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Transcript
Molecules that changed our Lives Synthetic Organic compounds used in Medicine Dr. E. R. Subrahmanyam Episode – XIII M. Sc., M. Phil., PhD Dr. Phani Kumar (45): Medical practitioner Dr. Prasanthi (43): Lecturer in Organic Chemistry Pranavi (17): Daughter, B. Sc student Sandeep (19): M. Sc Organic Chemistry student Dr. Prakash (52): Scientist. Scene – I Sunday 8A.M Atom (the narrator): Good Morning listeners. Last week we heard an interesting discussion on Inorganic and organic molecules for livingbeings.Today we shall know about synthetic organic chemicals used in medicine. Till the year 1856 scientists believed in the Vital Force Theory Proposed by Berzelius. According to this theory, a vital force( life force) is necessary for the production of organic compounds and so they cannot be synthesised in the laboratory as there is no life force in the test tube. The vital force theory had no scientific background but held the field till 1828, when a German chemist Wohler reported that lead cyanate when treated with ammonia gave urea,a well known organic compound,which had been isolated earlier from human urine by Roulle in 1780.It was thus Wohler who had prepared an organic compound in the laboratory for the first time.Although the synthesis of urea was recognised by the leading chemists of the day,the concept of vital force did not die quickly. It was only after Kolbe had synthesised acetic acid in 1845 and Berthelot had synthesised methane in 1856 that the belief in vital force theory was abandoned. Today, we have a very large number of organic compounds synthesised in the laboratory. Many of them are used in medicine for the treatment of several diseases and saved mankind. Let us go to the residence of Dr Phani,a noted physician to know several interesting facts about synthetic organic compounds used in medicine. Dr. Phani at his residence. Dr. Phani: Santhi, today is Sunday. Holiday for your college. Shall we go to the beach in the evening? Prasanthi: Ok. I’m ready. Pranavi also will come. But what about you! Aren’t you going to your hospital today? Dr. Phani: No, Santhi. I’m not going. I asked my juniors to visit the wards. They will consult me on phone, if necessary. So, I’m free now. Prasanthi: Ok. You have planned everything. Tiffin is ready. Where is Pranavi? Pranavi... (Loudly). Where are you? Pranavi: Here mom, coming. Dr. Phani: (Sitting in the chair at dining table) (Excited) Oh! Wonderful. Idly and Sambar! Thank you..... Santhi. Prasanti: I know you like this Tiffin. Pranavi: I too like it, mom. Prasanthi: It’s alright. Have the Tiffin first. I shall bring coffee. (Pranavi brings coffee cups on a tray) Prasanthi: How is coffee? Dr. Phani & Pranavi: Excellent! It’s filter coffee. Pranavi: Dad, you asked sandeep to come here today. Don’t you remember? Dr. Phani: Oh! I have just forgotten. I asked him to come today at 9 AM. Thank you for reminding me. I promised to help him. It’s nearly 9’o clock. He will come at any time. Pranavi: Dad, Sandeep told me that he has to submit a project report to HoD, Chemistry Dept. for internal assessment. He wants information from mom also. Dr. Phani: No problem. I will certainly spare sometime. We are going to beach in the evening. There is a lot of time Door bell rings Scene-II Prasanthi: Pranavi..... go and open the door. It may be Sandeep. Pranavi opens the door Pranavi: Hi! Sandeep. Come in. Sandeep: Hi! Pranavi. Is your dad inside? Pranavi: Yes. Dad is not going to hospital today. We are just expecting you. Mom is also inside. Sandeep: Ok. I’m lucky. Dr. Phani: Hi, Sandeep come in. Sandeep: Good morning uncle. Good morning aunt. Dr. Phani & Prasanthi: Good morning Sandeep. Prasanthi: Sandeep. Here is the chair. Sit and take this coffee. Dr. Phani: Ok Sandeep. What can I help you? Sandeep: Uncle, I have a project on synthetic organic compounds used in medicine and how they changed our lives Dr. Phani: Well, Mr. Sandeep. It’s indeed a very good and interesting topic. Your aunt also knows many things about it. Please settle down. She will come in 10min. after completing her work in the kitchen. Pranavi you too come here. We will have a useful discussion. (Prasanthi comes and sits in the sofa) Dr. Phani: Well, I shall give some basic information for discussion. We can touch upon each area though briefly without going deep into the scientific details. Organic medicinal substances may be of natural or synthetic origin. The drugs obtained from natural sources are many alkaloids, glycosides, vitamins and antibiotics.Compounds