<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 Norethisterone acetate and can you explain it in depth? [/INST] Norethisterone acetate (NETA), also known as norethindrone acetate and sold under the brand name Primolut-Nor among others, is a progestin medication which is used in birth control pills, menopausal hormone therapy, and for the treatment of gynecological disorders. The medication available in low-dose and high-dose formulations and is used alone or in combination with an estrogen. It is ingested orally.Side effects of NETA include menstrual irregularities, headaches, nausea, breast tenderness, mood changes, acne, increased hair growth, and others. NETA is a progestin, or a synthetic progestogen, and hence is an agonist of the progesterone receptor, the biological target of progestogens like progesterone. It has weak androgenic and estrogenic activity and no other important hormonal activity. The medication is a prodrug of norethisterone in the body.NETA was patented in 1957 and was introduced for medical use in 1964. It is sometimes referred to as a "first-generation" progestin. NETA is marketed widely throughout the world. It is available as a generic medication.

Medical uses
NETA is used as a hormonal contraceptive in combination with estrogen, in the treatment of gynecological disorders such as abnormal uterine bleeding, and as a component of menopausal hormone therapy for the treatment of menopausal symptoms.

Available forms
NETA is available in the form of tablets for use by mouth both alone and in combination with estrogens including estradiol, estradiol valerate, and ethinylestradiol. Transdermal patches providing a combination of 50 μg/day estradiol and 0.14 or 0.25 mg/day NETA are available under the brand names CombiPatch and Estalis.NETA was previously available for use by intramuscular injection in the form of ampoules containing 20 mg NETA, 5 mg estradiol benzoate, 8 mg estradiol valerate, and 180 mg testosterone enanthate in oil solution under the brand name Ablacton to suppress lactation in postpartum women.

Contraindications
Side effects
Side effects of NETA include menstrual irregularities, headaches, nausea, breast tenderness, mood changes, acne, increased hair growth, and others.

Overdose
Interactions
Pharmacology
NETA is a prodrug of norethisterone in the body. Upon oral ingestion, it is rapidly converted into norethisterone by esterases during intestinal and first-pass hepatic metabolism. Hence, as a prodrug of norethisterone, NETA has essentially the same effects, acting as a potent progestogen with additional weak androgenic and estrogenic activity (the latter via its metabolite ethinylestradiol).In terms of dosage equivalence, norethisterone and NETA are typically used at respective dosages of 0.35 mg/day and 0.6 mg/day as progestogen-only contraceptives, and at respective dosages of 0.5–1 mg/day and 1–1.5 mg/day in combination with ethinylestradiol in combined oral contraceptives. Conversely, the two drugs have been used at about the same dosages in menopausal hormone therapy for the treatment of menopausal symptoms. NETA is of about 12% higher molecular weight than norethisterone due to the presence of its C17β acetate ester.Micronization of NETA has been found to increase its potency by several-fold in animals and women. The endometrial transformation dosage of micronized NETA per cycle is 12 to 14 mg, whereas that for non-micronized NETA is 30 to 60 mg.NETA metabolizes into ethinylestradiol at a rate of 0.20 to 0.33% across a dose range of 10 to 40 mg. Peak levels of ethinylestradiol with a 10, 20, or 40 mg dose of NETA were 58, 178, and 231 pg/mL, respectively. For comparison, a 30 to 40 μg dose of oral ethinylestradiol typically results in a peak ethinylestradiol level of 100 to 135 pg/mL. As such, in terms of ethinylestradiol exposure, 10 to 20 mg NETA may be equivalent to 20 to 30 μg ethinylestradiol and 40 mg NETA may be similar to 50 μg ethinylestradiol. In another study however, 5 mg NETA produced an equivalent of 28 μg ethinylestradiol (0.7% conversion rate) and 10 mg NETA produced an equivalent of 62 μg ethinylestradiol (1.0% conversion rate). Due to its estrogenic activity via ethinylestradiol, high doses of NETA have been proposed for add-back in the treatment of endometriosis without estrogen supplementation </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 Interleukin 2 and can you explain it in depth? [/INST] Interleukin-2 (IL-2) is an interleukin, a type of cytokine signaling molecule in the immune system. It is a 15.5–16 kDa protein that regulates the activities of white blood cells (leukocytes, often lymphocytes) that are responsible for immunity. IL-2 is part of the bodys natural response to microbial infection, and in discriminating between foreign ("non-self") and "self". IL-2 mediates its effects by binding to IL-2 receptors, which are expressed by lymphocytes. The major sources of IL-2 are activated CD4+ T cells and activated CD8+ T cells.

