Isosorbide dinitrate

Isosorbide dinitrate (ISDN) (also known as Dilatrate) is a nitrate used pharmacologically as a vasodilator, e.g. in angina pectoris but also for anal fissure, a condition which is known to involve decreased blood supply leading to poor healing. It is also used as a direct vasodilator to treat congestive heart failure.

Isosorbide dinitrate is sold under the brand names Isordil^[1] by Biovail, Cedocard, Sorbitrate and Isotrate. In UK, Argentina and Hong Kong, a trade name of it is Isoket. It is also a component of BiDil.

Uses

It is more useful in preventing angina attacks than reversing them once they have commenced. It may be given as a tablet for the treatment of an angina attack.

[edit]Advantages

Long acting nitrates can be more useful as they are generally more effective and stable in the short term. It is more effective with African Americans.

[edit]Disadvantages

After long term use for treating chronic conditions, tolerance may develop in a patient reducing its effectiveness. The mechanisms of nitrate tolerance have been thoroughly investigated in the last 30 years and several hypotheses have been proposed. these include:

1. Impaired biotransformation of ISDN to its active principle NO (or a NO-related species)

2. Neurohormonal activation, causing sympathetic activation and release of vasoconstrictors such as endothelin and angiotensin II which counteract the vasodilation induced by ISDN

3. Plasma volume expansion

4. The oxidative stress hypothesis (proposed by Munzel et al. in 1995).

Recent evidence suggests that the latter hypothesis might represent a unifying hypothesis, and an ISDN-induced inappropriate production of oxygen free radicals might induce a number of abnormalities which include the ones described above. Furthermore, studies have shown that nitrate tolerance is associated with vascular abnormalities which have the potential to worsen patients prognosis (Nakamura et al.): these include endothelial and autonomic dysfunction (Gori et al.). In the short run, ISDN can cause severe headaches, necessitating analgesic (very rarely up to morphine) administration for relief of pain as well as severe hypotension, and, in certain cases, bradycardia. This makes some physicians nervous and should prompt caution when starting nitrate administration.

Dosification: Acute attack 5-10 mg sublingual way. Heart failure prophilaxis: 10-50 mg every 4 hours.

Adverse effects: Headache, expholiative dermatitis.

Castor oil - Ricin Oil

The United States Food and Drug Administration (FDA) has categorized castor oil as "generally recognized as safe and effective" (GRASE) for over-the-counter use as a laxative, with its major site of action thesmall intestine.^[14] Although it may be used for constipation, it is not a preferred treatment, because it can produce painful cramps and explosive diarrhea and its action can go on for hours, sometimes unpredictably. ^[15] Undecylenic acid, a castor oil derivative, is also FDA-approved for over-the-counter use on skin disorders or skin problems.^[16]

Castor oil penetrates deep into the skin due to its molecular mass, which is low enough to penetrate into the stratum corneum. Castor isostearate succinate is a polymeric mixture of esters with isostearic acid andsuccinic acid used for skin conditioning, such as in shampoo, lipstick and lip balm.^[17]

Ricinoleic acid is the main component of castor oil, and it exerts anti-inflammatory effects.^[18]

One study has found castor oil decreased pain more than ultrasound gel or Vaseline during extracorporeal shockwave application.^[19]

Therapeutically, modern drugs are rarely given in a pure chemical state, so most active ingredients are combined with excipients or additives. Castor oil, or a castor oil derivative such as Cremophor EL(polyethoxylated castor oil, a nonionic surfactant), is added to many modern drugs, including:

• Miconazole, an antifungal agent;^[20][21]
• Paclitaxel, a mitotic inhibitor used in cancer chemotherapy;^[22]
• Sandimmune (cyclosporine injection, USP), an immunosuppressant drug widely used in connection with organ transplant to reduce the activity of the patient's immune system;^[23]
• Nelfinavir mesylate, an HIV protease inhibitor;^[24]
• Saperconazole, a triazole antifungal agent (contains Emulphor EL-719P, a castor oil derivative);^[25]
• Tacrolimus, an immunosuppressive drug (contains HCO-60, polyoxyl 60 hydrogenated castor oil);^{[citation needed]}
• Xenaderm ointment, a topical treatment for skin ulcers, is a combination of Peru balsam, castor oil, and trypsin;^[26][27]
• Aci-Jel (composed of ricinoleic acid from castor oil, with acetic acid and oxyquinoline) is used to maintain the acidity of the vagina.^[

The normal daily dose is 2-10g.

