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<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Chloroquine and can you explain it in depth? [/INST] Chloroquine is a medication primarily used to prevent and treat malaria in areas where malaria remains sensitive to its effects. Certain types of malaria, resistant strains, and complicated cases typically require different or additional medication. Chloroquine is also occasionally used for amebiasis that is occurring outside the intestines, rheumatoid arthritis, and lupus erythematosus. While it has not been formally studied in pregnancy, it appears safe. It was studied to treat COVID-19 early in the pandemic, but these studies were largely halted in the summer of 2020, and is not recommended for this purpose. It is taken by mouth.Common side effects include muscle problems, loss of appetite, diarrhea, and skin rash. Serious side effects include problems with vision, muscle damage, seizures, and low blood cell levels. Chloroquine is a member of the drug class 4-aminoquinoline. As an antimalarial, it works against the asexual form of the malaria parasite in the stage of its life cycle within the red blood cell. How it works in rheumatoid arthritis and lupus erythematosus is unclear.Chloroquine was discovered in 1934 by Hans Andersag. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication.

Medical uses
Malaria
Chloroquine has been used in the treatment and prevention of malaria from Plasmodium vivax, P. ovale, and P. malariae. It is generally not used for Plasmodium falciparum as there is widespread resistance to it.Chloroquine has been extensively used in mass drug administrations, which may have contributed to the emergence and spread of resistance. It is recommended to check if chloroquine is still effective in the region prior to using it. In areas where resistance is present, other antimalarials, such as mefloquine or atovaquone, may be used instead. The Centers for Disease Control and Prevention recommend against treatment of malaria with chloroquine alone due to more effective combinations.

Amebiasis
In treatment of amoebic liver abscess, chloroquine may be used instead of or in addition to other medications in the event of failure of improvement with metronidazole or another nitroimidazole within 5 days or intolerance to metronidazole or a nitroimidazole.

Rheumatic disease
As it mildly suppresses the immune system, chloroquine is used in some autoimmune disorders, such as rheumatoid arthritis and has an off label indication for lupus erythematosus.

Side effects
Side effects include blurred vision, nausea, vomiting, abdominal cramps, headache, diarrhea, swelling legs/ankles, shortness of breath, pale lips/nails/skin, muscle weakness, easy bruising/bleeding, hearing and mental problems.
Unwanted/uncontrolled movements (including tongue and face twitching)
Deafness or tinnitus.
Nausea, vomiting, diarrhea, abdominal cramps
Headache.
Mental/mood changes (such as confusion, personality changes, unusual thoughts/behavior, depression, feeling being watched, hallucinating)
Signs of serious infection (such as high fever, severe chills, persistent sore throat)
Skin itchiness, skin color changes, hair loss, and skin rashes.Chloroquine-induced itching is very common among black Africans (70%), but much less common in other races. It increases with age, and is so severe as to stop compliance with drug therapy. It is increased during malaria fever; its severity is correlated to the malaria parasite load in blood. Some evidence indicates it has a genetic basis and is related to chloroquine action with opiate receptors centrally or peripherally.
Unpleasant metallic taste
This could be avoided by "taste-masked and controlled release" formulations such as multiple emulsions.
Chloroquine retinopathy
Electrocardiographic changesThis manifests itself as either conduction disturbances (bundle-branch block, atrioventricular block) or Cardiomyopathy – often with hypertrophy, restrictive physiology, and congestive heart failure. The changes may be irreversible. Only two cases have been reported requiring heart transplantation, suggesting this particular risk is very low. Electron microscopy of cardiac biopsies show pathognomonic cytoplasmic inclusion bodies.
Pancytopenia, aplastic anemia, reversible agranulocytosis, low blood platelets, neutropenia.

Pregnancy
Chloroquine has not been shown to have any harmful effects on the fetus when used in the recommended doses for malarial prophylaxis. Small amounts of chloroquine are excreted in the breast milk of lactating women. However, this drug can be safely prescribed to infants, the effects are not harmful. Studies with mice show that radioactively tagged chloroquine passed through the placenta rapidly and accumulated in the fetal eyes which remained present five months after the drug was cleared from the rest of the body. Women who are pregnant or planning on getting pregnant are still advised against traveling to malaria-risk regions.

Elderly
There is not enough evidence to determine whether chloroquine is safe to be given to people aged 65 and older. Since it is cleared by the kidneys, toxicity should be monitored carefully in people with poor kidney functions.

Drug interactions
Chloroquine has a number of drug–drug interactions that might be of clinical concern:
Ampicillin- levels may be reduced by chloroquine;
Antacids- may reduce absorption of chloroquine;
Cimetidine- may inhibit metabolism of chloroquine; increasing levels of chloroquine in the body;
Cyclosporine- levels may be increased by chloroquine; and
Mefloquine- may increase risk of convulsions.

Overdose
Chloroquine, in overdose, has a risk of death of about 20%. It is rapidly absorbed from the gut with an onset of symptoms generally within an hour. Symptoms of overdose may include sleepiness, vision changes, seizures, stopping of breathing, and heart problems such as ventricular fibrillation and low blood pressure. Low blood potassium may also occur.While the usual dose of chloroquine used in treatment is 10 mg/kg, toxicity begins to occur at 20 mg/kg, and death may occur at 30 mg/kg. In children as little as a single tablet can cause problems.Treatment recommendations include early mechanical ventilation, cardiac monitoring, and activated charcoal. Intravenous fluids and vasopressors may be required with epinephrine being the vasopressor of choice. Seizures may be treated with benzodiazepines. Intravenous potassium chloride may be required, however this may result in high blood potassium later in the course of the disease. Dialysis has not been found to be useful.

Pharmacology
Absorption of chloroquine is rapid and primarily happens in the gastrointestinal tract. It is widely distributed in body tissues. Protein binding in plasma ranges from 46% to 79%. Its metabolism is partially hepatic, giving rise to its main metabolite, desethylchloroquine. Its excretion is ≥50% as unchanged drug in urine, where acidification of urine increases its elimination. It has a very high volume of distribution, as it diffuses into the bodys adipose tissue.Accumulation of the drug may result in deposits that can lead to blurred vision and blindness. It and related quinines have been associated with cases of retinal toxicity, particularly when provided at higher doses for longer times. With long-term doses, routine visits to an ophthalmologist are recommended.Chloroquine is also a lysosomotropic agent, meaning it accumulates preferentially in the lysosomes of cells in the body. The pKa for the quinoline nitrogen of chloroquine is 8.5, meaning it is about 10% deprotonated at physiological pH (per the Henderson-Hasselbalch equation). This decreases to about 0.2% at a lysosomal pH of 4.6. Because the deprotonated form is more membrane-permeable than the protonated form, a quantitative "trapping" of the compound in lysosomes results.

Mechanism of action
Malaria
The lysosomotropic character of chloroquine is believed to account for much of its antimalarial activity; the drug concentrates in the acidic food vacuole of the parasite and interferes with essential processes. Its lysosomotropic properties further allow for its use for in vitro experiments pertaining to intracellular lipid related diseases, autophagy, and apoptosis.Inside red blood cells, the malarial parasite, which is then in its asexual lifecycle stage, must degrade hemoglobin to acquire essential amino acids, which the parasite requires to construct its own protein and for energy metabolism. Digestion is carried out in a vacuole of the parasitic cell.Hemoglobin is composed of a protein unit (digested by the parasite) and a heme unit (not used by the parasite). During this process, the parasite releases the toxic and soluble molecule heme. The heme moiety consists of a porphyrin ring called Fe(II)-protoporphyrin IX (FP). To avoid destruction by this molecule, the parasite biocrystallizes heme to form hemozoin, a nontoxic molecule. Hemozoin collects in the digestive vacuole as insoluble crystals.Chloroquine enters the red blood cell by simple diffusion, inhibiting the parasite cell and digestive vacuole. Chloroquine then becomes protonated (to CQ2+), as the digestive vacuole is known to be acidic (pH 4.7); chloroquine then cannot leave by diffusion. Chloroquine caps hemozoin molecules to prevent further biocrystallization of heme, thus leading to heme buildup. Chloroquine binds to heme (or FP) to form the FP-chloroquine complex; this complex is highly toxic to the cell and disrupts membrane function. Action of the toxic FP-chloroquine and FP results in cell lysis and ultimately parasite cell autodigestion. Parasites that do not form hemozoin are therefore resistant to chloroquine.

Resistance in malaria
Since the first documentation of P. falciparum chloroquine resistance in the 1950s, resistant strains have appeared throughout East and West Africa, Southeast Asia, and South America. The effectiveness of chloroquine against P. falciparum has declined as resistant strains of the parasite evolved.
Resistant parasites are able to rapidly remove chloroquine from the digestive vacuole using a transmembrane pump. Chloroquine-resistant parasites pump chloroquine out at 40 times the rate of chloroquine-sensitive parasites; the pump is coded by the P. falciparum chloroquine resistance transporter (PfCRT) gene. The natural function of the chloroquine pump is to transport peptides: mutations to the pump that allow it to pump chloroquine out impairs its function as a peptide pump and comes at a cost to the parasite, making it less fit.Resistant parasites also frequently have mutation in the ABC transporter P. falciparum multidrug resistance (PfMDR1) gene, although these mutations are thought to be of secondary importance compared to PfCRT. An altered chloroquine-transporter protein, CG2 has been associated with chloroquine resistance, but other mechanisms of resistance also appear to be involved.Verapamil, a Ca2+ channel blocker, has been found to restore both the chloroquine concentration ability and sensitivity to this drug. Other agents which have been shown to reverse chloroquine resistance in malaria are chlorpheniramine, gefitinib, imatinib, tariquidar and zosuquidar.As of 2014 chloroquine is still effective against poultry malaria in Thailand. Sohsuebngarm et al. 2014 test P. gallinaceum at Chulalongkorn University and find the parasite is not resistant.: 1237  Sertraline, fluoxetine and paroxetine reverse chloroquine resistance, making resistant biotypes susceptible if used in a cotreatment.

