By L. Saturas. University of Georgia.

Co- PHARMACOLOGIC PROPERTIES OF DRUGS caine and MP were found to have a large brain uptake (7% OF ABUSE IN THE HUMAN BRAIN to 10% injected dose) and to have an almost identical pat- tern of distribution in the human brain viagra 50mg cheap, where they bound The investigation of the pharmacologic properties of drugs entails studies of their pharmacokinetics (primarily using PET and the [11C]-labeled drug) as well as their pharmaco- TABLE 103 generic 25mg viagra with mastercard. DRUGS WITH ABUSE LIABILITY THAT dynamics (using PET or SPECT and a radiotracer with HAVE BEEN LABELED WITH A POSITRON EMITTER specificity for a particular molecular or biochemical target (CARBON-11) or using PET discount 75mg viagra visa, SPECT viagra 75 mg free shipping, and fMRI to assess brain function) buy generic viagra 100 mg online. Drug Class Specific Drug Reference or Review Because these studies are done in awake human subjects, one can investigate the relationship between the behavioral Psychostimulants Cocaine 5,6 effects of drugs and their effects on brain function and neu- Methylphenidate 113 Metamphetamine 114 rochemistry. Opiates Morphine 115 Heroin 115 Codeine 115 Pharmacokinetics Buprenorphine 116 Methadone 117 PET can be used to measure the absolute uptake, their re- Cannabinoids THC 118 11 Nicotine Nicotine 119–120 gional distribution, and the kinetics of [ C]-labeled drugs Caffeine Caffeine 112 in the human brain. Moreover, the labeled drug can also LSD LSD 121 be used to determine the target organs for the drug and Chapter 103: Application of Imaging Technologies in Drug Addiction 1477 rate of drug clearance is relevant in their reinforcing effects. In the case of cocaine, the fast rate of clearance enables repeated, frequent administration that is characteristic of cocaine bingeing (cocaine is taken every 15 to 30 minutes), whereas for MP, its relatively slow clearance from brain is likely to produce accumulation and toxicity that thus pre- vents frequent repeated administration. Pharmacodynamics Multiple parameters pertaining to the mechanisms of action of the drug of abuse can be investigated with imaging. These include measurement of the efficacy of the drug of abuse at the molecular target that is associated with the reinforcing effects of the drug of abuse (i. These parameters can be assessed both in nonaddicted control subjects and in ad- FIGURE 103. Left: Images at the level of the striatum obtained dicted patients to determine whether there are differences with [11C]cocaine and with [11C]methylphenidate at different in the responses between them. Right: Time activity curves for radiotracer concentration in striatum and temporal course for the 'high' expressed as a percentage from peak after pharmacologic doses of intravenous cocaine (upper panel) and of intravenous methylphenidate (lower panel). Studies on theirpharmacokinetics anddistribution inhuman brain. Arch Gen The efficacy of the drug of abuse at the molecular target is Psychiatry 1995;52:456–463, with permission. With PET and appropriate radiotracers, it is possible to measure the levels of DAT occupancy achieved by drugs that block predominantly to the striatum and where the specific bind- DAT in human subjects reproducibly (8). Both drugs had a very DAT occupancy by different doses of intravenous cocaine were assessed with PET and [11C]cocaine in active cocaine fast rate of uptake, with peak concentrations in striatum achieved for cocaine between 4 and 6 minutes and for MP abusers (9). This study showed that cocaine is very effective between 6 and 10 minutes after injection (6). For both drugs, 'high,' and that for cocaine to induce a 'high' it had to their fast uptake in striatum paralleled the temporal course block more than 60% of DAT function. A similar study for the experience of 'high' reported by subjects given phar- done with intravenous MP showed that the ED50 (the dose macologic doses of intravenous cocaine or of MP. However, required to block 50% of the DAT) was half that of cocaine whereas for cocaine the rate of clearance paralleled the de- (MP, 