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As a result best purchase for tadora, companies could more easily recruit patients and potential new drugs moved from the laboratory to the clinic more rapidly than in the past buy tadora with american express. They also provided direct assistance for patients in advanced stages of the disease purchase tadora 20mg with visa. Patients and activists generally agreed with government offcials that the 1976 Drug Law already accounted for contingencies associated with the emergence of a new and deadly disease. Access to test results, however, remained limited to the drug company, physicians conducting clinical trials, and government offcials. Since well-controlled boundaries distinguished between experts and patients, drug testing did not become a site for debates about representation or access to medicines. Compassionate Use and Underserved Patients In recent years, the compassionate use of pharmaceuticals still in various stages of pre-market testing has engaged patient groups, industry, and government agencies in ways that further illustrate the differences in regulatory approaches followed by the United States and Europe. Patients with terminal diseases have long occupied a special status and despite stronger regulatory controls implemented over the course of the 20th century, physicians have retained the right to prescribe medicines for off-label uses. Nevertheless, many cancer patients continue to fall outside the health status defned by sponsor companies for their experimental drugs. For companies required by law to report and investigate any adverse reactions or fatalities that occur when a patient is on their medicine, compassionate use programs pose a challenge. But frms are understandably nervous that if a patient dies while taking a still-experimental therapy, it can be diffcult to differentiate the natural course of disease from an adverse reaction to the treatment. Citing several tragic cases of terminally ill patients who failed to qualify for clinical trials of new anti-cancer agents due to their advanced disease, an organization called the Abigail Alliance (begun by Frank Burroughs and named for his deceased daughter) fled a lawsuit heard in D. Specifcally, the Alliance sought to make available any drug that had cleared phase I trials (which collect data about a chemical’s pharmacological properties in small numbers of healthy subjects; they generally do not determine dosage or effcacy in patients with the disease). In the United States it is now widely held that the production of information about drugs requires large, double-blinded, placebo- controlled studies. In this framework, the individual is served best by statistical analysis of large populations. Medical authorities and the industry worried that access to medicines outside of clinical trials would undermine incentives for patients to volunteer as subjects. As a consequence, the issue does not feature as prominently in legal circles or media coverage of pharmaceutical regulation. In Germany, for example, the prescribing physician performs an individual beneft-risk analysis and the pharmacy checks whether the drug qualifes for commerce, specifcally whether it is defned as “hazardous” under §5 of the Arzneimittelgesetz. One outcome of this difference is a greater tension in the United States than in Europe between the individual patient and large “n” populations needed for clinical trials. At the same time, policy changes have involved public debate and formal legal decisions resulting in a reaffrmation of the importance of clinical trials as a predictable and managed part of the drug development process. The less politicized local decision concerning a patient’s access to drugs through compassionate use programs in Europe ironically may be fostering uncertainty for frms developing and advancing new pharmaceuticals. Personalized Medicine The concept of consumer oriented or personalized medicine has attracted wide attention in recent years. Regulators in both the United States and in Europe are at present seeking to identify and validate biological markers that can serve as surrogate measures for clinical outcomes. To date, surrogate endpoints are proving contentious, with relatively little international agreement on which measures to use and how to prove that they correspond rigorously to actual health outcomes. While the area is in fux at present and likely to change in coming years, certain trends have emerged. With a cost that can reach up to $100,000 per year, Avastin has raised some concern in the United States; its use in Europe is even more contested. National Institute for Clinical Excellence