Antiviral
Chloroquine has antiviral effects against some viruses. It increases late endosomal and lysosomal pH, resulting in impaired release of the virus from the endosome or lysosome – release of the virus requires a low pH. The virus is therefore unable to release its genetic material into the cell and replicate.Chloroquine also seems to act as a zinc ionophore that allows extracellular zinc to enter the cell and inhibit viral RNA-dependent RNA polymerase.

Other
Chloroquine inhibits thiamine uptake. It acts specifically on the transporter SLC19A3.
Against rheumatoid arthritis, it operates by inhibiting lymphocyte proliferation, phospholipase A2, antigen presentation in dendritic cells, release of enzymes from lysosomes, release of reactive oxygen species from macrophages, and production of IL-1.

History
In Peru, the indigenous people extracted the bark of the Cinchona tree (Cinchona officinalis) and used the extract to fight chills and fever in the seventeenth century. In 1633 this herbal medicine was introduced in Europe, where it was given the same use and also began to be used against malaria. The quinoline antimalarial drug quinine was isolated from the extract in 1820.: 130–131 After World War I, the German government sought alternatives to quinine. Chloroquine, a synthetic analogue with the same mechanism of action was discovered in 1934, by Hans Andersag and coworkers at the Bayer laboratories, who named it Resochin. It was ignored for a decade, because it was considered too toxic for human use. Instead, in World War II, the German Africa Corps used the chloroquine analogue 3-methyl-chloroquine, known as Sontochin. After Allied forces arrived in Tunis, Sontochin fell into the hands of Americans, who sent the material back to the United States for analysis, leading to renewed interest in chloroquine.  United States government-sponsored clinical trials for antimalarial drug development showed unequivocally that chloroquine has a significant therapeutic value as an antimalarial drug.: 61–66  It was introduced into clinical practice in 1947 for the prophylactic treatment of malaria.

Chemical synthesis
The first synthesis of chloroquine was disclosed in a patent filed by IG Farben in 1937. In the final step, 4,7-dichloroquinoline was reacted with 1-diethylamino-4-aminopentane.

By 1949, chloroquine manufacturing processes had been established to allow its widespread use.

Society and culture
Formulations
Chloroquine comes in tablet form as the phosphate, sulfate, and hydrochloride salts. Chloroquine is usually dispensed as the phosphate.

Names
Brand names include Chloroquine FNA, Resochin, Dawaquin, and Lariago.

Other animals
Chloroquine, in various chemical forms, is used to treat and control surface growth of anemones and algae, and many protozoan infections in aquariums, e.g. the fish parasite Amyloodinium ocellatum </s>


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<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Hormone replacement therapy and can you explain it in depth? [/INST] Hormone replacement therapy (HRT), also known as menopausal hormone therapy or postmenopausal hormone therapy, is a form of hormone therapy used to treat symptoms associated with female menopause. These symptoms can include hot flashes, vaginal atrophy, accelerated skin aging, vaginal dryness, decreased muscle mass, sexual dysfunction, and bone loss. They are in large part related to the diminished levels of sex hormones that occur during menopause.Estrogens and progestogens are the main hormone drugs used in HRT. Progesterone is the main female sex hormone that occurs naturally and is also manufactured into a drug that is used in menopausal hormone therapy. Although both classes of hormones can have symptomatic benefit, progestogen is specifically added to estrogen regimens when the uterus is present to avoid the increased risk of endometrial cancer. Unopposed estrogen therapy promotes endometrial hyperplasia and increases the risk of cancer, while progestogen reduces this risk. Androgens like testosterone are sometimes used as well. HRT is available through a variety of different routes.The long-term effects of HRT on most organ systems vary by age and time since the last physiological exposure to hormones, and there can be large differences in individual regimens, factors which have made analyzing effects difficult. The Womens Health Initiative (WHI) is an ongoing study of over 27,000 women that began in 1991, with the most recent analyses suggesting that, when initiated within 10 years of menopause, HRT reduces all-cause mortality and risks of coronary disease, osteoporosis, and dementia; after 10 years the beneficial effects on mortality and coronary heart disease are no longer apparent, though there are decreased risks of hip and vertebral fractures and an increased risk of venous thromboembolism when taken orally."Bioidentical" hormone replacement is a development in the 21st century and uses manufactured compounds with "exactly the same chemical and molecular structure as hormones that are produced in the human body." These are mainly steroids derived from plants and can be a component of either registered pharmaceutical or custom-made compounded preparations, with the latter generally not recommended by regulatory bodies due to their lack of standardization and formal oversight. Bioidentical hormone replacement has inadequate clinical research to determine its safety and efficacy as of 2017.The current indications for use from the United States Food and Drug Administration (FDA) include short-term treatment of menopausal symptoms, such as vasomotor hot flashes or vaginal atrophy, and prevention of osteoporosis.

Medical uses
Approved uses of HRT in the United States include short-term treatment of menopausal symptoms such as hot flashes and vaginal atrophy, and prevention of osteoporosis. The American College of Obstetrics and Gynecology (ACOG) approves of HRT for symptomatic relief of menopausal symptoms, and advocates its use beyond the age of 65 in appropriate scenarios. The North American Menopause Society (NAMS) 2016 annual meeting mentioned that HRT may have more benefits than risks in women before the age of 60.A consensus expert opinion published by The Endocrine Society stated that when taken during perimenopause or the initial years of menopause, HRT carries fewer risks than previously published, and reduces all cause mortality in most scenarios. The American Association of Clinical Endocrinologists (AACE) has also released position statements approving of HRT when appropriate.Women receiving this treatment are usually post-, peri-, or surgically menopausal. Menopause is the permanent cessation of menstruation resulting from loss of ovarian follicular activity, defined as beginning twelve months after the final natural menstrual cycle. This twelve month time point divides menopause into early and late transition periods known as perimenopause and postmenopause. Premature menopause can occur if the ovaries are surgically removed, as can be done to treat ovarian or uterine cancer.
Demographically, the vast majority of data available is in postmenopausal American women with concurrent pre-existing conditions and an average age of over 60 years.

Menopausal symptoms
HRT is often given as a short-term relief from menopausal symptoms during perimenopause. Potential menopausal symptoms include:
Hot flashes – vasomotor symptoms
Vulvovaginal atrophy – atrophic vaginitis and dryness
Dyspareunia – painful sexual intercourse due to vaginal atrophy and lack of lubrication
Bone loss – decreased bone mineral density, which can eventually lead to osteopenia, osteoporosis, and associated fractures
Decreased sexual desire
Defeminization – diminished feminine fat distribution and accelerated skin aging
Sleep disturbances and joint painThe most common of these are loss of sexual drive and vaginal dryness.

Heart disease
The effect of HRT in menopause appears to be divergent, with lower risk of heart disease when started within five years, but no impact after ten. There may be an increase in heart disease if HRT is given twenty years post-menopause. This variability has led some reviews to suggest an absence of significant effect on morbidity. Importantly, there is no difference in long-term mortality from HRT, regardless of age.A Cochrane review suggested that women starting HRT less than 10 years after menopause had lower mortality and coronary heart disease, without any strong effect on the risk of stroke and pulmonary embolism. Those starting therapy more than 10 years after menopause showed little effect on mortality and coronary heart disease, but an increased risk of stroke. Both therapies had an association with venous clots and pulmonary embolism.HRT with estrogen and progesterone also improves cholesterol levels. With menopause, HDL decreases, while LDL, triglycerides and lipoprotein a increase, patterns that reverse with estrogen. Beyond this, HRT improves heart contraction, coronary blood flow, sugar metabolism, and decreases platelet aggregation and plaque formation. HRT may promote reverse cholesterol transport through induction of cholesterol ABC transporters. HRT also results in a large reduction in the pro-thrombotic lipoprotein a. Studies on cardiovascular disease with testosterone therapy have been mixed, with some suggesting no effect or a mild negative effect, though others have shown an improvement in surrogate markers such as cholesterol, triglycerides and weight. Testosterone has a positive effect on vascular endothelial function and tone with observational studies suggesting that women with lower testosterone may be at greater risk for heart disease. Available studies are limited by small sample size and study design. Low sex hormone binding globulin, which occurs with menopause, is associate with increased body mass index and risk for type 2 diabetes.

Blood clots
Effects of hormone replacement therapy on venous blood clot formation and potential for pulmonary embolism may vary with different estrogen and progestogen therapies, and with different doses or method of use. Comparisons between routes of administration suggest that when estrogens are applied to the skin or vagina, there is a lower risk of blood clots, whereas when used orally, the risk of blood clots and pulmonary embolism is increased. Skin and vaginal routes of hormone therapy are not subject to first pass metabolism, and so lack the anabolic effects that oral therapy has on liver synthesis of vitamin K-dependent clotting factors, possibly explaining why oral therapy may increase blood clot formation.While a 2018 review found that taking progesterone and estrogen together can decrease this risk, other reviews reported an increased risk of blood clots and pulmonary embolism when estrogen and progestogen were combined, particularly when treatment was started 10 years or more after menopause and when the women were older than 60 years.The risk of venous thromboembolism may be reduced with bioidentical preparations, though research on this is only preliminary.

