By U. Murat. Framingham State College.

Xenometrix offers a broad range of cyto- toxicity assays for the in vitro evaluation of cells in response to pharmaceutical or chemical compounds buy detrol 4 mg with amex treatment statistics. They are based on well established purchase 4mg detrol otc treatment 9mm kidney stones, sensitive and reliable endpoints of cytotoxicity and growth inhibition and are adapted for high throughput in microtiter plates. Pharmacogenetics in Clinical Trials Currently, the most significant polymorphisms in causing genetic differences in phase I drug metabolism are known and therapeutic failures or adverse drug reac- tions caused by polymorphic genes can be predicted for several drugs. Further investigations need to be done on the consequences of each pharmacogenetic phe- nomenon. Pharmacokinetic or pharmacodynamic changes my determine drug selec- tion or dose adjustment. Application of benefit of this approach in needs to be verified in prospective clinical trials using the parameters of Universal Free E-Book Store Role of Pharmacogenetics in Pharmaceutical Industry 133 reduction in adverse drug reactions, improved outcome and cost-effectiveness. Candidate Gene Approach This approach involves generation of specific hypoth- eses about genes that cause variations in drug responses, which are then tested in responders and non-responders. Candidate drugs that are selectively metabolized by polymorphic enzymes can be dropped early in drug screening. Based on the results of clinical trials, pharmacogenetic genotyping can be introduced into routine clinical practice. This provides significant opportunities to enhance current drug surveillance systems by collecting data that would enable rare serious adverse events to be predicted in subsequent patients before the medicine is prescribed. An important challenge in defining pharmacogenetic traits is the need for well- characterized patients who have been uniformly treated and systematically evalu- ated to make it possible to quantitate drug response objectively. Because of marked population heterogeneity, a specific genotype may be important in deter- mining the effects of a medication for one population or disease but not for another; therefore, pharmacogenomic relations must be validated for each therapeutic indi- cation and in different racial and ethnic groups. Between 3 % and 5 % of the patients are hypersensitive to abacavir and have risk of various reactions including anaphylactic shock. The company is aiming to design a test, which would help the physicians to decide which patients can receive it safely. A retrospective case-control study is being conducted in two phases all subjects identified from GlaxoSmithKline studies. This will enable detection of a difference in frequency of 15–20 % with 80 % power. Genotype-Based Drug Dose Adjustment Genotype-based drug dose adjustment information can be useful when the drug is introduced into clinical practice and would enable the dose adjustment for individu- alized therapy. Genetically determined interpatient variability or variations in Universal Free E-Book Store Clinical Implications of Pharmacogenetics 135 Table 4. The clinical significance of genetic polymorphisms and other genetic factors may be related to substrate, metabolite, or the major elimination pathway. Genetic polymorphism has been linked to three classes of phenotypes based on the extent of drug metabolism. Considering the relative abundance of this enzyme and the significant number of pharmaceutical substrates, clinical signifi- cance is likely to be significant. Functional information on the variant is essential for justifying its clinical use. Discovery of new genetic variants is outstripping the generation of knowledge on the biological meanings of existing variants. Therefore, candidates for sulfasalazine ther- apy should be genotyped to identify those patients who might benefit from the drug. These results offer the potential to improve the safety profile of lumiracoxib by identifying indi- viduals at elevated risk for liver injury and excluding them from lumiracoxib treatment. The results from this study therefore pose a difficult challenge to decision makers. Tranilast inhibits the release or production of cyclooxygenase-2 and restores cytokine-induced nitric oxide production. Pharmacogenetic studies showed that it to be Gibert’s syndrome due to polymorphism in the uridine diphosphat glucuronosyltransferase 1A1 gene − mild chronic hyperbilirubinemia that can occur in the absence of liver disease and hemolysis and is not life-threatening. Such a collaborative project would probably not be possible until companies were at the point where they had genotyped at least 100,000 patients on high-density arrays. Recommendations for the Clinical Use of Pharmacogenetics Due to the rapid development of cost-effective methods for genotyping and the need to genotype only once in the lifetime of a patient, it would be advisable to include the genotype in the patient’s record. It is also desirable to include the genotypes of trans- port proteins and drug receptors, which can reveal highly predictive genetic informa- tion. This would provide the physician with valuable information to individualize the treatment. Besides development of personalized medicines, the impact of genotyping on medical practice would shift the emphasis from present diagnosis-based treatment to detection of disease prior to clinical manifestation and preventive treatment with appropriate medicine and a dose that is most effective and safest for an individual. Predicted clinical developments from application of pharmacogenetics are: • Establishment of prescribing guidelines, based on clinical studies, for drugs that are subject to substantial polymorphic metabolism • Prescribing advice will relate dose to genotype and will highlight the possibility of drug interactions when multiple drugs are prescribed concomitantly • Establishment and recording of individual patient genotypes that is, “personal pharmacogenetic profiles” • Pharmacogenetic testing will substantially reduce the need for hospitalization, and its associated costs, because of adverse drug reactions • Development of new drugs for patients with specific genotypes that is, “drug stratification” Limitations of Pharmacogenetics Inherited component of the response to drugs is often polygenic.

