Indian Journal of Pharmaceutical Education & Research

Indian Journal of Pharmaceutical Education & Research

ijper Vol. 41(4), Oct – Dec, 2007

PAST EDITORS

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Dr. Nagavi B.G. Mysore 1997 - 2006 Dr. Rao M.N.A. Manipal 1995-1996 Dr. Gundu Rao P. Manipal 1985-1995

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Dr. Kasture A.V. Nagpur 1981 - 1984 Dr. Saoji A.N. Nagpur 1980 - 1980 Dr. Lakhotiya C. L. Nagpur 1979 - 1980

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Dr. Chopde C.T. Nagpur 1978 - 1978 Dr. Gundu Rao P. Manipal 1975 - 1978 Dr. Mithal B. M. Pilani 1967 – 1974

EDITOR–IN–CHIEF

Dr. Sanjay Pai P.N. [email protected]

ASSOCIATE EDITORS Dr. Srinivasa Murthy [email protected]

Dr. Mallikarjuna Rao C. [email protected]

Dr. Kulkarni P.K. [email protected]

Dr. Mueen Ahmed K. K. [email protected]

EDITORIAL OFFICE INDIAN JOURNAL OF PHARMACEUTICAL EDUCATION AND RESEARCH The Official Publication of Association of Pharmaceutical Teachers of India H.Q.: Al-Ameen College of Pharmacy, Opp. Lalbagh Main Gate, Hosur Road, Bangalore 560 027, INDIA Mobile: 91-9448207428 | 91-9242898028 | 91-9845655732 | 91-9880423041 | 91-9448445612 Fax: 080-22225834; 080-22297368 email: [email protected] | Website: www.ijper.org


ijper Vol. 41(4), Oct – Dec, 2007

EDITORIAL ADVISORY BOARD Dr. Betgeri G.V., USA. Dr. Mrs.Claire Anderson, UK. Mr. Frank May, USA. Dr. Gaud R.S., Mumbai. Dr. Goyal R.K., Ahmedabad. Dr. Harkishan Singh, Chandigarh. Dr. Hukkeri V.I., Bangalore. Dr. Jagdeesh G., USA. Dr. Katare O.P., Chandigarh. Dr. Khar R.K., New Delhi. Dr. Madan A. K., Rohtak. Dr. Madhusudhan Rao Y., Warangal. Dr. Manavalan R., Annamalai Nagar. Publication Committee • Pharmaceutics

Dr. Miglani B.D., New Delhi. Dr. Murthy R.S.R., Vadodara. Dr. Nagavi B.G., Dubai. Dr. Pulok K Mukherjee, Kolkata. Dr. Rao M.N.A., Hyderabad. Dr. Ravi T.K., Coimbatore. Prof. Shivananda B.G., Bangalore. Dr. Shivakumar H.G., Mysore Dr. Subrahmanyam C.V.S, Hyderabad. Dr. Suresh B., Ooty. Dr. Tipnis H.P., Mumbai. Dr. Udupa N., Manipal. Dr. Vyas S.P., Sagar.

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• Pharmaceutical Chemistry and Analysis • Pharmacology

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• Pharmacognosy

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• Pharmacy Practice

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• Pharmaceutical Education

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• Pharmaceutical Marketing

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Dr. Paradkar A.R., Dr. Sarasija Suresh, Dr. Vavia P.R. Dr. Gopal Krishna Rao, Dr. Raghurama Rao A. Dr. Valliappan K. Dr. Krishna D.R., Dr. Kshama Devi, Dr. Sreenivasan B.P. Dr. Ganapaty S., Dr. Salma Khanam, Dr. Swati S.Patil Dr. Nagappa A.N., Dr. Rajendran S.D, Dr. Shobha Rani R.H. Dr. Raman Dang, Dr. Unnikrishnan M.K., Dr. Bhise S.B. Dr. Burande M.D., Dr. Gayathri Devi S., Dr. Kusum Devi V.