Stroke
Multiple studies suggest that the possibility of HRT related stroke is absent if therapy is started within five years of menopause, and that the association is absent or even preventive when given by non-oral routes. Ischemic stroke risk was increased during the time of intervention in the WHI, with no significant effect after the cessation of therapy and no difference in mortality at long term follow up. When oral synthetic estrogen or combined estrogen-progestogen treatment is delayed until five years from menopause, cohort studies in Swedish women have suggested an association with hemorrhagic and ischemic stroke. Another large cohort of Danish women suggested that the specific route of administration was important, finding that although oral estrogen increased risk of stroke, absorption through the skin had no impact, and vaginal estrogen actually had a decreased risk.

Endometrial cancer
In postmenopausal women, continuous combined estrogen plus progestin decreases endometrial cancer incidence. The duration of progestogen therapy should be at least 14 days per cycle to prevent endometrial disease.Endometrial cancer has been grouped into two forms in the context of hormone replacement. Type 1 is the most common, can be associated with estrogen therapy, and is usually low grade. Type 2 is not related to estrogen stimulation and usually higher grade and poorer in prognosis. The endometrial hyperplasia that leads to endometrial cancer with estrogen therapy can be prevented by concomitant administration of progestogen. The extensive use of high-dose estrogens for birth control in the 1970s is thought to have resulted in a significant increase in the incidence of type 1 endometrial cancer.Paradoxically, progestogens do promote the growth of uterine fibroids, and a pelvic ultrasound can be performed before beginning HRT to make sure there are no underlying uterine or endometrial lesions.Androgens do not stimulate endometrial proliferation in post menopausal women, and appear to inhibit the proliferation induced by estrogen to a certain extent.There is insufficient high‐quality evidence to inform women considering hormone replacement therapy after treatment for endometrial cancer.

Breast cancer
Studies regarding the association of breast cancer with hormone replacement are inconsistent and vary with type of replacement and time since menopause. While some evaluations suggest an increased risk, in others it is decreased. This inconsistency of effect has been suggested to imply a lack of meaningful impact of HRT on breast cancer risk.There is a non-statistically significant increased rate of breast cancer for hormone replacement therapy with synthetic progesterone. The risk may be reduced with bioidentical progesterone, though the only prospective study that suggested this was underpowered due to the rarity of breast cancer in the control population. There have been no randomized controlled trials as of 2018. The relative risk of breast cancer also varies depending on the interval between menopause and HRT and route of synthetic progestin administration.The most recent follow up of the Womens Health Initiative participants demonstrated a lower incidence of breast cancer in post-hysterectomy participants taking equine estrogen alone, though the relative risk was increased if estrogen was taken with medroxy-progesterone. Estrogen is usually only given alone in the setting of a hysterectomy due to the increased risk of vaginal bleeding and uterine cancer with unopposed estrogen.HRT has been more strongly associated with risk of breast cancer in women with lower body mass indices (BMIs). No breast cancer association has been found with BMIs of over 25. It has been suggested by some that the absence of significant effect in some of these studies could be due to selective prescription to overweight women who have higher baseline estrone, or to the very low progesterone serum levels after oral administration leading to a high tumor inactivation rate.Evaluating the response of breast tissue density to HRT using mammography appears to help assessing the degree of breast cancer risk associated with therapy; women with dense or mixed-dense breast tissue have a higher risk of developing breast cancer than those with low density tissue.Micronized progesterone does not appear to be associated with breast cancer risk when used for less than five years with limited data suggesting an increased risk when used for longer duration.A retrospective Cox proportional hazards analysis from Richard Neapolitan endorsed the reduced risk breast cancer with conjugated equine estrogen usage alone, but also suggested that conjugated equine estrogen with medroxyprogesterone acetate was associated with a risk reduction in breast cancer and that bioidentical hormone therapy was not associated with a statistically significant effect. There have been no prospective randomized clinical trials comparing the two routes of administration with regards to breast cancer.For women who previously have had breast cancer, it is recommended to first consider other options for menopausal effects, such as bisphosphonates or selective estrogen receptor modulators (SERMs) for osteoporosis, cholesterol-lowering agents and aspirin for cardiovascular disease, and vaginal estrogen for local symptoms. Observational studies of systemic HRT after breast cancer are generally reassuring. If HRT is necessary after breast cancer, estrogen-only therapy or estrogen therapy with a progestogen may be safer options than combined systemic therapy. In women who are BRCA1 or BRCA2 mutation carriers, HRT does not appear to impact breast cancer risk. The relative number of women using HRT who also obtain regular screening mammograms is higher than that in women who do not use HRT, a factor which has been suggested as contributing to different breast cancer detection rates in the two groups.With androgen therapy, pre-clinical studies have suggested an inhibitory effect on breast tissue though the majority of epidemiological studies suggest a positive association.

Ovarian cancer
HRT is associated with an increased risk of ovarian cancer, with women using HRT having about one additional case of ovarian cancer per 1,000 users. This risk is decreased when progestogen therapy is given concomitantly, as opposed to estrogen alone, and also decreases with increasing time since stopping HRT. Regarding the specific subtype, there may be a higher risk of serous cancer, but no association with clear cell, endometrioid, or mucinous ovarian cancer. Hormonal therapy in ovarian cancer survivors after surgical removal of the ovaries is generally thought to improval survival rates.

Other malignancies
Colorectal cancer
In the WHI, women who took combined estrogen-progesterone therapy had a lower risk of getting colorectal cancer. However, the cancers they did have were more likely to have spread to lymph nodes or distant sites than colorectal cancer in women not taking hormones. In colorectal cancer survivors, usage of HRT is thought to lead to lower recurrence risk and overall mortality.

Cervical cancer
There appears to be a significantly decreased risk of cervical squamous cell cancer in post menopausal women treated with HRT and a weak increase in adenocarcinoma. No studies have reported an increased risk of recurrence when HRT is used with cervical cancer survivors.

Sexual function
HRT can help with the lack of sexual desire and sexual dysfunction that can occur with menopause. Epidemiological surveys of women between 40 and 69 years suggest that 75% of women remain sexually active after menopause. With increasing life spans, women today are living one third or more of their lives in a postmenopausal state, a period during which healthy sexuality can be integral to their quality of life.Decreased libido and sexual dysfunction are common issues in postmenopausal women, an entity referred to hypoactive sexual desire disorder (HSDD); its signs and symptoms can both be improved by HRT. Several hormonal changes take place during this period, including a decrease in estrogen and an increase in follicle-stimulating hormone. For most women, the majority of change occurs during the late perimenopausal and postmenopausal stages. Decreases in sex hormone-binding globulin (SHBG) and inhibin (A and B) also occur. Testosterone is present in women at a lower level than men, peaking at age 30 and declining gradually with age; there is less variation during the menopausal transition relative to estrogen and progesterone.A global consensus position statement has advised that postmenopausal testosterone replacement to premenopausal levels can be effective for HSDD. Safety information for testosterone treatment is not available beyond two years of continuous therapy however and dosing above physiologic levels is not advised. Testosterone patches have been found to restore sexual desire in post menopausal women. There is insufficient data to evaluate the impact of testosterone replacement on heart disease, breast cancer, with most trials having included women taking concomitant estrogen and progesterone and with testosterone therapy itself being relatively short in duration. In the setting of this limited data, testosterone therapy has not been associated with adverse events.Not all women are responsive, especially those with preexisting sexual difficulties. Estrogen replacement can restore vaginal cells, pH levels, and blood flow to the vagina, all of which tend to deteriorate at the onset of menopause. Pain or discomfort with sex appears to be the most responsive component to estrogen. It also has been shown to have positive effects on the urinary tract. Estrogen can also reduce vaginal atrophy and increase sexual arousal, frequency and orgasm.The effectiveness of hormone replacement can decline in some women after long-term use. A number of studies have also found that the combined effects of estrogen/androgen replacement therapy can increase libido and arousal over estrogen alone. Tibolone, a synthetic steroid with estrogenic, androgenic, and progestogenic properties that is available in Europe, has the ability to improve mood, libido, and physical symptomatology. In various placebo-controlled studies, improvements in vasomotor symptoms, emotional response, sleep disturbances, physical symptoms, and sexual desire have been seen, though it also carries a similar risk profile to conventional HRT.

Neurodegenerative disorders
For prevention, the WHI suggested that HRT may increase risk of dementia if initiated after 65 years of age, but have a neutral outcome or be neuroprotective for those between 50 and 55 years. Other studies in perimenopause have shown HRT to be consistently associated with a lower risk of Alzheimers. With Parkinsons the majority of clinical and epidemiological studies show have demonstrated either no association or inconclusive results. A Danish study suggested an increased risk of Parkinsons with HRT in cyclical dosing schedules.With regards to treatment, randomized trials have shown that HRT improves executive and attention processes outside of the context of dementia in postmenopausal women, both in those that are asymptomatic and those with mild cognitive impairment. Estrogen replacement appears to improve motor symptoms and activities of daily living in post menopausal women with Parkinsons, with significant improvement of UPDRS scores. Clinical trials have also shown testosterone replacement to be associated with small statistically significant improvements in verbal learning and memory in postmenopausal women. DHEA has not been found to improve cognitive performance after menopause. Pre-clinical studies indicate that endogenous estrogen and testosterone are neuroprotective and can prevent brain amyloid deposition.

