graph shows the dose- response curve for two different 100 drugs. As you can see, at low C D doses of each drug, a dosage increase results in only a small increase in drug response (for example, from point A to point B for drug X). At higher doses, an Drug X Drug Y increase in dosage produces a 50 much greater response (from point B to point C). As the dosage continues to climb, however, an increase in dosage B produces very little increase in response (from point C to point A E D). When choosing a drug to treat a particular condition, health care providers consider not only the drug’s effectiveness but also other factors such as the type of therapy the patient will receive. Coinciding medical condi- a drug tions and personal lifestyle characteristics must be considered Because no two people when selecting drug therapy. Drug tolerance occurs when a patient develops a decreased • age response to a drug over time. The patient then requires larger dos- • cardiovascular es to produce the same response. Drug interactions Drug interactions can occur between drugs or between drugs and foods. They can interfere with the results of a laboratory test or produce physical or chemical incompatibilities. The more drugs a patient receives, the greater the chances that a drug interaction Memory will occur. The effects are equivalent to the sum of either drug’s effects if it were administered alone in higher doses. Giving two drugs together, such as two analgesics (pain reliev- ers), has several potential advantages: lower doses of each drug, decreased probability of adverse reactions, and greater pain con- trol than from one drug given alone (most likely because of differ- ent mechanisms of action). There’s a decreased risk of adverse ef- fects when giving two drugs for the same condition because the patient is given lower doses of each drug—the higher the dose, the greater the risk of adverse effects. A synergistic situation A synergistic effect, also called potentiation, occurs when two drugs that produce the same effect are given together and one drug potentiates (enhances the effect of) the other drug. Fighting it out An antagonistic effect occurs when the combined response of two drugs is less than the response produced by either drug alone. An absorbing problem Two drugs given together can change the absorption of one or both of the drugs: • Drugs that change the acidity of the stomach can affect the abil- ity of another drug to dissolve in the stomach. Sometimes, an absorption-related drug interaction can be avoided by administering the drugs at least 2 hours apart. Bound and determined After a drug is absorbed, the blood distributes it throughout the body as a free drug or one that’s bound to plasma protein. When two drugs are given together, they can compete for protein-binding sites, leading to an increase in the effects of one drug as that drug is displaced from the protein and becomes a free, unbound drug. Toxic waste Toxic drug levels can occur when a drug’s metabolism and excre- tion are inhibited by another drug. Some drugs stimulate enzyme production, increasing metabol- ic rates and the demand for vitamins that are enzyme cofactors (which must unite with the enzyme in order for the enzyme to function). For instance, when food that contains Vitamin K (such as green, leafy vegeta- bles) is eaten by a person taking warfarin, the drug’s anticoagula- tion properties are decreased and blood clots may form. Grapefruit can inhibit the metabolism of certain medications, resulting in toxic blood levels; examples include fexofenadine, albendazole, and atorvastatin. Because of all the interactions food can have with drug metabolism, being aware of drug interactions is essential. Adverse drug reactions A drug’s desired effect is called the expected therapeutic re- sponse. An adverse drug reaction (also called a side effect or ad- verse effect), on the other hand, is a harmful, undesirable re- sponse. Adverse drug reactions can range from mild ones that dis- appear when the drug is discontinued to debilitating diseases that become chronic. Adverse reactions can appear shortly after start- ing a new medication but may become less severe with time. Dosage dilemma Adverse drug reactions can be classified as dose-related or patient sensitivity–related. Most adverse drug reactions result from the known pharmacologic effects of a drug and are typically dose- related. Dose-related reactions include: • secondary effects • hypersusceptibility • overdose • iatrogenic effects. For example, morphine used for pain control can lead to two extreme sensitivity to undesirable secondary effects: constipation and respiratory de- a drug. Diphenhydramine used as an antihistamine produces se- dation as a secondary effect and is sometimes used as a sleep aid. Enhanced action A patient can be hypersusceptible to the pharmacologic actions of a drug. Such a patient experiences an excessive therapeutic re- sponse or secondary effects even when given the usual therapeu- tic dose. Hypersusceptibility typically results from altered pharmacoki- netics (absorption, metabolism, and excretion), which leads to higher-than-expected blood concentration levels. Increased recep- tor sensitivity also can increase the patient’s response to therapeu- tic or adverse effects.
