Arthritis Australia

By Z. Gnar. University of California, Merced. 2018.

The disease result- ing from the compromised enzymatic activity of any one of the degradation steps is shown in italics order fluoxetine 20 mg otc. Substrate degradation in the lysosome occurs as sequential processes buy fluoxetine 10 mg overnight delivery, with disruption of any specic step resulting in the accumulation of one or more substrate(s), cellular dysfunction and the manifestation of disease pathology. In addition, currently approved therapies as well as investigational drugs, both past and present, are pre- sented. It is now understood that compromised lysosomal enzyme activity is frequently the result of mutations in the genes that encode these enzymes. While some of these mutations involve large insertions or deletions, frame shis, or premature stop codons that lead to the synthesis of no enzyme or a catalytically inactive enzyme, some mutations are fairly subtle and lead to the production of enzymes that differ from wild type only by a single amino acid residue (i. A large number of analogues of these inhibitors have also been synthesised and evaluated for their ability to bind and stabilise mutant lysosomal enzymes, many of which have recently been reviewed. It has been argued that small fragment libraries can more efficiently probe drug space for protein or receptor binding compared to larger drug-like molecules. Although this approach is quite new, some recent success in the identication of active leads for some non-lysosomal protein targets, and even a clinical candidate, has been reported. As will be described below, many of these assays clearly distinguish active site versus allosteric binding, although in some cases follow-up assays are required to clearly elucidate the mechanism of action. These assays have been well characterised and are readily adapt- able to 96-, 384- and 1536-well formats. Typically, these are end-point assays using a single concentration of test compound, although variations have been incorporated in certain cases. Rather than the conventional end-point uorescence determi- nation that can produce a signicant number of false-negatives and/or false- positives due to auto-uorescence and uorescence quenching, respectively, this modied assay technique relied on continuous monitoring of a uores- cent product over a 25 minute period. Interestingly, it was discovered that assays run using tissue homogenates (normal or N370S) yielded dramatically different results compared to assays run with the puried recombinant enzymes. The reasons for this are not entirely clear, but do probably reect the activity of the natural cofactors present in tissue homogenates. A second series of compounds was later found that increased enzyme activity in this assay; again medicinal chemistry led to the identication of 38 as the optimised lead for this series. While this series of compounds has produced the rst evidence of enzyme stabilisation through allosteric binding, questions around their ability to reduce endogenous substrate levels remain unanswered. Multiple approaches have been used to demonstrate changes in the physical stability of lysosomal enzymes as a function of pH, temperature and/or small molecule binding. To this end, thermal denaturation of many proteins causes signicant changes in the tertiary structure, thereby exposing hydrophobic amino acid residues, which are normally conned to the inner View Online 152 Chapter 6 core of these macromolecules, to the surrounding aqueous environment. Consequently, these uorophores can be used to evaluate protein stability (or melting) as a function of temperature. A signicant advantage of this approach is the ability to screen a wide variety of proteins/enzymes with a single assay set- up. However, alternative readouts for enzyme stability have been utilised and can help minimise this problem (vide infra). A variation of the thermostability assay that uses an activity-based readout as the end point also can be used. For this approach, activity measurements of enzyme preparations that have been incubated at an elevated temperature for a given period of time are compared to the enzyme activities of control samples that have been maintained in an ice bath. Typically, the elevated temperatures lead to relatively rapid protein denaturation, which is measured as a loss of activity using a simple enzyme activity assay. Haemoglobin level and platelet count as well as spleen and liver volume were monitored. Although results did not reach statistical signicance, positive results were seen in some patients, suggest- ing a follow-up study is warranted. In general, these assays tend to be more complex and difficult to utilise in large screening campaigns. They do, however, provide an effective way to prioritise compounds that have been identied via various screening strat- egies, and provide important information on mechanism of action. First, Western blot analysis is used to separate cellular proteins based on molecular weight, followed by detection and quantitation using chemiluminescence- or uorescence-based techniques. It is important to point out that increased protein levels, even increases in the fully mature isoforms, do not necessarily indicate that the mutant enzyme is active in situ and able to metabolise accumulated lysosomal substrates; other assays are necessary for these purposes (vide infra). As lysosomal hydrolases tend to have highest activity in an acidic environment, these assays typically utilise low pH buffers to minimise metabolism of the articial substrates by related cellular hydrolases that have higher pH optima. Alternatively, parallel assays can be run in the presence of selective inhibitors that can help quantify the contribution of substrate metabolism by non-lysosomal enzymes. Subcellular fractionation is the classical method for monitoring protein trafficking. As an alternative, and as discussed above, proteolytic processing of precursor proteins into mature forms can be used as an indirect marker for protein trafficking, provided that the processing is coupled to trafficking.