It is contra-indicated in pregnancy and acute abdominal pathology.

Anastrozole

Anastrozole (INN) marketed under the trade name Arimidex by AstraZeneca, is a drug used to treat breast cancer after surgery and for metastases in both pre and post-menopausal women. Anastrozole is an aromatase inhibitor, which means that it interrupts a critical step in the body's synthesis of estrogen. Some breast cancer cells require estrogen to grow, and eliminating estrogen suppresses their growth. Annual sales approx $2.2bn. The first patent for Arimidex expired in June 2010. Although this patent was originally set to expire in December 2009, the manufacturer was given an extension for performing much needed pediatric studies.^[1]

Clinical trials

The ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial was an international randomised controlled trial of 9366 women with localized breast cancer who received either anastrozole, tamoxifen, or both for five years, followed by five years of follow-up.^[2] After more than 5 years the group that received anastrozole had significantly better clinical results than the tamoxifen group.^{[citation needed]} The trial suggested that anastrozole is the preferred medical therapy for postmenopausal women with localized breast cancer that is estrogen receptor (ER) positive.^{[citation needed]} Another study found that the risk of recurrence was reduced 40% (with some risk of bone fracture) and that ER negative patients also benefited from switching to Arimidex.^[3]

[edit]Mechanism of action

Anastrozole inhibits the enzyme aromatase, which is responsible for converting androgens to estrogens in peripheral tissues.^[4] Anastrozole binds reversibly to the aromatase enzyme through competitive inhibition. Elevated levels of estrogens may increase the severity of breast cancer, as sex hormones can cause hyperplasia anddifferentiation at estrogen receptor sites.^{[citation needed]}

[edit]Side effects

Bone weakness has been associated with anastrozole. Women who switched to anastrozole after two years on tamoxifen reported twice as many fractures as those who continued to take tamoxifen (2.1% compared to 1%).^[3] Bisphosphonates are sometimes prescribed to prevent the osteoporosis induced by aromatase inhibitors but have another serious side effect, osteonecrosis of the jaws. Since statins have a bone strengthening effect,^[5] combining a statin with an aromatase inhibitor may avoid both fractures and possible cardiovascular risks^[6] without jaw osteonecrosis.^[7] In one study of women with breast cancer taking anastrozole, statin use was associated with a 38% reduced fracture risk, or about the equivalent of 10 mg Fosamax daily.^[8]

[edit]Usage in men

While officially indicated for women, this drug has proven effective in the off-label use of reducing estrogens (in particular and more importantly, estradiol) in men.^{[citation needed]} Excess estradiol in men can cause benign prostatic hyperplasia, gynecomastia, and symptoms of hypogonadism.^{[citation needed]} Some athletes andbody builders will also use anastrozole as a part of their steroid cycle to reduce and prevent symptoms of excess estrogens; in particular, gynecomastia and water retention.^{[citation needed]} Study data currently suggest that dosages of 0.5 mg to 1 mg a day reduce serum estradiol by about 50% in men, which differs from the typical reduction in postmenopausal women.^{[citation needed]} However the reduction may be different for men with grossly elevated estradiol (clinical data are currently lacking).^{[citation needed]}