Muscle and bone
There is a significant decrease in hip fracture risk during treatment that to a lesser degree persists after HRT is stopped. It also helps collagen formation, which in turn improves intervertebral disc and bone strength.Hormone replacement therapy in the form of estrogen and androgen can be effective at reversing the effects of aging on muscle. Lower testosterone is associated with lower bone density and higher free testosterone is associated with lower hip fracture rates in older women. Testosterone therapy, which can be used for decreased sexual function, can also increase bone mineral density and muscle mass.

Side effects
Side effects in HRT occur with varying frequency and include:

Contraindications
The following are absolute and relative contraindications to HRT:

Absolute contraindications
Undiagnosed vaginal bleeding
Severe liver disease
Pregnancy
Severe coronary artery disease
Aggressive breast, uterine or ovarian cancer

Relative contraindications
Migraine headaches
History of breast cancer
History of ovarian cancer
Venous thrombosis
History of uterine fibroids
Atypical ductal hyperplasia of the breast
Active gallbladder disease (cholangitis, cholecystitis)
Well-differentiated and early endometrial cancer – once treatment for the malignancy is complete, is no longer an absolute contraindication.

History and research
The extraction of CEEs from the urine of pregnant mares led to the marketing in 1942 of Premarin, one of the earlier forms of estrogen to be introduced. From that time until the mid-1970s, estrogen was administered without a supplemental progestogen. Beginning in 1975, studies began to show that without a progestogen, unopposed estrogen therapy with Premarin resulted in an eight-fold increased risk of endometrial cancer, eventually causing sales of Premarin to plummet. It was recognized in the early 1980s that the addition of a progestogen to estrogen reduced this risk to the endometrium. This led to the development of combined estrogen–progestogen therapy, most commonly with a combination of conjugated equine estrogen (Premarin) and medroxyprogesterone (Provera).

Trials
The Womens Health Initiative trials were conducted between 1991 and 2006 and were the first large, double-blind, placebo-controlled clinical trials of HRT in healthy women. Their results were both positive and negative, suggesting that during the time of hormone therapy itself, there are increases in invasive breast cancer, stroke and lung clots. Other risks include increased endometrial cancer, gallbladder disease, and urinary incontinence, while benefits include decreased hip fractures, decreased incidence of diabetes, and improvement of vasomotor symptoms. There is also an increased risk of dementia with HRT in women over 65, though at younger ages it appears to be neuroprotective. After the cessation of HRT, the WHI continued to observe its participants, and found that most of these risks and benefits dissipated, though some elevation in breast cancer risk did persist. Other studies have also suggested an increased risk of ovarian cancer.The arm of the WHI receiving combined estrogen and progestin therapy was closed prematurely in 2002 by its Data Monitoring Committee (DMC) due to perceived health risks, though this occurred a full year after the data suggesting increased risk became manifest. In 2004, the arm of the WHI in which post-hysterectomy patients were being treated with estrogen alone was also closed by the DMC. Clinical medical practice changed based upon two parallel Womens Health Initiative (WHI) studies of HRT. Prior studies were smaller, and many were of women who electively took hormonal therapy. One portion of the parallel studies followed over 16,000 women for an average of 5.2 years, half of whom took placebo, while the other half took a combination of CEEs and MPA (Prempro). This WHI estrogen-plus-progestin trial was stopped prematurely in 2002 because preliminary results suggested risks of combined CEEs and progestins exceeded their benefits. The first report on the halted WHI estrogen-plus-progestin study came out in July 2002.Initial data from the WHI in 2002 suggested mortality to be lower when HRT was begun earlier, between age 50 to 59, but higher when begun after age 60. In older patients, there was an apparent increased incidence of breast cancer, heart attacks, venous thrombosis, and stroke, although a reduced incidence of colorectal cancer and bone fracture. At the time, The WHI recommended that women with non-surgical menopause take the lowest feasible dose of HRT for the shortest possible time to minimize associated risks. Some of the WHI findings were again found in a larger national study done in the United Kingdom, known as the Million Women Study (MWS). As a result of these findings, the number of women taking HRT dropped precipitously. In 2012, the United States Preventive Task Force (USPSTF) concluded that the harmful effects of combined estrogen and progestin therapy likely exceeded their chronic disease prevention benefits.In 2002 when the first WHI follow up study was published, with HRT in post menopausal women, both older and younger age groups had a slightly higher incidence of breast cancer, and both heart attack and stroke were increased in older patients, although not in younger participants. Breast cancer was increased in women treated with estrogen and a progestin, but not with estrogen and progesterone or estrogen alone. Treatment with unopposed estrogen (i.e., an estrogen alone without a progestogen) is contraindicated if the uterus is still present, due to its proliferative effect on the endometrium. The WHI also found a reduced incidence of colorectal cancer when estrogen and a progestogen were used together, and most importantly, a reduced incidence of bone fractures. Ultimately, the study found disparate results for all cause mortality with HRT, finding it to be lower when HRT was begun during ages 50–59, but higher when begun after age 60. The authors of the study recommended that women with non-surgical menopause take the lowest feasible dose of hormones for the shortest time to minimize risk.The data published by the WHI suggested supplemental estrogen increased risk of venous thromboembolism and breast cancer but was protective against osteoporosis and colorectal cancer, while the impact on cardiovascular disease was mixed. These results were later supported in trials from the United Kingdom, but not in more recent studies from France and China. Genetic polymorphism appears to be associated with inter-individual variability in metabolic response to HRT in postmenopausal women.
The WHI reported statistically significant increases in rates of breast cancer, coronary heart disease, strokes and pulmonary emboli. The study also found statistically significant decreases in rates of hip fracture and colorectal cancer. "A year after the study was stopped in 2002, an article was published indicating that estrogen plus progestin also increases the risks of dementia." The conclusion of the study was that the HRT combination presented risks that outweighed its measured benefits. The results were almost universally reported as risks and problems associated with HRT in general, rather than with Prempro, the specific proprietary combination of CEEs and MPA studied.
After the increased clotting found in the first WHI results was reported in 2002, the number of Prempro prescriptions filled reduced by almost half. Following the WHI results, a large percentage of HRT users opted out of them, which was quickly followed by a sharp drop in breast cancer rates. The decrease in breast cancer rates has continued in subsequent years. An unknown number of women started taking alternatives to Prempro, such as compounded bioidentical hormones, though researchers have asserted that compounded hormones are not significantly different from conventional hormone therapy.The other portion of the parallel studies featured women who were post hysterectomy and so received either placebo progestogen or CEEs alone. This group did not show the risks demonstrated in the combination hormone study, and the estrogen-only study was not halted in 2002. However, in February 2004 it, too, was halted. While there was a 23% decreased incidence of breast cancer in the estrogen-only study participants, risks of stroke and pulmonary embolism were increased slightly, predominantly in patients who began HRT over the age of 60.Several other large studies and meta-analyses have reported reduced mortality for HRT in women younger than age 60 or within 10 years of menopause, and a debatable or absent effect on mortality in women over 60.Though research thus far has been substantial, further investigation is needed to fully understand differences in effect for different types of HRT and lengths of time since menopause.

Available forms
There are five major human steroid hormones: estrogens, progestogens, androgens, mineralocorticoids, and glucocorticoids. Estrogens and progestogens are the two most often used in menopause. They are available in a wide variety of FDA approved and non–FDA-approved formulations.In women with intact uteruses, estrogens are almost always given in combination with progestogens, as long-term unopposed estrogen therapy is associated with a markedly increased risk of endometrial hyperplasia and endometrial cancer. Conversely, in women who have undergone a hysterectomy or do not have a uterus, a progestogen is not required, and estrogen can be used alone. There are many combined formulations which include both estrogen and progestogen.
Specific types of hormone replacement include:
Estrogens – bioidentical estrogens like estradiol and estriol, animal-derived estrogens like conjugated estrogens (CEEs), and synthetic estrogens like ethinylestradiol
Progestogens – bioidentical progesterone, and progestins (synthetic progestogens) like medroxyprogesterone acetate (MPA), norethisterone, and dydrogesterone
Androgens – bioidentical testosterone and dehydroepiandrosterone (DHEA), and synthetic anabolic steroids like methyltestosterone and nandrolone decanoateTibolone – a synthetic medication available in Europe but not the United States– is more effective than placebo but less effective than combination hormone therapy in postmenopausal women. It may have a decreased risk of breast and colorectal cancer, though conversely it can be associated with vaginal bleeding, endometrial cancer, and increase the risk of stroke in women over age 60 years.Vaginal estrogen can improve local atrophy and dryness, with fewer systemic effects than estrogens delivered by other routes. Sometimes an androgen, generally testosterone, can be added to treat diminished libido.

Continuous versus cyclic
Dosage is often varied cyclically to more closely mimic the ovarian hormone cycle, with estrogens taken daily and progestogens taken for about two weeks every month or every other month, a schedule referred to as cyclic or sequentially combined. Alternatively, continuous combined HRT can be given with a constant daily hormonal dosage. Continuous combined HRT is associated with less complex endometrial hyerplasia than cyclic. Impact on breast density appears to be similar in both regimen timings.

