Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. These contrast with benign tumors, which do not spread to other parts of the body.Possible signs and symptoms include a lump, abnormal bleeding, prolonged cough, unexplained weight loss and a change in bowel movements. While these symptoms may indicate cancer, they may have other causes. Over 100 types of cancers affect humans.
Mercaptopurine 50mg (Tab: Leukin50mg)
| Clinical data | |
|---|---|
| Trade names | Purinethol, others |
| Synonyms | 6-mercaptopurine (6-MP) |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a682653 |
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| Routes of administration |
by mouth |
| ATC code |
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| Legal status | |
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| Pharmacokinetic data | |
| Bioavailability | 5 to 37% |
| Metabolism | xanthine oxidase |
| Biological half-life | 60 to 120 min., longer for its active metabolites |
| Excretion | kidney |
| Identifiers | |
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| PubChem CID |
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| IUPHAR/BPS |
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| DrugBank |
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Mercaptopurine (6-MP), sold under the brand name Purinethol among others, is a medication used for cancer and autoimmune diseases.Specifically it is used to treat acute lymphocytic leukemia (ALL), chronic myeloid leukemia (CML), Crohn’s disease, and ulcerative colitis. For ALL it is generally used with methotrexate. It is taken by mouth.
Common side effects include bone marrow suppression, liver toxicity, vomiting, and loss of appetite. Other serious side effects include an increased risk of future cancer and pancreatitis. Those with a genetic deficiency in thiopurine S-methyltransferase are at higher risk of side effects. Use in pregnancy may harm the baby. Mercaptopurine is in the thiopurine and antimetabolite family of medications.
Mercaptopurine was approved for medical use in the United States in 1953. It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system. The wholesale cost in the developing world is about 18.42 to 200.16 USD a month. In the United Kingdom this costs the NHS about 121.13 pounds per month. In the United States the wholesale cost is about 99.16 USD per month as of 2016.
Contents
Allopurinol inhibits xanthine oxidase, the enzyme that breaks down mercaptopurine. Those taking allopurinol (often used to prevent gout) are at risk for mercaptopurine toxicity. The dose should be reduced or allopurinol should be discontinued. Several published studies have demonstrated that the use of allopurinol in combination with low dose 6-MP helps reduce 6-MP levels, which are toxic to liver tissue, whilst increasing the therapeutic levels of 6-MP for some inflammatory conditions.
Mechanisms of action
This section may be too technical for most readers to understand.
Mercaptopurine (6-MP) competes with the purine derivatives hypoxanthine and guanine for the enzyme HGPRT and is itself converted to the inosine monophosphate (TIMP).Official information from the package insert for Purinethol:
- TIMP inhibits several chemical reactions involving inosinic acid (IMP), including the conversion of IMP to xanthylic acid (XMP) and the conversion of IMP to adenylic acid (AMP) via adenylosuccinate (SAMP).
- In addition, 6-methylthioinosinate (MTIMP) is formed by the methylation of TIMP. Both TIMP and MTIMP have been reported to inhibit glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis. Experiments indicate that radiolabeled mercaptopurine may be recovered from the DNA in the form of deoxythioguanosine.
- Some mercaptopurine is converted to nucleotide derivatives of 6-thioguanine (6-TG) by the sequential actions of inosinate (IMP) dehydrogenase and xanthylate (XMP) aminase, converting TIMP to thioguanylic acid (TGMP).
- Animal tumors that are resistant to mercaptopurine often have lost the ability to convert mercaptopurine to TIMP. However, it is clear that resistance to mercaptopurine may be acquired by other means as well, particularly in human leukemias.
- It is not known exactly which of any one or more of the biochemical effects of mercaptopurine and its metabolites are directly or predominantly responsible for cell death.
6-MP ribonucleotide inhibits purine nucleotide synthesis and metabolism by inhibiting an enzyme called Phosphoribosyl pyrophosphate amidotransferase (PRPP Amidotransferase). PRPP Amidotransferase is the rate limiting enzyme of purine synthesis. This alters the synthesis and function of RNA and DNA.[citation needed] Mercaptopurine interferes with nucleotide interconversion and glycoprotein synthesis.
