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Some of the side effects of taking cholesterol-lowering Statin drugs and even certain antibiotics can be a decrease in our natural levels of carnitine an amino acid found abundantly in skeletal and heart muscle ; and fumarate an important component of the energy production cycle in our bodies. ; Symptoms of low LCarnitine fumarate levels include low energy, muscular. The Group's interest rate risk exposure arises from the fact that most of its debt is floating-rate credit facilities, commercial paper and floating rate notes ; , predominantly in euros. To limit risk and optimize the cost of its short-term and medium-term debt, sanofi-aventis uses interest rate swaps, cross-currency swaps, and interest rate options purchases of caps, or combined purchases of caps and sales of floors ; . The table below shows instruments of this type held at December 31, 2005, because salmeterol xinafoate fluticasone.
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Plan Design: Plan design was held constant for this analysis. PCMA assumed a $250 deductible and monthly premium of $32 in every case. PCMA did not assume plan coverage during the donut hole. By statute, the donut hole is reached when both patient and plan costs reach $2, 250 in 2006 and catastrophic coverage begins when patient out-of-pocket costs reach $3, 600 in 2006. Premium payments do not count toward the donut hole or catastrophic thresholds. Calculations: For each of the five profiles, PCMA calculated full-year cost savings to the beneficiary using the following scenarios: when the patient used only branded drugs; when the patient used generic versions of branded products when available; and when the patient used both available generics and a mail-service pharmacy. Full-year cost savings to the beneficiary were then calculated based on the extended length of time in the initial coverage period and lower out-of-pocket costs in the donut hole and at the catastrophic level, if applicable. PCMA then averaged the additional days of coverage and cost savings for the 5 patient profiles.
Symptom Text: Submitted to Docket No. 1980N-0208; 69 FR 78281, December 29, 2004 - Bacterial Vaccines & Toxoids Efficacy Review Proposal. I like all the other soldiers, received the series of shots before deploying. While the majority of soldiers vaccinated noticed no other symptoms than the usual swelling, several of us have been adversely affected, and permanently injured. I witnessed each soldier receive the vaccination, in total, about 400 soldiers. There were, at my best count, approximately 15 of us with severe reactions to the series. These numbers alone are not overwhelming, 5% at best. In the news lately, I seeing drugs pulled off of the market because they have been deemed potentially unsafe to people who might take dosages much higher than the recommended amount. It seems like a drastic response has been taken tot he pharmaceutical companies on a drug that might pose a threat in an unlikely scenario. I personally suffer from a permanent neurological disorder from this vaccine series. Others I have met, or know personally, have problems much worse. Some have died. These are not might be cases. They did not take doses that were higher than recommended. They took the normal dose that they were ordered to, under penalty of a dishonorable discharge from their country for refusing. Other Meds: Lab Data: History: Prex Illness: Prex Vax Illns, because salmeterol copd.

Journal article palmqvist m, persson g, lazer l, rosenborg j, larsson p, lö tvall j inhaled dry-powder formoterol and salmeterol in asthmatic patients: onset of action, duration of effect and potency.