Note : The Editor does not claim any responsibility, liability for statements made and opinions expressed by authors. INDIAN JOURNAL OF PHARMACEUTICAL EDUCATION AND RESEARCH The Official Publication of Association of Pharmaceutical Teachers of India H.Q.: Al-Ameen College of Pharmacy Opp. Lalbagh Main Gate, Hosur Main Road, Bangalore - 560027 INDIA Mobile : 91-9448207428 | 91-9242898028 | 91-9845655732 | 91-9880423041 | 91-9448445612 Fax: 080-22225834; 080-22297368; email: [email protected] | Website : www.ijper.org


ijper Vol. 41 (4), Oct– Dec, 2007

CONTENTS Editorial Review Articles • Huntington’s Disease: A Review Puneet Kumar, PS Naidu, SSV Padi and Anil Kumar...........................................................................287-294 • Gastric Floating Drug Delivery Systems: A Review Gangadharappa.H.V., Pramod Kumar T.M and Shiva Kumar H.G…………………..........................295-305 • In vitro-In vivo Correlation: A Ground Discussion Kalaskar S. G., Yadav A. V and Patil V. B…………………………………………..................................306-318 Research Article • Formulation and in vitro evaluation of taste masked orodispersible dosage form of Levocetirizine dihydrochloride Chaudhari P.D, Chaudhari S.P., Lanke S.D. and Patel Nakul.............................................................319-328 • A study on the effect of different polymers on frusemide loaded calcium alginate micropellets prepared by ionotropic gelation technique Ghosh Amitava, Nath L.K, Dey B.K and Roy Partha............................................................................329-336 • Phytochemical investigation and Immunomodulator activity of Amaranthus spinosus linn. Tatiya A.U., Surana S.J., Khope S.D., Gokhale S.B and Sutar M.P………………..…..........................337-341 • Pharmacodynamic drug interaction of mexiletine with tolbutamide in rats S. Satyanarayana, M. Nitin and K. Prasad...........................................................................................342-346 • Validated, Reversed Phase High Performance Liquid Chromatography Method for the Estimation of Etoposide in Bulk and Formulations Movva Snehalatha, Bende Girish, Kolachina Venugopal and Ranendra N. Saha...............................347-352 • Spectrophotometric Estimation of Bisoprolol Fumarate in Bulk Drug and Tablets Akmar Sandip, Paramane Sonali, Kothapalli Lata, Thomas Asha, Jangam Sumitra, Mohite Mukesh and Deshpande Avinash...............................................................................................................................353-357 • Preparation and in Vitro Evaluation of Mucoadhesive Microcapsules of Atenolol Swamy P.V., Hada Amit, Shirsand S.B., Hiremath S.N and Raju S.A...................................................358-364 • Evaluation of Analgesic activity of root tuber of Curculigo orchioides Gaertn. V. Madhavan, Joshi Richa, Murali Anita and S.N. Yoganarasimhan...................................................365-368 • Effect of Eclipta alba Linn on learning and memory in rats G.P.Rajani and KVSRG Prasad............................................................................................................369-372 • Application of Hibiscus Leaves Mucilage as Suspending Agent Edwin Jarald, Edwin Sheeja, Dosi Shweta, Amal Raj and Gupta Smita..............................................373-375 • The New Patent Regime – Implications for Indian Pharma Industry K.Madhavi.............................................................................................................................................376-382

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Marketing and Advertising of Prescription and Over the Counter (OTC) Products – Ethical Issues Manthan D.Janodia and Udupa N……………………………………………………….............................383-387 Development and Evaluation of Propranolol Hydrochloride Transdermal Patches by using Hydrophilic and Hydrophobic Polymer Dey B.K, Nath L.K, Mohanti B and Bhowmik B.B…………………………………….............................388-393 Free Radical Scavenging Activity of Ficus Racemosa roots Surendra Kumar Sharma and Vivek Kumar Gupta..............................................................................394-396 INSTRUCTIONS TO AUTHORS -2008

