- Email: [email protected]
Drowning in drugs: interesting marine products
TIPS -June 1983
249
normally absent in Nelson's syndrome, was restored in 2 subjects and regression of a pituitary microadenoma was observed in another. Moreover, pigmentation was reduced in 60% of the individuals and, in those receiving the lower dose of valproate (600 mg day-t), a subjective improvement in the intensity of fatigue and headaches was also noted. As before, discontinuation of the treatment resulted, some weeks later, in the return of high circulating levels of ACTH but, disappointingly, in this study only l of 3 patients responded to a further c o ~ of treatment. The mechanisms by which valproate reduces ACTH secretion in Nelson's syndrome are not yet clear. However, there is a wealth of evidence from studies done in laboratory animals which indicates that central GABA-ergic pathways inhibit the secretion of the hypothalamic corticotrophin releasing factor (CRF) which controls the production of ACTHa~. Hence, the suggestion ~z that valproate, which inhibits GABA-breakdown 7 and potentiates GABA activity at the post-synaptic membrane 8, effectively reduces the hypothalamic drive of the pituitary gland is well founded. Indeed, as Jones and his colleagues propose 1, Nelson's syndrome may well arise as a result of dysfunction of a central GABAergic system. On the other hand, the possibility that valproate acts at the pituitary level cannot be excluded for, although GABA and drugs which antagonize its actions do not affect the adrenocorticotrophic activity of adenohypophysial tissue from healthy animals9, tumour tissue, on which there are few reports of comparable studies, may behave quite differently. J. C. BUCKINGHAM
Academic Department of Pharmacology, Royal Free Hospital School of Medicine, Rowland Hill Street, London NW3 2 P F, UK.
Rrading list l Jones, M. T., Gdlham, B., Beekford, U., Domhurst, A., Abraham, R. R., Seed, M. and Wyn, V. (1981) Lancet (i) 1179-1181 2 Dornhurst, A., Jenkins, J. S., Abraham, R. R., Beckford, U., Gillham, B. and Jones, M. T.J. Clin. Endocrtnol. Metab. (in press) 3 Makara, G. B. and Stark, E. (1974) Neuroendocrinology 16, 178-190 4 Jones, M. T. and Hillhouse, E. W, (1977)Ann. N Y. Acad. Sci. 297,536-560 5 Acs, Z. and Stark, E. (1978) J. Endocrinol. 77, 137-141 6 Buckingham, J. C and Hodges, J. R. (1979) J. Physiol. (London) 290, 421-431 7 Godin, y . , Heiner, L., Mark, J. and Madel, P. (1969)J Neurochem. 16, 869-873 8 Ke~vm, R. W,, Olpe, H. R. and Schrnutz, M. (1980) Br. J. Pharmacol. 71,545-551 9 Buckingham, J. C. and Hodges, J. R. (1977) J. Physiol. (London) 272,469-479
Drowning in drugs: interesting marine products A recent paper by Shibata and his colleagues a reinforces the view of many that the sea is a vast and poorly tapped container of novel pharmacological agents. The increasing sophistication of synthetic organic chemistry has yet to match nature in the production of peculiar structures with interesting activities. A high percentage of the prescriptions written each year in North America are for natural products or agents closely related to them 2. Many of the pharmaceutical agents used in the West fall into one of the following four categories: (1) substances obtained from natural sources (morphine, quinine, emetine, cardiac glycosides); (2) chemically synthesized agents that were first found as natural products (ephedrine, salicylic acid); (3) simple derivatives of natural products, obtained by chemical modification (oral contraceptive steroids, aspirin and heroin); or (4) synthetic analogues of natural products, first synthesized with the intent of mimicking or antagonizing the action of a natural product (methadone, and many other opiate analogues). It is not coincidence, but historical bias, that all the examples given are from the plant kingdom, and from land plants at that. This is the group that we know most about. They are still the source of 25% of the prescriptions dispensed in the USA. Even within this group, our ignorance is extensive, and the knowledge we have is unevenly distributed. For example, we know more about the plants of temperate climates than we do of the rich complexity of tropical rain forest plants. There are probably well in excess of 500 000 angiosperms, or flowering plants, in the worlds. Only a few of this vast array have been thoroughly explored for biodynamic constituents. Both lay-people and scientists are often surprised when they find how little is known of the chemical constituents of some of the commonest plants in our gardens. Many of the plants that have been culturally exploited for centuries have never had the skimpiest pharmacological, toxicological or chemical evaluation - except for the empirical observation that people do not die within a few minutes of consuming them. For example, comfrey (Symphytum offu;inale) has been cultivated for consumption as a vegetable or drink since the times of classical Greece. Its name (Sympho - to unite) derives from its supposed healing qualifies. It is grown as a cash crop in North America and Europe. It was only in 1980 that analysis showed the presence of toxic (carcinogenic) pyrrolizidine