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Million. The goal for this year alone was $1.2 million. The program continues to grow each year." He says he appreciates people like the employees of Medical City who complete the two- to three-mile walks come rain or come shine. "For the 2005 Dallas walk, we had some of the Participants at the Light The Night walk on October 21st show their support for the Leukemia and Lymphoma most horrific weather, " Society. Altogether, Medical City employees raised over $120, 000. says Vincik. "Trees were blowing over, but nothing in the world be eradicated." from the umbilical cord of delivering was going to make those people get in When asked why she thinks she and mothers--which is rich in stem cells--to their cars and go home." her co-workers at Medical City are so treat these potentially fatal diseases. Carol Ansley, Medical City's vice generous with their time and energy in "It's a great opportunity for moms president of strategic development, was these charitable endeavors, Ansley replied, who deliver at Medical City to be able one of those dedicated walkers this year. "People who work in healthcare typically to donate their cord blood which may be Not only that, but Ansley, along with like to help people. They identify with used to help save another child's life. This Dallas Stars president Jim Lites, served people in need and once they know exactly cord blood is normally discarded after as corporate chair of the 2006 Light The what they can do to help, they're all over delivery, and we have had a tremendous Night campaign. it. In fact, our departments battle against response from our moms wanting to donate "My job was to speak at corporate one other to see who can raise the most their cord blood, " says Janice Medlock, functions and with various business money. It's very competitive." director of Medical City Women's and contacts to get them involved, " says In addition to its employees' volunteer Medical City Children's Hospital. "We Ansley. "I asked them to think about polio efforts, Medical City is helping patients would love to have 100 percent of our and smallpox. Money that was raised to with leukemia, lymphoma and other blood moms be able to donate, " says Medlock. fund research led to the eradication of cancers in one final way. The hospital Given the caring and generous spirit that both. We have the opportunity to raise recently became the first North Texas pervades Medical City and their patients, money for research on leukemia and donor site for the Texas Cord Blood Bank, Medlock wouldn't be surprised if that lymphoma so that one day, they too, will a public repository that collects blood wish comes true and fluticasone. This formulary covers selected over-the-counter OTC ; products. You are encouraged to prescribe them when clinically appropriate. A prescription written or telephoned ; is required and refills are permitted. The prescription expires under Maryland Pharmacy Law in 12 months. Condoms do not require a prescription. Refer to pages 9-11 for covered products. PHARMACY AND THERAPEUTICS P&T ; COMMITTEE The Helix Family Choice P&T Committee includes physicians, pharmacists, and nurses. The Committee meets bimonthly to evaluate drugs for formulary inclusion, and to develop policies concerning formulary and drug utilization management. The decisions of the Helix Family Choice P&T Committee will be communicated in the Helix Family Choice Provider newsletter. The formulary may also be found at: mdmahealthchoicerx . This Maryland Department of Health and Mental Hygiene D.H.M.H. ; sponsored site contains the formularies of all the Managed Care Organizations MCO ; and is updated frequently. PRODUCT SELECTION CRITERIA The Helix Family Choice Pharmacy and Therapeutics Committee considers clinical information on new-to-market drugs that are typically included in an outpatient pharmacy benefit. The evaluation includes all or part of the following: Safety Efficacy Comparison studies Approved indications Adverse effects Contraindications Warnings Precautions Pharmacokinetics Patient administration compliance considerations When a new drug is considered for formulary inclusion, it will be reviewed relative to similar drugs currently on formulary. In addition, the entire Helix Family Choice Prescribing Guide is reviewed on an annual basis.

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Figure 1. Mean Percent Change From Baseline in FEV1 in Patients With Asthma Previously Treated With Either Inhaled Corticosteroids or Swlmeterol Study 1 and advil.