Editorial The APTI 12th Annual National Convention at Chandigarh was an opportunity for the Pharmacy teachers and educationalists to deliberate upon many issues facing them in the wake of globalization. The emergence of a globalized world underscoring a framework of competition, and coupled with the pressures of an exploding knowledge base has given birth to new challenges. It was time for introspection and gave an occasion to think of the current developments in technological innovations, manufacturing practices and health trends. Are the recent trends in pharmaceutical sciences a part of our curriculum? If the pharmaceutical education imparted to our learners is not revised periodically with the change in time, the consequences are going to be mind boggling. Concerns were raised on disharmony of curriculum content on global levels. Disparity in the pharmaceutical knowledge horizon pertaining to biotechnology, genomics, disaster management and polymer sciences have started creating vacuum in the knowledge base of our students. They are not in a position to compete with their counterparts at the global level. The challenges are complicated further with the amendments to Patent laws. More focus now needs to be laid on new drug discovery and R&D programmes. Have we generated the platforms for our students to work in these areas? Do we have adequate facilities to promote world-class research, train world-class scientists, regulatory officials and managers for the drug sector? How many universities and departments in the country have opportunities to collaborate with foreign research/ teaching institutes and industries? I am sure the situation is not encouraging. It is also quite alarming to know further that the number of pharmacy colleges in the country is growing at an alarming rate. Are these institutions of learning equipped with proper infrastructure? Are we in a position to supply quality teaching staff for these institutions? Are the teachers appointed in such large numbers competent enough to facilitate proper training to the students? The knowledge dissemination consistent with the country’s growth and opportunities should be the top most priority of the teachers. Nurturing, retaining and hiring such excellent faculty is the back bone for an institution. The paradigm shift of achieving the objective to produce a ‘seven star pharmacist’ has now made a beginning in our country after the Vancouver declaration in 1997 (preparing the future pharmacist) with the introduction of Pharm. D programme. In reality, time is now ripe enough for our graduate course curriculum to adorn a new look consistent with the global needs. The new generation pharmacy teachers should now give the best of their time and energy to critically identify the issues which need to be addressed, in order to enhance effectiveness and efficiency in student learning. Teachers should take stock of the current curriculum, identify demand-supply gaps in terms of skill development like information, communication and technology (ICT) and address these issues on a war footing. It is necessary that we should respond to changing realities. Responsibilities need to be redefined; teachers become more empowered and should equip themselves to face emerging challenges. As the country is moving closer towards becoming a knowledge centre, quality education has become determinate for the well being of one and all. Let us all come together and make India a better place to groom the next generation pharma professionals. In this era of fiery competitiveness, the catch word is – PERFORM or PERISH. Dr. Sanjay Pai P.N. Editor-in-Chief

Indian J.Pharm. Educ. Res. 41(4), Oct – Dec, 2007

APTI

ijper Huntington’s disease: A Review Puneet Kumar, PS Naidu, SSV Padi and Anil Kumar* Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh-160014, India. Email: [email protected]

Abstract Huntington's disease (HD), inherited genetic disorder is characterized by abnormal body movements called chorea, and cognative dysfunction. George Huntington, Ohio physician described it precisely in 1872. HD is a dominantly inherited disorder characterized by a progressive neurodegeneration of the striatum that also involves other regions, primarily the cerebral cortex. The mutation responsible for this fatal disease is an abnormally expanded and unstable CAG repeat within the coding region of the gene encoding huntingtin. The pathogenic mechanisms by which mutant huntingtin cause neuronal dysfunction and cell death remain uncertain. HD is considered as important disease, embodying many of the major themes in modern neuroscience, including molecular genetics, selective neuronal vulnerability, excitotoxicity, mitochondrial dysfunction, apoptosis, and transcriptional disregulation. A number of recent reports concluded that oxidative stress plays a key role in the pathogenesis of HD. Although there is no treatment to fully stop the progression of the disease, there are treatments available to help control the chorea. The present review deals with the pathophysiology and current drug treatment options and future therapeutic interventions for HD. Present review focuses on the animal models (behavioural and genetic) emplyoed for unraveling pathogenetic mechanisms and identification of novel drug targets. Key words- Excitotoxicity, Gait abnormalities, Huntington’s disease, Memory, Oxidative stress, INTRODUCTION Huntington's disease is a genetic, progressive, neurodegenerative disorder characterized by the gradual development of involuntary muscle movements affecting the hands, feet, face, and trunk and progressive deterioration of cognitive processes and memory (dementia). Neurologic movement abnormalities may include uncontrolled, irregular, rapid, jerky movements (chorea) and athetosis, a condition characterized by relatively slow, writhing involuntary movements 1-2 . Dementia is typically associated with progressive disorientation and confusion, personality disintegration, impairment of memory control, restlessness and agitation. In individuals with the disorder, disease duration may range from approximately 10 years up to 25 years or more. Life-threatening complications may result from pneumonia or other infections, injuries related to falls, or other associated developments 3-4.