0. As for co- cline in the 'high,' for MP the 'high' declined while there caine, the magnitude of the DAT occupancy was signifi- was still significant binding of the drug in brain (Fig. Although the sponds to 640 and 390 nM, respectively) (11). In analyzing rate at which psychostimulants enter the brain had been the implications of the similar in vivo efficacy for DAT recognized as an important variable in their reinforcing ef- blockade by cocaine and MP, regarding the low abuse po- fects (7), the relevance of their rate of clearance had not. Because the rapid- is relevant for understanding their toxicity as it relates to ity of drug effects is an important variable in the reinforcing cerebrovascular disease. The discrepancy could also reflect effects of drugs of abuse (12) and routes of administration the finding that changes in metabolism reflect an average affect drug pharmacokinetics, the results with intravenous of the changes that occur over the uptake period of FDG MP cannot be extrapolated to oral MP. SPECT studies measuring the levels of receptor occupancy by the benzodiazepine drug lorazepam showed that only a few receptors are occupied at pharmacologic doses (13), findings that support the no- CHRONIC EFFECTS OF DRUGS OF ABUSE IN tion that in humans there is a 'reserve' of benzodiazepine THE HUMAN BRAIN receptors. Imaging studies have been done to assess neurochemical Effects on Dopamine Concentration and functional changes in the brain of addicted subjects that are associated with the process of addiction as well as Because the ability of drugs of abuse to increase extracellular changes associated with drug toxicity. Functional imaging DA concentration is considered crucial for their reinforcing strategies have also been used to assess the brain region in- effects, the estimation of DA changes becomes particularly volved in drug-related states such as drug craving. PET and SPECT enable one to carry such mea- Chapter 110. For this purpose, subjects are scanned twice, at baseline and after administration of the drug of abuse, Drug toxicity can be assessed with imaging techniques for and the difference in the binding of the radioligand between brain as well as for other organs. Toxicity from drugs has both conditions is mostly a reflection of drug induced been documented in abusers of cocaine, methamphetamine, changes in extracellular DA. Studies to measure changes in and ecstasy, and the findings from these studies are covered DA concentration induced by drugs of abuse in the human under the subsection of the drug class. In addition, the brain have been carried out for amphetamine, cocaine, and ability to label the drug with a positron emitter and to follow MP (14–16).

Drachenberg CB buy viagra 75 mg on-line, Papadimitriou JC generic viagra 50mg overnight delivery, Klassen DK buy viagra 100 mg with mastercard, et al discount viagra 100 mg otc. Kuo PC viagra 50mg free shipping, Johnson LB, Schweitzer EJ, Bartlett ST: Simultaneous pancreas/ pancreas transplant needle biopsy. N akhleh RE, Sutherland DER: Pancreas rejection: significance of histopathologic findings with implication for classification of rejection. ATGAM induction therapy in pancreas transplant recipients. A prospective trial of tacrolim us im m unosuppression with percuta- 23. Abendroth D, Landgraf R, Illner W -D, Land W : Evidence for Prograf® and CellCept®in com bination therapy. Transplantation Proc reversibility of diabetic m icroangiopathy following pancreas trans- 1997, 29:334–336. Levy any patients receiving renal allografts become identified simply as recipients of kidney transplantation. All subsequent events M involving changes in renal function are attributed to the process and natural history of transplantation itself: acute and chronic rejection, immunosuppressive drug nephrotoxicity, graft vasculature thrombosis or stenosis, ischemia, infection, and lymphoproliferative disorders. H owever, it is important to remember the nature of the underlying disease that caused the initial renal failure, even if the disease occurred many years previously. Recurrence of the primary disease