College publisher network join the college publisher network advertise across the network view network affiliates top national college news money books movies quick contacts: editorial advertising classifieds - iowa state daily home news opinion fyi sports classifieds print pdf the daily archive forums calendar police blotter classifieds advertise about us staff staff login login register undefined section penalties for marijuana possession to go up iowa house passes strict new anti-drug bill on wednesday by jason young special to the daily ; print e-mail blogger digg del. Influenza virus vaccine should be given every fall to anyone with airflow obstruction. This is particularly important in people over the age of 50. Pneumococcal vaccine should be given at least once in a lifetime, and probably repeated every six years. Today, two new products, oseltamivir TamifluTM ; , and zanamivir Relenza ; , can modify the clinical course of both influenza A and B. Amantadine and Ranitidine are effective only in A strains of influenza. Inhaled bronchodilators have been shown to work in the majority of patients with early- stage disease. Ipratropium is the first step in therapy. Beta agonists such as albuterol, are also of significant value. Ipratropium and albuterol are available in the same metereddose inhaler Combivent ; . A long-acting beta agonistic preparation salmeterol Serevent ; , is compatible with the use of ipratropium. Together, both medications may improve lung function and mitigate symptoms. All patients must learn the proper technique of using metered-dose inhalers or newer inhalation devices coming to the market, for use of anticholinergics, beta agonists, combinations, or corticosteriods. Inhaled corticosteriods have not been shown to alter the rate of decline in FEV1 in at least five randomized, controlled, clinical trials. However, inhaled budesonide, fluticasone, and triamcinolone have all been shown to improve symptoms, and to reduce the consumption of healthcare resources in patients with severe COPD. However, a reduction of bone density was found during the conduct of these long-term trials. Thus, any symptomatic benefits should be weighted against potential systemic side effects in the long-term and theophylline. Arber, S. OLDER PEOPLE, FOOD AND HEALTH: THE IMPACT OF GENDER AND SOCIAL NETWORKS ON THE QUALITY OF FOOD CONSUMPTION IN LATER LIFE. The pharmacologic effects of beta2-adrenoceptor– agonist drugs, including salmeterol, are at least in part attributable to stimulation of intracellular adenyl cyclase and albenza. Total Prescribing Spend increased by 4.2% for the seven months April to October 2004. A decrease of 4.0% for October reflects problems with supplies of influenza vaccines this year, which cost the PCT 26, 913 less than forecast for the month. This was the largest variance from expected performance in any BNF category. Use of atorvastatin and rosuvastatin fell considerably short of forecast spend for October, but as this group of 5 drugs is showing the largest growth over 3 years 47% ; , October figures may reflect a period of fewer issues of 56 and 84-day prescriptions. Respiratory products were prescribed at a substantially lower rate than forecast for October tiotropium, fluticasone, budesonide, terbutaline and salmeterol ; . This may reflect work ongoing on implementing recent NICE guidance on Chronic Obstructive Pulmonary Disease COPD ; . Use of drugs to prevent osteoporosis was also considerably less than forecast for October alendronate, risedronate ; . There does not appear to be an obvious reason for this. Prescribing of several drugs used in heart failure and hypertension ACE inhibitors and Angiotensin II receptor blockers ; cost considerably less than forecast for October. Reasons for this will be investigated in the new financial year, when the Prescribing Team begins a programme of work around hypertension. Drugs and products used in diabetes also fell short of forecast cost. This may reflect the beginnings of a trend to halt inappropriate use of newer insulins and test strips, but it is too early to be certain of this. Prescribing of some Red Light Drugs was also less than forecast drugs used for anaemia in chronic renal failure, and growth hormones ; . Interestingly, whilst recent adverse publicity around the antidepressant, Venlafaxine, has influenced a downward cost trend, there is no comparable change in cost of prescribing of COX II inhibitors following the withdrawal in September of rofecoxib. Comparison of budget out-turn position compared with other PCTs in Cumbria and Lancashire.
OR patients with asthma, the main effect of longacting -agonists LABAs ; is to improve lung function, while leukotriene receptor antagonists LTRAs ; work to reduce exacerbation rates. The effects of these two drugs in combination--particularly compared with the standard combination of a LABA plus an inhaled corticosteroid--are unknown. A montelukast-salmeterol combination was evaluated for efficacy in moderate asthma. The randomized, crossover trial included 192 patients with moderate asthma, aged 12 to 65 years. Each completed 14 weeks of treatment with montelukast-salmeterol and 14 weeks with beclomethasonesalmeterol, with a 4-week washout period. The main outcome was time to treatment failure, defined by clinical, home, and other measures. The study was halted after 3 months after the data and safety monitoring board concluded that the main study question had been answered. The treatment failure rate was 26% for patients taking montelukast-salmeterol, compared with 9% with beclomethasone-salmeterol. Time to treatment failure also tended to be shorter with the LTRA LABA combination. Secondary outcomes also favored the standard corticosteroid LABA arm, including a 26 L min difference in morning peak expiratory flow, a 0.22-point difference in Asthma Control Questionnaire score, and reductions in markers of inflammation and airway reactivity. For patients with moderate asthma, standard treatment with a corticosteroid and LABA provides better clinical outcomes than an LTRA LABA combination. The synergistic effect of montelukast and salmeterol is inferior to that of beclomethasone plus salmeterol. COMMENT: This again reinforces the guidelinebased directive that long-acting beta agonist is superior to LTRA as add on therapy with ICS. Also see the editorial in same issue by Neal Barnes J Respir and albendazole. Manufacturers must provide written notification to healthcare providers regarding the new warnings, for example, salmeterol asthma.
