1045
USA: Antihistamines in cold remedies Americans spend more than$1 billion every
year
on
of which contain antihistamines, which may be worthless and possibly even harmful, a US congressional subcommittee was told on April 8. The panel is investigating why the Food and Drug Administration (FDA) permits antihistamines in cold common
cold
medicines,
most
remedies. "Since antihistamines have the potential to cause harmful effects, the risks associated with their use outweigh any meagre benefit. It is my opinion that these drugs should be removed from all non-prescription products promoted for the relief of cough and cold symptoms", said Dr Leslie Hendeles, professor of pharmacy and paediatrics at the University of Florida. Dr Nancy Hutton, assistant professor of paediatrics at Johns Hopkins University School of Medicine, testified that her study of 96 children, who received an antihistamine-decongestant, a placebo, or no treatment at all, showed no difference between the groups in symptom relief (7 Pediatr 1991; 118: 125-30). Mr William Soller, senior vice president of Non Prescription Drug Manufacturers Association defended the use of antihistamines, saying that they were safe and effective for treatment of cold symptoms. "People wouldn’t continue using these products if they didn’t work", he said. Dr Richard Gorman of Maryland Poison Control Center said that in 1990 about 7% of poisonings were related to agents containing anithistamines. He pointed out that care should be taken in making antihistamines readily available since there is no antidote for an overdose. Dr Carl Peck, director of the Center for Drug Evaluation and Research at FDA, said that "FDA would not allow any drug to remain on the market that was either ineffective or unsafe. Antihistamines are known to be effective for allergies. Evaluations of the effectiveness of antihistamines in the common cold were undertaken in the late 1970s and evaluated by the agency in the early 1980s. And a tentative conclusion was published in 1985 which was the basis for the current marketing. The FDA is, however, undertaking a review and will come to a final conclusion in the near future".
Syed
Rizwanuddin Ahmad
Medicine and the Law Cosmetic surgery for
(and had retired in 1974). A writ was issued in December, 1987, claiming not that the surgery had been negligently performed but that the surgeon had been negligent in embarking on the series of procedures. The plaintiff only obtained experts’ reports to support her case in February, 1989. She had consulted solicitors some years before, though later than 1978, when the usual 3-year period after she had achieved the then age of majority had expired. 1989
portwine stain
The decision to remove a portwine stain from the face of a
5-year-old girl-which required thirteen operations, ending in 1974 when she was 17-was held to be negligent by Mr Justice Henry, in a 1991 case recently reported. The judge awarded damages on the basis that in 1962, when the operations began and in 1963, by which time there was no turning back, no responsible body of opinion would have approved such a course. The stain should have been left alone to be covered by make-up when the child became older. The case raises two important issues, one legal and the other more clinical. Should the claim have been heard, almost 30 years after the first operation, and is it ever appropriate to try to remove by surgery a portwine stain from the face of a young child? The defendants had resisted trial on the basis that the claim was too late (statute barred). The delay had effectively deprived the defendant health authority from being able to call the surgeon as a witness. He had had a stroke in January,
An expert medical report at that time had been unfavourable but a year later the patient saw a television programme on medical accidents and was put in touch with the Association of Victims of Medical Accidents (AVMA), which recommended a solicitor. Even then matters progressed slowly. However, the judge recognised that the plaintiff had been going through a difficult time in 1982, with the birth of a severely handicapped baby, followed by a divorce, and he felt that he should use his discretion to allow the action to continue. This treatment had blighted the plaintiffs childhood, and affected her whole life, the judge said. "I do not find her personally blameworthy in not having commenced this action by the time she was 21.... Is it then equitable that she must, in all the circumstances, put up with not having a claim so important to her investigated by the court? Only a belief that a fair trial would not now be possible would have driven me to such a conclusion." The judge said that there was a large measure of agreement between the experts, including the fact that none of them would have operated in this case. An expert called by the plaintiff said that "The management of portwine stains is influenced by the fact that the lesion is quite benign and does not have to be removed because of any danger to life. The quality of the skin in portwine stains