alkaloids in the planP. The secondary metabolites of plants are a major resource in the search for new drugs. However, the number of unexamined plants is so large that it would be inefficient to pick species at random for investigation. There is a certain logic in choosing plants in the same genera or family as plants with known constituents of interest, but to do this exclusively would prevent the discovery of completely new types of natural products with novel pharmacological actions. A useful point at which to begin examination of plants is the ethno-botany of various cultures. This has been, and should still be, a rich source of pharmacologically significant substances. When we move away from the plant kingdom, our ignorance of pharmacologically active metabolites is even more extensive. Molds, bacteria, and fungi have been explored mainly as sources of antibiotics. A limited number of substances, such as cantharides and cochineal, are obtained from insects. Our ignorance of secondary metabolites is probably most marked, however, when it comes to marine life. Over 70% of the world's surface is covered by sea water. About 80% of all animal species live in or on the water. About 85% of edible plant mass in the world is produced in the seal Marine products are used by many cultures for many purposes, yet ethnic marine medicine is almost unstudied. The simplification of marine flora and fauna through man-induced extinction has probably led to the loss of species we shall never know about, and the concomitant loss of natural products of unusual structure and properties. This loss is the more serious in that we can never know what it was we lost. Who cared much about the fate of an obscure group of Mexican yams (Dioscorea) a few decades ago? Yet from these yams is now produced the starting material for the synthesis of oral contraceptive steroids. The studies that have been done on marine products have resulted in such important agents as tetrodotoxin (from a fish), saxitoxin (from a protozoan dinoflagellate), and carageenan (from algal seaweed). Kainic acid, an important tool for neurochemists and neuropharmacologists, was obtained from an otherwise obscure marine alga, and the cephalosporin antibiotics from a marine fungus, lncidently, more than 1 000 species of dinoflagellates have been identified, of which the toxicity of only four has been examined G. The first symposium on marine toxico1-
© tgs3 Elsev~r$ ¢ ~
Pulfltflt=~B V . Amsterdam 0165-6147183/$0100
TIPS -June 1983
250 ogy and pharmacology was held as recendy as 1960L The increased use of marine products as foods has led to a more practical concern with marine toxins, and now over 1 000 species are known to be toxic. Among the animals unique to the sea are the sponges, phylum Porifera. Over 4 000 species are known. This group has been little studied for chemical constituents, but is known to contain many bioactive substances, including brominated antibiotics. Shibata and his colleagues 1 have been studying okadaic acid (Fig. 1), a substance isolated from a common black sponge (Halichondria). Okadaic acid is described as having a unique molecular structure, which in itself is not unique, as that property is shared by every other compound. However, this polyspiroketal has unusual, or even unique, pharmacological properties. Okadaic acid causes tonic contraction of smooth muscle both in the presence and the absence of calcium. The contraction is slow developing and long lasting. Thus, after four 5-min washouts from human umbilical arteries, the vasoconstrictive action of okadalc acid had not worn off 7 h later. This suggests either that okadaic acid binds tightly, or that it initiates a virtually irreversible process. Tonic contraction is produced in the presence of the calcium chelator, EGTA, or the calcium antagonist, lanthanum, which blocks the movement of calcium across the cell membrane. Furthermore, the calcium, slow-channel antagonists, nifedipine and verapamil, are also without effect. The structure of okadaic acid is reminiscent of the calcium ionophores A23187 and X537A. However, the action of okadaic acid is quite different, in that vasoconstriction produced by calcium ionophores is inhibited in a calcium-free medium, and is abolished and markedly lessened by all the conditions described above. This peculiar action of okadaic acid has yet to be explained. The action is not affected by the a-blocker, phentolamine, an antihistamine, diphenhydramine, or a serotonin antagonist, methysergide. This appears to eliminate the involvement of a-, histamine I-h-, or serotonin-receptors. Tetrodotoxin and procaine, which block the response to electrical stimulation in rabbit aortic strips, do not affect the action of okadaic acid in umbilical artery preparation. Indometacin blocks the aortic response to thromboxane Avlike substances, generated in situ, but like all other agents tried, is without effect on the response to okadaic acid. The authors tested a number of other agents and conditions. The one effect they found was that although the absence of glucose did not alter the response to okadaic
CH5
CH
| 3H
~,~o ^_ f'~ I H H u r ~ _ o L
OH
H C
~I~//CHa
HOOC--C--C--'f'v"l,-,.,.,,'-c-c-?::.,"%v.'V"I" "I I H I I v j -~ k • L .o "-I"o.