Intrinsic factor deficiencies are common in patients who have had total or partial gastrectomies or total ileal resection buy generic fluoxetine 10 mg on-line. Adverse reactions to vitamin B12 therapy No dose-related adverse reactions occur with vitamin B12 therapy cheap fluoxetine 20 mg without prescription. However, some rare reactions may occur when vitamin B12 is adminis- tered parenterally. Parenteral problems Adverse reactions to parenteral administration can include hypersensi- tivity reactions that could result in anaphylaxis and death, pulmonary edema, heart failure, peripheral vascular thrombosis, polycythemia vera, hypokalemia, itching, transient rash, hives, and mild diarrhea. Oral vitamin B12 preparations are used to supplement nutri- tional deficiencies of the vitamin. The parenteral and intranasal formulations are used to treat patients with pernicious anemia. Drug interactions Alcohol, aspirin, neomycin, chloramphenicol, and colchicine may decrease the absorption of oral cyanocobalamin. This type of anemia usually occurs in patients who have tropical or nontropical sprue, although it can also result from poor nutritional intake during pregnancy, infancy, or childhood. Pharmacokinetics Folic acid is absorbed rapidly in the first third of the small intes- tine, distributed into all body tissues, and metabolized in the liver. Excess folate is excreted unchanged in urine, and small amounts of folic acid are excreted in stool. Adverse Pharmacotherapeutics reactions to Folic acid is used to treat folic acid deficiency. Patients who are folic acid pregnant or undergoing treatment for liver disease, hemolytic ane- Adverse reactions to mia, alcohol abuse, or skin or renal disorders typically need folic folic acid include: acid supplementation. Serum folic acid levels below 5 ng/ml indi- • erythema cate folic acid deficiency. Folic drugs usually acid, iron, vitamin B12, replace one of Erythropoietin agents amino acids, copper, these missing and cobalt are all parts. After subQ administration, serum levels of epoetin alfa peak in 5 to 24 hours, while serum levels of darbepoetin alfa peak in 24 to 72 hours. The circulating half-life of epoetin alfa is also shorter at 4 to 13 hours, compared to 49 hours for darbepoetin alfa. The therapeutic effect of these agents lasts for several days after ad- ministration. Nor- mally, erythropoietin is formed in the kidneys in response to hy- poxia (reduced oxygen) and anemia. Adverse Pharmacotherapeutics reactions to Epoetin alfa is used to: erythropoietin • treat patients with anemia associated with chronic renal failure agents • treat anemia associated with zidovudine therapy in patients with human immunodeficiency virus infection Hypertension is the most • treat anemia in cancer patients receiving chemotherapy common adverse reac- • reduce the need for allogenic blood transfusions in surgical pa- tion. Major categories of anticoagulants include: • heparin and its derivatives • oral anticoagulants • antiplatelet drugs Heparin prevents • direct thrombin inhibitors clots from forming • factor Xa inhibitor drugs. Heparin Heparin, prepared commercially from animal tissue, is an anti- thrombolytic agent used to treat and prevent clot formation. Be- cause it doesn’t affect the synthesis of clotting factors, heparin can’t dissolve already-formed clots. This relationship between dose and effect is the rationale for using low-dose heparin to pre- vent clotting. Howev- er, these times may be only slightly prolonged with low or ultra- low preventive doses. Pharmacotherapeutics Heparin may be used in a number of clinical situations to prevent the formation of new clots or the extension of existing clots. Dosage adjust- ments, based on the test results, are typically necessary to ensure ther- apeutic effectiveness without increased risk of bleeding. Heparin-induced thrombocytopenia Platelet counts should be monitored in all patients receiving heparin therapy. Circulate freely Heparin can be used to prevent clotting whenever the patient’s blood must circulate outside the body through a machine, such as the cardiopulmonary bypass machine or hemodialysis machine, and during blood transfusions. Adverse reactions to heparin One advantage of heparin is that it produces relatively few adverse re- actions. Even so, these reactions can usually be prevented if the pa- tient’s partial thromboplastin time is maintained within the therapeutic Heparin increases range. If a ly by administering protamine sulfate, which binds to heparin to form a patient is also taking stable salt. Other adverse reactions include bruising, hematoma formation, necrosis of skin or other tissue, and thrombocytopenia. Drug interactions • Because heparin acts synergistically with all oral anticoagu- lants, the risk of bleeding increases when the patient takes both drugs together.

