Protease inhibitors with insulin

When diabetic rabbits (24) were treated with 50 IU of bovine insulin imbibed at 50 mg/g poly (acrylic acid) (Figure 14) no reduction in serum glucose over that achieved by the dry blend control could be detected. Pretreatment of the animals with oral doses of either a penetration enhancer, sodium taurocholate, or a protease inhibitor, aproteinin, failed to improve the insulin activity. One possible explanation for this unexpected lack of activity might be that the diseased animals exhibit impaired ileal absorption of fluids (25). 

In one of these studies, an effort was made to understand the observed dislipidemia and insulin resistance associated with long-term HIV protease inhibitor therapy [25]. Five HIV protease inhibitors (lopinavir, nelfinavir,... 

The hormone-hke peptide incretin stimulates the release of insuhn by a feedback process that involves cleaving the molecule to an inactive form. The protease enzyme dipeptidal peptidase (DPP) in turn cleaves incretin, in effect inactivating this enzyme. Inhibition of DPP consequently extends the action of incretin. This inhibition thus prevents the increased levels of blood glucose that mark diabetes. The protease inhibitor vidagliptin, which is modeled in part on the terminal sequence in DPP, has been found to sustain levels of insulin in Type II diabetics. The inhibition is apparently reversible in spite of the presence in the structure of the relatively reactive a-aminonitrile function. Construction of one intermediate in the convergent synthesis comprises the reaction of amino adamantamine (21-1) with a mixture of nitric and... 

Diabetes mellitus in a 36-year-old man with acute pancreatitis could not be controlled with continuous subcutaneous insulin infusion, even with doses up to 1800 U/ day, because of insulin resistance (168). Intravenous insulin by pump had to be stopped because of a catheter infection. The continuous subcutaneous infusion of freeze-dried insulin and the addition of aprotinin, a protease inhibitor, soluble dexamethasone or prednisolone, and intravenous immunoglobulin was ineffective. An implantable pump for intraperitoneal delivery established good regulation at a dosage of 30 U/day. 

Dyslipidemia is a common accompaniment of the lipodystrophy syndrome observed in HIV-infected patients. This syndrome presents as a combination of peripheral lipoatrophy and the metabolic syndrome (central adiposity, insulin resistance, and dyslipidemia). The term lipodystrophy syndrome was first used in two case reports to describe a clinical picture of subcutaneous fat wasting in the face and limbs of HIV infected patients treated with indinavir, reminiscent of the rare congenital lipodystrophy syndromes (138,139). In addition, benign symmetric lipomatoses on the trunk and neck were described. A systematic study of this syndrome in the Australian HIV cohort showed co-existence of peripheral lipoatrophy with abdominal visceral obesity, dyslipidemia, and insulin resistance in HIV-infected patients with or without treatment with protease inhibitors (140). 

In the HIV infected population, further evidence suggested that visceral fat accumulation, dyslipidemia, and insulin resistance are closely linked and associated with antiretroviral treatment, most pronounced with the use of protease inhibitors. In contrast, subcutaneous fat wasting is primarily determined by the choice of nucleoside reverse transcriptase inhibitor (NRTI). Switching studies have supported this notion, since substitution of stavudine has been associated with improvement in fat wasting, while switching a protease inhibitor had no beneficial effect in more than 30 clinical trials (142). 

Metabolic disturbances are frequent in patients with HIV infection and represent a multifactorial condition related both to the underlying disease and to the antiviral treatment. HIV infection itself appears to cause hyperlipidemia and insulin resistance in some patients. Protease inhibitor therapy is a major contributor to fat accumulation, hyperlipidemia, and insulin resistance. NNRTIs contribute mainly through augmentation of lipid concentrations and NRTIs to the development of lipid-associated toxicity. NRTIs can cause mitochondrial dysfunction. 

Protease inhibitors are associated with hyperglycemia and possible diabetes mellitus. In a prospective study in 12 patients indinavir caused hyperglycemia and reduced insulin sensitivity (486). 

Soon after the introduction of highly active antiretroviral combination treatments (HAART), lipodystrophy was associated with the use of protease inhibitors, and several reports have confirmed that a syndrome of peripheral lipodystrophy, central adiposity, breast hypertrophy in women, hyperlipidemia, and insulin resistance with hyperglycemia is an adverse event associated with the use of potent combination antiretroviral therapy, particularly including HIV-1 protease inhibitors (982-987). 

Dieterle C, Bogner JR, Landgraf R, Goebel FD. Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1-infected patients. AIDS... 

Morishita, I., et al. 1992. Hypoglycemic effect of novel oral microspheres of insulin with protease inhibitor in normal and diabetic rats. Int J Pharm 78 9. 

Yamamoto et al. [4] showed that 0.01% aprotinin (a serine protease inhibitor) reduced the metabolism of insulin and proinsuHn in homogenates of albino rabbit buccal mucosa, which otherwise would have occurred at 70-80% within 2.5 hours. Moreover, Lehr et al. suggest that polycar-bophil, a bioadhesive polymer, may protect some peptides from proteolysis, though the mechanism of this is unknown [5]. Others [6] have developed a series of pro-dmgs for peptides, with the aim of overcoming the metabohc barrier imposed by different peptidases. Stable prodrugs proved to be N-hydroxymethylated derivatives of the assessed dipeptides Gly-L-Leu and Gly-L-Ala [6]. 

Adverse effects of protease inhibitors are similar to those seen with reverse transcriptase inhibitors. In addition, this group of drugs causes metabolic disturbances, particularly insulin resistance and hyperglycaemia, and fat redistribution leading to raised plasma lipid levels, which increases the risk of heart disease. These effects are collectively known as lipodystrophy syndrome, which appears to be similar to what happens with long-term corticosteroid use. 

D. Effects on Carbohydrate and Lipid Metaboiism The use of protease inhibitors in HAART drug combinations has led to the development of disorders in carbohydrate and lipid metabolism. It has been suggested that this is due to the inhibition of lipid-regulating proteins which have active sites with structural homology to that of HIV protease. The syndrome includes hyperglycemia and insulin resistance or hyperlipidemia, with altered body fat distribution. Buffalo hump, gynecomastia, and truncal obesity may occur with facial and peripheral lipodystrophy. The syndrome has been observed with protease inhibitors used in HAART regimens, with an incidence of 30-50% and a median onset time of approximately 1 year s duration of treatment. 

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