By H. Gorn. Saint Norbert College.
The direct pathway (2) the striatum to SNpr) becomes less active cheap 100 mg aurogra overnight delivery what medication causes erectile dysfunction, whereas the indirect pathway (3) striatum to globus pallidus to STN to SNpr) increases in activity discount aurogra 100mg erectile dysfunction treatment ppt. The consequence is an enhanced activation of SNpr outﬂow neurons (4), which exert an overall reduction of the thalamic–cortical pathway (5). DA, dopamine; Glu, glutamate, excitatory transmitter; GABA, - amino butyric acid, inhibitory transmitter; ACh, acetylcholine, excitatory intrastriatal transmitter. GP, globus pallidus; SNpc, substantia nigra pars compacta; SNpr, substantia nigra, pars reticulate; STN, subthalamic nucleus. Dopamine is a catecholamine (see Chapter 10 and The inability of the neurons to eliminate the oxidative Fig. Dopamine actions on D3 4 1 receptors ex- source of oxidative stress may be dopamine metabolism ert an excitatory effect, whereas the actions of (Fig. The stantia nigra created by the loss of dopamine actions loss of striatal dopamine produces an imbalance in in- within the striatum could lead to excitotoxicity that is formation processing in the neostriatum that modiﬁes mediated by glutamate. Also impor- tant in neural transmission are the striatal interneurons Therapy of Parkinsonism that are found within the conﬁnes of the striatum, that use the excitatory neurotransmitter acetylcholine, and Since there is no cure for parkinsonism, the aim of phar- that modulate the activity of striatal output neurons. This is obtained through the use of drugs that either in- crease dopaminergic actions or diminish neuronal out- Possible Mechanisms ﬂow from the striatum. These drugs include levodopa, of Neurodegeneration which increases brain dopamine levels; dopamine ago- The mechanisms responsible for the degeneration of nists, which directly stimulate dopamine receptors; dopamine neurons are not known, but hypotheses in- monoamine oxidase (MAO) inhibitors, which prevent clude effects such as oxidative stress and excitotoxicity. Dopamine itself does not cross the Levodopa and Carbidopa blood-brain barrier and therefore has no CNS effects. Levodopa (L-DOPA), the most reliable and effective However, levodopa, as an amino acid, is transported drug used in the treatment of parkinsonism, can be con- into the brain by amino acid transport systems, where it SYNTHESIS COOH CH2 CH NH2 HO Tyrosine Tyrosine Hydroxylase COOH HO CH2 CH NH2 HO DOPA Aromatic Amino Acid Decarboxylase HO CH2 CH2 NH2 HO DA METABOLISM 2 H2O Catechol-O-methyl Monoamine H2O2 2 Oxidase Fe Transferase • OH OH Fe 3 CH3O CH2 CH2 NH2 HO CH2COOH HO HO MTA DOPAC Monoamine Catechol-O-methyl Oxidase Transferase CH3O CH2COOH HO HVA FIGURE 31. The metabolism of dopamine produces hydrogen peroxide, which can be converted to water by glutathione peroxidase (GPX) or can in the presence of iron produce reactive hydroxyl radicals. DOPA, dihydroxyphenylalanine; DA, dopamine; MTA, 3-methoxytyramine; DOPAC, dihydroxyphenyl acetic acid; HVA, homovanillic acid; GPX, glutathione peroxidase; H2O2, hydrogen peroxide. If levodopa is administered alone, it is extensively Other disturbing behaviors that can be produced by metabolized by L-aromatic amino acid decarboxylase in levodopa therapy are the dyskinesias. To prevent sive and abnormal choreiform movements of the limbs, this peripheral metabolism, levodopa is coadministered hands, trunk, and tongue. These dyskinesias eventually with carbidopa (Sinemet), a peripheral decarboxylase occur in 40 to 90% of patients receiving long-term high- inhibitor. The mechanism underlying lowers the necessary dose of levodopa and reduces pe- these abnormal movements is unclear, but it may be re- ripheral side effects associated with its administration. The parkinsonism except those associated with antipsy- dyskinesias can be reduced by lowering the dosage; chotic drug therapy. However, as parkinsonism pro- however, the symptoms of parkinsonism may then reap- gresses, the duration of beneﬁt from each dose of levo- pear. Patients can also dyskinesia if their mobility can be improved by levo- develop sudden, unpredictable ﬂuctuations between dopa therapy. Cardiac arrhythmias oc- lence, and fatigue are common adverse effects of cur in some patients and are attributed to the stimula- bromocriptine and pergolide therapy and can limit the tion of cardiac - and -adrenoceptors by dopamine. Centrally mediated adverse effects of levodopa ther- Because of these adverse effects, the drugs are gen- apy include vivid dreams, delusions, hallucinations, con- erally ﬁrst administered at low doses and then the dose fusion, and sleep disturbances, especially in the elderly. Also, be- odopa, since the combination can precipitate a life- cause pramipexole and ropinirole are better tolerated, threatening hypertensive crisis and hyperpyrexia. Patients with a history Blockade of dopamine metabolism makes more of cardiac arrhythmias or recent cardiac infarction dopamine available for stimulation of its receptors. Selegiline, as monotherapy, may be effective in the Also, proteins ingested with meals may produce sufﬁ- newly diagnosed patient with parkinsonism because its cient amounts of amino acids to compete effectively with pharmacological effect enhances the actions of endoge- levodopa transport both in the gastrointestinal tract and nous dopamine. Levodopa therefore should be administered Selegiline is also used in conjunction with levodopa– at least 30 minutes before meals. Dopamine receptor agonists are considered by many It has also been proposed that selegiline may slow the clinicians as the ﬁrst approach to therapy. They have a progression of the disease by reducing the formation of long duration of action and are less likely to cause dys- toxic free radicals produced during the metabolism of kinesias than levodopa. However, any neuroprotective ef- dopamine agonists is that they provide a means of di- fect of selegiline in parkinsonian patients remains to be rectly stimulating dopamine receptors and do not de- established. As Most of the adverse reactions to selegiline are re- monotherapy, the dopamine agonists are less effective lated to actions of increased levels of dopamine, as dis- than levodopa but are often used early in the disease to cussed earlier.
