Medical Updates @ SBAmin.com

Oral Rivaroxaban completes Phase III

2007-07-08T23:55:00.000-04:00

In a race to replace warfarin and smoothen management issues of thromboembolic disorders by avoiding need for stringent therapeutic monitoring, newer oral anticoagulants are making their debut in the market soon. Rivaroxaban (BAY 59-7939) along with two newly developed molecules, Apixaban and Dabigatran etexilate are oral form of anticoagulant agents with a convenient fixed once or twice daily dose regime. ¹ Compare to Warfarin, these drugs do not require coagulation monitoring as being highly specific direct inhibitor of Factor Xa (Rivaroxaban, Apixaban) and Factor IIa (aka, Direct thrombin inhibitor - Dabigatran etexilate). Dabigatran is about to launch in market with completed phase 3 trial in orthopedics and currently running trials in stroke prevention ⁴.

Phase 3 trial, RECORD3 (REgulation of Coagulation in major Orthopaedic surgery reducing the Risk of DVT and PE) data from 2531 patients, lead by Michael R. Lassen, MD announced today at the XXI International Society on Thrombosis and Haemostasis (ISTH) Congress showed once-daily rivaroxaban (Xarelto®) achieved superior efficacy in the prevention of venous thromboembolism (VTE) in patients undergoing knee replacement surgery in a head-to-head comparison with enoxaparin, the current standard of care therapy [49% relative risk reduction (RRR) (p<0.001)]. ² Importantly, rivaroxaban also demonstrated a similarly low rate of major bleeding compared to enoxaparin (0.6% and 0.5%, respectively). Considering potential hepatotoxiciy of direct thrombin inhibitors (i.e.: withdrawal of the direct thrombin inhibitor ximelagatran shortly after it reached the market ³), complete saftey profile of rivaroxaban is due till ongoing RECORD3 trial ends by 2007 end. To date, rivaroxaban is the most studied oral direct factor Xa inhibitor in development. More than 15,000 patients have been evaluated in the completed phase II programs and enrolled thus far in the phase III programs. More than 40,000 patients are expected to be evaluated in total. ⁴

Rivaroxaban is being jointly developed by Bayer HealthCare AG and Johnson & Johnson Pharmaceutical Research &amp;amp; Development (J&JPRD), L.L.C.

References:
1. Rivaroxaban Looks Promising in DVT - Medscape Heartwire
2. Phase III Trial Results Show Superiority of Rivaroxaban over Enoxaparin for the Prevention of Venous Thromboembolism in Patients Undergoing Knee Replacement Surgery - Pressnote at Bayer Inc. | ISTH 2007 website
3. AstraZeneca Decides to Withdraw Exanta™ (melagatran / ximelagatran)
4. Currently active clinical trials from ClinicalTrials.gov

Oral Eltrombopag - A possible answer to Platelet Transfusions

2007-06-17T00:29:00.000-04:00

A newer oral form of therapy is expected soon in market for patients of chronic ITP and possibly for other patients suffering from symptomatic thrombcytopenia. Eltrombopag (Promacta ® - GSK pharma) is an investigational agent (SB 497115) of a new drug class, thrombopoeitin receptor (TPO-R) agonist which in turn showed significant increase in megakaryocyte proliferation and differentiation and thereby, raising platelet count with oral dosage of 50-75 mg/day for six-weeks and producing less frequent chances of bleeding. This was concluded from phase III trials, involving 114 patients from worldwide having platelet count less than 30000/cmm. Being a non-peptide, small molecule, drug has less immunogenic potential, compare to platelet antibody issue with platelet transfusions. Till date, no serious side effects have been reported in controlled trials and drug is in phase III trial for further safety checkup. Though drug showed impressive results in chronic ITP non-responders from conventional treatments (steroids, immunotherapy), it is currently not being evaluated in other causes of thrombocytopenia, especially in drug-induced thrombocytopenic cases.

Image courtesy: 57th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)

References:

1. Press Release at GSK | Medical News Today 12 June 2007

2. Ongoing clinical trials:

RAISE (RAndomized placebo controlled ITP Study with Eltrombopag)
REPEAT (Repeat ExPosure to Eltrombopag in Adults with Idiopathic Thrombocytopenic Purpura)
EXTEND (Eltrombopag Extended Dosing Study) and four others at clinicaltrials.gov

3. Original article presented presented at the 12th congress of the European Hematology Association (EHA) in Vienna, Austria

Bussel, J., Provan A., Shamsi T et al. Eltrombopag Raises Platelet Count and Reduces Bleeding compared with Placebo during Short-term Treatment in Chronic Idiopathic Thrombocytopenic Purpura: A Phase III Study. Presented 9th June 2007, 12th Congress of the European Hematology Association, Vienna, Austria

Related articles and Recent Study Outcomes:

Rosiglitazone update and Clinical Practice Guidelines: Type 2 DM

2007-06-06T00:26:00.000-04:00

FDA has released ¹ MedWatch alert for Avandia (rosiglitazone) in management of DM, concerning about risk of ischemic cardiovascular events which might be linked with the drug use. Alert is based on pooled analysis of 42 clinical trials. However, there is no definite evidence so far showing Avandia as a cause of such cardiac events.

Joslin Diabetes Center (JDC) has released (Jan 2007) updated clinical practice guidelines on adult with diabetes and pharmacological management of type 2 DM in non-pregnant adults. These evidence based guidelines contain essential points in managing diabetic patients with a systematic approach for an optimal blood glucose control and preventing diabetic complications. Guidelines are available in text layout at NGC and also in easy-to-follow algorithms at JDC's website ².