IL-2 receptor
IL-2 is a member of a cytokine family, each member of which has a four alpha helix bundle; the family also includes IL-4, IL-7, IL-9, IL-15 and IL-21. IL-2 signals through the IL-2 receptor, a complex consisting of three chains, termed alpha (CD25), beta (CD122) and gamma (CD132). The gamma chain is shared by all family members.The IL-2 receptor (IL-2R) α subunit binds IL-2 with low affinity (Kd~ 10−8 M). Interaction of IL-2 and CD25 alone does not lead to signal transduction due to its short intracellular chain but has the ability (when bound to the β and γ subunit) to increase the IL-2R affinity 100-fold. Heterodimerization of the β and γ subunits of IL-2R is essential for signalling in T cells. IL-2 can signalize either via intermediate-affinity dimeric CD122/CD132 IL-2R (Kd~ 10−9 M) or high-affinity trimeric CD25/CD122/CD132 IL-2R (Kd~ 10−11 M). Dimeric IL-2R is expressed by memory CD8+ T cells and NK cells, whereas regulatory T cells and activated T cells express high levels of trimeric IL-2R.

IL-2 signaling pathways and regulation
The pleiotropic effects of IL-2 are enabled due to the fact that IL-2 signal can be transduced via 3 different signaling pathways; JAK-STAT, PI3K/Akt/mTOR and MAPK/ERK pathway. After IL-2 binding to its receptor, cytoplasmatic domains of CD122 and CD132 heterodimerize. This leads to the activation of Janus kinases JAK1 and JAK3 which subsequently phosphorylate T338 on CD122. This phosphorylation recruits STAT transcription factors, predominantly STAT5, which dimerize and migrate to the cell nucleus where they bind to DNA.Gene expression regulation for IL-2 can be on multiple levels or by different ways. One of the checkpoints is signaling through TCR, antigen receptor of T-lymphocytes after recognizing MHC-peptide complex. Signaling pathway from TCR then goes through phospholipase-C (PLC) dependent pathway. PLC activates 3 major transcription factors and their pathways: NFAT, NFkB and AP-1. After costimulation from CD28 the optimal activation of expression of IL-2 and these pathways is induced.
At the same time Oct-1 is expressed. It helps the activation. Oct1 is expressed in T-lymphocytes and Oct2 is induced after cell activation.
NFAT has multiple family members, all of them are located in cytoplasm and signaling goes through calcineurin, NFAT is dephosphorylated and therefore translocated to the nucleus.
AP-1 is a dimer and is composed of c-Jun and c-Fos proteins. It cooperates with other transcription factors including NFkB and Oct.
NFkB is translocated to the nucleus after costimulation through CD28. NFkB is a heterodimer and there are two binding sites on the IL-2 promoter.

Function
IL-2 has essential roles in key functions of the immune system, tolerance and immunity, primarily via its direct effects on T cells. In the thymus, where T cells mature, it prevents autoimmune diseases by promoting the differentiation of certain immature T cells into regulatory T cells, which suppress other T cells that are otherwise primed to attack normal healthy cells in the body. IL-2 enhances activation-induced cell death (AICD). IL-2 also promotes the differentiation of T cells into effector T cells and into memory T cells when the initial T cell is also stimulated by an antigen, thus helping the body fight off infections. Together with other polarizing cytokines, IL-2 stimulates naive CD4+ T cell differentiation into Th1 and Th2 lymphocytes while it impedes differentiation into Th17 and folicular Th lymphocytes.IL-2 increases the cell killing activity of both natural killer cells and cytotoxic T cells.Its expression and secretion is tightly regulated and functions as part of both transient positive and negative feedback loops in mounting and dampening immune responses. Through its role in the development of T cell immunologic memory, which depends upon the expansion of the number and function of antigen-selected T cell clones, it plays a key role in enduring cell-mediated immunity.

Role in disease
While the causes of itchiness are poorly understood, some evidence indicates that IL-2 is involved in itchy psoriasis.

Medical use
Pharmaceutical analogues
Aldesleukin is a form of recombinant interleukin-2. It is manufactured using recombinant DNA technology and is marketed as a protein therapeutic and branded as Proleukin. It has been approved by the Food and Drug Administration (FDA) and in several European countries for the treatment of cancers (malignant melanoma, renal cell cancer) in large intermittent doses and has been extensively used in continuous doses.Interking is a recombinant IL-2 with a serine at residue 125, sold by Shenzhen Neptunus.Neoleukin 2/15 is a computationally designed mimic of IL-2 that was designed to avoid common side effects. It is currently being commercialized into a therapeutic.

Dosage
Various dosages of IL-2 across the United States and across the world are used. The efficacy and side effects of different dosages is often a point of disagreement.
The commercial interest in local IL-2 therapy has been very low. Because only a very low dose IL-2 is used, treatment of a patient would cost about $ 500 commercial value of the patented IL-2. The commercial return on investment is too low to stimulate additional clinical studies for the registration of intratumoral IL-2 therapy.

