- Email: [email protected]
Fibrillin and Marfan's syndrome: a real clue?
973
disturbing cellular energy metabolism. In: Schultheiss H-P, ed. New concepts in viral heart disease. Berlin: Springer, 1988: 243-58. 21. Yousef GE, Bell EJ, Mann GF, et al. Chronic enterovirus infection in patients with postviral fatigue syndrome. Lancet 1988; i: 146-50. 22. Schönian U, Maisch B. Cytomegalovirus DNA in endomyocardial biopsies of patients with (peri) myocarditis. Presented at 2nd International Symposium on Inflammatory Heart Disease, Marburg, FRG, June, 1990. 23. Calabrese LH, Proffitt MR, Yen-Lieberman B, Hobbs RE, Ratliff NB. Congestive cardiomyopathy and illness related to the acquired immune deficiency syndrome (AIDS). Association with isolation of retrovirus from myocardium. Ann Intern Med 1987; 107: 691-92.
Fibrillin and Marfan’s syndrome: a real clue? Marfan’s syndrome, a heritable multisystem disorder with a variable phenotype, is serious largely because of its cardiovascular complications, which cause 95% of deaths in patients with the condition and reduce mean life expectancy by up to 40%.1-3 Although the clinical features suggest that an important component of connective tissue is structurally unsound, the search for its identity has been fruitless, despite some isolated observations.4,s Since linkage analysis with restriction fragment length polymorphisms has excluded the genes for the major structural collagens,6-9 and less clearly those for clastin," as mutant loci, attention must turn elsewhere. A promising signpost points to the microfibrillar system. This system is widely distributed in the extracellular space, often in association with elastin, but also on its own, especially in the ciliary zonule (the suspensory ligament of the lens.)11,12 Fibrillin is a component of these elastin-associated fibrils, which also contain several glycoproteins. 13,14 Hollister and his colleagues have raised antibodies specific to fibrillin, which allow detection of this substance by indirect immunofluorescence. Using two such antibodies, they have shown that in both skin sections and dermal fibroblasts grown from patients with Marfan’s syndrome there is a striking lack of fibrillin compared with normal subjects .15 " By immunofluorescence contrast, staining with monoclonal antibodies to collagen III, IV, VI, and VII shows no such deficiency. Moreover, this fibrillin deficiency appears to segregate in Marfan families, where it is confined to affected members. In a patient with unilateral features of Marfan’s syndrome, attributed to a post-zygotic mutation, fibrillin was deficient only in tissues from the affected side.18 A single-blind study has now been conducted in which specimens from patients with Marfan’s syndrome and other connective tissue disorders and from normal subjects seen at Johns Hopkins Hospital, Baltimore, were analysed in Portland, Oregon. 16 Of 27 Marfan patients, 24 were correctly identified by the decreased content of microfibrillar fibres in the skin, cultured fibroblasts, or both; 19 of 25 subjects with other heritable disorders of connective tissue and all 13 normal subjects were identified as non-Marfan by
these assays.