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As in conventional pyelonephritis order detrol 2mg overnight delivery medications diabetic neuropathy, there is inflammatory change of the perinephric fat discount detrol 1mg amex symptoms after embryo transfer, but in contrast, there is much more frequent involvement of adjacent structures, particularly the ipsilateral psoas muscle, with rare involvement of other structures such as the colon. Unlike in conventional pyelonephritis, the previously mentioned staghorn calculus is usually present or rarely some other chronically obstructing lesion, such as tumor. Clinical and Radiologic Diagnosis of Renal Abscess Focal or multifocal bacterial infections can result in formation of renal abscess. Cortical abscesses result from hematogenous spread of infection, with Staphylococcus aureus being the most common pathogen. Much more commonly, in contrast, corticomedullary abscesses result from ascending spread of infection from organisms in the urine. The latter type of abscess is more likely to extend to the renal capsule and perforate, resulting in perinephric abscess formation (Fig. Corticomedullary abscesses are uncommon complications of urinary tract infections; risk factors for their development include recurrent infections, untreated or ineffectively treated infections, renal calculi, instrumentation, vesicoureteral reflux, and diabetes mellitus (4). Plain radiographs may show radiopaque stones or intraparenchymal gas in patients with emphysematous pyelonephritis, but are generally not helpful for the identification of abscess alone. The “comet sign,” consisting of internal echogenic foci, indicates the presence of gas within the lesion. Gas may or may not be present within the lesion, and there is no enhancement centrally within the lesion. Uptake of indium-111-labeled leukocytes within the abscess can be seen, although false-negative results may occur if the patient has already been on antibiotic therapy, if the abscess is walled off, or if there is a poor inflammatory response (3,4). Mimic of Renal Abscess Renal cell carcinoma may mimic renal abscess on imaging examinations. Both are mass-like lesions within the kidney; however, unlike renal abscess, which does not enhance centrally, renal cell carcinoma typically demonstrates heterogeneous enhancement. Clinical and Radiologic Diagnosis of Psoas Abscess Primary psoas abscess is rare and usually idiopathic. Immunocompromised patients are at risk Radiology of Infectious Diseases and Their Mimics in Critical Care 79 for infection by opportunistic agents. Secondary psoas abscess is more common and may result from spread of infection from adjacent structures, including colon, kidney, and bone (6). Other findings include obliteration of normal fat planes as well as bone destruction and gas formation. Gas within a psoas abscess may also be related to an underlying bowel fistula, such as in Crohn’s disease or diverticulitis. Abnormal uptake on a Ga-67 scan may also be used for diagnosis, although other entities, such as lymphoma, also show increased uptake; this finding is therefore not specific. An indium-111 white blood cell scan alternatively can be used to confirm infection if needed and should be more specific, although percutaneous aspiration (and drainage) can be performed for more definitive diagnosis and therapy (6–8). Mimic of Psoas Abscess Differentiation from tumor, such as lymphoma, can be difficult with imaging alone, as both can present as low-attenuation lesions, although the presence of gas makes the diagnosis of abscess far more likely. Adjacent structures should be examined to determine if there is a source of secondary infection. In the case of lymphoma originating from para-aortic lymph nodes, a potential helpful differentiating feature is that there may be medial or lateral displacement of the muscle by tumor, rather than extension into the muscle, as would be seen in an abscess (9,10). Clinical and Radiologic Diagnosis of Prostate Abscess Prostatic abscess occurs as a complication of acute bacterial prostatitis. Diabetic and immunocompromised patients are especially prone to this complication. The symptoms are similar to acute bacterial prostatitis, including fever, chills, and urinary frequency, with focal prostatic tenderness on physical exam (11). Abscesses can occur anywhere in the prostate, although they are usually centered away from the midline. Findings on ultrasound include focal hypoechoic or anechoic masses, with thickened or irregular walls, septations, and internal echoes. Mimic of Prostate Abscess A potential mimicker of prostate abscess is prostate carcinoma. Prostate cancer is the most common noncutaneous cancer in American men and the second most common cause of male cancer deaths after lung cancer. Unlike prostate abscess, which can occur anywhere in the gland, prostate cancer occurs mainly in the peripheral zones. Ultrasound findings are somewhat similar to abscess in that carcinoma appears as an anechoic to hypoechoic mass. The contour is classically asymmetric or triangular with the base close to the capsule and extending centrally into the gland based on the pattern of tumor growth. Clinical and Radiologic Diagnosis of Liver Abscess There are three main types of liver abscess: pyogenic, amebic, and fungal. Pyogenic abscesses occur most often in the United States and are usually polymicrobial. Pyogenic liver abscesses occur by direct extension from infected adjacent structures or by hematogenous spread via the portal vein or hepatic artery.