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A sample of the subject drug sent for test under Rule 40 of the Drugs and cosmetics Rule from a consignment imported by M/s……………………………………………………… (Name and full address of the importers) order grifulvin v 125 mg on line antifungal wipes for dogs, has since been reported by the Director grifulvin v 125mg on line fungus on lips, C purchase grifulvin v 125 mg janssen antifungal. Value ……………………………………………………………………………………………… The Customs authorities have been advised to take necessary action under Rule 41(1) of the Drugs and Cosmetics Rules in respect of the above goods which are lying in the Docks / were cleared on Letter of undertaking for test buy grifulvin v 250 mg otc fungus zombie humans. The import of these goods are prohibited under Section 10(a) of the Drugs and Cosmetics act read with Section 11 of the same act and liable to absolute confiscation under Section 111 (d) of the Customs act, 1962. You are hereby required to show cause why action should not be taken to confiscate the goods under Section…………………………………of the Customs Act. You are required to indicate whether you would like to re-export the goods to the country of origin as per option given in rule 41 (1) of the Drugs and Cosmetics Rules, 1945. You are further required to show cause why a personal penalty should not be imposed on you under the aforesaid section. Your written explanation should be presented within …………………day hereof to the undersigned along with all the documentary evidence. You should also indicate in the written explanation whether you wish to be heard in person before the case is adjudicated. If you fail to submit the written explanation in time or do not appear before the adjudicating authority when the case is posted for hearing, the case will be adjudicated on the basis of the evidence on record without any further reference to you. Office of the Assistant Drugs Controller (India) Mumbai / Kolkata / Chennai / Delhi Ahmadabad / Hyderabad/Cochin Dt. Date The import of these goods are prohibited under Section 10 (bb) --- of the Drugs & Cosmetics Act, read with Section 11 of the same Act and the goods are liable to absolute confiscation u/s. Wherever required the officials of the Drugs Control Department posted at the port offices shall retain a sample of the subject consignment for the purpose of reference and tracking of the manufacturer / exporter of the subject product. Gujral) Director General of Foreign Trade & Ex-Officio Additional Secretary to the Govt. Selection of studies Inspection can be carried out as a routine surveillance or for any specific cause(s). The inspector should provide verbal summary of methods and procedures to be followed during the inspection. In case of no compensation has been paid, reason for the same should be obtained and documented from both the Sponsors and Ethics Committee. The inspector may also issue a list of observation at the conclusion of inspection. In case of no compensation has been paid, reason for the same should be obtained and documented from both the Sponsors and Ethics Committee. If the test article was not returned to the sponsor, describe the method of disposition and determine if adequate records were maintained. General organization of the site Activity Ask for the presentation of the laboratory and its general activities. Quality Assurance Ask for a description of the quality assurance system set up at the laboratory. Are records of qualifications, training, experience and job description for each professional and technical individual maintained. Does the design of the test facility provide an adequate degree of separation of the different activities to assure the proper conduct of the study? Facilities for Handling Test and Reference Items To prevent contamination or mix-ups, are there separate rooms or areas for receipt and storage of the test and reference items. Archive Facilities Are archive facilities provided for the secure storage and retrieval of study plans, raw data, final reports and samples of test items? Does the archives design and conditions protect the contents from untimely deterioration? Waste Disposal Is the handling and disposal of wastes carried out in such a way that the integrity of studies is not jeopardized? Is calibration, where appropriate, traceable to national or international standards of measurement? Does the apparatus and materials used in a study interfere adversely with the test systems? Are chemicals, reagents and solutions labelled to indicate identity (with concentration if