is usually excellent". When the surgeon who did the operations saw the child there had been no lumps, growths, or bleeding and no interference with function. The contemporary notes and photographs showed that, and the series of skin grafts was for cosmetic reasons alone. The final result was far from that envisaged by the plaintiff and her parents. As the plaintiff’sexpert’s report put it, the whole process had "not been successful in that some of the portwine stain remains and the skin grafts used to resurface the defects are rather irregular and unsightly. Further plastic surgical treatment is unlikely to be of much benefit". The experts agreed that the patchwork effect of the skin grafts and the number of operations were unavoidable once surgery had been decided on. The outcome was, in the defendant expert’s view, "a predictable disappointment", and it was common ground that the surgeon should have discussed the predictability of a disappointing outcome with the parents. It was clear from his letter to the referring general practitioner that he contemplated surgery from the start. There had been no real dialogue with the parents, and they had found him daunting and deferred to his judgment. The judge was satisfied that the surgeon would not have dwelt on the risks but would have told the parents in general terms what he hoped to achieve, and their recollection was that their daughter would be beautiful though some scarring would be visible in cold weather. The judge had no doubt that the course of operations had had a devastating effect on the child who had been teased and bullied at school, responding aggressively and thus becoming yet more isolated. Her suffering had been borne in the belief of a substantial improvement which could never have been. The judge found it difficult to arrive at a sum to award for pain, suffering, and loss of amenity. Old cases in relation to scarring, when scaled up with reference to the _
1046
retail
price index,
came to
surprisingly high figures in the judge’s
of the 1991 scale of damage. That said, the award of only £ 30 000 looks very low to me. context
Doughtyv North Staffordshire Health Authority. [1992] (Queen’s Bench Division, Henry J, April 9, 1991.)
3 Med LR 81.
Diana Brahams
Conference Hormones and cell death Tissue necrosis is often equated with cell death and can take place after injuries due to complement attack, severe hypoxia, hyperthermia, lytic viral infection, or exposure to toxins, for example. The final common path of these insults is to increase membrane permeability to Na’, K +, Ca2+, and Mg2+, thus severely compromising cell water balance. However, cell death also occurs in healthy tissues as a physiologically regulated process, sometimes called programmed cell death or apoptosis. This subject was the focus of a symposium at the British Endocrine Societies’ meeting on March 23-26 in Harrogate, UK. Apoptosis encompasses cell death occurring as part of normal organised tissue reactions in embryogenesis, metamorphosis, endocrine-dependent tissue atrophy, and normal cell turnover. It is characterised by cytoplasmic shrinkage, loss of cell contents, chromatin condensation, cell fragmentation, and phagocytosis. Dr Andrew Wyllie (Edinburgh), one of the first investigators to study this process, said that only two molecular events in apoptosis are well defined: sustained increase in intracellular free Ca2+, associated with activation of a Ca2+ and Mg2dependent endonuclease; and expression of sugar residues on the cell membrane to allow recognition, and hence promote phagocytosis of the cell. The molecular process controlling and coordinating these precisely regulated reactions have remained obscure but are now being unravelled by the use of new techniques. Dr Christine Dive (Manchester) described how flow cytometry allowed an understanding of the tempoal correlation of events during apoptosis. An increase in intracellular Ca 2concentrations is followed by changes in pH and gene expression. What regulates this sequence of events? The answer seems to be growth factors and hormones. But instead of asking why cells need these factors to live, investigators have now focused on why cells die without them. If cells are deprived of growth factors and hormones, they produce proteins that ultimately cause cell death. Dr Gerard Evan (London) described how hormones and growth factors stimulate proto-oncogene expression in target cells. Some proto-oncogenes encode proteins that localise to the cell nucleus and are rapidly induced when quiescent cells are stimulated by mitogenic growth factors. The protein products of such "nuclear oncogenes" are probably transcription factors that serve to regulate expression of genes mediating and controlling molecular processes of proliferation and differentiation. The c-fos and c-jun proto-oncogene products comprise the dimeric AP-11 transcription factor that specifically recognises the DNA motif TGACTCA. Abrupt and transient expression of both c-fos and c-jun is induced in many cell types by many stimuli-for instance, differentiation signals, neural stimulation, and physical damage. Expression of AP-1 has been shown to follow several stimuli that cause apoptosis in various cell types. Presumably, AP-1 is part of a general T