terminated the review of Avastin in June 2008, effectively making it unavailable to women with breast cancer through the National Health Service. While it has been compared to the Critical Path initiative, it is likely to spend far more to support research in areas such as brain disorders and metabolic disease 43 Gina Kolata and Andrew Pollack, “Costly Cancer Drug Offers Hope, but Also a Dilemma,” New York Times (6 July 2008). Hamermesh, “Realizing the Promise of Personalized Medicine,” Harvard Business Review (October 2007), 109-117, cite at 115. In Germany, for example, the Bundesinstitut fur Arzneimittel- und Medizinprodukte (BfArM) has convened several expert assessments and conferences. At a meeting in June 007, BfArM put the onus on industry and academic researchers to change the design of clinical trials: To date, genetic biomarkers have rarely been incorporated in well-controlled late phases of clinical trials for the purpose of a proactive patient selection or patient stratifcation. Application of pharmacogenetics-based diagnostics in therapeutic decisions would be facilitated if pharmacogenetic analyses were already included in the clinical studies during the development of drugs, but currently this diagnostic approach is still far from being applied in general clinical practice. Third, at a broad conceptual level, fnding a ft between protection of “the patient” and providing information to “consumers” is being conceptualized differently in the United States and Europe. Senate Majority Leader William Frist described a fctional patient and the overall healthcare system in the year 015 in a manner that succinctly captured a trend in the United States of envisioning a personalized therapeutic approach. Interviewed by the journal Personalized Medicine, Dolores Ibarreta of the European Commission Joint Research Center, Institute for Prospective Technological Studies, explained: In the specifc context of personalized medicine, we are looking at barriers for development and clinical implementation in Europe. Frist, “Health Care in the 1st Century,” New England Journal of Medicine 352 (2005), 267-272. Interestingly, the tensions emerging in the United States between making health care responsive to consumers while protecting patients and ensuring they have treatment and care are notably less pronounced in Europe. Conclusion: The Interface of Innovation and Regulation Since 1980 and at a rate that accelerated in the 1990s, the United States became the leading worldwide location for pharmaceutical research, clinical testing, and marketing. The “pharmacy to the world,” once located in Germany, Switzerland, or France, today is found in the United States. Studies of the industry have attributed this sustained competitive advantage to a variety of factors, including U. Government regulation of the pharmaceutical market is revealing a country’s concept of innovation at a specifc historical moment; intriguingly, regulations also shed light on enduring cultural differences between nations. Historically, legislative interventions in the United States were predicated on the notion that patients must be protected by the state from the worst ravages of free-market capitalism. In the 1980s and 1990s, however, patients represented by disease-based organizations agitated for greater access to drugs and speedier approvals. At the same time, critics warned that the country’s competitive standing depended on the pharmaceutical and biotech sectors. Regulation of pharmaceuticals in the United States has followed an overall progression from medical profession to the state to a new consumer/patient oversight model. In Germany, by contrast, the medical profession exercised a near-monopoly over constructions of “the patient” and drug laws codifed existing power-sharing arrangements. Instead of the state claiming authority over pre-market testing, it acted as one member of a network overseeing pharmaceutical drugs. A fexible boundary between testing and market was predicated on informal trial protocols, a structured system for collecting reports of adverse reactions, and compromises among organized interests and government offcials. The drug approval process thus only rarely became a signifcant site for debates over national competitiveness or industry innovation. Nevertheless, Germany too has seen different waves of regulatory style, from physicians to a networked approach that incorporates the state, select disease-based organizations, and the medical profession. The comparative perspectives developed in this chapter suggest that despite recent convergences in government efforts to stimulate and steer innovation, for example through support for small biotech ventures, national regulatory differences infuence the competitive status of the pharmaceutical sector. In contrast to the argument that it is German and European healthcare cost containment that has undermined its domestic pharmaceutical industry, this chapter suggests instead that regulation also plays a role in the success and failure of industry.
