Baclofen

Baclofen (brand names Kemstro, Lioresal, and Gablofen) is a derivative of gamma-aminobutyric acid (GABA). It is primarily used to treat spasticity and is under investigation for the treatment of alcoholism.

It is an agonist for the GABA_B receptors.^[1][2] Its beneficial effects in spasticity result from actions at spinal and supraspinal sites. Baclofen can also be used to treathiccups, and has been shown to prevent rises in body temperature induced by the drug MDMA in rats.^[3]

In addition, research has shown baclofen to be effective in the treatment of alcohol dependence and withdrawal, by inhibiting both withdrawal symptoms andcravings.^[4][5]

A very beneficial property of baclofen is that tolerance does not seem to occur to any significant degree — baclofen retains its therapeutic anti-spasmodic effects even after many years of continued use.^[6] However, oral dosage must be carefully regulated; significantly high doses of the drug, particularly 80 milligrams per day or higher, can cause excessive drowsiness that can interfere with daily function

Use

Baclofen is widely used for the treatment of spastic movement disorders, especially in instances of spinal cord injury, spastic diplegia cerebral palsy, multiple sclerosis,amyotrophic lateral sclerosis (Lou Gehrig's disease), peripheral neuropathy and trigeminal and glossopharyngeal neuralgias.^{[citation needed]}

Baclofen is often the primary, or at least preliminary, drug treatment for spastic diplegia and more general spasticity-based mobility impairments. Research has not, however, shown it to be consistently effective in improving function for people with these issues.^[7][8] Sometimes, effects are immediate and clear; other times, effects may be mild, vague, or nonexistent. What is known for sure is that, for unknown reasons, in about 5% of the spastic cerebral palsy people who try intrathecally-administered baclofen, the drug has no effect whatsoever on the person's spasticity. It does appear that intrathecal baclofen may be more effective than oral baclofen, but some believe the long-term risks of an intrathecal pump (including potential sudden infection, sudden malfunction leading to coma and death, etc.) outweigh the potential benefits. Many clinicians and/or patients choose not to administer baclofen intrathecally at all for such reasons. (Most manufacturers of intrathecal pumps strongly disagree with the belief that an intrathecal pump carries with it a significant or even remote risk of serious complication, despite such things having occurred often enough to warrant concern.) Manufacturers argue that a pump that fails shuts down, but this does not itself mean that a suddenly punctured or similarly compromised pump would not pose a deathly risk to its wearer.

Intrathecal pumps are much more commonly used for the delivery of morphine than baclofen alone, although a mixture of both for chronic pain sufferers is common. A failure of the type alleged with an intrathecal pump with morphine would be fatal if it occurred when the pump was full or near to full where even a small amount suddenly was released into the Cerebral Spinal Fluid. It would likely be fatal if released into the abdominal cavity. Similar circumstances are used as arguments against intrathecal baclofen.

Baclofen has been shown to be as effective as diazepam in uncomplicated alcohol withdrawal syndrome.^[4] An Italian study showed that it was effective in promoting alcohol abstinence in patients with severe livercirrhosis.^[9]

Due to its phenethylamine structure and properties, baclofen is useful in the treatment of tardive dyskinesia.^[10]

Oral baclofen, taken as needed, can be used to alleviate painful low back spasms in patients with spinal abnormalities. It is generally seen, for this use, as more effective than medications such as cyclobenzaprinee.g. Flexeril and Metaxalone e.g. Skelaxin but not as strong (or abusable) as carisoprodol e.g. Soma

Mechanism of action

Baclofen produces its effects by modulating the GABA_B receptor, similar to the drug GHB which also activates this receptor and shares some of its effects. However, baclofen does not have significant affinity for theGHB receptor, and has no known abuse potential.^[11][12] The modulation of the GABA_B receptor is what produces baclofen's range of therapeutic properties.

[edit]History

Historically baclofen was designed to be a drug for epilepsy. It was synthesized for the first time in Ciba-Geigy by the Swiss chemist Heinrich Keberle in 1962.^[13] The effect on epilepsy was disappointing but it was found that in certain patients spasticity decreased. Baclofen was and is still given orally with variable effects. In severely affected children, the oral dose is so high that side effects appear and the treatment loses its benefit. How and when baclofen came to be used in the spinal sac is not really clear but this is now an established method for the treatment of spasticity in many conditions.

