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Linplant - Product Instructions
(Regular Dose For Animals)

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Linplant Clinical Pack

The following sections contain helpful suggestions on the proper uses of the Linplant implant. As the severity of diabetes, health status, and response to insulin may vary in different animals, it is advisable to closely monitor the initial phase of therapy by the implant and to use a lower starting dose which may be augmented subsequently.

A) Recommended Implantation Sites:

Implants can be inserted subcutaneously, under the upper abdominal skin, dorsal skin, or any other convenient site. If removal is planned, insertion under the abdominal skin is preferred.

B) Anesthesia:

Use a volatile halohydrocarbon liquid or any short-acting anesthetic agent for small animals and local analgesics for large animals.

C) Insertion:

1) After cleaning the shaved area with Betadine (a 10% povidone-iodine solution), pinch the skin between the thumb and index fingers.
2) Pierce the skin with a 16G disposable hypodermic needle and withdraw.
3) Briefly immerse the trocar in a 2% Betadine solution then push it through the skin orifice just created to a length of at least 2 cm.
4) Immerse the implant briefly (5 sec.) in the 2% Betadine solution and insert it into the proximal end of the trocar.
5) After dipping in the ~2% Betadine solution, use the stylet to push the implant until it exits from the distal end of the inserted trocar.
6) Repeat steps 4 and 5 when required.
7) Pinch the skin over the last inserted implant, before withdrawing the trocar and stylet.
8) Add a drop of the 10% Betadine solution over the skin opening.
9) The skin defect will soon contract and requires no suturing or clips for closure.

D) After Care:

For small animals, make sure that food and water are available ad libitum. For large animals, feed in the morning and late afternoon, with extras in between if feasible. No other care is required unless otherwise stated. Test blood glucose preprandially, if possible. Otherwise sample in mid or late afternoon.

E) Dosages:

1) Do NOT use Linplant in mice (try the ultra-low dose LinBit implants) or in very young, old, pregnant, lactating or prepubertal animals.
2) Do not equate or correlate the daily injection dose with the sustained release dose. The sustained release may potentiate the insulin action.
3) For streptozotocin-induced diabetic rats of body weight >300 g, use 2 full-size (7 mm long) implants. For smaller rats or mild diabetes (late afternoon blood glucose <16 mmol/L), use 1 implant to start.
4) For healthy young adult diabetic BB rats (<300 g), with late afternoon blood glucose persistently >22 mmol/L, use 1 full-size and 1 half-size piece (cut the 7 mm long implant in half with a utility knife) to start. Another half size piece may be implanted in a few days if the diabetes is very severe and a urinary ketone test is positive.
For female adult diabetic BB rats and diabetic BB rats with recurring respiratory ailment, only 1 full-size implant or less is recommended.
For fully matured adult BB rats with severe diabetes, 2 full-size implants or more on subsequent occasions may be used accordingly.
For BB rats (young or matured adult) with mild diabetes (persistently <16 mmol/L in the late afternoon), use only 1 full-size implant.
5) For pigs and dogs with streptozotocin-induced diabetes, use 1 full-size implant/4 kg in body weight to start. Increase the dose by 1 full-size implant with frequent checks of blood glucose for better management of hyperglycemia.
For diabetic rabbits (induced by alloxan), use 1 full-size implant/1.5 kg in body weight.
6) At the start of titration for any animal when the initial dose is close to optimal, blood glucose may decrease on the first day. Thereafter it may rise, and remain high, for a few days, then decrease again. On other occasions, the blood glucose may decrease gradually over 3 days. When the optimal dose is used at once, or on the next implantation, the blood glucose may decrease close to the normal level (usually ± 1.5 mmol/L of the normoglycemic range, preprandially) in a few hours and remains steady for >40 days.
7) For all other large animals with spontaneous diabetes, use the same precautions as in step 5. In addition, the animal must be closely monitored for a few days. If morbidity occurs due to hyperglycemia, supplement with 1/2 or less of the previously used daily injection dose, until the appropriate sustained release dose is found by titration for the individual requirement.
8) By using a different number of implants in diabetic animals, various degrees of severity in sustained hyperglycemia or hypoglycemia may be obtained for physiopathological or nutritional studies.
9) For hypertension research using non-diabetic rodents as a model, it is advised to start with 1 implant/300 g in body weight. However, it may be necessary to supplement the drinking water with 10% sugar for the first 3 days to help stabilize hypoglycemia.