United States
Usually, in the U.S., the higher dosage option is used, affected by cancer type, response to treatment and general patient health. Patients are typically treated for five consecutive days, three times a day, for fifteen minutes. The following approximately 10 days help the patient to recover between treatments. IL-2 is delivered intravenously on an inpatient basis to enable proper monitoring of side effects.A lower dose regimen involves injection of IL-2 under the skin typically on an outpatient basis. It may alternatively be given on an inpatient basis over 1–3 days, similar to and often including the delivery of chemotherapy.Intralesional IL-2 is commonly used to treat in-transit melanoma metastases and has a high complete response rate.

Local application
In preclinical and early clinical studies, local application of IL-2 in the tumor has been shown to be clinical more effective in anticancer therapy than systemic IL-2 therapy, over a broad range of doses, without serious side effects.Tumour blood vessels are more vulnerable than normal blood vessels to the actions of IL-2. When injected inside a tumor, i.e. local application, a process mechanistically similar to the vascular leakage syndrome, occurs in tumor tissue only. Disruption of the blood flow inside of the tumor effectively destroys tumor tissue.In local application, the systemic dose of IL-2 is too low to cause side effects, since the total dose is about 100 to 1000 fold lower. Clinical studies showed painful injections at the site of radiation as the most important side effect, reported by patients. In the case of irradiation of nasopharyngeal carcinoma the five-year disease-free survival increased from 8% to 63% by local IL-2 therapy

Toxicity
Systemic IL-2 has a narrow therapeutic window, and the level of dosing usually determines the severity of the side effects. In the case of local IL-2 application, the therapeutic window spans several orders of magnitude.Some common side effects:
flu-like symptoms (fever, headache, muscle and joint pain, fatigue)
nausea/vomiting
dry, itchy skin or rash
weakness or shortness of breath
diarrhea
low blood pressure
drowsiness or confusion
loss of appetiteMore serious and dangerous side effects sometimes are seen, such as breathing problems, serious infections, seizures, allergic reactions, heart problems, kidney failure or a variety of other possible complications. The most common adverse effect of high-dose IL-2 therapy is vascular leak syndrome (VLS; also termed capillary leak syndrome). It is caused by lung endothelial cells expressing high-affinity IL-2R. These cells, as a result of IL-2 binding, causes increased vascular permeability. Thus, intravascular fluid extravasate into organs, predominantly lungs, which leads to life-threatening pulmonary or brain oedema.Other drawbacks of IL-2 cancer immunotherapy are its short half-life in circulation and its ability to predominantly expand regulatory T cells at high doses.Intralesional IL-2 used to treat in-transit melanoma metastases is generally well tolerated. This is also the case for intralesional IL-2 in other forms of cancer, like nasopharyngeal carcinoma.

Pharmaceutical derivative
Eisai markets a drug called denileukin diftitox (trade name Ontak), which is a recombinant fusion protein of the human IL-2 ligand and the diphtheria toxin. This drug binds to IL-2 receptors and introduces the diphtheria toxin into cells that express those receptors, killing the cells. In some leukemias and lymphomas, malignant cells express the IL-2 receptor, so denileukin diftitox can kill them. In 1999 Ontak was approved by the U.S. Food and Drug Administration (FDA) for treatment of cutaneous T cell lymphoma (CTCL).

Preclinical research
IL-2 does not follow the classical dose-response curve of chemotherapeutics. The immunological activity of high and low dose IL-2 show sharp contrast. This might be related to different distribution of IL-2 receptors (CD25, CD122, CD132) on different cell populations, resulting in different cells that are activated by high and low dose IL-2. In general high doses are immune suppressive, while low doses can stimulate type 1 immunity. Low-dose IL-2 has been reported to reduce hepatitis C and B infection.IL-2 has been used in clinical trials for the treatment of chronic viral infections and as a booster (adjuvant) for vaccines. The use of large doses of IL-2 given every 6–8 weeks in HIV therapy, similar to its use in cancer therapy, was found to be ineffective in preventing progression to an AIDS diagnosis in two large clinical trials published in 2009.More recently low dose IL-2 has shown early success in modulating the immune system in disease like type 1 diabetes and vasculitis. There are also promising studies looking to use low dose IL-2 in ischaemic heart disease.