[edit]As a treatment for alcohol and other addictions

Dr. Olivier Ameisen, a French-American associate professor of medicine and a cardiologist at Weill Cornell Medical College of Cornell University, reported in 2004 that he successfully used baclofen to completely suppress his own alcohol addiction.^[14] Ameisen called for randomized trials of high-dose baclofen to be conducted to test the therapeutic model he had proposed.^[15] Ameisen believes, based on his own experience and other anecdotal evidence, that baclofen acts on some mechanism within the brains of addicts to suppress cravings brought on by addiction to various substances such as alcohol, cocaine, and heroin.^[15] However, a few randomized clinical trials have shown mixed results to date.^[15] A more extensive clinical trial will take place starting in 2011.^[15]

Ameisen authored Le Dernier Verre (The Last Glass, titled The End of My Addiction and Heal Thyself in English) to inform public opinion and physicians.^[16][17]

Based on Ameisen's therapeutic model, some trials have been conducted in using baclofen to treat cocaine addiction. In 2007, an Italian team demonstrated the effectiveness and the safety of baclofen as a treatment for alcohol addiction^[5] There is also a report that baclofen has beneficial role in the management of reflux disease.^[18]

Inspired by reading Olivier Ameisen’s The End of My Addiction, a person who wishes to remain anonymous donated $750,000 to the University of Amsterdam (UvA) in the Netherlands to initiate the clinical trial of high-dose baclofen Ameisen had called for since 2004.^[15] The trial is scheduled to start in January 2011 and will be led by the team of Pr. Dr. Reinout Wiers. Ameisen has been contacted by the team.^[19] In May 2011 a Scottish team from Glasgow presented: "Baclofen at a Tailored Dose Reduces Alcohol Use, Craving and Consequences of Drinking in Alcoholics with Medical Disease due to Alcohol Dependence" at the "Royal College of Pscychiatrists Faculty of Addictions Psychiatry Annual Meeting". They used doses between 15 and 360 mg of baclofen per day and winning the conference prize for the best poster raised the profile and increased interest in baclofen as anticraving drug.

In 2010, a small study in Minnesota replicated findings from Italy indicating that off-label use of the gamma-aminobutyric acid–derivative baclofen is effective in treating symptoms of alcohol withdrawal syndrome (AWS).^[20]

[edit]Description of compound

Baclofen is a white (or off white) mostly odorless crystalline powder, with a molecular weight of 213.66 g/mol. It is slightly soluble in water, very slightly soluble in methanol, and insoluble in chloroform

Pharmacokinetics

The drug is rapidly absorbed after oral administration and is widely distributed throughout the body. Biotransformation is low and the drug is predominantly excreted in the unchanged form by the kidneys.

Routes of administration

Baclofen can be administered either orally or intrathecally (directly into the cerebral spinal fluid) using a pump implanted under the skin.

Oral doses are typically 5–20 mg given 2-4 times/day. The maximum daily dosage is 80 mg. Titration generally occurs in 3 day increments e.g. 20 mg/day for days 1-3, 40 mg/day for days 4-6, 60 mg/day for days 7-9, and finally 80 mg/day for days 10-12. Careful titration of the medication upwards from the minimum dose should provide a good enough indicator of how much is needed for adequate spasticity relief. Baclofen can also be used on an as needed basis, such as for pain relief of low back spasms; in these cases dosing is the same (5–20 mg given 2-4 times/day, with the same 80 mg/day maximum) but taken only when symptoms arise.

Intrathecal pumps offer much lower doses of baclofen because they are designed to deliver the medication directly to the spinal fluid rather than going through the digestive and blood system first. They are often preferred in spasticity patients such as those with spastic diplegia, as very little of the oral dose actually reaches the spinal fluid. Besides those with spasticity, intrathecal administration is also used in patients with multiple sclerosis who have severe painful spasms which are not controllable by oral baclofen. With pump administration, a test dose is first injected into the spinal fluid to assess the effect, and if successful in relieving spasticity, a chronic intrathecal catheter is inserted from the spine through to the abdomen and attached to the pump which is implanted under the abdomen's skin, usually by the ribcage. The pump is computer-controlled for automatic dosage and the reservoir in the pump can be replenished by percutaneous injection.

In about 5% of patients, the intrathecal route has absolutely no effect on the nervous system, no matter how great a dose is administered.^{[citation needed}] A similar lack of any effect have been reported by those with spasticity who try the oral route,^{[citation needed]} but for some, the oral route works while the intrathcal route does not. Again, there are no known clinical theories as to why these discrepancies are present in the baclofen-spastic CP pairing. Additionally, for some people with spasticity, a lower dose of baclofen may be less effective, while for others that same dose will be very effective. This is why clinicians always insist to a spastic diplegic or similar person that s/he must start out with a low dose of baclofen and increase the dosage slowly.