I (4–1–10 Edition) different food discount 10 mg fluoxetine, shall provide nutrition (vi) Ounces with an appropriate vis- information for each variety or food ual unit of measure buy fluoxetine 20mg free shipping, as described in per serving size that is derived from paragraph (b)(5)(iii) of this section, the reference amount in §101. The serving household measures, except as speci- size may be provided in accordance fied in paragraphs (b)(5)(iv), (b)(5)(v), with the provisions of paragraphs (b)(5)(vi), and (b)(5)(vii) of this section, (b)(2)(i), (b)(2)(ii), and (b)(2)(iii) of this the following rules shall be used: section, or alternatively in ounces with (i) Cups, tablespoons, or teaspoons an appropriate visual unit of measure, shall be used wherever possible and ap- as described in paragraph (b)(5)(iii) of propriate except for beverages. Cups shall be expressed in about 2/3 cup)" and "1 oz dry cheese 1/4- or 1/3-cup increments. Tablespoons mix (28 g/about 2 tbsp);" declared as a shall be expressed as 1, 1 1/3, 1 1/2, 1 2/ composite value: "4 oz (112 g/about 2/3 3, 2, or 3 tablespoons. Teaspoons shall cup macaroni and 2 tbsp dry cheese be expressed as 1/8, 1/4, 1/2, 3/4, 1, or 2 mix)"). A description of the indi- labeled as one serving except for prod- vidual unit shall be used for other ucts that have reference amounts of 100 products in discrete units (e. Packages sold individually that are usually divided for consump- that contain 200 percent or more of the tion (e. The number of should be rounded to the nearest whole servings between 2 and 5 servings shall number except for quantities that are be rounded to the nearest 0. The gram (mL) Rounding should be indicated by the quantity between 2 and 5 g (mL) should use of the term about (e. The ounce quantity equivalent the number of servings per container to the metric quantity should be ex- provided the nutrition information is pressed in 0. The manufacturer abbreviations for units, the following may provide the typical number of abbreviations shall be used: tbsp for ta- servings in parenthesis following the blespoon, tsp for teaspoon, g for gram, "varied" statement. I (4–1–10 Edition) of individual packages within the total eggs, butter, margarine), and multipur- package. No nutrients or food compo- basis of food as packaged or purchased nents other than those listed in this with the exception of raw fish covered paragraph as either mandatory or vol- under §101. Except as provided for in fish or game meat as provided for in paragraph (j)(11) of this section, and of paragraphs (f) or (j) of this section, nu- foods that are packed or canned in trient information shall be presented water, brine, or oil but whose liquid using the nutrient names specified and packing medium is not customarily in the following order in the formats consumed (e. Declaration of nu- (1) "Calories, total," "Total cal- trient and food component content of ories," or "Calories": A statement of raw fish shall follow the provisions in the caloric content per serving, ex- §101. Declaration of the nutrient and pressed to the nearest 5-calorie incre- food component content of foods that ment up to and including 50 calories, are packed in liquid which is not cus- and 10-calorie increment above 50 cal- tomarily consumed shall be based on ories, except that amounts less than 5 the drained solids. En- (10) Another column of figures may ergy content per serving may also be be used to declare the nutrient and expressed in kilojoule units, added in food component information: parentheses immediately following the (i) Per 100 g or 100 mL, or per 1 oz or statement of the caloric content. Where either (ii) Per one unit if the serving size of specific or general food factors are a product in discrete units in a multi- used, the factors shall be applied to the serving container is more than 1 unit; actual amount (i. Amounts shall be ex- (D) Using data for specific food fac- pressed to the nearest 0. Except as total fat as defined in paragraph (c)(2) provided for in paragraph (f) of this of this section in a serving, expressed section, if a statement of the saturated to the nearest 5-calorie increment, up fat content is not required and, as a re- to and including 50 calories, and the sult, not declared, the statement "Not nearest 10-calorie increment above 50 a significant source of saturated fat" calories, except that label declaration shall be placed at the bottom of the of "calories from fat" is not required table of nutrient values. I (4–1–10 Edition) grams and to the nearest gram incre- cept that when polyunsaturated fat is ment above 5 grams. The (3) "Cholesterol": A statement of the word "trans" may be italicized to indi- cholesterol content in a serving ex- cate its Latin origin. Trans fat content pressed in milligrams to the nearest 5- shall be indented and expressed as milligram increment, except that label grams per serving to the nearest 0. Except as or