Menthofuran is considered the major while oxidation at C-5 also yields the menthone proximate toxic metabolite; however order tadora online from canada, pulegone metabolite buy 20 mg tadora with mastercard. Te formation of α tadora 20mg on-line,α,4-trime- oxidation produces other metabolites that may thyl-1-cyclohexene-1-methanol from pulegol also be toxic (see Fig. In a glucuronidase cannot be totally excluded (Engel, study by Khojasteh-Bakht et al. In summary, from a general perspective, Although 10-hydroxypulegone was shown to minimal data existed on the excretion of pule- convert to menthofuran in vitro, menthofuran gone in humans. It might the toxic stereoisomer (R)-(+)-pulegone, which is be possible that pulegone is also reduced at the natural component of pennyroyal oil, but the carbonyl group frst; however, no trace of pulegol (S)-(–)-isomer is also metabolized in the same was found in the urine. Observed metabolites account for pylidene substituent of pulegone is subjected to only 3% of total radiolabel typically excreted in regiospecifc allylic oxidation to yield 9-hydroxy- bile, with glucuronide conjugates and minimal pulegone, which forms menthofuran cyclically glutathione conjugates being found in highest (Gordon et al. Te most common As a minor pathway, it is presumed that the biliary metabolites observed were the glucuro- exocyclic alkene of pulegone is oxidized (with nide conjugates of hydroxylated pulegone and the assumption of an epoxide intermediate) to pulegol (Speijers, 2001). Te metabolism of pulegone involves three Additionally, pulegone is reduced to pulegol major metabolic pathways: (i) hydroxylation which is then rearranged to isopulegone with to give monohydroxylated pulegones at C-5 or the aid of a supposed free-radical intermediate methyl (9- or 10-), followed by conjugation with (Gordon et al. Most of the metabolites of pulegone is also generated via pulegone metabolism and are derived from menthofuran and piperitenone, also depletes glutathione with minor hepatotoxic and 4-methyl-2-cyclohexenone is one of these efects (Chen et al. A γ-ketoenal is generated as a major In addition to cyclizing to obtain mentho- electrophilic metabolite from both pulegone and furan, 9-hydroxypulegone can also be oxidized menthofuran (Tomassen et al. Tis reactive enonal may be derived directly 9-carboxy-pulegone, also called 5-methyl-2-(1- from incipient oxycarbonium ions formed in methyl-1-carboxyethylidene) cyclohexanone the oxidation of menthofuran by cytochrome (Speijers, 2001). Mintlactones are oxidized and hydrated to hydroxyacids that are formed as stable products of the γ-ketoenal, but eliminated through urine (Speijers, 2001). Studies also may be formed by direct proton loss from an of oral administration in rats have shown piperi- incipient oxycarbonium ion (Chen et al. In subsequent analogous furan metabolite and to the γ-ketoenal reactions, the tertiary ring carbon (C-5) is (Chen et al. Tis product is then dehydrated treated orally, gastrointestinally absorbed pule- to piperitenone, which is further metabolized in gone is excreted in the urine within 24 hours. In B6C3F1 mice given pulegone at doses up to 150 mg/kg bw per day by gavage for 3 months, 4. In the frst two studies, pulegone approximately 250 mg/kg bw may result in death was not mutagenic with or without metabolic (Anderson et al. Bacterial strains tested in the frst Adverse physiological reactions following exces- study included S. Functionally, reactive metabolites of pule- gone and menthofuran bind to cellular proteins. On a molecular level, diminished incidence of cellular proliferation in the group concentrations of pulegone-induced glutathione at the highest dose (150 mg/kg bw) (Da Rocha result from the generation of electrophili- et al. Examination of urine collected cally metabolites that form covalent adducts during week 6 of treatment revealed the pres- with glutathione (Anderson et al. Tus, ence of pulegone, piperitone, piperitenone, and N-acetylcysteine serves as a protectant against menthofuran. Piperitenone was concentrated in pennyroyal oil poisoning within the frst few the urine at cytotoxic levels in rats treated with hours afer ingestion and may also protect pulegone at the highest dose. Most importantly, generates electrophilic species that can bind to characteristic