Drugs & Discovery in Central Nervous System Diseases

By: Pharma Tips | Views: 3898 | Date: 30-Mar-2013

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.

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.

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 Neuro scientists Summit at Indo-American Hospital, Vaikom, Kerala on March 3rd 2012
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