Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Hormone or other secreted growth regulatory factor,...
Reexamination Certificate
1999-12-30
2004-02-24
Housel, James (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Hormone or other secreted growth regulatory factor,...
C514S002600, C530S399000
Reexamination Certificate
active
06696063
ABSTRACT:
FIELD OF THE INVENTION
The present invention is directed to a method for treating HIV-associated dysmorphia/dysmetabolic syndrome or HIV-associated adipose redistribution syndrome, and related syndromes.
BACKGROUND OF THE INVENTION
Advances in antiviral treatment of HIV infection, along with developments in the prophylaxis and therapy of opportunistic infections, have greatly improved the long-term health of HIV-infected individuals. However, along with improved antiretroviral therapy a new syndrome has developed, which is identified herein as HIV-associated dysmorphia/dysmetabolic syndrome, or HIV-associated adipose redistribution syndrome (HARS), or hereafter abbreviated HADDS.
HADDS involves pathological accumulation of adipose tissue in specific regional depots. The pathologic adipose tissue accumulation of HADDS may also be associated with abnormal adipose tissue depletion elsewhere (lipodystrophy or lipoatrophy), with or without associated metabolic abnormalities, premature atherosclerotic lesions, depletion of lean body mass, and/or other abnormal physiology.
This recently discovered clinical disorder, which has been referred to by a number of terms, including HIV lipodystrophy syndrome and other terminology, has important public health consequences, as described further below.
HADDS patients typically present with abnormal accumulation of adipose tissue in the abdomen, specifically in the visceral adipose tissue compartment (Miller et al, 1998, Kotler et al, 1999; Engelson et al, 1999). HADDS patients may also present with abnormal adipose tissue accumulation in the dorsocervical area (“buffalo hump”), the submandibular area (“horse collar”), the pectoral, mammary, and/or supraclavicular areas, and/or with subcutaneous lipomas (encapsulated benign fatty tumors, single or multiple).
Abnormal, involuntary, pathological, and often dysmorphic accumulation of adipose tissue is sufficient to diagnose a HIV-infected patient with HADDS. However, in addition to developing abnormal adipose accumulation, some HADDS patients develop abnormally depleted subcutaneous adipose tissue, termed “peripheral lipodystrophy” (or lipoatrophy) at other specific sites. This adipose depletion is typically observed in the face (buccal, parotid, and periauricular fat pads), and in the subcutaneous adipose tissue surrounding the limbs, trunk, and/or gluteal regions. Also, some HADDS patients may present with metabolic abnormalities (Carr et al, 1998a, 1998b, 1999a, 1999b; Lipodystrophy Rapid Report, 1999).
The metabolic abnormalities associated with HADDS and lipodystrophy syndrome typically involve disordered lipid and glucose metabolism. Clinical manifestations may include fasting hypertriglyceridemia, hyperlipidemia, and abnormalities of the insulin/glucose axis (elevated fasting insulin, elevated C-peptide, insulin resistance or reduced insulin sensitivity), with or without overt diabetes (Carr et al, 1998a, 1998b, 1999a, 1999b; Henry et al, 1998; Grunfeld, 1999).
Abnormal adipose tissue accumulation abnormalities occur more frequently in female than male cases diagnosed with HADDS, while fat depletion, hyperglycemia, and hyperlipidemia are more commonly observed in male cases (Muurahainen, 1999). Hence the presentation of HADDS appears to vary by gender.