hepatotoxicity fndings included proteins. Tis may result in chronic regenera- hepatomegaly, poor perfusion, and dark blood tive cell proliferation that may be related to the from the nasogastric tube and rectum. Te carcinogenicity in the liver and urinary bladder second case presented with hepatic dysfunction that is observed in experimental animals (see and severe epileptic encephalopathy and had Section 3). Summary of Data Reported pulegone intake is associated with marked hepa- totoxicity (Bakerink et al. Pulegone is also induces diminished hepatic function, increased found in Buchu leaf oils. Pennyroyal oil has been used as favouring in confectionery, as a spice, liver and kidney weight, gastrointestinal and and in brewing teas. Pennyroyal leaves and oil nasal epithelial irritation, and atrophy of female reproductive organs (Chen et al. Pennyroyal oil pulegone orally at a dose of 0, 75, or 150 mg/kg has also been used as a fragrance in foods and bw per day, 5 days per week, for 4 or 6 weeks. Given the which is then hydroxylated at the 9-position and wide range of uses of mint, there is a possibility further converted to an analogous furan metab- of exposure to pulegone on a daily basis. Further metabolism to the use of pulegone have been issued for foods of the γ-ketoenal produces 4-methyl-2-cyclohex- and beverages. Tis may result in chronic regenerative cell proliferation, which may be related to the 5. Pulegone was tested for carcinogenicity afer oral administration in one study in mice and one study in rats. Evaluation In male and female mice given pulegone by gavage, there was a signifcant increase in the inci- dences of hepatocellular adenoma, and hepato- 6. In female mice, the incidence of osteoma or osteosarcoma (combined) was higher than that in historical controls. Mutagenic investigation of hydroxypulegone, predominantly by hepatic of peppermint oil in the Salmonella/mammalian-mi- oxidation at the 5-, 9-, and 10-positions. Pennyroyal and Pulegone (Mentha Council of 16 December 2008 on favourings and pulegium L. In: Medical Toxicology of Natural certain food ingredients with favouring properties for Substances: Foods, Fungi, Medicinal Herbs, Plants and use in and on foods and amending Council Regulation Venomous Animals. Of J Eur Cappello G, Spezzaferro M, Grossi L, Manzoli L, Marzio Union L, 354:34 L (2007). Te natural variation of of irritable bowel syndrome: a prospective double the pulegone content in various oils of peppermint. Drug Metab Dispos, Insecticidal and Genotoxic activities of mint essential 29:1567–1577. Statement on the use of herbal medicinal products Kaiser R, Lamparsky D, Schudel P (1975). Metabolism of (R)-(+)-pulegone and (R)-(+)- explanation for the toxicity diferences between (S)-(-)- menthofuran by human liver cytochrome P-450s: and (R)-(+)-pulegone. Profts of Indian menthol mint Mentha Brussels, Belgium: Scientifc Committee on Food. Berlin: Springer- botanical and geographical origin of spearmint oils by Verlag; Vol 5, p. Partial characterization of biliary metabolites of pule- Peppermint oil quality diferences and the reason for gone by tandem mass spectrometry.
Evidence of hepatocyte cell-specific gene expression in vivo has been obtained with the use of hepatocyte-specific promoters buy discount tadora 20mg. However tadora 20 mg mastercard, prolonged gene expression required partial (66%) hepatectomy 15 minutes before intravenous injection of the complex into rats tadora 20mg overnight delivery, probably due to stimulation of liver cell regeneration. Hepatocyte-specific gene expression has been shown using synthetic peptide-based gene delivery. Several approaches of cancer gene therapy are currently being investigated: • enhancing cellular and humoral immune responses to tumors; • inserting genes into tumor cells to evoke “cell suicide”; • modifying tumor suppressor genes or anti-oncogenes. Cytokine genes Several cytokine genes have been found to reduce tumors by stimulating localized inflammatory and/or immune responses. Upregulation of the immune system The immune system has the ability to react very strongly to foreign histocompatability antigens, even ones that have not been seen before. This property of the immune system has been utilized to generate immune responses against tumors. This may also facilitate the presentation of tumor-specific antigens to the immune system, and help the development of tumor-specific immunity. Tumor suppressor genes Tumor suppressor genes actively repress cell growth and their loss leads to tumor development. Introduction of the wild-type p53 gene in a colon cancer xenograft model has been shown to induce tumor regression due to apoptosis. Lung cancer