(WO/2008/081233) CISSUS QUADRANGULARIS PLANT EXTRACTS FOR TREATING OSTEOPOROSIS AND THE EXTRACTION PROCESS THEREOF
Cissus quadrangularis plant extracts for treating Osteoporosis and the extraction process thereof
Field of Invention
The invention relates to compositions and methods for preventing, treating, or managing osteoporosis or other related disorders such as bone loss, bone fracture, glucocorticoid induced osteoporosis, Pagets disease, osteoarthritis, peri-prosthetic osteolysis, cartilage degeneration, osteogenesis imperfecta and the like, comprising administration of a prophylactically and therapeutically effective amount of Cissus quadrangularis plant or extracts thereof to a mammal in need of such therapy. Preferably the mammal is human and the compositions comprise of single extract or a combination of extracts thereof.
The present invention further relates to extracts which are isolated from different parts of Cissus quadrangularis plant, the preparation of such extracts, the medicaments containing said extracts, and the use of these extracts and constituents for the preparation of a medicament.
The present invention also relates to the process for preparing the extracts from the whole plant of Cissus quadrangularis plant.
Background of Invention
Osteoporosis is a skeletal disorder that is characterized by low bone mass and micro- architectural deterioration of bone tissue. Affecting 200 million individuals world-wide, osteoporosis is the most common metabolic bone disorder which leads to an increased level of bone fragility and susceptibility to fracture (Walker-bone, et al. 2002; Lin and Lane, 2004).
A. Classification of Osteoporosis
Based on its etiology, osteoporosis is categorized as a primary or secondary disease. The latter involves the onset of osteoporosis as a result of an existing condition such as an endocrine disorder, the use of certain medications, a hematopoietic disorder, immobilization, or a nutritional, gastrointestinal or connective tissue disorder (Lin and Lane, 2004). Primary osteoporosis is further subdivided into two types. Type I generally occurs in postmenopausal women and is attributed to loss of gonadal hormone function, such as estrogen deficiency associated with menopause (Lin and Lane, 2004; Simon, 2004). Type II osteoporosis generally called as senile osteoporosis is age-related, affecting both men and women over the age of 60. (Lin and Lane 2004) Through the assessment of bone mineral density (BMD; in g/cm 2) using dual energy x-ray absorptiometry (DEXA), the World Health Organization has defined osteoporosis as a BMD more than 2.5 standard deviations below the mean of normal, healthy individuals at their peak bone mass (Lin and Lane, 2004; Simon, 2004; Christodoulou and Cooper, 2003).
B. Normal and Abnormal Bone Remodeling
Through regulation by sywhole plantic hormones, including vitamin D, growth hormone (GH) and parathyroid hormone (PTH), as well as local signaling through cytokines and growth factors, bone undergoes continuous remodeling even after complete skeletal growth has been attained. Bone remodeling occurs at specific sites on the bone surface known as basic multicellular units and is carried out by osteoclasts (bone resorption cells) and osteoblasts (bone formation cells) (Tolstoi 2004, Manolagas and Weinstein, 1999). Both osteoblasts and osteoclasts are derived from precursors originating in the bone marrow and the formation and activation of these cells is regulated by cytokines and growth factors also produced in the bone marrow, which are in turn controlled by sywhole plantic factors and mechanical stimuli (Manolagas and Weinstein 1999). The bone remodeling cycle is highly dependent on a- delicate balance between regulatory
signaling and cellular activity. Loss of the capacity to recruit active osteoblasts or deactivate osteoclasts results in a net bone loss and can lead to the onset of osteoporosis.
//Z The Etiology of Osteoporosis
Although numerous risk factors have been identified to increase the likelihood of developing this disease, including Caucasian race, advanced age, female gender, history of fracture, smoking and alcoholism, the exact cause of osteoporosis has not yet been identified. Despite this, numerous theories have been proposed in an attempt to explain its etiology. Some theories regarding the etiology of osteoarthritis include bone cell senescence, lifestyle factors (primarily exercise and nutrition) and loss of vitamin D metabolism with age (Tsai, et al., 1984). The latter hypothesis infers that aging leads to an impaired metabolism of vitamin D. Activated vitamin D is a signaling molecule that is largely involved in the regulation of intestinal calcium absorption Tsai, et al., 1984). Therefore, poor vitamin D metabolism leads to a decrease in intestinal calcium absorption and results in PTH signaling, by the endocrine sywhole plant, to withdraw calcium from the bones. Over time, this continuous removal of calcium from the bones leads to decreased bone mass and development of osteoporosis.
IV. Treatment
There are different types of drugs used to treat osteoporosis: antiresorptive drugs, which slow the progressive thinning of bone, bone forming drugs which help to rebuild the skeleton, and drugs with a more complex mechanism of action. In addition to drug therapy, calcium and vitamin D supplements might also be prescribed to ensure adequate intake and to ensure maximum effectiveness of the drug therapy.
Bisphosphonates inhibit bone resorption. They are currently the first choice of treatment in a variety of bone metabolism disorders characterised by high bone resorption.