such as penicillin G and cocaine are called natural products. Some of these are prepared synthetically. Atom ( The Narrator ):Friends, please listen. The knowledge of structure of atom made the synthesis of large number of organic compounds possible. Once the structure of carbon atom and its ability to form rings, chains, and multiple bonds became known, an infinite number of organic compounds could be conceived. Chemists synthesise hundreds of thousands of them each year. Let us listen to what our friends are discussing. Prasanthi: Sandeep... Vitamins, Hormones, Antibiotics are among the synthetically prepared medicinal compounds. Dr. Phani: Anti cancer drugs, anti-HIV drugs, sulpha drugs, anti malarials, anti viral agents, anti diabetic agents, disinfectants and antiseptics etc are among the long list of synthetic organic compounds used as medicines. Sandeep: Uncle,why do chemists synthesise natural products? Dr.Phani: Good question Sandeep!Of cource there are many reasons. One reason is to provide us with greater supply of these compounds than nature can produce. Sandeep: Please give an example. Dr. Phani:O.K. I shall give an example. Taxol-a compound known to be successful in treating certain types of cancer-is extracted from the bark of Taxus,the pacific yew tree.The supply of natural Taxol is limited because yew trees are uncommon and grow very slowly and stripping the bark kills the tree.Once chemistsdetermined the structure of Taxol, a successful synthesis has been accomplished. Prasanthi: Now, you got the clue, Mr. Sandeep. These synthetic organic compounds compounds have literally changed our lives by saving us from several dreaded diseases. Sandeep: Yes, aunt. Drugs are now available for diseases like Tuberculosis, for which there was no effective treatment a few decades back. Dr. Phani: Well said Sandeep. You know there are some drugs which can be prepared semi-synthetically by involving simple or more complex modifications of the structure of the natural drugs. Pranavi: Dad, our chemistry lecturer gave a lecture on semi-synthetic penicillins last week. Dr. Phani: Pranavi, we will talk about them later. Prasanthi: There are several other drugs of that category. It has now been possible to prepare new analgesics, local anaesthetics, sympathomimetics, etc. by carrying out changes in the structures of natural and synthetic drugs. Sandeep: Aunt, which drugs are of pure synthetic origin? Prasanthi: There are several drugs which are of pure synthetic origin. Sandeep: Some examples please. Prasanthi: Ok. I will tell you. By the way are you noting down all the points? Sandeep: Yes, aunt. Prasanthi: Barbiturates, antihistamines, certain antihypertensives, many diuretics. Sandeep: Aunt, please explain the terms. Prasanti:O.K. I will tell you.Barbiturates are drugs that act as central nervous system depressants They produce many effects such as mild sedation to total anesthesia.Allobarbital is an example.Antihistamines are drugs that inhibit the action of histamine. These are commonly used for relief of allergies.Anti hypertensives are drugs used in the treatment of high blood pressure.Diuretics are drugs that increase urine output by kidneys. Dr. Phani: The list is long. Some antimalarials, sulphonamides, surface active agents etc. Sandeep: Uncle, how all these synthetic organic compounds have become available as drugs? Dr. Phani: A good question Sandeep. Listen carefully. A lot of research is needed before an organic compound is marketed as a drug. A medicinal chemist ought to know the mode of action of drugs at molecular level. He has to understand what a drug does to the biological system and what the body does to a drug molecule. He should acquire knowledge about absorption, distribution, biotransformation and excretion of drugs. Prasanthi: Yes. This is how chemotherapy developed. Pranavi: Mom, what is chemotherapy? Prasanthi: I will tell you Pranavi .It’s a very relevant question. Sandeep you also note it. As you know most of the diseases are caused by microorganisms. In case the micro-organisms gain entry into the body they multiply very fast. If they overcome the body defences, they cause diseases. To put it in simple words, Chemotherapy is the use of chemicals to selectively destroy infectious microorganisms without simultaneously destroying the host. Is it clear? Sandeep:O.K aunt. These chemicals are called drugs. Am I right? Prasanthi: Yes. A substance which is used as a cure for an ailment or for alleviation of symptoms is called a drug or medicine. Dr. Phani: Ok. Now let me tell you an incident