Online Pharmacy

Amitriptyline

2007-10-18T09:12:00.000-07:00

Systematic (IUPAC) name
3-(10,11-dihydro-5H-dibenzo[[a,d]] cycloheptene-5-ylidene)-N, N-dimethyl-1-propanamine

Identifiers: CAS number 50-48-6; ATC code N06AA09; PubChem 2160; DrugBank APRD00227.
Chemical data: Formula C20H23N;
Mol. mass 277.403 g/mol.
Pharmacokinetic data: Bioavailability 40%; Metabolism Hepatic
Half life 12-24 hours; Excretion Renal.
Therapeutic considerations: Pregnancy cat. D(US);
Legal status Unscheduled(AU) POM(UK); Routes Oral.

Amitriptyline (or Amitryptyline) hydrochloride (sold as Elavil, Tryptanol, Endep, Elatrol, Tryptizol, Trepiline, Laroxyl) is a tricyclic antidepressant drug. It is a white, odorless (but tastes like licorice), crystalline compound which is freely soluble in water; it is usually dispensed in tablet form. In terms of its mechanism of action, amitriptyline inhibits serotonin and noradrenaline reuptake almost equally.

Uses:
Approved: Amitriptyline is approved for the treatment of endogenous depression and involutional melancholia (depression of late life, which is no longer seen as a disease in its own right.) Adult typical dosages are 25 to 150 mg daily, with half this initially for elderly or adolescents.
It may also be used to treat nocturnal enuresis (bed wetting). Children between the ages of 7 to 10 years having a dose of 10 to 20 mg, older children 25 to 50 mg at night. It should be gradually withdrawn at the end of the course, which overall should be of no more than 3 months.
In some European countries it is also approved as prophylaxis for patients with frequent migraines (usually 25 to 75 mg).
Unapproved/Off-Label/Investigational: Amitriptyline may be prescribed for other conditions such as insomnia, migraine, rebound headache, chronic pain, postherpetic neuralgia (persistent pain following a shingles attack), fibromyalgia, vulvodynia, interstitial cystitis, irritable bowel syndrome, diabetic peripheral neuropathy, neurological pain, and painful paresthesias related to multiple sclerosis and as a preventative (prophylaxis) for patients with frequent migraines. It is also used in small (10 mg) doses to act as a painkiller and ease the effects of Carpal Tunnel Syndrome. Typically lower dosages are required for pain modification of 10 to 50 mg daily.
Amitriptyline in very small doses (5 mg a day) is also sometimes prescribed to help ease the symptoms of chronic fatigue syndrome. It is thought to help combat symptoms of insomnia primarily, in addition to other selected symptoms of the affliction.
A randomized controlled trial published in June 2005 found that amitriptyline was effective in functional dyspepsia refractory to famotidine and mosapride combination therapy.

Side effects: Common side effects of using amitriptyline are extreme weight gain, drowsiness, nervousness, dizziness, and insomnia. Some rare side effects include tinnitus, hypotension, mania, psychosis, anticholinergic effects, heart block, arrhythmias, extrapyramidal symptoms, depression, and hepatic toxicity.
Overdose: The symptoms and the treatment of an overdose are largely the same as for the other tricyclic antidepressants.

Alfentanil

2007-10-18T08:57:00.000-07:00

Systematic (IUPAC) name
N-[1-[2-(4-ethyl-5-oxo-1,4-dihydrotetrazol-1-yl)ethyl]-
4-(methoxymethyl)-4-piperidyl]-N-phenyl-propanamide

Identifiers: CAS number 71195-58-9; ATC code N01AH02; PubChem 189496
DrugBank APRD00726.
Chemical data: Formula C21H32N6O3; Mol. mass 416.517 g/mol
Physical data: Melt. point 140.8 °C (285 °F).
Pharmacokinetic data: Bioavailability Not applicable; Protein binding 92%
Metabolism Hepatic; Half life 90–111 minutes; Excretion ?
Therapeutic considerations: Pregnancy cat. ?; Legal status Schedule II(US)
Routes Intravenous.

Alfentanil (trade name Alfenta) is a potent but short-acting synthetic opioid analgesic drug, used for anaesthesia in surgery. It is an analogue of fentanyl with 10-20% the potency of fentanyl. It is an OP3 mu-agonist.
While alfentanil tends to cause less cardiovascular complications than other similar drugs such as fentanyl and remifentanil it tends to give stronger respiratory depression and so requires careful monitoring of breathing and vital signs. Alfentanil is administered by the parenteral (injected) route for fast onset of effects and precise control of dosage.
Alfentanil is a restricted drug which is classified as Schedule II in the USA, according to the U.S. DEA website.
Alfentanil was discovered at Janssen Pharmaceutica in 1976.

Actiq

2007-10-18T08:41:00.000-07:00

Actiq, by Cephalon, is a solid formulation of fentanyl citrate on a plastic stick that dissolves slowly in the mouth for absorption across the buccal mucosa. Generically Actiq is a form of oral transmucosal fentanyl citrate (OTFC). Fentanyl is a Schedule II controlled substance per the Controlled Substance Act. Other pharmaceutical preparations consisting of fentanyl are Duragesic (72 hour continuous-release fentanyl patches) and Fentora, a rapidly dissolving fentanyl lozenge which, like Actiq, is administered transmucosally over the buccal mucosa. OTFC is absorbed much like how nicotine is absorbed when dip is placed in one's mouth between the gum and cheek.

Administration: Actiq is intended for opiate-tolerant individuals and is effective in treating breakthrough cancer pain. It is also useful for breakthrough pain for those suffering bone injuries, migraines, severe back pain, neuropathy, arthritis, and other situations of moderate to severe chronic, non-malignant pain. The Actiq dosage unit is a white, berry-flavored lozenge on a stick which is swabbed on the buccal mucosa, between cheek and gum to release the fentanyl quickly into the bloodstream. It is most effective when the lozenge is consumed in exactly 15 minutes, as the balance of the drug absorbed through the cheeks and the amount swallowed is maintained.

Absorption: Normally 25% of the drug is absorbed via the buccal mucosa directly into the bloodstream while the remaining 75% is swallowed and then slowly absorbed in the gastrointestinal tract. Two-thirds of the swallowed Actiq (or 50% of the total dose) is metabolized by the liver and becomes unavailable for any pain relief function. This is why the drug is far less potent if consumed orally compared to transmucosally.

Dosing: Actiq is available in 6 dosages, measured in micrograms: 200, 400, 600, 800, 1200, & 1600 mcg. Each dosage strength has its own color box and plastic handle:
Actiq 200 mcg--gray Actiq 400 mcg--blue Actiq 600 mcg--orange Actiq 800 mcg--purple Actiq 1200 mcg--green Actiq 1600 mcg--burgundy.

Side-effects: Actiq, like all opioids, has a potential for abuse and can be habit forming. Actiq should not be taken with alcohol.
An Actiq lozenge contains 2 grams of sugar (8 calories), making weight gain and tooth decay a conceivable concern for patients who consume many Actiqs per day. Diabetics also need to take Actiq's sugar content into account. A sugar-free version, called Actiq-SF, is in development, and should be available beginning first quarter 2007. Side effects include the normal side effects found with this class of narcotic analgesic plus constipation and dry mouth. Other side effects include rash, sweating, hot flashes, and dizziness.
As with all opioids, there have also been reports of illicit use on the street.

Generic Alternatives: Beginning late September, 2006, a generic version of Actiq has been available, made by Barr Pharmaceuticals. Cephalon has begun marketing its own version of generic Actiq to compete in the generic OTFC market. The generic versions of Actiq, simply called "oral transmucosal fentanyl citrate," are packaged just like name brand Actiq, and there is no difference in appearance, active and inactive ingredients, or function as compared to the name brand Actiq. Because Actiq is extremely expensive, the generic OTFC just hitting the market will likely make the drug more accessible.