Route of administration
The medications used in menopausal HRT are available in numerous different formulations for use by a variety of different routes of administration:
Oral administration – tablets, capsules
Transdermal administration – patches, gels, creams
Vaginal administration – tablets, creams, suppositories, rings
Intramuscular or subcutaneous injection – solutions in vials or ampoules
Subcutaneous implant – surgically-inserted pellets placed into fat tissue
Less commonly sublingual, buccal, intranasal, and rectal administration, as well as intrauterine devicesMore recently developed forms of drug delivery are alleged to have increased local effect lower dosing, fewer side effects, and constant rather than cyclical serum hormone levels. Transdermal and vaginal estrogen, in particular, avoid first pass metabolism through the liver. This in turn prevents an increase in clotting factors and accumulation of anti-estrogenic metabolites, resulting in fewer adverse side effects, particularly with regard to cardiovascular disease and stroke.Injectable forms of estradiol are no longer recommended in menopausal hormone therapy due to the availability of other formulations.

Bioidentical hormone therapy
Bioidentical hormone therapy (BHT) is the usage of hormones that are chemically identical to those produced in the body. Although proponents of BHT claim advantages over non-bioidentical or conventional hormone therapy, the FDA does not recognize the term bioidentical hormone, stating there is no scientific evidence that these hormones are identical to their naturally occurring counterparts. There are, however, FDA approved products containing hormones classified as bioidentical.Bioidentical hormones can be used in either pharmaceutical or compounded preparations, with the latter generally not recommended by regulatory bodies due to their lack of standardization and regulatory oversight. Most classifications of bioidentical hormones do not take into account manufacturing, source, or delivery method of the products, and so describe both non-FDA approved compounded products and FDA approved pharmaceuticals as bioidentical. The British Menopause Society has issued a consensus statement endorsing the distinction between "compounded" forms (cBHRT), described as unregulated, custom made by specialty pharmacies and subject to heavy marketing and "regulated" pharmaceutical grade forms (rBHRT), which undergo formal oversight by entities such as the FDA and form the basis of most clinical trials. Some practitioners recommending compounded bioidentical HRT also use salivary or serum hormonal testing to monitor response to therapy, a practice not endorsed by current clinical guidelines in the United States and Europe.Bioidentical hormones in pharmaceuticals may have very limited clinical data, with no randomized controlled prospective trials to date comparing them to their animal derived counterparts. Some pre-clinical data has suggested a decreased risk of venous thromboembolism, cardiovascular disease, and breast cancer. As of 2012, guidelines from the North American Menopause Society, the Endocrine Society, the International Menopause Society, and the European Menopause and Andropause Society endorsed the reduced risk of bioidentical pharmaceuticals for those with increased clotting risk.

Compounding
Compounding for HRT is generally discouraged by the FDA and medical industry in the United States due to a lack of regulation and standardized dosing. The U.S. Congress did grant the FDA explicit but limited oversight of compounded drugs in a 1997 amendment to the Federal Food, Drug, and Cosmetic Act (FDCA), but they have encountered obstacles in this role since that time. After 64 patient deaths and 750 harmed patients from a 2012 meningitis outbreak due to contaminated steroid injections, Congress passed the 2013 Drug Quality and Security Act, authorizing creation by the FDA of a voluntary registration for facilities that manufactured compounded drugs, and reinforcing FDCA regulations for traditional compounding. The DQSA and its reinforcement of provision §503A of the FDCA solidifies FDA authority to enforce FDCA regulation of against compounders of bioidentical hormone therapy.In the United Kingdom, on the other hand, compounding is a regulated activity. The Medicines and Healthcare products Regulatory Agency regulates compounding performed under a Manufacturing Specials license and the General Pharmaceutical Council regulates compounding performed within a pharmacy. All testosterone prescribed in the United Kingdom is bioidentical, with its use supported by the National Health Service. There is also marketing authorisation for male testosterone products. National Institute for Health and Care Excellence guideline 1.4.8 states: "consider testosterone supplementation for menopausal women with low sexual desire if HRT alone is not effective". The footnote adds: "at the time of publication (November 2015), testosterone did not have a United Kingdom marketing authorisation for this indication in women. Bioidentical progesterone is used in IVF treatment and for pregnant women who are at risk of premature labour."

Society and public perception
Wyeth controversy
Wyeth, now a subsidiary of Pfizer, was a pharmaceutical company that marketed the HRT products Premarin (CEEs) and Prempro (CEEs + MPA). In 2009, litigation involving Wyeth resulted in the release of 1,500 documents that revealed practices concerning its promotion of these medications. The documents showed that Wyeth commissioned dozens of ghostwritten reviews and commentaries that were published in medical journals to promote unproven benefits of its HRT products, downplay their harms and risks, and cast competing therapies in a negative light. Starting in the mid-1990s and continuing for over a decade, Wyeth pursued an aggressive "publication plan" strategy to promote its HRT products through the use of ghostwritten publications. It worked mainly with DesignWrite, a medical writing firm. Between 1998 and 2005, Wyeth had 26 papers promoting its HRT products published in scientific journals.These favorable publications emphasized the benefits and downplayed the risks of its HRT products, especially the "misconception" of the association of its products with breast cancer. The publications defended unsupported cardiovascular "benefits" of its products, downplayed risks such as breast cancer, and promoted off-label and unproven uses like prevention of dementia, Parkinsons disease, vision problems, and wrinkles. In addition, Wyeth emphasized negative messages against the SERM raloxifene for osteoporosis, instructed writers to stress the fact that "alternative therapies have increased in usage since the WHI even though there is little evidence that they are effective or safe...", called into question the quality and therapeutic equivalence of approved generic CEE products, and made efforts to spread the notion that the unique risks of CEEs and MPA were a class effect of all forms of menopausal HRT: "Overall, these data indicate that the benefit/risk analysis that was reported in the Womens Health Initiative can be generalized to all postmenopausal hormone replacement therapy products."Following the publication of the WHI data in 2002, the stock prices for the pharmaceutical industry plummeted, and huge numbers of women stopped using HRT </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Hyaluronic acid and can you explain it in depth? [/INST] Hyaluronic acid (; abbreviated HA; conjugate base hyaluronate), also called hyaluronan, is an anionic, nonsulfated glycosaminoglycan distributed widely throughout connective, epithelial, and neural tissues. It is unique among glycosaminoglycans as it is non-sulfated, forms in the plasma membrane instead of the Golgi apparatus, and can be very large: human synovial HA averages about 7 million Da per molecule, or about 20,000 disaccharide monomers, while other sources mention 3–4 million Da.The average 70 kg (150 lb) person has roughly 15 grams of hyaluronan in the body, one-third of which is turned over (i.e., degraded and synthesized) per day.As one of the chief components of the extracellular matrix, it contributes significantly to cell proliferation and migration, and is involved in the progression of many malignant tumors. Hyaluronic acid is also a component of the group A streptococcal extracellular capsule, and is believed to play a role in virulence.

Physiological function
Until the late 1970s, hyaluronic acid was described as a "goo" molecule, a ubiquitous carbohydrate polymer that is part of the extracellular matrix.  For example, hyaluronic acid is a major component of the synovial fluid and was found to increase the viscosity of the fluid. Along with lubricin, it is one of the fluids main lubricating components.
Hyaluronic acid is an important component of articular cartilage, where it is present as a coat around each cell (chondrocyte). When aggrecan monomers bind to hyaluronan in the presence of HAPLN1 (hyaluronic acid and proteoglycan link protein 1), large, highly negatively charged aggregates form.  These aggregates imbibe water and are responsible for the resilience of cartilage (its resistance to compression). The molecular weight (size) of hyaluronan in cartilage decreases with age, but the amount increases.A lubricating role of hyaluronan in muscular connective tissues to enhance the sliding between adjacent tissue layers has been suggested. A particular type of fibroblasts, embedded in dense fascial tissues, has been proposed as being cells specialized for the biosynthesis of the hyaluronan-rich matrix. Their related activity could be involved in regulating the sliding ability between adjacent muscular connective tissues.Hyaluronic acid is also a major component of skin, where it is involved in repairing tissue. When skin is exposed to excessive UVB rays, it becomes inflamed (sunburn), and the cells in the dermis stop producing as much hyaluronan and increase the rate of its degradation. Hyaluronan degradation products then accumulate in the skin after UV exposure.While it is abundant in extracellular matrices, hyaluronan also contributes to tissue hydrodynamics, movement, and proliferation of cells and participates in a number of cell surface receptor interactions, notably those including its primary receptors, CD44 and RHAMM. Upregulation of CD44 itself is widely accepted as a marker of cell activation in lymphocytes. Hyaluronans contribution to tumor growth may be due to its interaction with CD44. Receptor CD44 participates in cell adhesion interactions required by tumor cells.
Although hyaluronan binds to receptor CD44, there is evidence hyaluronan degradation products transduce their inflammatory signal through toll-like receptor 2 (TLR2), TLR4, or both TLR2 and TLR4 in macrophages and dendritic cells. TLR and hyaluronan play a role in innate immunity.
There are limitations including the in vivo loss of this compound limiting the duration of effect.

Wound repair
As a major component of the extracellular matrix, hyaluronic acid has a key role in tissue regeneration, inflammation response, and angiogenesis, which are phases of wound repair. As of 2016, however, reviews of its effect on wound healing in burns, diabetic foot ulcers or surgical skin repairs show only limited positive clinical research evidence. Hyaluronic acid combines with water and swells to form a gel, making it useful in skin treatments as a dermal filler for facial wrinkles; its effect lasts for about 6 to 12 months, and treatment has regulatory approval from the US Food and Drug Administration.