[edit]Usage in children

This drug is frequently used in the treatment of children with growth disorder to stop or slow the onset of puberty and in the treatment of moderate-to-severe pubertal gynecomastia.^{[citation needed]} The cause of the growth disorder is through hormones which may trigger the early onset of puberty.^{[citation needed]} At the onset of puberty the bone growth plates begin to close.^{[citation needed]} This can occur in children as young as 5 years old, so for children severely behind in growth, the opportunity for increased growth is diminished.^{[citation needed]} Arimidex is shown to slow or stop this processes.^{[citation needed]}

[edit]Chemistry

Arimidex (anastrozole) 1 mg tablets (AU)

The synthesis begins with nucleophilic substitution of two benzylic bromides in α,α'-dibromomesitylene (prepared by radical bromination of mesitylene, not shown on the scheme) with cyanide by treatment with potassium cyanide under phase transfer conditions, affording the dinitrile.^{[citation needed]} Exhaustive methylation withmethyl iodide and sodium hydride leads to the replacement of the more acidic side chain hydrogen atoms by methyl groups.^{[citation needed]} Treatment with bromine in the presence of benzoyl peroxide leads to the formation of the corresponding benzyl bromide.^{[citation needed]} Reaction of that product with 1,2,4-triazole in the presence of a base completes the synthesis of the aromatase inhibitor

Clindamycin

Clindamycin

Clindamycin is a chlorine-substituted derivative of lincomycin, an antibiotic that is elaborated by Streptomyces lincolnensis.

Antibacterial Activity

Streptococci, staphylococci, and pneumococci are inhibited by clindamycin, 0.5–5 mcg/mL. Enterococci and gram-negative aerobic organisms are resistant. Bacteroides species and other anaerobes, both gram-positive and gram-negative, are usually susceptible. Clindamycin, like erythromycin, inhibits protein synthesis by interfering with the formation of initiation complexes and with aminoacyl translocation reactions. The binding site for clindamycin on the 50S subunit of the bacterial ribosome is identical with that for erythromycin. Resistance to clindamycin, which generally confers cross-resistance to macrolides, is due to (1) mutation of the ribosomal receptor site; (2) modification of the receptor by a constitutively expressed methylase (see section on erythromycin resistance, above); and (3) enzymatic inactivation of clindamycin. Gram-negative aerobic species are intrinsically resistant because of poor permeability of the outer membrane.

Pharmacokinetics

Oral dosages of clindamycin, 0.15–0.3 g every 8 hours (10–20 mg/kg/d for children), yield serum levels of 2–3 mcg/mL. When administered intravenously, 600 mg of clindamycin every 8 hours gives levels of 5–15 mcg/mL. The drug is about 90% protein-bound. Clindamycin penetrates well into most tissues, with brain and cerebrospinal fluid being important exceptions. It penetrates well into abscesses and is actively taken up and concentrated by phagocytic cells. Clindamycin is metabolized by the liver, and both active drug and active metabolites are excreted in bile and urine. The half-life is about 2.5 hours in normal individuals, increasing to 6 hours in patients with anuria. No dosage adjustment is required for renal failure.

Clinical Uses

Clindamycin is indicated for the treatment of skin and soft-tissue infections caused by streptococci and staphylococci. It is often active against community-acquired strains of methicillin-resistant S aureus, an increasingly common cause of skin and soft tissue infections. Clindamycin is also indicated for treatment of anaerobic infection caused by bacteroides and other anaerobes that often participate in mixed infections. Clindamycin, sometimes in combination with an aminoglycoside or cephalosporin, is used to treat penetrating wounds of the abdomen and the gut; infections originating in the female genital tract, eg, septic abortion and pelvic abscesses; and aspiration pneumonia. Clindamycin is now recommended rather than erythromycin for prophylaxis of endocarditis in patients with valvular heart disease who are undergoing certain dental procedures. Clindamycin plus primaquine is an effective alternative to trimethoprim-sulfamethoxazole for moderate to moderately severe Pneumocystis jiroveci pneumonia in AIDS patients. It is also used in combination with pyrimethamine for AIDS-related toxoplasmosis of the brain.