Pharmacogenetics
The enzyme thiopurine S-methyltransferase (TPMT) is responsible, in part, for the inactivation of 6-mercaptopurine. TPMT catalyzes the methylation of 6-mercaptopurine into the inactive metabolite 6-methylmercaptopurine – this methylation prevents mercaptopurine from further conversion into active, cytotoxic thioguanine nucleotide (TGN) metabolites. Certain genetic variations within the TPMT gene can lead to decreased or absent TPMT enzyme activity, and individuals who are homozygous or heterozygous for these types of genetic variations may have increased levels of TGN metabolites and an increased risk of severe bone marrow suppression (myelosuppression) when receiving mercaptopurine. In many ethnicities, TPMT polymorphisms that result in decreased or absent TPMT activity occur with a frequency of approximately 5%, meaning that about 0.25% of people are homozygous for these variants. However, an assay of TPMT activity in red blood cells or a TPMT genetic test can identify people with reduced TPMT activity, allowing for the adjustment of mercaptopurine dose or avoidance of the drug entirely. The FDA-approved drug label for mercaptopurine recommends testing for TPMT activity to identify people at risk for myelotoxicity. Indeed, testing for TPMT activity is currently one of the few examples of pharmacogenetics being translated into routine clinical care.
- What Mercaptopurine is and what it is used for mercaptopurine tablets contain the active substance called 6-mercaptopurine. 6-mercaptopurine belongs to a group of medicines called cytotoxics (also called chemotherapy) and works by reducing the number of new blood cells your body makes. Mercaptopurine is used to treat cancer of the blood (leukemia) in adults, adolescents, and children.
- What you need to know before you take Mercaptopurine Do not take Mercaptopurine. If you are allergic to 6-mercaptopurine or any of the other ingredients of this medicine (listed in section 6).
Warnings and precautions
Talk to your doctor or pharmacist before taking Mercaptopurine
- If you have recently received, or are due to receive, a vaccination (vaccine). If you take Mercaptopurine, you should not have a live organism vaccine (for example; flu vaccine, measles vaccine, BCG vaccine, etc.) until advised it is safe to do so by your doctor. This is because some vaccines may give you an infection if you receive them while you are taking Mercaptopurine
- If you have reduced liver function or liver damage
- If you have a genetic condition called TPMT (thiopurine methyltransferase) deficiency
- If you have an allergy to a medicine called azathioprine (also used to treat cancer)
- If you have a kidney problem.
- Tell your doctor whether you have, or have not, had chickenpox, shingles or hepatitis B (a liver disease caused by a virus).
- If you have a genetic condition called Lesch-Nyhan Syndrome
If you are receiving immunosuppressive therapy, taking Mercaptopurine could put you at greater risk of:
Tumours, including skin cancer. Therefore, when taking Mercaptopurine, avoid excessive exposure to sunlight, wear protective clothing and use protective sunscreen with a high protection factor.
lymphoproliferative disorders:
- treatment with Mercaptopurine increases your risk of getting a type of cancer called lymphoproliferative disorder. Witha treatment regimen containing multiple immunosuppressants (including thiopurines), this may lead to death.
- a combination of multiple immunosuppressants, given concomitantly increases the risk of disorders of the lymph system due to a viral infection (Epstein-Barr virus (EBV) – associated lymphoproliferative disorders).
Taking Puri-nethol could put you at greater risk of
- developing a serious condition called Macrophage Activation Syndrome (excessive activation of white blood cells associated with inflammation), which usually occurs in people who have certain types of arthritis.
Blood tests
- Treatment with Mercaptopurine may affect your bone marrow. This means you may have a reduced number of white blood cells, platelets and (less commonly) red blood cells in your blood. Your doctor will carry out blood tests daily when you are at the beginning of your treatment (induction) and at least weekly when you are further along into your treatment (maintenance). This is in order to monitor the levels of these cells in your blood. If you stop treatment early enough, your blood cells will return to normal.