References:

1. FDA MedWatch: 21 May 2007 Avandia (rosiglitazone)

2. Guidelines may show update after actual posting date:

Clinical guideline for adults with diabetes: NGC | JDC (PDF)
Clinical guideline for pharmacological management of type 2 diabetes: NGC | JDC (PDF)

oropharyngeal cancer and oral sex

2007-05-13T04:07:00.000-04:00

Security is mostly a superstition. It does not exist in nature,....
(Helen Keller)

The quote seems true even in a personal life! Oropharyngeal cancer showed strong association with high-risk sexual behaviors, people having more than 5 oral-sex partners during lifetime and especially among partners having HPV-16 and other serotypes positive status, results recently published in NEJM. A Case-control study involving newly diagnosed oropharyngeal cancer and 200 control patients without cancer to evaluate associations between HPV infection and oropharyngeal cancer.

The degree of association increased with the number of vaginal-sex and oral-sex partners. Since this is a single study with fairly ok sample size, cause-and-effect association can not be established; but there is a strong correlation between oropharyngeal cancer and oral HPV infection, apart from use of alcohol and tobacco as an independent risk factors. Apart from oro-genital sex, even mouth-to-mouth direct contact may be linked to increase risk of acquiring oral HPV infection and subsequently oropharyngeal cancer.

Authors suggest public health implication of this study by expecting rise in oropharyngeal cancer cases because of increase oral sex practices behavior among adoloscents. Recently launched HPV vaccine (Gardasil, Merck Inc.), now under US national immunization schedule for girls between 11 to 12 years (extended 9-26 years age) can be a rational approach to prevent oral HPV infection and decreasing cancer risk in boys too. However, more clinical studies are demanded before arriving at conclusion to implement HPV vaccination among boys.

Reference:
1. D'Souza G et al. | Case–Control Study of Human Papillomavirus and Oropharyngeal Cancer | N Engl J Med 2007(10 May);356:1944-1956 (free access)
2. Oral Sex Can Add to HPV Cancer Risk | Time magazine
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Helen Keller says to dare and face the outright danger. However, there are few exceptions prudent followers should know about. Play safe:-)

Cumulative Updates: Stroke Guideline | New Anti-Platelet drug in Phase 3

2007-04-25T02:14:00.001-04:00

Here are cumulative updates (shortlist) happened in recent two weeks. I am unable to post frequent regular updates because of tight schedule and limited internet connectivity. Alternately, use feed station for keeping eye on medical news.

1. Updated guidelines for treatment of acute ischemic stroke:
By American Heart Association/American Stroke Association (Apr 19, 2007, ahead of print issue of Stroke)

Major Recommendations/Changes since 2003 guidelines

Intravenous tPA is still recommended as the key treatment of stroke in patients presenting within 3 hours of the onset of stroke symptoms
Time is the key, activation of emergency medical services ASAP is the topmost priority
Upcoming role of intra-arterial tPA in patients with inaccessible intravenous line
Comaprision of benefits Vs risks using Mechanical Embolus Removal in Cerebral Embolism (MERCI) retriever (FDA approved) or tPA.
CT scan still remains preferred modality with only primary intetion to exclude hemorrhage event and plan for tPA treatment
MRI is acceptable alternative provided quick access is available

..... guidelines truncated

Refer Medscape article (link) or Stoke journal (May 2007 issue) for complete guidelines.

2. Newer Anti-platelet drug in Phase 3 clinical trial:
Newer class of oral anti-platelet drug (platelet PAR-1 receptor blocker) named TRA-SCH 530348 (Schering-Plough Inc.). In fact, it blocks the platelet PAR-1 receptor to which thrombin binds, thus inhibiting thrombin-induced activation of platelets, and is therefore classified as a thrombin-receptor antagonist (TRA). Recently reported phase 2 trial showed fewer ischemic events without increasing bleeding when added to standard antiplatelet therapy with aspirin and clopidogrel in patients undergoing PCI. Researchers from Duke and TIMI group have now planned two major phase 3 trials which will be accessing effect of this novel agent compare to placebo without adjuvant standard anti-platelet regime. Two groups of patients will include one for the treatment of acute coronary syndrome (ACS) patients (more than 10000 patients), and one for secondary-prevention in patients who have had a prior MI or stroke or who have existing peripheral arterial disease.
.....update truncated

Original press release at http://www.schering-plough.com/schering_plough/news/release.jsp?releaseID=987054
Courtesy: Medscape

SBAmin.com is down: Server Shifting In Progress

2007-04-21T03:36:00.000-04:00

Copy of original post:

Site Status: DOWN | Blog Status: Healthy

Dear Visitor,

Because of an ongoing data corruption error, we are shifting site servers to new, stable ones. Henceforth, SBAmin.com may not be available for next 24-48 hours. However, Blog Junction (status: Healthy) is active throughout site maintenance period.
Also, please note change in email contact information. Kindly do not email me at Instead use this link OR email me at till further update.

I'll be updating here soon as site status becomes OK.

Sorry for inconvenience!

Regards,
Samir
21 April 2007 1227 +0530
Baroda India
T: (0091) 93762 26975
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Declining Breast Cancer & HRT effect

2007-04-19T11:18:00.003-04:00

Hormone Replacement Therapy (HRT) is again in the news, once again with possible causal association for developing breast cancer. Statistical analysis performed by M.D.Anderson's team revealed strong association (but no cause-to-effect relationship) between declining breast cancer cases and parallel decline in use of HRT in post-menopausal women since mid-2002. The decline occurred primarily in women age 50-69, the researchers find, and was predominantly seen in estrogen-receptor(ER)-positive cancer. Ravdin and Berry strongly stress, however, that their study is not suggesting that all women stop their use of HRT. "This study is not saying that an individual woman will reduce her absolute risk of developing breast cancer by 15 percent by immediately discontinuing use of HRT," Berry says.

