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Parkinson's Disease - Medications
amantadine (Symmetrel ®)
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CLINICAL PHARMACOLOGY Pharmacodynamics Mechanism of Action: Antiviral The mechanism by which amantadine exerts its antiviral activity is not clearly understood. It appears to mainly prevent the release of infectious viral nucleic acid into the host cell by interfering with the function of the transmembrane domain of the viral M2 protein. In certain cases, amantadine is also known to prevent virus assembly during virus replication. It does not appear to interfere with the immunogenicity of inactivated influenza A virus vaccine. Antiviral Activity Amantadine inhibits the replication of influenza A virus isolates from each of the subtypes, i.e., H1N1, H2N2 and H3N2. It has very little or no activity against influenza B virus isolates. A quantitative relationship between the in vitro susceptibility of influenza A virus to amantadine and the clinical response to therapy has not been established in man. Sensitivity test results, expressed as the concentration of amantadine required to inhibit by 50% the growth of virus (ED50) in tissue culture vary greatly (from 0.1 µg/mL to 25.0 µg/mL) depending upon the assay protocol used, size of virus inoculum, isolates of influenza A virus strains tested, and the cell type used. Host cells in tissue culture readily tolerated amantadine up to a concentration of 100 µg/mL. Drug Resistance Influenza A variants with reduced in vitro sensitivity to amantadine have been isolated from epidemic strains in areas where adamantane derivatives are being used. Influenza viruses with reduced in vitro sensitivity have been shown to be transmissible and to cause typical influenza illness. The quantitative relationship between the in vitro sensitivity of influenza A variants to amantadine and the clinical response to therapy has not been established. Mechanism of Action: Parkinson's Disease The mechanism of action of amantadine in the treatment of Parkinson's disease and drug-induced extrapyramidal reactions is not known. Data from earlier animal studies suggest that SYMMETREL may have direct and indirect effects on dopamine neurons. More recent studies have demonstrated that amantadine is a weak, non-competitive NMDA receptor antagonist (Ki = 10µM). Although amantadine has not been shown to possess direct anticholinergic activity in animal studies, clinically, it exhibits anticholinergic-like side effects such as dry mouth, urinary retention, and constipation. Dosing: Adults: ------------------------------ Drug-induced extrapyramidal symptoms: 100 mg twice daily; may increase to 300-400 mg/day, if needed Parkinson's disease or Creutzfeldt-Jakob disease (unlabeled use): 100 mg twice daily as sole therapy; may increase to 400 mg/day if needed with close monitoring; initial dose: 100 mg/day if with other serious illness or with high doses of other anti-Parkinson drugs Influenza A viral infection: 100 mg twice daily; initiate within 24-48 hours after onset of symptoms; discontinue as soon as possible based on clinical response (generally within 3-5 days or within 24-48 hours after symptoms disappear). Influenza A prophylaxis: 100 mg twice daily Note: Continue treatment throughout the peak influenza activity in the community or throughout the entire influenza season in patients who cannot be vaccinated. Development of immunity following vaccination takes ~2 weeks; amantadine therapy should be considered for high-risk patients from the time of vaccination until immunity has developed ------------------------------ Elderly: Adjust dose based on renal function; some patients tolerate the drug better when it is given in 2 divided daily doses (to avoid adverse neurologic reactions). ------------------------------ Dosing interval in renal impairment: Clcr 30-50 mL/minute: Administer 200 mg on day 1, then 100 mg/day Clcr 15-29 mL/minute: Administer 200 mg on day 1, then 100 mg on alternate days Clcr<15 mL/minute: Administer 200 mg every 7 days Hemodialysis: Administer 200 mg every 7 days Peritoneal dialysis: No supplemental dose is needed Continuous arterio-venous or venous-venous hemofiltration: No supplemental dose is needed Supplied: Capsule, as hydrochloride: 100 mg Syrup, as hydrochloride (Symmetrel®): 50 mg/5 mL (480 mL) Tablet, as hydrochloride (Symmetrel®): 100 mg |
benztropine (Cogentin ®)