Acetyldihydrocodeine

2007-10-18T08:22:00.000-07:00

Systematic (IUPAC) name
3-methoxy-6-acetoxy-(5α,6α)-7,8-Didehydro-4,5-epoxy-17-methylmorphinan

Identifiers: CAS number 3861-72-1; ATC code R05DA12
PubChem 5463874.
Chemical data: Formula C20H25NO4; Mol. mass 343.417 g/mol; Synonyms Acetyldihydrocodeine, Dihydrothebacone, 6-acetyl-7,8-dihydrocodeine.

Acetyldihydrocodeine is an opiate derivative developed as a cough suppressant and analgesic. It is not commonly used, but has activity similar to other opiates. Acetyldihydrocodeine can be described as the 6-acetyl derivative of dihydrocodeine and is metabolised in the liver by demethylation and deacetylation to produce dihydromorphine.
Since acetyldihydrocodeine has higher lipophilicity than codeine and is converted into dihydromorphine rather than morphine, it can be expected to be more potent and longer lasting, and also have higher bioavailability than codeine; however its action is still limited by the rate at which liver enzymes demethylate it into dihydromorphine. Side effects are similar to those of other opiates and include itching, nausea and respiratory depression.

Vardenafil

2007-10-17T10:26:00.001-07:00

Searc Vardenafil : Buy Vardenafil : Searh Levitra

Systematic (IUPAC) name
4-[2-ethoxy-5-(4-ethylpiperazin-1-yl)sulfonyl-phenyl]-
9-methyl-7-propyl- 3,5,6,8-tetrazabicyclo[4.3.0]
nona-3,7,9-trien-2-one

Identifiers: CAS number 224785-90-4; ATC code G04BE09;
PubChem 110634; DrugBank APRD00699.
Chemical data: Formula C23H32N6O4S; Mol. mass 488.604 g/mol.
Pharmacokinetic data: Bioavailability 15%; Protein binding 95%;
Metabolism Hepatic (CYP3A4); Half life 4–5 hours; Excretion Biliary.
Therapeutic considerations: Pregnancy cat. B3 (Au), B (U.S.);
Legal status Prescription Only (S4)(AU) POM(UK) -only(US); Routes Oral.

Vardenafil (INN) is a PDE5 inhibitor used in the treatment of erectile dysfunction. It can assist men with this disorder in achieving and maintaining an erection during sexual activity. It is commonly marketed under the trade name Levitra (Bayer AG).

History: Vardenafil was co-marketed by Bayer Pharmaceuticals and GSK under the trade name Levitra. As of 2005, the co-promotion rights of GSK on Levitra have been "transferred back" to Bayer in many markets outside of the United States. In Italy, Bayer markets the product as Levitra and GSK markets the product as Vivanza. Due to European Union trade rules, parallel imports may result in the Vivanza branded packs being seen alongside Levitra packs in pharmacies in other EU member states.

Clinical use: Main article: PDE5 inhibitor.
Indications and contraindications are as for other PDE5 inhibitors. As a PDE5 inhibitor, vardenafil is closely related in both function and marketing to sildenafil and tadalafil. Structurally, the vardenafil molecule differs from sildenafil (Viagra) by only a methyl group and the position of one nitrogen atom in its structure. It has a relatively short effective time, comparable to sildenafil.

Adverse drug reactions: More common adverse drug reactions (ADRs) are as per other PDE5 inhibitors and are listed on that page.
Common vardenafil-specific ADRs include: nausea. Infrequent ADRs include: abdominal pain, back pain, photosensitivity, abnormal vision, eye pain, facial oedema, hypertension, palpitation, tachycardia, arthralgia, myalgia, rash, itch, priapism. (Rossi, 2004)
The use of products containing vardenafil has also been associated with serious side-effects which include serious cardiac events such as heart attacks. In rare cases, the use of vardenafil may result in penile tissue damage and permanent loss of potency. Health Canada (2006).

Drug interactions: Products containing vardenafil should not be used by individuals who are taking any nitrate medication because combining these products could result in the development of potentially life-threatening low blood pressure.

Dose forms: It is available in 2.5 mg, 5 mg, 10 mg, and 20 mg doses in round orange tablets. The normal starting dose is 10 mg (roughly equivalent to 50 mg of sildenafil). Vardenafil should be taken 25–60 minutes prior to sexual activity, with a maximum dose frequency of once per day. In some territories, such as the UK, only certain doses may be available, i.e. 5 mg, 10 mg, and 20 mg.

Sildenafil

2007-10-17T09:55:00.000-07:00

Serch Sildenafil : Buy Sildenafil

Systematic (IUPAC) name
(6R-trans)-6-(1,3-benzodioxol-5-yl)- 2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino [1', 2':1,6] pyrido[3,4-b]indole-1,4-dione

Identifiers: CAS number 171596-29-5; ATC code G04BE08;
PubChem 110635; DrugBank APRD00071.
Chemical data: Formula C22H19N3O4;
Mol. mass 389.404 g/mol;
SMILES search in eMolecules, PubChem.

Pharmacokinetic data:
Bioavailability ?;
Protein binding 94%;
Metabolism ?; Half life 17.5 hours; Excretion ?.

Tadalafil is an orally adminstered drug used to treat male erectile dysfunction (impotence). It was initially developed by the biotechnology firm ICOS but subsequently developed and marketed worldwide by a joint venture of ICOS and Eli Lilly and Company (Lilly ICOS LLC) under the brand name Cialis.
In the United States, tadalafil has Food and Drug Administration approval and became available in December, 2003 as the third impotence pill after sildenafil (Viagra) and vardenafil (Levitra). Due to its 36-hour effect it is also known as the weekend pill. Tadalafil has not been formally studied in regard to multiple sexual attempts during a 36 hour period.
Tadalafil is also currently undergoing Phase 3 clinical trials for the treatment of pulmonary arterial hypertension.

History: The history of Cialis cannot be discussed without mentioning Pfizer's drug, Viagra (sildenafil). The FDA's approval of Viagra on March 27, 1998, was a groundbreaking success as sales reached over a billion dollars. However, things changed considerably for the giant of erectile dysfunction drugs when the FDA subsequently approved Levitra (vardenafil) on August 19, 2003, and Cialis (tadalafil) on November 21, 2003.
In 1993 the Bothell, Washington-based biotechnology company Icos began studying IC351, which is a phosphodiesterase type 5 (PDE5) enzyme inhibitor. In 1994, Pfizer scientists discovered that sildenafil citrate, which also inhibits the PDE5 enzyme, caused patients that were participating in a clinical study of a heart medicine to have erections. Although the ICOS scientists were not testing the chemical compound IC351 for erectile dysfunction, it was recognized that the compound could have potential usefulness for the treatment of erectile dysfunction. Soon Icos received a patent in 1994 for IC351, and Phase 1 clinical trials began in 1995. In 1997, Phase 2 clinical studies were initiated in patients with erectile dysfunction. Phase 2 lasted about two years, and after that Phase 3 began.
In 1998, ICOS Corporation, and Eli Lilly and Company, formed a joint venture (Lilly ICOS LLC) to develop and commercialize the drug for erectile dysfunction, and two years later they filed a New Drug Application with the U.S. Food and Drug Administration for IC351 (under the generic name tadalafil and the brand name Cialis). In May of 2002, Lilly ICOS reported to the American Urological Association that clinical trial testing in men with erectile dysfunction showed that tadalafil works for up to 36 hours, and one year later tadalafil was approved. One advantage that Cialis has over Viagra and Levitra is that tadalafil has a half-life of 17.5 hours (and thus Cialis is advertised to work for up to 36 hours, after which time there is still about one quarter of the absorbed dose in the body) as compared to 4 hours half-life for sildenafil (Viagra).
Eli Lilly purchased ICOS Corporation for $2.1 billion dollars in 2006.