[edit]Dosage

Baclofen therapy is usually started with an initial low dose of about 10 mg daily in divided doses and gradually titrated up in a stepwise fashion until symptomatic relief occurs. The usual maximum dose is 80 mg per day. However, it is common to titrate the dosage until symptomatic control or relief is attained; there is no inherent danger of baclofen in any dose in people with non-impaired renal function as long as the dose is titrated properly, so as not to cause undue side-effects such as oversedation. It is more common to use higher dosages when attempting to treat drug cravings instead of spasticity.^[5][21]

[edit]Withdrawal syndrome

Discontinuation of baclofen can be associated with a withdrawal syndrome which resembles benzodiazepine withdrawal and alcohol withdrawal. Withdrawal symptoms are more likely if baclofen is used for long periods of time (more than a couple of months) and can occur from low or high doses. The severity of baclofen withdrawal depends on the rate at which baclofen is discontinued. Thus to minimise baclofen withdrawal symptoms the dose should be tapered down slowly when discontinuing baclofen therapy. Abrupt withdrawal is most likely to result in severe withdrawal symptoms. Acute withdrawal symptoms can be stopped by recommencing baclofen.^[22]

Withdrawal symptoms may include auditory hallucinations, visual hallucinations, tactile hallucinations, delusions, confusion, agitation, delirium, disorientation, fluctuation of consciousness, insomnia, dizziness,Nausea, Feeling Faint, inattention, memory impairments, perceptual disturbances, pruritus/itching, anxiety, depersonalization, hypertonia, hyperthermia, formal thought disorder, psychosis, mania, mood disturbances, restlessness, and behavioral disturbances, tachycardia, seizures, tremors, autonomic dysfunction, hyperpyrexia, extreme muscle rigidity resembling neuroleptic malignant syndrome and reboundspasticity.^[22][23]

Butylscopolamine

Butylscopolamine, also known as scopolamine butylbromide, butylhyoscine and hyoscine butylbromide, is a peripherally acting antimuscarinic, anticholinergic agent^[1] used as an abdominal-specific antispasmodic. It is a quaternary ammonium compound and a semisynthetic derivative of scopolamine. It is marketed under the trade name Buscopan by Boehringer Ingelheim GmbH, Germany, who also offer a combination of butylscopolamine and paracetamol, marketed under the nameBuscopan Plus (in some countries, Buscopan Compositum).

Butylscopolamine is used to treat pain and discomfort caused by abdominal cramps, menstrual cramps, or other spasmodic activity in the digestive system. It is also effective at preventing bladder spasms. It is not an analgesic in the normal sense, since it doesn't 'mask' or 'cover over' the pain, but rather works to prevent painful cramps and spasms from occurring in the first place. The attachment of the butyl-bromide moiety effectively prevents the movement of this drug across the blood-brain barrier, effectively minimising undesirable CNS side-effects associated with scopolamine/hyoscine

Zidovudine

Zidovudine

Zidovudine (azidothymidine; AZT) is a deoxythymidine analog (Figure 49–2) that is well absorbed (63%) and distributed to most body tissues and fluids, including the cerebrospinal fluid, where drug levels are 60–65% of those in serum. Although the serum half-life averages 1.1 hours, the intracellular half-life of the phosphorylated compound is 3–4 hours, allowing twice-daily dosing. Zidovudine is eliminated primarily by renal excretion following glucuronidation in the liver.

Zidovudine is often co-administered with lamivudine, and a combination formulation is available.

Zidovudine was the first antiretroviral agent to be approved and has been well studied. The drug has been shown to decrease the rate of clinical disease progression and prolong survival in HIV-infected individuals. Efficacy has also been demonstrated in the treatment of HIV-associated dementia and thrombocytopenia. In pregnancy (Table 49–5), a regimen of oral zidovudine beginning between 14 and 34 weeks of gestation, intravenous zidovudine during labor, and zidovudine syrup to the neonate from birth through 6 weeks of age has been shown to reduce the rate of vertical (mother-to-newborn) transmission of HIV by up to 23%.

High-level zidovudine resistance is generally seen in strains with three or more of the five most common mutations: M41L, D67N, K70R, T215F, and K219Q. However, the emergence of certain mutations that confer decreased susceptibility to one drug (eg, L74V for didanosine and M184V for lamivudine) may enhance zidovudine susceptibility in previously zidovudine-resistant strains. Withdrawal of zidovudine exposure may permit the reversion of zidovudine-resistant HIV-1 isolates to the susceptible wild-type phenotype.