Read brief report at EurekAlert! 18 Apr 2007
Original article: Ravdin PM et al. | The Decrease in Breast-Cancer Incidence in 2003 in the United States | N Engl J Med 2007(Apr 19);356:1670-1674

Inhaled Insulin (Exubera) - Falling Star

2007-04-19T11:18:00.001-04:00

Inhaled Insulin (Exubera) was brought in market in early-2006 and since then, it's being criticized for its added efficacy and long-term safety profile over standard subcutaneous insulin regime. Recently, National Institute for Health and Clinical Excellence (NICE, UK Government) has published guideline on use of inhaled insulin for the treatment of type 1 and 2 diabetes. Authors of guideline group do not recommend inhaled insulin for the routine treatment of diabetes.

Also, inhaled insulin should be used as an alternative option in only those subgroup of diabetic patients in whom other treatment modalities are ineffective or intolerable and interestingly, in patients suffering from specific phobia of "blood injection injury type" who are not willing to take standard subcutaneous insulin injections. Several other studies also recommend data collection for evaluating long-term safety profile of inhaled insulin and it's effect on lung functions.

Reference:
1. NICE guideline (Dec 2006): Inhaled insulin for the treatment of diabetes (types 1 and 2)
2. Exubera | Pfizer Inc.
3. FDA approval of Exubera
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Vasopressin Antagonist in Acute Heart Failure - Mixed Results | EVEREST trial (ACC.07)

2007-03-30T14:49:00.000-04:00

American College of Cardiology's 56th annual scientific session (ACC.07) Update | March 26, 2007:

Vasopressin V2 receptor antagonist tolvaptan¹ is again showing mixed results with efficacy limited only to short-term benefits in fluid overload status. Previously, tolvaptan was found to be effective in patients with euvolemic or hypervolemic hyponatremia in increasing serum sodium concentrations at day 4 and day 30; with recurrence of hyponatremia was noted in a week after discontinuation of tolvaptan on day 30.² Now, EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Trial) outcome presented at ACC.07 ³ suggested tolvaptan moderate efficacy only in short-term cure of acute decompensated hear failure (ADHF) without difference in all-cause mortality or the composite of CV death or heart failure hospitalization compared with placebo at long-term follow-up; suggesting that early, in-hospital therapy with tolvaptan is beneficial but longer therapy may be unnecessary. Explaining study results, Dr Marvin A Konstam said, tolvaptan can "facilitate fluid management" and alleviate symptoms in this population " with a well-defined and acceptable long-term safety profile." ⁴ This might because of drug action in decreased body weight, reduction in edema, and subsequent improvement in patient assessed dyspnea. The results of the present study are similar to those observed in the ACTIV in CHF trial⁵, which also showed improvements in acute heart failure symptoms but no difference in clinical endpoints with chronic therapy.

Reference:
1. Tolvaptan (OPC-41061) - In process of New Drug Application | Otsuka Pharmaceutical Development & Commercialization, Inc. (OPDC) is developing tolvaptan for the treatment of congestive heart failure, hyponatremia and polycystic kidney disease.
2. Previous article on SBAmin.com | N Engl J Med 2006;355:2099-2112 | ClinicalTrials.gov numbers, NCT00072683 [SALT-1]and NCT00201994 [SALT-2]
3. ACC.07 EVEREST trial link
4. EVEREST: "Modest" Gains, No Apparent Harm From Vasopressin Antagonist in Acute Heart Failure | Heartwire (WebMD) article
5. ACTIV in CHF | ACC.07 link
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Ranolazine (Ranexa) has no role in Acute Coronary Syndrome (ACS) cases

2007-03-29T12:10:00.000-04:00

Hello All!
I am lagging behind updating this blog with several important clinical trial updates¹ recently presented at American College of Cardiology's 56th annual scientific session (ACC.07) and Innovation in Intervention: i2 Summit 2007 (see reference for official outline links)
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ACC.07 update (March 27, 2007): Ranolazine (Ranexa) has no role in Acute Coronary Syndrome (ACS) cases | MERLIN TIMI-36 results
Ranolazine (Ranexa)² is a new class of anti-anginal drug, approved by FDA³ in January 2006 for the treatment of chronic angina patients who have failed to other forms of angina treatments (long-acting nitrates, calcium channel blockers and beta blockers). This indication was based on initial clinical trials, namely ERICA⁴ (Efficacy of Ranolazine in Chronic Angina) and CARISA⁴ (Combination Assessment of Ranolazine In Stable Angina) involving more than 1300 patients. Studies found prolong QT interval as a adverse reaction which might lead to proarrythmic effects and hence, drug is restricted for use in chronic angina patients as a second-line option.

The new trial named, MERLIN TIMI-36 (Metabolic Efficiency with Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes)⁴ was started in May 2006 which was a multi-national, double-blind, randomized, placebo-controlled, parallel-group clinical trial designed to evaluate the efficacy and safety of Ranexa during acute and long-term treatment in approximately 6,500 patients with non-ST elevation ACS treated with standard therapy. The primary efficacy endpoint in MERLIN TIMI-36 is time to first occurrence of any element of the composite of cardiovascular death, myocardial infarction or recurrent ischemia in patients with non-ST elevation ACS receiving standard therapy. The study was also evaluating the safety of long-term treatment with Ranexa compared to placebo.⁵ Results of MERLIN TIMI-36 were presented at ACC.07 which showed no role of Ranolazine in management of patient with ACS and also it has not disease-modifying effects in stable angina patients. However, trial showed no adverse effects of drug in terms of arrhythmia and increase mortality because of its prolong QT interval side-effect and suggested that it might have antiarrhytmic effects.

