Joseph H.Hulse Trends in Food Science Technology 15(2004)3-18 小 through chemistry.Ancient remedies and plant extracts substances found in medicinal plants.The first propri- were the first raw materials of pharmaceutical indus- etary drug Aspirin-acetylsalicylic acid-was synthesized tries.Several drugs in early pharmacopoeias were later by reacting acetic anhydride with salicylic acid from declared ineffective or dangerous. willow bark (Salix spp).Later,codeine was produced by Active substances were dissolved in ethanol and/or methylation of morphine. water;compounded with diluents and pressed into pills In the late 1900s,Paul Ehrlich observed how certain coated with gelatin or sugar;or into tablets with poly- dyes injected into animals,stained specific tissues.Ehr- saccharide gums as binders,and lubricants to permit lich explored whether similar dyes would stain and release from tableting machines.For treatment of skin inactivate microorganisms.He unsuccessfully tested 500 wounds and infections,antiseptic drugs were dispensed dyes on 2000 mice inoculated with pathogenic trypano- as ointments in lanolin or water-in-oil emulsions. somes.He then synthesized more than 600 arsenic compounds with chemical structures similar to diazo Drugs:natural and traditional dyes.His 606th compound inactivated the trypano- Though today roughly 20%of all commercial phar- somes without adverse effect on the mice.The effective maceuticals are derived from natural and genetically compound,named 'salvarsan',contained an -As=As- modified microorganisms,there is lively commercial group analagous to the -N=N-group in diazo dyes and interest in natural and traditional sources.The Pfizer showed affinity with protein in the pathogen compar- drug company was among the first to collect and screen able to the affinity of diazo compounds with protein botanical specimens from tropical forests.Merck in fibres in wool.Salvarsan and its successor neosalvarsan. cooperation with the national Institute of Biodiversity is effective against Spirochaeta pallida the pathogen that screening plants,insects and microorganisms from causes syphilis,laid the basis for chemotherapy. Costa Rica.Ethnobotanical expeditions in the tropical In 1919,Heidelberger and Jakobs in Germany dis- forests of the Amazon have delivered more than 10,000 covered that some azo derivatives of sulphanilamide species for examination.From Colombia over 1500 destroyed bacteria.In 1935,a scientist at the Bayer species,reported by local people to be biologically use- company found the red azo dye prontosil to be effective ful,are being studied. against Streptococci that caused puerperal and scarlet The ethical issue of biopiracy is being raised where fevers.In the 1930s,scientists at May and Baker in foreign companies and their agents,engaged in botani- Britain synthesized over 600 sulphanilamide derivatives. cal collecting,are taking away biological materials and The 693rd.which effectively treated bacterial pneumo- indigenous experience in traditional medicine without nia,was named M&B693.May and Baker synthesized reimbursement to local people.As observed by an Asian over 3000 related compounds,several being effective scientist:"We have the biodiversity,they [the affluent bactericides. nations]steal it to support their biotechnologies".In In 1936,the British Medical Research Council defined response to public interest in ancient and traditional 'Chemotherapy'as medical treatment by synthetic che- medicines,in 1992 the United States National Institutes mical compounds that react specifically with infective of Health established an Office of Alternative Medi- organisms.The process of synthesizing chemother- cines.Data bases on 'natural medicinals'exist at the apeutic substances and determining potency in labora- Royal Danish School of Pharmacy in Copenhagen,and tory animals is expensive and time consuming.Between at the University of Illinois,Chicago School of Medi- 1936 and 1960,one of Britain's largest pharmaceutical cine.The latter,known as NARPALERT,is adminis- companies tested over 45,000 synthetics out of which tered by Professor Norman Farnsworth. only 16 became marketable drugs.During World War Across the planet,there exists a vast unexplored II,Britain lost access to Peruvian bark,the natural source of plants and microorganisms.Of over 100.000 source of the anti-malarial quinine.Antimalarials were identified species,fewer than 200 microorganisms pro- urgently needed to protect armed forces men and duce substances used by food,pharmaceutical or other women posted to humid tropical countries.The only industries.The higher orders of terrestrial plants repre- two synthetics available caused undesirable side effects sent more than 65%of the world's biomass but fewer Between 1942 and 1946.the ICI Pharmaceutical com- than 6%of identified species are commercially culti- pany tested ca 1700 synthetics before discovering pro- vated.Of the 80.000 plants believed to be edible,fewer guanil hydrochloride,given the trade name Paludrine than 20 provide 90%of the world's food calories. 