Biopharmareporter , fda rejects new use for gsk' s advair - aug 10, 2007 rength of advair diskus fluticasone propionate and salmeterol inhalation powder ; to treat patients with chronic obstructive pulmonary disease copd and spironolactone!
6. Casaburi R, Mahler DA, Jones PW, et al. A longterm evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur Respir J. 2002; 19: 217224. Gross NJ, Skorodin MS. Anticholinergic, antimuscarinic bronchodilators. Rev Respir Dis. 1984; 129: 856870. Barnes P. Novel approaches and targets for treatment of chronic obstructive pulmonary disease. J Respir Crit Care Med. 1999; 160 5 pt 2 ; S72S79. 9. Sin DD, Tu JJ. Inhaled corticosteroids and the risk of mortality and readmission in elderly patients with chronic obstructive pulmonary disease. J Respir Crit Care Med. 2001; 164: 580584. Soriano JB, Vestbo J, Priden B, et al. Survival in COPD patients after regular use of fluticasone propionate and salmeterol in general practice. Eur Respir J. 2002; 20: 819825. Alsaeedi A, Sin DD, McAlister FA. The effects of inhaled corticosteroids in chronic obstructive pulmonary disease: a systematic review of randomized placebo-controlled trials. J Med. 2002; 113: 5965. Saetta M, Turato G, Maestrelli P, et al. Cellular and structural bases of chronic obstructive pulmonary disease. J Respir Crit Care Med. 2001: 163: 13041309. Sturton G, Fitzgerald M. Phosphodiesterase 4 inhibitors for the treatment of COPD. Chest. 2002; 121 Suppl 5 ; : 192S196S. 14. Culpitt SV, de Matos C, Russell RE, et al. Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in chronic obstructive pulmonary disease. J Respir Crit Care Med. 2002; 165: 13711376. De Boer WI. Cytokines and therapy in COPD: a promising combination? Chest. 2002; 121 Suppl 5 ; : 209S218S.
The Toward Optimized Practice Program supports the right of the patient to make an informed decision about his her health care options. Patient education is important in decisions surrounding testing for H. pylori. It is paramount that patients recognize that the success of eradication therapy hinges on compliance with treatment recommendations, and, that the opportunity for treatment failure and antibiotic resistance increases with poor compliance and glimepiride.
SMART was a multi-center, randomised, double-blind, parallel-group, placebo-controlled, single visit surveillance study conducted over a period of 28 weeks. The demographics of the subjects are shown in Table 1. Males and non-pregnant females 12 years of age, with a clinical diagnosis of asthma who had no previous use of inhaled LABA were enrolled into the study. Patients were allowed to continue with their usual anti-asthma drugs, except LABAs. Salmeterool 42 mcg twice-daily via metered dose inhaler MDI ; added to concurrent pharmacotherapy was compared with a matched placebo twice-daily via MDI added to concurrent therapy. In both groups, 47% of patients were taking inhaled corticosteroid ICS ; at entry to the study. The SMART study was terminated when an interim analysis conducted on the then enrolled 26, 355 patients showed a statistically significant increase in the risk of ARD, a secondary outcome variable, in the salmeterlo group when compared to the placebo group 13 vs 3 deaths, relative risk [RR] 4.37, 95% CI 1.25-15.34 ; . In addition, another secondary outcome variable, the combined ARD or respiratory life-threatening adverse events intubation and mechanical ventilation, LAEs ; , was also higher in the.