cells are frequently deficient in p53 and are susceptible to the induction of apoptosis by overexpressed p53, making this tumor particularly suitable for gene therapy by p53. Systemic administration of the tumor suppressor gene p53 complexed with cationic liposomes significantly reduced tumor growth and metastases of nude mice injected with cancer cells. The pulmonary endothelium may act as a bioreactor for the production and secretion of therapeutic proteins, such as clotting factors and erythropoietin into the blood circulation. There is a potential benefit for acquired lung diseases, as well as cancers, to be controlled and possibly treated by expression of cytokines, surfactant, antioxidant enzymes, or mucoproteins within lung cells. Plasmid can be delivered to the lung by intravenous injection, intratracheal by instillation or inhalation. Gene delivery to the submucosal glands of the upper airway is of particular interest, though challenging for treatment of cystic fibrosis, where correction of the genetic defects in the glands may improve the alterations in the patients’ secretions. Aerosolization requires monodisperse particles, since the deposition of inhaled particles in the airway depends on particle size (see Section 10. As has been detailed in Chapter 10, larger particles (>5 μm mass median diameter) tend to deposit mainly in the larynx and upper airways. With droplets < 5 μm , there is an increase in airway and alveoli deposition, but alveolar deposition is far greater. The inhaled dose is dependent on the minute volume and entrainment efficiency of the subject and therefore has considerable intersubject variability. Such variability will only be accentuated in many diseases in which the airways are obstructed by mucus. Still, aerosolization of plasmid/lipid complexes has been successfully used for gene delivery into the airways of mice and rabbits with a pump spray device and is under clinical trials for gene delivery to the nasal epithelium. Intratracheal instillation bypasses the barrier of the endothelial cell layer that is associated with systemic gene delivery. Almost 80–90% of the starting material is wasted in aerosol gene delivery irrespective of the inhalation device employed. Therefore, intratracheal instillation of plasmid/lipid complexes is being investigated as an alternative to deliver transgenes to the lung. Plasmid/lipid complexes, not plasmid alone, are effective in aerosolization, whereas plasmids alone can efficiently be transfected to rat and mouse airway epithelial tissues when given by the intratracheal route. Altering the physicochemical characteristics of the formulated plasmids can vary the distribution of plasmid to the bronchial tree. Immunohistochemical studies of lung tissues after intratracheal administration of plasmid/lipid complexes have shown gene expression mainly within the epithelial cell layer lining the bronchus. Depending on the site of expression and the nature of antigen, in vivo expression of plasmids encoding antigen can provide superior cellular, humoral and mucosal immunity. The efficacy of genetic vaccines could be enhanced or modulated through the use of formulations that increase nucleic acid stability or distribution in the tissue, the coexpression of immune molecules that affect the processing of antigens, or through the use of adjuvants that affect the immune response. Genetic vaccines have been applied to several systems, including immune responses against cancer antigens, mycoplasma, tuberculosis, malaria, parasites, and viral infections. Two types of immunity may be induced in response to an antigen, namely humoral immunity mediated by antigen-specific antibodies produced by B lymphocytes, and cell-mediated immunity produced by activated macrophages and cytotoxic T lymphocytes. Antibodies may neutralize pathogens, whereas 355 cytotoxic T lymphocytes can destroy infected cells or control infection by noncytolytic means. Antibody- mediated immunity effectively prevents infection by binding to the infectious organisms and then eliminating either directly or via phagocytic ingestion by neutrophils and/or monocytes. Antibodies also bind to the surface of infected cells expressing the specific antigen. Several routes, including intramuscular, subcutaneous, intravenous, intradermal, nasal, and oral administration, have been investigated for the administration of genetic vaccines. Of these routes, intramuscular injection of genetic vaccines generated the best response. Mature myotube has been shown to be the target for the uptake of plasmid after intramuscular administration. Plasmid can enter the bloodstream and lymphatic system after intramuscular administration