'Malaria'(literally 'bad air'),is also known as palud- ism'or swamp fever (Latin 'palus'='swamp'). Synthetic drugs and chemotherapy During the late 19th century,encouraged by their Antibiotics success with synthetic dyes,the German companies While pursuing his microscopic studies,Pasteur sug- Bayer.Hoechst and Merck began chemical synthesis of gested that microorganisms might be induced to attack drugs,first making analogues and derivatives of active one another.In 1928,Alexander Fleming,at Londonthrough chemistry. Ancient remedies and plant extracts were the first raw materials of pharmaceutical indus￾tries. Several drugs in early pharmacopoeias were later declared ineffective or dangerous. Active substances were dissolved in ethanol and/or water; compounded with diluents and pressed into pills coated with gelatin or sugar; or into tablets with poly￾saccharide gums as binders, and lubricants to permit release from tableting machines. For treatment of skin wounds and infections, antiseptic drugs were dispensed as ointments in lanolin or water-in-oil emulsions. Drugs: natural and traditional Though today roughly 20% of all commercial phar￾maceuticals are derived from natural and genetically modified microorganisms, there is lively commercial interest in natural and traditional sources. The Pfizer drug company was among the first to collect and screen botanical specimens from tropical forests. Merck in cooperation with the national Institute of Biodiversity is screening plants, insects and microorganisms from Costa Rica. Ethnobotanical expeditions in the tropical forests of the Amazon have delivered more than 10,000 species for examination. From Colombia over 1500 species, reported by local people to be biologically use￾ful, are being studied. The ethical issue of biopiracy is being raised where foreign companies and their agents, engaged in botani￾cal collecting, are taking away biological materials and indigenous experience in traditional medicine without reimbursement to local people. As observed by an Asian scientist: ‘‘We have the biodiversity, they [the affluent nations] steal it to support their biotechnologies’’. In response to public interest in ancient and traditional medicines, in 1992 the United States National Institutes of Health established an Office of Alternative Medi￾cines. Data bases on ‘natural medicinals’ exist at the Royal Danish School of Pharmacy in Copenhagen, and at the University of Illinois, Chicago School of Medi￾cine. The latter, known as NARPALERT, is adminis￾tered by Professor Norman Farnsworth. Across the planet, there exists a vast unexplored source of plants and microorganisms. Of over 100,000 identified species, fewer than 200 microorganisms pro￾duce substances used by food, pharmaceutical or other industries. The higher orders of terrestrial plants repre￾sent more than 65% of the world’s biomass but fewer than 6% of identified species are commercially culti￾vated. Of the 80,000 plants believed to be edible, fewer than 20 provide 90% of the world’s food calories. Synthetic drugs and chemotherapy During the late 19th century, encouraged by their success with synthetic dyes, the German companies Bayer, Hoechst and Merck began chemical synthesis of drugs, first making analogues and derivatives of active substances found in medicinal plants. The first propri￾etary drug Aspirin—acetylsalicylic acid—was synthesized by reacting acetic anhydride with salicylic acid from willow bark (Salix spp). Later, codeine was produced by methylation of morphine. In the late 1900s, Paul Ehrlich observed how certain dyes injected into animals, stained specific tissues. Ehr￾lich explored whether similar dyes would stain and inactivate microorganisms. He unsuccessfully tested 500 dyes on 2000 mice inoculated with pathogenic trypano￾somes. He then synthesized more than 600 arsenic compounds with chemical structures similar to diazo dyes. His 606th compound inactivated the trypano￾somes without adverse effect on the mice. The effective compound, named ‘salvarsan’, contained an –As¼As– group analagous to the –N¼N– group in diazo dyes and showed affinity with protein in the pathogen compar￾able to the affinity of diazo compounds with protein fibres in wool. Salvarsan and its successor neosalvarsan, effective against Spirochaeta pallida the pathogen that causes syphilis, laid the basis for chemotherapy. In 1919, Heidelberger and Jakobs in Germany dis￾covered that some azo derivatives of sulphanilamide destroyed bacteria. In 1935, a scientist at the Bayer company found the red azo dye prontosil to be effective against Streptococci that caused puerperal and scarlet fevers. In the 1930s, scientists at May and Baker in Britain synthesized over 600 sulphanilamide derivatives. The 693rd, which effectively treated bacterial pneumo￾nia, was named M&B693. May and Baker synthesized over 3000 related compounds, several being effective bactericides. In 1936, the British Medical Research Council defined ‘Chemotherapy’ as medical treatment by synthetic che￾mical compounds that react specifically with infective organisms. The process of synthesizing chemother￾apeutic substances and determining potency in labora￾tory animals is expensive and time consuming. Between 1936 and 1960, one of Britain’s largest pharmaceutical companies tested over 45,000 synthetics out of which only 16 became marketable drugs. During World War II, Britain lost access to Peruvian bark, the natural source of the anti-malarial quinine. Antimalarials were urgently needed to protect armed forces men and women posted to humid tropical countries. The only two synthetics available caused undesirable side effects. Between 1942 and 1946, the ICI Pharmaceutical com￾pany tested ca 1700 synthetics before discovering pro￾guanil hydrochloride, given the trade name Paludrine. ‘Malaria’ (literally ‘bad air’), is also known as ‘palud￾ism’ or swamp fever (Latin ‘palus’=‘swamp’). Antibiotics While pursuing his microscopic studies, Pasteur sug￾gested that microorganisms might be induced to attack one another. In 1928, Alexander Fleming, at London Joseph H. Hulse / Trends in Food Science & Technology 15 (2004) 3–18 7