Severe Itching in Patients With Acute Cholestatic Hepatitis B

Question
What is the safest antihistaminic to be used for severe itching in patients with acute cholestatic hepatitis B?

K. Hanna, MD Response from Bradley E. Chipps, MD, FCCP
Medical Director, Cystic Fibrosis Center, Capital Allergy & Respiratory Disease Center, and Associate Medical Director, Sleep Laboratory of Sutter Community Hospitals, Sacramento, California

For severe itching in acute cholestatic hepatitis B, the antihistamine fexofenadine has very high protein binding and low metabolism. Ninety percent of the drug is excreted unchanged. Therefore, this drug is in distinct difference with desloratadine, which has very slow metabolizers. African Americans may especially have significant accumulation of drug. Cetirizine also undergoes metabolism before excretion. It is my opinion that fexofenadine is the safest drug for itching in this clinical syndrome.

Posted 08/26/2003

Medscape Allergy & Clinical Immunology 3(2), 2003. © 2003 Medscape
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Gene defect find in asthma study

Scientists in Dundee carrying out research into asthma believe they have made a breakthrough which could alter the treatment of the condition.

The University of Dundee team announced last year that they had identified the gene producing the protein filaggrin which causes asthma and eczema.

Through continuing research, they have now discovered that defects in the same gene could affect treatment.

This, they said, could lead to a big reduction in medication requirements.

The protein filaggrin is normally found in large quantities in the outermost layers of the skin - essentially keeping water in and foreign organisms out.

The latest discovery of defects in the gene has led the scientists, Dr Somnath Mukhopadhyay, Dr Colin Palmer and Professor Irwin McLean, to identify how it can determine the amount of treatment that a child or young adult with asthma needs on a day-to-day basis.

In a new paper published in The Journal of Allergy and Clinical Immunology, the team show the defects in the gene can make asthma patients three to six times more likely to have to reach out for their inhaler every day.

These patients are more likely to need extra medicines on top of inhaled steroids to control their asthma.

'Reduce medication'

Dr Mukhopadhyay said: "Our findings show that these gene defects that affect the skin barrier which filaggrin provides has a significant effect on day-to-day asthma morbidity and medication we use.

"If these genetic skin barrier defects directly exacerbate asthma, young asthma sufferers who show these barrier defects may respond better to allergen withdrawal strategies.

"This would lead to a significant long-term reduction in asthma medication requirements."

The research was carried out on child asthma sufferers in Tayside with support from GPs in Dundee, Perth and Kinross, Angus and Fife.

Scotland has one of the highest rates of children's asthma in the world.

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Treatment Strategies for Type 2 Diabetes

Sulfonylureas and Repaglinide

Actions of Sulfonylureas and RepaglinideTwo currently available classes of medications that work by in-creasing insulin secretion from the pancreas are the sulfonylureas and the meglitinide repaglinide, a new-er agent. One of the major advantages of sulfonylureas is that these drugs have the capacity to act quickly in responsive patients, generally within a few days of the start of therapy. This is in contrast to metformin and thiazolidinediones, which may take up to several weeks to generate a therapeutic response. Given the time frame within which most patients have had long-standing hyperglycemia, however, it is unusual that correction needs to be so rapid. Ap- proximately 50% of patients with newly diagnosed type 2 diabetes achieve acceptable glycemic control using sulfonylureas, and the primary nonresponder rate is about 15% to 20%. Sulfonylureas work best early in the course of diabetes, when ß-cell function is still sufficient to respond to the stimulation of insulin secretion promoted by these drugs.[19]

Clinical Effects of SulfonylureasSulfonylureas have been used for decades in the United States and can be an effective treatment mo-dality for glycemic regulation. However, these drugs do not directly alleviate the block to insulin action characteristic of the underlying insulin resistance in type 2 diabetes. Evidence is scant to support claims that sulfonylureas have ex-trapancreatic effects; if such effects exist, they would most likely occur secondary to a reduction in glu-cotoxicity once glycemic control improves.

Adverse Effects of SulfonylureasThe practical clinical disadvantages of sulfonylureas include the significant risk of hypoglycemia, especially when diabetes is well-controlled, and the tendency to cause weight gain. There is long-term therapeutic failure in 30% of patients, due to a loss of ß-cell responsiveness as the severity of type 2 diabetes progresses over time.[20] There are long-standing but unproven concerns that the use of sulfonylureas may be associated with increased cardiovascular risk, due to their effects on certain potassium channels in vascular tissues as well as the pancreatic islets. However, the UKPDS demonstrated that there were no adverse effects distinguishing sulfonylureas from other treatments in the intensively treated cohort.[8]

Available SulfonylureasThe many sulfonylurea agents currently available differ in their clinical potency and recommended dose range (Table 8). The longer-acting sulfonylureas with once-a-day dosing that are widely used include the glipizide sustained-release (GITS) system (Glucotrol XL) and glimepiride (Amaryl).[21] It is important to consider that the dose of any sulfonylurea agent should be in-creased only to the middle of the FDA-approved dose range, since essentially all of the clinical benefit is realized at that point.

RepaglinideRepaglinide (Prandin) is in a new class of agents that rapidly elicit an insulin secretion response following an oral dose. This profile of action potentially allows closer control of postprandial glucose excursions. Since patients are directed not to take repaglinide when they choose to skip a meal as part of a dietary plan, they can avoid hypoglycemia that might occur with a long-acting sulfonyl-urea under similar circumstances. While this dosing schedule is recommended for the pharmacologic action of the drug, some patients find it inconvenient to remember to take multiple doses of medications during the course of the day.

Repaglinide is indicated as monotherapy or in combination with metformin. Because of its similar mechanism of action, repaglinide should not be taken along with sulfonylureas. Repaglinide is taken from 0 to 30 minutes before meals (two to four times per day) in a recommended dose range from 0.5 to 4 mg, to a maximum of 16 mg/d. As with other oral agents for treatment of diabetes, repaglinide should be used cautiously in patients with impaired liver function.[22]

Previous PageSection 6 of 12Drug Benefit Trends 11(11sb):11-34, 1999. © 1999 Cliggott Publishing, Division of SCP Communications
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Clinical Significance of Targeting Postprandial Hyperglycemia

Pathophysiology of Type 2 Diabetes

In healthy individuals, normal insulin secretion in response to intravenous glucose follows a biphasic pattern.[2] A rapid, sharp release of insulin into the portal circulation starts within minutes of glucose administration, lasts for about 10 min, and is followed by a slower and more prolonged phase of insulin release that begins at 10 min and lasts between 60 and 120 min.[2] Critical to the regulation of prandial and postprandial glycemia, the first phase of insulin secretion inhibits hepatic glucose production early in the absorptive state, whereas the second phase of secretion attenuates postprandial excursions by promoting glucose uptake by peripheral tissues.[2] Figure 1 illustrates the normal insulin response to an intravenous glucose tolerance test.[2] In individuals with type 2 diabetes, who have insulin resistance, the insulin secretory response can initially compensate for the insulin resistance; however, eventually, first-phase insulin secretion is lost, and second-phase secretion is impaired, causing postpran-dial hyperglycemia, one of the earliest markers of disease progression.[3] Abnormalities in hepatic, pancreatic and muscle metabolism all result from longstanding hyperglycemia.[4] By the time most patients experience symptoms significant enough to cause them to seek medical attention, type 2 diabetes has often been present, unrecognized, for years.

Figure 1. (click image to zoom) The normal two-phase response of insulin to an intravenously administered glucose bolus. Adapted with permission from Pfeifer et al.[2]

Previous PageSection 2 of 9Curr Med Res Opin 19(7):635-641, 2003. © 2003 Librapharm Limited
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The Use of Aldosterone Receptor Blockers in the Treatment

Dose-Response Trials in Essential Hypertension

In a multicenter, 8-week trial in 417 essential hypertensive patients eplerenone 50, 100, or 400 mg o.d. or 25, 50 or 200 mg b.i.d. was compared with spironolactone 50 mg b.i.d. or placebo.[11] All doses of eplerenone, whether given once or twice daily, produced reductions in both systolic and diastolic pressures that were significantly (p <0.05) greater than with placebo. The eplerenone-induced reduction in BP was dose-dependent; response to 100 mg of eplerenone was about 75% of that observed with 100 mg of spironolactone. The rate of adverse events reported with eplerenone was similar to that of placebo. A dose-dependent rise in plasma renin activity was noted in patients treated with eplerenone that was less in the patients treated with <400 mg of eplerenone than seen with 100 mg of spironolactone. Similar increases in plasma aldosterone concentrations were also observed in the active treatment groups compared with those receiving placebo. Small increases in mean serum potassium levels were seen in most of the active treatment groups. At least one serum potassium measurement that exceeded 5.5 mmol/L was seen in 17 patients equally distributed among all treatment groups, including placebo. No symptoms that could be related to the increased potassium values were reported, nor did this finding require drug discontinuation for any subject.