Chemistry: The empirical formula for tadalafil is C22H19N3O4, and its official organic name is (6R,12aR)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a- hexahydro-2-methyl-pyrazino [1 ,2 :1,6]pyrido[3,4-b]indole-1,4-dione. The molecular weight is 389.41. Tadalafil tablets are yellow, film-coated, and almond-shaped, and are produced in 5, 10, or 20 mg doses.

Mechanism of action: Although Viagra, Levitra, and Cialis all work by inhibition of PDE5, tadalafil's distinguishing pharmacologic feature is its longer half-life (17.5 hours) compared with Viagra and Levitra (4-5 hours). This longer half-life results in a longer duration of action and is, in part, responsible for the Cialis nickname of the "weekend pill." This longer half-life also is the basis of current investigation for tadalafil's use in pulmonary arterial hyperension as a once-daily therapy. At present, sildenafil (trade name Revatio) is approved in various regions worldwide as a 3-times daily therapy for pulmonary arterial hypertension .
Part of the physiological process of erection involves the parasympathetic nervous system causing the release of nitric oxide (NO) in the corpus cavernosum of the penis. NO binds to the receptors of the enzyme guanylate cyclase which results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation (vasodilation) in the corpus cavernosum, resulting in increased inflow of blood and an erection. Tadalafil works in erectile dysfunction by inhibiting PDE5, and relaxing arterial wall smooth muscle tissue of the penis to increase local blood flow. A 20 mg dose of tadalafil is comparable to a 100 mg dose of sildenafil (Viagra).[citation needed] By inhibiting PDE5, tadalafil relaxes blood vessels in the penis, thereby increasing blood flow and aiding in erection.
The molecular structure of tadalafil is similar to that of cGMP and acts as a competitive binding agent of PDE5 in the corpus cavernosum, resulting in more cGMP and better erections. Without sexual stimulation, and therefore lack of activation of the NO/cGMP system, tadalafil should not cause an erection.
Tadalafil is currently undergoing clinical trials for the treatment of pulmonary arterial hypertension. In patients with pulmonary arterial hypertension, it is believed that there is an imablance of the PDE5/NO system in the pulmonary vasculature that favors selective vasoconstriction of the pulmonary artery. Investigation of tadalafil in this disease assumes that PDE5 inhibition will result in pulmonary artery vasodilation, thus lowering pulmonary artery pressure and pulmonary vascular resistance. These physiologic changes may then reduce the workload of the right ventricle of the heart. Right heart failure is the main consequence of pulmonary arterial hypertension.

Side effects: Tadalafil has been used in approximately 15,000 men participating in clinical trials, and over 8 million men wordwide (primarily in the post-approval/post-marketing setting). The most common side effects when using tadalafil are headache, indigestion, back pain, muscle aches, flushing, and stuffy or runny nose. These side effects reflect the ability of PDE5 inhibition to vasodilate (cause blood vessels to widen) and usually go away after a few hours. Back pain and muscle aches can occur 12 to 24 hours after taking the drug, and the symptom usually disappears after 48 hours.
In May 2005, the U.S. Food and Drug Administration found that tadalafil (along with other PDE5 inhibitors) was associated with vision impairment related to NAION (non-arteritic anterior ischemic optic neuropathy) in certain patients taking these drugs in the post-marketing (outside of clinical trials) setting. Most, but not all, of these patients had underlying anatomic or vascular risk factors for development of NAION unrelated to PDE5 use, including: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. Given the small number of NAION events with PDE5 use (less than 1 in 1 million), the large number of users of PDE5 inhibitors (millions) and the fact that this event occurs in a similar population to those who do not take these medicines, the FDA concluded that they were not able to draw a cause and effect relationship, given these patients underlying vascular risk factors or anatomical defects. However, the label of all three PDE5 inhibitors was changed to highlight clinicians to a possible association.

Drug interactions: Since PDE5 inhibitors such as tadalafil may cause transiently low blood pressure (hypotension), organic nitrates should not be taken for at least 48 hours after taking the last dose of tadalafil. Using organic nitrates (such as the sex drug amyl nitrite) within this timeframe may increase the risk of life-threatening hypotension.
Since people who have taken tadalafil within the past 48 hours cannot take organic nitrates to relieve angina (such as glyceryl trinitrate spray), these patients should seek immediate medical attention if they experience anginal chest pain. In the event of a medical emergency, paramedics and medical personnel should be notified of any recent doses of tadalafil.

Marketing: In the United States, Eli Lilly has a multiyear agreement to promote tadalafil (Cialis) with professional golf's PGA Tour. Cialis is one of the most frequent offerings of spam.

Trivia: Some individuals with the surname of "Cialis" objected to Lilly's naming of the drug, but the company insists that the drug's trade name has nothing to do with the surname.

Diazepam

2007-10-16T08:20:00.000-07:00

Search Diazepam : Buy Diazepam : Best Price on Diazepam

Systematic (IUPAC) name
7-chloro-1-methyl-
5-phenyl-1,3-dihydro-2H-
1,4-benzodiazepin-2-one

Identifiers: CAS number 439-14-5; ATC code N05BA01
N05BA17; PubChem 3016; DrugBank APRD00642.
Chemical data: Formula C16H13ClN2O;
Mol. mass 284.7 g/mol.
Pharmacokinetic data: Bioavailability 93%;
Metabolism Hepatic; Half life 20-100 hours; Excretion Renal.
Therapeutic considerations: Pregnancy cat. C(AU) D(US)
Legal status Prescription Only (S4)(AU) Schedule IV(CA); Schedule IV(US) Schedule IV (International); Routes Oral, IM, IV, suppository.

Diazepam, first marketed as Valium by Hoffmann-La Roche) is a benzodiazepine derivative drug. It possesses anxiolytic, anticonvulsant, sedative, skeletal muscle relaxant and amnestic properties. It is commonly used for treating anxiety, insomnia, seizures, alcohol withdrawal, and muscle spasms. It may also be used before certain medical procedures (such as endoscopies) to reduce tension and anxiety, and in some surgical procedures to induce amnesia.
Diazepam is a core medicine in the World Health Organization's "Essential Drugs List", which is a list of minimum medical needs for a basic health care system.[3] Diazepam is used to treat a wide range of conditions and has been one of the most frequently prescribed medications in the world for the past 40 years.

History: Diazepam was the second benzodiazepine to be invented by Leo Sternbach of Hoffmann-La Roche, and was approved for use in 1963. It is two and a half times more potent than its predecessor, chlordiazepoxide, which it quickly surpassed in terms of sales. After this initial success, other pharmaceutical companies began to introduce other benzodiazepine derivatives.
The benzodiazepines gained popularity among medical professionals as an improvement upon barbiturates, which have a comparatively narrow therapeutic index, and are far more sedating at therapeutic doses. The benzodiazepines are also far less dangerous; death rarely results from diazepam overdose, except in cases where it is consumed with large amounts of other depressants (such as alcohol or other sedatives).
Diazepam was the top-selling pharmaceutical in the United States from 1969 to 1982, with peak sales in 1978 of 2.3 billion pills. Diazepam along with oxazepam, nitrazepam and temazepam represent 82% of the benzodiazepine market in Australia. While psychiatrists continue to prescribe diazepam for the short-term relief of anxiety, neurology has taken the lead in prescribing diazepam for the palliative treatment of certain types of epilepsy and spastic activity, e.g., forms of paresis. It is also the first line of defense for a rare disorder called stiff-person syndrome.
Diazepam is also found in nature. Several plants, such as potato and wheat, contain trace amounts of naturally occurring diazepam and other benzodiazepines.