HO
3
I
1 o
H H~L_~,'*'
"~
CH 5
Fig. 1 The structure o/okadaic ~id.
acid, the combination of anaerobic conditions and absence of glucose abolished the response to okadaic acid. One observation that may be germane to the action of okadaic acid is that the calcium content of umbilical arteries exposed to okadaic acid for 1 h decreased from 2.25 to 1.96 nmole kg -1 wet weight (sic). These units are probably incorrect, but the point being made is that calcium content falls. This decrease, combined with the absence of an effect of okadaic acid on myosin ATPase, and the lack of effect of the cardiac glycoside, ouabain, on the response to okadaic acid, allows certain tentative conclusions to be reached. First, cell surface calcium which is of supreme importance in the contractile process of cardiac cells, and is also involved in the effects of other pharmacological agents on smooth muscle, is not involved in the response to okadaic acid. As okadalc acid is not altering the responsiveness of myosin ATPase, it must be altering (increasing) the delivery of calcium to this ATPase. All indications are that this calcium comes from an intracellular source. Thus, okadaic acid may alter the handling of calcium by mitochondria, sarcoplasmic reticulum, or other sites within the cell that store calcium. There may be other possibilities. For example, does okadaic acid alter proton transport across the mitochondria, with a resultant effect on cellular pH? There are other studies with okadaic acid it would be interesting to do. What effect does it have on the heart, or on striated muscle? What effect does caffeine, an agent known to release calcium from sarcoplasmic reticulum, have on the response to okadaic acid? Okadaic acid, in its unique pharmacological action, that of producing sustained contractility independent of extracellular calcium, is a foretaste of what may be waiting to be discovered in the sea. Among the known peculiarities of marine pharmacology is the observation that sea water itself has bactericidal and viricidal properties which are lost on heating or storage. Flatworms, ribbonworms, molluscs, snails and other creatures that swim, crawl or squirm through the ocean contain cardioactive substances, some peptide in nature, some not. The information that is known about marine toxicology and pharmacology has been collated into some exceptionally free
books. A stunning collection of color photographs of poisonous fish is contained in Russell's vade mecum, including one of a particularly malevolent Diodon hystrix s. A recent major publication is one by Bruce Halstead 6. 'Marine' is interpreted in a liberal sense, and this volume even includes a section on poisonous polar bears. Poisoning is caused by eating polar bear liver, although I cannot escape a conviction that catching the bear might prove to be a bigger risk than eating it. For those of nervous temperament who may be contemplating a trip to polar bear country, we are assured that, 'polar bear poisoning is of minor public health importance. Intoxication is most likely to occur among uninformed travellers in the Arctic.' The toxicity is due t o . . . On second thoughts, why should I spoil a good mystery? I encourage everyone to examine this marvellous book. A final tidbit of information concerning the pharmacological etymology of the sponge is that the word 'sponge' derives from the Greek root spoggos, which is cognate with the Latin word 'fungus '9. Wasson believes that the Greek root in turn derives from the Finno-Ugfic root pon or penk, a mushroom, or more specifically, fly agaric x°. This mushroom is known to science asAmanita muscaria, which, like the sponges, is a rich source ofpharmacological agents, including muscimole and muscarine. With this, I think I have squeezed the sponge dry. RYAN J. HUXTABLE
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, A Z 85724, USA.
Reading list 1 Shibata, S., Isinda, Y., Kitano, H., Ol~zunu, Y., Habon, J., Tsuldtani, Y. and Kikuchi, H. (1982) J. Pharmacol. Exp. Ther. 223, 135-143 2 Farnswot~, N. R. (1977) in Major Medicinal Plants: Botany, Culture and Uses (Morton, J. F., ed.), pp v-vin, C C Thomas, Springfield, Illinois 3 Schultes, R. E. (1975) in Plants in the Development of Modern Medicine (Swain, T., ed.), pp. 103-124, Harvard University Press, Cambridge, MA and London 4 Culvenor, C. C. J., Clarke, M., Edgar, J. A., Frahn, J. L., Jago, M. V., Peterson, J. E. and Smith, L. W. (1980) Experientia 36, 377-379 5 Marderosian, A. der (1969)J. Pharm. Sci. 58, 1-33 6 Halstead, B. W. (1978)Poisonous and Venom-
251
TIPS -June 1983 ous Marine Animals of the World, Darwin Press 7 Nigrelli, R. F. (ed.) (1960)Ann. N. Y. Acad. Sci. 90, 615-950 8 Russell, F. E. (1971) Marine Toxins and Ven-
omous and Poisonous Marine Animals, "IVH Publicauons, Academic Press, London 9 Shipley, J. T. (1945) Dicaonary of Word Or/g/ns, Philosophical Library, New York
@
Computer Club The world o f pharmacology computing
Computers in pharmacology teaching The use of computers in teaching pharmacology is an immediately attractive proposition. It requires the acquisition of familiarity with an 'in' technology, it holds the prospect of a reduced teaching load and it provides some'body' to blame when students fail to learn!