HISTORY HD has rich historical literature stretching back well over a century and involves some of the most prominent figures in medicine and neurology. The description by George Huntington in 1872 of the disease that has subsequently borne his name is one of the most remarkable in the history of medicine 5, 6. Until recently the history of research on HD has been one of gradual progress rather than of sudden leaps. Initially development in this area arose from the illness of Woody Guthrie, the American folk singer, who developed HD symptoms around 1952 and died in 1967 at the age of 55. His widow Marjorie devoted the later part of her life for promoting all aspects of HD. Now a day’s number of HD research groups is working on this disease 7. EPIDEMIOLOGY Huntington’s disease is currently found in many different countries and ethnic groups around the world. There are varying rates of prevalence in different racial groups 2. HD has a worldwide prevalence of five to

Indian Journal of Pharmaceutical Education & Research Received on 06/11/06; Modified on 13/3/2007 Accepted on 4/6/2007 © APTI All rights reserved

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eight per 100,000 people with no gender found in Europe and countries of European origin. The lowest frequencies are documented in Africa, China, Japan, and Finland. In the USA Estimates of the prevalence of HD range from 4.1-8.4 per 100,000 people. In the United States, it is estimated that 25000 individuals have HD with another 125,000 individuals at risk 8. In India: A recent study on the distribution of C-A-G repeats in the normal population suggests a higher prevalence of HD in India closer to that seen in Western Europe. Based on the results, haplotype analysis suggested the presence of a founder mutation in a subset of families and provide evidences for multiple and geographically distinct origins for HD mutation in India 9. One of the studies conducted on 124 (94 male and 30 female) elderly patients (aged more than 60 years) in a teaching hospital in India reported that there were 2.4% cases of HD, Parkinson's disease in India9. NEUROPSYCHOLOGICAL AND NEUROPSYCHIATRIC ASPECTS OF HD HD, an inherited neurodegenerative disease, damages specific areas of the brain resulting in movement difficulties as well as cognitive and behavioral changes. The cognitive changes in HD have traditionally been referred to as dementia. People with HD have specific and characteristic cognitive difficulties, with other aspects of cognitive function remaining well preserved. Behavioral changes are a characteristic feature of HD and are often the most distressing aspect of the condition for individuals and families dealing with HD8. Behavioral changes associated with HD Psychomotor function - Early motor signs of HD typically include the gradual onset of clumsiness, balance trouble, tremor and brief random, fidgeting movements. The primary involuntary movement abnormality and often the earliest symptom, is chorea or choreoathetosis, continuous and irregular writhing and jerking movements 10. Many HD patients develop a distinctive manner of walking (gait) that may be unsteady, disjoined, or lurching as disease progresses 11, 12 . Frustration, Irritability, Aggression & AnxietyPeople suffering from HD may remain even-tempered; others may lose the ability to control their emotions.

preponderance. The highest frequencies of HD are Emotional volatility may evident in increased irritability or episodes of explosiveness 10. These individuals may become irritable, frustrated or aggressive if demands are not met. Anxiety, a behavioral symptom of HD, is characterized by nervousness, restlessness, fidgeting, shallow breathing, sweating, fear, and panic rapid heart rate 13. For individuals with HD, continual life changes as HD progresses can be a source of anxiety. Depression is often dismissed as an understandable reaction being diagnosed with HD14. Altered Sexuality- A very common behavioral symptom of HD is altered sexuality. Possible cause is that the delicate balance of hormones in the brain is disrupted by the progression of HD causing changes in behaviors regulated by hormone levels. Most commonly, people with HD suffer from a decreased sex drive. Increased sex drive and inappropriate sexual behavior are less common alterations of sexuality resulting from HD 15. Cognitive changes in HD The term “cognitive” refers to tasks of the brain that involve knowing, thinking, remembering, organizing and judging. Cognitive changes in the HD may be due to the disruption of striatal –frontal circuits 16. Memory and Visual spatial ability An individual suffering from the cognitive symptoms of HD may have memory difficulties. Several investigators have shown that memory recall is generally affected more than memory storage in HD 16. It is important to note that the memory problems that can occur in people with HD are different from the memory difficulties that can occur in people with Alzheimer’s disease (AD)17. Most commonly, the individual suffering from cognitive symptoms of HD is aware of his or her visual spatial impairment. Reading difficulties may also be the result of visual spatial impairment; however, the inability to maintain attention may be a contributing factor as well 18. NEUROPATHOLOGY OF HUNTINGTON’S DISEASE The specific symptoms and progression of HD can be related to its pathology, which is characterized by the loss of specific neuronal populations in many brain regions. Motor dysfunction in HD results from the