The most common adverse effect of zidovudine is myelosuppression, resulting in macrocytic anemia (1–4%) or neutropenia (2–8%). Gastrointestinal intolerance, headaches, and insomnia may occur but tend to resolve during therapy. Extremity fat loss may be more common with zidovudine than with other agents. Less common toxicities include thrombocytopenia, hyperpigmentation of the nails, and myopathy. High doses can cause anxiety, confusion, and tremulousness. Zidovudine causes vaginal neoplasms in mice; however, no human cases of genital neoplasms have been reported to date. Short-term safety has been demonstrated for both mother and infant.

Increased serum levels of zidovudine may occur with concomitant administration of probenecid, phenytoin, methadone, fluconazole, atovaquone, valproic acid, and lamivudine, either through inhibition of first-pass metabolism or through decreased clearance. Zidovudine may decrease phenytoin levels. Hematologic toxicity may be increased during co-administration of other myelosuppressive drugs such as ganciclovir, ribavirin, and cytotoxic agents. Combination regimens containing zidovudine and stavudine should be avoided due to in vitro antagonism

Oral: 100 mg capsules, 300 mg tablets, 50 mg/5 mL syrup

Oral (Combivir): 300 mg tablets in combination with 150 mg lamivudine

Oral (Trizivir): 300 mg tablets in combination with 150 mg lamivudine and 300 mg zidovudine

Parenteral: 10 mg/mL

Dosification: 2 times per day.

Sulfinpirazon

SULFINPIRAZON (Sulfinpyrazone) *. 1, 2-Difenil-1, 4-[2 - (fenilsulfinil) - ethyl] -3, 5-pirazolidindion.

Synonyms : Anturan, Anturan, Anturanil, Anturidin, Enturan, Pyrocard, Sulfazone, Sulfizone and others.

He is one of the metabolites butadiona (see).

Express analgeticheskogo and antiinflammatory actions will not help, but an active urikozuricheskim funds.

Applied to treat gout. Enhance the allocation of uric acid through the kidneys, especially in the first stage of treatment.

The drug is well absorbed. Duration of a single dose of 8 - 12 hours Since the drug has not analgeticheskogo action to appoint a nenarkoticheskie analgetiki (Phenylbutazone or etc.).

Assign inside usually a daily dose of 0.3 - 0.4 g (2 - 4 admission). Adopt after eating; Preferably zapivat milk.

Usually sulfinpirazon well tolerated, but may increase gastric ulcer and duodenal ulcer.

Early treatment may increase in gout attacks. In appointing the treatment must first enter the body enough liquid to alkalinization of urine (reception gidrokarbonata sodium); In response urine acidic deposition may concrements in the urinary track.

Contraindications : gastric ulcer disease and gastrointestinal cancer, increased sensitivity to pirazolona derivative (see Phenylbutazone), heavy damage liver and kidneys.

Please note that the small doses salitsilatov weaken urikozuricheskoe sulfinpirazona effect. Effects of oral anticoagulants, oral antidiabetics funds sulfanilamidov, penicillin drug increases (see Etamid).

Product : pills to 0.1 g. In higher doses sulfinpirazon reduces aggregation and adgezivnost platelets. As antiagregatsionnoe tool (see Antiagreganty) applied in the form of pills to 0.2 g; Nominated for 1 - 2 4 pills twice a day (800 mg / day). Applied to patients after myocardial infarction (starting after 4 weeks of treatment after a heart attack)

Metamizole or Dipirone

Metamizole sodium or dipyrone is a powerful analgesic and antipyretic. It is marketed under various trade names, including Algozone, Algocalmin, Analgin, Dipirona, Novalgin, and Neo-Melubrina. Metamizole was first synthesized by the German company Hoechst AG (now part of Sanofi-Aventis) in 1920, and its mass production started in 1922. It remained available worldwide until the 1970s, when it was discovered that the drug carries a small risk of causing agranulocytosis - a potentially fatal condition. Controversy remains regarding the level of risk. Several national medical authorities have banned metamizole either totally or have restricted it to be available only on prescription, while others have maintained its availability over the counter

Risk of agranulocytosis

According to comments by Dr. Anthony Wong of the University of São Paulo in a World Health Organization newsletter,[1] recent studies estimate that the incidence rate of metamizole-induced agranulocytosis is between 0.2 and 2 cases per million person days of use, with approximately 7% of all cases fatal (provided that all patients have access to urgent medical care). In other words, one should expect 60 to 600 deaths annually due to metamizole in a country of 300 million, assuming that every citizen takes the drug once a month. This is not a very high rate compared to other drugs - for example, the prescription drug clozapine is known to be at least 50 times more likely to trigger agranulocytosis. However, at the time the risk was assumed to be much greater and, as such, excessive for an over-the-counter analgesic, especially considering the existence of safer alternatives (e.g., aspirin and ibuprofen).