Effect of Ranolazine in preventing recurrent angia is supported by all major clinical trials. It is a unique agent that, unlike other classes of anti-anginal therapy, does not significantly reduce heart rate or blood pressure. As MERLIN study has shown better safety profile of Ranolazine, it is likely that Ranolazine will gain one more indication as a first-line therapy in stable angina patients in coming years.⁶ Precise mechanism of action of Ranolazine is unclear but it is believed to be a selective inhibitor of the late sodium current relative to peak sodium channel current, and via this mechanism, it may decrease sodium-dependent intracellular calcium overload during ischemia and reperfusion.⁷

Reference:
1. ACC.07 | i2 Summit 2007 : Official Text and Multimedia Resources | MERLIN TIMI-36 outline
2. Ranolazine (Ranexa)^® prescribing information from CV Therapeutics
3. FDA approval of Ranolazine: January 31, 2006
4. Clinical trial summary from ACC: CARISA | ERICA | MERLIN TIMI-36 (May require ACC account access)
5. CV Therapeutics article, dated 9 July 2006 - medicalnewstoday.com
6. MERLIN: No Role for Ranolazine in ACS but First-Line Indication in Stable Angina Now Likely - Heartwire (WebMD) news
7. Hale SL, Kloner RA | Ranolazine, an inhibitor of the late sodium channel current, reduces postischemic myocardial dysfunction in the rabbit | J Cardiovasc Pharmacol Ther. 2006 Dec;11(4):249-55 | PMID: 17220471
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Patch: Pfizer stopped phase 3 trial of potential HDL raising drug

2007-03-26T12:44:00.000-04:00

This is a patch to an update posted earlier 03 Dec 2006.

Today NEJM has published (available free at this time) early release articles¹ to coincide with presentations at a meeting of the American College of Cardiology². These articles elaborate possible mechanisms of adverse effects of CETP inhibitor torceptrapib (Pfizer Inc.) because of which Pfizer has terminated phase III clinical trials³ of promising HDL lowering agent drug.

Reference:
1. Articles available free for the time being at NEJM homepage. These articles will be in print format in March 29 and April 19, 2007 issue of NEJM.
2. American College of Cardiology 56th annual scientific session in New Orleans & 2nd Annual Innovation in Intervention | ACC.07 and i2 Summit 2007
3. Terminated clinical trials: Investigation of Lipid Level Management to Understand Its Impact in Atherosclerotic Events (ILLUMINATE) (ClinicalTrails.gov search: Torcetrapib/Atorvastatin) | Investigation of Lipid Level Management Using Coronary Ultrasound to Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation (ILLUSTRATE) trial (NCT00134173)
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Original post - 03 Dec 2006:

On December 2, 2006, FDA was notified that Pfizer will suspend a large, Phase 3 trial evaluating the investigational cardiovascular therapy torceptrapib/atorvastatin (T/A) due to an increased rate of mortality (death) in patients receiving the combination compared to those receiving atorvastatin alone...excerpt from FDA News

Torceptrapib was a potent inhibitor of cholesteryl ester transfer protein (CETP). Read Effects of an Inhibitor of Cholesteryl Ester Transfer Protein on HDL Cholesterol NEJM 350:1505-1515 (2004)
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Creatine for Parkinson's Disease - Phase III trial

2007-03-23T13:12:00.000-04:00

The National Institute of Neurological Disorders and Stroke (NINDS), NIH institute yesterday¹ launched double-blind, placebo-controlled, phase III study to learn if the nutritional supplement creatine can slow the progression of Parkinson's disease (PD). Currently there is no treatment that has been shown to slow the progression of PD. It is one of the largest PD clinical trials to date, enrolling 1720 people with early-stage PD at 51 medical centers in the United States and Canada. Till date, creatine is not an approved therapeutic agent for PD or any other condition. Earlier studies² suggest its ability to improve exercise performance possibly by improving mitochondrial function and potential neuroprotection by antioxidant property. Creatine - a widely used dietary supplement has been investigated as a possible therapeutic approach for the treatment of muscular, neurological, neuromuscular diseases and neuroprotective effects.³ Participation in this study lasts a minimum of 5 years and includes at least 9 follow-up clinic visits and at least 3 telephone calls.

Reference:
1. NET-PD LS-1 Creatine in Parkinson’s Disease | NCT00449865
2. PubMed search using keywords: creatine parkinson
3. Creatine and treatment of muscular diseases | Wikipedia.org

Estriol pills for Multiple Sclerosis

2007-03-23T12:21:00.000-04:00

UCLA researchers have begun phase II/III multi-center clinical trial¹ of Estriol treatment for Relapsing Remitting Multiple Sclerosis (RRMS). Multiple sclerosis (MS) relapses are known to be significantly decreased during pregnancy as described in earlier clinical studies. This proposal will establish whether oral treatment with estriol, the major estrogen of pregnancy, induces a decrease in relapses in relapsing remitting multiple sclerosis (RRMS) subjects when used in combination with injectable Copaxone (glatiramer acetate)². Previously, in a pilot study, it has been demonstrated that treatment of RRMS subjects with oral estriol for six months resulted in a significant reduction (approximately 80%) in gadolinium enhancing lesions on serial brain MRIs³ and caused a favorable shift in immune responses⁴. Current study is an add-on study aiming to extend these previous findings by treating longer and focusing on clinical outcomes. The combination of Copaxone injection plus estriol pill (8 mg per day) will be compared to Copaxone injection plus placebo pill in a double blind trial. The duration of treatment will be two years and the primary outcome measure will be relapse rate. Treatment with estriol is believed to be a neuroprotective against new MS attacks as well as to reduce severity of inflammatory reaction seen with MS. Trial is expected to be completed by July 2011 and team expect to come up with promising results which would be helpful to cut down existing expensive MS treatment with cheaper hormone pills. Recently University of Calgary team shown protective effect of hormone prolactin in preventing demyelinating episodes in animal studies.