such products may state the choles- provided for in paragraph (f) of this terol content as zero. Except as pro- section, if a statement of the trans fat vided for in paragraph (f) of this sec- content is not required and, as a result, tion, if cholesterol content is not re- not declared, the statement "Not a sig- quired and, as a result, not declared, nificant source of trans fat" shall be the statement "Not a significant placed at the bottom of the table of nu- source of cholesterol" shall be placed trient values. Insoluble gram" may be used as an alternative, fiber content shall be indented under or if the serving contains less than 0. Total carbohydrate content shall tains less than 1 gram, the statement be calculated by subtraction of the sum "Contains less than 1 gram" or "less of the crude protein, total fat, mois- than 1 gram" may be used as an alter- ture, and ash from the total weight of native, and if the serving contains less the food. Sugars shall be not required or, alternatively, the defined as the sum of all free mono- statement "Contains less than 1 gram" and disaccharides (such as glucose, or "less than 1 gram" may be used, and fructose, lactose, and sucrose). Except as provided for in para- serving contains less than 1 gram, the graph (f) of this section, if dietary fiber statement "Contains less then 1 gram" content is not required and as a result, or "less than 1 gram" may be used as not declared, the statement "Not a sig- an alternative, and if the serving con- nificant source of dietary fiber" shall tains less than 0. Soluble fiber in the food, sugar alcohol content shall content shall be indented under dietary be declared. In lieu of the term protein content by weight: The state- "sugar alcohol," the name of the spe- ment "not a significant source of pro- cific sugar alcohol (e. Other carbo- adjacent to the declaration of protein hydrates shall be defined as the dif- content. Protein content may be cal- ference between total carbohydrate and culated on the basis of the factor of 6. Other car- tion of Official Analytical Chemists), bohydrate content shall be indented 15th Ed. The (i) For purposes of declaration of per- protein digestibility-corrected amino cent of Daily Value as provided for in acid score shall be determined by paragraphs (d), (e), and (f) of this sec- methods given in sections 5. For foods rep- include vitamin A, vitamin C, calcium, resented or purported for infants, the and iron, in that order, and shall in- corrected amount of protein (grams) clude any of the other vitamins and per serving is equal to the actual minerals listed in paragraph (c)(8)(iv) amount of protein (grams) per serving of this section when they are added as multiplied by the relative protein qual- a nutrient supplement, or when a claim ity value.

Chapter 9 details how patients may present to either primary or secondary care in states of acute withdrawal purchase fluoxetine 20mg with amex. In these instances order 10 mg fluoxetine with visa, healthcare professionals have a responsibility to manage the clinical emergency, stabilise the individual, and slow the rate of change so that their physiology can adapt and the distressing and uncomfortable symptoms of withdrawal are reduced. Doctors are also responsible for addressing the individual healthcare needs of patients who use drugs. In addition to harm-reduction measures, an essential part of managing this aspect of drug use should include offering immunisation against hepatitis to patients who want it. Harm reduction focuses on the safe use of drugs, and includes provision of clean injecting equipment and education on how to use drugs safely. There have been arguments over the ethics of harm reduction,28 and there is a perception among some healthcare professionals that harm-reduction techniques may lead to an increase in drug use by individuals who would otherwise be deterred. Those who support harm reduction assert that, rather than encouraging drug use, it offers a realistic way to help keep drug users safe, as well as respecting their choice and individual freedoms. Maintaining patients in high-quality treatment is the most effective preventative measure for these risks. Clinicians can also prevent the risk of drug overdose by providing education to drug users on the risks of overdose, the dangers of combining drugs, and how to respond effectively if overdose takes place. In the event of an overdose at a healthcare facility, all services working with drug users should have an emergency protocol in place that covers the management of drug overdoses (see Section 8. The drug debate, both nationally and internationally, has been influenced by emotions and ideologies, when, in reality, a subject as important as the use of drugs should be based on rationality and scientific evidence. What is needed is a solid and pragmatic approach to drug use, which is informed by the best available evidence and puts health at the