Louis F. Amorosa

Cyproheptadine-Induced Remission of Cushing's Disease

Abstract Experimental evidence suggests a Central-nervous-system origin of Cushings disease and a role for serotonin in the regulation of ACTH release. The efficacy of cyproheptadine therapy, ther...

Ten-Year Experience with an Exercise-Based Outpatient Life-Style Modification Program in the Treatment of Diabetes Mellitus

Exercise is frequently recommended in the treatment of diabetes mellitus. Nevertheless, its use has been limited in clinical practice, and concerns about safety and efficacy persist. We have reviewed a 10-yr experience with 255 patients enrolled in a comprehensive diabetes program that emphasized physical training. A low maximal oxygen uptake () was found in patients with non-insulin-dependent diabetes mellitus compared with sedentary control subjects. This was not accounted for by autonomic neuropathy and is unlikely to be due to subtle differences in life-style. Exercise-related proteinuria was common and occurred in 29% of patients and was associated with higher blood pressure levels at rest and during exercise, impaired , and decreased R-R interval variation. Regular exercise was associated with a modest decrease in resting and exercise blood pressure. Glycosylated hemoglobin levels and plasma triglycerides improved only in patients with non-insulin-dependent diabetes mellitus. Insulin requirements were significantly reduced in patients with insulin-dependent diabetes mellitus. Compliance for up to 3 mo in the program was acceptable but longer-term compliance was poor. Serious complications during the program were rare. Our experience suggests a program of regular aerobic training can be safely and effectively used in an outpatient population with diabetes mellitus for up to 3 mo.

Fluvastatin with and without niacin for hypercholesterolemia

Seventy-four patients with plasma low-density lipoprotein cholesterol levels > or = 160 mg/dl after an American Heart Association phase 1 diet were randomized to double-blind treatment with fluvastatin, 20 mg/day, or placebo for 6 weeks. Immediate-release niacin was then added to both treatment regimens and titrated to a maximum of 3 g/day for a further 9 weeks. After 6 weeks of fluvastatin monotherapy, low-density lipoprotein cholesterol levels decreased by 21% (p < 0.001 vs placebo), and after the addition of niacin, response was potentiated to 40% compared with 25% for the niacin control group at study end point (p < 0.001). Fluvastatin, alone and in combination with niacin, also significantly improved high-density lipoprotein cholesterol (increases of about 30%) and triglyceride profiles (decreases of approximately 28%) from baseline. Lipoprotein(a) decreased by 37% in those receiving fluvastatin-niacin but was unaltered in those receiving fluvastatin alone. No serious adverse events were ascribed to fluvastatin, and no cases of myositis were observed. Small, transient, asymptomatic increases in aspartate aminotransferase were noted with fluvastatin-niacin treatment but were not considered clinically relevant. Although the fluvastatin-niacin combination in this study was without evidence of significant transaminitis, myopathy, or rhabdomyolysis, it would seem prudent to continue to monitor its safety with longer term use. In conclusion, fluvastatin, both as monotherapy and in combination with niacin, proved to be an effective, safe, and well-tolerated therapeutic alternative for hypercholesterolemia.

Combination therapy with fluvastatin and niacin in hypercholesterolemia: A preliminary report on safety

A double-blind, randomized study was undertaken to evaluate the efficacy and safety of fluvastatin as monotherapy and as combination therapy with niacin in the treatment of hypercholesterolemia refractory to diet. Seventy-four patients with plasma low-density lipoprotein cholesterol (LDL-C) levels > or = 160 mg/dL were treated with fluvastatin, 20 mg/d, or placebo for 6 weeks. Thereafter, immediate-release niacin, at a dosage titrated to a maximum of 3 g/d, was added to both regimens for another 9 weeks. All adverse events were monitored, with particular attention to the evaluation of liver and muscle enzymes. Initial analysis of the data shows that fluvastatin and its combination with niacin was well tolerated and was not associated with any serious adverse events. Small, transient, asymptomatic rises in aspartate aminotransferase (AST) occurred in 28.9% of fluvastatin-niacin treated patients compared to 8.3% in the niacin-placebo control arm (p < 0.05). These were considered clinically insignificant in that no transaminase elevations > 3 times the upper limit of normal occurred. No evidence of myopathy, creatine kinase levels exceeding 10 times the upper limit of normal, myositis, or rhabdomyolysis were demonstrated in this short-term trial. The majority of adverse events resulting in patient withdrawals were ascribed to niacin therapy and included cutaneous vasodilatation, flushing, itching, and rash. These preliminary results suggest that fluvastatin, both alone and combined with niacin, is an effective, safe, and well-tolerated treatment for hypercholesterolemia.

