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June 07, 2012

Brugada Syndrome: EKG findings

You always hear about it when working up syncope and sudden cardiac arrest in young patients, but it's so easy to forget what it looks like on EKG. We so rarely see it... or DO we?!
This Brugada Syndrome is to help emblazon these EKG tracings in our mind, so that we don't miss the subtle findings which place a patient at risk for sudden cardiac death. Pay special attention to Type 1, which is most specific for Brugada Syndrome.
Brugada Syndrome
  1. Genetically linked, cardiac sodium channelopathy
  2. High risk for sudden death in young, healthy adults because VTach/VFib
  3. Mean age of sudden death = 41 ± 15 years
  4. Higher prevalence in males and Asian descent
  5. Atrial fibrillation associated in 10-20% cases
EKG findings: 3 types
Type 1 – Most specific for Brugada Syndrome
    – Highest risk for symptoms of syncope and sudden death
Differential diagnosis:
  • After electrical cardioversion 
  • Arrhythmogenic RV dysplasia 
  • Atypical right BBB
  • Acute MI, esp RV infarct
  • Acute myopericarditis
  • Compression of RV outflow tract 
  • Disorders of central/auton nerv systems 
  • Dissecting aortic aneurysm
  • Duchenne muscular dystrophy
  • Friedreich ataxia 
  • Early repolarization, especially in athletes 
  • Hypothermia
  • Pericardial effusion 
  • Pulmonary embolism
  • Left ventricular hypertrophy 
  • Mediastinal tumor 
  • Pectus excavatum 
Treatment:
Implantable cardiac defibrillator for Brugada Type 1 PLUS:
  • Aborted sudden cardiac death
  • Syncope, seizure, or noctural agonal respirations without alternative cause
  • Family hx of sudden cardiac death (likely from Brugada) AND positive EPS study
  • A positive EPS study
-- Otherwise: close followup with cardiologist
by
AKSHAYA SRIKANTH
Pharm.D
India

June 05, 2012

SEROTONIN SYNDROME

Serotonin syndrome is a potentially life-threatening adverse drug reaction that may occur following therapeutic drug use, inadvertent interactions between drugs, overdose of particular drugs, or the recreational use of certain drugs. Serotonin syndrome is not an idiosyncratic drug reaction; it is a predictable consequence of excess serotonergic activity at central nervous system (CNS) and peripheral serotonin receptors.It may also be called serotonin storm, hyperserotonemia, or serotonergic syndrome.
The excess serotonin activity produces a spectrum of specific symptoms including cognitive, autonomic, and somatic effects. The symptoms may range from barely perceptible to fatal. 
The symptoms are often described as a clinical triad of abnormalities:
  • Cognitive effects: headache, agitation, hypomania, mental confusion, hallucinations, coma
  • Autonomic effects: shivering, sweating, hyperthermia, hypertension, tachycardia, nausea, diarrhea.
  • Somatic effects: myoclonus (muscle twitching), hyperreflexia (manifested by clonus), tremor.
Numerous drugs and drug combinations have been reported to produce serotonin syndrome.
 OTC Medications or Supplements:
  • l-tryptophan
  • Chlorpheniramine (an antihistamine for allegies)
  • Dextromethorphan (a cough suppresant)
  • St. John's Wort (an herb, sometimes used for depression)
Prescription Medications:
  • Cyclobenzaprine (a muscle relaxer)
  • SSRI Antidepressants (e.g. citalopram, fluoxetine, sertraline)
  • SNRI Antidepressants (e.g. Cymbalta, Effexor, Pristiq)
  • Clomipramine (an antidepressant)
  • Imipramine (an antidepressant)
  • Meperidine (for pain)
  • Methadone (for pain)
  • Tramadol ( for pain)
  • Trazodone (an antidepressant, sometimes used for sleep)
  • MAO Inhibitors (e.g. isocarboxazid, phenylzine, selegiline)
  • Linezolide (an antibiotic)
  • Migraine medications known as "triptans" (e.g. Imitrex, Amerge, Axert, Relpax, Zomig)
  • Lisergic Acid Diethylamine
  • methylenedioxymethamphetamine
I would emphasize that the likelihood of serotonin syndrome while taking just 1 of these at normal dosages if very rare. At inappropriately high doses though, or in combination, the potential if far more likely.
Diagnosis of serotonin syndrome includes observing the symptoms produced and a thorough investigation of the patient's history. The syndrome has a characteristic picture but can be mistaken for other illnesses in some patients, particularly those with neuroleptic malignant syndrome. No laboratory tests can currently confirm the diagnosis.
Treatment consists of discontinuing medications which may contribute and in moderate to severe cases administering a serotonin antagonist. An important adjunct treatment includes controlling agitation with benzodiazepine sedation.
by
Akshaya Srikanth
Pharm.D Resident
India