Other laboratory tests
- Additional laboratory tests (urine, blood, etc.) may also be carried out as directed by your doctor.
Liver function
- Mercaptopurine is toxic to your liver. Therefore, your doctor will carry out weekly liver function tests when you are taking Mercaptopurine. If you already have liver disease, or if you are taking other medications which may affect your liver, your doctor will carry out more frequent tests. If you notice the whites of your eyes or your skin turn yellow (jaundice) tell your doctor immediately as you may need to stop your treatment immediately.
Infections
- When you are taking Mercaptopurine you may be more likely to get infections caused by viruses, bacteria and fungus and your reaction to these infections may be more severe than people who are not being taking Mercaptopurine. If you think you have an infection, talk to your doctor immediately.
Children and adolescents
Low blood sugar levels (sweating more than usual, nausea, dizziness, confusion, etc.) have been reported in some children receiving Mercaptopurine; however, most of the children were under the age of six years old and had a low body weight.
If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before taking Mercaptopurine.
Other medicines and Mercaptopurine
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.
In particular, tell your doctor or pharmacist if you are taking any of the following:
- Ribavirin (used to treat viruses)
- Other cytotoxic medicines (chemotherapy – used to treat cancer)
- Allopurinol, thiopurinol, oxipurinol or febuxostat (used to treat gout)
- Olsalazine (used to treat a bowel problem called ulcerative colitis)
- Mesalazine (used to treat Crohn’s Disease and ulcerative colitis)
- Sulfasalazine (used to treat rheumatoid arthritis or ulcerative colitis)
- Methotrexate (used to treat rheumatoid arthritis or severe psoriasis)
- Infliximab (used to treat Crohn’s Disease and ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis or severe psoriasis)
- Warfarin or acenocoumarol (used to ‘thin’ the blood)
Having vaccines while you are taking Mercaptopurine
- If you are going to have a vaccination speak to your doctor or nurse before you have it. If you take Mercaptopurine, you should not have a live vaccine (for example; flu vaccine, measles vaccine, BCG vaccine, etc.) until advised it is safe to do so by your doctor. This is because some vaccines may give you an infection if you have them whilst you are taking Mercaptopurine.
- Mercaptopurine with food and drink, You can take Mercaptopurine with food or on an empty stomach but the choice of method should be consistent from day to day. You should take your medicine at least 1 hour before or 2 hours after having milk or dairy products.
Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.
Pregnancy
Treatment with Mercaptopurine is not recommended during pregnancy, particularly in the first trimester (three months) because it may cause damage to the foetus. If you are pregnant your doctor will consider the risks and benefits to you and your baby before prescribing Mercaptopurine for you.
If you or your partner are taking Mercaptopurine, you must use a reliable form of contraception to avoid pregnancy for the whole course of Mercaptopurine treatment and for at least 3 months after receiving the last dose of Mercaptopurine. This applies to both men and women.
Bone marrow suppression
Treatment with 6-mercaptopurine causes bone marrow suppression leading to leukopenia and thrombocytopenia and, less frequently, to anaemia. Full blood counts must be taken frequently during remission induction. During maintenance therapy, complete blood counts, including platelets, should be regularly monitored and more frequently if high dosage is used or if severe renal and/or hepatic disorder is present.
Increased haematological monitoring of the patient is advised when switching between different pharmaceutical formulations of mercaptopurine.
The leukocyte and platelet counts continue to fall after treatment is stopped, so at the first sign of an abnormally large fall in the counts, treatment should be interrupted immediately.
Bone marrow suppression is reversible if 6-mercaptopurine is withdrawn early enough.
During remission induction in acute myelogenous leukaemia, the patient may frequently have to survive a period of relative bone marrow aplasia and it is important that adequate supportive facilities are available.
The dosage of 6-mercaptopurine may need to be reduced when this agent is combined with other medicinal products whose primary or secondary toxicity is myelosuppression (see Section 4.5 Interaction with other medicinal products and other forms of interactions: Myelosuppressive agents).