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Anticholinergic. CLINICAL PHARMACOLOGY Benztropine mesylate possesses both anticholinergic and antihist-aminic effects, although only the former have been established as therapeutically significant in the management of parkinsonism. In the isolated guinea pig ileum, the anticholinergic activity of this drug is about equal to that of atropine; however, when adminis-tered orally to unanesthetized cats, it is only about half as active as atropine. In laboratory animals, its antihistaminic activity and duration of action approach those of pyrilamine maleate. --------------------------- Dosing: Adults: 1-4 mg/dose 1-2 times/day Acute dystonia: Adults: I.M., I.V.: 1-2 mg Parkinsonism: Oral: Adults: 0.5-6 mg/day in 1-2 divided doses; if one dose is greater, administer at bedtime; titrate dose in 0.5 mg increments at 5- to 6-day intervals Elderly: Initial: 0.5 mg once or twice daily; increase by 0.5 mg as needed at 5-6 days; maximum: 4 mg/day --------------------------- Supplied: Injection, solution, as mesylate (Cogentin®): 1 mg/mL (2 mL) Tablet, as mesylate: 0.5 mg, 1 mg, 2 mg |
bromocriptine (Parlodel ®)
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Dopamine agonist. CLINICAL PHARMACOLOGY Parlodel® (bromocriptine mesylate) is a dopamine receptor agonist, which activates post-synaptic dopamine receptors. The dopaminergic neurons in the tuberoinfundibular process modulate the secretion of prolactin from the anterior pituitary by secreting a prolactin inhibitory factor (thought to be dopamine); in the corpus striatum the dopaminergic neurons are involved in the control of motor function. Clinically, Parlodel significantly reduces plasma levels of prolactin in patients with physiologically elevated prolactin as well as in patients with hyperprolactinemia. The inhibition of physiological lactation as well as galactorrhea in pathological hyperprolactinemic states is obtained at dose levels that do not affect secretion of other tropic hormones from the anterior pituitary. Experiments have demonstrated that bromocriptine induces longlasting stereotyped behavior in rodents and turning behavior in rats having unilateral lesions in the substantia nigra. These actions, characteristic of those produced by dopamine, are inhibited by dopamine antagonists and suggest a direct action of bromocriptine on striatal dopamine receptors. Bromocriptine mesylate is a nonhormonal, nonestrogenic agent that inhibits the secretion of prolactin in humans, with little or no effect on other pituitary hormones, except in patients with acromegaly, where it lowers elevated blood levels of growth hormone in the majority of patients. In about 75% of cases of amenorrhea and galactorrhea, Parlodel therapy suppresses the galactorrhea completely, or almost completely, and reinitiates normal ovulatory menstrual cycles. Menses are usually reinitiated prior to complete suppression of galactorrhea; the time for this on average is 6-8 weeks. However, some patients respond within a few days, and others may take up to 8 months. Galactorrhea may take longer to control depending on the degree of stimulation of the mammary tissue prior to therapy. At least a 75% reduction in secretion is usually observed after 8-12 weeks. Some patients may fail to respond even after 12 months of therapy. In many acromegalic patients, Parlodel produces a prompt and sustained reduction in circulating levels of serum growth hormone. Bromocriptine mesylate produces its therapeutic effect in the treatment of Parkinson's disease, a clinical condition characterized by a progressive deficiency in dopamine synthesis in the substantia nigra, by directly stimulating the dopamine receptors in the corpus striatum. In contrast, levodopa exerts its therapeutic effect only after conversion to dopamine by the neurons of the substantia nigra, which are known to be numerically diminished in this patient population. Dosing: Adults: (May be taken with food to decrease GI distress.) Parkinsonism: 1.25 mg 2 times/day, increased by 2.5 mg/day in 2- to 4-week intervals (usual dose range is 30-90 mg/day in 3 divided doses), though elderly patients can usually be managed on lower doses Neuroleptic malignant syndrome: 2.5-5 mg 3 times/day Hyperprolactinemia: 2.5 mg 2-3 times/day Acromegaly: Initial: 1.25-2.5 mg increasing as necessary every 3-7 days; usual dose: 20-30 mg/day Prolactin-secreting adenomas: Initial: 1.25-2.5 mg/day; may be increased as tolerated every 2-7 days until optimal response (range: 2.5-15 mg/day) --------------------------- Monitoring: Monitor blood pressure closely as well as hepatic, hematopoietic, and cardiovascular function --------------------------- Supplied: Capsule, as mesylate: 5 mg Tablet, as mesylate: 2.5 mg |
entacapone (Comtan ®)