that laid the foundation of modern chemotherapy. Gerhard Domagk was a doctor working in a German dye factory. In 1935 his daughter suffered from severe streptococci infection contracted from an unsterilized needle. As she was on death bed, Domagk gave her an oral dose of a dye called prontosil which was by that time shown to inhibit the growth of streptococci in mice. Surprisingly, the fever dropped quickly and the girl recovered within a short time. This amazing event not only saved the life of the girl but also laid the foundation of modern chemotherapy. Domagk was awarded the Noble prize in medicine in 1939. Sandeep: very interesting. What was the follow up to Domagk own experience. Dr. Phani: The therapeutic action of prontosil paved the way for further investigations. In 1936 Ernest Fourneau demonstrated that in the human body Prontosil breaks down to produce sulphanilamide which is the actual agent specifically lethal to streptococci. This led to the emergence of sulpha drugs. Sandeep: Uncle, what are sulpha drugs? Dr. Phani: The sulpha drugs are the derivatives of sulphanilamide and these were the first synthetic compounds found to be effective against pathogenic organisms or bacteria that cause pneumonia, tuberculosis, diphtheria, scarlet fever etc. Sandeep: Wonderful! How was it possible, uncle! Dr. Phani: As I said, Fourneau announced that sulphanilamide was the actual active agent against streptococci. This finding led to a search for other derivatives of sulphanilamide with better chemotherapeutic effects. Literally thousands of chemical variations were obtained by varying the structure of sulphanilamide in almost every imaginable way. Best therapeutic results were obtained with those derivatives in which one hydrogen of the –SO2NH2 group was replaced by a heterocyclic amine. Thus, sulphapyridine, sulphadiazine, sulphaguanine, sulphathiazole, sulphacetamide etc. were some successful variations of sulphanilamide. Sandeep: Great! Prasanthi: You know sandeep! Prior to 1938 thousands of people used to die of Pneumonia every year. In 1938 sulpha pyridine was found to be effective cure of this dreaded disease. Dr. Phani: You are right Prasanti. 1941, Sulphacetamide was used successfully for curing urinary tract infections. In 1942 succinyl sulphathiazole and phthalylsylphathiazole were found to be specific cure for gastrointestinal tract infections. Inside the body both these drugs are slowly hydrolysed to give sulphathiazole. Sandeep & Pranavi(Jointly): Then why can’t we use sulphathiazole directly? Dr. Phani: Yes. Sulphathiazole was used during the Second World War. Administration of sulphathiazole saved the lives of thousands of wounded soldiers. It was so popular that soldiers used to carry packages of sulpha drugs to sprinkle on the open wounds to prevent infection. Sandeep: Uncle, what is the mode of action of sulpha drugs? Dr. Phani: Good question Sandeep. Listen. Para amino benzoic acid is an essential nutrient for those bacteria which are sensitive to sulpha drugs. p – Amino benzoic acid is needed by the enzyme within these bacteria for the synthesis of folic acid, another essential compound. Sulphanilamide acts as an inhibitor for those enzymatic steps which are involved in the synthesis of folic acid by the bacteria. This results in the death of bacteria. Pranavi: Dad, in that case sulphanilamide should be toxic to humans also. Dr. Phani: No! No! Humans do not synthesise their own folic acid but they get it from dietary sources. Thus they are unaffected by sulpha drugs. Knowledge of this mode of action of sulpha drugs has led to the discovery of a large number of more effective antimetabolites i.e.,chemicals which inhibit the use of a metabolite, which is another chemical that is part of normal metabolism. Prasanthi: Sandeep.. I think this much is enough about sulpha drugs for your project. We shall now talk about another important class of drugs known as Antibiotics. Sandeep: Aunt, what are antibiotics? Prasanthi: Antibiotics are chemical substances produced by microorganisms (bacteria, fungi and mold) which inhibit the growth or destroy microorganisms. However, most of these antibiotics are synthesised in the laboratory. Sandeep: Ok, aunt. I know that Penicillin is one of the most widely used antibiotics. Dr. Phani: Sandeep. Do you know? Penicillin was an accidental discovery. It is one of the most interesting stories of science. Prasanthi: Shall I tell the story? Dr. Phani: It’s alright Santhi. But be brief. Prasanthi: Ok. I shall be brief. On a September morning in 1928, Alexander Fleming sat at his