Insulin resistance syndrome treatment using

Benzothiophenes, (in), prepared by Yamasaki (2) and thiazole-benzoisothiazole dioxide derivatives, (IV), prepared by Petry (3) were effective as cGMP-PDE inhibitors and used as blood sugar level-depressing agents in the treatment of insulin resistance syndrome associated with Type II diabetes. 

Insulin resistance has been associated with a number of other cardiovascular risks, including abdominal obesity, hypertension, dyslipidemia, hypercoagulation, and hyperinsulinemia. The clustering of these risk factors has been termed metabolic syndrome. It is estimated that 50% of the United States population older than 60 years of age have metabolic syndrome. The most widely used criteria to define metabolic syndrome were established by the National Cholesterol Education Program Adult Treatment Panel III Guidelines (summarized in Table 40-2). 

Metformin works best in patients with significant hyperglycemia and is often considered first-line therapy in the treatment of mild to moderate type II overweight diabetics who demonstrate insulin resistance. The United Kingdom Prospective Diabetes Study demonstrated a marked reduction in cardiovascular comorbidities and diabetic complications in metformin-treated individuals. Metformin has also been used to treat hirsutism in individuals with polycystic ovarian syndrome and may enhance fertility in these women, perhaps by decreasing androgen levels and enhancing insulin sensitivity. 

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). 

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). 

Furthermore, a diet with low contents of FA may be involved in the development of insulin resistance, which suggests that an appropriate dietary intake of n-3 PUFA is considered protective against metabolic syndrome [183]. In addition, diverse psyquiatric impairs (depression, bipolar disorders, schizophrenia, autism) and neurodegenerative diseases such as Alzheimer disease have been associated to decreased blood levels of n-3 HUFA. Besides, there are many examples about the use of pol)nmsaturated FA as drugs. Thus, EPA has shown efficacy as adjunctive treatment, and in some cases as the only treatment in several psyquiatric disorders [184]. It is suggested that the potential of n-3 FA to prevent recurrence and metastasis of mammary cancer when used in adjuvant therapy is associated with a n-6 to n-3 ratio lower than 2 1 [185], On the other hand, fish intake is considered as a protective factor for preventing prostate cancer in addition, in humans low levels of ALA in mammary adipose tissue are associated with an increased risk of breast cancer in women [186]. 

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. 

Monoester 4-(methoxycarbonyl)bicyclo[2.2.1]heptane-l-carboxylic acid 59 (Figure 4.17) is a building block of many potential therapeutic candidates for inhibitors of 11-p-hydroxysteroid dehydrogenase type 1 enzyme and their use in the treatment of non-insulin-dependent type 2 diabetes, insulin resistance, obesity, lipid disorders, metabolic syndrome, and CNS disorders. It is also required for the synthesis of 5-hydroxytryptamine receptor agonists, useful for the treatment of anxiety disorders and schizophrenia [90,91]. 

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