Marfan’s syndrome is heterogeneous. Apart from variable tissue expression it may easily have more than This one cause and one mutant gene locus. lack was not could fibrillin heterogeneity explain why found in all patients, but cannot account for those rare instances when a deficiency in the skin is not confirmed by fibroblast culture, or vice versa (both tests were done in only 14 Marfan patients). The Marfan-positive results in some of the patients with non-Marfan inherited connective tissue disorders are not easily explained; such cases included a patient with homocystinuria, which is clinically very similar to Marfan’s syndrome. If a lack of microfibrils (and more specifically fibrillin) is almost constantly associated with Marfan’s syndrome, how does this come about and where should we go from here? The distribution of microfibrils corresponds closely to the tissues affected in Marfan’s syndrome. Microfibrils per se probably have little strength. One tissue in which they are the main component is the suspensory ligament of the lens-hence the tendency to lens dislocation in the syndrome. (It is interesting that for many years the ocular zonules were thought to be composed of a form of collagen.12) In other elastin-containing tissues microfibrillar deficiency could predispose to slow aortic dilatation and rupture. The distribution of the microfibrillar fibres could also account for the striae of the skin, the pulmonary bullae, the dural ectasia, and even the skeletal overgrowth (due to the diminished forces generated by the perichondrial and periosteal membranes which normally limit bone growth.16) Is fibrillin deficiency a real clue? It provides a neat and plausible explanation for Marfan’s syndrome, but at its best is unlikely to account for all affected patients. 20 We need to find out much more about the chemistry of the microfibrils and the genes that control their synthesis. We also need to take note of a new Finnish study of five informative Marfan families which provides strong evidence that the mutant gene (or genes) is on chromosome 15.21 What, if any, is the relation between fibrillin deficiency and chromosome 15? Whatever the answer, we suddenly have far more information about the likely cause of Marfan’s
syndrome. Pyeritz RE, McKusick VA. The Marfan syndrome: diagnosis and management. N Engl J Med 1979; 300: 772-77. 2. Pyeritz RE. Marfan syndrome. In: Emery AEH, Rimoin DL, eds. Principles and practice of medical genetics. 2nd ed. New York: Churchill Livingstone (in press). 3. Murdoch JL, Walker BA, Halpern BL. Life expectancy and causes of death in the Marfan syndrome. N Engl J Med 1972; 286: 804-08. 4. Boucek RJ, Noble NL, Gunga-Smith Z, Butler WT. The Marfan syndrome: a deficiency in chemically stable collagen cross links. N Engl J Med 1981; 305: 988-91. 5. Byers PH, Seigel RC, Peterson KE, et al. Marfan syndrome: abnormal alpha 2 chain in type I collagen. Proc Natl Acad Sci USA 1981; 78: 1.
7745-49. 6.
Tsipouras P, Borresen A-L, Bamforth S, Harper PS, Berg K. Marfan syndrome: exclusion of genetic linkage to the COLIA2 gene. Clin Genet
7.
Dalgleish R, Hawkins JR, Keston M. Exclusion of the alpha 2(I) and alpha 1(III) collagen genes as the mutant loci in a Marfan syndrome family. J Med Genet 1987; 24: 148-51.
1986; 30: 428-32.
974
8.
Ogilvie DJ, Wordsworth P, Priestley LM, et al. Segregation of all four major fibrillar collagen genes in the Marfan syndrome. Am J Hum
Genet 1987; 41: 1071-82. 9. Francomano CA, Streeten EA, Meyers DA, Pyeritz RE. Marfan syndrome: exclusion of genetic linkage to three major collagen genes. Am J Med Genet 1988; 29: 457-62. 10. Huttunen K, Kaitila I, Savolainen A, Palotie A, Peltonen L. The linkage analysis with RFLP markers of elastin and type III collagen genes in Finnish Marfan families. Am J Med Genet 1989; 32: 244 (abstr). 11. Low FN. Microfibrils: fine filamentous components of the tissue space. Anat Rec 1962; 142: 131-37. 12. Raviola G. The fine structure of the ciliary zonule and ciliary epithelium. Invest Ophthalmol 1971; 10: 851-69. 13. Streeten BW, Swann DA, Licari PA, et al. The protein composition of the ocular zonules. Invest Ophthalmol Vis Sci 1983; 24: 119-23. 14. Colombatti A, Bonaldo P, Volpin D, Bressan GM. The elastin associated glycoprotein gp 115. J Biol Chem 1988; 263: 17534-40. 15. Hollister DW, Godfrey MP, Keene DR, Sakai LY, Pyeritz RE. Marfan syndrome: abnormalities of the microfibrillar array detected by immunohistopathologic studies. Am J Med Genet 1989; 32: 244 (abstr). 16. Hollister DW, Godfrey M, Sakai LY, Pyeritz RE. Immunohistologic abnormalities of the microfibrillar-fiber system in the Marfan syndrome. N Engl J Med 1990; 323: 152-59. 17. Godfrey M, Menashe V, Weleber RG, et al. Cosegregation of
elastin-associated microfibrillar abnormalities with the Marfan phenotype in families. Am J Hum Genet 1990; 46: 652-60. 18. Godfrey M, Olson S, Burgio RG, et al. Unilateral microfibrillar abnormalities in a case of asymmetric Marfan syndrome. Am J Hum Genet 1990; 46: 661-71. 19. Beighton P, de Paepe A, Danks D, et al. International nosology of heritable disorders of connective tissue, Berlin, 1986. Am J Med Genet 1988; 29: 581-94. 20. Tsipouras P. Marfan syndrome: light at the end of the tunnel? Am J Hum Genet 1990; 46: 643-45. 21. Kainulainen K, Pulkkinen L, Savolainen A, Kaitila I, Peltonen L. Location on chromosome 15 of the gene defect causing Marfan syndrome. N Engl J Med 1990; 323: 935-39.