work bench at St. Mary’s hospital in London after having returned from a vacation with his family. Before he had left on a vacation he had piled a number of his Petri dishes to the side of the bench. After returning from the two-week vacation, he found that a mold had developed on an accidentally contaminated staphylococcus culture plate. Upon examination of the mold he noticed that the culture prevented the growth of Staphylococci. Subsequent experiments proved that the mold could be grown in a special medium and that the culture contained a potent antibacterial substance. The material was shown to be effective against a variety of gram-positive organisms and to be nontoxic to animals. Fleming gave the name Penicillin to this antibiotic substance. Sandeep & Pranavi: Wonderful! Dr. Phani: Fleming was really great! You know? Fleming wrote in a report, “One sometimes finds what one is not looking for. When I woke up just after dawn on September 28, 1928, I certainly didn’t plan to revolutionize all medicine by discovering the world’s first antibiotic or bacteria killer. But I guess that was exactly what I did”. Prasanthi: He was so great. The discovery of Penicillin changed the world of medicine enormously. Subsequently, scientists discovered a host of new antibiotics such as Streptomycin, amino glycosides, tetracycline and the like. Sandeep: Aunt, what are semi-synthetic antibiotics? Dr. Phani: semi synthetic antibiotics are partially modified natural antibiotics in the pharmaceutical laboratory in order to improve the efficacy of the natural product, reduce its side effects, circumvent developing resistance by the targeted bacteria and expand the antibiotic spectrum. Cephalosporins refer to semi-synthetic antibiotics Sandeep: Uncle, please give some examples, I will note down. Dr. Phani: penicillin derivatives, cephalosporin derivatives and tetracycline derivatives are there. Tygecycline is a semi synthetic tetracycline. Phinethicillin is semi synthetic penicillin. Choxacillin and blucloxacillin are also semi synthetic penicillins. Prasanthi: By the way, Sandeep have you heard the name of Yellapragada Subbarao? Sandeep: Yes aunt. He was born in Bhimavaram in West Godavari district, Andhra Pradesh. Prasanthi: You are right. He discovered several important drugs. Under Subbarao, Benjamin Duggar made his first discovery of the world’s first tetracycline antibiotic Aureomycin in 1945. Atom( Narrator ):Well, Listeners. We all should be proud of Dr Subbarao.He was a great Indian biochemist. He had his early education at Rajahmundry and matriculated from Hindu High School,Madras. After passing Intermediate Examination from the Presidency College, he entered Madras Medical College. Later he earned a diploma from the Harward Medical School and joined Harward as a junior faculty member. With Cyrus Fiske, he developed a method for the estimation of phosphorus in the body fluids and tissues. He discovered the role of phosphocreatine and Adenosine Triphosphate (ATP )in muscular activity,which earned him an entry into biochemistry textbooks .He obtained his Ph.D degree the same year. He joined Lederle Laboratories, a division of American Cyanamid. At Lederle, he developed a method to synthesise Folic Acid, Vitamin B9. Later he developed athe important anti-cancer drugMethotrexate-one of the very first cancer chemotherapy agents which is still in clinical use.Dr Subbarao also discovered the drug Hetrazan which was used by WHO against filariasis.Under Subbarao,Benzamin Duggar Discovered the world’s first tetracycline antibiotic ,Aureomycin.A new fungus was named in his honour by American Cyanamid: Subbaromyces. He did not market his work. What a great Indian! Now let us again listen to the discussion at Dr Phani’s house Dr. Phani: We should note an important point. With the passage of time bacteria becomes resistant to certain antibiotics. So we need stronger antibiotic to destroy these resistant strains. The search for more effective antibiotics goes on. Resistance to sulpha drugs has emerged among many microorganisms. However these are still used in many countries because of their low cost. Prasanthi: The chemistry of antibiotics is vast. I think we can have a pause in our discussion. I will go to kitchen and bring coffee for all. Pranavi, come with me. Scene change Music Scene – III Prasanthi: Coffee ready. Take your cups, Biscuits also. (Sounds of coffee cups being taken from the tray) Sandeep: Thank you aunt. Coffee, very good! Aunt, coffee contains caffeine. Prasanti: you are right, Sandeep. A cup of coffee or tea contains about 