Physical properties: Diazepam occurs as solid white or yellow crystals and has a melting point of 131.5 to 134.5°C. It is odorless, and has a slightly bitter taste. The British Pharmacopoeia lists diazepam as being very slightly soluble in water, soluble in alcohol and freely soluble in chloroform. The United States Pharmacopoeia lists diazepam as soluble 1 in 16 of ethyl alcohol, 1 in 2 of chloroform, 1 in 39 of ether, and practically insoluble in water. The pH of diazepam is neutral (i.e. pH = 7). Diazepam has a shelf-life of 5 years for oral tablets and 3 years for IV/IM solution. Diazepam is structurally related to quinazolines and is a hapten.
Diazepam should be stored at room temperature (15°-30°C). The solution for parenteral injection should be protected from light and kept from freezing. The oral forms should be stored in air-tight containers and protected from light.
Diazepam can absorb into plastic, and therefore diazepam solution is not stored in plastic bottles or syringes. It can absorb into plastic bags and tubing used for intravenous infusions. Absorption appears to be dependent on several factors such as temperature, concentration, flow rates and tube length. Diazepam should not be administered if a precipitate has formed and will not dissolve.

Pharmacology: Diazepam and other benzodiazepines may influence neurosteroid metabolism and progesterone levels which in turn may adversely influence the functions of the brain and reproductive system. The pharmacological actions of benzodiazepines at the GABAa receptor are similar to those of neurosteroids. Neuroactive steroids are positive allosteric modulators of the GABAa receptor, enhancing GABA function. Many benzodiazepines (diazepam, medazepam, estazolam, flunitrazepam and nitrazepam) potently inhibit the enzymes involved in the metabolism of neurosteroids. Long-term administration of benzodiazepines may influence the concentrations of endogenous neurosteroids, and thereby would modulate the emotional state. Factors which effects benzodiazepines ability to alter neurosteroid levels depend on the molecular make up of the individual benzodiazepine molecule. Presence of a substituent at N1 position of the diazepine ring and/or the chloro or nitro group at position 7 of the benzene ring contribute to potent inhibition of the isoenzymes, and in turn a bromo group at position 7 (for bromazepam) and additional substituents (3-hydroxy group for oxazepam and tetrahydroxazole ring for cloxazolam and oxazolam) decrease the inhibitory potency of benzodiazepines on neurosteroids.
Diazepam at high doses has been found to decrease histamine turnover via diazepam's action at the benzodiazepine-GABA receptor complex.

Mechanism of action: See also: Benzodiazepine.
Diazepam is a benzodiazepine that binds to a specific subunit on the GABAA receptor at a site that is distinct from the endogenous GABA molecule. The GABAA receptor is an inhibitory channel which, when activated, decreases neurologic activity.
Due to the role of diazepam as a positive allosteric modulator of GABA, when it binds to benzodiazepine receptors it causes inhibitory effects. This arises from the hyperpolarization of the post-synaptic membrane, due to the control exerted over negative chloride ions by GABAA receptors.
Diazepam appears to act on areas of the limbic system, thalamus and hypothalamus, inducing anxiolytic effects. Its actions are due to the enhancement of GABA activity.
The anticonvulsant properties of diazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to be limited by benzodiazepines effect of slowing recovery of sodium channels from inactivation.
The muscle relaxant properties of diazepam are produced via inhibition of polysynaptic pathways in the spinal cord.

Pharmacokinetics: Diazepam can be administered orally, intravenously, intramuscularly, or as a suppository.
When diazepam is administered orally, it is rapidly absorbed and has a fast onset of action. The onset of action is 1-5 minutes for IV administration and 15-30 minutes for IM administration. The duration of the diazepam's main pharmacological effects is 15 minutes to 1 hour for both routes of administration.
Peak plasma levels are achieved 30 minutes to 2 hours after oral administration. When diazepam is administered as an intramuscular injection, absorption is slow, erratic and incomplete.
Diazepam is highly lipid-soluble, and is widely distributed throughout the body after administration. It easily crosses both the blood-brain barrier and the placenta, and is excreted into breast milk. After absorption, diazepam is redistributed into muscle and adipose tissue. Continual daily doses of diazepam will quickly build up to a high concentration in the body (mainly in adipose tissue), which will be far in excess of the actual dose for any given day.
There is preferential storage of diazepam in some organs including the heart. Absortion by any administered route and the risk of accumulation is significantly increased in the neonate and there are clinical justification to recommend the withdrawal of diazepam during pregnancy and breast feeding.
Diazepam is metabolised via oxidative pathways in the liver via the cytochrome P450 enzyme system. It has a biphasic half-life of 1-2 and 2-5 days, and has several pharmacologically active metabolites. The main active metabolite of diazepam is desmethyldiazepam (also known as nordazepam or nordiazepam). Diazepam's other active metabolites include temazepam and oxazepam. These metabolites are conjugated with glucuronide, and are excreted primarily in the urine. Because of these active metabolites, the serum values of diazepam alone are not useful in predicting the effects of the drug.
Diazepam has a half-life (t1/2α) of 20-50 hours, and desmethyldiazepam has a half-life of 30-200 hours and is considered to be a long acting benzodiazepine.
Most of the drug is metabolised; very little diazepam is excreted unchanged.
In humans, the protein binding of diazepam is around 98.5%.
The elimination half life of diazepam and also the active metabolite desmethyldiazepam increases significantly in the elderly which may result in prolonged action as well as accumulation of the drug during repeated administration.

Indications: Diazepam is mainly used to treat anxiety, insomnia, and symptoms of acute alcohol or opiate withdrawal. It is also used as a premedication for inducing sedation, anxiolysis or amnesia prior to certain medical procedures (e.g. endoscopy).
Diazepam is rarely used for the long-term treatment of epilepsy. This is due to the fact that tolerance to the anticonvulsant effects of diazepam usually develops within 6 to 12 months of treatment, effectively rendering it useless for this purpose and also due to side effects in particular sedation.
Diazepam has a broad spectrum of indications (most of which are off-label), including:
- Treatment of anxiety, panic attacks, and states of agitation.
- Treatment of status epilepticus, adjunctive treatment of other forms of epilepsy.
- Treatment of the symptoms of alcohol and opiate withdrawal.
- Short-term treatment of insomnia.
- Treatment of tetanus, together with other measures of intensive-treatment.
- Initial management of mania, together with firstline drugs like lithium, valproate or other antipsychotics[citation needed]
- Adjunctive treatment (with antidepressants) of depression with symptoms of anxiety[citation needed]
- Adjunctive treatment (with antipsychotics), in patients who develop early extrapyramidal side-effects[citation needed]
- Adjunctive treatment of painful muscle conditions
- Adjunctive treatment of spastic muscular paresis (para-/tetraplegia) caused by cerebral or spinal cord conditions such as stroke, multiple sclerosis, spinal cord injury (long-term treatment is coupled with other rehabilitative measures)
- Palliative treatment of stiff person syndrome.
- Pre-/postoperative sedation, anxiolysis and/or amnesia (e.g. before endoscopic or surgical procedures)
- Treatment of overdosage with hallucinogens or CNS stimulants.
- Adjunctive treatment of drug-induced seizures, resulting from exposure to sarin, VX, soman (or other organophosphate poisons; See CANA), lindane, chloroquine, physostigmine, or pyrethroids.
- Emergency treatment of eclampsia, along with IV magnesium sulfate
- Prophylactic treatment of oxygen toxicity during hyperbaric oxygen therapy.
- Used in the treatment for irritable bowel syndrome.
- Used to treat pain resulting from muscle spasms caused by various spastic dystonias, including blepharospasm, spasmodic dysphonia and Meige's Syndrome.

Veterinary uses - Diazepam is used as a short term sedative and anxiolytic for cats and dogs. It is also used for short-term treatment of seizures in dogs and short-term and long-term treatment of seizures in cats. For emergent treatment of seizures, the typical dose is 0.5 mg/kg intravenously or 1-2 mg/kg per rectum of the injectable solution.