Acute Changes in Heart Rate Variability in Subjects With Diabetes Following a Highway Traffic Exposure

Objective: To pilot a protocol to evaluate acute cardiovascular effects in in-vehicle exposure to traffic air pollutants in people with diabetes. Methods: Twenty-one volunteers with type 2 diabetes were passengers on 90- to 110-minute car rides on a busy highway. We measured in-vehicle particle number and mass (PM2.5) nitrogen dioxide, and carbon monoxide and heart rate, heart rate variability (HRV), and blood pressure. Results: Compared with pre-ride measurements, we found a decrease in high frequency (HF) HRV from pre-ride to next day (ratio 0.66, 95% CI = 0.47 to 0.93) and an increase in low frequency to HF ratio at post-ride (ratio 1.92, 95% CI = 1.21 to 3.05) at post-ride. Interquartile range increases in measured pollutants were associated with next-day decreases in HR HRV. Conclusions: This protocol appears useful for assessing acute adverse cardiovascular effects of in-vehicle exposures among people who have diabetes.

Proteolytic Cleavage of AMPKα and Intracellular MMP9 Expression Are Both Required for TLR4-Mediated mTORC1 Activation and HIF-1α Expression in Leukocytes

LPS-induced TLR4 activation alters cellular bioenergetics and triggers proteolytic cleavage of AMPKα and HIF-1α expression in leukocytes. In human leukocytes, and more specifically neutrophils, AMPKα cleavage yields 55- and 35-kDa protein fragments. In this study, we address the mechanism by which AMPKα is cleaved and its relevance to human health. Our data indicate that AMPKα cleavage is linked to MMP9 expression and that both are required for mammalian target of rapamycin complex-1 and S6K1 activation and HIF-1α expression in LPS-stimulated human and mice leukocytes. Three key observations support this conclusion. First, no changes in AMPKα and TLR4 signaling intermediates (mammalian target of rapamycin complex-1/S6 kinase 1/HIF-1α) were detected in LPS-stimulated MMP9-deficient mice leukocytes. Second, rMMP9 cleaved human AMPKα ex vivo, producing degradation products similar in size to those detected following LPS stimulation. Third, MMP9 inhibitors prevented AMPKα degradation and HIF-1α expression in LPS-activated human leukocytes, whereas AMPK activators blocked MMP9 and HIF-1α expression. Significantly, AMPKα degradation, MMP9, and TLR4 signaling intermediates were all detected in leukocytes from patients with type 2 diabetes mellitus and patients following cardiopulmonary bypass surgery. Plasma from these two patient cohorts induced AMPKα cleavage and TLR4 signaling intermediates in healthy donor leukocytes and either a TLR4 inhibitor or polymyxin prevented these outcomes. Detection of AMPKα degradation, MMP9 expression, and TLR4 signaling intermediates described in this study in leukocytes, the most readily available human cells for clinical investigation, may provide a powerful tool for further exploring the role of TLR4 signaling in human diseases and lead to identification of new, context-specific therapeutic modalities for precision medicine.

Insulin-Dependent Regulation of mTORC2-Akt-FoxO Suppresses TLR4 Signaling in Human Leukocytes: Relevance to Type 2 Diabetes.

Leukocyte signaling in patients with systemic insulin resistance is largely unexplored. We recently discovered the presence of multiple Toll-like receptor 4 (TLR4) signaling intermediates in leukocytes from patients with type 2 diabetes or acute insulin resistance associated with cardiopulmonary bypass surgery. We extend this work to show that in addition to matrix metalloproteinase 9, hypoxia-inducible factor 1α, and cleaved AMPKα, patient leukocytes also express IRS-1 phosphorylated on Ser312, Akt phosphorylated on Thr308, and elevated TLR4 expression. Similar signaling intermediates were detected in leukocytes and neutrophils treated with lipopolysaccharide (LPS), a ligand of TLR4, in vitro. In contrast, insulin, but not LPS, induced mammalian target of rapamycin complex 2 (mTORC2)–dependent phosphorylation of Akt on Ser473 and FoxO1/O3a on Thr24/32 in leukocytes and neutrophils. Insulin suppressed LPS-induced responses in a dose- and time-dependent manner. AS1842856, a FoxO1 inhibitor, also suppressed TLR4 signaling. We propose that insulin is a homeostatic regulator of leukocyte responses to LPS/TLR4 and that the signaling intermediates expressed in leukocytes of patients with type 2 diabetes indicate TLR4 signaling dominance and deficient insulin signaling. The data suggest that insulin suppresses LPS/TLR4 signals in leukocytes through the mTORC2-Akt-FoxO signaling axis. Better understanding of leukocyte signaling in patients with type 2 diabetes may shed new light on disease causation and progression.