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Safety Clinical adverse experiences were reported by 530 71.0% ; and 538 72.4% ; patients in the montelukastfluticasone and salmeterol-fluticasone groups, respectively. Patients receiving salmeyerol and fluticasone had a significantly higher incidence of drug related adverse experiences compared with patients receiving montelukast and fluticasone 10.0% v 6.3%, P 0.01 ; . Patients receiving salmetero and fluticasone also had a significantly higher incidence of serious adverse experiences 7.4% v 4.6%, P 0.022 ; . One patient in the salmeterolfluticasone group died 15 days after the start of treatment with a severe asthma attack that was reported by the investigator as possibly related to study treatment. Laboratory adverse experiences were reported by 83 11.4% ; and 85 11.7% ; patients in the montelukast-fluticasone and salmeterol-fluticasone groups, respectively. One patient reported serious laboratory adverse experiences neutropenia; and increased lymphocytes, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase ; in the salmeterol-fluticasone group, and none in the montelukast-fluticasone group. Board Certified in Internal Medicine Board Certified in Cardiovascular Diseases & Interventional Cardiology 61 Memorial Medical Pkwy. Suite 3816 Inside Florida Hospital-Flagler ; Palm Coast, Florida 32164 873 Sterthaus Ave. Suite 202 Florida Hospital Medical Office Bldg. ; Ormond Beach, Florida 32174 and panadol and salmeterol, because inhaled salmeterol.
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Salmeterol inhibits histamine-induced plasma protein extravasation and inhibits platelet-activating factor-induced eosinophil accumulation in the lungs of guinea pigs when administered by the inhaled route. 2 February, 2007 unique pharmacology in advanced heart failure patients to produce either a hyper-response a beta1 receptor polymorphism ; or avoid an adverse effect an alpha2c receptor polymorphism ; . ARCA anticipates filing an application with the FDA for approval of bucindolol in 2007. Bucindolol will have market exclusivity through 2024. 2. Ambry Genetics Ambry Genetics is a leading genetic testing company. The company offers a research test that comprises beta 2 ; adrenergic receptor ADRB2 ; sequencing, including the exon, 5' UTR and 5' leader cistron, to aid in research and clinical studies. ADRB2 is a significant disease modifier in asthma and bronchial disorders. Associations between ADRB2 polymorphism status and phenotypes of asthma activity, asthma drug response, nocturnal asthma and bronchial hyperresponsiveness have been reported. Research studies have shown that the polymorphism status can alter receptor function and expression, and ADRB2 shows potential to be an important disease modifier. 3. ARUP Laboratories ARUP offers a PCR fluorescence monitoring-based genotyping test for the beta 2-adrenergic receptor gene. The company indicates that potential applications of the test include pharmacogenomics for using the beta 2-adrenergic receptor gene to examine the genetic variation in the receptor as a response to beta-blockers. The technology can also directly determine haplotypes of multiple polymorphisms in a closed-tube environment, making it a potential clinical genetic test from individual samples. 4. Nitromed The company has promoted data from the GRAHF clinical study which examined variations in the beta-1 adrenergic receptor, represented by Gly389Arg polymorphism. The beta-1 adrenergic receptor is involved in the regulation of cardiac rhythm and fluency. The Arg389 allele is associated with increased receptor activity and has previously been linked to greater beta-blocker impact. In GRAHF, 32 percent of black heart failure patients, and in GRACE 49 percent of white heart failure patients, possessed an Arg389Arg variation. In A-HeFT, self-identified black patients with the Arg389Arg variation who received standard heart failure therapies including beta-blockers ; were shown to have a greater risk for death or heart failure hospitalization, while the Arg389Arg patients treated with BiDil in addition to their standard therapy experienced significantly better primary composite scores compared to Arg389Arg patients treated with placebo and standard therapy. 