centre of any decisions. There is a widely held view within the drugs field that the prohibition of production and supply of certain drugs has not only failed to deliver its intended goals, but has been counterproductive. Before this can occur, rational debate is needed to inform an understanding of what is, and what may not be, working with the current approach to drug use, and options for change. An essential component of this will be ensuring that all relevant parties, including health professionals, and the organisations that represent them, are consulted, so that a clear, unbiased and effective approach is achieved. The report recommends establishment of a Royal Commission – to be set up immediately and report in 2015 – to ‘consider the best ways of reducing the harm caused by drugs’ and ‘instigate a public debate on all of the alternatives to the current drug policy’. It presents strong arguments for focusing on problem drug users, with interventions that are ‘tailored to the individual’, and calls for the setting of measurable targets that are based on evidence of what works. Recognising the lack of reliable data in some areas, it further recommends allocation of ring-fenced funding to drugs policy research. Dependent drug users have the same rights to medical treatment as any other individuals with a chronic disorder, and effective medical management is likely to include harm reduction, maintenance treatment and support to eventually abstain from drug use. An effective drug policy must take account of the complex biological, psychological and social factors involved in illicit drug use and aim to distinguish the harms associated with drug use from the unintended adverse consequences of attempts to minimise drug use. An effective policy that significantly reduces the harms associated with illicit drug use would have enormous benefit for individuals and generate large savings to society in terms of the cost of medical treatment and the financial and social costs of associated crime. There is a widely held view within the drugs field that the current legal framework has failed to deliver its intended goals of reducing illicit drug use. There are strong views on both sides of this debate, but it should be informed by the best evidence. While it must be accepted that international consensus dictates that supply and possession of illicit drugs must remain a criminal offence, this framework deserves to be re-examined in a way that takes account of all the evidence available. Doctors are ideally placed to play a key role in refocusing debate and influencing global drug policy, so that it is based on public health principles, and founded on rigorous scientific evidence. Dr James Bell Professor Bailey was dual trained in child Consultant in Addictions Medicine, and adolescent psychiatry and forensic South London and Maudsley psychiatry. Dr Bell has been complex mental health needs who present active in the development of training as high risk of harm to others and programmes for health professionals, and themselves. She has worked in specialist was a leading figure in establishing the inpatient and community services, and has Chapter of Addiction Medicine within the interests in human rights in practice, and Royal Australasian College of Physicians. His mental health and social care policy in major research interest is the treatment of national and international contexts. Through opioid dependence but he has also recently various roles in the Royal College of developed a ‘party drugs’ clinic in South Psychiatrists, Professor Bailey has worked London, and has been involved in to support stronger partnerships between developing a new clinical pathway for users, carers and families. She has sought to management of acute alcohol withdrawal increase recognition of the importance of presenting to emergency departments. He has been Declaration of interests: funded to attend conferences and seminars Professor Bailey declares no support from by Reckittbenckiser, Schering-Plough any organisation for the submitted work and Corporation and Titan Pharmaceuticals. The Foundation has organised Addiction Psychiatry at the Chelsea and nine influential international drug policy Westminster Hospital and Honorary Senior seminars, hosted mainly at the House of Lecturer at Imperial College. He oversees Lords, and has commissioned over 35 books, three teams providing treatment for alcohol, drug policy reports and proceedings drugs and mental health problems. Dr Bowden-Jones is the drugs conventions that would give individual Chair of the Faculty of Addictions, Royal signatory countries more freedom to College of Psychiatrists. In this role he sits on experiment with alternative drug policies; a number of working groups. The position and (2) A cost/benefit analysis of a regulated also requires regular meetings with and taxed cannabis market in England and Government and other professional groups.