June 04, 2012

Drugs and Discovery in Central Nervous System Diseases

 It has generally been believed over the last several decades that communicable diseases are the major problems of poor and economically backward developing countries , notably in Africa, Asia and Latin America. While in terms of population, they constitute over 75 per cent of the world’s population of 6.2 billion, in terms of resources they contribute a meagre 20 per cent. 
The fact  that today, 90 per cent of the world’s resources are used by 10 per cent of the world’s affluent population calls for a rethinking of ways and means for  ensuring a balance between needs and available resources. Diseases such as infections of bacterial, viral and fungal aetiology, as well as of  those of intestinal parasites have over the years been major causes of morbidity and mortality in these countries. 
Much progress has been attained in these areas through multiple interventions including improved public health services, higher nutritional status, vector control measures  , prophylactic approaches such as vaccinations and equally importantly appropriate medicines. Through a combination of such approaches, small pox has been eradicated and polio, guinea worm, filariasis and cholera have been on the way out .  Pulmonary TB. Malaria and respiratory diseases and pneumonia are still major killers. While  some of the recent new diseases such as Avian Flu, Swine Flu, SARS and various new mutant strains of haemophilus influenza, dengue, leptospirosis, chiken gunea etc  had threatened to result in epidemics, that has not happened. In fact even the incidence of the dreaded HIV/AIDS has plateaued, particularly in countries which had access to  the  cocktail of anti retroviral drugs. 
While  all  these  communicable  diseases still are cause for concern in developing countries, what has been of even greater worry and more alarming, is the rising incidence of non-communicable diseases. On the top of the list of these diseases are ischemic heart disease, diabetes and other metabolic disorders, mental diseases, stroke,   genetic and auto immune disorders and a  variety of cancers affecting different parts and tissues of the body. 
Accidents of diverse nature, most notably motor accidents and those that occur at the work place result in large number of trauma cases leading to  chronic disabilities and heavy dependence by patients on others to manage even day to day chores. The chronic nature of these ailments and their impact and the  increase in their incidence in younger populations particularly in countries like India, have put a very heavy  social and economic burden on society in general. In the absence of universal insurance in India, over 70 per cent of the costs of treatment are borne by the patients themselves.