appropriate), expiry date and specific storage instructions? Are handling, sampling and storage procedures identified in order that the homogencity and stability are assured to the degree possible and contamination or mix-up are precluded? Does storage container(s) carry identification information, expiry date, and specific storage instructions? Were the qualification, background and experience of the study director appropriate? Was a pre study meeting organized where adequate information was given to all staff involved in the trial? Note: The wash out period should ideally be equal to or more than five half life‘s of the moieties to be measured. Was the duration of the storage of the solution supported by the stability study data? Were the number of Quality Control and number of calibration samples prepared, consistent with the number of results reported? Note: The validation of the analytical method can be envisaged to consist of two distinct phases. The prestudy involves the validation of the method on biological matrix human plasma samples and spiked plasma samples. The study phase in which the validated bioanalytical method is applied to actual analysis of samples to confirm the stability, accuracy and precision. Pre Study: Does following characteristics of the bioanalytical method evaluated and documented to ensure the acceptability of the performance and reliability of analytical results. Was the data generated to demonstrate that assay does not suffer from interference by endogenous compounds, degradation products, other drug likely to be present in study samples, and metabolites of the drug (s) under study? Note: For linear relationships, a standard curve should be defined by at least five concentrations. If the concentration response function is non-linear, additional points would be necessary to define the non-linear portions of the curve. Note: A minimal design would be to run analytical standards at the beginning and at end of the analytical run. Study Phase: In general, with acceptable variability as defined by validation data, the 471 analysis of biological sample can be done by single determination without a need for a duplicate or replicate analysis. Quality control samples: Was the quality control sample prepared and stored as recommended. Were the source documents (chromatograms, validation data of analytical methods used and calibration status of the instruments) identified, dated and signed? General organization of the site Ask for an organization chart of the company and note the following points: - Number of staff including Doctors (Physician fulltime/On call), (Pharmacist and Nurse, Nursing assistant and Lab. Check the existence, availability, accessibility and validity of the standard operating procedures.
Rubbish shall be made into an adequate sewer- and any offal shall be so conveyed cheap grifulvin v 250mg otc fungus strategy plague inc, age system or disposed of through stored order 250mg grifulvin v visa azamax for fungus gnats, and disposed of as to minimize other adequate means best 125 mg grifulvin v fungus link to cancer. Each plant shall potential for the waste becoming an at- provide its employees with adequate grifulvin v 125mg on-line fungus gnats wiki, tractant and harborage or breeding readily accessible toilet facilities. Hand- shall preclude the adulteration of food washing facilities shall be adequate with lubricants, fuel, metal fragments, and convenient and be furnished with contaminated water, or any other con- running water at a suitable tempera- taminants. Compliance with this require- installed and maintained as to facili- ment may be accomplished by pro- tate the cleaning of the equipment and viding: of all adjacent spaces. Food-contact (1) Hand-washing and, where appro- surfaces shall be corrosion-resistant priate, hand-sanitizing facilities at when in contact with food. They shall each location in the plant where good be made of nontoxic materials and de- sanitary practices require employees signed to withstand the environment of to wash and/or sanitize their hands. Food- (3) Sanitary towel service or suitable contact surfaces shall be maintained to drying devices. Appropriate quality control shall be smoothly bonded or main- operations shall be employed to ensure tained so as to minimize accumulation that food is suitable for human con- of food particles, dirt, and organic mat- sumption and that food-packaging ma- ter and thus minimize the opportunity terials are safe and suitable. All reasonable food shall be so constructed that it can precautions shall be taken to ensure be kept in a clean condition. Chemical, microbial, or extra- pneumatic, closed, and automated sys- neous-material testing procedures tems, shall be of a design and construc- shall be used where necessary to iden- tion that enables them to be main- tify sanitation failures or possible food tained in an appropriate sanitary con- dition. All food