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NPH insulin, also known as isophane insulin (INN) and by various trade names, is an intermediate-acting insulin given to help control the blood sugar level of people with diabetes. It is a neutral-pH suspension of crystalline zinc insulin combined with positively charged protamine (a fish protein). When injected subcutaneously, it has an intermediate duration of action, meaning longer than that of regular and rapid-acting insulin, and shorter than ultralente, glargine or detemir.
NPH stands for neutral protamine Hagedorn, and the words refer to neutral pH (pH = 7), protamine (a protein), and Hans Christian Hagedorn (an insulin researcher). NPH insulin was created in 1936 when Nordisk formulated "isophane" porcine insulin]] by adding neutral protamine to regular insulin.
Hans Christian Hagedorn (1888–1971) and August Krogh (1874–1949) obtained the rights for insulin from Banting and Best in Toronto, Canada. In 1923 they formed Nordisk Insulinlaboratorium, and in 1926 with August Kongsted he obtained a Danish Royal Charter as a non-profit foundation.
In 1936, Hagedorn and B. Norman Jensen discovered that the effects of injected insulin could be prolonged by the addition of protamine obtained from the "milt" or semen of river trout. The insulin would be added to the protamine, but the solution would have to be brought to pH 7 for injection. University of Toronto, Canada later licensed protamine zinc insulin (PZI), to several manufacturers. This mixture only needed to be shaken before injection. The effects of PZI lasted for 24–36 h.
In 1946, Nordisk was able to form crystals of protamine and insulin and marketed it in 1950 as NPH insulin. NPH insulin has the advantage that it can be mixed with an insulin that has a faster onset to complement its longer lasting action, which is the primary reason NPH remains on the market today, because manufacturers sell a variety of premixed insulin formulations. However, numerous medical studies have suggested that NPH has one of the least consistent absorption rates when injected subcutaneously, and a majority of head-to-head comparisons with Lente insulin usually found Lente provided superior glycemic control.
Eventually all animal insulins made by Novo Nordisk were replaced by synthetic, recombinant 'human' insulin. Synthetic 'human' insulin is also complexed with protamine to form NPH.
NPH insulin is cloudy and has an onset of 1–4 hours. Its peak is 6–10 hours and its duration is about 10–16 hours.
NPH insulin may be combined with faster acting insulin to allow more accurate dosing and better blood sugar level control. When administered this way, the two insulin types will normally be combined in the same syringe. NPH and fast-acting insulin bind when mixed, so they should not be combined until it is time to inject. Patients are instructed on the proper procedure to prepare this type of injection to minimize the likelihood of combining two types of insulin in the same vial. The proper order for withdrawing NPH insulin and fast-acting insulin into the same syringe can be remembered by the mnemonic "clear before cloudy", or fast acting clear insulin first, followed by NPH (cloudy). Aspiration, or pulling back on the plunger of the syringe after the needle has been injected to check for blood, is not appropriate for subcutaneous injections.
- 1926 Nordisk receives Danish charter to produce insulin
- 1936 Hagedorn discovers that adding protamine to insulin prolongs the effect of insulin
- 1936 Canadians D.M. Scott and A.M. Fisher formulate zinc insulin mixture and license to Novo
- 1946 Nordisk crystallizes a protamine and insulin mixture
- 1950 Nordisk markets NPH insulin
- 1953 Nordisk markets "Lente" zinc insulin mixtures.
Trade names (brands) include Humulin N, Novolin N, Novolin NPH, Gensulin N, SciLin N, and NPH Iletin II.
- Baganz, H. M.; Carfagno, S. C.; Cowan, B. Y.; Dillon, E. S. (1951). "NPH insulin; its comparison with previous insulin regimens". The American journal of the medical sciences. 222 (1): 1–6. doi:10.1097/00000441-195107000-00001. PMID 14846799.
- Burnham, D. K. (1951). "Insulin and insulin mixtures; nph insulin". California medicine. 75 (6): 412–415. PMC . PMID 14886746.
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- Deckert, T.; Hansen, B.; Kølendorf, K.; Poulsen, J. S.; Smith, M. (1982). "Absorption of NPH-insulin from subcutaneous tissue: A methodological study in pigs". Acta pharmacologica et toxicologica. 51 (1): 30–37. doi:10.1111/j.1600-0773.1982.tb01059.x. PMID 6751023.
- Kølendorf, K.; Bojsen, J. (1982). "Kinetics of subcutaneous NPH insulin in diabetics". Clinical pharmacology and therapeutics. 31 (4): 494–500. doi:10.1038/clpt.1982.66. PMID 7060331.