Courtesy: EurekAlert! 22-Mar-2007

Reference:
1. A Combination Trial of Copaxone Plus Estriol in RRMS (Estriol in MS) | NCT00451204
2. Copaxone prescribing information | PDF
3. Annals of Neurology, 2002; 52:421-428
4. Journal of Immunology, 2003; 171:6267-6274

Eculizumab (Soliris) for paroxysmal nocturnal hemoglobinuria (PNH)

2007-03-21T18:44:00.001-04:00

FDA recently (March 19) approved Eculizumab - a humanized monoclonal antibody with long-acting C5 terminal complement inhibitor property. It is a new class in immunotherapy selectively blocking terminal complement activation - one of the main component of innate immune system. Patients with PNH are hypersensitive to complement mediated intravascular hemolysis as their RBCs lacks complement-regulating surface proteins, i.e. decay-accelerating factor (DAF) or CD55, homologous restriction factor (HRF) or C8 binding protein, and membrane inhibitor of reactive lysis (MIRL) or CD59. However, Soliris helps only in preventing complement mediated hemolysis and decreasing need for excess blood transfusions but it does not alter the course of PNH as well as potential risks of thrombosis and aplastic anemia associated with PNH. A boxed warning showing risk for serious meningococcal infection and need for meningococcal vaccination is affixed following results of clinical trials.

Reference:
1. FDA Okays Eculizumab (Soliris) for Paroxysmal Nocturnal Hemoglobinuria - MedPage Today
2. Hilmen P et al. | Effect of Eculizumab on Hemolysis and Transfusion Requirements in Patients with Paroxysmal Nocturnal Hemoglobinuria | N Engl J Med 2004;350:552-559
3. eMedicine.com article on PNH
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Don't kiss, focus on chest

2007-03-19T18:45:00.001-04:00

I mean title for cardiopulmonary resuscitation (CPR) !

Chest compressions alone are more life saving than combined chest compressions with mouth-to-mouth rescue breathing in adults having cardiac arrest - based on results from a large scale study in Japan involving 4000 cases of cardiac arrest outside hospital in presence of bystanders. This is because patients in whom heart has just stopped working can have adequate oxygen saturation in flowing blood to support brain and other vital organs functions until heart recovers and restart pumping oxygenated blood. Hence, rather spending time on rescue breathing from those precious early life-saving minutes, it is prudent to deliver continuous effective chest compressions in anticipation of restarting heart pump and preventing ischemic brain damage.

However, this conclusion was based from a single study data involving patients having failing heart and it is important to note that rescue breathing can be a vital task when it comes to respiratory component in cardiac arrest. i.e. narcotic and drug over-dosage, drowning and others. There have been no change in CPR guidelines so far from American Red Cross and American Heart Association (AHA).

Reference:
1. 'Kiss of life' increases risk after heart attack - NewScientist News 16 March 2007
2. American Red Cross - Video showing current CPR technique
3. Cooper et al. | Cardiopulmonary Resuscitation: History, Current Practice, and Future Direction | Circulation 2006;114:2839-2849
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FDA MedWatch: Erythropoiesis Stimulating Agents & Interferon Gamma 1-b

2007-03-19T12:28:00.000-04:00

Erythropoiesis Stimulating Agents
FDA MedWatch has issued black box warning for use of Erythropoiesis Stimulating Agents (ESAs) namely, darbepoetin (Aranesp) and epoetin alfa (Epogen and Procrit)

Studies showed aggressive use of ESAs to correct hemoglobin 12 g/dl or more is associated with increase risk of thrombotic events and stimulate progression of some cancers. (DAHANCA 10, CREATE, CHOIR and other studies)

in raising hemoglobin to 12 g/dl or higher in cancer patients which is associated with higher chance of serious and life-threatening side effects or death. Revision took place after results of four clinical trials evaluating an unapproved dosing regimen, a patient population for which ESAs are not approved, or a new unapproved ESA. Patients treated with Aranesp had a higher death rate and no reduction in the need for transfusions compared to those treated with placebo. The findings in the Aranesp study may apply to other ESAs. Additionally, the findings show that treating anemic cancer patients not currently on chemotherapy with an ESA may offer no benefit and may cause serious harm.

Current recommendation for all indicated patients are:

To start the lowest possible dose of ESAs.
Checking hemoglobin twice a week for two to six weeks after any dosage change to ensure that hemoglobin has stabilized in response to the dose change.
Withhold the dose of the ESAs if the hemoglobin increase reaches 12 g/dL or more or rises by 1g/dL in any two-week period.

[FDA Source]

Interferon Gamma 1-b
FDA has not approved Interferon Gamma 1-b (Actimmune) for the treatment of idiopathic pulmonary fibrosis (IPF) based on early termination of the INSPIRE clinical study of Actimmune for IPF because of an interim analysis showed that patients with IPF who received Actimmune did not benefit compare to placebo.