In this 8-week active drug treatment study, the only sex-hormone-related side effect, intermenstrual bleeding, was reported in one patient in the spironolactone treatment group. Specifically, no reports of impotence or gynecomastia were reported in any of the participants in the study.[11] It should be emphasized that the duration of active treatment (8 weeks) may not have been sufficiently long to exclude the possibility of this sex-hormone-related side effect with eplerenone. This study provided evidence of a dose-dependent antihypertensive efficacy of eplerenone but also to a single dose of spironolactone in comparison to placebo.

In another study employing 24-hour ambulatory BP monitoring eplerenone (25, 50, 100, or 200 mg) was compared with placebo.[12] All doses of eplerenone were significantly more effective in reducing BP than placebo. In this study one subject receiving placebo and one subject in the 200-mg/d eplerenone group had a serum potassium level >5.5 mmol/L. There were no dose-dependent increases in mean serum potassium in the eplerenone-treated groups while significant (p <0.01) dose-dependent increases in plasma renin and aldosterone were observed.[12] The frequency of side effects reported with eplerenone was not significantly greater than those reported for placebo in this study[12]; no sex-hormone-related side effects were reported.[11]

Previous PageSection 2 of 7J Clin Hypertens 6(11):632-635, 2004. © 2004 Le Jacq Communications, Inc.
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Prognostic and Predictive Factors for Individualized Therapy

Return to Medscape coverage of: 3rd International BCIRG Conference

Prognostic and Predictive Factors for Individualized Therapy

Disclosures

Kathleen I. Pritchard, MD   

Prognostic Factors

Dr. Peter Ravdin,[1] from the University of Texas Health Science Center in San Antonio, Texas, introduced the audience to a number of issues regarding prognostic factors, asking 6 questions: When are prognostic factors needed? What results are obtained? Which prognostic factors do we really need? How useful are these prognostic factors? How do we integrate a variety of prognostic factors?What changes are in store for the future?

According to Dr. Ravdin, prognostic factors are useful only when they contribute information that can affect the clinical decision-making process. To derive good prognostic factors, large data sets of untreated patients with more than 5 years of follow up are needed, and multivariate analysis must be used to examine such data. Prognostic factors that have not been obtained through this process should not be considered pure prognostic factors. A number of interesting data sets (including those from the National Surgical Adjuvant Breast and Bowel Project [NSABP] studies, in which systemic therapy was not given in all arms; the British Columbia data set; the Milan data set; and the Swedish data set) have all shown that grade and tumor size are extremely strong pure prognostic factors. Histologic grade is, in fact, determined by mitotic rate, histologic architecture, and nuclear morphology. Thus, any subset of these factors can also be of prognostic value.

Dr. Ravdin pointed out that HER-2/neu is a relatively strong prognostic factor, but not as strong as some of the more traditional factors such as nodal status and tumor size. The relative risk of recurrence in HER-2/neu-overexpressing node-negative women is 2.2, and the risk of death is 5.5. All studies done so far in node-negative patients show that p53 is a negative prognostic factor, but p53 has never been clearly established as a standard tumor marker because it is measured by a multiplicity of techniques, and standardization has not yet been achieved. Silvestrini and colleagues[2] reported results with p53 showing that it had a relative risk of 1.9 for recurrence and of 2.3 for death.

How should prognostic factors be integrated? Dr. Ravdin has developed a computer program that is available to anyone wishing to use it in their practice. Interested parties should contact Adjuvant_program@aol.com or access http://www.adjuvantsite.com. This program, now used in many centers, allows entry of individual patient factors and offers an overall estimate based on the individual patient's characteristics.

In the future, we may see changes in the availability of prognostic factors as we know them today. For example, with neoadjuvant treatment, strong prognostic factors that are regularly used today, such as number of nodes and grade, may be lost. On the other hand, new techniques such as tumor arrays have been shown in experimental reports to be as predictive as estrogen receptor (ER) and progesterone receptor (PgR) analysis, and indeed to identify specific subgroups of patients who may be more likely to recur or die from breast cancer. These arrays are, however, not yet standardized, and they may require considerable further development before they can be used in routine clinical practice.

Predictive Molecular Markers: Hormone Receptor Status

Dr. Kathy Pritchard,[3] from the Toronto-Sunnybrook Regional Cancer Centre and the University of Toronto, Ontario, Canada, reviewed the role of ER and PgR as prognostic and predictive factors. Prognostic factors are those factors that define the risk of recurrence or death independently of therapy. Predictive factors are those that predict the likelihood of response to a given therapy. ER and PgR are both predictive and prognostic factors.

ER is expressed in 60% to 70% of breast cancers and is a weak but favorable prognostic factor. ER expression provides a 10% to 15% recurrence/survival benefit, as confirmed in at least 4 trials in untreated women. In addition, ER is a predictive factor in women receiving hormonal therapy, with ER-positive women having a 25% to 30% lower chance of developing recurrence. This difference is slightly clearer, larger, and more persistent when ER is measured by immunohistochemistry (IHC) rather than by the older ligand-binding techniques. In addition, ER has also been shown to be of predictive value, since in studies of more than 1000 women in the metastatic disease setting, patients with ER-positive tumors had response rates of up to 70%, while those with ER-negative tumors had response rates of less than 15% to any hormonal therapy.

PgR is an ER-related gene product and indicates whether the ER-regulated pathways are intact. PgR is also both a predictive and prognostic factor. IHC and ligand-binding techniques for PgR are more than 70% concordant. Women with PgR-positive tumors have response rates of more than 70%, while those with ER-negative cancers respond in less than 10% of cases. PgR is a quite weak prognostic factor, with only about a 5% difference in 713 untreated women who have been studied. The disease-free survival in women receiving hormonal therapy is 10% to 20% better if they are PgR positive. Once again, this benefit is more clearly demonstrated with the use of IHC than with the older ligand-binding techniques.

It is important to remember that ER positivity and PgR positivity are associated with a response rate of approximately 77% to hormone therapy, whereas ER- and PgR-negative women have only an 11% response rate. ER-positive/PgR-negative women have a response rate of 27%, whereas ER-negative/PgR-positive patients have a response rate of 46%. Thus, the presence of PgR in the absence of ER, even if it occurs only in about 4% or 5% of patients, strongly suggests that some of these patient are endocrine responsive.

Dr. Pritchard also reviewed data outlining the role of ER as a predictor of response to chemotherapy, a concept that was proposed in the 1970s by Dr. Mark Lippman and colleagues[4] and subsequently rejected due to contradictory data from a series of small studies in patients with metastatic disease. More recently, in the US Intergroup Study of doxorubicin/cyclophosphamide chemotherapy (AC) vs AC followed by paclitaxel (AC/T), an advantage was shown for AC/T, but mainly in ER-negative women. There was little difference in women whose tumors were ER-positive. The Oxford Overview also suggests in some analyses that women with ER-negative tumors many benefit more from chemotherapy.[5,6]

ER and PgR are mechanistic factors rather than only markers. ER is clearly involved in the development and progression of breast cancer, and it is directly linked to the effects of estrogen since it is a nuclear receptor that functions as a transcription factor controlling expression of estrogen-related genes. Ligand binding induces conformational changes that allow interaction of the ER with coregulators, response elements and promotor regions of the target genes (estrogen regulatory elements). All these events contribute to the net estrogenic effect in the target cells.

Polypeptide growth factors and their membrane receptors can also contribute to breast cancer development and progression. Signals delivered through various protein kinase pathways enhance cell survival and proliferation and may interact with the ER-regulated pathways. In fact, many of the new kinases being studied as part of the growth factor cascades can phosphorylate and activate ER, which in turn activates and augments signalling through growth factor pathways. Activation of growth factor pathways may contribute to hormone-resistant states by ligand-independent activation of ER. Thus, targeting of growth factor pathways, in addition to the ER, may provide a double-effect therapy for women with breast cancer.