- Diazepam is also used as a muscle relaxant for horses, to be given intravenously, the usual dose is 0.02 - 0.1 mg/kg in conjunction with or just after induction of general anesthesia.

Dosage: Dosages should be determined on an individual basis, depending upon the condition to be treated, the severity of symptoms, the body weight of the patient, and any comorbid conditions the patient may have.
Typical dosages for healthy adults range from 2mg per dose to 30mg per dose, depending on such factors as body weight and condition being treated. For the elderly or people with liver disorders, initial dose is at the low end of the range, with the dose being increased as required.

Pregnancy: There is inconclusive evidence that diazepam if taken early in pregnancy may result in reduced IQ, neurodevelopmental problems, physical malformations in cardiac or facial structure as well as other malformations in some new borns, however the data is inconclusive. Diazepam when taken during late in pregnancy, the third trimester, causes a definite risk of a severe benzodiazepine withdrawal syndrome in the neonate with symptoms including hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. Floppy infant syndrome and sedation in the new born may also occur. Symptoms of floppy infant syndrome and the neonatal benzodiazepine withdrawal syndrome have been reported to persist from hours to months after birth.

Dependence: Diazepam as with other benzodiazepine drugs can cause physical dependence, addiction and what is known as the benzodiazepine withdrawal syndrome. Withdrawal from diazepam or other benzodiazepines often leads to withdrawal symptoms which are similar to those seen during alcohol and barbiturate withdrawal. The higher the dose and the longer the drug is taken for the greater the risk of experiencing unpleasant withdrawal symptoms. Withdrawal symptoms can however occur from standard dosages and also after short term use. Benzodiazepine treatment should be discontinued as soon as possible via a slow and gradual dose reduction regime.

Misuse and abuse: Diazepam is a drug of potential dependence and addiction. Between 50 and 64% of rats will self administer diazepam. Benzodiazepines including diazepam in animal studies have been shown to increase reward seeking behaviours by increasing impulsivity which may suggest an increased risk of addictive behavioural patterns with usage of diazepam or other benzodiazepines. Diazepam is often found as an adulterant in heroin. This may be because diazepam greatly amplifies the effects of opioids.
Sometimes diazepam is used by stimulant users to 'come down' and sleep and to help control the urge to binge.
Benzodiazepines, including diazepam, temazepam, nitrazepam and flunitrazepam account for the largest volume of forged drug prescriptions in Sweden, a total of 52% of drug forgeries being for benzodiazepines.
Diazepam was detected in 26% of cases of people suspected of driving under the influence of drugs in Sweden and its active metabolite nordazepam was detected in 28% of cases. Other benzodiazepines and zolpidem and zopiclone also were found in high numbers. Many drivers had blood levels far exceeding the therapeutic dose range suggesting a high degree of abuse potential for benzodiazepines and zolpidem and zopiclone. In Northern Ireland in cases where drugs were detected in samples from impaired drivers who were not impaired by alcohol, benzodiazepines were found to be present in 87% of cases. Diazepam was the most commonly detected benzodiazepine.
It is sometimes referred to by street names, including 'blues', 'mother's little helper', 'drunk pills', 'vals', 'V', and occasionally 'ludes', mistaken for quaaludes. As well as less specific street terms, 'candy'(pills), 'benzos' (benzodiazepines), or downers(depressants).

Legal status: Internationally, diazepam is a Schedule IV drug under the Convention on Psychotropic Substances. In the UK, it is classified as a Class C drug.

Toxicity: Laboratory tests assessing the toxicity of diazepam, nitrazepam and chlordiazepoxide on mice spermatozoa found that diazepam produced toxicities in sperm including abnormalities involving both the shape and size of the sperm head. Nitrazepam however caused more profound abnormalities than diazepam.

Tramadol

2007-10-16T07:37:00.000-07:00

Systematic (IUPAC) name
rac-(1R,2R)-2-(dimethylaminomethyl)-1-
(3-methoxyphenyl)-cyclohexanol

Identifiers: CAS number 27203-92-5; ATC code N02AX02
PubChem 33741; DrugBank APRD00028.
Chemical data: Formula C16H25NO2; Mol. mass 263.4 g/mol
SMILES search in eMolecules, PubChem.
Pharmacokinetic data: Bioavailability 68–72% Increases with repeated dosing; Protein binding 20%;
Metabolism Hepatic demethylation and glucuronidation;
Half life 5–7 hours; Excretion Renal.
Therapeutic considerations: Pregnancy cat. C(AU) C(US);
Legal status Prescription Only (S4)(AU) POM(UK); Routes oral, IV, IM.

Tramadol (INN) is an atypical opioid which is a centrally acting analgesic, used for treating moderate to severe pain. It is a synthetic agent, as a 4-phenyl-piperidine analogue of codeine, and appears to have actions on the GABAergic, noradrenergic and serotonergic systems. Tramadol was developed by the German pharmaceutical company Grünenthal GmbH and marketed under the trade name Tramal. Grünenthal has also cross licensed the drug to many other pharmaceutical companies that market it under various names.
Tramadol is usually marketed as the hydrochloride salt (tramadol hydrochloride) and is available in both injectable (intravenous and/or intramuscular) and oral preparations. It is also available in conjunction with paracetamol (acetaminophen).
Tramadol is approximately 10% as potent as morphine, when given by the IV/IM route. Oral doses range from 50–400 mg daily, with up to 600 mg daily when given IV/IM. The 'combination' pills each contain 37.5 mg of tramadol and 325 mg of paracetamol, with the recommended dose being one or two pills every four to six hours.
Unlike most other opioids, Tramadol is not considered a controlled substance in many countries (the U.S., Canada and Australia, among others), and is available with a normal prescription. Tramadol is also available over-the-counter without prescription in a few countries.

Uses: Tramadol is used to treat moderate and severe pain and most types of neuralgia, including trigeminal neuralgia.[citation needed] It has been suggested that tramadol could be effective for alleviating symptoms of depression and anxiety because of its action on GABAergic, noradrenergic and specifically serotonergic systems. However, health professionals have not yet endorsed its use on a large scale for disorders such as this.

Off-label and investigational uses diabetic neuropathy; postherpetic neuralgia; fibromyalgia; restless legs syndrome; opiate withdrawal management; migraine headache; obsessive-compulsive disorder; premature ejaculation.

Veterinary - Tramadol is used to treat post-operative and/or chronic (e.g. cancer-related) pain in dogs and cats.

Mechanism of action: The mode of action of tramadol has yet to be fully understood, but it is believed to work through modulation of the GABAergic, noradrenergic and serotonergic systems, in addition to its mild agonism of the μ-opiod receptor. The contribution of non-opioid activity is demonstrated by the analgesic effects of tramadol not being fully antagonised by the μ-opioid receptor antagonist naloxone.
Tramadol is marketed as a racemic mixture with a weak affinity for the μ-opioid receptor (approximately 1/6th that of morphine). The (+)-enantiomer is approximately four times more potent than the (-)-enantiomer in terms of μ-opioid receptor affinity and 5-HT reuptake, whereas the (-)-enantiomer is responsible for noradrenaline reuptake effects (Shipton, 2000). These actions appear to produce a synergistic analgesic effect, with (+)-tramadol exhibiting 10-fold higher analgesic activity than (-)-tramadol (Goeringer et al., 1997).
The serotonergic modulating properties of tramadol mean that it has the potential to interact with other serotonergic agents. There is an increased risk of serotonin syndrome when tramadol is taken in combination with serotonin reuptake inhibitors (e.g. SSRIs), since these agents not only potentiate the effect of 5-HT but also inhibit tramadol metabolism. Tramadol is also thought to have some NMDA-type antagonist effects which has given it a potential application in neuropathic pain states.