Hepatotoxicity
6-mercaptopurine is hepatotoxic and liver function tests should be monitored weekly during treatment. Gamma glutamyl transferase (GGT) levels in plasma may be particularly predictive of withdrawal due to hepatotoxicity. More frequent monitoring may be advisable in those with pre-existing liver disease or receiving other potentially hepatotoxic therapy. The patient should be instructed to discontinue 6-mercaptopurine immediately if jaundice becomes apparent.
Tumour lysis syndrome
During remission induction when rapid cell lysis is occurring, uric acid levels in blood and urine should be monitored as hyperuricaemia and/or hyperuricosuria may develop, with the risk of uric acid nephropathy.
TPMT Deficiency
There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effect of 6-mercaptopurine and prone to developing rapid bone marrow depression following the initiation of treatment with 6-mercaptopurine. This problem could be exacerbated by co-administration with medicinal products that inhibit TPMT, such as olsalazine, mesalazine or sulfazalazine. Also, a possible association between decreased TPMT activity and secondary leukaemias and myelodysplasia has been reported in individuals receiving 6–mercaptopurine in combination with other cytotoxics (see Section 4.8 Undesirable effects). Approximately 0.3 % (1:300) of patients have little or no detectable enzyme activity. Approximately 10 % of patients have low or intermediate TPMT activity and 90 % of individuals have normal TPMT activity. There may also be a group of approximately 2 % who have very high TPMT activity. Some laboratories offer testing for TPMT deficiency, although these tests have not been shown to identify all patients at risk of severe toxicity. Therefore close monitoring of blood counts is still necessary.
Cross Resistance
Cross resistance usually exists between 6-mercaptopurine and 6-thioguanine.
Hypersensitivity
Patients suspected to have previously presented with a hypersensitivity reaction to 6-mercaptopurine should not be recommended to use its pro-drug azathioprine, unless the patient has been confirmed as hypersensitive to 6-mercaptopurine with allergological tests, and tested negative for azathioprine. As azathioprine is a pro-drug of 6-mercaptopurine, patients with a previous history of hypersensitivity to azathioprine must be assessed for hypersensitivity to 6-mercapopurine prior to initiating treatment.
Renal and/or hepatic impairment
Caution is advised during the administration of 6-mercaptopurine in patients with renal impairment and/or hepatic impairment. Consideration should be given to reducing the dosage in these patients and haematological response should be carefully monitored (see section 4.2 Posology and method of administration and section 5.2 Pharmacokinetic properties: Special populations).
Mutagenicity and carcinogenicity
Patients receiving immunosuppressive therapy, including mercaptopurine, are at an increased risk of developing lymphoproliferative disorders and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi’s and non-Kaposi’s) and uterine cervical cancer in situ. The increased risk appears to be related to the degree and duration of immunosuppression. It has been reported that discontinuation of immunosuppression may provide partial regression of the lymphoproliferative disorder.
A treatment regimen containing multiple immunosuppressants (including thiopurines) should therefore be used with caution as this could lead to lymphoproliferative disorders, some with reported fatalities. A combination of multiple immunosuppressants, given concomitantly increases the risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders.
Increases in chromosomal aberrations were observed in the peripheral lymphocytes of leukaemic patients, in a hypernephroma patient who received an unstated dose of 6-mercaptopurine and in patients with chronic renal disease treated at doses of 0.4 to 1.0 mg/kg/day.
Two cases have been documented of the occurrence of acute non-lymphatic leukaemia in patients who received 6-mercaptopurine, in combination with other medicinal products, for non-neoplastic disorders. A single case has been reported where a patient was treated for pyoderma gangrenosum with 6-mercaptopurine and later developed acute non-lymphatic leukaemia, but it is not clear whether this was part of the natural history of the disease or if the 6-mercaptopurine played a causative role.
A patient with Hodgkin’s disease treated with 6-mercaptopurine and multiple additional cytotoxic agents developed acute myelogenous leukaemia.
