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Shellfish toxin points to cystic fibrosis therapy
SCIENCE AND MEDICINE
Shellfish toxin points to cystic fibrosis therapy
A
n analogue of okadaic acid, a diarrhoea-inducing shellfish toxin, could be put to use in the treatment of cystic fibrosis (CF), says Stephen Shears of the Laboratory of Signal Transduction, US National Institute of Environmental Health Sciences (Research Triangle Park, NC, USA). “We knew that okadaic acid stimulates fluid flow in the gut”, he notes, “and thought that maybe, if we understood the mechanism, we could get it to work in another tissue—namely, the lung”. In CF, a genetic defect blocks a major pathway of salt and fluid output in airway epithelial cells, leading to a build-up of dehydrated mucus in the lungs, and susceptibility to bacterial infection. Drugs have been developed to stimulate fluid secretion via a second, viable, pathway involving calcium-dependent chloride channels, but such agents are thwarted by the action of a naturally occurring enzyme inositol 3,4,5,6-tetrakisphosphate [Ins(3,4,5,6)P4], which inhibits this
pathway to help conserve fluid. Shears and colleagues studied single cells in vitro, and found that okadaic acid prevents the Ins(3,4,5,6)P4-inhibition of the calcium-dependent chloride channels, thus defeating the body’s fluid conservation mechanism (J Physiol 1998; 510: 661–73). The team are now trying to reproduce these effects in an epithelial layer of CF cells. “If that works, the next step is to interest a pharmaceutical company in identifying an analogue of okadaic acid without toxic effects”, for possible use as CF therapy. Shears notes that the same mechanism could be used in reverse. For example, drugs could be developed that increase inhibition of the calcium-dependent chloride channels by Ins(3,4,5,6)P4 or other mechanisms. Such agents could be useful in the treatment of salmonella infection, which causes excessive salt and fluid secretion in the form of chronic diarrhoea. Marilynn Larkin
Mitosis does occur in adult cardiac myocytes new study has challenged the longstanding belief that adult ventricular myocytes are terminally differentiated cells and therefore incapable of division, by revealing that mitotic division occurs in healthy and diseased hearts. Tissue was collected from 12 patients undergoing heart transplantation for ischaemic heart disease and 15 patients with idiopathic dilated cardiomyopathy. A further nine control specimens were obtained at necropsy of individuals who died of causes other than cardiovascular disease (Proc Natl Acad Sci USA 1998: 95; 8801–05). Using immunocytochemistry and confocal microscopic analysis, Jan Kajstura and colleagues (New York Medical College, Valhalla, NY, USA) found that 14 myocytes per million were in mitosis in the control specimens. About ten times this number of dividing cells were found in samples taken from patients with idiopathic dilated
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cardiomyopathy (131 per 106) and marginally more in those from patients with end-stage ischaemic heart disease (152 per 106). The original dogma is that a person attains an adult number of myocytes within a few months of birth and that these contract on average 70 times per minute throughout life. Myocytes must therefore be structurally and functionally immortal which, the authors say, “contradicts the concept of cellular aging, programmed cell death, and the logic of a slow turnover of cells with the progression of life”. The team calculate that, because mitosis lasts for less than 1 hour, 0·61 x 109 myocytes could be formed in a healthy left ventricle each year, which is roughly one-tenth of the total number (5·8 x 109) found in the average heart of a 45-year-old man. Peter Moore
News in brief Early enoxaparin benefits A study of 68 patients with nonQ-wave myocardial infarction or unstable angina has found a significant benefit from enoxaparin treatment compared with heparin in reducing death, myocardial infarction, recurrent angina, or revascularisation in the first 30 days (nine vs 17 patients, p=0·04). In the first 48 hours, the rise in plasma von Willebrand factor (vWF) was “a significant and independent predictor of the composite end point” at both 14 and 30 days. The early increase in vWF was significantly less frequent and severe in patients who received enoxaparin compared with those treated with heparin (Circulation 1998: 98: 294–99). Cervical cancer concerns 1036 women have been recalled for further assessment after concerns over the management of patients with moderately or severely abnormal cervical smear tests were raised at St George’s Hospital (London, UK). The controversy centres on the standard of management after colposcopic examination. The recalled women are thought to have had either no biopsies done or inadequate loop excision biopsies. Viagra deaths report From late March through June, 1998, the US FDA received 77 reports of deaths associated with the anti-impotence drug, sildenafil. Of the 39 US patients whose deaths were verified, all were men (mean age 66 years, range 48–67), 24 had cardiac events, two had strokes, and 13 died of unknown causes. Six men were coadministered a nitrate drug, and 14 died or developed symptoms leading to death during or within 2 hours of sexual activity, said FDA. Toothache in sickle-cell disease Painful crises are common in sicklecell disease (SCD). But in such patients, is orofacial pain a sign of sickling or dental disease? In a casecontrol study, 49% of patients with SCD compared with 8% of controls had had maxillary or mandibular pain in the previous 12 months. 68% of SCD patients with such pain had no dental pathology whereas no controls had pain in the absence of dental pathology (Br Dent J 1998; 185: 90–92).