HASTENING GUT TRANSIT known to modulate the function of the gut, and new agents are being developed that enhance gastrointestinal motor function and accelerate transit. These drugs will offer a wider variety of therapeutic approaches for the numerous conditions in which gut hypomotility is a symptom-inducing component--eg, oesophageal reflux, with inefficient clearance of gastric acid; poor gastric emptying after surgery or in diabetes; small bowel hypomotility of pseudo-obstruction; and slow colonic transit in some patients with constipation. These so-called prokinetic agents are likely to find a wider market in the treatment of nausea and vomiting, and possibly of other gastrointestinal symptoms. Functional alterations of muscarinic, dopaminergic, motilin, and cholecystokinin receptors are other promising avenues.’ Gastrointestinal motor activity is the end result of convergent signals from the enteric nervous system; activity is modified by extrinsic innervation from vagal and sympathetic fibres, hormonal activity, and intrinsic reflex arcs. Much of the excitatory input of the enteric nervous system to the gastrointestinal smooth muscle is via muscarinic receptors activated by acetylcholine. Ordered firing of these neurons, with neural control of propagation, seems to lead to propulsive contractions. Bethanechol, a muscarinic agonist, has been used to stimulate contractions, but with limited clinical success.2 The dopamine antagonists metoclopramide and domperidone exert their prokinetic action by enhancing smooth muscle activity by two mechanisms: they block inhibitory type 1 dopamine receptors on smooth muscle cells and they also block dopaminergic inhibitory modulation of enteric neuronal acetylcholine release via type 2 dopamine receptors.3 Motilin is now known to induce bursts of intense
Many receptor types
are now
in the stomach and small bowel that resemble the activity of phase IIIin the fasting state. Phase III of the interdigestive complex is the main migrating complex which results in a coordinated propulsive contraction down the small bowel every 90-120 min during fasting; this peak of reflex activity coincides with peaks of serum motilin. Motilin probably stimulates excitatory myenteric receptors directly and also releases acetylcholine via a vasovagal reflex.4 Cholecystokinin (CCK) receptors are present on smooth muscle cells of the gallbladder, stomach, small intestine, and colon. CCK acts directly on smooth muscle receptors and indirectly by release of acetylcholine.CCK infusions inhibit gastric emptying of a saline drink and CCK analogues accelerate small intestinal transit. CCK stimulates contractions of muscle strips from human taenia coli and increases the frequency of electrical spike potentials in human colon. Cisapride exerts its prokinetic action by enhancing release of acetylcholine from enteric neurons; the mechanism of action has not been established. This agent heals mild oesophagitis by improving the clearance of refluxate, by increasing lower oesophageal sphincter tone, and by enhancing gastric emptying. At a dose of 10 mg four times a day it is as efficacious as ranitidine 150 mg twice daily.’The hastening of gastric emptying leads to symptomatic benefit in patients with diabetic gastroparesisf there is little evidence of benefit in non-diabetics. In small studies cisapride reduced symptoms in patients with non-ulcer dyspepsia but it is probably no better in this respect than
propulsive motor activity
metoclopramide8
or
domperidone.9 Constipated patients
may benefit from regular cisapride (5-10 mg three times a day); increased stool frequency and consistency" and reduced laxative use" have been reported. The drug has not been compared with other treatments. Intravenous infusions of erythromycin and related macrolides cause a burst of motor activity in the gut similar to phase III activity. Macrolides are now known to act as motilin receptor agonists.12 The high density of motilin receptors in the stomach and duodenum suggested that these agents might increase gastric emptying, as has now been shown for patients with diabetic gastroparesis, both for single intravenous doses and to a lesser extent with four weeks’ oral treatment.13 Tachyphylaxis may develop, but to what degree is unclear. Erythromycin-induced