Disrupted Nitric Oxide Metabolism from Type II Diabetes and Acute Exposure to Particulate Air Pollution.

Type II diabetes is an established cause of vascular impairment. Particulate air pollution is known to exacerbate cardiovascular and respiratory conditions, particularly in susceptible populations. This study set out to determine the impact of exposure to traffic pollution, with and without particle filtration, on vascular endothelial function in Type II diabetes. Endothelial production of nitric oxide (NO) has previously been linked to vascular health. Reactive hyperemia induces a significant increase in plasma nitrite, the proximal metabolite of NO, in healthy subjects, while diabetics have a lower and more variable level of response. Twenty type II diabetics and 20 controls (ages 46–70 years) were taken on a 1.5hr roadway traffic air pollution exposure as passengers. We analyzed plasma nitrite, as a measure of vascular function, using forearm ischemia to elicit a reactive hyperemic response before and after exposure to one ride with and one without filtration of the particle components of pollution. Control subjects displayed a significant increase in plasma nitrite levels during reactive hyperemia. This response was no longer present following exposure to traffic air pollution, but did not vary with whether or not the particle phase was filtered out. Diabetics did not display an increase in nitrite levels following reactive hyperemia. This response was not altered following pollution exposure. These data suggest that components of acute traffic pollution exposure diminish vascular reactivity in non-diabetic individuals. It also confirms that type II diabetics have a preexisting diminished ability to appropriately respond to a vascular challenge, and that traffic pollution exposure does not cause a further measureable acute change in plasma nitrite levels in Type II diabetics.

What are the Clinically Important Consequences of ESRD-Associated Endocrine Dysfunction?

Most of the pioneering studies of hormonal abnormalities and sexual dysfunction in dialysis patient were done over ten years ago. The use of erythropoietin and the changing standards of dialysis adequacy as well as the change in the composition of the ESRD population make a reevaluation necessary. Some initial investigations have been undertaken. Two recent reports indicate that sexual dysfunction is still a common problem in dialysis patients (21, 22). Steele et aI. specifically addreksed sexual function in CAPD patients, finding that 63% of CAPD patients never had sexual intercourse. Half the patients who never had intercourse or had intercourse infrequently reported that they wanted improvement in sexual function. The group studied included 46% women and 34% diabetic patients. Holly and colleagues have recently begun reevaluating menstrual patterns and sexual activity in women on dialysis in an effort to fill the current gap in our knowledge (13). A registry for pregnancy in women treated with dialysis was established in 1992 to determine the frequency of conception in this group and to analyze treatment regimens with the aim of identifying interventions that improve outcome ( 1 1). Questions about sexual function need to be included in studies of the effects of different dialysis intensities on patient well being. An evaluation of hormonal abnormalities should be part of some of the research on bone disease or cardiovascular disease. Despite the deficiencies in the current state of our knowledge, what we have learned has implications for therapy. Estrogen deficient women should be treated with replacement therapy, testosterone should be normalized in men and hyperprolactinemia treated in both sexes by avoiding drugs which raise prolactin and by dopamine agonists if tolerated. A trial of increased dialysis can be undertaken. Although men with renal failure have not been specifically studied, they should be routinely offered the therapy for erectile dysfunction now available to men with normal renal function. The possibility of conception and contraception should be discussed with all women of childbearing age. The treatment of these problems is often frustrating and labor intensive, but we owe it to our patients to use the knowledge that we have and acquire the knowledge that we lack. I

CYPROHEPTADINE-INDUCED REMISSION OF CUSHINGʼS DISEASE

Experimental evidence suggests a central-nervous-system origin of Cushings disease and a role for serotonin in the regulation of ACTH release. The efficacy of cyproheptadine therapy, therefore, was studied in three patients with such disease. Administration of 24 mg daily over a period of three to six months was associated with prompt and sustained clinical and laboratory remission. Lessening of the physical manifestations of hypercorticism occurred, together with marked improvement in muscular weakness. Urinary corticosteroid excretion and cortisol secretory rate returned to normal. The urinary corticosteroid response to dexamethasone (2 mg per day) became normal; a paradoxical increase followed 8 mg per day. Abnormal circadian periodicity of plasma cortisol concentrations persisted. Return of normal amounts of Stage III to IV sleep occurred in the one patient so studied, who previously had markedly decreased periods of these stages. Discontinuance of therapy in one patient was associated with return of laboratory evidence of hypercorticism.