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Up to some point detrol 1mg amex symptoms 4dp5dt fet, then discount detrol 4mg on line medications via g-tube, we are capable of studying things causally, taking our starting-point from sense-perceptions in each case; but when we proceed to the extreme and primary entities, we are no longer capable of doing so, either owing to the fact that they do not have a cause, or through our lack of strength to look, one would say, at the brightest things’ (¨€ kaª toÓtì Šporon £ oÉ ç†€di»n ge e«pe±n, m”cri p»sou kaª t©nwn zhtht”on a«t©av ¾mo©wv ›n te to±v a«sqhto±v kaª nohto±vá ¡ g‡r e«v Špeiron ¾d¼v –n ˆmfo±n ˆllotr©a kaª ˆnairoÓsa t¼ frone±n. For example, Diocles’ way of expressing himself in section 8 certainly reminds us of Aristotle, who also often uses the combination of ‘in a certain way’ (tr»pon tin†) and ‘look like’ (›oike) in order to qualify the similarities he sees between different entities or phenomena; the combination ˆrca±v ›oike (‘look like starting-points’) is also attested several times in Aristotle’s works. Similar searches for combinations of tr»pon tina and a form of ›oika yielded the following results: Aristotle, Gen. For pretty much all animals in some way seem to produce grubs to start with; 94 Hippocratic Corpus and Diocles of Carystus against claims one and two sounds very Aristotelian (although he does not use the typically Aristotelian terminology of kaqì aËt», kat‡ sumbebhk»v, or the qualifier ¨€). The advice not to take unknown, disputed or implausible items as starting-points is perfectly in keeping with the principles and the practice of Aristotelian dialectic. For once the fig is closed neither dew nor drizzle can make it miscarry, and it is dew and drizzle that get warmed and cause the drop, as with the pomegranate blossom. That these are responsible (and they are cited by some people) is indicated by what happens: there is more dropping of the fruit when light rain follows its first appearance’ ( ïEoike dì e­per ¡ Šnoixiv poie± tŸn –pimonŸn eÎpnoi†n te kaª ˆp”rasin poioÓsa paraplžsion tr»pon tin‡ [t¼] sumba±non kaª –pª tän –n A«gÅptw€ sukam©nwná ˆll‡ toÓto diamfisbhtoÓs© tinev Þv Šrì oÉk ˆno©gousin o¬ y¦nev ˆll‡ summÅein poioÓsin Âtan e«sdÅwsin Âqen kaª tŸn a«t©an –stªn –k toÓ –nant©ou f”rein Þv toÅtou c†rin –rinazom”nwná –‡n g‡r summÅwsin oÎqì ¡ dr»sov oÎte t‡ yak†dia dÅnatai diafqe©rein Ëfì æn ˆpop©ptousi diugrain»menoi ãsper kaª o¬ kÅtinoi tän çoäná Âti d• taÓta a­tia mhnÅei t¼ sumba±non Á dŸ kaª l”gous© tinevá ˆpob†llousi g‡r mŽllon Ëdat©wn –piginom”nwn;tr. It seems that of the two opposites, namely sweet and bitter, the sweet is the origin (as it were) of good flavour, whereas the bitter is the origin of fragrance and in some way the bitter is to a greater extent the origin of fragrance. For it is hard to find any fragrant thing that is not bitter, but many non-sweet things have excellent flavour’ ( v –pª pŽn d• t† gì eÎosma p†nta pikr†á toÅtou m•n oÔn tŸn a«t©an Ìsteron lekt”on. I am aware that linguistic resemblances do not prove intellectual exchange or even similarity of doctrine (for the abuse of linguistic ‘evidence’ by Jaeger see von Staden (1992) 234–7) and that the Aristotelian corpus is so much larger than the Hippocratic that the significance of the fact that only occurrences in Aristotle and Theophrastus are found may be doubted (the computer also found Plato, Phaedo 100 e 6–a 1: ­swv m•n oÔn æ€ e«k†zw tr»pon tin‡ oÉk ›oiken, but this passage is not quite comparable with the Diocles fragment). Diocles of Carystus on the method of dietetics 95 Connections of Diocles’ views with Aristotle’s have, of course, been made by earlier scholars, especially by Werner Jaeger, in whose picture of Diocles as a pupil of Aristotle fragment 176 played a central part. He argued that the fragment could not have been written without the influence of the great Stagirite on the Carystian physician, and from this and other considerations drew far-reaching conclusions concerning Diocles’ date. Yet this should not make us a priori hostile to any attempt to associate Diocles with the Lyceum. The resemblance is not so much between Diocles’ ar- gument that knowledge of the cause is often not necessary for practical purposes and similar statements found in Aristotle’s Nicomachean Ethics (which Jaeger emphasised) – it has been shown that what is at issue in those passages is rather different from what Diocles is concerned with. While, to my knowledge, no parallels of this idea can be found in the Hippocratic Corpus, it clearly re- sembles statements in Aristotle and Theophrastus (see note 41) to the effect that the search for causes should stop somewhere and that further analy- sis even ‘destroys’ our understanding. It will probably remain a matter of dispute whether this resemblance is actually to be interpreted as evidence of intellectual exchange between Diocles, Aristotle and Theophrastus. It should be noted, however, that Jaeger’s views have been setting the agenda for Dioclean studies for quite a long time and are sometimes still determining the kind of questions asked by scholars who are at the same time in doubt concerning the validity of his conclusions (see, e. For a plea for a study of Diocles in his own right (with the question of his date and his being ‘influenced’ by this or that particular ‘school’ being kept away from the study of the individual fragments as long as possible) see van der Eijk (1993b) and (2001a) xxi–xxxviii. Gottschalk (private correspondence) points out to me that the doctrine of the limits of causal explanation, which is a very sophisticated piece of philosophy, is presented by Aristotle as his invention, whereas Diocles alludes to it very briefly: ‘his sentence presupposes a knowledge of Aristotle or something very like it’. The latter are either – in the case of real undemonstrable principles such as definitions or logical postulates – concerned with the avoidance of an infinite regress or with the consideration that within the limits of a particular branch of study some things should be accepted as starting-points, the demonstra- tion of which belongs to another discipline: the ignorance of this is seen by them as a sign of ‘being uneducated’ (ˆpaideus©a). While Aristotle’s warnings against pursuing causal analysis too far in these latter contexts look like methodological prescriptions based on considerations of fruit- fulness and economy (one should not ask for a cause here because it is useless – although it may be possible to state one), Diocles’ point is that in the field of dietetics many things simply do not allow of explanation, because when pursuing the search for causes too far, one passes the level of the ‘whole nature’ of a foodstuff and loses the connection with the actual explanandum. On the other hand, it is not unlikely that some sort of contact between Diocles and the Lyceum took place. Diocles enjoyed a good reputation in Athens – although our source for this does not specify in what times he did. It has been doubted whether this should be taken as applying to the Carystian physician, seeing that the name Diocles was very common in Greek and that several persons named Diocles in fourth- century Athens are known from literary and epigraphical sources. The fact that he is credited by Theophrastus with an opinion on a mineralogical topic is a weak argument, which is based on doubtful presuppositions concerning a ‘division of labour’ between the sciences. Diocles may have had various interests, just as Theophrastus himself, or Aristotle, or the authors of such 48 (Pseudo-)Vindicianus, On the Seed 2: ‘Diocles, a follower of Hippocrates, whom the Athenians gave the name of younger Hippocrates’ (Diocles, sectator Hippocratis, quem Athenienses iuniorem Hippocratem vocaverunt). The use of the Attic dialect may be an indication that Diocles lived or practised in Athens (although several fragments preserved in Oribasius also – in some manuscripts – show Ionic forms [see van der Eijk 2001a, xxiv n. The fact that Theophras- tus refers to Diocles without further specification is regarded by Eichholz as evidence that the Carys- tian is meant (1965) 107–8; but this argument will not do, for two different people named Diocles are also mentioned in the will of the Peripatetic Strato (Diogenes Laertius 5. We can only say that it must have been evident to Theophrastus and his audience which Diocles was meant [see van der Eijk (2001a) 416–19]. Diocles of Carystus on the method of dietetics 97 Hippocratic writings as On Fleshes or On Regimen for that matter. Of course we cannot prove that the Diocles mentioned by Theophrastus is the Carystian physician; but then there are a great number of other testimonies about a Diocles where this proof cannot be given. What we can say, I think, is that Diocles marks a methodological aware- ness of the limits of causal explanation that was not anticipated in the Hippocratic Corpus and that showed several significant resemblances to remarks found in Aristotle and Theophrastus. These resemblances may have been the result of intellectual exchange and discussion between them (the existence of which is likely), but this cannot be proved, and we are in no position to decide who was ‘influenced’ by whom. Finally, it seems that any association of Diocles with Empiricism or Scepticism should be abandoned once and for all.

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