stimulation of phase IIIactivity has also been documented in the upper gut of patients with small bowel hypomotility due to chronic intestinal pseudo-obstruction; clinical evidence of benefit has not been established. Motilin receptors have been found in the colon. In normal subjects erythromycin increases the frequency of bowel actions by 50% .14 This action may prove useful in patients with constipation. Loxiglumide is a potent and specific antagonist for CCK and its effects on gut motility have been assessed in healthy young men. It blocks gallbladder contraction, accelerates gastric emptying, and shortens colonic transit time but does not appear to have an effect on small bowel transit time.15 Research interest in prokinetic agents has focused on the possible benefits in patients with rare conditions. The place of these drugs in reflux oesophagitis is probably in patients
who do
respond to H2 antagonists, although high-dose H2 antagonists or proton-pump inhibitors are potent not
alternatives. Good controlled trials are needed before such agents are adopted in patients with troublesome but not life-threatening conditions such as reflux oesophagitis and irritable bowel syndrome.
disturbing cellular energy metabolism. In: Schultheiss H-P, ed. New concepts in viral heart disease. Berlin: Springer, 1988: 243-58. 21. Yousef GE, Bell EJ, Mann GF, et al. Chronic enterovirus infection in patients with postviral fatigue syndrome. Lancet 1988; i: 146-50. 22. Schönian U, Maisch B. Cytomegalovirus DNA in endomyocardial biopsies of patients with (peri) myocarditis. Presented at 2nd International Symposium on Inflammatory Heart Disease, Marburg, FRG, June, 1990. 23. Calabrese LH, Proffitt MR, Yen-Lieberman B, Hobbs RE, Ratliff NB. Congestive cardiomyopathy and illness related to the acquired immune deficiency syndrome (AIDS). Association with isolation of retrovirus from myocardium. Ann Intern Med 1987; 107: 691-92.
Fibrillin and Marfan’s syndrome: a real clue? Marfan’s syndrome, a heritable multisystem disorder with a variable phenotype, is serious largely because of its cardiovascular complications, which cause 95% of deaths in patients with the condition and reduce mean life expectancy by up to 40%.1-3 Although the clinical features suggest that an important component of connective tissue is structurally unsound, the search for its identity has been fruitless, despite some isolated observations.4,s Since linkage analysis with restriction fragment length polymorphisms has excluded the genes for the major structural collagens,6-9 and less clearly those for clastin," as mutant loci, attention must turn elsewhere. A promising signpost points to the microfibrillar system. This system is widely distributed in the extracellular space, often in association with elastin, but also on its own, especially in the ciliary zonule (the suspensory ligament of the lens.)11,12 Fibrillin is a component of these elastin-associated fibrils, which also contain several glycoproteins. 13,14 Hollister and his colleagues have raised antibodies specific to fibrillin, which allow detection of this substance by indirect immunofluorescence. Using two such antibodies, they have shown that in both skin sections and dermal fibroblasts grown from patients with Marfan’s syndrome there is a striking lack of fibrillin compared with normal subjects .15 " By immunofluorescence contrast, staining with monoclonal antibodies to collagen III, IV, VI, and VII shows no such deficiency. Moreover, this fibrillin deficiency appears to segregate in Marfan families, where it is confined to affected members. In a patient with unilateral features of Marfan’s syndrome, attributed to a post-zygotic mutation, fibrillin was deficient only in tissues from the affected side.18 A single-blind study has now been conducted in which specimens from patients with Marfan’s syndrome and other connective tissue disorders and from normal subjects seen at Johns Hopkins Hospital, Baltimore, were analysed in Portland, Oregon. 16 Of 27 Marfan patients, 24 were correctly identified by the decreased content of microfibrillar fibres in the skin, cultured fibroblasts, or both; 19 of 25 subjects with other heritable disorders of connective tissue and all 13 normal subjects were identified as non-Marfan by
these assays.