and traffic to the spleen, liver, kidney, lymph nodes and bone marrow. It is not clear whether the production of antigens in muscle has unique properties with respect to the elicitation of a prolonged immune response or whether expression in any tissue in the periphery is sufficient for the induction of an antigen-specific immune response. Single injection provides for a full humoral and T cell response for 60–70 weeks, with the antibody titer being higher than that achieved by intramuscular injection. Skin is rich in dendritic cells, which are potent initiators of immune responses and possess the co- stimulatory and adhesion molecules required for T cell activation. Thus, transfection of plasmids into these cells is likely to elicit both cellular and humoral responses. Specific targeting of dendritic cells residing in the lymph nodes will likely represent an attractive strategy for providing a robust immune response with nucleic acid vaccines. Plasmid-based (or non-viral) gene therapy has generated considerable research interest because of many inherent advantages over the viral vectors in terms of safety, immunogenicity and ease of manufacture. Gene therapy offers unique opportunities in the development of novel products that produce intracellular proteins. Several plasmid-based approaches are already in clinical trials and offer the potential of safe and effective gene therapy. To enhance the therapeutic efficacy of 356 proteins using plasmid-based expression systems, many fundamental questions related to their pharmaceutical formulation, biodistribution and intracellular trafficking still need to be addressed.
Thus illness cheap tadora 20 mg with mastercard, and particularly mental illness discount tadora 20mg, would allow the prisoner to escape the role dilemma cheap tadora 20mg on-line, and since illness is such a widespread excuse, special personality characteristics may not be necessary for selecting this role under extreme circumstances. Furthermore, if one conceives of malin- -281- gering as antisocial behavior (Szasz, 83), then there is much evidence to indicate that many people are dishonest at one time or another (15, 17, 39, 51, 59). This is one way of interpreting the rather consistent finding that poor students who are having difficulty maintaining their roles as students are more likely to cheat (15, 17, 39). This also seems to be congruent with the finding that a person will take a particular role if it is seen as satisfying an important need (66). As pointed out by several writers, the person who simulates is an actor who portrays an illness as he understands it (8, 58, 69). It would appear that the characteristics and behaviors which are perceived as crucial to the role are acquired through experience and observation. Personal experiences may have occurred with friends or relatives who were psychotic. In the two cases described by Atkin (4), the role perceptions necessary for the malingering were built up by confinement in mental hospitals at eariler times. The cultural stereotype of the deranged person also seems to be used as a basis for role enactment. Observations made of criminal cases being psychiatrically evaluated prior to trial tend to support this. Many Negro patients who are thought to be malingering tend to play the part of a slow, somewhat confused and defective person who understands little of what is going on around him. Like members of other oppressed minorities, some Negroes have adopted a mask of dullness and unawareness when interacting with the Caucasian majority (5). The cultural determination of the ingredients Which are perceived as comprising the psychotic -282- role is also evident in the work of Benedict (6). Her investigation of trancelike states in primitive cultures led her to conclude that the content of the hallucinations experienced is relatively constant within groups but highly variable between groups. This suggests that the role of the person in trance is learned from interaction with his own group. As she states, "Even in trance the individual holds strictly to the rules and expectations of his culture, and his experience is as locally patterned as a marriage rite or an economic exchange" (6, p. Sarbin (76) gives a similar interpretation to the behavior of the hypnotized subject which can also be approximated through simulation. This principle appears central to the indices of malingering which are reported in the literature. Although the simulator may have some understanding of psychosis, his understanding is usually spotty. He fails to appreciate the underlying disturbance and portrays isolated symptoms instead (19, 87). Thus, he may complain of hallucinations or