[FDA source]

Oral Amphotericin B - Bypassing Renal toxicity

2007-03-05T13:43:00.000-05:00

Researchers at the University of British Columbia (Canada) discovered new drug delivery system for Amphotericin B (AmB), bypassing notable renal toxicity associated with currently available intravenous AmB formulation. Newer oral preparation containing lipid-based AmB targets specifically fungal cells while inhibiting drug's interaction with kidney cells - thereby avoiding lethal toxicity and increasing efficacy. This can be a boon for thousands of patients suffering from dreaded fungal infections associated with HIV/AIDS and other immuno compromised diseases by providing more effective, less toxic and cheaper alternative to intravenous AmB. A clinical study of the drug delivery system, involving 50-100 patients, is planned for later this year. Study led by Wasan KM will be presented today at a meeting sponsored by the American Association of Pharmaceutical Scientists in Washington, D.C. Findings will be published in July 2007 in Drug Development and Industrial Pharmacy.

Use of Liposomal AmB (AmBisome®) is associated with raised serum creatinine level in 18% to 40%; hematuria in 14% of cases and acute renal failure and/or toxic renal nephropathy in 2% to 10% of cases. However, incidence of decreased renal function and infusion-related events are lower than rates observed with conventional amphotericin B deoxycholate (Amphocin®, Fungizone®).²

Reference:
1. EurekAlert! 5-March-2007
2. Drug information by Merck Inc. - Liposomal AmB
3. AmBisome monograph
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Clinical Practice Alert: For Entecavir and Vancomycin use

2007-03-01T00:19:00.000-05:00

Clinical Practice Alert:

1. Entecavir (Baraclude ^TM) in patients suffering from both - Chronic Hepatitis B and HIV infection:
Hopkins researchers proved deleterious effect of Entecavir in patients suffering from HBV / HIV co-infection using both laboratory and clinical tests. Entecavir - A selective HBV polymerase inhibitor is indicated for chronic active HBV and being widely used since arrival in March 2005. As there have been cases showing decrease viral load of HIV with use of entecavir in such co-infected patients, current practice widely favors use of entecavir in treating HBV in HIV/HBV patients not simultaneously receiving highly active antiretroviral therapy (HAART) in anticipation of decreasing HIV load. However, Hopkins study cautions clinicians not to use entecavir in HIV/HBV patients they revealed mutation in HIV (M184V type) which nurtures HIV resistance to more widely used Lamivudine (3TC) and related Nucleoside reverse transcriptase inhibitors (NRTIs) which might be needed for HIV therapy in later phase for those patients. At present, there is no box warning for use of entecavir in HIV/HBV co-infected patients. On 24-Feb-2007, FDA included entecavir in MedWatch [Excerpt: Current treatment guidelines recommend Baraclude as an option for treatment of HBV in the HIV/HBV co-infected adult patient who does not qualify for HAART. Healthcare professionals are advised that when considering therapy with Baraclude in an HIV/HBV co-infected patient not receiving HAART, the risk of developing HIV resistance cannot be excluded based on current information]
Reference:
1. EurekAlert! 28-Feb-2007
2. Conference on Retroviruses and Opportunistic Infections (CROI) 2007
3. Baraclude: official website | mechanism of action

2. Vancomycin dependant immune thrombocytopenia:
A study from the Medical College of Wisconsin, published today in NEJM reports development of vancomycin-dependant antiplatelet antibody and subsequent thrombocytopenia with significant bleeding. Study found 29 patients developing such antibodies and 3 of which had fatal bleeding outcome. Vancomycin, commonly used for MRSA is out in clinical practice for 25 years and therefore, this new finding reflects possibility of rarest side-effect and/or other unknown etiology of such antibody development despite study documented exclusion of other causes of thrombocytopenia. Authors recommend to actively watch for decreasing platelet counts / asking hematology consultation if justified and to discontinue/substitute vancomycin for few days to expect improvement in platlet counts.
Reference:
1. Aster et al. | Vancomycin-Induced Immune Thrombocytopenia | N Engl J Med 2007;356:904-910

Fulvestrant for Advanced ER positive Breast Cancer

2007-02-26T20:30:00.000-05:00

Fulvestrant (Faslodex®) - a competitive estrogen-receptor antagonist is relatively new class of endocrine treatment option in treatment of advanced breast cancer, besides commonly prescribed Tamoxifen (SERM - see reference) and Anastrozole (ARIMIDEX® - selective non-steroidal aromatase inhibitor). Approved in 2002 for use in post-menopausal estrogen receptor (ER) positive female with advanced metastatic breast cancer after failure of anti-estrogen therapy (i.e. tamoxifen), earlier studies (see Reference) clearly shown fulvestrant is as effective as anastrozole.

Recently published (Oct 2006)

Clinical implications:

Investigate role of Fulvestrant as a first-line adjuvant endocrine therapy for metastatic breast cancer
To study role of fulvestrant in delaying initiation of chemotherapy and associated side effects in endocrine resistant breast tumors

results of phase II Swiss Group for Clinical Cancer Research Trial (SAKK 21/00) stated significant clinical benefit in 30 % cases who had progressed despite prior aromatase inhibitor (AI) treatment. This benefit with fulvestrant was noted irrespective of response to an AI. Study concluded fulvestrant as a safe, well tolerated and effective therapy advanced metastatic breast cancer in post-menopausal patients with failure of anti-estrogen therapy and/or resistant to AI treatment.