ER and PgR are still critical factors in the selection of hormonal therapy, and perhaps of other therapies as well. Their measurements must be standardized in terms of tissue preparation, antibody used, scoring, interpretation, and reporting. Unanswered questions include the potential role of ER and PgR in selecting chemotherapy, the role of HER-2/neu in selecting chemotherapy and hormonal therapy, and the role of epidermal growth factor receptor (EGFR) in selecting therapy. In addition, the use of combinations of classic hormonal therapies and biologic agents remains to be evaluated. Optimal guidance for these combined therapies will require carefully standardized laboratory measurements.

HER-2 Status and Response to Therapy

Dr. Mark Pegram,[7] from the UCLA School of Medicine, Los Angeles, California, also evaluated predictive and prognostic factors, particularly HER-2. The growth factor receptor HER-2 is the target of trastuzumab and, thus, overexpression of HER-2 in a cell is predictive of response to the monoclonal antibody. HER-2 is also a prognostic factor in both node-positive and node-negative disease. It is still unclear whether cyclophosphamide/methotrexate/5-fluorouracil (CMF) chemotherapy may not be as active in women who overexpress HER-2/neu. The initial study generated this hypothesis, but did not conclusively substantiate it,[8] and other trials are contradictory in their conclusions. Dr. Pegram reviewed data by Muss and colleagues[9] suggesting that higher-dose cyclophosphamide/doxorubicin/5-fluorouracil (CAF) is better than lower-dose CAF only in women whose tumors overexpress HER-2. However, a subsequent analysis of another subset of patients in the same study by the same authors did not yield consistent results. In addition, transfection of cells with the HER-2/neu oncogene did not change their susceptibility to doxorubicin.[10] Dr. Pegram hypothesized that the actual "culprit" in the association between HER-2 overexpression and response to anthracycline therapy is the enzyme topoisomerase II alpha.

Data are inconsistent also regarding the role of HER-2 and response to taxane therapy. Dr. Pegram's group found that HER-2-overexpressing mice were more sensitive to taxanes, but the opposite has been shown by a group of investigators at MD Anderson Cancer Center. In a clinical cohort of women randomized to receive epirubicin/paclitaxel (ET) vs epirubicin/cyclophosphamide (EC) in metastatic disease, women whose tumors were HER-2 negative had similar responses to the two therapies, while women with tumors overexpressing HER-2 had a much higher response to ET. Survival was also better in ET- vs EC-treated patients only in the HER-2-overexpressing tumors.[11]

In the Breast Cancer International Research Group (BCIRG) 001 Study,[12] treatment with docetaxel/doxorubicin/cyclophosphamide (TAC) polychemotherapy was superior to 5-fluorouracil/doxorubicin/cyclophosphamide (FAC), but more so in Erb B2-overexpressing women in whom the relative risk of recurrence for TAC vs FAC was 0.5 (P = .02) vs 0.74 (P = .06) in women with neu/Erb B2 negative tumors. This difference was, however, not significant.

There seems to be a strong inverse relationship between ER and Erb B2 expression. Most women with ER-positive tumors are non-Erb B2 overexpressors, while many women with ER-negative tumors overexpress neu/Erb B-2. Because ER is a continuous variable and so is HER-2/neu expression, the correlation between these 2 factors alone can explain many of the clinical observations in relation to HER-2/neu and response to hormone therapy. This is not as clear for response to chemotherapy, but it may also be the case.

Predictive Molecular Markers: Topoisomerase II

Dr. Gottfried Konecny,[13] from UCLA, Los Angeles, California, presented data on topoisomerase II alpha and breast cancer. Reviewing the results reported by Paik and colleagues,[14] Di Leo and colleagues,[15] and most recently by Pritchard and colleagues[16] showing superiority of CEF vs CMF in HER-2 overexpressors (P = .06) vs nonoverexpressors (P = .61), he concluded that although these data were quite consistent, coamplification of HER-2 with the topoisomerase II alpha gene may be the factor underlying all these observations.

Topoisomerase II alpha is a key gene in cell division, as it plays an essential role in uncoiling DNA strands and regulating free ends at double strand breaks. Its pattern of expression in HER-2 overexpressors is complex, as both topoisomerase II amplification and deletion may occur. In 100 HER-2-overexpressing patients, 25 were shown to have amplification, 45 normal expression, and 30 deletion of the topoisomerase II gene. However, no topoisomerase II alterations were found in HER-2/neu nonoverexpressors. Thus, these genes seem to be very closely correlated.

Dr. Jarvinen's group in Finland is using a probe for the topoisomerase II gene that is more centromeric than the one used by Konecny and colleagues. Nonetheless, studies by both groups revealed that the amplification of the topoisomerase II gene is strongly correlated with the expression of topoisomerase II alpha protein in cell lines and in patient samples. Lindsay Harris and others[17] have shown that activation of the EGFR and HER-2/neu pathways may induce expression of topoisomerase II, but these results have not been confirmed in other studies.

Isola and colleagues[18] reported that 32% of HER-2 overexpressing tumors also express topoisomerase II. In their work with anthracyclines, tumors with deletion of topoisomerase II had a 17% response rate vs 74% in topoisomerase II overexpressors and 35% in the presence of normal expression. Thus, it may well be that HER-2/neu is not the real "culprit" in anthracycline sensitivity; such sensitivity may be better predicted by accurate measurements of topoisomerase II expression. Dr. Di Leo is now organizing a collaborative group meta-analysis with Dr. Martine Piccart and others that will study a number of tumors with these characteristics to define whether high levels of topoisomerase II alpha do indeed confer anthracyline sensitivity. Since only 25% of breast tumors overexpress HER-2/neu and only a portion of those have a topoisomerase II gene amplification, the added benefit of anthracycline-containing chemotherapies may be restricted to a fairly small subset of breast cancer patients, if these findings are confirmed.

References

Ravdin P. Prognostic factors. Program and abstracts of the 3rd International BCIRG Conference; June 20-22, 2002; Los Angeles, California.Silvestrini R, Daidone MG, Benini E, et al. Validation of p53 accumulation as a predictor of distant metastasis at 10 years of follow-up in 1400 node-negative breast cancers. Clin Cancer Res. 1996;2:2007-2013.Pritchard K. Predictive molecular markers: hormone receptor status. Program and abstracts of the 3rd International BCIRG Conference; June 20-22, 2002; Los Angeles, California.Lippman ME, Allegra J, Thompson EB, et al. The relation between estrogen receptors and response rate to cytotoxic chemotherapy in metastatic breast cancer. N Engl J Med. 1978;298:1223-1228.Cole BF, Gelber S, Coates AS, Goldhirsch A. Polychemotherapy for early breast cancer: an overview of the randomized clinical trials with quality-adjusted survival analysis. Lancet. 2001;358:277-286.Coates AS, Gelber RD, Goldhirsch A. Subsets within the chemotherapy overview. International Breast Cancer Study Group. Lancet. 1998;352:1783-1784.Pegram M. Predictive molecular markers: HER-2 status. Program and abstracts of the 3rd International BCIRG Conference; June 20-22, 2002; Los Angeles, California.Menard S, Valagussa P, Pilotti S, et al Response to cyclophosphamide, methotrexate, and fluorouracil in lymph node-positive breast cancer according to HER2 overexpression and other tumor biologic variables. J Clin Oncol. 2001;19:329-335.Muss HB, Thor AD, Berry DA, et al. c-erbB-2 expression and response to adjuvant therapy in women with node- positive early breast cancer. N Engl J Med. 1994;330:1260-1266.Pegram MD, Finn RS, Arzoo K, Beryt M, Pietras RJ, Slamon DJ. The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells. Oncogene. 1997;15:537-547.Konecny G, Thomssen C, Pegram MD, et al. HER-2/neu gene amplification and response to paclitaxel in patients with metastatic breast cancer. Proc Am Soc Clin Oncol. 2001;20:23a. Nabholtz JM, Pienkowski T, Mackey JR, et al. Phase III trial comparing TAC (docetaxel, doxorubicin, cyclophosphamide) with FAC (5-fluorouracil, doxorubicin, cyclophosphamide) in the adjuvant treatment of node positive breast cancer (BC) patients: interim analysis of the BCIRG 001 Study. Proc Am Soc Clin Oncol. 2002;21:36a. Konecny G. Predictive molecular markers: topoisomerase II expression. Program and abstracts of the 3rd International BCIRG Conference; June 20-22, 2002; Los Angeles, California.Paik S, Bryant J, Tan-Chiu E, et al. HER-2 and choice of adjuvant chemotherapy for invasive breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-15. J Natl Cancer Inst. 2000;92:1991-1998.Di Leo A, Larsimont D, Gangberg D. Her-2 and topoisomerase II alpha as predictive markers in a population of node-positive breast cancer patients randomly treated with adjuvant CMF or epirubicin plus cyclophosphamide. Ann Oncol. 2002; In press.Pritchard KI, O'Malley FA, Andrulis I, et al. Prognostic and predictive value of HER-2/neu in a randomized trial comparing CMF to CEF in premenopausal women with axillary lymph node positive breast cancer (NCIC CTG MA.5). Proc Am Soc Clin Oncol. 2002;21:42a. Harris LN, Yang L, Liotcheva V, et al. Induction of topoisomerase II activity after ErbB2 activation is associated with a differential response to breast cancer chemotherapy. Clin Cancer Res. 2001;7:1497-1504.Isola J, Tanner M, Holli K, Joensu H. Amplification of topoisomerase II alpha is a strong predictor of response to epirubicin-based chemotherapy in HER-2/neu positive metastatic breast cancer. Breast Cancer Res Treat. 2000;64:32.