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disruption of basal ganglia-thalamocortical pathways regulating movement control 19-20. The primary site of neuronal loss and atrophy in HD brain is in the caudateputamen21. Vulnerability in HD The striatum is composed of a variety of medium to large neurons that differ in their size and dendritic profile as well as neurochemical content and output. Severe loss of medium sized striatal neurons was seen in the HD brain. They have large dendritic tree and use GABA as their neurotransmitter 22. As these neurons degenerate in HD, the neurochemical they contain, including glutamic acid decarboxylase (GAD), substance-P, enkephalin, calcineurin, calbindin, adenosine receptors and dopamine receptors, also decrease. Number of theories has been presented, to determine the exact events involved in the progression of cell deaths caused by HD. One theory proposes that neurons die in HD because of an over-accumulation of normal excitatory chemicals involved in nerve impulses. Excitatory neurotransmitters (mainly glutamate) are normally present in the brain, but, if they are released in excessive amounts or if brain cells are weak, these excitatory chemicals can cause cell damage and become chemicals known as “excitotoxins.” Studies show that when glutamate is injected into the basal ganglion region of brains of living rats, the rats exhibit symptoms of HD23. This first theory had to be modified when high levels of glutamate were not found in the brains of all HD patients. The mitochondrial dysfunction plays a role in pathogenesis of HD. The mitochondria of striatal cells may be damaged with the onset of HD. Scientists today believe that the damaged mitochondria of people with HD make striatal cells unable to produce as much energy as they need, which then makes the cells more susceptible to normal levels of glutamate 24. Another theory to explain the death of nerve cells postulates that the cells actually kill themselves in response to chemical changes caused by HD. HD triggers the early death of neurons by accelerating a normal process called apoptosis 25.3-Nitropropionic acid and malonate also induce apoptotic profiles and induce pro-apoptotic proteins 26. To sum up, the neurobiological effects of HD appear to be the result of a number of different changes that

ultimately go out of control. Many studies have shown that neurodegeneration is not confined to the basal ganglia but also occurs widely in cortical and other sub cortical regions. NEUROCHEMISTRY OF HUTINGTON’S DISEASE Neurochemical alterations in HD have long attention from researchers. It is now clear that some of the earliest pathological changes in HD are indeed neurochemical. It is conceivable that these neurochemical alterations not only produce the characteristic clinical symptoms of HD but also accelerate the process of cell death, and are thus essential mediators of disease pathogenesis21 GENETICS OF HD The disease gene for HD, huntingtin, was identified in 1993 and it encodes a large protein (348kDa) with a polyglutamine stretch named huntingtin (Htt) 3, 35. Genetic defect in HD is an expansion of an unstable CAG repeats encoding polyglutamines at the 5’ end of a huntingtin [also termed “interesting transcript 15” (IT15)] gene on chromosome 4 2, 26. The biological function of the huntingtin protein is still unknown; it is known that the alteration of this protein ultimately results in HD 23, 36. INFLAMMATION AND HUNTINGTON’S DISEASE Studies of the HD brain indicate that long-term inflammation plays a significant role in the progression of HD. It is suggested that excitotoxic amino acids such as glutamate induce a direct activation and proliferation of cells involved in inflammation. Since glutamate activity is also implicated in the progression of HD, it is possible that the glutamate molecules in the HD brain induce an inflammatory response 37. One of the first steps in excitotoxic neuronal damage involves the hyperstimulation of N-methyl-D-aspartate (NMDA) receptors leading to a massive calcium influx that activates, among other processes, the calcium dependent phospholipase A2 (PLA2). Further, PLA2 cleaves membrane phospholipids to yield arachidonic acid (AA), a free fatty acid, which is converted by cyclooxygenases (COX) into prostaglandins (PGs). The inflammatory response results in the activation of various types of cells and the production of different molecules that can lead to cell death 38. An example of