In 1998, Andrade et al. conducted a meta-analysis to compare epidemiologic studies from 1975 to 1995 and estimated that the excess mortality per million from community acquired cases of agranulocytosis, aplastic anaemia, anaphylaxis and serious upper gastrointestinal complications was 592 for diclofenac, 185 for aspirin, 25 for metamizole, and 20 for paracetamol.[2] CIOMS IV in the same year reported the excess mortality risk for the same conditions to be: diclofenac = 5.92; aspirin = 2.03; metamizole = 0.20; and paracetamol=0.25. These studies certainly suggest that the risks from adverse reactions to metamizole are similar to those posed by paracetamol, a drug widely reputed to be safe. According to the CIOMS IV conclusion “Newer methods of epidemiological studies have shown that the risk of agranulocytosis (1.7 per million) due to metamizole was exaggerated in the 70’s”.[3]

A study in Sweden published in 2002 estimated the total risk during metamizole therapy for patients in hospitals (inpatients) and outside of hospital (outpatients) about 3 to 100 times greater than that estimated by Dr. Wong: "Given certain assumptions including the actual amounts prescribed the calculated risks of agranulocytosis would be approximately one out of every 31,000 metamizole-treated inpatients and one of every 1400 metamizole-treated outpatients."[4]

When considering the data available on the risks and benefits of metamizole, it is important to note that this generic NSAID is very inexpensive when compared to newer COX-2 selective preparations. This has the potential to reduce profits for pharmaceutical companies, theoretically producing financial motivation for its discontinuation.[5]

[edit]Antipyretic effect

A randomized, double blind, multinational study involving 555 children showed that metamizole and ibuprofen were significantly more effective than paracetamol in achieving normal body temperatures; metamizole produced a significantly greater temperature reduction than ibuprofen and paracetamol, and helped maintain low temperatures for a longer duration.[6]

[edit]Media attention

Metamizole received a brief period of attention by American media in 2001,[7] when a Latino boy was admitted into a Salt Lake City clinic with symptoms of agranulocytosis. It was discovered that the drug remained freely available in Latino shops and highly popular among Mexican immigrants, despite the ban. The ongoing "LATIN" Study, a multicenter international case-control study, is examining the incidence of agranulocytosis in Latin America and the role of metamizole.

[edit]Availability around the world

Metamizole was banned in Sweden in 1974, and in the United States in 1977. Since then, more than 30 countries (including Japan, Australia, Iran, and several of the European Union member nations) have followed suit. In these countries, metamizole is still occasionally used as a veterinary drug. In Germany, Hungary, Italy, Portugal and Spain it is a prescription drug. Some European pharmaceutical companies, notably Hoechst and Merck Serono, continue to develop metamizole-containing drugs and market them in some countries. In Sweden, the ban was lifted in 1995 only to be re-introduced in 1999.

In other countries including Brazil, Bulgaria, Egypt, India, Israel, the Republic of Macedonia, Mexico, Poland, Romania, Russia, Spain, and Turkey, metamizole is still widely available over-the-counter, remains one of the most popular analgesics, and plays an important role in self-medication. For example, metamizole and metamizole-containing drugs account for 80% of OTC analgesic market in Russia, whereas ibuprofen accounts for 2.5%.[citation needed] In Israel, metamizole is often used as a first line analgesic in hospitals. As of April 1 2011, drugs containing metamizole cannot be sold over the counter in Romania.

In Brazil, metamizole products, although over-the-counter, carry warnings to avoid usage by those under 19 years old, and include some information about early detection and treatment of agranulocytosis. Use of metamizole has declined somewhat in Brazil as pharmaceutical companies and doctors have recommended aspirin, paracetamol and ibuprofen-based products, especially in children. Despite this, it is still widely used by adults. Metamizole has such high usage in Brazil, that in late 2008 Sanofi-Aventis released a new version of the product with 1 g of metamizole per tablet (twice the normal 500 mg dosage available before), still under the Novalgina name.