IL-2/anti-IL-2 mAb immune complexes (IL-2 ic)
IL-2 cannot accomplish its role as a promising immunotherapeutic agent due to significant drawbacks which are listed above. Some of the issues can be overcome using IL-2 ic. They are composed of IL-2 and some of its monoclonal antibody (mAb) and can potentiate biologic activity of IL-2 in vivo. The main mechanism of this phenomenon in vivo is due to the prolongation of the cytokine half-life in circulation. Depending on the clone of IL-2 mAb, IL-2 ic  can selectively stimulate either CD25high (IL-2/JES6-1 complexes), or CD122high cells (IL-2/S4B6). IL-2/S4B6 immune complexes have high stimulatory activity for NK cells and memory CD8+ T cells and they could thus replace the conventional IL-2 in cancer immunotherapy. On the other hand, IL-2/JES6-1 highly selectively stimulate regulatory T cells and they could be potentially useful for transplantations and in treatment of autoimmune diseases.

History
According to an immunology textbook: "IL-2 is particularly important historically, as it is the first type I cytokine that was cloned, the first type I cytokine for which a receptor component was cloned, and was the first short-chain type I cytokine whose receptor structure was solved. Many general principles have been derived from studies of this cytokine including its being the first cytokine demonstrated to act in a growth factor–like fashion through specific high-affinity receptors, analogous to the growth factors being studied by endocrinologists and biochemists".: 712 In the mid-1960s, studies reported "activities" in leukocyte-conditioned media that promoted lymphocyte proliferation.: 16  In the mid-1970s, it was discovered that T-cells could be selectively proliferated when normal human bone marrow cells were cultured in conditioned medium obtained from phytohemagglutinin-stimulated normal human lymphocytes.: 712  The key factor was isolated from cultured mouse cells in 1979 and from cultured human cells in 1980. The gene for human IL-2 was cloned in 1982 after an intense competition.: 76 Commercial activity to bring an IL-2 drug to market was intense in the 1980s and 90s. By 1983, Cetus Corporation had created a proprietary recombinant version of IL-2 (Aldesleukin, later branded as Proleukin), with the alanine removed from its N-terminal and residue 125 replaced with serine.: 76–77 : 201  Amgen later entered the field with its own proprietary, mutated, recombinant protein and Cetus and Amgen were soon competing scientifically and in the courts; Cetus won the legal battles and forced Amgen out of the field.: 151   By 1990 Cetus had gotten aldesleukin approved in nine European countries but in that year, the U.S. Food and Drug Administration (FDA) refused to approve Cetus application to market IL-2 </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 Clotrimazole and can you explain it in depth? [/INST] Clotrimazole, sold under the brand name Lotrimin, among others, is an antifungal medication. It is used to treat vaginal yeast infections, oral thrush, diaper rash, tinea versicolor, and types of ringworm including athletes foot and jock itch. It can be taken by mouth or applied as a cream to the skin or in the vagina.Common side effects when taken by mouth include nausea and itchiness. When applied to the skin, common side effects include redness and a burning sensation. In pregnancy, use on the skin or in the vagina is believed to be safe. There is no evidence of harm when used by mouth during pregnancy but this has been less well studied. When used by mouth, greater care should be taken in those with liver problems. It is in the azole class of medications and works by disrupting the fungal cell membrane.Clotrimazole was discovered in 1969. It is on the World Health Organizations List of Essential Medicines. It is available as a generic medication.

Medical uses
It is commonly available without a prescription in various dosage forms, such as a topical cream, ointment, or vaginal suppository. It is also available as an oral troche or throat lozenge as a prescription only. Topically, clotrimazole is used for vulvovaginal candidiasis (yeast infection) or yeast infections of the skin. For vulvovaginal candidiasis, clotrimazole tablets and creams are inserted into the vagina. Topical clotrimazole is usually not effective in treatment of fungal infections of the scalp or nails. When using over-the-counter drug clotrimazole products, use should be discontinued if condition does not improve after treatment for 2 weeks for jock itch or after 4 weeks for athletes foot or ringworm.Throat lozenge preparations are used for oropharyngeal candidiasis (oral thrush) or prevention of oral thrush in people with neutropenia.Clotrimazole is usually used five times daily for 14 days for oral thrush, twice daily for 2 to 8 weeks for skin infections, and once daily for 3 or 7 days for vaginal infections.Clotrimazole may be compounded with a glucocorticoid, such as betamethasone, in a topical cream for the treatment of tinea corporis (ringworm), tinea cruris (jock itch) and tinea pedis (athletes foot). Although FDA approved, clotrimazole–betamethasone combination cream is not the preferred treatment for dermatophyte infections due to increased side effects from the topical glucocorticoid.Although temporary relief and partial suppression of symptoms may be observed with the combination therapy, glucocorticoids can elicit an immunosuppressive response and rebound effect that results in more severe infection typically requiring systemic antifungal agents to treat the disease. Combination creams are best avoided in order to improve treatment outcome, reduce the possibility of skin atrophy associated with prolonged topical glucocorticoid use, and to limit the cost of treatment. It can be effective in treating chronic paronychia. The preferred treatment of tinea infections is therefore with clotrimazole monotherapy.Topical and oral clotrimazole can be used in both adults and children.
Additionally, clotrimazole may be used to treat the sickling of cells (related to sickle cell anemia).It can be taken by mouth as a lozenge or troche or applied as a topical cream to the skin or in the vagina.