often causes pathologic changes within the allograft; clinical manifes- tations such as proteinuria and hematuria; and less commonly, renal failure. Thus, focal segmental glomerulosclerosis (FSGS) frequently causes recurrent proteinuria after transplantation, which may begin as early as minutes after the graft is vascularized. All patients with diabetes develop recurrent basement membrane and mesangial pathology within their allografts, and recurrent oxalate deposition can cause rapid renal allograft failure in patients with oxalosis. Identifying patients at particular risk of primary disease recurrence allows consideration of therapeutic maneuvers that may minimize the incidence of recurrence. For many nephritides good evidence exists for an increased incidence of recurrent primary disease in related as opposed to cadaveric grafts. Data from the Eurotransplant Registry suggests a fourfold increased incidence of recurrence of glomerulonephritis, causing graft loss in grafts from living related donors (16. Finally, the recurrence of glomerulonephritis after transplantation, C H A P T ER in particular, can cause specific diagnostic problems. It may be caused by recurrent disease, development of de novo glomerulonephritis in the transplanted organ, or transplanted glomerulonephritis from a donor with unrecognized disease. Glomerulonephritis after transplantation must be distinguished from chronic rejection causing glomerulopathy and cyclosporine-induced glomerulotoxicity. Each of the following diseases can present diagnostic dilemmas and cause graft failure: 17 17. Overall, three groups of diseases recur in patients with Confirmed recurrence of all the glomerulonephritides causes transplantations: metabolic disorders, especially primary hyper- graft loss in 4% of adults and 7% of children receiving allografts oxaluria and diabetes; systemic diseases, including systemic [4,5]. Although few data exist on the treatment of most forms lupus erythematosus, sickle cell disease, systemic sclerosis, of recurrent nephritis, plasma exchange or immunoadsorption hepatitis C virus–associated nephropathies and system ic are proving beneficial at reducing nephrotic range proteinuria vasculitis; and a variety of glomerulonephritides. For immune- in recurrent FSGS [6,7], and recurrent renal oxalate deposition m ediated system ic diseases the standard transplantation often can be abrogated after transplantation in patients with immunosuppressive regimens often prevent recurrence of primary primary hyperoxaluria [8,9]. FIGURE 17-1 DISEASES THAT RECUR AFTER M any diseases can recur in transplanted kidneys, although fewer KIDNEY TRANSPLANTATION cause graft failure. Those disorders that can cause loss of allografts include oxalosis (primary hyperoxaluria) and some glomerulonephri- tides, particularly m esangiocapillary glom erulonephritis (M CGN ), Metabolic Systemic Glomerulonephritis focal segm ental glom erulosclerosis, and som etim es hem olytic urem ic syndrom e. Diabetes recurs alm ost universally in isolated renal grafts Diabetes mellitus Systemic lupus Immunoglobulin A nephropathy but rarely causes graft failure. H epatitis C virus is now recognized as a cause of a num ber Hepatitis C virus– MCGN of problem s after transplantation, including an increased risk of associated nephropathy Hemolytic uremic syndrome recurrent and de novo glomerulonephritis (M CGN and membranous) Systemic sclerosis Anti–glomerular basement and allograft glom erulopathy. Recurrent hem olytic urem ic syndrom e, however, can cause a KIDNEY TRANSPLANTATION m icroangiopathy sim ilar to cyclosporine toxicity, with erythrocyte fragm ents visible both in blood film s and within glom erular capillary loops. The m ajor diagnostic difficulty lies with chronic rejection, especially in the form of transplantation glom erulopathy, and de De novo glomerulonephritis novo or transplanted glom erulonephritis. Chronic transplantation glom erulopathy occurs Transplanted glomerulonephritis in 4% of renal allografts and usually is associated with proteinuria of m ore than 1 g/d, beginning a few m onths after transplantation.