that has be- (e) Each freezer and cold storage come contaminated to the extent that compartment used to store and hold it is adulterated within the meaning of food capable of supporting growth of the act shall be rejected, or if permis- microorganisms shall be fitted with an sible, treated or processed to eliminate indicating thermometer, temperature- the contamination. Raw (f) Instruments and controls used for materials shall be washed or cleaned as measuring, regulating, or recording necessary to remove soil or other con- temperatures, pH, acidity, water activ- tamination. Water used for washing, ity, or other conditions that control or rinsing, or conveying food shall be safe prevent the growth of undesirable and of adequate sanitary quality. Containers and carriers of (g) Compressed air or other gases me- raw materials should be inspected on chanically introduced into food or used receipt to ensure that their condition to clean food-contact surfaces or equip- has not contributed to the contamina- ment shall be treated in such a way tion or deterioration of food. Compliance with this require- specting, transporting, segregating, ment may be verified by any effective preparing, manufacturing, packaging, means, including purchasing raw mate- and storing of food shall be conducted rials and other ingredients under a sup- in accordance with adequate sanitation plier’s guarantee or certification. One way to comply with this re- ment may be accomplished by pur- quirement is careful monitoring of chasing raw materials and other ingre- physical factors such as time, tempera- dients under a supplier’s guarantee or ture, humidity, aw, pH, pressure, flow certification, or may be verified by rate, and manufacturing operations analyzing these materials and ingredi- such as freezing, dehydration, heat ents for aflatoxins and other natural processing, acidification, and refrigera- toxins. Compliance with this requirement cluding purchasing the materials under may be accomplished by any effective a supplier’s guarantee or certification, means, including: or examination of these materials for (i) Maintaining refrigerated foods at contamination. If erating, controlling pH or controlling thawing is required prior to use, it aw that are taken to destroy or prevent shall be done in a manner that pre- the growth of undesirable microorga- vents the raw materials and other in- nisms, particularly those of public gredients from becoming adulterated health significance, shall be adequate within the meaning of the act. I (4–1–10 Edition) other ingredients, or refuse are unpro- passing it to subsequent manufacturing tected, they shall not be handled si- without delay. Thermophilic growth multaneously in a receiving, loading, and contamination in blanchers should or shipping area if that handling could be minimized by the use of adequate result in contaminated food. Food operating temperatures and by periodic transported by conveyor shall be pro- cleaning. Where the blanched food is tected against contamination as nec- washed prior to filling, water used essary. Com- (10) Mechanical manufacturing steps pliance with this requirement may be such as washing, peeling, trimming, accomplished by any effective means, cutting, sorting and inspecting, mash- including: ing, dewatering, cooling, shredding, ex- (i) Use of a quality control operation truding, drying, whipping, defatting, in which the critical control points are and forming shall be performed so as to identified and controlled during manu- protect food against contamination. Compliance with this requirement may (ii) Adequate cleaning and sanitizing be accomplished by providing adequate of all food-contact surfaces and food physical protection of food from con- containers. Protection may be tainers and food- packaging materials provided by adequate cleaning and that are safe and suitable, as defined in sanitizing of all food-contact surfaces, §130. The Food and (iii) Protecting finished food from Drug Administration establishes max- moisture pickup, by use of a moisture imum levels for these defects in foods barrier or by other means, so that the produced under current good manufac- aw of the food does not increase to an turing practice and uses these levels in unsafe level. These lev- microorganisms shall be monitored and els are subject to change upon the de- maintained at a pH of 4. Evidence indicating is safe and of adequate sanitary qual- that such a violation exists causes the ity, and shall be used only if it has food to be adulterated within the been manufactured in accordance with meaning of the act, even though the current good manufacturing practice amounts of natural or unavoidable de- as outlined in this part. The equipment used for manufacturing manufacturer, distributor, and holder human food should not be used to man- of food shall at all times utilize quality ufacture nonhuman food-grade animal control operations that