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CLINICAL PHARMACOLOGY Mechanism of Action Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT). In mammals, COMT is distributed throughout various organs with the highest activities in the liver and kidney. COMT also occurs in the heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells, and neuronal tissues, especially in glial cells. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, and epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa, catalyzing the metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery. The mechanism of action of entacapone is believed to be through its ability to inhibit COMT and alter the plasma pharmacokinetics of levodopa. When entacapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are greater and more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that at a given frequency of levodopa administration, these more sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson's Disease. The higher levodopa levels also lead to increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa. --------------------------- Dosing: Oral: Adults: 200 mg with each dose of levodopa/carbidopa, up to a maximum of 8 times/day (maximum daily dose: 1600 mg/day). To optimize therapy, the dosage of levodopa may need reduced or the dosing interval may need extended. Patients taking levodopa >/= 800mg/day or who had moderate-to-severe dyskinesias prior to therapy required an average decrease of 25% in the daily levodopa dose. Dosage adjustment in hepatic impairment: Treat with caution and monitor carefully; AUC and Cmax can be possibly doubled --------------------------- Administration Always administer in association with levodopa/carbidopa; can be combined with both the immediate and sustained release formulations of levodopa/carbidopa. Can be taken with or without food. Should not be abruptly withdrawn from patient's therapy due to significant worsening of symptoms. --------------------------- Supplied: Tablet: 200 mg |
pergolide (Permax ®)
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Pergolide mesylate is a potent dopamine receptor agonist. Pergolide is
10 to 1,000 times more potent than bromocriptine on a milligram per
milligram basis in various in vitro and in vivo test systems. Pergolide
mesylate inhibits the secretion of prolactin in humans; it causes a
transient rise in serum concentrations of growth hormone and a decrease
in serum concentrations of luteinizing hormone. In Parkinsons disease,
pergolide mesylate is believed to exert its therapeutic effect by
directly stimulating postsynaptic dopamine receptors in the
nigrostriatal system. Dosing: When adding pergolide to levodopa/carbidopa, the dose of the latter can usually and should be decreased. Patients no longer responsive to bromocriptine may benefit by being switched to pergolide. Adults: Parkinson's disease: Start with 0.05 mg/day for 2 days, then increase dosage by 0.1 or 0.15 mg/day every 3 days over next 12 days, increase dose by 0.25 mg/day every 3 days until optimal therapeutic dose is achieved, up to 5 mg/day maximum; usual dosage range: 2-3 mg/day in 3 divided doses --------------------------- Monitoring: Blood pressure (both sitting/supine and standing), symptoms of parkinsonism, dyskinesias, mental status --------------------------- Supplied: Tablet: 0.05 mg, 0.25 mg, 1 mg |
pramipexole (Mirapex ®)
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Mechanism of Action Pramipexole is a nonergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors, binding with higher affinity to D3 than to D2 or D4 receptor subtypes. Parkinson's Disease The precise mechanism of action of pramipexole as a treatment for Parkinson's disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum. This conclusion is supported by electrophysiologic studies in animals that have demonstrated that pramipexole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum. The relevance of D3 receptor binding in Parkinson's disease is unknown. Restless Legs Syndrome (RLS) The precise mechanism of action of Mirapex® (pramipexole dihydrochloride) tablets as a treatment for Restless Legs Syndrome (RLS) is unknown. Although the pathophysiology of RLS is largely unknown, neuropharmacological evidence suggests primary dopaminergic system involvement. Positron Emission Tomographic (PET) studies suggest that a mild striatal presynaptic dopaminergic dysfunction may be involved in the pathogenesis of RLS. --------------------------- Dosing: (May be taken with food to decrease nausea.) Adults: Oral: Initial: 0.375 mg/day given in 3 divided doses, increase gradually by 0.125 mg/dose every 5-7 days; range: 1.5-4.5 mg/day --------------------------- Dosage adjustment in renal impairment: Clcr 35-59 mL/minute: Initial: 0.125 mg twice daily (maximum dose: 1.5 mg twice daily) Clcr 15-34 mL/minute: Initial: 0.125 mg once daily (maximum dose: 1.5 mg once daily) Clcr<15 mL/minute (or hemodialysis patients): Not adequately studied --------------------------- Supplied: Tablet, as dihydrochloride monohydrate: 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, 1.5 mg |
ropinirole (Requip ®)