Rifampin

Rifampin

Rifampin is a semisynthetic derivative of rifamycin, an antibiotic produced by Streptomyces mediterranei. It is active in vitro against gram-positive and gram-negative cocci, some enteric bacteria, mycobacteria, and chlamydia. Susceptible organisms are inhibited by less than 1 mcg/mL. Resistant mutants are present in all microbial populations at approximately 1 in 10⁶ and are rapidly selected out if rifampin is used as a single drug, especially in a patient with active infection. There is no cross-resistance to other classes of antimicrobial drugs, but there is cross-resistance to other rifamycin derivatives, eg, rifabutin and rifapentine.

Antimycobacterial Activity, Resistance, & Pharmacokinetics

Rifampin binds to the subunit of bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis. Resistance results from any one of several possible point mutations in rpoB, the gene for the subunit of RNA polymerase. These mutations result in reduced binding of rifampin to RNA polymerase. Human RNA polymerase does not bind rifampin and is not inhibited by it. Rifampin is bactericidal for mycobacteria. It readily penetrates most tissues and penetrates into phagocytic cells. It can kill organisms that are poorly accessible to many other drugs, such as intracellular organisms and those sequestered in abscesses and lung cavities.

Rifampin is well absorbed after oral administration and excreted mainly through the liver into bile. It then undergoes enterohepatic recirculation, with the bulk excreted as a deacylated metabolite in feces and a small amount in the urine. Dosage adjustment for renal or hepatic insufficiency is not necessary. Usual doses result in serum levels of 5–7 mcg/mL. Rifampin is distributed widely in body fluids and tissues. Rifampin is relatively highly protein-bound, and adequate cerebrospinal fluid concentrations are achieved only in the presence of meningeal inflammation.

Clinical Uses

Mycobacterial Infections

Rifampin, usually 600 mg/d (10 mg/kg/d) orally, must be administered with isoniazid or other antituberculous drugs to patients with active tuberculosis to prevent emergence of drug-resistant mycobacteria. In some short-course therapies, 600 mg of rifampin are given twice weekly. Rifampin 600 mg daily or twice weekly for 6 months also is effective in combination with other agents in some atypical mycobacterial infections and in leprosy. Rifampin, 600 mg daily for 4 months as a single drug, is an alternative to isoniazid prophylaxis for patients with latent tuberculosis only, who are unable to take isoniazid or who have had exposure to a case of active tuberculosis caused by an isoniazid-resistant, rifampin-susceptible strain.

Other Indications

Rifampin has other uses. An oral dosage of 600 mg twice daily for 2 days can eliminate meningococcal carriage. Rifampin, 20 mg/kg/d for 4 days, is used as prophylaxis in contacts of children with Haemophilus influenzae type b disease. Rifampin combined with a second agent is used to eradicate staphylococcal carriage. Rifampin combination therapy is also indicated for treatment of serious staphylococcal infections such as osteomyelitis and prosthetic valve endocarditis.

Adverse Reactions

Rifampin imparts a harmless orange color to urine, sweat, tears, and contact lenses (soft lenses may be permanently stained). Occasional adverse effects include rashes, thrombocytopenia, and nephritis. It may cause cholestatic jaundice and occasionally hepatitis. Rifampin commonly causes light-chain proteinuria. If administered less often than twice weekly, rifampin causes a flu-like syndrome characterized by fever, chills, myalgias, anemia, and thrombocytopenia and sometimes is associated with acute tubular necrosis. Rifampin strongly induces most cytochrome P450 isoforms (CYPs 1A2, 2C9, 2C19, 2D6, and 3A4), which increases the elimination of numerous other drugs including methadone, anticoagulants, cyclosporine, some anticonvulsants, protease inhibitors, some nonnucleoside reverse transcriptase inhibitors, contraceptives, and a host of others. Administration of rifampin results in significantly lower serum levels of these drugs.

Alendronic Acid

Alendronic acid (INN) or alendronate sodium (USAN, sold as Fosamax by Merck) is a bisphosphonate drug used for osteoporosis and several other bone diseases. It is marketed alone as well as in combination with vitamin D (2,800 U and 5600 U, under the name Fosamax+D). Merck's U.S. patent on alendronate expired in 2008 and Merck lost a series of appeals to block a generic version of the drug from being certified by the U.S. Food and Drug Administration (FDA).