Benefits Computer-aided teaching allows students to work at times convenient to them and to proceed through material at their own rate; features particularly useful to pharmacology students who may have very different educational backgrounds, timetables and abilities. Material can be provided for small groups; those with poor mathematics or only elementary biology, for example. Students can repeat teaching material as often as necessary to acquire understanding without using staff time. Finally, students enjoy learning through a computer which is relatively anonymous, and more timid students take the risk of making answers without embarrassment or inhibition. Problems Teachers developing computer-aided programs will discover that it is surprisingly difficult to write concise, easily understood material and present it in an interesting and absorbable manner on a video-display unit (VDU). The lecture can be enlivened with an anecdote or gesture; a story which takes only moments to tell and revives flagging interest may occupy several screens-full of text and then seem very unfunny. The lecturer can respond to the mood of the class and though an assessment of the mood of a VDU user can be attempted (by measuring reading speed, response latency and error frequency), such assessments lack sophistication and are uncertain. A teacher using a VDU as an information channel must learn to communicate in a new way, as the skills employed in a lecture are not necessarily those which make for
10 Wasson, R G. (1979) m Ethnopharmacologic Search ]:or Psychoactive Drugs (Efron, D. H., Holmstedt, B and Kline, N . S . , eds), pp. 405,-.414, Raven Press, New York
effective teaching through a VDU. The student also has to ~ and acquire new skills. Facts tend to be diluted and repeated in a verbal delivery while a very concise style is used in computer-aided teaching to reduce the number of words on the screen. Many large computers use involved procedures to obtain access to teaching material. Some students feel that it is pointless to acquire these new skills unless a substantial amount of teaching material is available. Barriers to the initial use oftbe system must be minimal; once familiar with the procedures students use the system freely but the initial step into unfamiliar ground must be as easy as possible. Types of program
Simulations Where biological systems can be defined by mathematical relationships a simulation can greatly increase a student's understanding. The absorption, distribution, metabolism and excretion of drugs are very amenable to this treatment. Colour graphics produce impressive illustrations through which students obtain insight into the interdependence of these processes in biological systems and their relevance to successful drug use. My own experience has been with simulations of simple isolated tissues, but more complex systems would be interesting, e.g. the cardiovascular system. Simulations should never replace practical experience, but, used in conjunction with practicals, they extend students' knowledge and experience. Should an experiment fail, mock data may be obtained from a simulation and then processed in the normal way. Correct experimental designs and the inclusion of appropriate control experiments may be limited by time constraints in practical classes but can be given more prominence in simulations as responses are obtained quickly and antagonists removed easily. Simulations should not place unueces-
sary restraints on students' conceptions or curiosity. Thus, in my guinea-pig ileum simulation, it is possible to 'add' a great variety of agonists in any concentration or sequence and in the presence or absence of a variety of antagonists, again, at any concentration. The interactions must be quantitatively correct and enable, for example, p,M values to be obtained as well as 'unknown' agents to be characterized. These simulations increase understanding in a variety of fields and, like the practical experiments they emulate, do not simply allow a student to learn the characteristics of the preparation being used.
Programmed learning Large lumps of text are difficult to read, absorb and manipulate on a VDU. Such presentations are better made on printed sheets and understanding can then be aided or examined by the computer. Many systems based on text present& tion start with questions which establish the existing level of knowledge. At some point along the main line of questions the user gives an incorrect answer and is then deflected into a loop in which questions and text information attempt to teach the missing knowledge. The loop returns the student to the main line of questions to which correct responses should now be given; if not, a second, more extensive loop should exist. Loops may exist within loops and these programs are complex, permit no deviation from the path mapped by the teacher and often fail to anticipate all possibilities; hence the well-used message 'I am a small computer and cannot explain more clearly - consult your lecturer' and other, more forthright, comments.