Metabolism: Tramadol undergoes hepatic metabolism via the cytochrome P450 isozyme CYP2D6, being O- and N-demethylated to five different metabolites. Of these, M1 is the most significant since it has 200 times the μ-affinity of (+)-tramadol, and furthermore has an elimination half-life of nine hours, compared with six hours for tramadol itself. In the 6% of the population who have slow CYP2D6 activity, there is therefore a slightly reduced analgesic effect. Phase II hepatic metabolism renders the metabolites water-soluble and they are excreted by the kidneys. Thus reduced doses may be used in renal and hepatic impairment.

Adverse effects: The most commonly reported adverse drug reactions are nausea, vomiting and sweating. Drowsiness is reported, although it is less of an issue than for other opioids. Respiratory depression, a common side effect of most opioids, is not clinically significant in normal doses. By itself, it can decrease the seizure threshold. When combined with SSRIs, tricyclic antidepressants, or in patients with epilepsy, the seizure threshold is further decreased. Seizures have been reported in humans receiving excessive single oral doses (700 mg) or large intravenous doses (300 mg). An Australian study found that of 97 confirmed new-onset seizures, eight were associated with Tramadol, and that in the authors' First Seizure Clinic, "Tramadol is the most frequently suspected cause of provoked seizures" (Labate 2005). Dosages of coumadin/warfarin may need to be reduced for anticoagulated patients to avoid bleeding complications.

Dependence: Some controversy exists regarding the dependence liability of tramadol. Grünenthal has promoted it as an opioid with a lower risk of opioid dependence than that of traditional opioids, claiming little evidence of such dependence in clinical trials. They offer the theory that since the M1 metabolite is the principal agonist at μ-opioid receptors, the delayed agonist activity reduces dependence liability. The noradrenaline reuptake effects may also play a role in reducing dependence.
Despite these claims, it is apparent, in community practice, that dependence to this agent does occur. However, this dependence liability is considered relatively low by health authorities, such that tramadol is classified as a Schedule 4 Prescription Only Medicine in Australia, rather than as a Schedule 8 Controlled Drug like other opioids (Rossi, 2004). Similarly, tramadol is not currently scheduled by the U.S. DEA, unlike other opioid analgesics. Nevertheless, the prescribing information for Ultram warns that tramadol "may induce psychological and physical dependence of the morphine-type". In addition, there are widespread reports by consumers of extremely difficult withdrawal experiences.
A controlled study that compared different medications found "the percent of subjects who scored positive for abuse at least once during the 12-month follow-up were 2.5% for NSAIDs, 2.7% for tramadol, and 4.9% for hydrocodone. When more than one hit on the dependency algorithm was used as a measure of persistence, abuse rates were 0.5% for NSAIDs, 0.7% for tramadol, and 1.2% for hydrocodone. Thus, the results of this study suggest that the prevalence of abuse/dependence over a 12-month period in a CNP population that was primarily female was equivalent for tramadol and NSAIDs, with both significantly less than the rate for hydrocodone".

Recreational use: As an opioid analgesic, tramadol can be used recreationally. It can, via agonism of μ opiate receptors, produce effects similar to those of other opiods (e.g., morphine or hydrocodone), although not nearly as intense due to tramadol's much lower affinity for the receptor. In addition to acting as an opioid, tramadol is also a very weak but rapidly acting serotonin-norepinephrine reuptake inhibitor. When taken in amounts larger than normal therapeutic doses, tramadol can cause seizures (typically tonic-clonic) and severe nausea, which could deter abuse to some extent. Tramadol has been known to produce severe withdrawal symptoms with abrupt cessation after prolonged use.

Atorvastatin

2007-10-16T07:02:00.000-07:00

Buy Atorvastatin : Best Prais on Atorvastatin

Systematic (IUPAC) name
[R-(R*, R*)]-2-(4-fluorophenyl)-beta, delta-dihydroxy-5- (1-methylethyl)-3-phenyl-4- [(phenylamino)carbonyl]-1H- pyrrole-1-heptanoic acid

Identifiers : CAS number 134523-00-5; ATC code C10AA05; PubChem 60823
DrugBank APRD00055.
Chemical data: Formula C33H34FN2O5; Mol. mass 558.64
Pharmacokinetic data: Bioavailability 12%; Metabolism Liver; Half life 14 hours;
Excretion Bile.
Therapeutic considerations: Pregnancy cat. D(AU) X(US); Legal status Prescription Only (S4)(AU) POM(UK) -only(US)
Routes oral.

Atorvastatin, marketed under the trade name Lipitor and several others, is a member of the drug class known as statins, used for lowering cholesterol. Atorvastatin inhibits the rate-determining enzyme located in hepatic tissue that produces mevalonate, a small molecule used in the synthesis of cholesterol and other mevalonate derivatives. This lowers the amount of cholesterol produced which in turn lowers the total amount of LDL cholesterol. With 2006 sales of US$12.9 billion under the brand name Lipitor, it is the largest selling drug in the world.

Pharmacology: Main article: Statin
As with other statins, atorvastatin is a competitive inhibitor of HMG-CoA reductase. Unlike most others, however, it is a completely synthetic compound. HMG-CoA reductase catalyzes the reduction of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, which is the rate-limiting step in hepatic cholesterol biosynthesis. Inhibition of the enzyme decreases de novo cholesterol synthesis, increasing expression of low-density lipoprotein receptors (LDL receptors) on hepatocytes. This increases LDL uptake by the hepatocytes, decreasing the amount of LDL-cholesterol in the blood. Like other statins, atorvastatin also reduces blood levels of triglycerides and slightly increases levels of HDL-cholesterol.
In clinical trials, adding Zetia (ezetimibe) to Lipitor lowered cholesterol more effectively than Vytorin (ezetimibe + simvastatin). The combination of ezetimibe with atorvastatin could be an important contributor controlling cholesterol.

Clinical use:
Indications: Atorvastatin is indicated as an adjunct to diet for the treatment of dyslipidaemia, specifically hypercholesterolaemia. It has also been used in the treatment of combined hyperlipidemia.
In 2005, the PROVE IT-TIMI 22 trial compared 40mg/day pravastatin with 80mg/day atorvastatin. Taken directly from the results of the trial: "Standard treatment (statin) with a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (pravastatin 40 mg/day) resulted in a 22% reduction in LDL cholesterol levels at 30 days compared with a 51% reduction with intensive therapy (atorvastatin 80 mg/day). At 2 years, a relative risk reduction of 16% (95% confidence interval, 5%-26%; P = 0.005) in the primary end point rate (death, myocardial infarction, documented unstable angina requiring hospitalization, coronary revascularization, or stroke) was seen in patients receiving intensive statin treatment compared with standard statin therapy. The benefit of intensive treatment was apparent as early as 30 days and was consistent over time. The PROVE IT-TIMI 22 data indicate that patients recently hospitalized for an ACS benefit from early and continued lowering of LDL cholesterol to levels substantially below current guideline recommendations."

Available forms: Atorvastatin calcium tablets are currently marketed by Pfizer under the trade name Lipitor, in tablets (10, 20, 40 or 80 mg) for oral administration. Tablets are white, elliptical, and film coated. In some countries it may also be known as: Sortis, Torvast, Torvacard, Totalip, Tulip, Xarator, Atorpic, or Liprimar. It is also packaged in combination with other drugs, such as is the case with Pfizer's Caduet.

Adverse effects: For additional information see: Statins
Common adverse drug reactions (≥1% of patients) associated with atorvastatin therapy include: myalgia, mild transient gastrointestinal symptoms (diarrhea, constipation, passing gas), elevated hepatic transaminase concentrations, headache, insomnia, joint pain, and/or dizziness.
Myopathy and rhabdomyolysis occur in <0.1%>

Patent challenge: The size of the market for atorvastatin has prompted the generic drug manufacturing company Ranbaxy to challenge the validity of some of Pfizer's patents in patent courts across the world. As of March 2007, courts had mostly upheld the validity of Pfizer's original patent for atorvastatin, which is due to expire in European territories in 2011 (but 2007 in Canada). However a later patent for the specific enantiomer of the atorvastatin formula that is medically useful, which would have given Pfizer longer protection, has fared less well. Although upheld in the United States, Spain, and Ecuador, the enantiomer patent has been declared invalid by courts in Austria, Australia, Canada, the Netherlands and the United Kingdom.