Marfan’s syndrome is heterogeneous. Apart from variable tissue expression it may easily have more than This one cause and one mutant gene locus. lack was not could fibrillin heterogeneity explain why found in all patients, but cannot account for those rare instances when a deficiency in the skin is not confirmed by fibroblast culture, or vice versa (both tests were done in only 14 Marfan patients). The Marfan-positive results in some of the patients with non-Marfan inherited connective tissue disorders are not easily explained; such cases included a patient with homocystinuria, which is clinically very similar to Marfan’s syndrome. If a lack of microfibrils (and more specifically fibrillin) is almost constantly associated with Marfan’s syndrome, how does this come about and where should we go from here? The distribution of microfibrils corresponds closely to the tissues affected in Marfan’s syndrome. Microfibrils per se probably have little strength. One tissue in which they are the main component is the suspensory ligament of the lens-hence the tendency to lens dislocation in the syndrome. (It is interesting that for many years the ocular zonules were thought to be composed of a form of collagen.12) In other elastin-containing tissues microfibrillar deficiency could predispose to slow aortic dilatation and rupture. The distribution of the microfibrillar fibres could also account for the striae of the skin, the pulmonary bullae, the dural ectasia, and even the skeletal overgrowth (due to the diminished forces generated by the perichondrial and periosteal membranes which normally limit bone growth.16) Is fibrillin deficiency a real clue? It provides a neat and plausible explanation for Marfan’s syndrome, but at its best is unlikely to account for all affected patients. 20 We need to find out much more about the chemistry of the microfibrils and the genes that control their synthesis. We also need to take note of a new Finnish study of five informative Marfan families which provides strong evidence that the mutant gene (or genes) is on chromosome 15.21 What, if any, is the relation between fibrillin deficiency and chromosome 15? Whatever the answer, we suddenly have far more information about the likely cause of Marfan’s
syndrome. Pyeritz RE, McKusick VA. The Marfan syndrome: diagnosis and management. N Engl J Med 1979; 300: 772-77. 2. Pyeritz RE. Marfan syndrome. In: Emery AEH, Rimoin DL, eds. Principles and practice of medical genetics. 2nd ed. New York: Churchill Livingstone (in press). 3. Murdoch JL, Walker BA, Halpern BL. Life expectancy and causes of death in the Marfan syndrome. N Engl J Med 1972; 286: 804-08. 4. Boucek RJ, Noble NL, Gunga-Smith Z, Butler WT. The Marfan syndrome: a deficiency in chemically stable collagen cross links. N Engl J Med 1981; 305: 988-91. 5. Byers PH, Seigel RC, Peterson KE, et al. Marfan syndrome: abnormal alpha 2 chain in type I collagen. Proc Natl Acad Sci USA 1981; 78: 1.
7745-49. 6.
Tsipouras P, Borresen A-L, Bamforth S, Harper PS, Berg K. Marfan syndrome: exclusion of genetic linkage to the COLIA2 gene. Clin Genet
7.
