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By K. Ugrasal. Alabama A&M University.

FH2 is reduced to FH4 by dihydrofolate reductase and FH is converted to N5 cheap 100 mg avanafil amex,N10 methylene FH using serine as a car- 4 4 bon donor avanafil 200mg online. Shaded bars indicate the steps at which the antimetabolites 5-fluorouracil (5-FU) and methotrexate act order avanafil 50mg otc. This is the anemia was treated avanafil 50mg low price, in part buy avanafil 200 mg lowest price, with only reaction involving FH in which the folate group is oxidized as the one-carbon 4 folate supplements (see Clinical group is donated to the recipient. Recall that DHFR is also required to reduce the Comments). Within 48 hours of the initiation oxidized form of the vitamin, which is obtained from the diet (see Fig. Thus, of folate therapy, megaloblastic or “ineffec- DHFR is essential for both regenerating FH2 in the tissues and from the diet. These tive” erythropoiesis usually subsides, and reactions contribute to the effect of folate deficiency on DNA synthesis because effective erythropoiesis begins. A megaloblastic anemia is caused by a dTMP is only required for the synthesis of DNA. These deficiencies lead to an 4 inability of hematopoietic (and other) cells to deficiency would also hinder these reactions, contributing to an inability to replicate synthesize DNA and, therefore, to divide. Their persistently thwarted attempts at nor- After the carbon group carried by FH4 is reduced to the methyl level, it is trans- mal DNA replication, DNA repair, and cell ferred to vitamin B12. This is the only reaction through which the methyl group can division produce abnormally large cells leave FH (recall that the reaction creating N5-methyl FH is not reversible). Some of these large cells, although immature, are A. Structure and Forms of Vitamin B12 released early from the marrow in an attempt The structure of vitamin B12 (also known as cobalamin) is complex (Fig. Thus, periph- contains a corrin ring, which is similar to the porphyrin ring found in heme. The eral blood smears will also contain mega- corrin ring differs from heme, however, in that two of the four pyrrole rings are loblasts. Many of the large immature cells, however, are destroyed in the marrow and joined directly rather than by a methylene bridge. Its most unusual feature is the never reach the circulation. In the The average daily diet in Western body, it reacts with the carbon of a methyl group, forming methylcobalamin, or countries contains 5–30 g vitamin with the 5 -carbon of 5 -deoxyadenosine, forming 5 -deoxyadenosylcobalamin B12, of which 1–5 g is absorbed (note that in this case the deoxy designation refers to the 5 carbon, not the 2 car- into the blood. Absorption and Transport of Vitamin B12 dietary deficiency of B12 is uncommon and is only observed after a number of years on Although vitamin B12 is produced by bacteria, it cannot be synthesized by higher a diet deficient in this vitamin. The major source of vitamin B12 is dietary meat, eggs, dairy In spite of Jean Ann Tonich’s relatively products, fish, poultry, and seafood. The animals that serve as the source of these malnourished state because of chronic alco- foods obtain B12 mainly from the bacteria in their food supply. The absorption of holism, her serum cobalamin level was still B12 from the diet is a complex process (Fig. If her under- Ingested B12 can exist in two forms, either free or bound to dietary proteins. If nourished state had continued, a cobalamin deficiency would eventually have developed. If the ingested B12 is bound to proteins, it must be released from the proteins by the action of digestive proteases both in the stomach Individuals with non-Hodgkin’s lymphoma receive a number of drugs to treat the tumor, including the use of methotrexate. NH COO– 2 CH3 O N H N 5 9 N C H 6 CH 10 7 2 8 CH2 H2N CH2 – COO Methotrexate What compound does methotrexate resemble? CHAPTER 40 / TETRAHYDROFOLATE, VITAMIN B12, AND S-ADENOSYLMETHIONINE 739 O Methotrexate has the same struc- ture as folate except that it has an NH2 2 amino group on C4 and a methyl C CH2 group on N10. Anticancer drugs such as CH3 CH2 CH2 methotrexate are folate analogs that act by X inhibiting dihydrofolate reductase, thereby H CH3 preventing the conversion of FH to FH (see O 2 4 H Fig. Thus, the cellular pools of FH4 are CH2 C NH2 CH not replenished, and reactions requiring FH4 O 2 CH3 CH2 cannot proceed. C N N CH3 H2N 3+ Pernicious anemia, a deficiency of Co intrinsic factor, is a relatively com- N N H mon problem caused by malab- O sorption of dietary cobalamin. It may result CH3 from an inherited defect that leads to a CH2 C NH2 decreased ability of gastric parietal cells to CH3 H synthesize intrinsic factor or from partial H CH3 resection of the stomach or of the ileum. CH CH Production of intrinsic factor often declines O 2 CH3 2 CH2 with age and may be low in elderly individu- C CH2 als. An alternative circumstance that leads to H2N C the development of a B12 deficiency is pan- CH3 N NH creatic insufficiency or a high intestinal pH, CH which would result from too little acid being N 2 CH3 produced by the stomach.