Granulation
Granulation tissue is the perfused, fibrous connective tissue that replaces a fibrin clot in healing wounds. It typically grows from the base of a wound and is able to fill wounds of almost any size it heals. HA is abundant in granulation tissue matrix. A variety of cell functions that are essential for tissue repair may attribute to this HA-rich network. These functions include facilitation of cell migration into the provisional wound matrix, cell proliferation, and organization of the granulation tissue matrix. Initiation of inflammation is crucial for the formation of granulation tissue; therefore, the pro-inflammatory role of HA as discussed above also contributes to this stage of wound healing.

Cell migration
Cell migration is essential for the formation of granulation tissue. The early stage of granulation tissue is dominated by a HA-rich extracellular matrix, which is regarded as a conducive environment for the migration of cells into this temporary wound matrix. HA provides an open hydrated matrix that facilitates cell migration, whereas, in the latter scenario, directed migration and control of related cell mechanisms are mediated via the specific cell interaction between HA and cell surface HA receptors. It forms links with several protein kinases associated with cell locomotion, for example, extracellular signal-regulated kinase, focal adhesion kinase, and other non-receptor tyrosine kinases. During fetal development, the migration path through which neural crest cells migrate is rich in HA. HA is closely associated with the cell migration process in granulation tissue matrix, and studies show that cell movement can be inhibited, at least partially, by HA degradation or blocking HA receptor occupancy.By providing the dynamic force to the cell, HA synthesis has also been shown to associate with cell migration. Basically, HA is synthesized at the plasma membrane and released directly into the extracellular environment. This may contribute to the hydrated microenvironment at sites of synthesis, and is essential for cell migration by facilitating cell detachment.

Skin healing
HA plays an important role in the normal epidermis. HA also has crucial functions in the reepithelization process due to several of its properties. These include being an integral part of the extracellular matrix of basal keratinocytes, which are major constituents of the epidermis; its free-radical scavenging function, and its role in keratinocyte proliferation and migration.
In normal skin, HA is found in relatively high concentrations in the basal layer of the epidermis where proliferating keratinocytes are found. CD44 is collocated with HA in the basal layer of epidermis where additionally it has been shown to be preferentially expressed on plasma membrane facing the HA-rich matrix pouches. Maintaining the extracellular space and providing an open, as well as hydrated, structure for the passage of nutrients are the main functions of HA in epidermis. A report found HA content increases in the presence of retinoic acid (vitamin A). The proposed effects of retinoic acid against skin photo-damage and photoaging may be correlated, at least in part, with an increase of skin HA content, giving rise to increased tissue hydration. It has been suggested that the free-radical scavenging property of HA contributes to protection against solar radiation, supporting the role of CD44 acting as a HA receptor in the epidermis.
Epidermal HA also functions as a manipulator in the process of keratinocyte proliferation, which is essential in normal epidermal function, as well as during reepithelization in tissue repair. In the wound healing process, HA is expressed in the wound margin, in the connective tissue matrix, and collocating with CD44 expression in migrating keratinocytes.

Medical uses
Hyaluronic acid has been FDA-approved to treat osteoarthritis of the knee via intra-articular injection. A 2012 review showed that the quality of studies supporting this use was mostly poor, with a general absence of significant benefits, and that intra-articular injection of HA could possibly cause adverse effects. A 2020 meta-analysis found that intra-articular injection of high molecular weight HA improved both pain and function in people with knee osteoarthritis.Hyaluronic acid has been used in various formulations to create artificial tears to treat dry eye.Hyaluronic acid is a common ingredient in skin care products. Hyaluronic acid is used as a dermal filler in cosmetic surgery. It is typically injected using either a classic sharp hypodermic needle or a micro-cannula. Some studies have suggested that the use of micro-cannulas can significantly reduce vessel embolisms during injections. Currently, hyaluronic acid is used frequently as a soft tissue filler due to its bio-compatibility and reversibility. Complications include the severing of nerves and microvessels, pain, and bruising. Some side effects can also appear by way of erythema, itching, and vascular occlusion; vascular occlusion is the most worrisome side effect due to the possibility of skin necrosis, or even blindness in a patient. In some cases, hyaluronic acid fillers can result in a granulomatous foreign body reaction.

Structure
Hyaluronic acid is a polymer of disaccharides, which are composed of D-glucuronic acid and N-acetyl-D-glucosamine, linked via alternating β-(1→4) and β-(1→3) glycosidic bonds. Hyaluronic acid can be 25,000 disaccharide repeats in length. Polymers of hyaluronic acid can range in size from 5,000 to 20,000,000 Da in vivo. The average molecular weight in human synovial fluid is 3–4 million Da, and hyaluronic acid purified from human umbilical cord is 3,140,000 Da; other sources mention average molecular weight of 7 million Da for synovial fluid. Hyaluronic acid also contains silicon, ranging 350–1,900 μg/g depending on location in the organism.Hyaluronic acid is energetically stable, in part because of the stereochemistry of its component disaccharides. Bulky groups on each sugar molecule are in sterically favored positions, whereas the smaller hydrogens assume the less-favorable axial positions.

Biological synthesis
Hyaluronic acid is synthesized by a class of integral membrane proteins called hyaluronan synthases, of which vertebrates have three types: HAS1, HAS2, and HAS3. These enzymes lengthen hyaluronan by repeatedly adding D-glucuronic acid and N-acetyl-D-glucosamine to the nascent polysaccharide as it is extruded via ABC-transporter through the cell membrane into the extracellular space. The term fasciacyte was coined to describe fibroblast-like cells that synthesize HA.Hyaluronic acid synthesis has been shown to be inhibited by 4-methylumbelliferone (hymecromone), a 7-hydroxy-4-methylcoumarin derivative.
This selective inhibition (without inhibiting other glycosaminoglycans) may prove useful in preventing metastasis of malignant tumor cells. There is feedback inhibition of hyaluronan synthesis by low-molecular-weight hyaluronan (<500 kDa) at high concentrations, but stimulation by high-molecular-weight hyaluronan (>500 kDa), when tested in cultured human synovial fibroblasts.Bacillus subtilis recently has been genetically modified to culture a proprietary formula to yield hyaluronans, in a patented process producing human-grade product.

Fasciacyte
A fasciacyte is a type of biological cell that produces hyaluronan-rich extracellular matrix and modulates the gliding of muscle fasciae.Fasciacytes are fibroblast-like cells found in fasciae. They are round-shaped with rounder nuclei and have less elongated cellular processes when compared with fibroblasts. Fasciacytes are clustered along the upper and lower surfaces of a fascial layer.
Fasciacytes produce hyaluronan, which regulates fascial gliding.

Biosynthetic mechanism
Hyaluronic acid (HA) is a linear glycosaminoglycan (GAG), an anionic, gel-like, polymer, found in the extracellular matrix of epithelial and connective tissues of vertebrates. It is part of a family of structurally complex, linear, anionic polysaccharides. The carboxylate groups present in the molecule make it negatively charged, therefore allowing for successful binding to water, and making it valuable to cosmetic and pharmaceutical products.HA consists of repeating β4-glucuronic acid (GlcUA)-β3-N-acetylglucosamine (GlcNAc) disaccharides, and is synthesized by hyaluronan synthases (HAS), a class of integral membrane proteins that produce the well-defined, uniform chain lengths characteristic to HA. There are three existing types of HASs in vertebrates: HAS1, HAS2, HAS3; each of these contribute to elongation of the HA polymer. For an HA capsule to be created, this enzyme must be present because it polymerizes UDP-sugar precursors into HA. HA precursors are synthesized by first phosphorylating glucose by hexokinase, yielding glucose-6-phosphate, which is the main HA precursor. Then, two routes are taken to synthesize UDP-n-acetylglucosamine and UDP-glucuronic acid which both react to form HA. Glucose-6-phosphate gets converted to either fructose-6-phosphate with hasE (phosphoglucoisomerase), or glucose-1-phosphate using pgm (α -phosphoglucomutase), where those both undergo different sets of reactions.UDP-glucuronic acid and UDP-n-acetylglucosamine get bound together to form HA via hasA (HA synthase).

Synthesis of UDP-glucuronic acid
UDP-glucuronic acid is formed from hasC (UDP-glucose pyrophosphorylase) converting glucose-1-P into UDP-glucose, which then reacts with hasB (UDP-glucose dehydrogenase) to form UDP-glucuronic acid.

Synthesis of N-acetyl glucosamine
The path forward from fructose-6-P utilizes glmS (amidotransferase) to form glucosamine-6-P. Then, glmM (Mutase) reacts with this product to form glucosamine-1-P. hasD (acetyltransferase) converts this into n-acetylglucosamine-1-P, and finally, hasD (pyrophosphorylase) converts this product into UDP-n-acetylglucosamine.

Final step: Two disaccharides form hyaluronic acid
UDP-glucuronic acid and UDP-n-acetylglucosamine get bound together to form HA via hasA (HA synthase).

Completion of HA Synthesis.