Diseases of the central nervous system
Health management of CNS diseases including their control, cure and elimination including  of   congenital neurological abnormalities,  most of which today can be detected in-utero, through amniocentesis and ultrasound has become a major issue for healthcare planning and implementation. They arise out of  various pathophysiological conditions as well as degenerative processes. 
Conditions of epilepsy, depression, anxiety, neurosis,  chronic pain, schizophrenia, migraine, insomnia, Parkinson Disease, Alzheimers disease, Senile Dementia, Muscular Dystrophy, Myasthenia gravis, Multiple sclerosis and tumours in the brain and spinal cord affect millions of people the world over. Even for India the  incidence  of  one  or  more  of  the  above in the general population,  who require treatment and care has been estimated at 10 to  20 per thousand.   
According   to   WHO,   depression  is likely to be the   largest disease in terms of morbidity in another decade. It affects at some time  or the other, 1 out of 5 women and 1 out of 12 men . Effective remedies for many of these whether through surgery, radiation  or chemotherapy or a combination of one or more of these, are still unsatisfactory in many cases, even though  early detection can provide better management and longer life. 
Most of these diseases being chronic, life long treatment becomes mandatory and due to many adverse reactions of the drugs and increasing resistance to the drug with consequent use of higher doses,  patients’ quality of life suffers. The economic burden on the patient is also often unbearable. In the U.S. alone, there are an estimated 5.3 million people with Alzheimers diseases and  the overall cost of this alone to society is stated as $ 172 billion. Similar is the case with most countries in the World. While figures on the burden of these diseases is available their economic burden on society in India is not has not been precisely evaluated.
An analysis of the burden of diseases in India as Disease Adjusted Life Years (DALYs) shows that under the category of non-communicable diseases, mental illnesses  are second only to cardiovascular diseases in terms of morbidity. Numbers have been quoted as high as 66 million in India constituting > 6% of the population. Their aetiology can be traced to a variety of factors ranging from, traumas and accidents, infections of bacterial, viral and fungal origins,  congenital or structural defects in the brain, stroke, tumours, autoimmune disorders and genetic factors.
Social and environmental factors including  broken homes, erosion of values, disappearance of the joint family systems, rapid urbanisation, environmental pollution and an ageing population  have all contributed to increase  in mental ailments.  
The problems of mental disorders is further compounded by lack of awareness among the public,  of the nature of the disorders, their manifestations and ability to manage the impact of the disease on the patients’ behaviour patterns  and  the social stigma attached to them even among close family circles.
The treatments available are less than adequate in most cases and in addition  the adverse reactions the drugs produce are often unacceptable. With little understanding of the disease processes and their causative factors attempts to discover appropriate therapy have been largely unsuccessful. 
The disciplines of CNS pharmacology, neurobiology and neurochemistry have evolved only during the last six decades; so too research efforts. The approaches to discovery of drugs have  been largely empirical since very little was known about the physiological and biochemical pathways leading to the diseases and their progression. In spite of considerable progress during the last 50 years  in our understanding of the brain and its functioning, drug discovery for CNS disorders continue to be at the cross roads. So far the massive investments in R&D for CNS drug discovery research has not paid off.
Drugs for CNS disorders
While treatment  with drugs for many of CNS disorders , even if they are not fully satisfactory, are available, most of them are palliative and do not address the causative factors or offer any mid or long term solutions. In the history of drug development, one of the  problems has been related to lack of understanding of the diseases processes , the mechanisms of their origin and progression and the absence of appropriate in-vitro or animal models.
Through an approach of hit and miss, aided with serendipity, a number of early drugs   such as phenothiazines, tricyclic anti depressants. MAO inhibitors and benzodiazepines were discovered.  Imipramine, Amitryptylline, Haloperidol,  Tranylcypromine, Librium, Valium, Lithium and others were some of  the first CNS drugs which had major impact not only on the diseases themselves but also on  evolution of CNS pharmacology and understanding of drug action. The distinction between minor and major tranquillisers was clinically useful for determining treatment modalities, so too appropriate treatments for different types of epilepsy.  Subsequently , a  large  number  of  drugs based on the above structural types ,  many  of  them “me-too” ,  with marginal advantages over the earlier ones, were developed  and marketed for conditions of depression, mania and even schizophrenia. 
During the period,  mid sixties to eighties, the golden era for new drug discovery, a better understanding of disease processes and the functioning of the brain led to  some major breakthroughs with the discovery of the role of brain amines, neurotransmitters and selective serotonin uptake inhibitors on CNS disorders. The role of dopamine in Parkinsons disease and the mechanisms of the progression of the disease  led to the development of enzyme inhibitors and replacement therapy. 