This intravenous preparation discount avanafil 50 mg fast delivery, however generic avanafil 50 mg with mastercard, is not available for use in the United States (8) generic 200 mg avanafil overnight delivery. The bioavailability of amantadine is nearly 100% in oral form buy 100 mg avanafil fast delivery. It is excreted virtually unmetabolized via the kidneys and has a large volume of distribution buy 100 mg avanafil with mastercard. In fasting, healthy patients, peak plasma concentration was found 1–4 hours after a single oral dose of 2. Plasma half-life in healthy elderly men has been reported between 18 to 45 hours, suggesting that steady state may take up to 9 days (9). Serum amantadine levels are not routinely drawn and are probably of limited clinical utility. Pharmacological studies have reported serum levels between 0. Few drug interactions have been reported with amantadine. Other than a case report suggesting amantadine toxicity from an interaction with Copyright 2003 by Marcel Dekker, Inc. Because of the relatively long half-life, increases are generally not recommended any sooner than once per week. Doses up to 500 mg have been reported for the use of diminishing motor complications in PD patients (13). The maximum tolerable doses are suggested at 400–500 mg each day in patients with normal renal function (14). Doses over 400 mg produce no added benefit and an increased incidence of side effects. Clinical Uses Early Parkinson’s Disease Amantadine is generally considered a mild antiparkinsonian agent with effects on rigidity and bradykinesia and a very well tolerated side effect profile. In this context, major uses have been in early treatment of PD or as a mild adjunctive agent in moderate PD. Its use in early PD may be helpful when considering levodopa-sparing strategies or when symptoms are mild and do not warrant more aggressive therapy. Amantadine has been studied in early PD as monotherapy and in combination with anticholinergics in limited series and small controlled studies with relatively short follow-up (15–17). Part of the rationale for considering amantadine monotherapy are suggestions that amantadine itself may have neuroprotective properties to slow the progression of PD. Uitti and colleagues (18) found that amantadine use was an independent predictor of improved survival in a retrospective analysis of all parkinsonism patients (92% PD) treated with amantadine compared to those not using this medication. The results are suggestive of either an ongoing symptomatic improvement or the presence of an inherent neuroprotective property. There has been no confirmatory evidence to suggest neuroprotection from studies in PD patients, although basic science work on potential neuroprotective mechanisms with amantadine remains intriguing (see below). In the 2002 American Academy of Neurology (AAN) guidelines on initiation of PD treatment, amantadine is not mentioned. The bulk of discussion has now focused on current literature involving selegiline, levodopa, and dopamine agonists (19). Moderate Parkinson’s Disease In moderate PD, where symptoms necessitate treatment with levodopa or dopamine agonists, amantadine may be of benefitas an adjunctive medication. Many patients report that they may be initial non-responders to amantadine, but that they may respond at a later point in time as their PD progresses (20). Patients with moderate PD who require additional mild benefit to their existing dopaminergic therapy are good candidates for amantadine. Late Parkinson’s Disease Use of amantadine in managing late-stage PD motor complications was first described in 1987 by Shannon et al. They reported improved motor fluctuations using a qualitative scale weighing changes in relative ‘‘on’’ and ‘‘off’’ function in 20 PD patients. This notion has gained further support from Metman et al. They described a 60% reduction in both peak dose ‘‘on’’ choreiform dyskinesias and severity of ‘‘off’’ periods along with a decreased duration of ‘‘off’’ time (21). One year later, these patients had maintained significant benefit (5). The recognition of different motor dyskinesia phenomenology may be potentially important in the response to amantadine. For instance, dystonic dyskinesias have shown varied interindividual effects (some improving, some worsening) with amantadine in a few studies (3,4).

