1. INSULIN, ISOPHANE ID DB08914 C257H383N65O77S6 5808 Daltons CATEGORY
Hypoglycemic Agents and Antidiabetic Agents

2. DESCRIPTION
Isophane insulin or NPH insulin (neutral protamine Hagedorn) is an intermediate-acting insulin to improve glycemic control. It is synthesized using a strain of Escherichia coli bacteria that has been genetically altered to produce human insulin. Human insulin isophane suspension consists of a crystalline suspension of human insulin with protamine and zinc. This combination results in an intermediate-acting insulin with a slower onset of action and longer duration of activity than regular human insulin.
INDICATION
Used to improve glycemic control in patients with type 1 or type 2 diabetes mellitus.
PHARMACODYNAMICS
When 0.3 Units/kg of NPH insulin was subcutaneously administered, the onset of action was approximately 0.8 hours. The duration of action was 13.2 hours. The peak activity of NPH insulin occurs 4-6 hours post-dose. Compared to insulin glargine, NPH insulin has a quicker onset of action and shorter duration of action.

3. MECHANISM OF ACTION
The primary activity of insulin is the regulation of glucose metabolism. Insulin promotes glucose and amino acid uptake into muscle and adipose tissues, and other tissues except brain and liver. It also has an anabolic role in stimulating glycogen, fatty acid, and protein synthesis. Insulin inhibits gluconeogenesis in the liver. Insulin binds to the insulin receptor (IR), a heterotetrameric protein consisting of two extracellular alpha units and two transmembrane beta units. The binding of insulin to the alpha subunit of IR stimulates the tyrosine kinase activity intrinsic to the beta subunit of the receptor. The bound receptor is able to autophosphorylate and phosphorylate numerous intracellular substrates such as insulin receptor substrates (IRS) proteins, Cbl, APS, Shc and Gab 1. These activated proteins, in turn, lead to the activation of downstream signaling molecules including PI3 kinase and Akt. Akt regulates the activity of glucose transporter 4 (GLUT4) and protein kinase C (PKC) which play a critical role in metabolism and catabolism
TOXICITY
Hypoglycemia is one of the most frequent adverse events experienced by insulin users.

4. METABOLISM
Insulin is predominantly cleared by metabolic degradation via a receptor-mediated process
ABSORPTION
NPH insulin is generally well and rapidly absorbed from the site of injection. Absorption does not differ if it is subcutaneously administered in the thigh or abdomen. when 0.5 IU/kg of NPH insulin was given to adult type 1 diabetes patients before breakfast, the pharmacokinetic parameters are as follows: AUC (0-24hours) = 111,941 ± 77,941 pmol · l-1 · min-1; Cmax = 149 ± 121 pmol/l; Tmax = 480 ± 237 minute. It is important to note that NPH insulin has a high degree of patient variability in its absorption profile.
ROUTE OF ELIMINATION
The route of elimination of certolizumab pegol has not been studied in human subjects. Studies in animals indicate that the major route of elimination of the PEG component is via urinary excretion.
VOLUME OF DISTRIBUTION = 0.15 L/kg

5. SEQUENCE
A chain GIVEQCCTSICSLYQLENYCN
B chain FVNQHLCGSHLVEALYLVCGERGFFYTPKT
TARGETS
Insulin receptor

6. Humulin N, Novolin N, Novolin NPH, NPH Iletin II, and isophane insulin
DESCRIPTION
When mixed with insulin, protamines slow down the onset and increase the duration of insulin action (see NPH insulin). Protamines are small, arginine-rich, nuclear proteins that replace histones late in the haploid phase of spermatogenesis and are believed essential for sperm head condensation and DNA stabilization. Human Insulin Isophane Suspension (recombinant DNA origin) is a 3 mL disposable prefilled insulin syringe
100 units/mL (U-100). NPH insulin (or neutral protamine Hagedorn) (also known as Humulin N, Novolin N, Novolin NPH, NPH Iletin II, and isophane insulin), is an intermediate-acting insulin given to help control the blood sugar level of those with diabetes. NPH was created in 1936 when Nordisk formulated "isophane" porcine insulin by adding neutral protamine to regular insulin

7. Obtained from Saccharomyces cerevisiae
Insulin isophane and insulin regular is a long-acting form of insulin that is slightly different from other forms of insulin that are not man-made.
ADVERSE REACTION:
any change of insulin should be made cautiously and only under medical supervision. changes in purity, strength, brand (manufacturer), type (regular, nph, lente®, etc.), species (beef, pork, beef-pork, human), and/or method of manufacture (recombinant dna versus animal-source insulin) may result in the need for a change in dosage.
special care should be taken when the transfer is from a standard beef or mixed species insulin to a purified pork or human insulin. if a dosage adjustment is needed, it will usually become apparent either in the first few days or over a period of several weeks. any change in treatment should be carefully monitored.
please read the sections "insulin reaction and shock" and "diabetic ketoacidosis and coma" for symptoms of hypoglycemia (low blood glucose) and hyperglycemia (high blood glucose).

8. DOSAGE:
Novolin® N in an InnoLet® disposable prefilled insulin syringe. Novolin N is commonly known as NPH, Human Insulin Isophane Suspension (recombinant DNA origin). The concentration of this product is 100 units of insulin per milliliter. It is a cloudy or milky suspension of human insulin with protamine and zinc. The insulin substance (the cloudy material) settles at the bottom of the insulin reservoir, therefore, the Novolin N InnoLet (nph, human insulin isophane suspension 3 ml disposable prefilled syringe) must be rotated up and down so that the contents are uniformly mixed before a dose is given. Novolin N has an intermediate duration of action. The effect of Novolin N begins approximately 1½ hours after injection. The effect is maximal between 4 and 12 hours. The full duration of action may last up to 24 hours after injection.

9. REFERENCES
Lepore M, Pampanelli S, Fanelli C, Porcellati F, Bartocci L, Di Vincenzo A, Cordoni C, Costa E, Brunetti P, Bolli GB: Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes Dec;49(12): Pubmed
Owens DR, Coates PA, Luzio SD, Tinbergen JP, Kurzhals R: Pharmacokinetics of 125I-labeled insulin glargine (HOE 901) in healthy men: comparison with NPH insulin and the influence of different subcutaneous injection sites. Diabetes Care Jun;23(6): Pubmed
Danne T, Lupke K, Walte K, Von Schuetz W, Gall MA: Insulin detemir is characterized by a consistent pharmacokinetic profile across age-groups in children, adolescents, and adults with type 1 diabetes. Diabetes Care Nov;26(11): Pubmed
Owens DR, Bolli GB: Beyond the era of NPH insulin—long-acting insulin analogs: chemistry, comparative pharmacology, and clinical application. Diabetes Technol Ther Oct;10(5): doi: /dia Pubmed