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Mechanism of Action REQUIP is a non-ergoline dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 and D3 dopamine receptor subtypes, binding with higher affinity to D3 than to D2 or D4 receptor subtypes. Ropinirole has moderate in vitro affinity for opioid receptors. Ropinirole and its metabolites have negligible in vitro affinity for dopamine D1, 5-HT1, 5-HT2, benzodiazepine, GABA, muscarinic, alpha1-, alpha2-, and beta-adrenoreceptors. Parkinson's Disease: The precise mechanism of action of REQUIP as a treatment for Parkinson's disease is unknown, although it is believed to be due to stimulation of postsynaptic dopamine D2-type receptors within the caudate-putamen in the brain. This conclusion is supported by studies that show that ropinirole improves motor function in various animal models of Parkinson's disease. In particular, ropinirole attenuates the motor deficits induced by lesioning the ascending nigrostriatal dopaminergic pathway with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in primates. The relevance of D3 receptor binding in Parkinson's disease is unknown. Restless Legs Syndrome (RLS): The precise mechanism of action of REQUIP as a treatment for Restless Legs Syndrome (also known as Ekbom Syndrome) is unknown. Although the pathophysiology of RLS is largely unknown, neuropharmacological evidence suggests primary dopaminergic system involvement. Positron emission tomographic (PET) studies suggest that a mild striatal presynaptic dopaminergic dysfunction may be involved in the pathogenesis of RLS. --------------------------- Dosing: Adults: Oral: The dosage should be increased to achieve a maximum therapeutic effect, balanced against the principal side effects of nausea, dizziness, somnolence and dyskinesia Recommended starting dose is 0.25 mg 3 times/day; based on individual patient response, the dosage should be titrated with weekly increments as described below: Week 1: 0.25 mg 3 times/day; total daily dose: 0.75 mg Week 2: 0.5 mg 3 times/day; total daily dose: 1.5 mg Week 3: 0.75 mg 3 times/day; total daily dose: 2.25 mg Week 4: 1 mg 3 times/day; total daily dose: 3 mg After week 4, if necessary, daily dosage may be increased by 1.5 mg per day on a weekly basis up to a dose of 9 mg/day, and then by up to 3 mg/day weekly to a total of 24 mg/day Removal by hemodialysis is unlikely. --------------------------- Supplied: Tablet, as hydrochloride: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg |
selegiline (Eldepryl ®)
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CLINICAL PHARMACOLOGY The mechanisms accounting for selegiline's beneficial adjunctive action in the treatment of Parkinson's disease are not fully understood. Inhibition of monoamine oxidase, type B, activity is generally considered to be of primary importance; in addition, there is evidence that selegiline may act through other mechanisms to increase dopaminergic activity. Selegiline is best known as an irreversible inhibitor of monoamine oxidase (MAO), an intracellular enzyme associated with the outer membrane of mitochondria. Selegiline inhibits MAO by acting as a 'suicide' substrate for the enzyme; that is, it is converted by MAO to an active moiety which combines irreversibly with the active site and/or the enzyme's essential FAD cofactor. Because selegiline has greater affinity for type B rather than for type A active sites, it can serve as a selective inhibitor of MAO type B if it is administered at the recommended dose. -------------------------- Dosing: Adults: Parkinson's disease: 5 mg twice daily with breakfast and lunch or 10 mg in the morning Elderly: Parkinson's disease: Initial: 5 mg in the morning, may increase to a total of 10 mg/day -------------------------- Supplied: Capsule, as hydrochloride (Eldepryl®): 5 mg Tablet, as hydrochloride: 5 mg |
Sinemet ® (carbidopa/levodopa):
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Mechanism of Action Current evidence indicates that symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson's disease apparently because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain. This is thought to be the mechanism whereby levodopa relieves symptoms of Parkinson's disease. ------------------------- Dosing: Oral: Adults: Parkinson's disease: Immediate release tablet: Initial: Carbidopa 25 mg/levodopa 100 mg 3 times/day Dosage adjustment: Alternate tablet strengths may be substituted according to individual carbidopa/levodopa requirements. Increase by 1 tablet every other day as necessary, except when using the carbidopa 25 mg/levodopa 250 mg tablets where increases should be made using 1 /2-1 tablet every 1-2 days. Use of more than 1 dosage strength or dosing 4 times/day may be required (maximum: 8 tablets of any strength/day or 200 mg of carbidopa and 2000 mg of levodopa) Sustained release tablet: Initial: Carbidopa 50 mg/levodopa 200 mg 2 times/day, at intervals not <6 hours Dosage adjustment: May adjust every 3 days; intervals should be between 4-8 hours during the