reduce natural feed or inedible products, unless there or unavoidable defects to the lowest is no reasonable possibility for the con- level currently feasible. Subpart G—Production and Process Con- Subpart K—Production and Process Control trol System: Requirements for Compo- System: Requirements for Manufac- nents, Packaging, and Labels and for turing Operations Product That You Receive for Pack- 111. Subpart M—Holding and Distributing Subpart I—Production and Process Control System: Requirements for the Batch 111. Component means any substance in- Subpart A—General Provisions tended for use in the manufacture of a dietary supplement, including those §111. Com- (a) Except as provided by paragraph ponent includes dietary ingredients (as (b) of this section, you are subject to described in section 201(ff) of the act) this part if you manufacture, package, and other ingredients. Examples of con- of Columbia, or the Commonwealth of tact surfaces include containers, uten- Puerto Rico. An ingredient in- retail establishment does not include a cludes, but is not necessarily limited warehouse or other storage facility for to, a dietary ingredient as defined in section 201(ff) of the act. This defini- Representative sample means a sample tion includes species that: that consists of an adequate number of (1) May have public health signifi- units that are drawn based on rational cance; criteria, such as random sampling, and (2) May cause a component or dietary that are intended to ensure that the supplement to decompose; sample accurately portrays the mate- (3) Indicate that the component or di- rial being sampled. Reserve sample means a representa- Physical plant means all or any part tive sample of product that is held for of a building or facility used for or in a designated period of time. Examples of product versely affecting the product or its complaints are: Foul odor, off taste, ill- safety for the consumer. I (4–1–10 Edition) the water vapor pressure of the sub- could result in microbial contamina- stance divided by the vapor pressure of tion of any components, dietary sup- pure water at the same temperature. In addition to this part, you must These hygienic practices include the comply with other applicable statutory following: provisions and regulations under the (1) Wearing outer garments in a man- act related to dietary supplements. If of any material, including components, hand jewelry cannot be removed, it dietary supplements, and contact sur- must be covered by material that is faces used in the manufacture, pack- maintained in an intact, clean, and aging, labeling, or holding of a dietary sanitary condition and that effectively supplement. Such measures include the protects against contamination of following: components, dietary supplements, or (1) Excluding from working in any contact surfaces; operations that may result in contami- (5) Maintaining gloves used in han- nation any person who, by medical ex- dling components or dietary supple- amination, the person’s acknowledge- ments in an intact, clean, and sanitary ment, or supervisory observation, is condition. You must keep the organisms, filth, or any other extra- grounds of your physical plant in a neous materials, including perspira- condition that protects against the tion, hair, cosmetics, tobacco, chemi- contamination of components, dietary cals, and medicines applied to the skin. Each person who is identified to parking lots so that they do not con- perform quality control operations stitute a source of contamination in must be qualified to do so and have dis- areas where components, dietary sup- tinct and separate responsibilities re- plements, or contact surfaces are ex- lated to performing such operations posed; from those responsibilities that the (3) Adequately draining areas that person otherwise has when not per- may contribute to the contamination forming such operations. The plumbing in your and adequate under the conditions of physical plant must be of an adequate use. Guard or guide for use in bathrooms or hand-washing dogs are allowed in some areas of your facilities. You must dispose dogs will not result in contamination of sewage into an adequate sewage sys- of components, dietary supplements, or tem or through other adequate means. You must provide your (2) You must take effective measures employees with adequate, readily ac- to exclude pests from the physical cessible bathrooms. The bathrooms plant and to protect against contami- must be kept clean and must not be a nation of components, dietary supple- potential source of contamination to ments, and contact surfaces on the components, dietary supplements, or premises by pests; and contact surfaces. You must migants, fungicides, or rodenticides, provide hand-washing facilities that unless you take precautions to protect are designed to ensure that an employ- against the contamination of compo- ee’s hands are not a source of contami- nents, dietary supplements, or contact nation of components, dietary supple- surfaces. You must convey, not become a component of the dietary store, and dispose of trash to: supplement.