Phentermine

2007-10-16T06:04:00.000-07:00

Systematic (IUPAC) name
2-methyl-1-phenylpropan-2-amine and 2-methyl-amphetamine

Identifiers:CAS number 122-09-8; ATC code A08AA01 C01CA11; PubChem 4771; DrugBank APRD00093.
Chemical data: Formula C10H15N; Mol. mass 149.233 g/mol.
Pharmacokinetic data: Bioavailability Peak plasma levels occur within 1 to 4.5 hours. Absorption is usually complete by 4 to 6 hours; Protein binding Approximately 96.3%; Metabolism hepatic; Half life 16 to 31 hours; Excretion Urinary elimination.
Therapeutic considerations: Pregnancy cat. C(United States); (Australia);
Legal status C-IV (US); Routes Oral.

Phentermine is an appetite suppressant of the amphetamine and phenethylamine class.
It is approved as an appetite suppressant to help reduce weight in obese patients when used short-term and combined with exercise, diet, and behavioral modification. It is typically prescribed for individuals who are at increased medical risk because of their weight and works by helping to release certain chemicals in the brain that control appetite.

Commercial trade names:
Adipex P (Immediate release)

Anoxine-AM®

Fastin®

Ionamin® (Slow Release Resin, Australia)

Duromine® (Slow Release Resin, New Zealand)

Obephen®

Obermine®

Obestin-30®

Phentrol®

Pro-Fast SA

Phentermine Trenker

Obenix

Oby-Trim

History: In 1959 phentermine first received approval from the FDA as an appetite suppressing drug. Phentermine hydrochloride then became available in the early 1970s. It was previously sold as Fastin® from King Pharmaceuticals for SmithKline Beecham, however in 1998 it was removed from the market. Medeva Pharmaceuticals sells the name brand of phentermine called Ionamin® and Gate Pharmaceuticals sells it as Adipex-P®. Phentermine is also currently sold as a generic. Since the drug was approved in 1959 there have been almost no clinical studies performed. The most recent study was in 1990 which combined phentermine with fenfluramine or dexfenfluramine and became known as Fen-Phen.
A study was published in 1992 that Fen-Phen was more effective than diet and exercise with few side effects. However, in 1997 after 24 cases of heart valve disease in Fen-Phen users, fenfluramine and dexfenfluramine were voluntarily taken off the market at the request of the FDA. Studies later proved that nearly 30% of people taking fenfluramine or dexfenfluramine had abnormal valve findings. The FDA did not ask manufacturers to remove phentermine from the market.
Phentermine is still available by itself in most countries, including the U.S. However, because it is similar to amphetamines, individuals may develop an addiction to it. Hence, it is classified as a controlled substance in many countries. Internationally, phentermine is a schedule IV drug under the Convention on Psychotropic Substances. In the United States, it is classified as a Schedule IV controlled substance under the Controlled Substances Act.

Mechanism of action:
Phentermine, like many other prescription drugs, works with neurotransmitters in the brain. It is a centrally-acting stimulant and is a constitutional isomer (not to be confused with stereoisomer) of methamphetamine. It stimulates neuron bundles to release a particular group of neurotransmitters known as catecholamines; these include dopamine, epinephrine (also known as adrenalin), and norepinephrine (noradrenaline). The anorectic activity seen with these compounds would thus seem likely due to this effect on the central nervous system, which is consistent with current knowledge about central nervous system systems and feeding behavior. This is the same mechanism of action as other stimulant appetite suppressants such as diethylpropion and phendimetrazine. The neurotransmitters signal a fight-or-flight response in the body which, in turn, puts a halt to the hunger signal. As a result, it causes a loss in appetite because the brain does not receive the hunger message.

Dosing and administration: Generally, it is recommended by the Food and Drug Administration (FDA) that phentermine should be used short-term (usually interpreted as 'up to 12 weeks'), while following nonpharmacological approaches to weight loss such as healthy dieting and exercise. However, recommendations limiting its use for short-term treatment may be controversial. One reason given behind limiting its use to 12 weeks is drug tolerance, whereby phentermine loses its appetite-suppressing effects after the body adjusts to the drug. On the contrary, it has been shown that phentermine did not lose effectiveness in a 36-week trial. Due to the risk of insomnia, it is generally recommended that the drug be taken either before breakfast or 1-2 hours after breakfast.

Contraindications and warnings:
- Patients with the following should not use Phentermine:
- An allergy to any ingredient in Phentermine or other sympathomimetics (eg, pseudoephedrine)
- Are also taking dexfenfluramine, fenfluramine, furazolidone, guanadrel, guanethidine, or have taken a monoamine oxidase inhibitor (MAOI) (eg, phenelzine) in the last 14 days
- Have moderate to severe high blood pressure, an overactive thyroid, glaucoma, heart or blood vessel disease, or severe narrowing of the blood vessels
- Are in an agitated state, or have a history of substance abuse
- Some medical conditions may interact with Phentermine, patients with the following should consult with their doctor before using phentermine:
- Are pregnant, planning to become pregnant, or are breast-feeding
- Are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement
- Have allergies to medicines, foods, or other substances
- Have a brain or spinal cord disorder, hardening of the arteries, high blood pressure, diabetes, or high cholesterol or lipid levels
- Some medicines may interact with Phentermine, such as the following:
- Dexfenfluramine, fenfluramine, furazolidone, or MAOIs (eg, phenelzine) because the risk of serious side effects, such as increasing headache, high blood pressure, slow heart rate, elevated temperature, or possibly fatal lung problems, may be increased
- Serotonin specific reuptake inhibitors (eg, fluoxetine) because the risk of their side effects may be increased by Phentermine
- Guanadrel or guanethidine because their effectiveness may be decreased by Phentermine

Side effects: Generally, phentermine appears to be relatively well tolerated. It can produce side effects consistent with its catecholamine-releasing properties, e.g., tachycardia (increased heart rate) and elevated blood pressure, but the incidence and magnitude of these appear to be less than with the amphetamines. Because phentermine acts through sympathomimetic pathways, the drug may increase blood pressure and heart rate. It may also cause palpitations, restlessness, and insomnia. Additionally, phentermine has the potential to cause physical and psychological dependence.

Viagra (Sildenafil citrate)

2007-10-15T11:24:00.000-07:00

Buy Viagra : Best Price on Viagra : Order Viagra

Systematic (IUPAC) name
1-[4-ethoxy-3-(6,7-dihydro-1-methyl-
7-oxo-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl)
phenylsulfonyl]-4-methylpiperazine citrate

Identifiers: CAS number 139755-83-2; ATC code G04BE03; PubChem 5281023;
DrugBank APRD00556
Chemical data: Formula C22H30N6O4S; Mol. mass base: 474.6 g/mol; SMILES search in eMolecules, PubChem
Pharmacokinetic data:Bioavailability 40%; Metabolism Hepatic; Half life 3-4h
Excretion CYP3A4
Therapeutic considerations: Pregnancy cat. N/A; Legal status; Prescription only
Routes Oral

Sildenafil citrate, sold under the names Viagra, Revatio and under various other names, is a drug used to treat male erectile dysfunction (impotence) and pulmonary arterial hypertension (PAH), developed by the pharmaceutical company Pfizer. Its primary competitors on the market are tadalafil (Cialis), and vardenafil (Levitra).