Dalgleish R, Hawkins JR, Keston M. Exclusion of the alpha 2(I) and alpha 1(III) collagen genes as the mutant loci in a Marfan syndrome family. J Med Genet 1987; 24: 148-51.
1986; 30: 428-32.
974
8.
Ogilvie DJ, Wordsworth P, Priestley LM, et al. Segregation of all four major fibrillar collagen genes in the Marfan syndrome. Am J Hum
Genet 1987; 41: 1071-82. 9. Francomano CA, Streeten EA, Meyers DA, Pyeritz RE. Marfan syndrome: exclusion of genetic linkage to three major collagen genes. Am J Med Genet 1988; 29: 457-62. 10. Huttunen K, Kaitila I, Savolainen A, Palotie A, Peltonen L. The linkage analysis with RFLP markers of elastin and type III collagen genes in Finnish Marfan families. Am J Med Genet 1989; 32: 244 (abstr). 11. Low FN. Microfibrils: fine filamentous components of the tissue space. Anat Rec 1962; 142: 131-37. 12. Raviola G. The fine structure of the ciliary zonule and ciliary epithelium. Invest Ophthalmol 1971; 10: 851-69. 13. Streeten BW, Swann DA, Licari PA, et al. The protein composition of the ocular zonules. Invest Ophthalmol Vis Sci 1983; 24: 119-23. 14. Colombatti A, Bonaldo P, Volpin D, Bressan GM. The elastin associated glycoprotein gp 115. J Biol Chem 1988; 263: 17534-40. 15. Hollister DW, Godfrey MP, Keene DR, Sakai LY, Pyeritz RE. Marfan syndrome: abnormalities of the microfibrillar array detected by immunohistopathologic studies. Am J Med Genet 1989; 32: 244 (abstr). 16. Hollister DW, Godfrey M, Sakai LY, Pyeritz RE. Immunohistologic abnormalities of the microfibrillar-fiber system in the Marfan syndrome. N Engl J Med 1990; 323: 152-59. 17. Godfrey M, Menashe V, Weleber RG, et al. Cosegregation of
elastin-associated microfibrillar abnormalities with the Marfan phenotype in families. Am J Hum Genet 1990; 46: 652-60. 18. Godfrey M, Olson S, Burgio RG, et al. Unilateral microfibrillar abnormalities in a case of asymmetric Marfan syndrome. Am J Hum Genet 1990; 46: 661-71. 19. Beighton P, de Paepe A, Danks D, et al. International nosology of heritable disorders of connective tissue, Berlin, 1986. Am J Med Genet 1988; 29: 581-94. 20. Tsipouras P. Marfan syndrome: light at the end of the tunnel? Am J Hum Genet 1990; 46: 643-45. 21. Kainulainen K, Pulkkinen L, Savolainen A, Kaitila I, Peltonen L. Location on chromosome 15 of the gene defect causing Marfan syndrome. N Engl J Med 1990; 323: 935-39.