5. Molecular Devices The company has utilized the AcuityXpress platform to analyze screening data for antagonists of the beta-2-adrenergic receptor with the LOPAC library. The application used the Transfluor high content assay for G-protein coupled receptor GPCR ; activation. Images were collected and analyzed demonstrating that the hits identified were consistent with the expected biology of the receptor. In addition, applying data clustering approaches for visualization revealed new findings in old datasets. 6. Boehringer Ingelheim Pharmaceuticals The company has sponsored clinical trials to evaluate the long-term efficacy and safety of tiotropium compared to salmeterol in moderate persistent asthmatic GINA step 3 ; patients and acetaminophen. Bronchodilators are the mainstay of therapy: Ipratropium and short-acting beta agonists fenoterol, salbutamol, terbutaline ; are an effective combination. Long-acting beta agonists formoterol, salmeterol ; and anticholinergics tiotropium ; are not currently indicated in the management of AECOPD but may be useful in chronic COPD.

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There are no fees for participating and receiving 1.75 CE credit hours for this activity. During the period March, 2006 through March, 2007, participants must complete the post-test below ; by recording the best answer to each question in the answer key. Once you have finished your test and completed the subsequent evaluation form, please send your responses to us. Your test will be reviewed and if you receive a passing grade of 70% or better 4 out of 5 questions ; , your certificate of completion will be mailed to you within 3 weeks. 1. Which of the following procedures is recommended prior to cetuximab infusion? a. Premedicate with an H1 antagonist b. Evaluate for a history of previous infusion reactions c. Obtain baseline vital signs d. All of the above e. A and B 2. The oral tyrosine kinase inhibitors TKIs ; erlotinib and gefitinib should be taken with food. a. True b. False 3. Reductions in EGFR TKI doses should be considered for patients experiencing more than episodes of diarrhea in a 24-hour period. a. 5 b. Systemic or topical steroids are often useful for managing the skin rash associated with EGFR inhibitors. a. True b. False 5. Which of the following statements regarding gefitinib is true? a. The ISEL trial failed to show a clear-cut survival advantage for gefitinib versus placebo in the second- and third-line settings. b. Patients who receive the greatest benefit from this compound are those with the following characteristics: males, squamous histology, smokers, and Caucasians. c. In the phase III trials, gefitinib in combination with paclitaxel and carboplatin demonstrated a survival advantage compared to chemotherapy alone in nonsmokers. d. None of the above. 6. In the BR21 trial, erlotinib delayed time to symptomatic progression for cough, dyspnea, and pain. a. True b. False.

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Mr Kubic mentioned that the PSI has an intelligent mission to collect, collate and disseminate information and a training mission to identify and satisfy training needs. He observed that counterfeit drug investigations by law enforcement agencies are often under resourced due to other crime problems. PSI key findings in 2003 included that there were 327 incidents of crime involving pharmaceuticals. 81% of these were counterfeits. Most incidents occurred in the US, followed by India and China. Key trends identified in 2003 were that there were more female offenders detected and that organizations involved in counterfeiting are small sized. 363 people were arrested and the average value of seizures was $3 million. A significant key finding was that most arrests, 53%, were made at the point of sale; 13% were manufacturers and only 5% were at borders. He made the point that these statistics indicate that further education of customs officials is required based on these statistics. Mr Kubic made predictions for 2004 - the US market would become a target for counterfeit medicines and drug diversion would re-emerge as a problem. He provided the results of a survey of international parcels entering the US both in mid and late 2003. On both occasions 88% of the parcels contained unapproved drugs, thus highlighting international mail as a distribution corridor exploited by medicine traffickers. He also gave an example of illicit Internet pharmacy sites purporting to be based in Canada. 432 Canadian sites were reviewed, he summarised 3 of those in detail, all 3 were investigated and found to be actually located in the US. 4 ; Mr Hector Bolanos, Director General of ILAR & Vice Chairman, World Self-Medication Industry WSMI ; for Latin America.
