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Tamoxifen is an orally active selective estrogen receptor modulator (SERM) that is used in the treatment of breast cancer and is currently the world’s largest selling drug for that purpose.

Tamoxifen was discovered by ICI Pharmaceuticals (now AstraZeneca) and is sold under the trade names Nolvadex, Istubal, and Valodex. However, the drug, even before its patent expiration, was and still is widely referred to by its generic name “tamoxifen.”

Breast cancer treatment

Tamoxifen is currently used for the treatment of both early and advanced ER+ (estrogen receptor positive) breast cancer in pre- and post-menopausal women. It is also approved by the FDA for the prevention of breast cancer in women at high risk of developing the disease. It has been further approved for the reduction of contralateral (in the opposite breast) cancer.

Comparative studies

In 2006, the large STAR clinical study concluded that raloxifene is equally effective in reducing the incidence of breast cancer, but after an average 4-year follow-up there were 36 % fewer uterine cancers and 29 % fewer blood clots than in women taking tamoxifen.

In 2005, the ATAC trial showed that after average 68 months following a 5 year adjuvant treatment, the group that received anastrozole (Arimidex) had significantly better results than the tamoxifen group. Anastrozole vs tamoxifen: deaths - 575 vs 651, recurrences - 402 vs 498, distant metastases - 324 vs 375, second breast cancer - 35 vs 59 (42% reduction). The trial suggested that anastrozole should be the preferred medication for postmenopausal women with localized breast cancer that is estrogen receptor (ER) positive. Another study found that the risk of reoccurrence was reduced 40% (with some risk of bone fracture) and that ER negative patients also benefited from switching to Arimdex.

Infertility

Tamoxifen is used to treat infertility in women with anovulatory disorders. A dose of 10–40 mg per day is administered in days 3–7 of a woman’s cycle. In addition, a rare condition occasionally treated with tamoxifen is retroperitoneal fibrosis.

Gynecomastia

In men, tamoxifen is sometimes used to treat gynecomastia that arises for example as a side effect of antiandrogen prostate cancer treatment. Tamoxifen is also used by bodybuilders to prevent or reduce drug-induced gynecomastia caused by the estrogenic metabolites of anabolic steroids. Tamoxifen is also sometimes used to treat or prevent gynecomastia in sex offenders undergoing treatment by temporary chemical castration.

Bipolar disorder

Tamoxifen has been shown to be effective in the treatment of mania in patients with bipolar disorder by blocking protein kinase C (PKC), an enzyme that regulates neuron activity in the brain. Researchers believe PKC is over-active during the mania in bipolar patients.

Angiogenesis and cancer

Tamoxifen is one of three drugs in an anti-angiogenetic protocol developed by Dr. Judah Folkman, a researcher at Children’s Hospital at Harvard Medical School in Boston. Folkman discovered in the 1970s that angiogenesis – the growth of new blood vessels – plays a significant role in the development of cancer. Since his discovery, an entirely new field of cancer research has developed. Clinical trials on angiogenesis inhibitors have been underway since 1992 using a myriad of different drugs. The Harvard researchers developed a specific protocol for a golden retriever named Navy who was cancer-free after receiving the prescribed cocktail of celecoxib, doxycycline, and tamoxifen – the treatment subsequently became known as the Navy Protocol. Furthermore tamoxifen treatment alone has been shown to have anti-angiogenetic effects in animal models of cancer which appear to be, at least in part, independent of tamoxifen’s estrogen receptor antagonist properties.

Control of gene expression

Finally tamoxifen is used as a research tool to trigger tissue specific gene expression in many conditional expression constructs in genetically modified animals including a version of the Cre-Lox recombination technique.

Mechanism of action

Crystallographic structure (PDB 3ERT) of 4-hydroxytamoxifen (white sticks) complexed with the ligand binding domain of the estrogen receptor (cyan cartoon diagram).

Tamoxifen competitively binds to estrogen receptors on tumors and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It is a nonsteroidal agent with potent antiestrogenic properties which compete with estrogen for binding sites in breast and other tissues. Tamoxifen causes cells to remain in the G0 and G1 phases of the cell cycle. Because it prevents (pre)cancerous cells from dividing but does not cause cell death, tamoxifen is cytostatic rather than cytocidal.

Tamoxifen itself is a prodrug, having relatively little affinity for its target protein, the estrogen receptor. It is metabolized in the liver by the cytochrome P450 isoform CYP2D6 and CYP3A4 into active metabolites such as 4-hydroxytamoxifen and N-desmethyl-4-hydroxytamoxifen (endoxifen) which have 30-100 times more affinity with the estrogen receptor than tamoxifen itself. These active metabolites compete with estrogen in the body for binding to the estrogen receptor. In breast tissue, 4-hydroxytamoxifen acts as an estrogen receptor antagonist so that transcription of estrogen-responsive genes is inhibited.