Carbamazepine initially discovered and developed for trigeminal neuralgia was later found to be the drug of choice for epilepsy.
New drug discovery for CNS diseases
It is obvious that there have been very few major discoveries in the area of CNS drugs during the last decade. The number of new drugs for all indications approved per year have been around 20 – 25 during the last decade and  2011 recorded the highest number in recent times of 34. Apart from the fact that number of  new CNS drugs approved have been very low, drugs with truly novel mechanisms of action have been even rarer. The reasons are:
CNS diseases’ pathophysiology is still not adequately understood
Pre-clinical models  are not readily available and if available may not be valid . They may not address the problems of the heterogenous nature of these diseases in humans.
Poor understanding of neurotransmitter receptor pharmacology
Issues of pharmacokinetics affecting drug’s efficacy and safety.  Even though target identification, biomarkers, functional genomics and proteomics are used for drug discovery, results have not been commensurate with efforts.
Overcoming the blood brain barrier for effective delivery of drugs at the target sites.
Possible approaches
The complexity and low innovative potential for discovery of new drugs for CNS, requires radically new approaches, if success is to be achieved in this area. Already the statistics are depressing. A TUFTS University study revealed that it takes an average of 18 years from bench to bedside to come out with one new drug in this area compared to 10 years for other therapeutic areas. Only 8.2 per cent of them survive after approval compared to 15 per cent in other disease areas. Estimated cost of a new drug (which includes the cost of failures) is over $ 2.3 billion. Less than half of the CNS drug candidates which reach Phase III trials survive that phase and get approved by the Regulatory Agencies.
Approaches for improving the Probability Of Success (POS) of new drug discovery would be to learn from the experiences of the past, e.g., of drugs so far developed for depression, schizophrenia, Parkinson’s disease etc and revisit those examples to gain a foothold on new modalities. Even though resorting to modern concepts such as the use of dedicated targets and biomarkers, functional genomics and proteomics are yet to deliver new drugs with novel mechanisms of action, that approach offers promise and needs to be vigorously followed in coming days.
Understanding disease pathology has led to the development of targets for CNS disorders. Such novel targets or target pathways represent a huge challenge when it comes to their validation to understand their relevance. Whether the ligand (candidate drug) engages the target in the Central Nervous System in humans and  if so, to what extent, is the basic question. To some extent, PET imaging of the brain could be a valuable tool in such studies.
There have been major attempts in recent times to have an integrated and where feasible, a collaborative approach to discover drugs  for two of the most   debilitating  CNS   diseases ,  Alzheimers    disease   and   Parkinsons disease. The Neuroimaging initiative and Parkinson’s biomarker initiative are programmes aimed at improving the probability of success in the drug discovery programmes for these diseases. 
In the case of Alzheimers, important features of disease pathophysiology that  could be therapeutic targets, have been identified such as levels of amyloid beta, the main constituent of amyloid plaques as a disease marker. The strategy then is to decrease AB levels by inhibiting AB aggregation and clearing AB from brain. Unfortunately validation in animals may have little relevance and validation through clinical trials have many problems , in addition to raising  many ethical issues.
Conclusion
Research in the area of discovery of new drugs for CNS disorders, with novel mechanisms of action is at the crossroads. In spite of massive investments, breakthrough drugs are still to emerge. In view of the enormous complexity of the process itself and the very low Probability Of Success (POS) , many pharmaceutical companies which have been active in the area  are steadily reconsidering their involvement, if not moving out of this area. That is unfortunate since with the current epidemiological , demographic and age distribution  patterns  among the population, evolving around the  world , management, control and cure of many of these chronic ailments should be  high priority   in terms of medical needs .
For success to be achieved, more understanding at the basic level of the  functioning of the brain, diseases of the brain and possible and relevant pathways which make every part of the brain function optimally and in unison is needed. Translation of the basic knowledge into designing and providing practical approaches and products  for preventive and curative outcomes are needed, if  major advances in the management of CNS disorders are to be achieved.
This raises an important question for serious consideration and development of new strategies and approaches for the management of at least some of the major chronic mental ailments. Can we take a serious look at the time tested traditional systems of medicine such as Ayurveda to see whether they could indeed contribute towards finding new and complementary treatment modalities?
Source:This article is based on a presentation at the International Neuroscientists Summit at Indo-American Hospital, Vaikom, Kerala on March 3rd 2012
by
Akshaya Srikanth
Pharm.D Resident
India