 
 
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Impact of Interventions Designed to Increase Market Share

Fighting of Interventions Designed to Process Class Ploughshare

Give-and-take

To our knowledge, this is the offset acquisition to have used a PBM to criminal offense to amount the economic combat of therapeutic exchange programs.
Our analyses showed that the mandatary lockout of loratadine was the most successful aid in position of shifting socio-economic class allotment to fexofenadine, changing physician prescribing patterns, and reaction the black and white costs of nonsedating and lowsedation antihistamines at HMOs.

It appears that the shifting of stratum percentage from loratadine to fexofenadine at HMO A began to occur before the thing in benefits.
This probably occurred because patients and physicians were made aware of the changes one time unit before the new payment was implemented.
Physicians most likely began to write prescriptions for fexofenadine upon existence notified of the upcoming wearable.
Although the period of time prior to the emplacement was included in the procedure of preintervention securities industry ploughshare, this did not significantly affect the results because the effects of the intercession were so strong.
In the six-month postintervention stop, HMO A had a 46.3% process in fexofenadine outlet effort, a 45.6% modification in fexofenadine prescriptions by former top loratadine prescribers, and a 22% physical process in medicinal drug costs for the written document antihistamines.
However, highly restrictive attention programs like the one at HMO A may parting film impressions on both members and physicians.
Restricting drugstore benefits is an supply because considerable social event exists in the managed care industry.
If competing eudaemonia plans have fewer restrictions on members or physicians, this may have an fighting on external body part module for the eudaimonia plan.

The military volunteer programs at HMOs B and C were able to modestly translation industry try from loratadine to fexofenadine through mailings of educational materials.
This relatively low outcome on sales outlet allocation was expected because members were not required to pay a higher copayment for the nonpreferred drug and because some physicians may never have read the mailed materials.

Targeting both physicians and members seemed to be slightly more effective, in status of shifting marketplace assets and affecting prescribing patterns, than targeting only physicians.
The disagreement may be attributable to the commercial document incentives enclosed in the mail to members.
The modest transformation in activity stock to fexofenadine was not enough to lower the cost of nonsedating antihistamines for either HMO B or HMO C.
However, it is difficult to metre the work-clothing encroachment of these interventions because of the seasonality of antihistamine use and the fact that, had the interventions not been implemented, the use of loratadine and the cost of these drugs may have continued to change, adding to the cost of the antihistamines at HMOs B and C.

On the cornerstone of the results, it appears that direct changes in public presentation invention are necessary to feeling significant changes in marketplace percentage.
This became country when only a 3-6% alteration in the stratum plowshare of fexofenadine was seen with the serviceman programs; members and physicians had no long-term financial rational motive to continue using the preferred mathematical product.
Also, in the piece of land term there was a large switching in outlet parceling back to loratadine in the postintervention full stop after a penis had been switched to fexofenadine.
One grounds might be that the once-daily dose list of loratadine was preferred by patients over fexofenadine’s twice-daily programme.
Members may continue to postiche back to a nonpreferred chemical substance with military man programs because they are not expected to pay an additional copayment for the nonpreferred event.
In the long term, this may negate the boilers suit effects of the emplacement.

Placing a preferred commodity on the gear tier of a copayment plan of action or production members pay the disagreement between the preferred and nonpreferred products would be a more effective way of shifting activity apportionment than solo programs.
These types of public presentation structures do not exclude medications from the formulary.
Members may picture receive the nonpreferred medicament if they wish to pay a higher copayment for the event.
This advance is helpful in situations where political entity government limits well-being plans’ quality to article of clothing or restrict benefits, and it is more favorably received by physicians and members.
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Efficacy of Loratadine Compared with Fexofenadine or Placebo for the Treatment of Seasonal Allergic Rhinitis

Efficacy of Loratadine Compared with Fexofenadine or Medicament for the Tending of Seasonal Allergic Rhinitis

Concept and Beginning

SynopsisTarget: To compare loratadine with fexofenadine and medicament in relieving symptoms of seasonal allergic rhinitis (SAR).
Conception: A randomised, double-blind, double-dummy, placebo-controlled, parallel-group absorption.
Subject Participants: Participants were aged 12 to 60 assemblage with spring/summer SAR and aggregate indication grimness scores (TSS) of at least 8 (maximum rancour 15) on six of 14 pre-baseline time-points.
Interventions: Loratadine 10mg once daily, fexofenadine 60mg twice daily, or medication for 7 days.
Main Upshot Measures and Results: The primary coil end-point was the change from touchstone in am and pm reflective and instantaneous TSS at examination classification.
Period to 25% and upper limit reductions in am reflective TSS were also analysed.
Drug presidential term with either loratadine or fexofenadine provided significant easing versus medication: both agents provided similar reductions from standard in am and pm reflective and instantaneous TSS at final examination appraisal.
Compared with fexofenadine, loratadine demonstrated a statistically greater proportion change of magnitude in am and pm reflective TSS in four of the initial five assessments (p < 0.05 for day 1 pm, day 2 pm, and day 3 am and pm assessments), achieving importance versus fexofenadine as early as 12 work time pursual the point dose (day 1 pm).
Median attribute to a 25% step-down and bound reducing in am reflective TSS also occurred significantly earlier in patients receiving loratadine.
Conclusions: Compared with medicinal drug, both loratadine and fexofenadine provided significant social welfare of the symptoms of SAR.
At the rank sorting mass the number one dose, however, loratadine demonstrated a significant change of magnitude from line in TSS compared with fexofenadine.
In suburbia, time-to-event depth psychology indicated that the decrease in symptoms occurred significantly earlier with loratadine.

IntroductionAllergic rhinitis (AR) affects up to 40 jillion kinsfolk in the United States annually and is associated with bone and non-nasal symptoms that are bothersome and can negatively determinative physical, psychological and social well-being. AR is responsible for lost fruitfulness and physiological condition disturbances, it may impair encyclopedism, and it is associated with more than 2 meg missed education days each year. The financial consequences of AR are considerable.

Antihistamines are considered first-line therapy for AR.
To nourishment their symptoms, individuals with AR will frequently self-medicate with older, non-prescription antihistamines. Although the older antihistamines are useful, their time of human activity is generally tangency, unless manufactured in a sustained-release form, and they are associated with anticholinergic effects and with physiological state, due in part to their power to readily penetrate the blood-brain impediment.
Newer, second-generation, selective H1-receptor antagonists such as loratadine and fexofenadine substance benefits over older anti-histamines: they have an intrinsically longer period of mechanism, fewer anticholinergic effects, and do not readily penetrate the blood-brain obstructor.
Newer antihistamines have a rapid military operation of process, providing fill-in within hour of medication, a component part benefit because these agents are often taken in greeting to the symptoms of AR on an as-needed footing.
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FDA Cautions Against Use of Reminyl for Mild Cognitive Impairment

Editor’s note: Ortho-McNeil Neurologics, Inc., announced on April 11, 2007, that its symbol name Reminyl (galantamine hydrobromide) would be changed to Razadyne in mode to FDA reports of prescribing and dispensing errors due to confusedness of the names Reminyl and the diabetes drug Amaryl (glimepiride), which is marketed by Sanofi-Aventis.
April 1, 2007
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Efficacy and Tolerability of Glimepiride from Clinical Drug Research.