Muzafer Sherif who offered valuable suggestions regarding certain aspects of this report buy generic grifulvin v 250mg on-line antifungal horse. The relevance of this review for the problem of the volume rests on the validity of the assumption that the dynamics of influence operate beyond the range of intensity of conflic order grifulvin v 125mg anti fungal bacterial cream. At the conclusion of this review we will consider the problem of extrapolation by briefly assessing the implications of the current knowledge of the dynamics of interpersonal influence cheap grifulvin v 250mg fungus gnats larvae jump. Several types of investigations have been excluded from this review: (a) anthropological reports in which conformity behavior has been noted but has not been subjected to experimental analysis; (b) investigations of audiences or meetings of larger assemblages where acceptance of or resistance to influence does not result from direct interaction among those composing the situation; (c) investigations dealing with shifts in reaction from knowledge or awareness of norms attributed by the experimenter to groups whose members are not psychologically present; (d) influence aspects of reference group behavior which contain variables that differ in kind and complexity from those inherent in influence exerted under face-to-face conditions; and (e) programmatic research reports and theoretical discussions of various aspects of the problem that are available in a number of other sources (2 buy 125mg grifulvin v otc antifungal nail oil, 17, 29, 39, 46, 65, 90, 91, 99, 121, 126). Characteristics of the Experimental Situations Material and Instructions Experimental situations used to study conformity, compliance, and conversion are described here according to the following characteristics: (a) types of stimulus materials employed; (b) contexts or background conditions in which pressures are exerted; (c) personal dimensions used to assess the contribution of individual differences to conformity and conversion behavior; and (d) methods of measuring the impact of conformity pressures on a critical subject. A variety of tasks and performances figured in the studies which -217- have been reviewed. Instructions and stimulus materials have been used to produce the following types of responses: (a) expressions of opinions, attitudes, preferences, and interpretations, (b) perceptual and factual judgments, (c) attempts at logical analyses, and (d) behavior in relation to a direct request or an explicit prohibition. Others have reported findings for a number of attitude statements without giving complete descriptions of their composition (8, 34, 64). The expression of opinions or attitudes regarding typical cases or problem issues has also been used (27, 81, 92, 114, 120, 134). Typical discussion topics include federal aid to education (47), labor-management relations (40, 48), nationalism vs. Ratings of personality and social characteristics of both self and others also have been used as stimulus tasks (24, 57). The expression of personal preferences has included such items as line drawings (8, 34), food preferences (38, 73, 95), ranking of camping equipment for a hypothetical trip (55, 56), and ranking men in order of desirability as President of the United States (108). Pictures that are subject to personal interpretation as the basis for composing a story (4), or unclear drawings that are named by the subject (88, 90, 131, 132, 133) comprise another type of problem. Making such judgments as the truthfulness of a person defending himself against charges of revealing a fictitious crime (25), the intelligence of people from photographs (49), the better one of two paintings (97), the driver at fault from a picture of an auto accident (129), or revealing of discrepancies in examination grades (93) constitute other tasks that have been used. Examples are requests for volunteers (9, 112, 113, 117) and for the endorsement of a petition (19); prohibitions, such as a poster forbidding entry to a building (45); a stoplight regulating pedestrian traffic (83); a sign prohibiting drinking from a fountain (78); a traffic light where turning signals are legal (5), or a command to stop a designated activity (53). The task involving the cutting of squares or other geometric forms under pressure from others to change the rate of production contains some elements of the direct request or prohibition stimulus (109, 110, 120). The first group includes the autokinetic problem (16, 21, 23, 30, 36, 42, 58, 69, 75, 79, 84, 85, 91, 101, 111, 121, 122, 124, 125, 130), estimation of the number of dots on a card or slide (37, 43, 74, 100), the number of beans in a jar (70), the length of rectangles (22, 65), the distance