Of these cheap 100mg aurogra otc erectile dysfunction at the age of 24, 118 were Caucasian cheap aurogra 100 mg amex erectile dysfunction age onset, one Symptoms of glutaric acidemia type I usually appear was black, and one was Native American; 65 were female within two years after birth and generally become appar- and 55 were male; and 112 were from the United States ent when a minor infection is followed by deficient mus- while the other eight were from Great Britain, Canada, cle tone, seizures, loss of head control, grimacing, and Australia, and Ireland. Glutaric acidemia type II symptoms fall into three categories: Signs and symptoms • Infants with congenital anomalies present symptoms Symptoms of organic acidemias vary with type and within the first 24 hours after birth, with symptoms of sometimes even within a specific disorder. Isovaleric deficient muscle tone, severe hypoglycemia, acidemia (IA) can present itself in two ways: acute severe hepatomegaly (enlarged liver), metabolic acidosis, and or chronic intermittent. In some patients, signs the acute sever disorder and half the chronic intermittent include a high forehead, low-set ears, enlarged kidneys, type. In acute severe cases, patients are healthy at birth excessive width between the eyes, a mid-face below but show symptoms between one to 14 days later. Other symptoms can include cient muscle tone, tachypnea (increased breathing rate), shaking, twitching, convulsions, and low body tempera- metabolic acidosis, hepatomegaly, and a “sweaty feet” ture (under 97. If left untreated, the infant can lapse into a coma and die from severe ketoacidosis, hemorrhage, or infec- • Mild or later onset symptoms in children that include tions. In the chronic intermittent type, symptoms usually vomiting, hypoglycemia, hepatomegaly, and myopathy occur within a year after birth and is usually preceded by (a disorder of muscle or muscle tissue). Symptoms of both disorders are gener- include diarrhea, thrombocytopenia, neutropenia, or pan- ally the same and include vomiting, refusal to eat, cytopenia. Other There is a wide range of symptoms for 3-methylcro- symptoms may include skin rash, ketoacidosis, irritabil- tonglycemia, which can occur in newborns, infants, and ity, metabolic acidosis, and a strong smelling urine com- young children. There are five types of organic acidemias of fatty Other symptoms can include hypoglycemia, alopecia, acid oxidation that involve deficiencies of acyl-CoA and involuntary body movements. Lysine—A crystalline basic amino acid essential to Alopecia—Loss of hair or baldness. Biotin—A growth vitamin of the vitamin B complex Metabolic acidosis—High acidity (low pH) in the found naturally in liver, egg yolks, and yeast. Neutropenia—A condition in which the number of Dystonia—Painful involuntary muscle cramps or leukocytes (a type of white or colorless blood cell) spasms. Homocysteine—An amino acid that is not used to produce proteins in the human body. Pancytopenia—An abnormal reduction in the num- ber of erythrocytes (red blood cells), leukocytes (a Hypotonia—Reduced or diminished muscle tone. Tryptophan—A crystalline amino acid widely dis- Ketonuria—The presence of excess ketone bodies tributed in proteins and essential to human life. In these disorders include influenza- or cold-like symptoms, infants, the most common symptoms include severe hyperammonemia, metabolic acidosis, hyperglycemia, metabolic acidosis, ketosis, vomiting, diarrhea (often vomiting, a “sweaty feet” odor, and delay in physical bloody), and upper respiratory or gastrointestinal infec- development. Adults with the disorder are usually asymptomatic include loss of hair, involuntary or uncoordinated muscle (showing no outward signs of the disease). In all types of organic acidemia, diagnosis cannot be There are two combined carboxylase deficiency made by simply recognizing the outward appearance of organic acidemias: holocarboxylase synthetase deficiency symptoms. Symptoms of holocarboxylase ing abnormal levels of organic acid cells in the urine deficiency include sleep and breathing difficulties, hypoto- through a urinalysis. The specific test used is called com- nia, seizures, alopecia, developmental delay, skin rash, bined gas chromatography-mass spectrometry. In gas metabolic acidosis, ketolactic acidosis, organic aciduria, chromatography, a sample is vaporized and its compo- and hyperammonemia. Mass spectrometry elec- include seizures, involuntary muscular movements, hypoto- tronically weighs molecules. Every molecule has a nia, rapid breathing, developmental delay, hearing loss, and unique weight (or mass). Skin rash, alopecia, metabolic acidosis, spectrometry analyzes blood to identify what amino organic acidemia, and hyper ammonemia can also occur. GALE ENCYCLOPEDIA OF GENETIC DISORDERS 845 The results can identify if the person tested has a specific and 20 mg of biotin daily. The prognosis of patients with organic acidemias Molecular DNA testing is also available for common varies with each disorder and usually depends on how mutations of MCAD and LCHAD. Some patients with organic acidemias are incor- screening of fetuses or newborns is not usually done and rectly diagnosed with other conditions, such as sudden are not widely available. With a quick diagnosis and aggressive monitor- Treatment and management ing and treatment, patients can often live relatively nor- mal lives. For example, children with either biotinidase There are few medications available to treat organic deficiency or holocarboxylase synthetase deficiency, acidemias.