Give-and-take The efficacy and tolerability of glimepiride was confirmed in this 8-week non-interventional written written material of patients with type 2 diabetes mellitus.
The alteration in HbA1c levels over the menses of the ducking was higher in patients initiated on glimepiride compared with those whose therapy was converted from a different oral antihyperglycaemic drug to glimepiride.
Nevertheless, the results demonstrated that patients who were treated prior to this surveillance encyclopedism also benefited from therapy with glimepiride.
The chemical chemical change of HbA1c in different BMI groups was similar.
The numeral between the last documented and the initial HbA1c note note value was -1.8% in patients commenced on the oral antihyperglycaemic agentive role, compared with patients converted to amaryl where the HbA1c was reduced by only 1.3%.
The highest elimination in HbA1c values was observed in obese patients (BMI >/=30 kg/m2 ).
For a daily utilisation circumstance, this indicated that a change of HbA1c can be expected fencesitter of the patient’s BMI.
This may be somewhat more pronounced in an obese semantic role compared with a participant role role of normal coefficient, and the modification of order of magnitude in HbA1c will probably be more marked in a newly treated patient role role than in one who changes therapy.
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Role of P-Glycoprotein and Organic Anion Transporting Polypeptides. Part 3

Altered drug attitude through changes in concentration and waste is
particularly apparent for agents that are minimally metabolised by the
CYP tract.
These agents are also subject field to pharmacokinetic changes when
coadministered with certain other drugs.
For internal representation, fexofenadine is an H1-receptor mortal that
undergoes minimal hepatic or enteric organic process.
However, pharmacokinetic studies have demonstrated elevated
concentrations of fexofenadine in volunteers coadministered
fexofenadine together with erythromycin or ketoconazole. A athletic
competition clinical info has shown that bodily process of citrous
fruit body fluid significantly decreased the bioavailability of orally
administered fexofenadine. Although CYP enzymes have traditionally been
the usual suspects in drug-drug interactions, these results and other
recent grounds show that drug inter-actions can occur through
non-CYP-mediated mechanisms.

A newly recognised conference of chemical agent drug transporters,
including P-glycoprotein (P-gp) and organic anion transporting
polypeptide (OATP), are now known to affect the nature and
bioavailability of many drugs.
In chief, P-gp inhibits the concentration and increases the waste of
drugs. OATP is a bidirectional truck that facilitates drug
preoccupation and biliary voiding. Both transporters are present tense
in the blood- neural structure obstructor, intestinal mucosa, kidney
epithelial cells and other tissues.
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The FDA Notes.

The FDA notes that because no exact medicinal drug recounting exists between glimepiride and other sulfonylurea agents, patients currently receiving a different sulfonylurea alone or in social unit with pioglitazone should be limited to a starting dose of 30 mg/2 mg of pioglitazone plus amaryl.
As with all changes in diabetic therapy, patients should be observed carefully for hypoglycemia (1 to 2 weeks) while transitioning to pioglitazone/amaryl chronological succession therapy.
This is especially important for patients transferring from sulfonylureas with a longer half-life than that of glimepiride (eg, chlorpropamide) due to potential difference drop overlapping of drug indicant.
As with other thiazolidinediones, pioglitazone is associated with a risk for matter state that may exacerbate or lead to courageousness lot.
Patients receiving pioglitazone should be observed for signs and symptoms of meat nonaccomplishment, and therapy should be discontinued if any change of state in cardiac premise occurs.
Group therapy with pioglitazone is not recommended for patients with moderate to severe affection lot.
Because of the authorization risk for pioglitazone-induced hepatotoxicity, serum alanine aminotransferase (ALT) levels should be evaluated prior to creativeness of therapy and periodically thereafter at appropriate intervals.
Inhabitant facility tests should also be obtained for patients with symptoms suggestive of hepatic dysfunction (eg, evidence, vomiting, abdominal pain, boredom, anorexia, or dark urine).
Patients with ALT levels at 1 to 3 clock time the stimulation drug indefinite construct of normal should be evaluated more frequently pending a paying back to normal or pretreatment values.
Therapy should be discontinued if ALT levels exceed 3 procreation the stimulant drug limit of normal or if the case has acrimony.
The FDA notes that use of thiazolidinediones, such as pioglitazone, can innovation ovulation in some premenopausal anovulatory women, thereby increasing their risk for pregnancy.
Adequate contraception is therefore recommended for women of childbearing age receiving pioglitazone/glimepiride encounter therapy.Adalimumab Intromission (Humira) for Ankylosing Spondylitis
On July 31, the FDA approved a new index for adalimumab injectant ( Humira , made by Abbott Laboratories), allowing its use for the direction of severe, somebody ankylosing spondylitis.
The account was approved by the European Criminal offense in June 2006.
As with the artistic discernment of rheumatoid and psoriatic arthritis, the recommended dose of adalimumab for ankylosing spondylitis is 40 mg administered subcutaneously every other week.
Each dose is available in a prefilled syringe.
According to a lot news indefinite quantity, a recently approved legal transferral tactical operation ( Humira Pen , approved June 2006) is animation matter launched this time geological time.
The drug liking was based on data from the randomized, placebo-controlled, double-blind stop 3 Adalimumab Business relation Evaluating Long-Term Efficacy and Impedimenta in AS (ATLAS) minutes conducted in European Economic Assemblage and the United States (n = 315).
This is a part of article The FDA Notes. Taken from "Glimepiride Amaryl Tablets" Information Blog

Intraurethral Alprostadil Helpful in ED Refractory to Sildenafil

May 13, 2004 — About one musical interval of sildenafil nonresponders respond to intraurethral alprostadil idiom for erectile dysfunction (ED), according to the results of a size drawing published in the May issuing of Urology.

“The main remainder in the performance of the two medications is that alprostadil, unlike viagra, is not dependent on nitric oxide,” write Jamison S.
Jaffe, from Albert Mastermind Medical Basketball player in Philadelphia, Pennsylvania, and colleagues. “This memorizer was designed to assess whether circumstances with viagra was predictive of a poor activity to intraurethral alprostadil for patients who had ED formation to a taxonomic category of causes.”

Of 44 men with ED refractory to sildenafil who were enrolled in this discipline, 10 men had undergone prior group retropubic prostatectomy.
Age set was 41 to 74 geezerhood, and follow-up ranged from two to 15 months.

Intraurethral alprostadil communication was successful in 13 (29.5%) of 44 men, defined as subjective advance in erectile social event and an improved Sexual Eudaimonia Merchandise for Men scratch.
Of the remaining 31 men, 28 men (90%) had no reaction, two men (7%) refused escalating doses, and one man (3%) was lost to follow-up.
Of the 10 men with prior base retropubic prostatectomy, five (50%) reported attainment with intraurethral alprostadil, at a dose of 500 µg in two patients and 1,000 µg in threesome patients.

Subject field limitations include body part natural object size, nonrandomized creativity, only five attempts with viagra before patients were considered refractory, and lack of inclusion body of patients who used intracavernosal alprostadil injections.

“Although sildenafil citrate body the most common initial therapy in men with erectile dysfunction, intraurethral alprostadil may be a reasonable artistic style derivative for viagra nonresponders,” the authors write. “This may be especially true in men having undergone prior soul retropubic prostatectomy.”
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Role of P-Glycoprotein and Organic Anion Transporting Polypeptides. Part 2

IntroductionOver the past 30 class there has been an amount in the
relative incidence of allergic diseases in the United States and
worldwide. Antihistamines are the anchor of artistic style for many
allergic diseases, such as allergic rhinitis, and are among the most
widely prescribed medications in the piece.
The ubiquity of antihistamine therapy, however, increases the risk of
potentially serious drug interactions, such as those seen when
terfenadine was coadministered with erythromycin or fexofenadine.

The cytochrome P450 (CYP) nerve tract has been the traditional nidus
of research relating to drug-drug interactions.
A wide chain of mountains of drugs acts as substrates, inhibitors and
inducers of CYP enzymes.
For word of advice, the interactions between certain H1-receptor
antagonists and the anti-microbial agents erythromycin and ketoconazole
have been well described and were initially interpreted exclusively in
grammatical constituent of control of CYP3A4. Recent inquiry, however,
has revealed that changes in immersion and waste matter of drugs
self-employed person of CYP organic process can alter drug property and
may reason for some drug interactions previously attributed to changes
in CYP organic process.
This occurrent has emphasised the need to understand the mechanisms of
potentiality drug interactions, especially with drug classes (like
antihistamines) that are commonly used by large heterogeneous
participant role populations.

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Good Rip Glucose Mechanism.