Reference:
1. Journal Watch | Fulvestrant for Aromatase-Inhibitor–Resistant Breast Cancer
2. Fulvestrant clinical trials | PubMed PMID: 12177099, 15937908, 17030543
3. Prescription Information: Faslodex® | ARIMIDEX®
4. Selective estrogen receptor modulator (SERM) - Wikipedia article
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Old is Gold | Circumcision in HIV prevention

2007-02-24T01:15:00.000-05:00

In a long running debate of questionable efficacy of adult male circumcision in preventing HIV infection, series of articles (including two recent study trials) published today in the Lancet showed more than 50 % relative reduction of HIV infection in circumcised adult heterosexual males and importantly without change in sexual behavior of studied population. NIH led trials conducted in Uganda and Kenya over duration of more than 24 months were stopped early as interim analysis showed significant benefit of circumcision. This would soon lead to integrate adult male circumcision as a new approach combined with other HIV prevention strategies

Till date more than 30 cross-sectional studies have found the prevalence of HIV to be significantly higher in uncircumcised men than in those who are circumcised and 14 prospective studies all show a protective effect, ranging from 48% to 88%. Current conclusion is primarily drawn from results of three major randomized control studies involving nearly 10000 adult males performed in South Africa, Uganda and Kenya by different researchers.

Pathophysiology and possible mechanism of HIV prevention by circumcision:

The protective effect of circumcision against HIV infection is thought to derive in part from postsurgical development of a barrier layer of keratinised squamous epithelial cells that limit viral entry to underlying HIV target cells (Langerhans’ cells, CD4+ T cells and macrophages). Without circumcision, inner mucosal surface of the human foreskin, when exposed upon erection, has nine times higher density of HIV target cells (and even more when person has recent history of sexually transmittable disease) than does cervical tissue and thereby increasing chance of acquring infection from vaginal cavity.
Other less satisfactory mechanisms among uncircumcised males include poor hygiene, greater incidence of ulcerative sexually transmitted infections and susceptibility of the foreskin to abrasions.

Obstacles in HIV prevention:

All three trials are stopped early may overestimate efficacy when compared with subsequent studies, and therefore demanding long-term post-circumcision trial surveillance is essential to determine the overall effectiveness of circumcision in populations with varying HIV prevalence.

When? Whether neonate circumcision would be effective strategy or not will at least take a generation to show any benefit if present and on the other side, performing adult male circumcision has its own challenges. i.e.: Complexity and safety of procedure, readiness for voluntary circumcision considering religious and cultural practices, public awareness and expenses related to current heath care system, especially in resource poor set-up.

At present, it is not sure whether or not male circumcision has any benefit in HIV prevention in female partners. Logically by creating herd of circumcised males, females risk of getting infection can be minimized.

Efficacy of circumcision in areas where male-to-male HIV transmission is greater than heterosexual transfer; importantly greater risk to recipient of anal intercourse.

Rising debate of male circumcision is mutilation, or whether it is justified for health, religious, and cultural reasons.

Upcoming global strategies:
The best way in halting HIV juggernaut is a multi-modality approach involving more than one existing preventive methods in co-operation with public, government and social agencies to create awareness and self-implication of central theme: Safe Sexual Practice

Courtesy and Ref.:

Lancet 24 Feb 2007 | Volume 369 Number: 9562

Editorial | Newer approaches to HIV prevention | Lancet 2007;369:615

Comment | Male circumcision to cut HIV risk in the general population | Lancet 2007;369:617-620

Bailey et al. | Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial | Lancet 2007;369:643-656

Gray et al. | Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial | Lancet 2007;369:657-666

Sawires et al. | Male circumcision and HIV/AIDS: challenges and opportunities | Lancet 2007; 369:708-713

Multiple Sclerosis (MS) linked with Prolactin

2007-02-21T00:28:00.000-05:00

For the first time, researchers from University of Calgary have found scientific basis of MS remission in pregnancy. Animal study involving pregnant mice showed increased level of Prolactin hormone during pregnancy promotes myelin production and thereby protect against demyelinating episodes. Although it is debatable whether prolactin has any potential for MS therapy, scientists expect to conduct clinical trials in coming years.

Ref.:
1. EurekAlert! Feb 20, 2007 post
2. Journal of Neuroscience Feb 21, 2007 issue

Recent update in MS:

FDA Approves Resumed Marketing of Natalizumab (Tysabri) Under a Special Distribution Program - FDA news June 5, 2006

European guidelines on the management of valvular heart disease (VHD)

2007-02-16T21:01:00.000-05:00

The European Society of Cardiology has issued (Jan 26, 2007) its first ever European guidelines on the management of valvular heart disease (VHD). Recommendations are based on EuroHeart Survey data and differ very little from those published by ACC/AHA (USA) recommendations last year. European experts are emphasizing on

Risk stratification among elderly patients to properly guide for surgical interventions,
Use of stress testing to select ideal candidates for intervention among rising pool of asymptomatic cases which are detected because of increase use of echocardiography and
Integrative approach involving patient and other medical disciplines rather single echo-based strategy for disease intervention

Guideline highlights are summarized here (For CME credit, visit links given in Ref.)

Ref.:
1. News source: Hearwire ©2007 Medscape Feb 15, 2007 (get CME here)
2. Guideline availability: Eur Heart J. 2007;28:230-268
3. ACC/AHA 2006 Guidelines for Management of Patients with Valvular Heart Disease - Executive Summary: Guidelines.gov (html), ACC and AHA websites (pdf)

Pulsed Corticosteroids Provide No Further Advantage in Kawasaki Disease

2007-02-15T13:05:00.001-05:00

Clinical trial performed by Harvard physicians showed no significant benefit of corticosteroids in controlling vasculitis associated with Kawasaki disease and long-term coronary complication. Randomized clinical trial revealed patients in the methylprednisolone group did have a shorter initial period of hospitalization (p=0.05) and, at week 1, a lower erythrocyte sedimentation rate (p=0.02), but the two groups had similar numbers of days spent in the hospital, numbers of days of fever, rates of re-treatment with immune globulin, and numbers of adverse events.
"Our data do not provide support for the addition of a single dose of pulsed intravenous methylprednisolone to conventional therapy in the routine primary treatment of Kawasaki disease" - Newburger's statement to HeartWire (Medscape Inc).