On February 6, 2008, the US FDA approved the first generic versions of alendronate, which were marketed by Barr Pharmaceuticals and Teva Pharmaceuticals USA. Teva Pharmaceuticals manufactures generic alendronate in 5-milligram, 10-milligram, and 40-milligram daily doses, and in 35-milligram and 70-milligram weekly doses, while Barr made generic alendronate in 70-milligram tablets, which were taken once weekly. ^[1]Barr pharmaceuticals were subsequently acquired by Teva in July 2008

Pharmacokinetics

As with all potent bisphosphonates, the systemic bioavailability after oral dosing is low, averaging only 0.6–0.7% in women and in men under fasting conditions. Intake together with meals and beverages other than water further reduces the bioavailability. The absorbed drug rapidly partitions, with approximately 50% binding to the exposed bone surface; the remainder is excreted unchanged by the kidneys. Unlike most drugs, the strong negative charge on the two phosphonate moieties limits oral bioavailability, and, in turn, the exposure to tissues other than bone is very low. After absorption in the bone, alendronate has an estimated terminal half-life of 10 years.^[2]

[edit]Pharmacology

Alendronate inhibits osteoclast-mediated bone-resorption. Like all bisphosphonates, it is chemically related to inorganic pyrophosphate, the endogenous regulator of bone turnover. Whereas pyrophosphate and the first bisphosphonate, etidronate, are capable of inhibiting both osteoclastic bone resorption as well as the mineralization of the bone newly formed by osteoblasts, alendronate and the other potent N-containing bisphosphonates such as risedronate, ibandronate, and zoledronate specifically inhibit bone resorption without any effect on mineralization at pharmacologically achievable doses. Its inhibition of bone-resorption is dose-dependent and approximately 1,000 times stronger than the equimolar effect of etidronate. Under therapy, normal bone tissue develops, and alendronate is deposited in the bone-matrix in pharmacologically inactive form. For optimal action, enough calcium and vitamin D are needed in the body in order to promote normal bone development. Hypocalcemiashould, therefore, be corrected before starting therapy.

[edit]Clinical data

Treatment of post-menopausal women with Fosamax has demonstrated normalization of the rate of bone turnover, significant increase in BMD (bone mineral density) of the spine, hip, wrist and total body, and significant reductions in the risk of vertebral (spine) fractures, wrist fractures, hip fractures, and all non-vertebral fractures. In the women with the highest risk of fracture (by virtue of pre-existing vertebral fractures) in the Fracture Intervention Trial, treatment with Fosamax 5 mg/day for two years followed by 10 mg/day for the third year (plus calcium and vitamin D) resulted in approximately 50% reductions in fractures of the spine, hip, and wrist compared with the control group taking placebos plus calcium and vitamin D.^{[citation needed]}

[edit]Uses

§ Prophylaxis and treatment of female osteoporosis

§ Treatment of male osteoporosis

§ Prevention and treatment of corticosteroid-associated osteoporosis together with supplements of calcium and vitamin D

§ Paget's disease

[edit]Contraindications and precautions

§ Acute inflammations of the gastrointestinal tract (esophagitis, gastritis, ulcerations)

§ Clinically manifest osteomalacia

§ Certain malformations and malfunctions of the esophagus (strictures, achalasia)

§ Inability to stand, walk, or sit for 30 minutes after oral administration

§ Renal impairment with a creatinine clearance below 30ml/min

§ Hypersensitivity to alendronate or another ingredient

§ Hypocalcemia

§ Pregnancy and breastfeeding

§ Patients below 18 yrs. of age, as no clinical data exists

[edit]Side-effects

§ Gastrointestinal tract: ulceration of the esophagus; this may require hospitalization and intensive treatment. Gastric and duodenal ulceration may also occur. December 31, 2008, the FDA reported alendronate and related drugs may carry an increased risk for esophageal cancer.^[3]

§ General: infrequent cases of skin rash, rarely manifesting as Stevens-Johnson syndrome and toxic epidermal necrolysis, eye problems (uveitis, scleritis) and generalized muscle, joint, and bone pain ^[4] (rarely severe) have been seen. In laboratory tests decreased calcium and phosphate values may be obtained but reflect action of the drug and are harmless.

§ Osteonecrosis of the Jaw - Deterioration of the Temporomandibular Joint (TMJ) may occur while on this drug, if dental work of any kind is carried out.^[5] Although osteonecrosis is uncommon, it occurs primarily in patients being administered intravenous biphosphonates, with most cases being reported in cancer patients.^{[citation needed]}

§ Neurological: Rare instances of auditory hallucinations and visual disturbances have been associated with alendronate and other bisphosphonates.^[6]