Fig. 8. The effect of salmeterol SM ; and salbutamol SB ; on the release of EPO from human eosinophils induced by 10 8 C5a a ; or 10 FMLP b ; , both in the presence of 5 g CB. The uninhibited releases 100% ; were in the range 16 to 33% for both stimuli. Cells were preincubated with SM or SB for 5 min before stimulation. Values are means S.D. of six independent experiments. * P .05; * P .01.
Figure 4. Percent Change in Serial 12-hour FEV1 in Patients With Asthma Previously Using Either Inhaled Corticosteroids or Salmete5ol Study 1 and fluticasone. Bronchodilators are currently the mainstay of drug therapy for COPD but do not alter the underlying disease process. Long-acting bronchodilators are the preferred therapy, including the anti-cholinergic tiotropium bromide or the LABA salmeterol and formoterol. There is an additive effect between tiotropium and formoterol, perhaps indicating that they have different mechanisms or that some patients respond better to one drug.14 This paves the way for the development of fixed combination inhalers containing a long-acting anticholinergic with a LABA. Several long-acting muscarinic antagonists LAMA ; with an action of over 24 hours, in addition to tiotropium, are now in development, including glycopyrrolate and LAS34273. Currently available LABAs need to be given twice a day, so are not ideal for the fixed LABA LAMA combination. However, several `ultralong-acting' 2-agonists, such as indacaterol and GSK159797 24 hour duration ; , are now in clinical development, so that a once-daily combination should.
Substituent does not affect the ability of the drug to bind to the 1-receptor but does affect the ability of the molecule to activate the receptor; that is, the stereochemistry of the methyl group affects intrinsic activity but not affinity. Because both stereoisomers are -agonists, with the ; -isomer about 10 times as potent as the ; -isomer, the net effect is -stimulation. Dobutamine is used as a cardiac stimulant after surgery or congestive heart failure. As a catechol, dobutamine is readily metabolized by COMT and has a short duration of action with no oral activity. 5.1.4 R4 Substitution on the Aromatic Ring. The natural 3 , 4 -dihydroxy substituted benzene ring present in norepinephrine provides excellent receptor activity for both and -sites, but such catechol-containing compounds have poor oral bioavailability and short durations of action, even when administered intravenously, because they are rapidly metabolized by COMT. Alternative substitutions have been found that retain good activity but are more resistant to COMT metabolism. For example, 3 , 5 -dihydroxy compounds are not good substrates for COMT and, in addition, provide selectivity for 2-receptors. Thus, because of its ring-substitution pattern, metaproterenol 18 ; is an orally active bronchodilator having little of the cardiac stimulatory properties possessed by isoproterenol 17 ; . Other substitutions are possible that enhance oral activity and provide selective 2activity, such as the 3 -hydroxymethyl, 4 -hydroxy substitution pattern of albuterol 13 ; , which is also not a substrate for COMT. A recently developed selective 2-agonist with an extended duration of action is salmeterol 21 ; , which has the same phenyl ring substitution R4 as that of 13 ; but an unusually long and lipophilic group R1 on the nitrogen. The octanol water partition coefficient log P for salmeterol is 3.88 vs. 0.66 for albuterol and the duration of action of salmeterol is 12 vs. 4 h for albuterol 88 ; . There is substantial evidence that the extended duration of action is attributed to a specific binding interaction of the extended lipophilic side chain with a specific region of the 2-receptor, affording salmeterol a unique binding mechanism 89 ; . The long. Can j cardiol , 4-20, 199 corresponding author lloyd matowe, faculty of pharmacy, kuwait university, box 24923, safat 13110, kuwait l.

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