between rectangles (65), the length of lines (98, 102, 18), the length of a slot of light (11, 97), the distance traversed by a moving light (118), the number of flashes of light in a standard time interval (76, 77), the number of clicks of a metronome (18, 103, 105, 123), the weight of a series of standard objects (60), size estimation of unspecified objects (72), and recognition of simple visual objects (115). Discrimination tasks include judging which is the shorter of two lines (87, 89), whether there is an odor in a bottle of odorless water (28), and which square has the largest number of dots (74). Common information types of items (31, 126), and memory tasks (80, 113), have also been used. Framework or Social Background Properties of the situation other than stimulus materials and instructions for reacting to them contribute to the particular adjustment that occurs. The effect of context or framework in modifying the response that designated stimulus materials produce is well known -219- in sensory and perceptual research. The analogue of context or framework is often provided by the reactions of others to the same or comparable stimulus materials. Social background may vary from simple awareness of the reactions by others to direct efforts by others to exert influence on the critical subject. An example of the latter is the judging situation where others present give uniformly incorrect reports before the response of the critical subject. A response conforming to the social background provides an index of conformity, whereas a response consistent with the stimulus material provides an index of resistance to the influence exerted by others. Direct influence also is exerted in the situation requiring group members to agree on a single option from among a set of alternatives, with the influence usually exerted in the direction of converting the deviant member. For some of the studies the discrepancy is "spontaneous" or "natural" (28, 36, 52, 84, 111, 118, 121, 124, 125), e. The degree of convergence toward the responses of another person constitutes an index of conformity. In other experiments the reports of instructed subjects are controlled by the experimenter. Face-to-face and other methods of communicating the reports of others to the critical subject have been employed. He is given a fixed position in the sequence of responding, with responses of others prearranged by the experimenter (1, 3, 4, 6, 7, 11, 21, 23, 24, 30, 35, 38, 43, 48, 50, 51, 57, 58, 64, 69, 71, 75, 80, 87, 88, 89, 90, 91, 96, 97, 98, 100, 101, 102, 105, 107, 114, 115, 122, 126, 128). Incorrect ones may diverge from the correct or appropriate answer in varying amounts. Reports by others also may be at variance with one another, with some correct and others incorrect by varying degrees. In other situations, one instructed assistant engages in the designated action prior to the -220- subject and serves as a model for him (5, 19, 45, 53, 72, 78, 83, 86, 94, 95, 112, 113, 117, 130). A modification of the face-to-face situation is the simulation of a group through the use of tape recordings (10, 18, 20, 31, 61, 63, 91, 103, 106, 109, 110). A naive subject participates under the impression that he is a member of a group composed of several persons, each of whom, like himself, is alone in adjoining rooms. The subject hears the instructions of the experimenter, experiences the stimulus materials to be judged, and hears the responses by the others. He reacts at the proper time by writing his responses in the blank spaces left for his reports. Another variation of the basic face-to-face situation is one where several people are tested together, with partitions or booths separating them from one another. Each has a panel with a row of signal lights that record the responses of others (8, 34, 35, 71). The task is constant for all members, and usually consists of materials presented by slides projected on a wall so that all subjects can see them simultaneously. The experimenter controls the presumed responses of the other subjects through a master switchboard. All respond at the same time, with their responses recorded at the central control panel. Also used is the requirement for requesting or relinquishing pieces of a puzzle or game by one member when members exchange parts to complete the puzzle. The participant understands that he must complete his puzzle or task before the group goal is achieved. Then they interact by requesting necessary pieces from one another in order to finish. Both the Group Squares Puzzle (33) and a Bingo game (32) have been used in this manner. The experimenter is able to arrange the responses of "other" members to requests for pieces or parts. After a subject has correctly completed his individual task, he is subjected to pressures from some other member to yield a part so that someone else may complete a puzzle.
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