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Effects of pharmacological agents upon a transgenic model of Parkinson’s disease in Drosophila melanogaster 50 mg avanafil visa. Ghorayeb I generic avanafil 50 mg otc, Puschban Z avanafil 200 mg discount, Fernagut PO generic 200mg avanafil fast delivery, Scherfler C quality 100 mg avanafil, Rouland R, Wenning GK, Tison F. Simultaneous intrastriatal 6-hydroxydopamine and quinolinic acid injection: a model of early-stage striatonigral degeneration. Wenning GK, Granata R, Puschban Z, Scherfler C, Poewe W. Neural transplantation in animal models of multiple system atrophy: a review. Scherfler C, Puschban Z, Ghorayeb I, Goebel GP, Tison F, Jellinger K, Poewe W, Wenning GK. Complex motor disturbances in a sequential double lesion rat model of striatonigral degeneration (multiple system atrophy). Ghorayeb I, Fernagut PO, Aubert I, Bezard E, Poewe W, Wenning GK, Tison F. Toward a primate model of L-dopa-unresponsive parkinsonism mimicking striatonigral degeneration. Barbieri S, Hofele K, Wiederhold KH, Probst A, Mistl C, Danner S, Kauffmann S, Sommer B, Spooren W, Tolnay M, Bilbe G, van der Putten H. Mouse models of alpha-synucleinopathy and Lewy pathology. Ishihara T, Hong M, Zhang B, Nakagawa Y, Lee MK, Trojanowski JQ, Lee VM. Age-dependent emergence and progression of a tauopathy in transgenic mice overexpressing the shortest human tau isoform. Wittmann CW, Wszolek MF, Shulman JM, Salvaterra PM, Lewis J, Hutton M, Feany MB. Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Mash University of Miami School of Medicine, Miami, Florida, U. INTRODUCTION The importance of dopamine in the motor functions of the striatum is evident in Parkinson’s disease (PD). The striatum controls motor activity by processing the flow of information arising from the cerebral cortex and projecting via direct and indirect pathways to the output nuclei of the basal ganglia. The degenerative loss of dopamine is a hallmark of this disease and leads to severe motor impairments that are relieved by dopamine agonists. However, dopamine plays a role not only in the execution of complex movement, but also in higher-order cognitive processes, including motor planning and sequencing, motor learning, and motivational drive and affect. Of the biogenic amine neurotransmitters, dopamine has been the best studied in the central nervous system (CNS). The actions of dopamine are segregated in different neural circuits. For example, dopamine in the nigrostriatal pathway is involved in the generation and execution of voluntary movement. In this function, dopamine is a prime modulator of Copyright 2003 by Marcel Dekker, Inc. Dopamine in the mesolimbic pathway plays a role in the control of various cognitive functions, including drive, reinforcement, attention, and in the addiction to psychostimulants. Five different receptor subtypes that are members of the large G- protein–coupled receptor superfamily mediate the central effects of dopamine. Dopamine receptors are divided into two major subclasses, D1-like and D2-like receptors, which differ in their second messenger transduction systems and anatomical locations. The cloning of these receptors and their genes in the last decade has led to the identification of multiple dopamine receptor subtypes termed D1, D2, D3, D4, and D5. The D1 and D5 subtypes of dopamine receptors exhibit overlapping functional and pharmacological properties that are related to the D1 receptor (D1- like), whereas the remaining members of this receptor family share pharmacological characteristics that are similar to the D2 receptor subtype (D2-like). The two receptor families have overlapping but distinct neuroanatomical distributions as determined by radioligand binding autoradiography and immunocytochemical localization.