Tamoxifen seems to require a protein PAX2 for its full anticancer effect. More specifically, the ratio of PAX2 and AIB-3 predicts the efficacy of tamoxifen therapy. In the presence of high PAX2 expression, the tamoxifen/estrogen receptor complex is able to supress the expression of the pro-proliferative ERBB2 protein. In contrast, when AIB-3 expression is higher than PAX2, tamoxifen/estrogen receptor complex upregulates the expression of ERBB2 resulting in stimulation of breast cancer growth. In about 35% of UK breast cancer patients treated with tamoxifen PAX2 is, or becomes, faulty leading to resistance to the drug.

Side effects

Tamoxifen is a selective estrogen receptor modulator. Even though it is an antagonist in breast tissue it acts as partial agonist on the endometrium and has been linked to endometrial cancer in some women. Therefore endometrial changes, including cancer, are among tamoxifen’s side effects.

The American Cancer Society lists tamoxifen as a known carcinogen, stating that it increases the risk of some types of uterine cancer while lowering the risk of breast cancer recurrence. The ACS states that its use should not be avoided in cases where the risk of breast cancer recurrence without the drug is higher than the risk of developing uterine cancer with the drug.

For some women, tamoxifen can cause a rapid increase in triglyceride concentration in the blood. In addition there is an increased risk of thromboembolism especially during and immediately after major surgery or periods of immobility. Tamoxifen is also a cause of fatty liver, otherwise known as steatorrhoeic hepatosis or steatosis hepatis.

A significant number of tamoxifen treated breast cancer patients experience a reduction of libido.

A beneficial side effect of tamoxifen is that it prevents bone loss by inhibiting osteoclasts by acting as an estrogen receptor agonist (i.e., mimicking the effects of estrogen) in this cell type, and therefore it prevents osteoporosis. When tamoxifen was launched as a drug, it was thought that tamoxifen would act as an estrogen receptor antagonist in all tissue, including bone, and therefore it was feared that it would contribute to osteoporosis. It was therefore very surprising that the opposite effect was observed clinically. Hence tamoxifen’s tissue selective action directly lead to the formulation of the concept of selective estrogen receptor modulators (SERMs).

Pharmacogenetics

Patients with variant forms of the gene CYP2D6 (also called simply 2D6) may not receive full benefit from tamoxifen because of too slow metabolism of the tamoxifen prodrug into its active metabolite 4-hydroxytamoxifen. On Oct 18, 2006 the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to include information about this gene in the package insert.

Recent studies suggest that taking selective serotonin reuptake inhibitor (SSRI) antidepressants such as Paxil, Prozac, etc., can decrease the effectiveness of tamoxifen, because these drugs compete for the CYP2D6 enzyme which is needed to metabolize tamoxifen into the active form endoxifen.

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Azithromycin is an azalide, a subclass of macrolide antibiotics.

Azithromycin (brand names ‘APO-Azithromycin’ in Canada; Zithromax in Italy, The United Kingdom, The United States, Australia, Portugal, South Africa, Canada and Belgium; ATM in India, Zithromac in Japan, Vinzam / Zitromax in Spain; Zmax; Sumamed in Croatia; Aztrin, Zitrocin, Azibiot, Azifine, AziCip, Azi Sandoz) is one of the world’s best-selling antibiotics

History

A team of Croatian pharmaceutical company Pliva researchers, Gabrijela Kobrehel, Gorjana Radobolja-Lazarevski and Zrinka Tamburašev led by Dr. Slobodan Đokić, discovered azithromycin in 1980. It was patented in 1981, and was later found by Pfizer’s scientists while going through patent documents. In 1986 Pliva and Pfizer signed a licensing agreement which gave Pfizer exclusive rights for the sale of azithromycin in Western Europe and the United States. Pliva brought their azithromycin on the market in Central and Eastern Europe under the brand name of Sumamed in 1988, Pfizer Zithromax in 1991, and Zentiva Azitrox. After several years, the US FDA approved AzaSite®, an ophthalmic formulation of azithromycin, for the treatment of eye infections. AzaSite is currently marketed in the US by Inspire Pharmaceuticals.

Mechanism of Action

Azithromycin prevents bacteria from growing by interfering with their protein synthesis. Azithromycin binds to the 50S subunit of the bacterial ribosome, and thus inhibits translation of mRNA. Nucleic acid synthesis is not affected.

Pharmacokinetics

Unlike erythromycin, azithromycin is acid-stable and can therefore be taken orally with no need of protection from gastric acids. It is readily absorbed,its absorption is more with empty stomach because food decreases its absorption and diffused into most tissues and phagocytes. Time to peak concentration in adults is 2.1 to 3.2 hours for oral dosage forms and 1 to 2 hours for intravenous (IV) forms. Due to the high concentration in phagocytes, azithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations of azithromycin are released. The concentration of azithromycin in the tissues can be over 50 times higher than in plasma. This is due to ion trapping and the high lipid solubility.