60 mg of caffeine. It works as a medicine for some kinds of headache. Dr. Phani: Now let us talk about Anti malarial drugs. In early days malaria was treated with bark of a tree called cinchona. Later on alkaloid Quinine was extracted from cinchona bark and its chloride or sulphate was used as a specific medicine for treatment of malaria for a long time. Quinine has now been replaced by more effective synthetic drugs. Atom ( The Narrator ):During and after World War 1,quinine and its derivatives were not available in sufficient quantities in Germany. Therefore the chemists of this country attempted to synthesise antimalarials which were to be independent of quinine structure. They started with methylene blue which had some antimalarial activity. They were successful in synthesising the first synthetic antimalarial pamaquine. However, it found limited applications due to its toxicity and ineffectiveness against acute attack of malaria. Further research led to other synthetic antimalarials. Sandeep is saying something. Let us listen. Sandeep: Uncle, I heard that there are several synthetic anti malarial drugs. Dr. Phani: Yes, Sandeep. There are several derivatives of Amino quinolines among the synthetic anti malarials. Sandeep: Uncle, please give some examples. Dr. Phani: Quinacrine is an important drug of the class . It is sold under the trade name mepacrine. Chloroquine is a drug of choice for treatment of malaria. Amodiaquine and hydroxychloroquine belong to this class. There are many other important antimalarials such as pamaquine, pentaquine, isopentaquine and primaquine. Prasanthi: I heard that pyrimethamine is the most powerful suppressive drug of choice. Dr. Phani: Yes, Santhi. It is a pyrimidine derivative. It is a tasteless white crystalline powder. Prasanthi: Let us know about analgesics and antipyretics. Sandeep: Ok, aunt. Pranavi: Mom, what are analgesics and antipyretics? Prasanthi: Antipyretics are drugs which reduce body temperature in high fever. Analgesics are the compounds which relieve pain. Sandeep: Aunt, how do antipyretics reduce body temperature? Prasanthi: They act through excessive sweating and there by cooling the body. Dr. Phani: Most of the antipyretics produce excessive secretion of the acid in the stomach and may cause ulcers. There excessive use should be discouraged. Sandeep: Uncle, please tell me about most commonly used antipyretics and analgesics. Dr. Phani: Aspirine is a well known analgesic and antipyretic. It is synthesised by the acetylation of salicylic acid. Paracetamol is the most widely used antipyretic and analgesic today. Analgin, Phenacetin, Brufen, Novalgin and a number of other synthetic organic compounds are used as analgesics and antipyretics. Some have anti-inflammatory action also. Sandeep: Uncle, paracetamol is very popular. How is it synthesised? Dr. Phani: Your aunt will tell you. Santhi... answer this question. Prasanthi: Paracetamol is para acetamido phenol. It is synthesised by the acetylation of para amino phenol with a mixture of acetic anhydride and acetic acid. Dr. Phani: Ok, Sandeep. Let us not go deep into the details of synthesis of all these drugs. But, Sandeep, you should mention about Anti diabetic agents, Anti HIV-AIDS drugs and Antineoplastic agents also in your report because they saved many lives. Sandeep: Ok Uncle. My report will be quite meaningful and interesting. Dr. Phani: Sandeep, my friend Dr. Prakesh is an expert in diabetology, HIV and cancer treatments. I will invite him to lunch. We will discuss with him. (Dr.Phani calls Dr. Prakash on Phone) Yes. Dr. Prakash is coming in 10 minutes. Prasanthi: Lunch is ready. Come to the dining table. Sandeep you too have lunch with us. Dr. Phani: Santhi.. Let us wait. Dr. Prakesh will join us for lunch. Prasanthi: Ok. Scene change Music Scene-IV (Dr. Phani, Prasanthi, Dr. Prakash, Sandeep and Pranavi all completed their lunch) Dr. Prakash: Lunch is very good. Prasanthi is from konaseema. She is good at cooking. Brinjal curry, coconut chutney, sambar all are good. All are popular Konaseema dishes. Thank you for inviting me. By the way, what is the occasion today? Prasanthi: Thanks for your compliments bhayya.We are all going to Konaseema in the month of May to spend summer there. Please come along with your family .We all shall go together and see several beautiful places there. Of course nothing special today. They are all discussing synthetic organic compounds used in medicine. Dr. Prakash: Thank you for your invitation .I am fond of visiting Konaseema. Coconut groves, banana orchards, meandering