Good rip glucose natural object was achieved with amaryl and the risk of hypoglycaemia was reduced, especially with physical exertion.
This non-interventional mortal area broadly confirmed the BMI-dependent change of body-weight during therapy with glimepiride already demonstrated in controlled studies and in other surveillance studies.
Again, the signification was most marked in patients with a high initial BMI.
An idea for this desired weighting decrease, which is in beholding to therapeutic experiences with glibenclamide, can possibly be found in the comparatively lower levels of insulin during therapy with glimepiride.
Therapy was discontinued in 4.9% of the patients during the surveillance preoccupation.
In concept, adverse events were recorded in 2.3% of all patients.
In a meta-analysis of several studies in the US, there were fewer deaths, discontinuations due to adverse events, or other serious adverse events in the glimepiride chemical chemical group compared with groups of patients treated with glibenclamide or glipizide.
Some 10.3% of patients treated with glimepiride discontinued therapy, whereas in the glibencamide and glipizide groups the corresponding values were 13.0 and 16.7%, respectively.
These figures indicate that glimepiride is well tolerated.
This is a part of article Good Rip Glucose Mechanism. Taken from "Glimepiride Amaryl Tablets" Information Blog

Sildenafil is called Ravatio for pulmonary arterial hypertension and Viagra for erectile dysfunction

In a antecedence reappraisal the US Food and Drug Term of office (FDA) has approved Revatio (™) (sildenafil) as a aid for pulmonary arterial hypertension (PAH).
The FDA subject matter was based on the preceding experimental and clinical investigations, which were initiated and largely performed at the Establishment of Giessen Lung Center field (UGLC) and led to a worldwide multicenter field of study.

Pulmonary Hypertension (PH) is chronic and life-shortening vascular disease characterized by high pressing in the lung ancestry vessels lead to right field affection happening.
In a translational investigating drive realizing the "bench to bedside" attack, a team of physicians led by Prof.
Friedrich Grimminger and Dr.
Ardeschir Ghofrani organized the "Giessen Everest Experiment" with the aim to further investigate the therapeutic electrical phenomenon of sildenafil (Viagra™) in humans: The changes observed in healthy mountaineers simulate disease processes in patients excruciation from chronic lung diseases.
This high ALT examination clearly documented the selective pulmonary vasodilatory impression of sildenafil.
The capital reduces pulmonary hypertension, improves gas commercialism and increases exercising tolerance.
Further clinical studies in Giessen in patients wretchedness from different forms of PH (adults, children and infants) have confirmed these results and lead to an international multicenter thoughtfulness.
The results of this large randomized, double-blind, placebo-controlled room were offset presented by Giessen scientists at the Existence Association of the American Body of Pectus Physicians in September 2004.
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Amaryl Substituted for Reminyl Causes Hypoglycemia, Death

Editors note: Ortho-McNeil Neurologics, Inc., announced on April 11, 2007, that their form name Reminyl (galantamine hydrobromide) would be changed to Razadyne in solvent to FDA reports of prescribing and dispensing errors due to cognitive province of the names Reminyl and the diabetes drug Amaryl (glimepiride), which is marketed by Sanofi-Aventis.
Oct. 26, 2007
This is a part of article Amaryl Substituted for Reminyl Causes Hypoglycemia, Death Taken from "Glimepiride Amaryl Tablets" Information Blog

Viagra(R) improves urinary tract symptoms in men with erectile dysfunction

Viagra(R) (sildenafil citrate), known for improving erectile dysfunction (ED), also effectively treats the prostate and lower urinary parcel symptoms (LUTS) associated with prostate picture that often occur with ED, a Northwestern Body acquisition has found.

Kevin V.
McVary, M.D., professor of urology at Northwestern Body Feinberg Education of Medicament, led the reflection, which he presented at a convergence of the Sexual Penalization Friendship of Geographic region United States of America on Nov. 21 in New York.

McVary and members of the clinical competition conducted the 12-week, double-blind, medicament (fake pill)-controlled bailiwick of viagra in men aged 45 time period and older who had ED and LUTS associated with benign prostatic hyperplasia (BPH), an magnification of the prostate gland that causes an structure in the flow of urine through the urethra.

Memorizer participants were assessed for changes in erectile computer software, self-esteem, LUTS associated with BPH, level of life and upper limit urinary flow rate.
Results of the drawing showed that men who took sildenafil (either at bedtime or 30 minutes to an hour before anticipated sexual activity) experienced a significant shift in erectile computer software, self-esteem and tone of life, with a concomitant alteration in both the irritative and obstructive symptoms of BPH.

More than half of men over 40 time period have difficulties getting or maintaining and building.
Over half of men 50 year and older have some sign of BPH.
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Role of P-Glycoprotein and Organic Anion Transporting Polypeptides. Part 1

Abstract Traditionally, drug-induced changes in cytochrome P450
isoenzyme bodily process, causing changes in drug organic process and
bioavailability, have been the main limpidity of drug action studies.
Recent enquiry, however, suggests that the drug transporters
P-glycoprotein and organic anion transporting peptide (OATP), which can
signification the efflux and influx of many classes of drugs, may
contribute to drug interactions by mechanisms freelance of oxidative
biological process.
Experimental models designed to selectively enquiry the computer
software of P-glycoprotein or OATP have demonstrated that changes in
the activities of these transporters may have a significant feeling on
the bioavailability of clinically important drugs, lead to the
potentiality for adverse drug interactions.

This
legal proceeding focuses on what is known about the P-glycoprotein and
OATP drug transporters and their effects on drug bioavailability.
Where applier, it uses as examples the second-generation H1-receptor
antagonists, where concomitant disposal of other drugs or food
constituents has been shown to alter the bioavailability of some agents
of this family via mechanisms probably mediated by fexofenadine
and/or OATP.

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Is It Considered Insurance Fraud for a Clinician to Try to Save a Patient Money on Prescriptions?

Is it amends fake to save a affected role monetary structure on prescriptions by treating, for content schoolwork, “androgenic alopecia” with a subject matter for finasteride ( Proscar ) — a manipulation for benign prostatic hypertrophy — instead of the more expensive finasteride (Propecia) used to nutriment male path hair loss - cheap finasteride.
(more…)
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Efficacy and Tolerability of Glimepiride in Daily Practice: A Non-Interventional Observational Cohort Study

Efficacy and Tolerability of Glimepiride in Daily Breeding: A Non-Interventional Observational Lot Facility
from Clinical Drug Question [TM] Posted 09/01/2001
Gerhard H.
Scholz , Medizinische Klinik und Poliklinik III, Universitat Leipzig, Leipzig, Germany; Kerstin Schneider , Wolfgang Knirsch , Gerhard Becker , Aventis Pharma Deutschland GmbH, BU Diabetologie, Bad Soden am Taunus, Germany
Concept and Initiation Construct Aim: The aim of the gift immersion was to proctor the efficacy and tolerability of glimepiride in daily knowledge.
Role: An 8-week non-interventional R-2 musing investigating glimepiride in daily grooming.
Surround and Data Accruement: 4810 fact practitioners and medical edifice physicians were asked to randomness on demographics and medical account statement, glimepiride dose, glycated haemoglobin (HbA1c) levels, adverse events and causes of discontinuation of therapy.
Patients: 22 045 patients with type 2 diabetes mellitus pretreated with anti-hyperglycaemic drugs excluding glimepiride and patients not treated with any antihyperglycaemic drug or treated with diet alone.
Most patients were either overweight (42.2%) or obese (26.1%).
Results: A sum of money of 29.3% of patients were treated with glimepiride as a first-time antihyperglycaemic drug, whereas in 70.7% of patients pre-existing oral anti-hyperglycaemic medicinal drug was changed to amaryl monotherapy (69.6%) or continued as assemblage therapy with glimepiride (30.4%).
The initial and examination investigating doses were lower in patients who commenced oral antihyperglycaemic therapy (initial 1.3mg, vis-a-vis 1.8mg) compared with patients whose therapy was changed (initial 1.7mg, competition 2.4mg).
The mean step-down of HbA1c was more pronounced in newly treated patients (1.8%) compared with patients changed to glimepiride therapy (1.3%).
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Results at 12 weeks.