Simple question and answer This by-passes many complexities referred to above; any format of multiple choice question (MCQ) is possible although I have chosen to use the 'stem and five completions'. The question is presented, the answer to each completion is elicited and then marked. Knowledge of the correct answers may enable the student to appreciate any error, but an explanation of the answers is
© 1983ElsewefSciencePubhshersB.V , ~
0165- 6147/83/$01130
249
normally absent in Nelson's syndrome, was restored in 2 subjects and regression of a pituitary microadenoma was observed in another. Moreover, pigmentation was reduced in 60% of the individuals and, in those receiving the lower dose of valproate (600 mg day-t), a subjective improvement in the intensity of fatigue and headaches was also noted. As before, discontinuation of the treatment resulted, some weeks later, in the return of high circulating levels of ACTH but, disappointingly, in this study only l of 3 patients responded to a further c o ~ of treatment. The mechanisms by which valproate reduces ACTH secretion in Nelson's syndrome are not yet clear. However, there is a wealth of evidence from studies done in laboratory animals which indicates that central GABA-ergic pathways inhibit the secretion of the hypothalamic corticotrophin releasing factor (CRF) which controls the production of ACTHa~. Hence, the suggestion ~z that valproate, which inhibits GABA-breakdown 7 and potentiates GABA activity at the post-synaptic membrane 8, effectively reduces the hypothalamic drive of the pituitary gland is well founded. Indeed, as Jones and his colleagues propose 1, Nelson's syndrome may well arise as a result of dysfunction of a central GABAergic system. On the other hand, the possibility that valproate acts at the pituitary level cannot be excluded for, although GABA and drugs which antagonize its actions do not affect the adrenocorticotrophic activity of adenohypophysial tissue from healthy animals9, tumour tissue, on which there are few reports of comparable studies, may behave quite differently. J. C. BUCKINGHAM
Academic Department of Pharmacology, Royal Free Hospital School of Medicine, Rowland Hill Street, London NW3 2 P F, UK.
Rrading list l Jones, M. T., Gdlham, B., Beekford, U., Domhurst, A., Abraham, R. R., Seed, M. and Wyn, V. (1981) Lancet (i) 1179-1181 2 Dornhurst, A., Jenkins, J. S., Abraham, R. R., Beckford, U., Gillham, B. and Jones, M. T.J. Clin. Endocrtnol. Metab. (in press) 3 Makara, G. B. and Stark, E. (1974) Neuroendocrinology 16, 178-190 4 Jones, M. T. and Hillhouse, E. W, (1977)Ann. N Y. Acad. Sci. 297,536-560 5 Acs, Z. and Stark, E. (1978) J. Endocrinol. 77, 137-141 6 Buckingham, J. C and Hodges, J. R. (1979) J. Physiol. (London) 290, 421-431 7 Godin, y . , Heiner, L., Mark, J. and Madel, P. (1969)J Neurochem. 16, 869-873 8 Ke~vm, R. W,, Olpe, H. R. and Schrnutz, M. (1980) Br. J. Pharmacol. 71,545-551 9 Buckingham, J. C. and Hodges, J. R. (1977) J. Physiol. (London) 272,469-479
Drowning in drugs: interesting marine products A recent paper by Shibata and his colleagues a reinforces the view of many that the sea is a vast and poorly tapped container of novel pharmacological agents. The increasing sophistication of synthetic organic chemistry has yet to match nature in the production of peculiar structures with interesting activities. A high percentage of the prescriptions written each year in North America are for natural products or agents closely related to them 2. Many of the pharmaceutical agents used in the West fall into one of the following four categories: (1) substances obtained from natural sources (morphine, quinine, emetine, cardiac glycosides); (2) chemically synthesized agents that were first found as natural products (ephedrine, salicylic acid); (3) simple derivatives of natural products, obtained by chemical modification (oral contraceptive steroids, aspirin and heroin); or (4) synthetic analogues of natural products, first synthesized with the intent of mimicking or antagonizing the action of a natural product (methadone, and many other opiate analogues). It is not coincidence, but historical bias, that all the examples given are from the plant kingdom, and from land plants at that. This is the group that we know most about. They are still the source of 25% of the prescriptions dispensed in the USA. Even within this group, our ignorance is extensive, and the knowledge we have is unevenly distributed. For example, we know more about the plants of temperate climates than we do of the rich complexity of tropical rain forest plants. There are probably well in excess of 500 000 angiosperms, or flowering plants, in the worlds. Only a few of this vast array have been thoroughly explored for biodynamic constituents. Both lay-people and scientists are often surprised when they find how little is known of the chemical constituents of some of the commonest plants in our gardens. Many of the plants that have been culturally exploited for centuries have never had the skimpiest pharmacological, toxicological or chemical evaluation - except for the empirical observation that people do not die within a few minutes of consuming them. For example, comfrey (Symphytum offu;inale) has been cultivated for consumption as a vegetable or drink since the times of classical Greece. Its name (Sympho - to unite) derives from its supposed healing qualifies. It is grown as a cash crop in North America and Europe. It was only in 1980 that analysis showed the presence of toxic (carcinogenic) pyrrolizidine