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The term am inoaciduria is applied when m ore carrier with the dibasic am ino acids lysine effective 75 mg viagra, arginine buy generic viagra 25mg on line, and ornithine viagra 75mg amex. Am inoaciduria The transport of all four am ino acids is disrupted in cystinuria purchase viagra 100 mg without a prescription. The can occur in the context of m etabolic defects cheap 100 mg viagra fast delivery, which elevate plasm a rarer disorder, lysinuric protein intolerance, results from defects in am ino acid concentrations and thus increase the glom erular filtered the basolateral transport of dibasic am ino acids but not cystine. In addition, am inoaciduria can arise from genetic defects in consequent hyperam m onem ia. Three distinct groups of inherited am inoacidurias are distin- H artnup disease, blue diaper syndrom e, m ethioninuria, im inogly- guished based on the net charge of the target am ino acids at neutral cinuria, and glycinuria. Several neutral am ino acid transporters pH : acidic (negative charge), basic (positive charge), and neutral have been cloned and characterized. H artnup disease involves a neutral am ino acid transport system Acidic am inoaciduria involves the transport of glutam ate and in both the kidney and intestine, whereas blue diaper syndrom e aspartate and results from a defect in the high-affinity sodium - involves a kidney-specific tryptophan transporter. M ethioninuria potassium –dependent glutam ate transporter. It is a clinically appears to involve a separate m ethionine transport system in the benign disorder. Case reports describe seizures, m ental retardation, Four syndrom es caused by defects in the transport of basic and episodic hyperventilation in affected patients. The patho- am ino acids or cystine have been described: cystinuria, lysinuric physiologic basis for this phenotype is unclear. Im inoglycinuria protein intolerance, isolated cystinuria, and isolated lysinuria. Differences in the urinary Category Phenotype Intestinal transport defect excretion of cystine in obligate heterozygotes and intestinal amino acid transport studies in I hom ozygotes have provided the basis for Heterozygote No abnormality defining three distinct phenotypes of cystin- Homozygote Cystinuria, basic aminoaciduria, cystine stones Cystinine, basic amino acids uria. Genetic studies have identified II m utations in the gene (SCL3A1) encoding a Heterozygote Excess excretion of cystine and basic amino acids Homozygote Cystinuria, basic aminoaciduria, cystine stones Basic amino acids only high-affinity transporter for cystine and the III dibasic am ino acids in patients with type I Heterozygote Excess excretion of cystine and basic amino acids cystinuria [10,11]. In patients with type III Homozygote Cystinuria, basic aminoaciduria, cystine stones None cystinuria, SCL3A1 was excluded as the disease-causing gene. A second cystin- uria-susceptibility gene recently has been From Morris and Ives; with permission. Excessive urinary excretion of cystine (250 to 1000 mg/d of cystine/g of creatinine) coupled with its poor solubility in urine causes cystine precipitation with the formation of characteris- tic urinary crystals and urinary tract calculi. Stone formation often causes urinary tract obstruction and the associated problems of renal colic, infection, and even renal failure. The treatment objective is to reduce urinary cystine concentration or to increase its solubility. High fluid intake (to keep the urinary cystine concentration below the solubility threshold of 250 mg/L) and urinary alkalization are the mainstays of therapy. For those patients refractory to conservative management, treatment with sulfhydryl-containing drugs, such as D-penicillamine, mercaptopropionylglycine, and even captopril can be efficacious [14,15]. These disorders include X-linked hypo- osteomalacia in adults. These disorders can be distinguished on phosphatemic rickets (HYP), hereditary hypophosphatemic rickets the basis of the renal hormonal response to hypophosphatemia, the with hypercalciuria (HHRH), hypophosphatemic bone disease (HBD), biochemical profile, and responsiveness to therapy. In addition, the autosomal dominant hypophosphatemic rickets (ADHR), autosomal rare disorder XLRH is associated with nephrolithiasis. The clinical recessive hypophosphatemic rickets (ARHR), and X-linked recessive features of the two most common disorders HYP and HHRH are hypophosphatemic rickets (XLRH). W hereas both disorders have defects in renal Pi two com m on features: persistent hypophosphatem ia caused by reabsorption, the renal hormonal response to hypophosphatemia is decreased renal tubular phosphate (Pi) reabsorption (expressed as im paired in H YP but not in H H RH. Indeed, in children with decreased ratio of plasma concentration at which maximal phosphate HHRH, phosphate supplementation alone can improve growth rates, reabsorption occurs [Tm P] to glom erular filtration rate [GFR], resolve the radiologic evidence of rickets, and correct all biochemical [TmP/GFR], a normogram derivative of the fractional excretion of abnormalities except the reduced TmP GFR. Cell culture, parabiosis, and transplantation experiments have demonstrated that Phosphatonin Degradation the defect in HYP is not intrinsic to the kidney but involves a circulat- ing humoral factor other than parathyroid hormone [16,17]. Phosphate is transported across the lum inal m em brane of the proximal tubule by a sodium-phosphate cotransporter (NaPi).