delusions but not show any of the formal characteristics of schizophrenic thought. Often he presents symptoms which are exceedingly rare, existing mainly in the fancy of the layan (8). This symptom is very unusual in true psychosis, but is used by a number of simulators (19). In schizophrenia, the onset tends to be gradual, delusions do not spring up full-blown overnight; in simulated disorders, the onset is usually fast and delusions may be readily available (47, 69). The feigned psychosis often contains many contradictory and inconsistent symptoms, rarely existing together (8, 47, 69, 87). The malingerer tends to go to extremes in his portrayal of his symptoms: he exaggerates, overdramatizes, grimaces, shouts, is overly bizarre, and calls attention to himself in other ways (8, 19, 47, 55, 69, 87). In doing this, the malingerer presents a childish, dadaistic, nonsensical picture rather than a psychotic one. On the other hand, Atkin (4) feels that the malingerer fails by not maintaining the simulation long enough rather than by failing to portray a psychotic picture accurately. Eissler (22) is more pessimistic and contends that a smart malingerer probably will maintain an accurate picture over a long period of time and may get away with it. Several of the more frequently feigned symptoms are delusions, hallucinations, depression, confusion, excitement, and mutism. Delusions The nondeteriorated schizophrenic is often reluctant to discuss his delusions because he has discovered that people are likely to scoff at him. If he is willing to talk about them, he will probably talk at great length and answer questions if the interviewer appears sympathetic and encouraging. The malingerer, on the other hand, feels that he must continually remind the examiner about his delusions and brings them up on each occasion. However, when pressed for particulars he may become evasive, especially if he sees a doubting attitude in the interviewer. Although some truly bizarre and complicated delusions may be fabricated on the spur of the moment, it is more likely that the delusions will be very vague and very limited. It is rare to find delusions as the only symptom of mental illness, but some malingerers present no other major symptoms. Visual hallucinations are rather rare and are more characteristic of acute delirium and hallucinosis due to toxicity than of schizophrenia. Again, in toxic conditions this should not be an isolated symptom, and one would also expect confusion, tremor, slurred speech, and disorientation along with the visual hallucinations. Auditory hallucinations, which are more characteristic of the schizophrenic, should also be accompanied by the types of thought disturbance characteristic of the schizophrenic. Depression Depression, especially psychotic depression, is considered difficult to simulate, primarily because the concomitant somatic and physiological changes are absent (19, 47, 58). The truly depressed patient will show a poor appetite, loss of weight, constipation, and a disturbance of his -284- sleep cycle. Even more difficult to feign are the alterations of the physiological processes which appear in prolonged depressions. These may include lowered metabolism, lowered temperature, dry skin and hair, and lowered red cell count. However, there is evidence to indicate that motivation, attitude, and intent will have an effect on physiologic processes; therefore the success of the malingerer in actuating some of these changes should not be discounted. However, the crude malingerer will probably not show these changes nor will he manifest the selfreproachful and self- condemnatory ideas which are characteristic of the depressed patient. Confusion Confusion, stupor, and amnesia may result from the stress and strain of combat, capture, or arrest. If it is a temporary anxiety state, it should respond to drugs and a sympathetic attitude. Also it should at the outset be associated with other symptoms, such as headache, agitation, restlessness, poor concentration, insomnia, nightmares, ideas of physical disease such as heart trouble, the effort syndrome, dyspepsia, tremor, poor appetite, and an exaggerated startle reaction. The malingerer who feigns a confused state is usually slow, puzzled, unaware, and unable to answer even simple questions. His responses to questions may be bizarre, but if he is repeatedly pressed for the correct answer, he may give it. Most important would be close observation during periods when the patient does not know that he is being observed. When alone or with friends, or even when talking about certain topics with the examiner, the malingerer may show a surprising amount of responsiveness and alertness.