Metabolism and excretion Therefore fluoxetine 10 mg low price, to raise Sodium citrate and sodium lactate are metabolized to the active the pH buy fluoxetine 10mg online, you use an ingredient, bicarbonate. Pharmacodynamics Sodium bicarbonate separates in the blood, providing bicarbonate ions that are used in the blood buffer system to decrease the hy- Alkalinizing drogen ion concentration and raise blood pH. Hitching up with hydrogen Tromethamine acts by combining with hydrogen ions to alkalinize the blood; the resulting tromethamine–hydrogen ion complex is excreted in urine. Pharmacotherapeutics Alkalinizing drugs are commonly used to treat metabolic acidosis. Other uses include raising urine pH to help remove certain sub- stances, such as phenobarbital, after an overdose. Drug interactions The alkalinizing drugs sodium bicarbonate, sodium citrate, and sodium lactate can interact with a wide range of drugs to increase or decrease their pharmacologic effects. Adverse reactions to alkalinizing drugs Adverse reactions to alkalinizing drugs vary. Sodium lactate • Metabolic alkalosis (with overdose) Sodium bicarbonate • Extravasation • Bicarbonate overdose • Water retention or edema (in patient with • Cerebral dysfunction, tissue hypoxia, and kidney disease or heart failure) lactic acidosis (with rapid administration for diabetic ketoacidosis) Tromethamine • Water retention and edema • Hypoglycemia • Respiratory depression Sodium citrate • Extravasation • Metabolic alkalosis, tetany, or aggravation of • Hyperkalemia existing heart disease (with overdose) • Toxic drug levels (if given for more than • Laxative effect (with oral administration) 24 hours) Acidifying drugs When your Acidifying drugs are used to correct metabolic alkalosis. These stomach include: doesn’t feel quite right, you • acetazolamide (used in treatment of acute mountain sickness) might need • ammonium chloride. Absorption, metabolism, and excretion Orally administered ammonium chloride is absorbed completely in 3 to 6 hours. Break it down Acetazolamide inhibits the enzyme carbonic anhydrase, which blocks hydrogen ion secretion in the renal tubule, resulting in in- creased excretion of bicarbonate and a lower pH. Acetazolamide also acidifies urine but may produce metabolic acidosis in normal patients. Adverse • Ascorbic acid directly acidifies urine, providing hydrogen ions reactions to and lowering urine pH. Overdose may A patient with metabolic alkalosis requires therapy with an acidi- lead to acidosis. Acetazolamide • Drowsiness Safe and easy • Seizures Most patients receive both types of ions in oral or parenteral dos- • Anorexia es of ammonium chloride, a safer drug that’s easy to prepare. Ammonium chloride Oral forms of • Metabolic acidosis Drug interactions ammonium and loss of electrolytes, Acidifying drugs don’t cause clinically signifi- chloride are safer and especially potassium cant drug interactions. However, concurrent easier to (with large doses) use of ammonium chloride and spironolac- prepare. Hypokalemia is a common occurrence in conditions that increase potassium excretion or depletion, such as adminis- tration of glucocorticoid, I. Potassium should be used cautiously in patients re- ceiving potassium-sparing diuretics, such as amiloride, to avoid hyperkalemia. Drugs and cancer In the 1940s, antineoplastic (chemotherapeutic) drugs were de- veloped to treat cancer. A brighter future Today, many of these toxicities can be lessened so they aren’t as devastating to the patient. With modern chemotherapy, childhood malignancies, such as acute lymphoblastic leukemia, and adult cancers, such as testicular cancer, are curable in most patients. New therapeutic strategies, such as using monoclonal antibodies or targeting specific proteins, are further improving the time that a patient’s cancer can remain in remission. In addition, drugs such as interferons are being used to treat patients with cancer. Alkylating drugs Alkylating drugs, given alone or with other drugs, effectively act against various malignant neoplasms. This means that their alkylating actions may take place at any phase of the cell cycle. Nitrogen mustards I see some nitrogen mustards Nitrogen mustards represent the largest group of alkylating headed my way. First and fast Mechlorethamine hydrochloride was the first nitrogen mustard in- troduced and is rapid-acting. Pharmacokinetics (how drugs circulate) The absorption and distribution of nitrogen mustards, as with most alkylating drugs, vary widely. Metabolism and excretion Alkylating Nitrogen mustards are metabolized in the liver and excreted by drugs deactivate the kidneys. C G C G C G C G C G C G A T A T C G Drug C G T A T A G C G C may develop resistance to the cytotoxic effects of nitrogen mus- tards. The calcium in dairy products reduces the Drug interactions absorption of estramustine. Nitrogen mustards interact with a wide variety of other drugs: • Calcium-containing drugs and foods, such as antacids and dairy products, reduce absorption of estramustine. It’s also used for treatment of leukemia during bone marrow transplant procedures. Metabolism and excretion Other adverse reactions Busulfan is extensively metabolized in the liver before urinary ex- include: cretion. A backup option Busulfan is also effective in treating polycythemia vera, although Adverse other drugs are usually used to treat it because busulfan can cause severe myelosuppression (halting of bone marrow function). Concurrent use of busulfan and marrow suppression, thioguanine may cause liver toxicity, esophageal varices (en- producing severe larged, swollen veins in the esophagus), or portal hypertension leukopenia, anemia, and (increased pressure in the portal vein of the liver).