History: Sildenafil (compound UK-92,480) was synthesized by a group of pharmaceutical chemists working at Pfizer's Sandwich, Kent research facility in England. It was initially studied for use in hypertension (high blood pressure) and angina pectoris (a form of ischaemic cardiovascular disease). Phase I clinical trials under the direction of Ian Osterloh suggested that the drug had little effect on angina, but that it could induce marked penile erections.[1][2] Pfizer therefore decided to market it for erectile dysfunction, rather than for angina. The drug was patented in 1996, approved for use in erectile dysfunction by the Food and Drug Administration on March 27, 1998, becoming the first pill approved to treat erectile dysfunction in the United States, and offered for sale in the United States later that year. It soon became a great success: annual sales of Viagra in the period 1999–2001 exceeded $1 billion.
The British press portrayed Peter Dunn and Albert Wood as the inventors of the drug, a claim which Pfizer disputes. Their names are on the manufacturing patent application drug, but Pfizer claims this is only for convenience.
Even though sildenafil is available by prescription from a doctor, it was advertised directly to consumers on US TV (famously being endorsed by former United States Senator Bob Dole and football star Pelé). Numerous sites on the Internet offer Viagra for sale after an "online consultation", a mere web questionnaire. The "Viagra" name has become so well known that many fake aphrodisiacs now call themselves "herbal Viagra" or are presented as blue tablets imitating the shape and colour of Pfizer's product. Viagra is also informally known as "Vitamin V", "the Blue Pill", as well as various other nicknames.
In February 2007, it was announced that Boots the Chemist would trial over the counter sales of Viagra in stores in Manchester, England. Men aged between 30 and 65 would be eligible to buy four tablets after a consultation with a pharmacist.
Pfizer's worldwide patents on sildenafil citrate will expire in 2011–2013. The UK patent held by Pfizer on the use of PDE5 inhibitors (see below) as treatment of impotence was invalidated in 2000 because of obviousness; this decision was upheld on appeal in 2002.

Mechanism of action: Part of the physiological process of erection involves the parasympathetic nervous system causing the release of nitric oxide (NO) in the corpus cavernosum of the penis. NO binds to the receptors of the enzyme guanylate cyclase which results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation (vasodilation) in the corpus cavernosum, resulting in increased inflow of blood and an erection.
Sildenafil is a potent and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE5) which is responsible for degradation of cGMP in the corpus cavernosum. The molecular structure of sildenafil is similar to that of cGMP and acts as a competitive binding agent of PDE5 in the corpus cavernosum, resulting in more cGMP and better erections. Without sexual stimulation, and therefore lack of activation of the NO/cGMP system, sildenafil should not cause an erection. Other drugs that operate by the same mechanism include tadalafil (Cialis®) and vardenafil (Levitra®).
Sildenafil is metabolised by hepatic enzymes and excreted by both the liver and kidneys. If taken with a high-fat meal, there may be a delay in absorption of sildenafil and the peak effect might be reduced slightly as the plasma concentration will be lowered.

Dosage and price: As with all prescription drugs, proper dosage is at the discretion of a licensed medical doctor. The dose of sildenafil is 25 mg to 100 mg taken once per day between 30 minutes and 4 hours prior to sexual intercourse.
It is usually recommended to start with a dosage of 50 mg and then lower or raise the dosage as appropriate. The drug is sold in three dosages (25, 50, and 100 mg), all three costing about US$10 per pill. Name-brand Viagra sildenafil is not scored and a fairly hard coating makes it more difficult to accurately cut the pills in half, even with a pill cutter.
Viagra pills are blue and diamond-shaped with the words "Pfizer" on one side, and "VGR xx" (where xx stands for "25", "50" or "100", the dose of that pill in milligrams) on the other.

Contraindications:
Contraindications include:
- When taking nitric oxide donors, organic nitrites and nitrates, such as glyceryl trinitrate (nitroglycerin), sodium nitroprusside, amyl nitrite ("poppers")
- In men for whom sexual intercourse is inadvisable due to cardiovascular risk factors
- Severe hepatic impairment (decreased liver function)
- Severe impairment in renal function
- Hypotension (low blood pressure)
- Recent stroke or heart attack
- Hereditary degenerative retinal disorders (including genetic disorders of retinal phosphodiesterases)

Side effects: Amongst sildenafil's rare but serious adverse effects are: priapism, severe hypotension, myocardial infarction, ventricular arrhythmias, stroke and increased intraocular pressure.
Common side effects include sneezing, headache, flushing, dyspepsia, prolonged erections, palpitations and photophobia. Visual changes including blurring of vision and a curious bluish tinge have also been reported.
Care should be exercised by patients who are also taking Protease inhibitors for the treatment of HIV. Protease inhibitors inhibit the metabolism of sildenafil, effectively multiplying the plasma levels of sildenafil, increasing the incidence and severity of side-effects. It is recommended that patients using protease inhibitors limit their use of sildenafil to no more than one 25-mg dose every 48 hours.
Some sildenafil users have complained of blurriness and loss of peripheral vision. In May of 2005, the U.S. Food and Drug Administration found that sildenafil could lead to vision impairment and a number of studies have linked sildenafil use with nonarteritic anterior ischemic optic neuropathy. When used with an alpha blocker, take them at least four hours apart to avoid hypotension.

Other uses:

Pulmonary hypertension:
As well as erectile dysfunction, sildenafil citrate is also effective in the rare disease pulmonary arterial hypertension (PAH). It relaxes the arterial wall, leading to decreased pulmonary arterial resistance and pressure. This in turn reduces the workload of the right ventricle of the heart and improves symptoms of right-sided heart failure. Because PDE-5 is primarily distributed within the arterial wall smooth muscle of the lungs and penis, sildenafil acts selectively in both these areas without inducing vasodilation in other areas of the body. Pfizer submitted an additional registration for sildenafil to the FDA, and sildenafil was approved for this indication in June 2005. The preparation is named Revatio, to avoid confusion with Viagra, and the 20 milligram tablets are white and round. Sildenafil joins bosentan and prostacyclin-based therapies for this condition.

Raynaud's phenomenon:
In 2005, Dr. Roland Fries and colleagues reported that sildenafil cut the frequency of Raynaud's phenomenon attacks, reduced their duration by roughly one half, and more than quadrupled the mean capillary blood velocity. This was a double-blind, placebo-controlled crossover trial and the patients had both the primary and secondary forms and had all discontinued the more conventional treatments for this.

Non-medical use:

Aphrodisiac:
Sildenafil is commonly and increasingly used as an aphrodisiac. While there is no clinical evidence that it has aphrodisiac activity, many seem to believe it will improve sexual performance as well as erectile function and enhance the sexual experience that will occur.[citation needed]

Recreational use:
Viagra's popularity with young adults has increased over the years. It is sometimes used recreationally. Some users mix Viagra with methylenedioxymethamphetamine (MDMA, ecstasy) in an attempt to compensate for the side effect common to many amphetamines of erectile dysfunction, a combination known as "sextasy", "rockin' and rollin'", or 'trail mix'."

Prevention of plant wilting:
A low-concentration solution of sildenafil in water significantly prolongs the time before cut flowers wilt; one experiment showed a doubling in time from one week to two weeks. The mechanism of action is similar to that in humans: nitric oxide leads to the production of cGMP whose degradation by PDE5 is inhibited by sildenafil.

Chemical synthesis:

The preparation steps for synthesis of Viagra (sildenafil citrate) are as follows:
1. Methylation of 3-propylpyrazole-5-carboxylic acid ethyl ester with hot dimethyl sulfate.
2. Hydrolysis with aqueous NaOH to free acid.
3. Nitration with oleum/fuming nitric acid.
4. Carboxamide formation with refluxing thionyl chloride/NH4OH.
5. Reduction of nitro group to amino.
6. Acylation with 2-ethoxybenzoyl chloride.
7. Cyclization.
8. Sulfonation to the chlorosulfonyl derivative.
9. Condensation with 1-methylpiperazine.