alkaloids in the planP. The secondary metabolites of plants are a major resource in the search for new drugs. However, the number of unexamined plants is so large that it would be inefficient to pick species at random for investigation. There is a certain logic in choosing plants in the same genera or family as plants with known constituents of interest, but to do this exclusively would prevent the discovery of completely new types of natural products with novel pharmacological actions. A useful point at which to begin examination of plants is the ethno-botany of various cultures. This has been, and should still be, a rich source of pharmacologically significant substances. When we move away from the plant kingdom, our ignorance of pharmacologically active metabolites is even more extensive. Molds, bacteria, and fungi have been explored mainly as sources of antibiotics. A limited number of substances, such as cantharides and cochineal, are obtained from insects. Our ignorance of secondary metabolites is probably most marked, however, when it comes to marine life. Over 70% of the world's surface is covered by sea water. About 80% of all animal species live in or on the water. About 85% of edible plant mass in the world is produced in the seal Marine products are used by many cultures for many purposes, yet ethnic marine medicine is almost unstudied. The simplification of marine flora and fauna through man-induced extinction has probably led to the loss of species we shall never know about, and the concomitant loss of natural products of unusual structure and properties. This loss is the more serious in that we can never know what it was we lost. Who cared much about the fate of an obscure group of Mexican yams (Dioscorea) a few decades ago? Yet from these yams is now produced the starting material for the synthesis of oral contraceptive steroids. The studies that have been done on marine products have resulted in such important agents as tetrodotoxin (from a fish), saxitoxin (from a protozoan dinoflagellate), and carageenan (from algal seaweed). Kainic acid, an important tool for neurochemists and neuropharmacologists, was obtained from an otherwise obscure marine alga, and the cephalosporin antibiotics from a marine fungus, lncidently, more than 1 000 species of dinoflagellates have been identified, of which the toxicity of only four has been examined G. The first symposium on marine toxico1-
© tgs3 Elsev~r$ ¢ ~
Pulfltflt=~B V . Amsterdam 0165-6147183/$0100
TIPS -June 1983
250 ogy and pharmacology was held as recendy as 1960L The increased use of marine products as foods has led to a more practical concern with marine toxins, and now over 1 000 species are known to be toxic. Among the animals unique to the sea are the sponges, phylum Porifera. Over 4 000 species are known. This group has been little studied for chemical constituents, but is known to contain many bioactive substances, including brominated antibiotics. Shibata and his colleagues 1 have been studying okadaic acid (Fig. 1), a substance isolated from a common black sponge (Halichondria). Okadaic acid is described as having a unique molecular structure, which in itself is not unique, as that property is shared by every other compound. However, this polyspiroketal has unusual, or even unique, pharmacological properties. Okadaic acid causes tonic contraction of smooth muscle both in the presence and the absence of calcium. The contraction is slow developing and long lasting. Thus, after four 5-min washouts from human umbilical arteries, the vasoconstrictive action of okadalc acid had not worn off 7 h later. This suggests either that okadaic acid binds tightly, or that it initiates a virtually irreversible process. Tonic contraction is produced in the presence of the calcium chelator, EGTA, or the calcium antagonist, lanthanum, which blocks the movement of calcium across the cell membrane. Furthermore, the calcium, slow-channel antagonists, nifedipine and verapamil, are also without effect. The structure of okadaic acid is reminiscent of the calcium ionophores A23187 and X537A. However, the action of okadaic acid is quite different, in that vasoconstriction produced by calcium ionophores is inhibited in a calcium-free medium, and is abolished and markedly lessened by all the conditions described above. This peculiar action of okadaic acid has yet to be explained. The action is not affected by the a-blocker, phentolamine, an antihistamine, diphenhydramine, or a serotonin antagonist, methysergide. This appears to eliminate the involvement of a-, histamine I-h-, or serotonin-receptors. Tetrodotoxin and procaine, which block the response to electrical stimulation in rabbit aortic strips, do not affect the action of okadaic acid in umbilical artery preparation. Indometacin blocks the aortic response to thromboxane Avlike substances, generated in situ, but like all other agents tried, is without effect on the response to okadaic acid. The authors tested a number of other agents and conditions. The one effect they found was that although the absence of glucose did not alter the response to okadaic
CH5
CH
| 3H
~,~o ^_ f'~ I H H u r ~ _ o L
OH
H C
~I~//CHa
HOOC--C--C--'f'v"l,-,.,.,,'-c-c-?::.,"%v.'V"I" "I I H I I v j -~ k • L .o "-I"o.