However buy generic viagra 25 mg, after the first session 50mg viagra sale, it became apparent that nurses: l would be unlikely to be able to dedicate a full unbroken half-day l may benefit from focusing the evidence further upon their own experience purchase viagra 100mg with amex. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed discount 25mg viagra amex, the full report) may be included in professional journals 95 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising cheap viagra 25 mg mastercard. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. APPENDIX 3 l may benefit from time to reflect on the evidence and the PCAM tool introduction, and some distance in time before trying to integrate it into their practice. In order to respond to this, the training was adapted over the course of the study: l advance creation and sending of three case studies each l 2. A list of local, regional or national groups/organisations/information sources for use by PNs as potential signposting/referral opportunities for patients with LTCs taking part in the PCAM study (intervention only). Design principles l Reference was to be made to ALISS, which is a search and collaboration resource tool for health and well-being resources in Scotland. It is used to collect, organise and share links to community support. ALISS is funded by the Scottish Government and is delivered by the ALLIANCE. Wherever possible, relevant leaflets were available. Design stages Preparation of the PCAM resource packs began following the randomisation of GP practices. Resource packs were prepared for only the three practices randomised to the intervention arm of the feasibility trial. Following randomisation, two researchers were allocated the relevant GP practice locations for initial preparation of the resource packs. Stage 1: internet search An internet search was structured and conducted using key search terms: l condition-specific descriptions (CHD, DM, COPD, LTCs) l PCAM domain headings (e. A range of search engines and directories were identified: l ALISS l NHS national and local search engines (e. Aberdeen City Council Community Contacts and Neighbourhoods directory) l third-sector community directories (e. Infobase, Glasgow Council for the Voluntary Sector) l other relevant websites. This issue may be freely reproduced for the purposes of private research and study and extracts (or indeed, the full report) may be included in professional journals 97 provided that suitable acknowledgement is made and the reproduction is not associated with any form of advertising. Applications for commercial reproduction should be addressed to: NIHR Journals Library, National Institute for Health Research, Evaluation, Trials and Studies Coordinating Centre, Alpha House, University of Southampton Science Park, Southampton SO16 7NS, UK. Most frequently, researchers verified information by either contacting organisations by telephone/e-mail or speaking to staff with knowledge of local services in the relevant GP practice. These staff helped the researcher to check and supplement the resource pack contents for that area. Stage 3: draft preparation of resource pack Draft PCAM resource packs were prepared using the information gathered from the primary search results. Information was organised in discrete sections, structured using the six principal PCAM domains: 1. Within each section, information comprised national resources (e. Information about each resource comprised: l name of resource (e. Each section was printed on plain white paper and placed together in a clip file with a front index for ease of use. To make the pack usable for nurses, the lists of resources were not exhaustive, but were targeted. In addition, the low-technology approach was somewhat influenced by the feasibility nature of the research, but was appreciated by nurses. Stage 4: presentation of draft resource packs to practice nurses Each PN was given a copy of the draft resource pack at their PCAM training session. The purpose and design strategy of the packs was explained by the researchers. PNs were invited to examine the resource packs during and after the training and to participate in the further design of the packs by (1) informing researchers of any inaccurate/outdated information and (2) supplementing the contents by contributing their knowledge of other resources, particularly local resources, that had not been found during the primary search.

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