Azithromycin’s half-life allows a large single dose to be administered and yet maintain bacteriostatic levels in the infected tissue for several days. The new “Zmax” formulation of azithromycin is an enteric-coated suspension that releases the drug in a single 2g dose once it has cleared the stomach, reducing the GI side-effects of high-dose azithromycin.

Metabolism

Following a single 500 mg dose, plasma concentrations of azithromycin declined in a polyphasic pattern with a mean apparent plasma clearance of 630 mL/min and a terminal elimination half-life of 68 hours. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues.

Biliary excretion of azithromycin, predominantly unchanged, is a major route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in urine.

Side effects

Most common side effects are gastrointestinal; diarrhea (5%), nausea (3%), abdominal pain (3%) and vomiting. Fewer than 1% of patients stop taking the drug due to side effects. Serious allergic reactions, nervousness, dermatologic reactions, and fatalities have been reported but are extremely rare. As with all antimicrobial agents, pseudomembranous colitis can occur during and up to several weeks after azithromycin therapy. This drug may interfere with the effectiveness of birth control pills; other forms of contraception may be required during the treatment period.

Allergic reaction

Patients who suffer from an allergic reaction to Azithromycin can experience blood in the stool 4-10 days after ingestion, although cases of this have been recorded as early as after the first day of ingestion. These allergies are usually non-severe if the treatment is immediately stopped. A severe reaction includes a severe rash, hives, breathing difficulties, or dizziness.

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Initial Diagnosis

In making a diagnosis of erectile dysfunction (ED), your doctor will start by taking a detailed medical and psychosexual history and conducting a thorough physical examination. If possible, interviewing your partner also is very helpful in obtaining an accurate history, planning treatment and a successful outcome.

In addition, ED is often associated with various medical conditions, such as diabetes mellitus, coronary artery disease, hypertension, hyperlipidemia, spinal cord compression and pituitary tumors. Therefore, your doctor may conduct a variety of laboratory tests to determine the cause of your ED. These tests may include the following:
Complete blood count
Urine test
Fasting blood glucose test
Serum creatinine test
Lipid profile
Morning serum testosterone test
Prolactin level test

Based on the results of these tests, your doctor will discuss with you — and if you would like, your partner — your goals, preferences and further diagnostic and therapeutic options. Experts at UCSF Medical Center believe that it is very important for patients (and their partners) to be well-informed and active participants in the decision making process regarding their care and treatment.

In some cases, your doctor may recommend that you have further testing for other medical conditions that may cause ED. In addition, if you are taking a drug — both prescribed or recreational — that is known to cause ED, or have vascular risk factors, a change in medication or lifestyle may be recommended.

Self-Report Tests for Measuring Sexual Function

A variety of self-report measures for assessing the levels of your sexual function are now available. These measures can be conducted on your own at home or in a private room at your doctor’s office. The most commonly used test is the International Index of Erectile Function. It has 15 items and assesses erectile function, orgasmic function, sexual desire, intercourse satisfaction and overall satisfaction, as well as the severity of your ED.

Advanced Testing for Erectile Dysfunction

Nocturnal Penile Tumescence (NPT) Test

Nocturnal erections occur in healthy males of all ages. Eighty percent of these happen during REM sleep. The average man has three to five episodes of NPT per night, lasing for 30 to 60 minutes each. With age, total nocturnal erection time decreases.

There are a variety of methods available for monitoring NPT. The monitoring is generally conducted with a simple outpatient device, rather than in NPT sleep labs. These devices electronically record the number, duration, rigidity and circumference of penile erections.

Psychological Evaluation

Psychological conditions, such as performance anxiety, a strained relationship, lack of sexual arousability and mental health disorders, including depression and schizophrenia, may cause erectile dysfunction. Therefore, your doctor may recommend an interview with a psychologist that focuses on current sexual problems, partner relationship and any psychiatric symptoms you may be experiencing.

Neurologic Tests

At UCSF Medical Center, our urologists and neurologists work together to better understand and identify the causes of erectile dysfunction. Neurologic testing for ED is conducted at the UCSF Neurology Center at our Mount Zion campus.

The goal of neuro-urologic testing is to uncover neurologic disease, such as diabetes mellitus or pelvic injury, or diagnose reversible neurologic conditions, such as nerve damage caused by long-distance bicycling. These tests also help determine whether a referral to a neurologist is necessary. The most commonly used tests include:

Combined Intracavernous Injection and Stimulation (CIS) Test — This is the simplest, and most commonly used test for evaluating and diagnosing ED. It uses penile injections, visual or manual sexual stimulation and a subsequent erection.

Color Doppler Ultrasound — This test uses harmless, non-invasive sound waves to produce a picture of the penile arteries, which enables experts to evaluate the arteries’ functions.

Pharmacologic Cavernosometry and Cavernosography — These tests evaluate penile veins and help identify any venous leakages.

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