F) Next Implantation:

1) Each implant contains enough insulin to last for 60 days at the specified release rate. However, insulin is also an anabolic hormone, and body weight gain often occurs even for fully matured adult animals. There is also the possibility of tolerance to the exogenous insulin. Therefore, at 45 ± 5 days, the initial sustained release dose may occasionally (10%) appear less than optimal (especially in dogs, thirst and frequent urination become noticeable at once). If the urinary glucose exceeds 111 mmol/L or urinary ketone is greater than 1.5 mmol/L for 2 consecutive days, repeat steps 1 to 8 in Secition C and/or Section E where applicable. If the inserted implants are removed at any time, new implants can be inserted at once by following steps 1 to 8 in Section C as before.
2. In most cases (90%), when the optimal dose is used particularly in rats with streptozotocin-induced diabetes, start a weekly test of blood glucose around day 40. If there are no other complications, the test will soon show when hyperglycemia recurs suddenly indicating termination of action of the implant. At sub-optimal doses, the termination may appear earlier due to the factors aforementioned in step 1. Even at this apparently early termination, there is enough insulin still being released to prevent ketonuria and appreciable loss of body weight. The remnants of the insulin-depleted implant will be completely absorbed in a few weeks and removal is not necessary. Repeat steps in Section C and/or Section E to continue the therapy.
3) When it is necessary to verify if enough insulin is still being released by the implant, reduce the feed (or withhold it altogether, especially if the preprandial blood glucose is ~16 mmol/L) at the end of the working day, and test the blood glucose early next morning, before the feed is completely restored. Without exogenous insulin, the blood glucose level of a severely diabetic animal does not fall below 16 mmol/L at any time, re-implantation may be considered, if the result of the "next morning" blood glucose test aforementioned is >12 mmol/L without overnight feeding.

G) Complications:

1) Occasionally, (<3%), skin tissue debris or hair bits are carrid into the implant site by the needle or trocar. An abscess may develop in 1-3 weeks, and the response to the action of the implant cease suddenly. The palpable abscess is nodular and soft, and can be drained before removing the implant. If left undisturbed, the abscess will eventually recede and bits of the implant will self-extrude in a few weeks. Do not replace the implant at the site of the drained abscess.
2) There is a 10% incidence of remission for mildly diabetic animals on the implant.
3) Do not attempt RIA of plasma insulin, because antibodies against the exogenous insulin will be present. For HPLC analysis of insulin extracted from plasma, please see Reference 1 given in Section J below.
4) Hypoglycemia may occur even with the recommended doses or less if the usual food intake is greatly reduced due to whatever causes, (i.e. deteriorating health, supplemental medications, new brand of chow, pregnancy, lactation, etc.).

H) Storage:

Store at room temperature. No refrigeration required.

I) Product Information:

Composition: Insulin & Palmitic Acid Micro-Crystals
Weight: 26 ± 2 mg per implant
Dimension: 2 mm in diameter, 7 mm in length (Insertable by a 12G Hypodermic Needle)
Release Rate: ~2 U/24 hour/implant for >40 days, subcutaneously (erodible in vivo)
Indication: For Laboratory Research with Diabetic Animals

Note: Implants have not been sterilized. They may be immersed briefly in dilute (2%) Povidone-Iodine solution, or exposed to UV. Do not put in alcohol.


J) References:

1. Hu, R.-M., Kevin, E.R., Pedram, A., & Frank, H.J.L. "Insulin stimulates production & secretion of endothelin from bovine endothelial cells." Diabetes 42, 351-358 (1993).

2. Golomb, G., Avramoff, A., & Hoffman, A. "A new route of drug administraion: Intrauterine delivery of insulin and calcitonin." Pharmaceut. Res. 10, 828-833 (1993).

3. Stevens, E.J., Carrington, A.L., Tomlinson, D.R. "Nerve ischemia in diabetic rats: Time-course of development, effect of insulin treatment plus comparison of streptozotocin and BB models." Diabetologia 37, 43-48 (1994).

4. Cooper, M.E., Rumble, J., Komers, R., Du., H.-C., Jandeleit, K. & Chou, S.-T., "Diabetes associated mesenteric vascular hypertrophy is attenuated by angiotensin-converting enzyme inhibition." Diabetes 43, 1221-1228 (1994).

5. Ziv, E., Kalman, R., Hershkop, K., Barash, V., Shafrir, E., Bar-On, H., "Insulin resistane in the NIDDM model Psammomys obesus in the normoglycaemic, normoinsulinaemic state." Diabetologia 39, 1269-1275 (1996).

6. Malkani, S., Nompleggi, D., Hansen, J.W., Greiner, D.L., & Rossini, A.A., "Dietary Cow's milk protein does not alter the frequency of diabetes in the BB rat." Diabetes 46, 1133-1140 (1997).

7. Ronfail, E., Soulis, T., Boel, E., Cooper, M.E., & Rees, S., "Depletion of nitric oxide synthase-containing neurons in the diabetic retina: reversal by aminoguanidine." Diabetologia 41, 1419-1425 (1998).

8. Havel, P.J., Hahn, T.M., Sendelar, D.K., Baskin, D.G., Dallman, M.F., Weigle, D.S., & Schwartz, M.W., "Effect of streptozotocin-induced diabetes & insulin treatment on the hypothalamic melanocortin system & muscle uncoupling protein 3 expression in rats." Diabetes 49, 244-252 (2000).

9. Chan, O., Inouye, K., Vranic, M., & Matthews, S. G., "Hyperactivation of the hypothalamo-pituitary-adrenocortical axis in streptozotocin diabetes is associated with reduced stress responsiveness and decreased pituitary and adrenal sensitivity." Endocrinology 143, 1761-1768 (2002).

U.S. PATENT 5 110 595 and others