Pramlintide Antidiabetic [6568

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CAS registry no:

151126-32-8 (anhydrous free base) 196078-30-5 (acetate salt hydrate) 187887-46-3 (anhydrous acetate salt)

Molecular weight:

3949.4 (acetate salt) 4027.49 (acetate salt hydrate)

Pramlintide is an injectable human amylin analog that has been launched for the treatment of both type 1 and type 2 diabetes, in conjunction with insulin. While it is also a 37-amino acid peptide, it differs from its parent predecessor by the substitution of Ala-25, Ser-28, and Ser-29 with prolines. Not only do these modifications improve the solubility of the peptide, they also eliminate the aggregation observed with amylin, resulting in a stable synthetic analog with retention of biological activity that is suitable for pharmaceutical use. As an indication of potency, pramlintide inhibits the binding of radioiodinated rat amylin to rat nucleus accumbens membranes with a K value of 23 pM. Its mechanism of action mimics amylin; as a neurohormone that is co-secreted with insulin from the pancreatic p cells in response to meals, it is involved in glucose homeostasis. Both peptides lower postprandial glucose levels by inhibiting glucagon and by restraining the vagus-mediated rate of gastric emptying, thereby, slowing intestinal carbohydrate absorption. Furthermore, amylin, or pramlintide, has the added benefit of inducing postprandial satiety resulting in weight loss in the patients with type 2 diabetes. Linear pramlintide is prepared on methylbenzhydrylamine resin using standard Boc chemistry. The peptide is cyclized on the resin by treatment with thallium(III) trifluoroacetate to remove the acetamidomethyl (Acm) protecting groups of the cysteines with concomitant oxidation to the disulfide. Subsequent cleavage of the cyclic peptide from the resin with removal of side chain protecting groups is accomplished with liquid HF using dimethylsulfide and anisole scavengers. Reverse phase HPLC affords pure pramlintide. Following subcutaneous injection, the absolute bioavailability is approximately 30-40%. Dose-dependent plasma concentrations and clearance are observed. Cmax is reached in approximately 20min and decreases over a 3-h period. The primary route of excretion is via the kidneys with a mean elimination half-life of 40-50 min. Pramlintide doses between 60 and 120 mg correlate with plasma levels induced by the endogenous release of amylin following a meal. Because of its wide therapeutic window, pramlintide does not require constant dose adjustments like its partner insulin; patients remain on a constant dose regardless of meal size, carbohydrate content, or blood glucose concentrations. The efficacy of pramlintide was evaluated in several, long-term (26-52 weeks) clinical trials enrolling 2375 patients with type 1 diabetes and 1688 patients with type 2 diabetes. In patients with type 1 diabetes on fixed-dose insulin, 30 or 60 ug of pramlintide administered prior to meals resulted in a —0.43% change in baseline glycosylated hemoglobin (HbA1c) compared to only a —0.10% change in patients receiving placebo with their fixed-dose insulin. In addition, patients receiving pramlintide experienced a —1.1kg change in weight compared to a + 0.6 kg weight change in the placebo group. Similar results were obtained in the clinical trials for type 2 diabetes; a 120 ug dose of pramlintide administered prior to meals effected a —0.57% change in baseline HbA1c compared to a —0.17% change in patients receiving placebo with their fixed-dose insulin. Since pramlintide slows gastric emptying, it is contraindicated in patients with gastroparesis and in patients taking drugs that alter gastrointestinal motility (anti-cholinergic agents, such as, atropine) or slow down the intestinal absorption of nutrients (such as a-glucosidase inhibitors). Pramlintide is also contraindicated in patients with hypoglycemic tendencies; due to co-administration with insulin, severe insulin-induced hypoglycemia is a risk. The most commonly reported adverse events include nausea, vomiting, anorexia, headache, abdominal pain, fatigue, dizziness, coughing, and pharyngitis.

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Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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