Pregnancy
Topical clotrimazole is categorized as pregnancy category B. Small amounts of clotrimazole may be absorbed systemically following topical and vaginal administration. However, topical clotrimazole is still considered safe to use to treat yeast infections in pregnant women and is a safer alternative to other antifungals.

Side effects
Side effects of the oral formulation include itching, nausea, and vomiting. Less than 10% of patients using the oral formulation may have abnormal liver function tests. Side effects include rash, hives, blisters, burning, itching, peeling, redness, swelling, pain or other signs of skin irritation. For this reason, liver function tests should be monitored periodically when taking the oral clotrimazole (troche). When used to treat vulvovaginal candidiasis (yeast infection), less than 10% of patients have vulvar or vaginal burning sensation </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 Brigatinib and can you explain it in depth? [/INST] Brigatinib, sold under the brand name Alunbrig among others, is a small-molecule targeted cancer therapy being developed by Ariad Pharmaceuticals, Inc. Brigatinib acts as both an anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) inhibitor.Brigatinib could overcome resistance to osimertinib conferred by the EGFR C797S mutation if it is combined with an anti-EGFR antibody such as cetuximab or panitumumab.

Mechanism of action
Brigatinib is an inhibitor of ALK and mutated EGFR.ALK was first identified as a chromosomal rearrangement in anaplastic large cell lymphoma (ALCL). Genetic studies indicate that abnormal expression of ALK is a key driver of certain types of non-small cell lung cancer (NSCLC) and neuroblastomas, as well as ALCL. Since ALK is generally not expressed in normal adult tissues, it represents a highly promising molecular target for cancer therapy.
Brigatinib inhibits ROS proto-oncogene-1 fusions and EGFR mutations and has a remarkable effect on the central nervous system.Epidermal growth factor receptor (EGFR) is another validated target in NSCLC. Additionally, the T790M "gatekeeper" mutation is linked in approximately 50 percent of patients who grow resistant to first-generation EGFR inhibitors. While second-generation EGFR inhibitors are in development, clinical efficacy has been limited due to toxicity thought to be associated with inhibiting the native (endogenous or unmutated) EGFR. A therapy designed to target EGFR, the T790M mutation but avoiding inhibition of native EGFR is another promising molecular target for cancer therapy.

History
Regulatory approval
Ariad Pharmaceuticals, Inc. filed an investigational new drug (IND) application to the US FDA on August 29, 2016.In 2016, brigatinib was granted orphan drug status by the FDA for treatment of NSCLC.On 28 April 2017, it was granted an accelerated approval from the U.S. Food and Drug Administration (FDA) for metastatic non-small cell lung cancer (NSCLC); as a 2nd-line therapy for ALK-positive NSCLC.In 2020, it was approved as first-line treatment for ALK-positive metastatic NSCLC patients.

Intellectual property
On 22 April 2015, Ariad Pharmaceuticals, Inc. announced the issuance of its first U.S </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 Carboplatin and can you explain it in depth? [/INST] Carboplatin, sold under the trade name Paraplatin among others, is a chemotherapy medication used to treat a number of forms of cancer. This includes ovarian cancer, lung cancer, head and neck cancer, brain cancer, and neuroblastoma. It is used by injection into a vein.Side effects generally occur. Common side effects include low blood cell levels, nausea, and electrolyte problems. Other serious side effects include allergic reactions and increased future risk of another cancer. Use during pregnancy may result in harm to the baby. Carboplatin is in the platinum-based antineoplastic family of medications and works by interfering with duplication of DNA.Carboplatin was patented in 1972 and approved for medical use in 1989. It is on the World Health Organizations List of Essential Medicines.

Medical uses
Carboplatin is used to treat a number of forms of cancer. This includes ovarian cancer, lung cancer, head and neck cancer, brain cancer, and neuroblastoma. It may be used for some types of testicular cancer but cisplatin is generally more effective.  It has also been used to treat triple-negative breast cancer.

Side effects
Relative to cisplatin, the greatest benefit of carboplatin is its reduced side effects, particularly the elimination of nephrotoxic effects. Nausea and vomiting are less severe and more easily controlled.
The main drawback of carboplatin is its myelosuppressive effect. This causes the blood cell and platelet output of bone marrow in the body to decrease quite dramatically, sometimes as low as 10% of its usual production levels. The nadir of this myelosuppression usually occurs 21–28 days after the first treatment, after which the blood cell and platelet levels in the blood begin to stabilize, often coming close to its pre-carboplatin levels. This decrease in white blood cells (neutropenia) can cause complications, and is sometimes treated with drugs like filgrastim. The most notable complication of neutropenia is increased probability of infection by opportunistic organisms, which necessitates hospital readmission and treatment with antibiotics.