canals,Oh!all will be a feast to our eyes. By the way I’m also interested in the discussion here. Dr. Phani:O.K., Prakash, let us go to the reading room. (All move to the reading room) Dr. Phani: Prakash, he is Mr. Sandeep doing PG course in organic chemistry. He is submitting a project report on synthetic organic compounds used in medicine. Till now we had a discussion on anti malarials, antibiotics, analgesics, sulpha drugs etc. He wants some information on Anti diabetic agents, Anti HIV-AIDS drugs and Anti- cancer drugs. Dr. Prakash: It’s alright. Sandeep, Diabetes has become very common now-a-days. In general, diabetes is caused due to the deficiency of effective insulin, a hormone secreted by the beta cells of the pancreas. Sandeep: Sir how is diabetes controlled? Dr. Prakash: Generally diabetes is treated by giving an injection of insulin at regular intervals to compensate for the amount that would normally be produced. In some cases, pancreas is capable of producing insulin but does not respond sufficiently to the glucose in the blood. In such cases drugs like tolbutamide which stimulate the secretion of insulin from the pancreas are used. Sandeep: What are the other drugs, sir? Dr. Prakash: Around 12000, sulphonyl urea derivatives have been synthesised as potential antidiabetic agents. Some of the important hypoglycaemic agents are glipizide and glibenlamide including Tolbutamide. Tolbutamide is a safe drug for elderly patients. Sandeep: How is it synthesised, sir? Dr. Prakash: Tolbutamide is synthesised starting with simple compounds like toluene sulphonyl chloride. Dr. Phani: Well Dr. Prakash. You are treating AIDS and HIV patients also. Mention a few synthetic drugs which are useful in the treatment. Dr. Prakash: Ok, Dr. Phani. Pranavi: Uncle, AIDS is an acronym for Acquired Immune Deficiency Syndrome. Dr. Prakash: Very good, Pranavi. Do you know what HIV stands for? Sandeep: I know sir, HIV stands for Human Immunodeficiency Virus. Dr. Prakash: Yes. AIDS is a disease caused by a virus called HIV. Most of the treatments for HIV and AIDS are still in the experimental phase. However some synthetic organic compounds are used in the treatment. They include Zidovudine, Zalcitabine, dideooxyadenosine, Lamivudine, Emtricitabine, FTC, Abacavir, etc. Sandeep: Thank you, sir. I shall write a brief note on vitamins also. Please give me some points. Dr. Prakash: Ok, Sandeep. In fact the discovery of the vitamins was a major scientific achievement in our understanding of health and disease. It was discovered that scurvy, beriberi, rickets, pellagra and xerophthalmia are specific vitamin deficiencies rather than diseases due to infections or toxins. Ultimately chemists isolated the various vitamins, deduced their chemical structure and developed methods for their synthesis. Vitamins are designated by English alphabets A, B, C, D, E, K. Sandeep: Sir, which of these vitamins are synthesised in the laboratory? Dr. Prakash: Many of the vitamins are now synthesised on a commercial scale. Total synthesis of vitamin B12 is also available. Thiamine (B1), Riboflavin (B2), Pantothenic acid (B5) etc are synthesised. Ascorbic acid (vitamin C) is also synthesised starting from D- glucose. Dr. Phani: I think we can stop our discussion at this stage. There are several other synthetic organic compounds used in medicine. Already you have collected a lot of information about synthetic organic compounds used in medicine. While writing your project report write their structures. Also include photographs of great scientists like Alexander Fleming, Domagk, Yellapragada Subbarao and others. Remember, carbon atom is the main constituent of all these organic compounds. Prasanthi: I brought tea for all. Dr. Phani: Thank you, Prakash for coming. Dr. Prakash: Ok. I shall take leave. Sandeep: Thank you uncle for helping me. I hope my report will be appreciated by our HoD. Dr. Phani: Ok, Sandeep. We will get ready to go to beach as planned. Atom ( The Narrator ): Dear listeners, you all heard how some synthetic organic compounds are used in medicine for the treatment of diseases. Of course,there are several other organic compounds used as antifilarial agents,hypnotics and sedatives,anaesthetics,central nervous system stimulants,antihistamines,etc. Next week we will meet again to hear another episode. Till then, Bye… -----------------------------------------------------------------//////////-------------------------------------------------------------Dr E.R.Subrahmanyam, Principal, SKBR Post Graduate College,Amalapuram-533201. East Godavari District, A.P. .