§ Bone: Alendronate has been linked in long-term users to the development of low-impact femoral fractures.^[7] Further, studies suggest that users of alendronate have an increase in the numbers of osteoclasts and develop giant, more multinucleated osteoclasts; the significance of this development is unclear.^[8] People who have taken Fosamax has been linked to a rare type of leg fracture that cuts straight across the upper thigh bone after little or no trauma. (Subtrochanteric fractures) ^[9] This is because Fosamax makes the thigh bone more brittle and stops the cells in the body that remodel the bone. Studies are showing that people who have taken Fosamax for more than five years are at risk for developing these kind of fractures. In some cases, patients have reported that, after weeks or months of unexplained aching, their thigh bones simply snapped while they were walking or standing. One doctor reports that a 59-year old previously healthy woman visiting New York City was riding a subway train one morning when the train jolted. She shifted all her weight to one leg, felt a bone snap, and fell to the floor of the train. An x-ray in a local emergency room revealed a comminuted spiral fracture involving the upper half of the right femur. She had been taking Fosamax for 7 years. ^[10] On Oct. 13, 2010 the Food and Drug Administration issued a warning about these fractures. ^[11]

[edit]Interactions

§ Milk, diet, and drugs containing high amounts of calcium, magnesium or aluminium (antacids): the resorption of alendronate is decreased. At least half an hour should pass after intake of alendronate before taking the supplement or drug.

§ Highly active vitamin D analogues or fluorides: no data is available. Concomitant treatment should be avoided.

§ The additional beneficial effect of HRT (hormone replacement therapy) with estrogens/progestins or raloxifene in postmenopausal women remains to be elucidated, but no interactions have been seen. The combination is therefore possible.

§ Intravenous ranitidine increases the oral bioavailability of alendronate. No clinical consequences are known.

§ The combination of NSAIDs and alendroate may increase the risk of gastric ulcers. Both these drugs have the potential to irritate the upper gastro-intestinal mucosa.

[edit]Dosage

§ Prophylaxis of osteoporosis in women: 5-10 mg daily or 35-70 mg weekly.

§ Therapy of osteoporosis in women and men : 10 mg daily or 70 mg weekly.

§ Osteoporosis under corticosteroids: 5-10 mg daily or 35-70 mg weekly in men and premenopausal women or those receiving concomitant HRT. In postmenopausal women not receiving HRT, the recommended dose is 10 mg daily or 70 mg weekly.

§ Paget's Disease: 40 mg daily for 6 months.

The drug is to be taken only upon rising for the day with three swallows of water, not to exceed 6-8 oz. Stand, walk, or sit, and remain fasting for 30-45 minutes afterwards, then eat breakfast. Lying down or reclining after taking the drug and prior to eating breakfast may cause gastroesophageal reflux and esophageal irritation. At least 30 minutes should be allowed to pass before meals or other beverages than water are taken in.

Alendronic acid 35 MG (as alendronate sodium 45.7 MG) Oral Tablet

On December 31, 2008, a letter in the New England Journal of Medicine cited a finding by the U.S. Food and Drug Administration that 23 cases of esophageal cancer, possibly linked to the use of the drug, have been seen since Fosamax's 1995 market debut.^[12]

[edit]Dosage forms

§ Fosamax solution 70 mg/75ml

§ Fosamax tablets 5 mg, 10 mg, 35 mg, 40 mg, and 70 mg

[edit]Litigation

By 2000, the FDA had received 139 spontaneous reports through the MedWatch system of osteonecrosis of the jaw (ONJ) in cancer patients treated with intravenous (IV) bisphopshonates, either IV pamidronate (Aredia) or IV zolendronate (Zometa).

At the 2004 ODAC meeting the number of spontaneous reports had increased since 2000, and although almost all of the reports remained in cancer patients treated with one of the IV bisphosphonates 13 of the reports were in patients taking oral alendronate or risedronate, most of which were reported on September 24, 2004, in the Journal of Oral and Maxillofacial Surgery. Although this small number of reports does not remotely indicate causality, given the millions of patients who have been treated with alendronate and risedronate, in order to be cautious the FDA asked the manufacturers of the oral bisphosphonates to issue a warning to healthcare professionals of the potential that bisphosphonates might increase the risk of ONJ.

Despite the fact that no data links the oral bisphosphonates causally to ONJ, product liability attorneys immediately filed suit maintaining that their claimants' ONJ is a direct result of the use of alendronate. Merck has stated the "underlying cause" of osteonecrosis of the jaw is "uncertain", though it might be triggered by a traumatic event like tooth extraction or oral surgery. As of May 13, 2007, hundreds of cases had been filed against Merck alleging Fosamax-induced ONJ. The first case is set to be tried in late 2008.

[edit]Bis-phossy jaw

The term given by scientists to the link between bisphosphonates and jaw necrosis is 'bis-phossy jaw.' This is derived from the 19th-century term phossy jaw, given its name after workers in match factories working with white phosphorus developed osteonecrosis of the jaw