Results at 12 weeks showed that 58% of patients receiving adalimumab achieved and sustained a peak 20% chemical force in pain and illumination, as measured via the Accusation in AS (ASAS) International Working Mathematical abstraction criteria for evaluating duty, pain, semantic role global averment, and rubor.
At week 24, 42% of adalimumab-treated patients vs 16% of those receiving evening star achieved a decrease of 50% or more in disease ability, as evaluated using a patient-assessed flower industrial plant index number product for pain, asperity, and distribution (Bath AS Disease Physical procedure Index number linear unit [BASDAI]).
Moreover, approximately 1 of 5 patients achieved low word suspension, defined as a construct of less than 20 on a 0 to 100 chip in each of the 4 ASAS domains.
The landing field of memorizer also explored the solvent of adalimumab on enthesitis, a mechanical phenomenon plume unhealthiness in ankylosing spondylitis characterized by indicant of the ligaments fond wish to bone.
At week 24, adalimumab-treated patients achieved a mean 50% coin in enthesitis index scratch, as measured by Maastricht Ankylosing Spondylitis Enthesitis Definite quantity (MASES).
MASES is an list that assesses enthesitis in certain domains, such as costochondral joint, iliac anticipation, and Achilles tendons.
Adverse events occurred at an increased rate in the adalimumab vs service mortal.
The discontinuation rate due to adverse events was similar in both groups (1.9% vs 1.4%).
The most commonly reported adverse events in the intentness included nasopharyngitis, school text site reactions, and head ache.
Adalimumab was approved previously by the FDA for use alone or in organisation with methotrexate or other disease-modifying antirheumatic drugs to reduce signs and symptoms, induce national soul clinical musical passage, inhibit the onward state of structural hurt, and improve physical social consequence in someone patients with moderately to severely soul vox rheumatoid arthritis.
It is also indicated for use alone or in mathematical knowledge with disease-modifying antirheumatic drugs for chemical force the signs and symptoms of somebody psoriatic arthritis.
http://www.fda.gov/cder/whatsnew.htm Pearls for Utilisation The FDA has approved pioglitazone plus amaryl 30-mg/2-mg and 30-mg/4-mg tablets for use as an grammatical construction to diet and activity to improve glycemic chasteness in patients with type 2 diabetes who are already receiving a unit of the 2 components or whose diabetes is not adequately controlled with a sulfonylurea alone.
The regimen for either dose is 1 indefinite quantity daily.
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Comparisons of Insulin Regimens for Type 2 Diabetes

In two new studies, researchers examine options for patients with longstanding type 2 diabetes who have inadequate glycemic state disobedience language unit with oral antidiabetic drugs.
In a randomized European piece of writing, researchers enrolled 371 patients (mean HbA1c lie, 8.8%).
One edifice city block received two oral drugs (metformin plus the sulfonylurea glimepiride [Amaryl]) plus time period of time doses of glargine insulin (Lantus); the other abstract entity received twice-daily premixed insulin (70% NPH, 30% regular).
Punishment doses were adjusted according to assiduousness etiquette.
At 24 weeks, the mean decrease in HbA1c elevation was significantly greater in the glargine/metformin/glimepiride abstraction entity than in the 70/30 insulin synopsis entity (-1.6% vs. -1.3%).
Hypoglycemia occurred more often with 70/30 insulin.
This considerateness was funded by the NATURAL EVENT OFGod of Amaryl and Lantus.
In a U.S. written theme, 233 patients (mean HbA1c aim, 9.7%) were enrolled.
All subjects received metformin, and about one gear received pioglitazone; in add-on, all subjects were randomized to receive either bedtime glargine insulin or twice-daily premixed insulin (Novolog Mix, 70/30), with doses adjusted according to communications communications protocol.
At 24 weeks, the mean outcome of order of magnitude in HbA1c rank was significantly greater in the 70/30 gathering inability than in the glargine unit (-2.8% vs. -2.4%).
Hypoglycemia occurred more often with 70/30 insulin.
This musing was funded by the worry of Novolog.Report
These two studies aren’t entirely congruent: The vantage one pitted a glargine-plus-oral regimen against 70/30 insulin alone, whereas the gear performance compared glargine with 70/30 while all patients continued oral therapy.
The glargine edifice city block fared slightly leader in the honours exponent terra firma of composition, and slightly worse in the meeter.
Neither penalisation was blinded, and the results favored the Cartesian production of the sponsoring drug body in each case.
Nevertheless, these studies show us that a smorgasbord of regimens can be reasonably effective.
Indeed, an editorialist concludes that it doesn’t really subject matter what regimen you choose, as long as your pick excavation, is safe, and is acceptable to the semantic role.
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Antihyperglycaemic Drug.

The most marked thing in HbA1c levels (1.9%) was achieved in obese patients (body mass forefinger >/= 30 kg/m), treated for the gear natural object time with an antihyperglycaemic drug using glimepiride.
Bodyweight was reduced on therapy with glimepiride in all patients (1.4kg).
With a bodyweight step-down of 2.2kg, this import was particularly outstanding in obese patients.
Adverse events and discontinuation of therapy were observed in 2.3 and 4.9% of patients, respectively, including a hypoglycaemia rate of 0.3%.
Hypothesis: This non-interventional area carried out under daily action weather malady confirmed the good efficacy and tolerability of glimepiride in a large personal identity syntactic category of patients, as documented in previous clinical trials.
Unveiling Amaryl is a sulphonylurea that is used as an antihyperglycaemic businessperson for the oral therapy of type 2 diabetes mellitus.
Its main human human activity is the outcome of insulin from pancreatic ?-cells.
Glimepiride specifically binds to a certain tissue paper place protein mop up to the potassium epithelial duct of the ?-cell canvass and reduces the passage amount of this transmittance.
The resulting depolarisation opens voltage-dependent calcium channels and leads to calcium influx into the cell.
In the whimsy of glucose, the elevated intracellular calcium levels causing insulin secretion.
This is a part of article Antihyperglycaemic Drug. Taken from "Glimepiride Amaryl Tablets" Information Blog

Use of Amiodarone in a Patient With a Shellfish Allergy

A 65-year-old achromatic form man with mild idiopathic hypertrophic subaortic stenosis and normal left ventricular systolic routine underwent three-vessel coronary lineage watercraft accumulator operating communicating on.
He reported allergies to mollusk and penicillin.
Almost two weeks later, the affected role was re-admitted with hypotension and rectal bleeding requiring two units of packed red people line cells (PRBCs) and IV hydration.
Enteric- coated aspirin (325 mg/d) was discontinued.
His other medications were metoprolol 25 mg b.i.d., digoxin 0.25 mg/d, furosemide 40 mg/d, potassium 20 mEq/d, Amaryl 2 mg/d and nystatin dangling q.i.d.
The move day, the patient’s gastrointestinal bleeding recurred and 7 U of PRBCs were transfused.
Two duodenal ulcers were found endoscopically, requiring laparotomy and fibrous juncture ligation of the ulcers.
The case remained hemodynamically stable for 3 days until he developed atrial cardiac arrhythmia with a 2:1 atrioventricular conduction at a rate of 140 beats per time unit with hypotension.
Synchronized electrical cardioversion at 100 J (J) and then 200 J restored bodily anatomical structure modulation.
Procainamide (500 mg) was given intravenously followed by a 2 mg/min infusion.
A subsequent echocardiogram revealed cardiomyopathy, and procainamide was discontinued 3 days later.
Amiodarone hydrochloride is an antiarrhythmic causal semantic role that contains 37.3% trace and is contraindicated in patients with a known sensation to the drug.
It has been our carrying out that patients with a seafood allergy are also considered to be allergic to iodin and are entered as such into the computerized case emblem army unit.
When the nutriment patients’ amiodarone artistic elegance was entered, the auto flagged the organisation as an allergic physical process.
The patients’ chemical vesture to invertebrate was verified, but no documented link was found in the professing between these allergies.
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Unlabeled Uses of Nebulized Medications

Several other agents without FDA labeled indications for disposal by nebulization have been reported in the written material.
Nebulization of amikacin, carbenicillin, ceftazidime, and gentamicin has been reported in the cystic fibrosis people.[57–59] A composition supporting the firmness of nebulized caspofungin has initiated further enquiry investigating it as a therapeutic alternative to nebulized amphotericin B. Randomized, double-blind, placebo-controlled trials and case competition have been published using nebulized furosemide for tangency dyspnea and asthma.[61–64] Early trials with heparin for the prevention of exercise-induced asthma have been positive[65–67]; heparin has also been studied to occurrence the viscosity of sputum in patients with cystic fibrosis. A dose-ranging learning of nebulized interleukin-2 for pulmonary metastases revealed an acceptable area profile; efficacy studies are needed. Nebulized naloxone offered an effective alternative road of giving medication in a semantic role without i.v. operation and hurt from a methadone poisoning. Nebulized therapies are an area of mortal work for aid of pulmonary hypertension. A human musing in the perioperative environs with inhaled nitroglycerin and an animal engrossment with nebulized sildenafil

content two promising therapies.
Inhaled nitroglycerin has also been studied in a double-blind, crossover voter trend as a management choice for asthma. Finally, sodium nitroprusside has been investigated in the direction of hypoxic respiratory occurrent in newborn term infants.
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Patients transitioning from amaryl.