Degradation
Hyaluronic acid can be degraded by a family of enzymes called hyaluronidases. In humans, there are at least seven types of hyaluronidase-like enzymes, several of which are tumor suppressors. The degradation products of hyaluronan, the oligosaccharides and very low-molecular-weight hyaluronan, exhibit pro-angiogenic properties. In addition, recent studies showed hyaluronan fragments, not the native high-molecular weight molecule, can induce inflammatory responses in macrophages and dendritic cells in tissue injury and in skin transplant.Hyaluronan can also be degraded via non-enzymatic reactions. These include acidic and alkaline hydrolysis, ultrasonic disintegration, thermal decomposition, and degradation by oxidants.

Etymology
Hyaluronic acid is derived from hyalos (Greek for vitreous, meaning ‘glass-like’) and uronic acid because it was first isolated from the vitreous humour and possesses a high uronic acid content. The term hyaluronate refers to the conjugate base of hyaluronic acid. Since the molecule typically exists in vivo in its polyanionic form, it is most commonly referred to as hyaluronan.

History
Hyaluronic acid was first obtained by Karl Meyer and John Palmer in 1934 from the vitreous body in a cows eye. The first hyaluronan biomedical product, Healon, was developed in the 1970s and 1980s by Pharmacia, and approved for use in eye surgery (i.e., corneal transplantation, cataract surgery, glaucoma surgery, and surgery to repair retinal detachment). Other biomedical companies also produce brands of hyaluronan for ophthalmic surgery.Native hyaluronic acid has a relatively short half-life (shown in rabbits) so various manufacturing techniques have been deployed to extend the length of the chain and stabilise the molecule for its use in medical applications. The introduction of protein-based cross-links, the introduction of free-radical scavenging molecules such as sorbitol, and minimal stabilisation of the HA chains through chemical agents such as NASHA (non-animal stabilised hyaluronic acid) are all techniques that have been used to preserve its shelf life.In the late 1970s, intraocular lens implantation was often followed by severe corneal edema, due to endothelial cell damage during the surgery. It was evident that a viscous, clear, physiologic lubricant to prevent such scraping of the endothelial cells was needed.The name "hyaluronan" is also used for a salt.

Other animals
Hyaluronan is used in treatment of articular disorders in horses, in particular those in competition or heavy work. It is indicated for carpal and fetlock joint dysfunctions, but not when joint sepsis or fracture are suspected. It is especially used for synovitis associated with equine osteoarthritis. It can be injected directly into an affected joint, or intravenously for less localized disorders. It may cause mild heating of the joint if directly injected, but this does not affect the clinical outcome. Intra-articularly administered medicine is fully metabolized in less than a week.Note that, according to Canadian regulation, hyaluronan in HY-50 preparation should not be administered to animals to be slaughtered for horse meat. In Europe, however, the same preparation is not considered to have any such effect, and edibility of the horse meat is not affected.Naked mole rats have very high molecular weight hyaluronan (6–12 MDa) that has been shown to give them resistance to cancer. This large HA is due to both differently sequenced HAS2 and lower HA degradation mechanisms.

Research
Due to its high biocompatibility and its common presence in the extracellular matrix of tissues, hyaluronan is gaining popularity as a biomaterial scaffold in tissue engineering research. In particular, a number of research groups have found hyaluronans properties for tissue engineering and regenerative medicine are significantly improved with cross-linking, producing a hydrogel </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Calamine and can you explain it in depth? [/INST] Calamine, also known as calamine lotion, is a medication used to treat mild itchiness. This includes from sunburn, insect bites, poison ivy, poison oak, and other mild skin conditions. It may also help dry out skin irritation. It is applied on the skin as a cream or lotion.Side effects may include skin irritation </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Brodalumab and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Cyclophosphamide and can you explain it in depth? [/INST] Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer, small cell lung cancer, neuroblastoma, and sarcoma. As an immune suppressor it is used in nephrotic syndrome, granulomatosis with polyangiitis, and following organ transplant, among other conditions. It is taken by mouth or injection into a vein.Most people develop side effects. Common side effects include low white blood cell counts, loss of appetite, vomiting, hair loss, and bleeding from the bladder. Other severe side effects include an increased future risk of cancer, infertility, allergic reactions, and pulmonary fibrosis. Cyclophosphamide is in the alkylating agent and nitrogen mustard family of medications. It is believed to work by interfering with the duplication of DNA and the creation of RNA.Cyclophosphamide was approved for medical use in the United States in 1959. It is on the World Health Organizations List of Essential Medicines.

Medical uses
Cyclophosphamide is used to treat cancers and autoimmune diseases. It is used to quickly control the disease. Due to its toxicity, it is replaced as soon as possible by less toxic drugs. Regular and frequent laboratory evaluations are required to monitor kidney function, avoid drug-induced bladder complications and screen for bone marrow toxicity.

Cancer
The main use of cyclophosphamide is with other chemotherapy agents in the treatment of lymphomas, some forms of brain cancer, neuroblastoma, leukemia and some solid tumors.Oncovet C (Chemovet S.A.), is the first-based drug approved in Latin America for veterinary use for canine and feline cancer (carcinomas of anal sacs, bladder carcinomas, urethral carcinomas, hemangiosarcomas, lymphomas, mast cell tumor, osteosarcomas, soft tissue sarcoma), feline cancers (mammary carcinomas, hemangiosarcomas, lymphomas, plasmacytomas, chronic lymphocytic leukemia, acute myelogenous leukemia, mast cell tumor). It can be administered in different treatment schemes, such as induction therapy, adjuvant, neoadjuvant, maintenance and metronomic chemotherapy.

Autoimmune diseases
Cyclophosphamide decreases the immune systems response, and although concerns about toxicity restrict its use to patients with severe disease, it remains an important treatment for life-threatening autoimmune diseases where disease-modifying antirheumatic drugs (DMARDs) have been ineffective.   For example, systemic lupus erythematosus with severe lupus nephritis may respond to pulsed cyclophosphamide. Cyclophosphamide is also used to treat minimal change disease, severe rheumatoid arthritis, granulomatosis with polyangiitis, Goodpasture syndrome and multiple sclerosis.Because of its potential side effects such as amenorrhea or ovarian failure, cyclophosphamide is used for early phases of treatment and later substituted by other medications, such as mycophenolic acid or ACA.

AL amyloidosis
Cyclophosphamide, used in combination with thalidomide or lenalidomide and dexamethasone has documented efficacy as an off-label treatment of AL amyloidosis. It appears to be an alternative to the more traditional treatment with melphalan in people who are ill-suited for autologous stem cell transplant.

Graft-versus-host disease
Graft-versus-host disease (GVHD) is a major barrier for allogeneic stem cell transplant because of the immune reactions of donor T cell against the person receiving them. GVHD can often be avoided by T-cell depletion of the graft. The use of a high dose cyclophosphamide post-transplant in a half matched or haploidentical donor hematopoietic stem cell transplantation reduces GVHD, even after using a reduced conditioning regimen.

Contraindications
Like other alkylating agents, cyclophosphamide is teratogenic and contraindicated in pregnant women (pregnancy category D) except for life-threatening circumstances in the mother. Additional relative contraindications to the use of cyclophosphamide include lactation, active infection, neutropenia or bladder toxicity.Cyclophosphamide is a pregnancy category D drug and causes birth defects. First trimester exposure to cyclophosphamide for the treatment of cancer or lupus displays a pattern of anomalies labeled "cyclophosphamide embryopathy", including growth restriction, ear and facial abnormalities, absence of digits and hypoplastic limbs.

Side effects
Adverse drug reactions from cyclophosphamide are related to the cumulative medication dose and include chemotherapy-induced nausea and vomiting, bone marrow suppression, stomach ache, hemorrhagic cystitis, diarrhea, darkening of the skin/nails, alopecia (hair loss) or thinning of hair, changes in color and texture of the hair, lethargy, and profound gonadotoxicity. Other side effects may include easy bruising/bleeding, joint pain, mouth sores, slow-healing existing wounds, unusual decrease in the amount of urine or unusual tiredness or weakness. Potential side effects also include leukopenia, infection, bladder toxicity, and cancer.Pulmonary injury appears rare, but can present with two clinical patterns: an early, acute pneumonitis and a chronic, progressive fibrosis. Cardiotoxicity is a major problem with people treated with higher dose regimens.High-dose intravenous cyclophosphamide can cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and a potentially fatal hyponatremia when compounded by intravenous fluids administered to prevent drug-induced cystitis. While SIADH has been described primarily with higher doses of cyclophosphamide, it can also occur with the lower doses used in the management of inflammatory disorders.

Bladder bleeding
Acrolein is toxic to the bladder epithelium and can lead to hemorrhagic cystitis, which is associated with microscopic or gross hematuria and occasionally dysuria. Risks of hemorrhagic cystitis can be minimized with adequate fluid intake, avoidance of nighttime dosage and mesna (sodium 2-mercaptoethane sulfonate), a sulfhydryl donor which binds and detoxifies acrolein. Intermittent dosing of cyclophosphamide decreases cumulative drug dose, reduces bladder exposure to acrolein and has equal efficacy to daily treatment in the management of lupus nephritis.

Infection
Neutropenia or lymphopenia arising secondary to cyclophosphamide usage can predispose people to a variety of bacterial, fungal and opportunistic infections. No published guidelines cover PCP prophylaxis for people with rheumatological diseases receiving immunosuppressive drugs, but some advocate its use when receiving high-dose medication.