There are preliminary reports suggesting that patients with HADDS exhibit preclinical evidence of increased risk for coronary heart disease (CHD). Preclinical indicators of CHD include increased coronary artery calcification (CAC) as quantified by electron beam computed tomography (EBCT), and extracoronary indicators such as increased intima media thickening (IMT) in the carotid artery and impaired blood flow-mediated dilation in the brachial artery, as quantified by ultrasonography, which signify endothelial dysfunction that may lead to atherosclerosis and CHD. In eight patients with HADDS who developed increased abnormal girth with abnormally accumulated visceral adipose tissue after initiation of HIV rotease inhibitor (PI) therapy who underwent EBCT, Kosmiski et al (1999) reported a mean CAC score consistent with minimal identifiable plaque burden. There are also preliminary reports indicating that HIV patients receiving PIs display abnormal carotid IMT (Maggi et al, 1999) and impaired brachial flow-mediated dilation (Stein, 1999), signifying endothelial dysfunction. However, it is unclear which, if any, of the patients in the two aforementioned preliminary reports were HADDS patients, and what percentage of HADDS patients have preclinical indicators of abnormal endothelial function.
There have also been case reports of premature coronary artery disease in HIV patients under age forty who have been receiving combination antiretroviral therapy that include a protease inhibitor (Henry et al, 1998). However, it may take years before well-designed, prospective, observational cohort studies precisely quantify the risk of premature coronary artery disease in patients with HADDS.
Some patients with HADDS also exhibit involuntary weight loss with depletion of lean body mass (AIDS wasting or cachexia), and possibly depletion of lean body mass without overt weight loss (occult wasting) (Muurahainen, unpublished observations, data on file, Serono Laboratories, Norwell, Mass.).
Other abnormal physiology that may be observed in patients with HADDS or lipodystrophy syndrome include gout and pancreatitis (presumably resulting from severe hypertriglyceridemia), hepatic steatosis (possibly reflecting chronic lactic acidosis), hypogonadism, and possibly other hormonal abnormalities (Henry et al, 1998; Brinkman, 1999; Lipodystrophy Rapid Report, 1999).
HADDS and lipodystrophy syndrome may or may not be associated with other abnormalities, such as cutaneous abnormalities (such as thinning hair, hair loss, hair brittleness, dry skin, abnormal nails, ingrown toenails), disorders of the coagulation syndrome that result in increased bleeding in hemophiliacs, osteoporosis or avascular necrosis of the hips, peripheral neuropathy, nausea, fatigue, weight loss, chronic diarrhea, fever, mennorhagia and menstrual abnormalities, impaired sexual dysfunction (decreased libido, erectile dysfunction), and abnormalities of the genitalia resembling Peyronie's Disease (Carr et al, 1998a, 1998b, 1999a, 1999b; Lipodystrophy Rapid Report, 1999).
In sum, HADDS is a recently discovered multisystemic, gender dimorphic disorder associated with HIV infection that includes (1) regional changes in adipose distribution, frequently dysmorphic, that result from abnormal regional accumulation of adipose tissue, with or without lipodystrophy, (2) occasionally observed in conjunction with abnormalities of lipid and glucose metabolism, and (3) possibly associated with other physiologic abnormalities, including premature atherosclerotic lesions, depletion of lean body mass, and other abnormalities.
Since HADDS and HIV-associated lipodystrophy syndrome have only recently been described, standardized nomenclature or consensus definition(s) for these syndromes are lacking. Kotler and Schambelan (1999) predict that we may eventually see an official case definition that has major and minor criteria, similar to what is already in place for rheumatic disorders such as systemic lupus erythematosis (Kotler and Schambelan, 1999).
In recent years, a plethora of terms and nomenclature have been used by scientists, clinicians, and patient advocates to describe the syndrome and its manifestations. Any of the manifestations may be observed in men, women, and children with HIV infection who develop the syndrome. The terms describing it may be found in the peer-reviewed scientific literature, posted in discussions and reviews on the internet. The terms provided below are non-inclusive. New terms are continually added.
Terms that have been used to describe the syndrome or subsets of it include: HIV-associated dysmorphia/dysmetabolic syndrome (HADDS); HIV-associated adipose redistribution syndrome (HARS); lipodystrophy syndrome and HIV-associated lipodystrophy syndrome (HALS); HIV-related peripheral lipodyst
Applied Research Systems ARS Holding N.V.
Browdy and Neimark
Foley Shanon
Housel James
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