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cells activated by the inflammatory response is the microglia (a type of immune cell), which have been found to be highly activated in the HD brain. Research has shown that there is a marked increase in microglia in the HD brain 37-38 . In the HD brain, an increase in activated microglia is found along the vicinity of nerve cells that contain neuronal inclusions (NIs) – accumulation of the huntingtin protein. This finding suggests that the huntingtin protein accumulation influences the activation of reactive microglia. Nerve cell injury due to excitotoxins such as glutamate also induces long-term microglial activation in the brain 3738 . MANAGEMENT OF HD Huntington’s disease is a devastating neurological disorder without effective treatment. There is an urgent need for developing effective therapies for HD. TREATMENT OF CHOREA Dopamine blocking or dopamine depleting medications Increased dopamine level plays a major role in the pathogenesis of HD. On the basis of these reports dopamine-depleting drug like Tetrabenzine was also used for the treatment of chorea in clinical trial 40. But due to lot of side effects the FDA did not approve this drug. Glutamate antagonism Excitotoxicity is the major cause of death of neurons in the HD. Increase in glutamate release activate the NMDA receptors and increase the level of Ca2+ and cause neurotoxicity. The drugs, which block the NMDA receptors, may be useful to decrease the symptoms of HD 41. GABAergic modulation GABA an inhibitory neurotransmitter is decreased in the HD brain and cerebrospinal fluid. Indeed the GABA mimetic drugs and GABA transminase inhibitors are also be used in the clinical trial for the treatment of HD42 Cannabinoids receptor agonists In the brain the cannabinoids and their receptors behave as neurotransmitters or neuromodulators in a variety of processes, such as the regulation of motor behaviour, cognition, learning, memory and antinociception. It is also reported that the cannabinoid receptors are destroyed in the basal ganglia 43. Therefore the

treatment with cannabinoids could be beneficial for HD. Antioxidants One component of excitoxicity in HD is oxidative stress and antioxidants may therefore have therapeutic utility. A novel antioxidant, BN-82451 improved motor ability and survival and ameliorated neurodegenration in R6/2 HD mice 35, 40. DEVELOPMENT OF NOVEL THERAPEUTICS FOR HD Agents that inhibit mutant huntingtin aggregation and Transglutaminase inhibitors The huntingtin aggregates and inclusions play a major role in the pathogenesis of HD. Inhibit mutant huntingtin from aggregation would provide a way to prevent the progression of the disease44. Congo red showed protective effect on survival, weight loss and motor function even after the onset of symptoms of HD in R6/2 transgenic mice 35. Transglutaminase (TGase) can use huntingtin as a substrate to cross-link huntingtin molecules. TGase activity was found to have increased in HD postmortem brains45. Cystamine is an inhibitor of TGase and showed a small but significant neuroprotective effect with improvement of motor function, survival and loss of bodyweight. Protease inhibitors Recent findings showed that huntington could be cleaved by proteases, including caspases, calpain, and aspartyl protease. Caspase and calpain-mediated partial cleavage of mutant huntingtin promotes huntingtin aggregation and cellular toxicity, inhibitors of huntingtin partial cleavage might have therapeutic values. Caspase inhibitors, z-VAD-fmk and z-DEVDfmk, can prevent cleavage of huntingtin by caspases and reduce cytotoxicity caused by expanded polyglutamine tract 46. Caspase inhibitor minocycline was able to inhibit huntingtin aggregation, retard disease progress and prolong the lifespan of HD mice. Protease inhibitors could reduce N-htt fragments and in turn, prevent or delay disease progression 47. Histone deacetylase (HDAC) inhibitors Inhibitors of histone deacetylase (HDAC) can increase gene transcription and have been examined as a potential therapy in both HD Drosophila and transgenic R6/2 HD mice. Suberoylanilide hydroxamic acid (SAHA), a selective HDAC inhibitor, reduced neurodegeneration in HD Drosophila 48. 290


Fig. 1. The basal ganglia of the human brain, showing the impact of HD on brain structure in this region. Note especially that the brain of a person with HD has bigger openings due to the death of nerve cells in that region

Population

Table.1 Worldwide prevalence of Huntington’s disease Frequency of HD (cases per million people)

South Africa (blacks) Japan Hong Kong Finland Europe & countries of European descent Northern Ireland South Wales Scotland (Grampian Region) United States