Twelve and a half years after 6-mercaptopurine treatment for myasthenia gravis, a female patient developed chronic myeloid leukaemia.
Reports of hepatosplenic T-cell lymphoma in the Inflammatory Bowel Disease (IBD) population (unlicensed indication) have been received when 6-mercaptopurine is used in combination with anti-TNF agents (see section 4.8 Undesirable effects).
Macrophage activation syndrome
Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in patients with autoimmune conditions, in particular with inflammatory bowel disease (IBD) (unlicensed indication), and there could potentially be an increased susceptibility for developing the condition with the use of mercaptopurine. If MAS occurs, or is suspected, evaluation and treatment should be started as early as possible, and treatment with mercaptopurine should be discontinued. Physicians should be attentive to symptoms of infection such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS.
Paediatric population
Cases of symptomatic hypoglycaemia have been reported in children with ALL receiving 6-mercaptopurine (see Section 4.8 Undesirable Effects). The majority of reported cases were in children under the age of six or with a low body mass index.
Infections
Patients treated with 6-mercaptopurine alone or in combination with other immunosuppressive agents, including corticosteroids, have shown increased susceptibility to viral, fungal and bacterial infections, including severe or atypical infection, and viral reactivation. The infectious disease and complications may be more severe in these patients than in non-treated patients.
Prior exposure to or infection with varicella zoster virus should be taken into consideration prior to starting treatment. Local guidelines may be considered, including prophylactic therapy if necessary. Serologic testing prior to starting treatment should be considered with respect to hepatitis B. Local guidelines may be considered, including prophylactic therapy for cases which have been confirmed positive by serologic testing. If the patient is infected during treatment appropriate measures should be taken, which may include antiviral therapy and supportive care.
Lesch-Nyhan syndrome
Limited evidence suggests that neither 6-mercaptopurine nor its pro-drug azathioprine are effective in patients with the rare inherited condition complete hypoxanthine-guanine-phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome). The use of 6-mercaptopurine or azathioprine is not recommended in these patients.
UV exposure
Patients treated with 6-mercaptopurine are more sensitive to the sun. Exposure to sunlight and UV light should be limited, and patients should be recommended to wear protective clothing and to use a sunscreen with a high protection factor.
Lactose
Patients with rare hereditary problems of galactose intolerance, complete lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Xanthine oxidase inhibitors
Patients treated with the xanthine oxidase inhibitors allopurinol, oxipurinol or thiopurinol, and 6-mercaptopurine should only receive 25 % of the usual dose of 6-mercaptopurine since allopurinol decreases the rate of catabolism of 6-mercaptopurine (see Section 4.2 Posology and method of administration and Section 4.5 Interaction with other medicinal products and other forms of interaction).
Anticoagulants
Inhibition of the anticoagulant effect of warfarin and acenocoumarol has been reported when co-administered with 6-mercaptopurine; therefore higher doses of the anticoagulant may be needed
Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Section 4.4 Special warnings and precautions for use).
The administration of 6–mercaptopurine with food may decrease systemic exposure slightly. 6-mercaptopurine may be taken with food or on an empty stomach, but patients should standardise the method of administration to avoid large variability in exposure. The dose should not be taken with milk or dairy products since they contain xanthine oxidase, an enzyme which metabolises 6–mercaptopurine and might therefore lead to reduced plasma concentrations of mercaptopurine.
Effect of concomitant medicinal products on 6-mercaptopurine
Ribavirin
Ribavirin inhibits the enzyme, inosine monophosphate dehydrogenase (IMPDH), leading to a lower production of the active 6-thioguanine nucleotides. Severe myelosuppression has been reported following concomitant administration of a pro-drug of 6-mercaptopurine and ribavirin; therefore concomitant administration of ribavirin and 6-mercaptopurine is not advised (see section 4.4 Special warnings and precautions for use and section 5.2 Pharmacokinetic properties: metabolism).
Myelosuppressive agents
When 6-mercaptopurine is combined with other myelosuppressive agents caution should be used; dose reductions may be needed based on haematological monitoring (see section 4.4 Special warnings and precautions for use).