Chemistry
In terms of its structure, carboplatin differs from cisplatin in that it has a bidentate dicarboxylate (the ligand is CycloButane DiCarboxylic Acid, CBDCA) in place of the two chloride ligands, which are the leaving groups in cisplatin. For this reason, "CBDCA" is sometimes used in the medical literature as an abbreviation referring to carboplatin. Carboplatin exhibits lower reactivity and slower DNA binding kinetics, although it forms the same reaction products in vitro at equivalent doses with cisplatin. Unlike cisplatin, carboplatin may be susceptible to alternative mechanisms. Some results show that cisplatin and carboplatin cause different morphological changes in MCF-7 cell lines while exerting their cytotoxic behaviour. The diminished reactivity limits protein-carboplatin complexes, which are excreted. The lower excretion rate of carboplatin means that more is retained in the body, and hence its effects are longer lasting (a retention half-life of 30 hours for carboplatin, compared to 1.5-3.6 hours in the case of cisplatin).

Mechanism of action
Two theories exist to explain the molecular mechanism of action of carboplatin with DNA:

Aquation, or the like-cisplatin hypothesis.
Activation, or the unlike-cisplatin hypothesis.The former is more accepted owing to the similarity of the leaving groups with its predecessor cisplatin, while the latter hypothesis envisages a biological activation mechanism to release the active Pt2+ species.

Dose
Calverts formula is used to calculate the dose of carboplatin. It takes under consideration the creatinine clearance and the desired area under curve </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 Metaxalone and can you explain it in depth? [/INST] Metaxalone, sold under the brand name Skelaxin, is a muscle relaxant medication used to relax muscles and relieve pain caused by strains, sprains, and other musculoskeletal conditions. Its exact mechanism of action is not known, but it may be due to general central nervous system depression. It is a moderately strong muscle relaxant, with relatively low incidence of side effects.Common side effects include nausea, vomiting, drowsiness, and central nervous system (CNS) side effects, such as dizziness, headache, and irritability.The metabolism of metaxalone involves enzymes CYP1A2 and CYP2C19 in the cytochrome P450 system. Because many medications are metabolized by enzymes in this system, precaution must be taken when administering it with other medications involving the P450 system to avoid interactions.Because of the potential for side effects, this drug is considered a high risk in the elderly.

Pharmacokinetics
Metaxalone exhibits increased bioavailability when taken with food </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 Adapalene/benzoyl peroxide 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 Caplacizumab 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 Decitabine and can you explain it in depth? [/INST] Decitabine, sold under the brand name Dacogen among others, acts as a nucleic acid synthesis inhibitor. It is a medication for the treatment of myelodysplastic syndromes, a class of conditions where certain blood cells are dysfunctional, and for acute myeloid leukemia (AML). Chemically, it is a cytidine analog.

Medical uses
Decitabine is used to treat myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and Intermediate-1, Intermediate-2, and High-Risk International Prognostic Scoring System groups. In patients with chronic kidney disease, Batty and colleagues reported the first case series on the feasibility of therapy with hypomethylating agents in patients with chronic kidney disease.It also has EU approval for acute myeloid leukemia (AML).

Pharmacology
Decitabine is a hypomethylating agent. It hypomethylates DNA by inhibiting DNA methyltransferase.
It functions in a similar manner to azacitidine, although decitabine can only be incorporated into DNA strands while azacitidine can be incorporated into both DNA and RNA chains.
It incorporates into DNA strands upon replication, and then when DNA methyltransferases (DNMTs) such as DNMT1, are engaged to bind the DNA and to replicate the methylation to the daughter strand, DNMTs are bound to decitabine irreversibly and cannot disengage. Therefore, the action of decitabine is division-dependent, meaning the cells have to divide in order for the pharmaceutical to act.
Therefore, cancer cells which divide much more rapidly than most other cells in the body will be more severely affected by decitabine just because they replicate more. In cancer cells, and more specifically in haematological malignancies, it seems that DNA hypermethylation is really critical for their development. Methylation of CpG islands upstream of tumor suppressor genes in order to silence them seems to be critical for these type of cancers. Thus at optimal doses, decitabine blocks this type of methylation and has an anti-neoplastic effect.