HASTENING GUT TRANSIT known to modulate the function of the gut, and new agents are being developed that enhance gastrointestinal motor function and accelerate transit. These drugs will offer a wider variety of therapeutic approaches for the numerous conditions in which gut hypomotility is a symptom-inducing component--eg, oesophageal reflux, with inefficient clearance of gastric acid; poor gastric emptying after surgery or in diabetes; small bowel hypomotility of pseudo-obstruction; and slow colonic transit in some patients with constipation. These so-called prokinetic agents are likely to find a wider market in the treatment of nausea and vomiting, and possibly of other gastrointestinal symptoms. Functional alterations of muscarinic, dopaminergic, motilin, and cholecystokinin receptors are other promising avenues.’ Gastrointestinal motor activity is the end result of convergent signals from the enteric nervous system; activity is modified by extrinsic innervation from vagal and sympathetic fibres, hormonal activity, and intrinsic reflex arcs. Much of the excitatory input of the enteric nervous system to the gastrointestinal smooth muscle is via muscarinic receptors activated by acetylcholine. Ordered firing of these neurons, with neural control of propagation, seems to lead to propulsive contractions. Bethanechol, a muscarinic agonist, has been used to stimulate contractions, but with limited clinical success.2 The dopamine antagonists metoclopramide and domperidone exert their prokinetic action by enhancing smooth muscle activity by two mechanisms: they block inhibitory type 1 dopamine receptors on smooth muscle cells and they also block dopaminergic inhibitory modulation of enteric neuronal acetylcholine release via type 2 dopamine receptors.3 Motilin is now known to induce bursts of intense
Many receptor types
are now
in the stomach and small bowel that resemble the activity of phase IIIin the fasting state. Phase III of the interdigestive complex is the main migrating complex which results in a coordinated propulsive contraction down the small bowel every 90-120 min during fasting; this peak of reflex activity coincides with peaks of serum motilin. Motilin probably stimulates excitatory myenteric receptors directly and also releases acetylcholine via a vasovagal reflex.4 Cholecystokinin (CCK) receptors are present on smooth muscle cells of the gallbladder, stomach, small intestine, and colon. CCK acts directly on smooth muscle receptors and indirectly by release of acetylcholine.CCK infusions inhibit gastric emptying of a saline drink and CCK analogues accelerate small intestinal transit. CCK stimulates contractions of muscle strips from human taenia coli and increases the frequency of electrical spike potentials in human colon. Cisapride exerts its prokinetic action by enhancing release of acetylcholine from enteric neurons; the mechanism of action has not been established. This agent heals mild oesophagitis by improving the clearance of refluxate, by increasing lower oesophageal sphincter tone, and by enhancing gastric emptying. At a dose of 10 mg four times a day it is as efficacious as ranitidine 150 mg twice daily.’The hastening of gastric emptying leads to symptomatic benefit in patients with diabetic gastroparesisf there is little evidence of benefit in non-diabetics. In small studies cisapride reduced symptoms in patients with non-ulcer dyspepsia but it is probably no better in this respect than
propulsive motor activity
metoclopramide8
or
domperidone.9 Constipated patients
may benefit from regular cisapride (5-10 mg three times a day); increased stool frequency and consistency" and reduced laxative use" have been reported. The drug has not been compared with other treatments. Intravenous infusions of erythromycin and related macrolides cause a burst of motor activity in the gut similar to phase III activity. Macrolides are now known to act as motilin receptor agonists.12 The high density of motilin receptors in the stomach and duodenum suggested that these agents might increase gastric emptying, as has now been shown for patients with diabetic gastroparesis, both for single intravenous doses and to a lesser extent with four weeks’ oral treatment.13 Tachyphylaxis may develop, but to what degree is unclear. Erythromycin-induced stimulation of phase IIIactivity has also been documented in the upper gut of patients with small bowel hypomotility due to chronic intestinal pseudo-obstruction; clinical evidence of benefit has not been established. Motilin receptors have been found in the colon. In normal subjects erythromycin increases the frequency of bowel actions by 50% .14 This action may prove useful in patients with constipation. Loxiglumide is a potent and specific antagonist for CCK and its effects on gut motility have been assessed in healthy young men. It blocks gallbladder contraction, accelerates gastric emptying, and shortens colonic transit time but does not appear to have an effect on small bowel transit time.15 Research interest in prokinetic agents has focused on the possible benefits in patients with rare conditions. The place of these drugs in reflux oesophagitis is probably in patients
who do
respond to H2 antagonists, although high-dose H2 antagonists or proton-pump inhibitors are potent not
alternatives. Good controlled trials are needed before such agents are adopted in patients with troublesome but not life-threatening conditions such as reflux oesophagitis and irritable bowel syndrome.