Ability Speed of processing Speech output Learning new information Free recall

Motor memory

S.No

0.6 1-4 3.7 6.0 40-100 64 76.1 99.4 100

Table.2 Comparison of Huntington’s disease and Alzheimer’s disease Comparison of Huntington’s Disease and Alzheimer Disease Huntington’s Disease Alzheimer Disease Slow, mostly accurate Slurred & slow, accurate Disorganized & slow, can learn Impaired • Cannot find the right words • Cannot recognize with choices • Benefits from clues Impaired •Cannot learn or recall motor memories

Slow, often inaccurate Normal rate & clarity; often inaccurate Rapid forgetting; cannot store information Impaired • Cannot recall memories • Cannot recognize with choices • Does not benefit from clues Impaired • Can learn& retain motor memories

Table.3. Level of different neurotransmitters in the HD brain Neurotransmitter

1. 2. 3. 4. 5. 6.

γ-Amino butyric acid (GABA) and GAD enzyme Substance P Enkephalin Dynorphin Acetylcholine Dopamine

7.

Glutamate

Level in HD brain Decrease 21-29 Decrease 30- 31. Decrease31 Decrease31 Decrease32 Decrease33 Increase34

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Other neuroprotective approaches Gene therapyIntracellular antibodies (intrabodies) and RNA interference (RNAi) are two potential methods that could be used for gene therapy of HD. Mitochondria dysfunction has been implicated in HD pathogenesis. Therefore, compounds enhancing energy metabolism have been evaluated for treatment of HD. Coenzyme Q10 and creatine are neuroprotective, putatively via enhancing cerebral energy metabolism 4, 21. Neural cell transplantation is also under development for the treatment of HD 60. Brain derived Neurotrophic factors: Brain derived neurotropic factor (BDNF) expression is reduced in the caudate and putamen of patients with HD. That enhanced expression of neurotropic factors may mitigate the effects of neurotoxins and thus be a potential therapeutic strategy was explored in animal and cell models 49-50. CONCLUSION The exact mechanisms underlying neuronal death in Huntington's disease remain unknown. Over past 10 years, the leading models of neurodegeneration in the disease have involved mitochondrial dysfunction and subsequent excitotoxic injury, oxidative stress, and apoptosis. Recent studies have lent support to these models, but additional theories involving abnormalities of protein metabolism and transcriptional dysregulation have emerged as well. Since the identification of the Huntington's disease gene in 1993, there have been great advances in the understanding of the molecular biology and pathophysiology of the disorder. These advances have suggested new therapeutic strategies aimed at slowing progression or forestalling onset of this devastating neurodegenerative disease. In preparation for future clinical trials, clinical studies have begun to provide more quantitative measures of disease onset and progression. Recent progress in the basic science and clinical realms raises hopes for affective therapies in the near future. REFERENCES 1. Bonelli RM, Hofmann P. A review of the treatment options for Huntington's disease. Expert Opin Pharmacother. 2004; 5: 767-776. 2. Kent A. Huntington’s disease. Nursing Standard. 2004; 21: 45-51.

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Gastric Floating Drug Delivery Systems: A Review Gangadharappa H. V, Pramod Kumar T. M and Shiva Kumar H. G. Dept. of Pharmaceutics. JSS College of Pharmacy, Mysore, Karnataka, India Abstract In the last three decades various attempts have been made to develop a novel and efficient gastroretentive dosage forms which can retain in the stomach for an extended period of time in a predetermined manner. This can be achieved by improving scientific and technological advancement to over come physiological problems like pH of the stomach, motility, gastric emptying time by altering physiological and formulation variables. Many approaches are utilized in the development of gastric retention drug delivery systems viz. hydrodynamically balanced systems, swelling, expanding, high density, super porous hydrogels, bioadhesive, modified shapes etc. By utilizing one of the above techniques it is possible to deliver drugs, which have narrow absorption window. Key words: Gastric floating systems; effervescent, noneffervescent, hydrodynamically balanced system. INTRODUCTION The primary aim of oral controlled DDS is to achieve better bioavailability and release of drug from the system, which should be predictable and reproducible. But this is difficult due to number of physiological problems such as fluctuation in the gastric emptying process, narrow absorption window and stability problem in the intestine. This can be over come by altering the physiological state and designing the formulations, by which gastric emptying process can be extended from few minutes to 12 hours. A drug can act locally in the stomach in case of H. Pylori (tetracycline) or in the proximal part of the intestine by prolonged contact with absorbing area1,2. A prolonged gastric retention increases bioavailability, decreases wastage of drugs, increases solubility of drugs, which are less soluble in alkaline pH e.g.verapamil3. It has been suggested to prepare a suitable dosage forms for the drugs that have narrow absorption window. These dosage forms prolongs the gastric residence time enabling an extended absorption phase for the local treatment of drugs4. Floating drug delivery systems provides better bioavailability for the drugs that are unstable in intestinal or colonic environment5. Indian Journal of Pharmaceutical Education & Research Received on 7/12/2006; Modified on 7/4/2007 Accepted on 8/6/2007 © APTI All rights reserved