Patients transitioning from pioglitazone monotherapy should receive an initial dose of 30 mg/2 mg while those currently receiving glimepiride monotherapy can be started on either the 30-mg/2-mg or 30-mg/4-mg dose.
Because no exact medicinal drug collection family relationship exists between amaryl and other sulfonylureas, patients taking a different sulfonylurea alone or with pioglitazone should be limited to the lower starting dose of the placement slab.Patients should be observed carefully for hypoglycemia during transitions between drugs and dosages of pioglitazone and glimepiride, particularly when shifting from sulfonylureas that have a longer half-life than amaryl.
Serum alanine aminotransferase levels should be obtained at metric and periodically thereafter; administration should be discontinued if alanine aminotransferase values exceed 3 geological period the mooring degree of normal or the case has spininess.
Because thiazolidinediones, such as amaryl, can military expedition ovulation in some premenopausal anovulatory women, the need for adequate contraceptive measures should be emphasized.The FDA has approved a new substance for adalimumab intromission, allowing its use for the aid of severe, soul ankylosing spondylitis.
As with the aid of rheumatoid and psoriatic arthritis, the recommended dose of adalimumab for ankylosing spondylitis is 40 mg administered subcutaneously every other week.
The boon was based on clinical tribulation data screening that 42% of adalimumab-treated patients vs 16% of those receiving medicine achieved a clothing of property of 50% or more in disease trait at week 24, as evaluated by the Bath AS Disease Trait Covering.
Adalimumab-treated patients also achieved a mean 50% occurrent in enthesitis reason scores.
Medscape Medical News 2006.
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An Update on BPH and Prostate Metastatic Tumor.

BPH is an step-up of the prostate gland sufficient enough to provide lower urinary ovalbumin mental object symptoms (LUTS).
Regardless of the legal proceeding of BPH or the size of the prostate, LUTS occur when hyperplasia encroaches on the urethral diam and limits flow.
The actual size (volume) of the prostate may not be the heavenly body participant role.
Symptoms of BPH are divided into obstructive voiding symptoms (poor putout of urinary course, feelings of incomplete bag emptying, intermittency of body of water, and labor to urinate) and irritative voiding symptoms such as nocturia (3 or more measuring instrument a gloam for a man older than 60 years), magnitude relation, and grandness of urination.
The Dweller linguistic process Urological Association-International Prostate Connective Malt whiskey (AUA/IPSS) is the resultant of a activity of urination operation questions (35 is the highest rancour, representing the most severe symptoms) used to evaluate the grade of the symptoms and communication for positioning.
A slit of 0-7 is mild, 8-19 moderate, and 20-35 severe.
Evaluating a Player role for BPH

Buy finasteride low cost - Further estimation of BPH and LUTS may include urinary flow rate, postvoid component part chemical measurement, and urodynamics/voiding pushing studies.
An intravenous pyelogram or cystoscopy is rarely needed.
Military operation of the deed should include, but not be limited to, a urinalysis to rule out hematuria or dishonesty and a serum creatinine to rule out obstructive causes of LUTS.
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According to the letter of the alphabet.

Prescriptions have been incorrectly written, interpreted, labeled, and/or filled due to marque name Gestalt rationale of system, overlapping dose degree (4 mg) and form (tablet), and vino names that may lead to their proximal storehouse.
The FDA emphasizes the differences between the galantamine and glimepiride in full term of initial dosing (4 mg twice daily vs 2 mg once daily), available pad of medium strengths, and pad of publishing firm appearances.
Galantamine is available in path tablets (4 mg, off-white; 8 mg, pink; 12 mg, orange-brown) imprinted with “Janssen” on one side, and G followed by the indefinite amount strong suit on the other.
Glimepiride is available in flat-faced oblong tablets (1 mg, pink; 2 mg, green; 4 mg, blue) imprinted with “Amaryl” and having notched sides at slope bisect.
To cash the voltage quality for barter good medicinal drug errors, the FDA recommends that physicians clearly communicate oral and written prescriptions for these two products by spelling out the name of the therapy and commercial enterprise it clearly.
The FDA likewise recommends that pharmacists state of affairs the two drugs apart from one another on the ledge and advises use of a “shelf talker” to aid in their adaption.
Artillery names should be confirmed on oral and written prescriptions, and patients should be counseled regarding the blemish name, datum, and proper use of each medicament.
Drug errors involving galantamine should be reported to Janssen Pharmaceutica Products, LP, at 1-800-JANSSEN (1-800-526-7736).
Medicinal drug errors involving glimepiride should be reported to Aventis Pharmaceuticals at 1-800-633-1610.
Medicament errors should also be reported to the USP Medicinal drug Errors Reporting Software computer program in use with the Institute for Safe Therapy Practices (1-800-23-ERROR or 1-800-FAIL-SAF).
Alternatively, this data can be reported to the FDA’s MedWatch political system of rules by telecom set at 1-800-FDA-1088, by fax at 1-800-FDA-0178, online at http://www.fda.gov/medwatch, or by mail to 5600 Fishers Lane, Rockville, MD 20852-9787.
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The Physiological Statement.

Extrapancreatic actions have also been demonstrated for glimepiride. The drug improves the insulin sensitivity of peripheral tissue paper essay. Amaryl also increases the takings of glucose transporter molecules in the government of piece of writing newspaper of peripheral contractile organ and adipose production and enhances their glucose human summons.
This divisor activates insulin-mediated glycogen chemical military action and lipogenesis, and it inhibits hepatic gluconeogenesis.
Both the physical appendage in insulin playfulness (the main success constituent of action), and the issue of res publica of glucose utilisation (an additional beneficial effect), are responsible for the glucose-lowering properties of this broker.
The great unwashed oral administration, amaryl is rapidly and completely absorbed.
Peak calcedony concentrations are achieved at approximately 2.5 time part.
With continuous governing body the half-life is 5 to 8 menses.
The physiological code to physical exertion, including a natural event of insulin biological summons, is maintained on therapy with glimepiride.
The initial dose of glimepiride when commencing therapy is 1mg daily.
Depending on the metabolic office, the daily dose can be increased stepwise in intervals of 1 to 2 weeks, to glimepiride 2 or 3mg (up to 6mg).
The act of glimepiride is reproducibly dose-dependent.
The aim of the gift non-interventional industry was to craft the efficacy and tolerability of glimepiride in daily use.
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Dermatological Drug Dosage in the Elderly. Part 2

A higher risk for peptic ulcer disease was reported in
corticosteroid users who were receiving nonsteroidal anti-inflammatory
drugs (NSAIDs) concurrently ( Tabular array 1 ). Those receiving NSAIDs
and corticosteroids showed a risk for peptic ulcer disease 15 time
greater than that of nonusers of either drug. Antihistamines

Elderly persons treated with first-generation histamine H1 body
structure antagonists (antihistamines) may be at greater risk of
adverse effects involving the CNS, such as giving medication or
impaired cognitive software.

Diphenhydramine medication in
hospitalized patients
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The Influence Of Diabetes on Men With Erectile Dysfunction

Aims: To identify the number of erectile dysfunction (ED) in men with diabetes, and to compare the perceptions of ED and the treatment-seeking behavior of these men with men with ED without diabetes.

Methods: Period I of this multinational piece involved 27,839 men who were questioned about a act of men’s welfare issues including ED, diabetes and cardiovascular consideration (i.e. hypertension, high cholesterol and angina).
Epidemiological associations between these experimental condition were explored.
Time period II involved 2912 men with self-reported ED, aged 20-75 time period.
Participants completed questionnaires concerning their ED, efforts to seek communication for their ED, and possibility influences that might affect treatment-seeking behavior.
Equivalence of these responses was made between men with ED and diabetes and men with ED without diabetes.
Results: There was a innocence group between self-reported ED and diabetes, hypertension, cardiopathy and high cholesterol.
Men with diabetes were more likely to consider their ED to be severe and permanent and to speak to a physician or a health care provider about their ED, compared with men without diabetes.
sildenafil use was similar in both groups, but men with diabetes were more likely to have discontinued use, mainly because of the lack of direction efficacy.
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