Research
Atherosclerosis
A number of investigators have shown a relationship between atherosclerosis and disturbed blood flow. This upregulates DNA methyltransferase expression, which leads to genome-wide DNA methylation alterations and global gene expression changes. These studies have revealed several mechanosensitive genes, such as HoxA5, Klf3, and Klf4, whose promoters were hypermethylated by disturbed blood flow, but rescued by DNA methyltransferases inhibitors such as 5-aza-2-deoxycytidine </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 Eszopiclone and can you explain it in depth? [/INST] Eszopiclone, sold under the brand-name Lunesta among others such as Night Calm in Egypt, is a medication used in the treatment of insomnia. Evidence supports slight to moderate benefit up to six months. It is taken orally.Common side effects include headache, dry mouth, nausea, and dizziness. Severe side effects may include suicidal thoughts, unhealthy non-medical use, hallucinations, and angioedema. Greater care is recommended in those with liver problems and older people. Rapid decreasing of the dose may result in withdrawal. Eszopiclone is classified as a nonbenzodiazepine sedative hypnotic and as a cyclopyrrolone. It is the S-stereoisomer of zopiclone. It works by interacting with the GABA receptors.Approved for medical use in the United States in 2004, eszopiclone is available as generic medication. In 2019, it was the 223rd most commonly prescribed medication in the United States, with more than 2 million prescriptions. Eszopiclone is not sold in the European Union, as in 2009 the European Medicines Agency (EMA) ruled that it was too similar to zopiclone to be considered a new patentable product.

Medical uses
A 2018 Cochrane review found that it produced moderate improvement in sleep onset and maintenance. The authors suggest that where preferred non-pharmacological treatment strategies have been exhausted, eszopiclone provides an efficient treatment for insomnia. In 2014, the USFDA asked that the starting dose be lowered from 2 milligrams to 1 milligram after it was observed in a study that even 8 hours after taking the drug at night, some people were not able to cope with their next-day activities like driving and other activities that require full alertness.Eszopiclone is slightly effective in the treatment of insomnia where difficulty in falling asleep is the primary complaint. Kirsch et al. found the benefit over placebo to be of questionable clinical significance. Although the drug effect and the placebo response were rather small and of questionable clinical importance, the two together produce a reasonably large clinical response. It is not recommended for chronic use in the elderly.

Elderly
Sedative hypnotic drugs including eszopiclone are more commonly prescribed to the elderly than to younger patients despite benefits of medication being generally unimpressive. Care should be taken in choosing an appropriate hypnotic drug and if drug therapy is initiated it should be initiated at the lowest possible dose to minimise side effects.In 2015, the American Geriatrics Society reviewed the safety information about eszopiclone and similar drugs and concluded that the "nonbenzodiazepine, benzodiazepine receptor agonist hypnotics (eszopiclone, zaleplon, zolpidem) are to be avoided without consideration of duration of use because of their association with harms balanced with their minimal efficacy in treating insomnia."
The review made this determination both because of the relatively large dangers to elderly individuals from zolpidem and other "z-drugs" together with the fact the drugs have "minimal efficacy in treating insomnia." This was a change from the 2012 AGS recommendation, which suggested limiting use to 90 days or less. The review stated: "the 90‐day‐use caveat [was] removed from nonbenzodiazepine, benzodiazepine receptor agonist hypnotics, resulting in an unambiguous avoid statement (without caveats) because of the increase in the evidence of harm in this area since the 2012 update."An extensive review of the medical literature regarding the management of insomnia and the elderly found that there is considerable evidence of the effectiveness and durability of non-drug treatments for insomnia in adults of all ages and that these interventions are underutilized. Compared with the benzodiazepines, the nonbenzodiazepine sedative-hypnotics, including eszopiclone appeared to offer few, if any, significant clinical advantages in efficacy or tolerability in elderly persons. It was found that newer agents with novel mechanisms of action and improved safety profiles, such as the melatonin receptor agonists, hold promise for the management of chronic insomnia in elderly people. Long-term use of sedative-hypnotics for insomnia lacks an evidence base and has traditionally been discouraged for reasons that include concerns about such potential adverse drug effects as cognitive impairment (anterograde amnesia), daytime sedation, motor incoordination, and increased risk of motor vehicle accidents and falls. In addition, the effectiveness and safety of long-term use of these agents remain to be determined. It was concluded that more research is needed to evaluate the long-term effects of treatment and the most appropriate management strategy for elderly persons with chronic insomnia.A 2009 meta-analysis found a higher rate of infections.

Adverse effects
Sleeping pills, including eszopiclone, have been associated with an increased risk of death.Hypersensitivity to eszopiclone is a contra-indication to its use. Some side effects are more common than others. Recommendations around use of eszopiclone may be altered by other health conditions. These conditions or circumstances may occur in people that have lowered metabolism and other conditions. The presence of liver impairment, lactation and activities requiring mental alertness (e.g., driving) may be considered when determining frequency and dosage.