Gastric retention can be achieved by the mechanism of mucoadhesion or bioadhesion systems6, expansion systems7,8, high density systems9,10,11, magnetic systems12,13,14, superporous hydrogels15,16, raft forming systems17,18,19, low density systems20,21,22 and floating ion exchange resins.23 Based on the mechanism of floatation, delivery systems can be classified into two types 1. Effervescent floating drug delivery system (EFDDS). 2. Non- effervescent floating drug delivery system. This article reviews gastroretentive dosage forms; technological developments and advantages of delivery systems. BASIC PHYSIOLOGY OF GASTROINTESTINAL TRACT The anatomy and physiology of GIT should be understood, while developing floating drug delivery systems. Factors affecting GI motility like, pH, nature and volume of gastric secretion and gastric mucus24,25. Anatomically stomach is mainly divided in to 3 parts: fundus, body and antrum (pylorus). The proximal part of the stomach is made up of fundus and body region, which serves as reservoir of the undigested substances. Where as distal region (antrum) is major site for mixing motion and acting as a pump for gastric emptying26. Gastric emptying occurs based on fed and fasted state of the stomach. Saliva, mucus and debris are

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commonly present in the fasted state of the stomach. The fasted state is characterized by intra gastric series of cyclic contractions or electrical events takes place, which is known as interdigestive migrating myloelectric complex or migrating myloelectrical cycle (MMC). This activity occurs both through stomach and intestine every 2-3 hours27, 28. Apparently MMC is further divided into four consecutive phases as described by Wilson and Washington29. Phase I (basal phase): It is a quiescent period which lasts from 30–60 minutes with rare contractions. Phase II: It consists of intermittent action potential and gradually increases in intensity and frequency as the phase progress and lasts for about 40-60 minutes. Phase III: This is a shorter period of intense, large regular distal and proximal gastric contractions (4-5 contractions per minutes) lasting for about 4-6 minutes. This cycle is also known as “house keeper wave “. Since it sweeps undigested gastric contents from stomach to intestine. Phase IV: A brief transitional phase about 0-5 minutes, which occurs between last part of phase III and beginning of phase I. After feeding this cycle leads to change in the pattern of contractions, which may last for many minutes. This frequent feeding of mixed meal may increase gastric retention time30. FACTORS AFFECTING GASTRIC RETENTION There are many factors that affect gastric emptying of an oral dosage forms, viz. density, size, shape of the dosage forms, concomitant intake of food, volume of meals and drugs like anticholinergic, laxatives, purgatives and biological factors such as gender, posture, age, sex, race body mass index and diseased state like diabetes, crohn’s disease31. Most important factors that influence the gastric emptying rate is caloric content of the meals. Oily layer formed by fats on other gastric contents such as fatty substances are emptied later than the other32. In addition to this, body exercise may also influence gastric emptying. Stress can increase the gastric emptying rate while it is decreased in case of depression33. Men and younger people have faster gastric emptying rate when compared to women and old people34, 35. Density also plays an important role in determining the location of the delivery systems in the stomach. If density of the delivery system is higher than the gastric

contents, then it sinks to the bottom of the stomach, while low-density drug delivery systems float on the surface. Both positions may isolate the system from pylorus15. It is observed that, multi particulate formulations are more reliable as compared to single unit formulations, which suffers “all or none concept”. The units of multiparticulate systems are freely distributed through out the GI tract10. Timmermans36, carried out a comparative evaluation of gastric transit floating (F) and non-floating (NF) matrix dosage forms and results were found that GRT of the non-floating forms were variable and greatly dependent on their size which are in the order small