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ADP + Pi 1 The system is poised to maintain very high levels of ATP at all times discount avanafil 50mg visa. In most tis- ATP H+ 2 sues avanafil 100 mg free shipping, the rate of ATP utilization is nearly constant over time buy avanafil 50mg on line. However avanafil 50 mg without a prescription, in skeletal muscles order avanafil 50mg on-line, the rates of ATP hydrolysis change dramatically as the muscle goes from Matrix Cytosolic side rest to rapid contraction. Even under these circumstances, ATP concentration decreases by only approximately 20% because it is so rapidly regenerated. The concentration of ADP (or the heart, Ca2 activation of TCA cycle enzymes provides an extra push to NADH gen- phosphate potential -[ATP]/[ADP][P ]) con-i eration, so that neither ATP nor NADH levels fall as ATP demand is increased. The release of the ATP requires proton flow through ATP synthase into the matrix. Uncoupling ATP Synthesis from Electron Transport for ATP synthesis decreases the proton gradi- When protons leak back into the matrix without going through the ATP synthase ent. This phenomenon is called “uncoupling” oxidative phosphorylation. Uncoupling of oxidative phosphorylation results in increased oxygen consumption and heat production as electron flow and proton pumping attempt to maintain the electrochemical gradient. CHEMICAL UNCOUPLERS OF OXIDATIVE PHOSPHORYLATION Chemical uncouplers, also known as proton ionophores, are lipid-soluble com- pounds that rapidly transport protons from the cytosolic to the matrix side of the inner mitochondrial membrane (Fig. Because the proton concentration is higher in the intermembrane space than in the matrix, uncouplers pick up protons from the intermembrane space. Their lipid solubility enables them to diffuse through the inner mitochondrial membrane while carrying protons and release these A skeletal muscle biopsy performed on Ivy Sharer indicated proliferation of subsarcolemmal mitochondria with degeneration of muscle fibers (ragged-red fibers) in approximately 55% of the total fibers observed. An analysis of mitochondrial (mtDNA) indi- cated no genetic mutations but did show a moderate quantitative depletion of mtDNA. Ivy Sharer’s AIDS was being treated with zidovudine (AZT), which also can act as an inhibitor of the mitochondrial DNA polymerase (polymerase ). A review of the drugs’ potential adverse effects showed that, rarely, it may cause varying degrees of mtDNA depeletion in different tissues, including skeletal muscle. The depletion may cause a severe mitochondrial myopathy, including “ragged-red fiber” accumulation within the skeletal muscle cells associated with ultrastructural abnormalities in their mitochondria. Dinitrophenol (DNP) is lipid soluble and can therefore diffuse across the mem- brane. Thus, in the intermembrane space where [H ] is high (pH low), DNP picks up a proton, which it carries across the membrane. At the lower proton concentration of the matrix, the H dissociates. As a consequence, cells cannot maintain their electrochemical gradient or synthesize ATP. DNP was once recom- mended in the United States as a weight loss drug, based on the principle that decreased [ATP] and increased electron transport stimulate fuel oxidation. The rapid influx of protons dissipates the electrochemi- cal potential gradient; therefore, the mitochondria are unable to synthesize ATP. Eventually, mitochondrial integrity and function are lost. UNCOUPLING PROTEINS AND THERMOGENESIS Uncoupling proteins (UCPs) form channels through the inner mitochondrial mem- brane that are able to conduct protons from the intermembrane space to the matrix, thereby short-circuiting ATP synthase. UCP1 (thermogenin) is associated with heat production in brown adipose tissue. The major function of brown adipose tissue is nonshivering thermogenesis, whereas the major function of white adipose tissue is the storage of triacylglycerols in white lipid droplets. The brown color arises from the large number of mitochondria that participate. Human infants, who have little voluntary control over their environment and may kick their blankets off at night, have brown fat deposits along the neck, the breastplate, between the scapulae, and around the kidneys to protect them from cold. However, there is very little brown fat in most adults. In response to cold, sympathetic nerve endings release norepinephrine, which activates a lipase in brown adipose tissue that releases fatty acids from triacylglyc- erols (Fig 21. When Salicylate, which is a degradation UCP1 is activated by purine nucleotides, fatty acids, and CoQ, it transports protons product of aspirin in the human, is from the cytosolic side of the inner mitochondrial membrane back into the mito- lipid soluble and has a dissociable chondrial matrix without ATP generation. In high concentrations, as in salicy- phosphorylation and generates additional heat. The decline of ATP expressed in brown adipose tissue; UCP2 is found in most cells, UCP3 is found concentration in the cell and consequent principally in skeletal muscle; UCP4 and UCP5 are found in the brain.

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