THE LANCET • Vol 352 • August 1, 1998
Shellfish toxin points to cystic fibrosis therapy
A
n analogue of okadaic acid, a diarrhoea-inducing shellfish toxin, could be put to use in the treatment of cystic fibrosis (CF), says Stephen Shears of the Laboratory of Signal Transduction, US National Institute of Environmental Health Sciences (Research Triangle Park, NC, USA). “We knew that okadaic acid stimulates fluid flow in the gut”, he notes, “and thought that maybe, if we understood the mechanism, we could get it to work in another tissue—namely, the lung”. In CF, a genetic defect blocks a major pathway of salt and fluid output in airway epithelial cells, leading to a build-up of dehydrated mucus in the lungs, and susceptibility to bacterial infection. Drugs have been developed to stimulate fluid secretion via a second, viable, pathway involving calcium-dependent chloride channels, but such agents are thwarted by the action of a naturally occurring enzyme inositol 3,4,5,6-tetrakisphosphate [Ins(3,4,5,6)P4], which inhibits this
pathway to help conserve fluid. Shears and colleagues studied single cells in vitro, and found that okadaic acid prevents the Ins(3,4,5,6)P4-inhibition of the calcium-dependent chloride channels, thus defeating the body’s fluid conservation mechanism (J Physiol 1998; 510: 661–73). The team are now trying to reproduce these effects in an epithelial layer of CF cells. “If that works, the next step is to interest a pharmaceutical company in identifying an analogue of okadaic acid without toxic effects”, for possible use as CF therapy. Shears notes that the same mechanism could be used in reverse. For example, drugs could be developed that increase inhibition of the calcium-dependent chloride channels by Ins(3,4,5,6)P4 or other mechanisms. Such agents could be useful in the treatment of salmonella infection, which causes excessive salt and fluid secretion in the form of chronic diarrhoea. Marilynn Larkin
Mitosis does occur in adult cardiac myocytes new study has challenged the longstanding belief that adult ventricular myocytes are terminally differentiated cells and therefore incapable of division, by revealing that mitotic division occurs in healthy and diseased hearts. Tissue was collected from 12 patients undergoing heart transplantation for ischaemic heart disease and 15 patients with idiopathic dilated cardiomyopathy. A further nine control specimens were obtained at necropsy of individuals who died of causes other than cardiovascular disease (Proc Natl Acad Sci USA 1998: 95; 8801–05). Using immunocytochemistry and confocal microscopic analysis, Jan Kajstura and colleagues (New York Medical College, Valhalla, NY, USA) found that 14 myocytes per million were in mitosis in the control specimens. About ten times this number of dividing cells were found in samples taken from patients with idiopathic dilated
A
376
cardiomyopathy (131 per 106) and marginally more in those from patients with end-stage ischaemic heart disease (152 per 106). The original dogma is that a person attains an adult number of myocytes within a few months of birth and that these contract on average 70 times per minute throughout life. Myocytes must therefore be structurally and functionally immortal which, the authors say, “contradicts the concept of cellular aging, programmed cell death, and the logic of a slow turnover of cells with the progression of life”. The team calculate that, because mitosis lasts for less than 1 hour, 0·61 x 109 myocytes could be formed in a healthy left ventricle each year, which is roughly one-tenth of the total number (5·8 x 109) found in the average heart of a 45-year-old man. Peter Moore
News in brief Early enoxaparin benefits A study of 68 patients with nonQ-wave myocardial infarction or unstable angina has found a significant benefit from enoxaparin treatment compared with heparin in reducing death, myocardial infarction, recurrent angina, or revascularisation in the first 30 days (nine vs 17 patients, p=0·04). In the first 48 hours, the rise in plasma von Willebrand factor (vWF) was “a significant and independent predictor of the composite end point” at both 14 and 30 days. The early increase in vWF was significantly less frequent and severe in patients who received enoxaparin compared with those treated with heparin (Circulation 1998: 98: 294–99). Cervical cancer concerns 1036 women have been recalled for further assessment after concerns over the management of patients with moderately or severely abnormal cervical smear tests were raised at St George’s Hospital (London, UK). The controversy centres on the standard of management after colposcopic examination. The recalled women are thought to have had either no biopsies done or inadequate loop excision biopsies. Viagra deaths report From late March through June, 1998, the US FDA received 77 reports of deaths associated with the anti-impotence drug, sildenafil. Of the 39 US patients whose deaths were verified, all were men (mean age 66 years, range 48–67), 24 had cardiac events, two had strokes, and 13 died of unknown causes. Six men were coadministered a nitrate drug, and 14 died or developed symptoms leading to death during or within 2 hours of sexual activity, said FDA. Toothache in sickle-cell disease Painful crises are common in sicklecell disease (SCD). But in such patients, is orofacial pain a sign of sickling or dental disease? In a casecontrol study, 49% of patients with SCD compared with 8% of controls had had maxillary or mandibular pain in the previous 12 months. 68% of SCD patients with such pain had no dental pathology whereas no controls had pain in the absence of dental pathology (Br Dent J 1998; 185: 90–92).
THE LANCET • Vol 352 • August 1, 1998