Allopurinol/oxipurinol/thiopurinol and other xanthine oxidase inhibitors
Xanthine oxidase activity is inhibited by allopurinol, oxipurinol and thiopurinol, which results in reduced conversion of biologically active 6-thioinosinic acid to biologically inactive 6-thiouric acid. When allopurinol, oxipurinol and/or thiopurinol and 6-mercaptopurine are administered concomitantly it is essential that only 25 % of the usual dose of 6-mercaptopurine is given (see section 4.2 Posology and method of administration: Medicinal product interactions).
Other xanthine oxidase inhibitors, such as febuxostat, may decrease the metabolism of 6-mercaptopurine. Concomitant administration is not recommended as data are insufficient to determine an adequate dose reduction.
Aminosalicylates
There is in vitro and in vivo evidence that aminosalicylate derivatives (e.g. olsalazine, mesalazine or sulfazalazine) inhibit the TPMT enzyme. Therefore, lower doses of 6-mercaptopurine may need to be considered when administered concomitantly with aminosalicylate derivatives (see Section 4.4 Special warnings and precautions for use).
Methotrexate
Methotrexate (20 mg/m2 orally) increased 6-mercaptopurine AUC by approximately 31% and methotrexate (2 or 5 g/m2intravenously) increased 6-mercaptopurine AUC by 69 and 93%, respectively. Therefore, when 6-mercaptopurine is administered concomitantly with high dose methotrexate, the dose should be adjusted to maintain a suitable white blood cell count.
Infliximab
Interactions have been observed between azathioprine, a pro-drug of 6-mercaptopurine, and infliximab. Patients receiving ongoing azathioprine experienced transient increases in 6-TGN (6-thioguanine nucleotide, an active metabolite of azathioprine) levels and decreases in the mean leukocyte count in the initial weeks following infliximab infusion, which returned to previous levels after 3 months.
Effect of 6-mercaptopurine on other medicinal products
Anticoagulants
Inhibition of the anticoagulant effect of warfarin and acenocoumarol has been reported when co-administered with 6-mercaptopurine; therefore higher doses of the anticoagulant may be needed. It is recommended that coagulation tests are closely monitored when anticoagulants are concurrently administered with 6-mercaptopurine.
Fertility
The effect of 6–mercaptopurine therapy on human fertility is unknown.
There are reports of successful fatherhood/motherhood after receiving treatment during childhood or adolescence.
Transient oligospermia has been reported following exposure to 6–mercaptopurine.
Pregnancy
Substantial transplacental and transamniotic transmission of 6-mercaptopurine and its metabolites from the mother to the foetus have been shown to occur.
The use of 6-mercaptopurine should be avoided whenever possible during pregnancy, particularly during the first trimester. In any individual case the potential hazard to the foetus must be balanced against the expected benefit to the mother.
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised if either partner is receiving 6-mercaptopurine tablets, during treatment and for at least three months after receiving the last dose.
Studies of 6-mercaptopurine in animals have shown reproductive toxicity (see Section 5.3 Preclinical safety data). The potential risk for humans is largely unknown.
Maternal exposure:
Normal offspring have been born after 6-mercaptopurine therapy administered as a single chemotherapy agent during human pregnancy, particularly when given prior to conception or after the first trimester.
Abortions and prematurity have been reported after maternal exposure. Multiple congenital abnormalities have been reported following maternal 6-mercatopurine treatment in combination with other chemotherapy agents.
Paternal exposure
Congenital abnormalities and spontaneous abortions have been reported after paternal exposure to 6-mercaptopurine.
Breast-feeding
6-mercaptopurine has been detected in the breast milk of renal transplant patients receiving immunosuppressive therapy with a pro-drug of 6-mercaptopurine. It is recommended that mothers receiving 6-mercaptopurine should not breast-feed.
There are no data on the effect of 6-mercaptopurine on driving performance or the ability to operate machinery. A detrimental effect on these activities cannot be predicted from the pharmacology of the medicinal product.
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