Adverse Effects

Common adverse effects are diarrhea, nausea, and skin rashes. Impaired liver function (with or without jaundice) and neutropenia sometimes occur. Severe diarrhea and enterocolitis have followed clindamycin administration. Administration of clindamycin is a risk factor for diarrhea and colitis due to Clostridium difficile.

Gemcitabine

Gemcitabine

Gemcitabine is a fluorine-substituted deoxycytidine analog that is phosphorylated initially by the enzyme deoxycytidine kinase to the monophosphate form and then by other nucleoside kinases to the diphosphate and triphosphate nucleotide forms. The antitumor effect is considered to result from several mechanisms: inhibition of ribonucleotide reductase by gemcitabine diphosphate, which reduces the level of deoxyribonucleoside triphosphates required for DNA synthesis; inhibition by gemcitabine triphosphate of DNA polymerase- and DNA polymerase- , thereby resulting in blockade of DNA synthesis and DNA repair; and incorporation of gemcitabine triphosphate into DNA, leading to inhibition of DNA synthesis and function. Following incorporation of gemcitabine nucleotide, only one additional nucleotide can be added to the growing DNA strand, resulting in chain termination.

This nucleoside analog was initially approved for use in advanced pancreatic cancer but is now widely used to treat a broad range of malignancies, including non-small cell lung cancer, bladder cancer, ovarian cancer, soft tissue sarcoma, and non-Hodgkin's lymphoma. Myelosuppression in the form of neutropenia is the principal dose-limiting toxicity. Nausea and vomiting occur in 70% of patients and a flu-like syndrome has also been observed. In rare cases, renal microangiopathy syndromes, including hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura have been reported.

Reference: Annals of internal medicine

IBOPAMINE

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What is the problem and what is known about it so far?

Ibopamine is a drug that was used in Europe to treat heart failure, a condition in which the heart cannot pump blood normally. In 1995, a study showed that ibopamine increased death rates in patients who had moderate to severe heart failure. In September 1995, doctors and pharmacists in the Netherlands were officially notified that ibopamine should be used only in patients with mild heart failure. Moreover, the official recommendations for when to use ibopamine were changed according to whether patients had mild or severe heart failure. Whether the change in recommendations resulted in fewer deaths related to ibopamine was not known.

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Why did the researchers do this particular study?

To see if an official change in the specific indications for using the drug ibopamine affected death rates related to that drug.

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Who was studied?

Researchers followed 739 patients who were taking ibopamine before September 1995 and 407 patients who were taking it after September 1995. All patients had heart failure.

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How was the study done?

The researchers identified patients who had received ibopamine from community-based drug-dispensing outlets in the Netherlands. They contacted these patients' general practitioners and asked about patients' medical history and heart failure severity. Prescription data were obtained from computer records. Patients were followed from the date of their first ibopamine prescription until death or the end of the study period.

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What did the researchers find?

About three fourths of the patients who died before 1995 were using ibopamine up to the time of their death. Only half of the patients who died after 1995 were taking ibopamine at the time of death. The risk for death increased among patients who took ibopamine before 1995 and decreased among those who took ibopamine after 1995. Overall, patients taking ibopamine before 1995 had about a threefold higher risk for death than patients who were taking ibopamine after 1995.

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What were the limitations of the study?

The actual severity of heart failure at the time of death was not clear and was not measured precisely in some patients.

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What are the implications of the study?

Certain drugs have different and seemingly opposite effects in patients, even when those drugs are used to treat the same condition or disease. Such confusing differences in effects may be related to several factors, including whether the drug is preferentially avoided in patients with severe underlying disease and whether the drug itself is harmful for particular groups of people but not others.

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Article and Author Information

• The summary below is from the full report titled “Confounding by Contraindication in a Nationwide Cohort Study of Risk for Death in Patients Taking Ibopamine.” It is in the 3 April 2001 issue of Annals of Internal Medicine (volume 134, pages 569-572). The authors are H Feenstra, RE Grobbee, BA in't Veld, and BHCh Stricker