HO
3
I
1 o
H H~L_~,'*'
"~
CH 5
Fig. 1 The structure o/okadaic ~id.
acid, the combination of anaerobic conditions and absence of glucose abolished the response to okadaic acid. One observation that may be germane to the action of okadaic acid is that the calcium content of umbilical arteries exposed to okadaic acid for 1 h decreased from 2.25 to 1.96 nmole kg -1 wet weight (sic). These units are probably incorrect, but the point being made is that calcium content falls. This decrease, combined with the absence of an effect of okadaic acid on myosin ATPase, and the lack of effect of the cardiac glycoside, ouabain, on the response to okadaic acid, allows certain tentative conclusions to be reached. First, cell surface calcium which is of supreme importance in the contractile process of cardiac cells, and is also involved in the effects of other pharmacological agents on smooth muscle, is not involved in the response to okadaic acid. As okadalc acid is not altering the responsiveness of myosin ATPase, it must be altering (increasing) the delivery of calcium to this ATPase. All indications are that this calcium comes from an intracellular source. Thus, okadaic acid may alter the handling of calcium by mitochondria, sarcoplasmic reticulum, or other sites within the cell that store calcium. There may be other possibilities. For example, does okadaic acid alter proton transport across the mitochondria, with a resultant effect on cellular pH? There are other studies with okadaic acid it would be interesting to do. What effect does it have on the heart, or on striated muscle? What effect does caffeine, an agent known to release calcium from sarcoplasmic reticulum, have on the response to okadaic acid? Okadaic acid, in its unique pharmacological action, that of producing sustained contractility independent of extracellular calcium, is a foretaste of what may be waiting to be discovered in the sea. Among the known peculiarities of marine pharmacology is the observation that sea water itself has bactericidal and viricidal properties which are lost on heating or storage. Flatworms, ribbonworms, molluscs, snails and other creatures that swim, crawl or squirm through the ocean contain cardioactive substances, some peptide in nature, some not. The information that is known about marine toxicology and pharmacology has been collated into some exceptionally free
books. A stunning collection of color photographs of poisonous fish is contained in Russell's vade mecum, including one of a particularly malevolent Diodon hystrix s. A recent major publication is one by Bruce Halstead 6. 'Marine' is interpreted in a liberal sense, and this volume even includes a section on poisonous polar bears. Poisoning is caused by eating polar bear liver, although I cannot escape a conviction that catching the bear might prove to be a bigger risk than eating it. For those of nervous temperament who may be contemplating a trip to polar bear country, we are assured that, 'polar bear poisoning is of minor public health importance. Intoxication is most likely to occur among uninformed travellers in the Arctic.' The toxicity is due t o . . . On second thoughts, why should I spoil a good mystery? I encourage everyone to examine this marvellous book. A final tidbit of information concerning the pharmacological etymology of the sponge is that the word 'sponge' derives from the Greek root spoggos, which is cognate with the Latin word 'fungus '9. Wasson believes that the Greek root in turn derives from the Finno-Ugfic root pon or penk, a mushroom, or more specifically, fly agaric x°. This mushroom is known to science asAmanita muscaria, which, like the sponges, is a rich source ofpharmacological agents, including muscimole and muscarine. With this, I think I have squeezed the sponge dry. RYAN J. HUXTABLE
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, A Z 85724, USA.
Reading list 1 Shibata, S., Isinda, Y., Kitano, H., Ol~zunu, Y., Habon, J., Tsuldtani, Y. and Kikuchi, H. (1982) J. Pharmacol. Exp. Ther. 223, 135-143 2 Farnswot~, N. R. (1977) in Major Medicinal Plants: Botany, Culture and Uses (Morton, J. F., ed.), pp v-vin, C C Thomas, Springfield, Illinois 3 Schultes, R. E. (1975) in Plants in the Development of Modern Medicine (Swain, T., ed.), pp. 103-124, Harvard University Press, Cambridge, MA and London 4 Culvenor, C. C. J., Clarke, M., Edgar, J. A., Frahn, J. L., Jago, M. V., Peterson, J. E. and Smith, L. W. (1980) Experientia 36, 377-379 5 Marderosian, A. der (1969)J. Pharm. Sci. 58, 1-33 6 Halstead, B. W. (1978)Poisonous and Venom-
251
TIPS -June 1983 ous Marine Animals of the World, Darwin Press 7 Nigrelli, R. F. (ed.) (1960)Ann. N. Y. Acad. Sci. 90, 615-950 8 Russell, F. E. (1971) Marine Toxins and Ven-
omous and Poisonous Marine Animals, "IVH Publicauons, Academic Press, London 9 Shipley, J. T. (1945) Dicaonary of Word Or/g/ns, Philosophical Library, New York
@
Computer Club The world o f pharmacology computing
Computers in pharmacology teaching The use of computers in teaching pharmacology is an immediately attractive proposition. It requires the acquisition of familiarity with an 'in' technology, it holds the prospect of a reduced teaching load and it provides some'body' to blame when students fail to learn!