A 2009 meta-analysis found a 44% higher rate of mild infections, such as pharyngitis or sinusitis, in people taking eszopiclone or other hypnotic drugs compared to those taking a placebo.

Dependence
In the United States eszopiclone is a schedule IV controlled substance under the Controlled Substances Act. Use of eszopiclone may lead to physical and psychological dependence. The risk of non-medical use and dependence increases with the dose and duration of usage and concomitant use of other psychoactive substances. The risk is also greater in patients with a history of alcohol use disorder or other substance use disorder or history of psychiatric disorders. Tolerance may develop after repeated use of benzodiazepines and benzodiazepine-like drugs for a few weeks.
A study funded and carried out by Sepracor, the manufacturer of eszopiclone, found no signs of tolerance or dependence in a group of patients followed for up to six months.

Non-medical use
A study of non-medical use potential of eszopiclone found that in persons with a known history of non-medical benzodiazepine use, eszopiclone at doses of 6 and 12 mg produced effects similar to those of diazepam 20 mg. The study found that at these doses which are two or more times greater than the maximum recommended doses, a dose-related increase in reports of amnesia, sedation, sleepiness, and hallucinations was observed for both eszopiclone (Lunesta) as well as for diazepam (Valium).

Overdose
According to the U.S. Prescribing Information, overdoses of eszopiclone up to 90 times the recommended dose have been reported in which the patient fully recovered. According to the May 2014 edition of the official U.S. Prescribing Information, fatalities have been reported only in cases in which eszopiclone was combined with other drugs or alcohol.Poison control centers reported that between 2005 and 2006 there were 525 total eszopiclone overdoses recorded in the state of Texas, the majority of which were intentional suicide attempts.If consumed within the last hour, eszopiclone overdose can be treated with the administration of activated charcoal or via gastric lavage.

Interactions
There is an increased risk of central nervous system depression when eszopiclone is taken together with other CNS depressant agents, including antipsychotics, sedative hypnotics (like barbiturates or benzodiazepines), antihistamines, opioids, phenothiazines, and some antidepressants. There is also increased risk of central nervous system depression with other medications that inhibit the metabolic activities of the CYP3A4 enzyme system of the liver. Medications that inhibit this enzyme system include nelfinavir, ritonavir, ketoconazole, itraconazole and clarithromycin. Alcohol also has an additive effect when used concurrently with eszopiclone. Eszopiclone is most effective if it is not taken after a heavy meal with high fat content.

Pharmacology
Eszopiclone acts on benzodiazepine binding site situated on GABAA neurons as a positive allosteric modulator.
Eszopiclone is rapidly absorbed after oral administration, with serum levels peaking between .45 and 1.3 hours. The elimination half-life of eszopiclone is approximately 6 hours and it is extensively metabolized by oxidation and demethylation. Approximately 52% to 59% of a dose is weakly bound to plasma protein. Cytochrome P450 (CYP) isozymes CYP3A4 and CYP2E1 are involved in the biotransformation of eszopiclone; thus, drugs that induce or inhibit these CYP isozymes may affect the metabolism of eszopiclone. Less than 10% of the orally administered dose is excreted in the urine as racemic zopiclone. In terms of benzodiazepine receptor binding and relevant potency, 3 mg of eszopiclone is equivalent to 10 mg of diazepam.

History
In a controversial 2009 article in the New England Journal of Medicine, "Lost in Transmission — FDA Drug Information That Never Reaches Clinicians", it was reported that the largest of three Lunesta trials found that compared to placebo Lunesta "was superior to placebo" while it only shortened initial time falling asleep by 15 minutes on average. "Clinicians who are interested in the drug’s efficacy cannot find efficacy information in the label: it states only that Lunesta is superior to placebo. The FDA’s medical review provides efficacy data, albeit not until page 306 of the 403-page document. In the longest, largest phase 3 trial, patients in the Lunesta group reported falling asleep an average of 15 minutes faster and sleeping an average of 37 minutes longer than those in the placebo group. However, on average, Lunesta patients still met criteria for insomnia and reported no clinically meaningful improvement in next-day alertness or functioning."

Availability in Europe
On September 11, 2007, Sepracor signed a marketing deal with British pharmaceutical company GlaxoSmithKline for the rights to sell eszopiclone (under the name Lunivia rather than Lunesta) in Europe </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 Calcium citrate and can you explain it in depth? [/INST] Calcium citrate is the calcium salt of citric acid.  It is commonly used as a food additive (E333), usually as a preservative, but sometimes for flavor.  In this sense, it is similar to sodium citrate.   Calcium citrate is also found in some dietary calcium supplements (e.g. Citracal or Caltrate). Calcium makes up 24.1% of calcium citrate (anhydrous) and 21.1% of calcium citrate (tetrahydrate) by mass </s>