Kawasaki disease, an acute idiopathic self-limiting vasculitis that occurs in childhood is most common in Japan, although it affects children of all ethnic backgrounds. About 4000 cases of Kawasaki disease occur in the US each year, and the incidence is on the rise; In fact, it has replaced acute rheumatic fever as the leading cause of acquired heart disease in children in the US and Japan. Coronary artery aneurysms develop in 15% to 25% of untreated children and can lead, over time, to ischemic heart disease. American Heart Association advise long-term follow-up to monitor for coronary involvement in all cases of Kawasaki disease. Intravenous immune globulin therapy plus aspirin has been shown to blunt the acute inflammation and reduce the risk of coronary artery damage, with routine treatment cutting the rate of coronary artery aneurysms detectable on echo to around 5%.

Ref.:
1. Medscape News Feb 15, 2007
2. Newburger et al., Randomized Trial of Pulsed Corticosteroid Therapy for Primary Treatment of Kawasaki Disease - N Engl J Med 2007;356:663-675

Drug-eluting Coronary Stents: Conflicting Evidences and Rising Concerns

2007-02-13T16:51:00.000-05:00

NEJM has published early release articles on safety and efficacy of drug-eluting coronary stents. Majority of articles shows meta-analysis of clinical trials and pivotal studies performed by researchers worldwide using commonly available drug-eluting stents - Cypher (sirolimus-eluting) and/or the Taxus(paclitaxel-eluting). Early release is intended as editors believe the recent concern that the implantation of drug-eluting stents, as compared with bare-metal stents, may be associated with a small increased risk of late stent thrombosis.

Excerpt from NEJM articles:

Significant increase in the rate of stent thrombosis with drug-eluting stents in the period following the initial 12 months post-implantation (defined as late stent thrombosis)
No significant differences in the stent thrombosis rate between drug-eluting and bare-metal stents.
Significant increase in mortality for diabetics who received Cypher (sirolimus-eluting) stents.
No difference between death or myocardial infarction rates for patients who received Cypher stents versus bare-metal stents.
Significant increase in three-year mortality for patients who received drug-eluting stents versus patients treated with bare metal stents.

Although above findings are conflicting with previous pivotal studies and importantly NEJM conclusions are drawn from meta-analysis of often same data by different authors, researchers agreed drug-eluting stents almost eliminate the problem of restenosis and significantly reduce the need for revascularization compared with bare-metal stents.

One of the priority action as suggested by Samin Sharma, M.D., director of the cardiac catheterization laboratory at Mount Sinai Heart Institute in New York is to consider use of anti-platelet agent Clopidogrel (Plavix) first before taking patient for balloon angioplasty, concurrent use of Clopidogrel for intial three years may be helpful preventing late-onset thrombosis of drug-eluting stents.

Alhtough FDA advisers in last December agreed that drug-eluting stents are both safe and effective when used in stable patients with single-vessel disease, it remains uncertain about long-term safety and efficacy of such stents.

Ref.:
1. N Engl J Med: Early Release Articles (Published online on Feb 12, 2007,ahead of print publication date: march 8, 2007 issue)
2. MedPageToday.com report: Drug-eluting Coronary Stents-A Wealth of Data and Little Agreement

Updated - Recommended immunization schedules for children and adolescents: United States, 2007

2007-02-12T14:35:00.000-05:00

American Academy of Pediatrics Committee on Infectious Diseases and Centers for Disease Control and Prevention have updated Recommended immunization schedules for children and adolescents:The changes to the previous childhood and adolescent immunization schedule, published January 2006, are as follows:

* The new rotavirus vaccine (Rota) is recommended in a 3-dose schedule at ages 2, 4, and 6 months. The first dose should be administered at ages 6 weeks through 12 weeks. With subsequent doses administered at 4 to 10 week intervals. Rotavirus vaccination should not be initiated for infants aged >12 weeks and should not be administered after age 32 weeks.
* The influenza vaccine is now recommended for all children aged 6 to 59 months.
* Varicella vaccine recommendations are updated. The first dose should be administered at age 12 to 15 months, and a newly recommended second dose should be administered at age 4 to 6 years.
* The new human papillomavirus vaccine (HPV) is recommended in a 3-dose schedule with the second and third doses administered 2 and 6 months after the first dose. Routine vaccination with HPV is recommended for females aged 11 to 12 years; the vaccination series can be started in females as young as age 9 years; and a catch-up vaccination is recommended for females aged 13 to 26 years who have not been vaccinated previously or who have not completed the full vaccine series.
* The main change to the format of the schedule is the division of the recommendation into two schedules: one schedule for persons aged 0 to 6 years and another for persons aged 7 to 18 years. Special populations are represented with purple bars; the 11 to 12 years assessment is emphasized with bold, capitalized fonts in the title of that column. Rota, HPV, and varicella vaccines are incorporated in the catch-up immunization schedule.

Updated guidelines and convenient tables are provided at CDC website (link). Tables reproduced here for information of health care professionals only.

Ref.:
1. Guidelines.gov ID:10393
2. Human papillomavirus vaccine (HPV) - Gardasil Prescription Information from Merck Inc.
3. FDA Safety Alert on Menactra (Meningococcal Conjugate Vaccine A, C, Y, and W135 from Sanofi Pasteur Inc.): Reports of Guillain Barre Syndrome (GBS) associated with vaccine use.

Click images to enlarge:

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