June 03, 2012

Prospects for clinical research industry in India

After more than a decade’s experience in participating in global clinical research, India has firmly established itself  as an emerging destination for global biopharmaceutical companies. India’s success story has been aided by uniquely differentiating factors which are well documented including a huge and growing disease burden, diseases unique to the region,  medical expertise, transforming healthcare market manifested by growing infrastructure and technology,  significant and diverse population, talented resources and an enabling regulatory environment that has swiftly adapted itself to global standards. The last decade saw these advantages being gradually translated from a foreseen business potential into reality. 
Recently, there have been mixed developments influenced by an evolving regulatory and legal framework, and adverse media reports, that have placed India’s clinical research in the limelight.   Product patent requirements that India has signed as a part of the TRIPS agreement make it  imperative for India to innovate and introduce products that are relevant to the country. The disease profile and burden of our population is also transforming from communicable diseases, rampant in the past, to lifestyle disorders in addition to certain neglected diseases. Hence, in many ways, we are now globalized even from a health stand point, which necessitates us to innovate and propagate clinical research to help alleviate the unmet health needs of India. 
On the regulatory front, there have been developments which have evoked a lot of response from industry stakeholders. The issue of compensation, which has been a  grey area for long, is now receiving much desired attention. The initiative by the Ministry of Health to engage various stake-holders in discussions on the draft compensation guidelines is a welcome move. The industry, academia and all relevant stakeholders agree and believe in-principle to compensate clinical research participants. A comprehensive framework on compensation will help plug the hole on a highly contentious issue.
The appointment and constitution of New Drug Appraisal committees (NDAC) to assist in reviewing clinical research proposals across therapeutic areas is a good initiative in strengthening  the technical review process by regulatory authorities  and has been well received by the industry. The time to review and comment is  expected to normalize once the process becomes well oiled. 
The recent media reporting and activism against clinical research has significantly impacted the decision making and future plans of various stakeholders in the clinical research industry. The intentions in most cases may be noble, but misconceptions and misreporting  have triggered  knee-jerk reactions that have led to unpredictability in decision making. Despite the clinical research journey in India being about 15 years, the industry has evolved significantly and has a fairly robust framework in place for the conduct of clinical trials.
 If anything, the recent turn of events have led to fortifying the fundamentals of conducting clinical research in India with the industry stepping up the ante on compliance, quality and zero tolerance towards unethical practices at sites and often going beyond their roles and responsibilities in doing so. Many of the sites have put in additional resources, procedures and processes to ensure that there is consistency and scalability in doing multiple projects. The depth of scrutiny and review of proposals by regulatory authorities is instilling more confidence amongst stakeholders, including sponsors and patients.  
Given the existing strong fundamentals in India and lessons learnt, it is reasonable to say that some of the current setbacks are temporary and that the clinical research paradigm will equilibrate to a better and balanced one in the near term future. 
The global biopharmaceutical industry is at an inflection point with rising costs and dwindling research pipelines. This is further compounded by the 2015 patent cliff when a significant number of molecules go off-patent. One of the big emerging opportunities for India is in the biosimilars space.  Indian biopharma companies are already partnering with global CROs, thereby reversing trends in global clinical development. 
The US FDA’s recent endorsement of risk-based approach to monitoring vide the draft monitoring guidance is expected to change the monitoring paradigm in the future. The single approach that was applied uniformly across all geographies and sites irrespective of the risk criteria could cease and be replaced with a smarter methodology of applying increasing or decreasing monitoring efforts depending on a variety of risk factors like geographies, type of sites, maturity of sites, compliance levels, previous track records and so on. 
Technology will be increasingly used as a driving force to develop services and solutions and we are already seeing this at Quintiles through Quintiles Infosario®, a comprehensive, fully integrated suite of data-driven services that enables optimized drug development. Given the technical expertise and skilled manpower available in India, we have the advantage in being an early adopter and driver in these technology-enabled services and to be able to service global needs in this domain.
India’s advantage in business processes has already been leveraged in preclinical services like data management and pharmacovigilance. This is expected to grow at a healthy rate in future as well. New models of engagement and outsourcing will emerge to  create a more efficient and effective delivery system.
Efforts to enhance communication to sites and patients as well as simplifying management of clinical studies at the hospitals has opened up new avenues for technology solution development, which requires a combination of experience in clinical research as well as software solution development. 
Central laboratory and related analysis for standardized safety testing is another area that will evolve  with the growth of clinical trials in India. The current offering by  central labs will have to move upstream in being able to perform sophisticated analysis of unconventional biomarkers. India in the past has always prided itself on replicating complex wet lab analysis. In the clinical research arena, complex tests that have been retained in western geographies could be expected to move East to countries like India and China.
Every difficult situation can be viewed as a problem or an opportunity. In the current environment of increased regulatory, legal and media related challenges, there will be avenues where entrepreneurs will convert challenges into opportunities. 
It will be fair to say that though there are temporary challenges in clinical research, the outlook in the medium to long term is bright given the strong fundamentals in this domain. When this happens it will open up opportunities on multiple fronts which will not be on the same template witnessed in early 2000.
India has every opportunity to rise stronger and become a region of excellence in multiple areas.
Source: PB
by
Akshaya Srikanth
Pharm.D Resident
India