waking day (maximum: 8 tablets/day) Restless leg syndrome (unlabeled use): Carbidopa 25 mg/levodopa 100 mg given 30-60 minutes before bedtime; may repeat dose once Elderly: Initial: Carbidopa 25 mg/levodopa 100 mg twice daily, increase as necessary ------------------------- Administration Space doses evenly over the waking hours. Give with meals to decrease GI upset. Sustained release product should not be crushed. Orally-disintegrating tablets do not require water; the tablet should disintegrate on the tongue's surface before swallowing. ------------------------- Supplied: Tablet immediate release (Sinemet®): 10/100: Carbidopa 10 mg and levodopa 100 mg 25/100: Carbidopa 25 mg and levodopa 100 mg 25/250: Carbidopa 25 mg and levodopa 250 mg Tablet, immediate release, orally-disintegrating (Parcopa™): 10/100: Carbidopa 10 mg and levodopa 100 mg 25/100: Carbidopa 25 mg and levodopa 100 mg 25/250: Carbidopa 25 mg and levodopa 250 mg Tablet, sustained release (Sinemet® CR): Carbidopa 25 mg and levodopa 100 mg Carbidopa 50 mg and levodopa 200 mg |
tolcapone (Tasmar ®)
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Mechanism of Action Tolcapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT). In mammals, COMT is distributed throughout various organs. The highest activities are in the liver and kidney. COMT also occurs in the heart, lung, smooth and skeletal muscles, intestinal tract, reproductive organs, various glands, adipose tissue, skin, blood cells and neuronal tissues, especially in glial cells. COMT catalyzes the transfer of the methyl group of S-adenosyl-L-methionine to the phenolic group of substrates that contain a catechol structure. Physiological substrates of COMT include dopa, catecholamines (dopamine, norepinephrine, epinephrine) and their hydroxylated metabolites. The function of COMT is the elimination of biologically active catechols and some other hydroxylated metabolites. In the presence of a decarboxylase inhibitor, COMT becomes the major metabolizing enzyme for levodopa catalyzing the metabolism to 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the brain and periphery. The precise mechanism of action of tolcapone is unknown, but it is believed to be related to its ability to inhibit COMT and alter the plasma pharmacokinetics of levodopa. When tolcapone is given in conjunction with levodopa and an aromatic amino acid decarboxylase inhibitor, such as carbidopa, plasma levels of levodopa are more sustained than after administration of levodopa and an aromatic amino acid decarboxylase inhibitor alone. It is believed that these sustained plasma levels of levodopa result in more constant dopaminergic stimulation in the brain, leading to greater effects on the signs and symptoms of Parkinson’s disease in patients as well as increased levodopa adverse effects, sometimes requiring a decrease in the dose of levodopa. Tolcapone enters the CNS to a minimal extent, but has been shown to inhibit central COMT activity in animals. Dosage Adults: Oral: Initial: 100-200 mg 3 times/day; levodopa therapy may need to be decreased upon initiation of tolcapone Supplied: Tablet: 100 mg, 200 mg |
trihexyphenidyl (Artane ®)
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Anticholinergic. CLINICAL PHARMACOLOGY Trihexyphenidyl HCl is the substituted piperidine salt, 3-(1-piperidyl)-1-phenyl-cyclohexyl-1-propanol hydrochloride, which exerts a direct inhibitory effect upon the parasympathetic nervous system. It also has a relaxing effect on smooth musculature; exerted both directly upon the muscle tissue itself and indirectly through an inhibitory effect upon the parasympathetic nervous system. Its therapeutic properties are similar to those of atropine, although undesirable side effects are ordinarily less frequent and severe than with the latter. INDICATIONS This drug is indicated as an adjunct in the treatment of all forms of parkinsonism (post-encephalitic, arteriosclerotic, and idiopathic). It is often useful as adjuvant therapy when treating these forms of parkinsonism with levodopa. Additionally, it is indicated for the control of extrapyramidal disorders caused by central nervous system drugs such as the dibenzoxazepines, phenothiazines, thioxanthenes, and butyrophenones. WARNINGS Patients to be treated with trihexyphenidyl HCl should have a gonioscope evaluation and close monitoring of intraocular pressures at regular periodic intervals Dosing: Adults: Oral: Initial: 1-2 mg/day, increase by 2 mg increments at intervals of 3-5 days; usual dose: 5-15 mg/day in 3-4 divided doses Supplied: Elixir, as hydrochloride: 2 mg/5 mL (480 mL) Tablet, as hydrochloride: 2 mg, 5 mg |
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any diagnosis or treatment made in reliance thereon. David F. McAuley, Pharm.D., R.Ph. GlobalRPh Inc. |
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