Infertility
Cyclophosphamide has been found to significantly increase the risk of premature menopause in females and of infertility in males and females, the likelihood of which increases with cumulative drug dose and increasing patient age. Such infertility is usually temporary, but can be permanent. The use of leuprorelin in women of reproductive age before administration of intermittently dosed cyclophosphamide may diminish the risks of premature menopause and infertility.

Cancer
Cyclophosphamide is carcinogenic and may increase the risk of developing lymphomas, leukemia, skin cancer, transitional cell carcinoma of the bladder or other malignancies. Myeloproliferative neoplasms, including acute leukemia, non-Hodgkin lymphoma and multiple myeloma, occurred in 5 of 119 rheumatoid arthritis patients within the first decade after receiving cyclophosphamide, compared with one case of chronic lymphocytic leukemia in 119 rheumatoid arthritis patients with no history. Secondary acute myeloid leukemia (therapy-related AML, or "t-AML") is thought to occur either by cyclophosphamide-inducing mutations or selecting for a high-risk myeloid clone.This risk may be dependent on dose and other factors, including the condition, other agents or treatment modalities (including radiotherapy), treatment length and intensity. For some regimens, it is rare. For instance, CMF-therapy for breast cancer (where the cumulative dose is typically less than 20 grams of cyclophosphamide) carries an AML risk of less than 1/2000, with some studies finding no increased risk compared to background. Other treatment regimens involving higher doses may carry risks of 1–2% or higher.
Cyclophosphamide-induced AML, when it happens, typically presents some years after treatment, with incidence peaking around 3–9 years. After nine years, the risk falls to background. When AML occurs, it is often preceded by a myelodysplastic syndrome phase, before developing into overt acute leukemia. Cyclophosphamide-induced leukemia will often involve complex cytogenetics, which carries a worse prognosis than de novo AML.

Pharmacology
Oral cyclophosphamide is rapidly absorbed and then converted by mixed-function oxidase enzymes (cytochrome P450 system) in the liver to active metabolites. The main active metabolite is 4-hydroxycyclophosphamide, which exists in equilibrium with its tautomer, aldophosphamide. Most of the aldophosphamide is then oxidised by the enzyme aldehyde dehydrogenase (ALDH) to make carboxycyclophosphamide. A small proportion of aldophosphamide freely diffuses into cells, where it is decomposed into two compounds, phosphoramide mustard and acrolein. The active metabolites of cyclophosphamide are highly protein bound and distributed to all tissues, are assumed to cross the placenta and are known to be present in breast milk.It is specifically in the oxazaphosphorine group of medications.Cyclophosphamide metabolites are primarily excreted in the urine unchanged, and drug dosing should be appropriately adjusted in the setting of renal dysfunction. Drugs altering hepatic microsomal enzyme activity (e.g., alcohol, barbiturates, rifampicin, or phenytoin) may result in accelerated metabolism of cyclophosphamide into its active metabolites, increasing both pharmacologic and toxic effects of the drug; alternatively, drugs that inhibit hepatic microsomal enzymes (e.g. corticosteroids, tricyclic antidepressants, or allopurinol) result in slower conversion of cyclophosphamide into its metabolites and consequently reduced therapeutic and toxic effects.Cyclophosphamide reduces plasma pseudocholinesterase activity and may result in prolonged neuromuscular blockade when administered concurrently with succinylcholine. Tricyclic antidepressants and other anticholinergic agents can result in delayed bladder emptying and prolonged bladder exposure to acrolein.

Mechanism of action
The main effect of cyclophosphamide is due to its metabolite phosphoramide mustard. This metabolite is only formed in cells that have low levels of ALDH. Phosphoramide mustard forms DNA crosslinks both between and within DNA strands at guanine N-7 positions (known as interstrand and intrastrand crosslinkages, respectively). This is irreversible and leads to cell apoptosis.Cyclophosphamide has relatively little typical chemotherapy toxicity as ALDHs are present in relatively large concentrations in bone marrow stem cells, liver and intestinal epithelium. ALDHs protect these actively proliferating tissues against toxic effects of phosphoramide mustard and acrolein by converting aldophosphamide to carboxycyclophosphamide that does not give rise to the toxic metabolites phosphoramide mustard and acrolein. This is because carboxycyclophosphamide cannot undergo β-elimination (the carboxylate acts as an electron-donating group, nullifying the potential for transformation), preventing nitrogen mustard activation and subsequent alkylation.Cyclophosphamide induces beneficial immunomodulatory effects in adaptive immunotherapy. Suggested mechanisms include:
Elimination of T regulatory cells (CD4+CD25+ T cells) in naive and tumor-bearing hosts
Induction of T cell growth factors, such as type I IFNs, and/or
Enhanced grafting of adoptively transferred, tumor-reactive effector T cells by the creation of an immunologic space niche.Thus, cyclophosphamide preconditioning of recipient hosts (for donor T cells) has been used to enhance immunity in naïve hosts, and to enhance adoptive T cell immunotherapy regimens, as well as active vaccination strategies, inducing objective antitumor immunity.

History
As reported by O. M. Colvin in his study of the development of cyclophosphamide and its clinical applications,

Phosphoramide mustard, one of the principal toxic metabolites of cyclophosphamide, was synthesized and reported by Friedman and Seligman in 1954 …It was postulated that the presence of the phosphate bond to the nitrogen atom could inactivate the nitrogen mustard moiety, but the phosphate bond would be cleaved in gastric cancers and other tumors which had a high phosphamidase content. However, in studies carried out after the clinical efficacy of cyclophosphamide was demonstrated, phosphoramide mustard proved to be cytotoxic in vitro (footnote omitted), but to have a low therapeutic index in vivo.
Cyclophosphamide and the related nitrogen mustard–derived alkylating agent ifosfamide were developed by Norbert Brock and ASTA (now Baxter Oncology).  Brock and his team synthesised and screened more than 1,000 candidate oxazaphosphorine compounds. They converted the base nitrogen mustard into a nontoxic "transport form". This transport form was a prodrug, subsequently actively transported into cancer cells. Once in the cells, the prodrug was enzymatically converted into the active, toxic form </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Mecasermin rinfabate and can you explain it in depth? [/INST] Mecasermin rinfabate (INN, USAN) (brand name Iplex), also known as rhIGF-1/rhIGFBP-3, is a drug consisting of recombinant human insulin-like growth factor 1 (IGF-1) and recombinant human insulin-like growth factor binding protein-3 (IGFBP-3) which is used for the treatment of amyotrophic lateral sclerosis (Lou Gehrigs disease).It is similar in action to mecasermin, but with fewer side effects (such as hypoglycemia).

Potential uses
Mecasermin rinfabate was developed by INSMED corporation for the treatment of growth failure in children with severe primary IGF-I deficiency (primary IGFD) or with growth hormone (GH) gene deletion who have developed neutralizing antibodies to GH. Due to a patent settlement, Iplex is being taken off the market for short stature related indications. However, Iplex is being studied as a treatment for other several serious medical conditions.
On March 11, 2009 the FDA announced that mecasermin rinfabate would be made available to Americans with amyotrophic lateral sclerosis (ALS), more commonly known as Lou Gehrigs disease, as a part of a clinical trial. The drug is currently available in Italy for this  condition.

Myotonic muscular dystrophy
Iplex was investigated in a Phase II clinical study at the University of Rochester School of Medicine, with funding provided by the Muscular Dystrophy Association and the National Institutes of Health. This Phase II program studied the safety and tolerability of once-daily, subcutaneous injection of Iplex in patients with MMD. While patients with MMD showed significant increases in total muscle weight, testosterone levels, and LDL levels, and significant decreases in triglyceride and HDL levels, functional assays such as grip strength and walk tests did not show improvement.

HIV-associated adipose redistribution syndrome
Iplex is also being explored as a possible therapy for HIV- Associated Adipose Redistribution Syndrome (HARS). Data is being collected from a Phase II open-label clinical study directed by Morris Schambelan, M.D., a professor of medicine at University of California San Francisco. Dr Schambelan serves as Chief of Endocrinology and Director of the General Clinical Research Center at San Francisco General Hospital. This study is designed to evaluate the safety and efficacy of Iplex treatment with the primary goal of determining the effects of Iplex on visceral fat distribution and glucose and lipid metabolism. Initial data from this trial is to be available in 2007, with Phase III trials initiating in 2009.

Retinopathy of prematurity
Clinical work is at an earlier stage in the development of Iplex to treat Retinopathy of Prematurity (ROP). This disease, affecting an estimated 14,000 to 16,000 premature infants each year, causes the lack of development of the small blood vessels in the back of the eye leading to blindness in the majority of cases. A Phase I clinical study investigating Iplex as a treatment for ROP has been initiated at the University of Gothenburg in Sweden, in collaboration with scientists at the Harvard Medical School in the U.S. results of this study are expected by the end of 2007.

Amyotrophic lateral sclerosis
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrigs Disease is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Motor neurons reach from the brain to the spinal cord and from the spinal cord to the muscles throughout the body. The progressive degeneration of the motor neurons in ALS eventually leads to their death. When the motor neurons die, the ability of the brain to initiate and control muscle movement is lost. With voluntary muscle action progressively affected, patients in the later stages of the disease may become totally paralyzed.
In January 2007, INSMED announced that the Italian Ministry of Health requested INSMED corporation to make Iplex available to treat Italian patients sufferings from ALS.
IGF-1, the main component of Iplex, was the subject of a recent clinical trial in ALS. It involved 330 people with ALS from 20 ALS treatment centres across the United States </s>