Benefits Computer-aided teaching allows students to work at times convenient to them and to proceed through material at their own rate; features particularly useful to pharmacology students who may have very different educational backgrounds, timetables and abilities. Material can be provided for small groups; those with poor mathematics or only elementary biology, for example. Students can repeat teaching material as often as necessary to acquire understanding without using staff time. Finally, students enjoy learning through a computer which is relatively anonymous, and more timid students take the risk of making answers without embarrassment or inhibition. Problems Teachers developing computer-aided programs will discover that it is surprisingly difficult to write concise, easily understood material and present it in an interesting and absorbable manner on a video-display unit (VDU). The lecture can be enlivened with an anecdote or gesture; a story which takes only moments to tell and revives flagging interest may occupy several screens-full of text and then seem very unfunny. The lecturer can respond to the mood of the class and though an assessment of the mood of a VDU user can be attempted (by measuring reading speed, response latency and error frequency), such assessments lack sophistication and are uncertain. A teacher using a VDU as an information channel must learn to communicate in a new way, as the skills employed in a lecture are not necessarily those which make for
10 Wasson, R G. (1979) m Ethnopharmacologic Search ]:or Psychoactive Drugs (Efron, D. H., Holmstedt, B and Kline, N . S . , eds), pp. 405,-.414, Raven Press, New York
effective teaching through a VDU. The student also has to ~ and acquire new skills. Facts tend to be diluted and repeated in a verbal delivery while a very concise style is used in computer-aided teaching to reduce the number of words on the screen. Many large computers use involved procedures to obtain access to teaching material. Some students feel that it is pointless to acquire these new skills unless a substantial amount of teaching material is available. Barriers to the initial use oftbe system must be minimal; once familiar with the procedures students use the system freely but the initial step into unfamiliar ground must be as easy as possible. Types of program
Simulations Where biological systems can be defined by mathematical relationships a simulation can greatly increase a student's understanding. The absorption, distribution, metabolism and excretion of drugs are very amenable to this treatment. Colour graphics produce impressive illustrations through which students obtain insight into the interdependence of these processes in biological systems and their relevance to successful drug use. My own experience has been with simulations of simple isolated tissues, but more complex systems would be interesting, e.g. the cardiovascular system. Simulations should never replace practical experience, but, used in conjunction with practicals, they extend students' knowledge and experience. Should an experiment fail, mock data may be obtained from a simulation and then processed in the normal way. Correct experimental designs and the inclusion of appropriate control experiments may be limited by time constraints in practical classes but can be given more prominence in simulations as responses are obtained quickly and antagonists removed easily. Simulations should not place unueces-
sary restraints on students' conceptions or curiosity. Thus, in my guinea-pig ileum simulation, it is possible to 'add' a great variety of agonists in any concentration or sequence and in the presence or absence of a variety of antagonists, again, at any concentration. The interactions must be quantitatively correct and enable, for example, p,M values to be obtained as well as 'unknown' agents to be characterized. These simulations increase understanding in a variety of fields and, like the practical experiments they emulate, do not simply allow a student to learn the characteristics of the preparation being used.
Programmed learning Large lumps of text are difficult to read, absorb and manipulate on a VDU. Such presentations are better made on printed sheets and understanding can then be aided or examined by the computer. Many systems based on text present& tion start with questions which establish the existing level of knowledge. At some point along the main line of questions the user gives an incorrect answer and is then deflected into a loop in which questions and text information attempt to teach the missing knowledge. The loop returns the student to the main line of questions to which correct responses should now be given; if not, a second, more extensive loop should exist. Loops may exist within loops and these programs are complex, permit no deviation from the path mapped by the teacher and often fail to anticipate all possibilities; hence the well-used message 'I am a small computer and cannot explain more clearly - consult your lecturer' and other, more forthright, comments.
Simple question and answer This by-passes many complexities referred to above; any format of multiple choice question (MCQ) is possible although I have chosen to use the 'stem and five completions'. The question is presented, the answer to each completion is elicited and then marked. Knowledge of the correct answers may enable the student to appreciate any error, but an explanation of the answers is
© 1983ElsewefSciencePubhshersB.V , ~
0165- 6147/83/$01130