Selective estrogen receptor modulators (SERMS) mimic estrogens in some tissues and anti-estrogens in others, and ideally provide the bone-retaining effects of estrogen without its unwanted side effects. Currently, the only marketed SERM is raloxifene. Raloxifene prevents bone loss and is indicated for the prevention and treatment of vertebral fractures in postmenopausal women.
A new drug has been approved for the treatment of osteoporosis - this time one that improves bone formation, as opposed to the action of available drugs that is usually the prevention or slowing bone resorption. It is teriparatide, a 34-amino-acid polypeptide produced by a recombinant DNA technique, which represents the biologically active part of human parathyroid hormone. It has to be given once daily by subcutaneous injection. They treat osteoporosis by stimulating bone-forming cells called osteoblasts. It has a dramatic effect on bone, increasing bone mineral density in the spine by as much as 13% in 18 months and reducing the risk of fracture by as much as 90%. The reason that patients are not using this drug is "cost". Forteo costs about $600 a month, and it also must be injected every day. For those reasons, it's generally only prescribed for patients with severe osteoporosis, or who have already had one or more fractures.
A nutritional approach would be an inexpensive means to achieve this goal. However, the effects of the nutritional strategies recommended today are rather modest. Thus, research into novel nutritional strategies preventing bone loss and improving bone formation is needed.
Cissus quadrangularis is an indigenous medicinal plant of India. The use of this plant by the common folk for promoting fracture-healing process is an old practice-. It has been prescribed in ancient Ayurvedic texts by Bhava Prakash and Chakra Dutta as a general tonic especially for the fractured patient. Since then it has been in extensive use by bonesetters both for external application and as an internal medicine to be taken with milk. The stem of Cissus quadrangularis is also reputed in Ayurveda as alterative, anthelmintic, dyspeptic, digestive, tonic, analgesic in eye and ear diseases, in the treatment of irregular menstruation and asthma, and in complaints of the back and spine.
Scientific studies have revealed the Cissus extract to possess cardiotonic and androgenic property.
Cissus quadrangularis contains high amount of vitamin C, carotene A, anabolic steroidal substances and calcium. These anabolic steroidal principles from Cissus quadrangularis showed a marked influence in the rate of fracture- healing by influencing early regeneration of all connective tissues of mesenchyma origin, namely the fibroblasts, the chondroblasts and osteoblasts involved in the healing and quicker mineralization of the callus. It has greater impact on osteoblastic proliferation than other cellular responses.
Cissus quadrangularis causes less amount of tissue reaction in the fractured region leading to optimum decalcification in the early stage with minimum of callus formation. Hence deposition of calcium is just enough to join the two broken segments of bone so that it's remodeling takes much faster. This early completion of calcification process and earlier remodeling phenomenon lead to early recovery of Cissus treated animals. Cissus is also shown to cause early gain in the tensile strength of fractured bones of about 90 per cent of its normal strength at the end of 6 week. Cissus quadrangularis builds up the chemical composition of the fractured bone namely its mucopolysaccharides, collagen, calcium, phosphorus and others as well as its functional efficiency. Mucopolysaccharides play an important role in the healing by supplying raw materials for repairs. Therefore it seems that in the early period of bone fracture healing the greater the accumulation of these materials more rapid will be the rate of healing. Rapid the utilization of these raw materials earlier will be completion of healing process. Cissus quadrangualris not only causes the greater accumulation of mucopolysaccharides but also an earlier disappearance of mucopolysaccharides from the fractured area, associated with the earlier calcification and firmer callus formation.
In clinical trials Cissus quadrangularis as per radiological and clinical observations has been found to cause considerable reduction in the healing time of fractures by 55-33 percent. In few of the treated cases, although radiologically only, an early callus formation was observed but clinically the symptoms of fracture such as pain, tenderness, and swelling were significantly absent.
Cissus quadrangularis is shown to neutralize the anti-anabolic effect of steroids like cortisone in' healing of fractures. Antianabolic effects of cortisone include inhibition of tissue regeneration and repair, also retarding formation of the specific skeletal structures. In such conditions even if the cartilage tissue is produced, its maturation and ultimate bone replacement do not take place in the normal pattern. It has main inhibitory action on fibroblasts and mast cells, which produce mucopolysaccharides of connective tissue. There have been reports that continuous intake of corticosteroids induces osteoporosis and pseudofractures in the bone.
Imbalance in the activities of osteoclasts (cells responsible for bone loss) and osteoblasts (cells responsible for bone formation) may lead to osteoporosis and fractures in postmenopausal women. In osteoporosis, the bones begin to deteriorate due to calcium deficiency as a result of the body's efficiency in maintaining mineral balance in the blood at the expense of bone integrity. During menopause the decrease in hormones affects the body's ability to maintain calcium levels resulting in an increased loss of minerals from the bones. Postmenopausal women are at particular risk to osteoporosis because the loss of estrogen associated with the menopause leads to bone loss of much greater magnitude than one would expect on the basis of age alone. Cissus quadrangularis with significant ability to inhibit antianabolic effects and bone fracture healing effects is likely to exert some beneficial effects on recovery of bone mineral density in postmenopausal osteoporosis.
In the light of its traditional use in bone healing and scientific evidence, this species appears to be a promising candidate for the antiosteoporotic activity.
Summary of the Invention....