transcription pathway that mediates long-term genetic changes of various kinds depending on the particular cellular context in which it is expressed. The c-myc proto-oncogene is also rapidly induced by mitogens. However, unlike c-fos and c-jun, expression of c-myc in normal cells is continuously dependent on the presence of mitogens; the removal of these mitogens causes rapid loss of both c-myc mRNA and protein because both have extremely short biological half lives. The c-myc protein product is a nuclear phosphoprotein that binds the DNA motif CACGTG. It is not known which genes are regulated by c-myc or to what biological end. Because down-regulation of c-myc expression takes place so rapidly in response to mitogen removal, it may be a signal for growth arrest in cells. To test this hypothesis, Evan and colleagues constructed untransformed fibroblasts and keratinocytes that contain a de-regulated c-myc, and that are refractory to down-regulation by growth-arresting signals. When such cells are deprived of mitogens, they fail to go into growth arrest. At this stage cells are usually faced with two choices-to divide or to die. Curiously, in cultures of these deregulated, mitogen-deprived cells, massive apoptosis ensues. Thus, c-myc induces proliferation only if cells have access to mitogens; if they do not, then apoptosis is activated in a large proportion of cells. These observations suggest that c-myc may have a general role in regulating the cell’s decision as to whether to proliferate or die. Evan suggested that choice is determined by the presence or absence of mitogens. The path from c-myc activation to cell death is "gated" by factors such as insulin-like growth factor-1. When insulin-like growth factor 1 is present, the death pathway is blocked. In the presence of mitogens, the cell is pushed towards cell proliferation. In the absence of exogenous
or
endogenous mitogens,
c-myc
expression can
also lead to cell death. The steps from c-myc to cell elimination remain to be defined but proto-oncogene expression is linked to phosphatidyl inositol hydrolysis and a subsequent increase in intracellular calcium. The clinical importance of apoptosis is now becoming clearer. Apoptosis occurs not only as part of normal physiological and developmental processes but also in malignant tumours, either spontaneously or when induced by radiation or cytotoxic drugs. Prof John Isaacs (Baltimore) described how apoptosis might be used as a therapeutic target for breast and prostate cancer. Metastatic cancers are usually heterogeneous and contain both hormonedependent and hormone-independent cancer cells. Oestrogen ablation for breast cancer and androgen ablation for prostate cancer are rarely curative, since such treatment does not eliminate hormone-independent cells. Effective therapy against these hormone-independent cells is required. Hormone-dependent cancer cells undergo classic apoptosis after appropriate hormonal ablation, exhibiting sustained increases in intracellular free Ca2’ and activation of a Ca2+ and Mg2+ dependent endonuclease. Hormoneindependent cancer cells do not exhibit the sustained rise in Ca2+ after hormonal ablation and do not enter the apoptosis pathway. A new approach to treat hormone-independent breast and prostate cancer cells would be the use of therapeutic agents to induce a sustained increase in free intracellular Ca 21Isaacs’ studies have shown that if an increase in calcium is sustained, even in hormoneindependent cancer cells, Ca2+ and Mg2’dependent endonuclease is activated and apoptosis results. Department of Clinical Chemistry, University of Birmingham
Ann
Logan
USA: Antihistamines in cold remedies Americans spend more than$1 billion every
year
on
of which contain antihistamines, which may be worthless and possibly even harmful, a US congressional subcommittee was told on April 8. The panel is investigating why the Food and Drug Administration (FDA) permits antihistamines in cold common
cold
medicines,
most
remedies. "Since antihistamines have the potential to cause harmful effects, the risks associated with their use outweigh any meagre benefit. It is my opinion that these drugs should be removed from all non-prescription products promoted for the relief of cough and cold symptoms", said Dr Leslie Hendeles, professor of pharmacy and paediatrics at the University of Florida. Dr Nancy Hutton, assistant professor of paediatrics at Johns Hopkins University School of Medicine, testified that her study of 96 children, who received an antihistamine-decongestant, a placebo, or no treatment at all, showed no difference between the groups in symptom relief (7 Pediatr 1991; 118: 125-30). Mr William Soller, senior vice president of Non Prescription Drug Manufacturers Association defended the use of antihistamines, saying that they were safe and effective for treatment of cold symptoms. "People wouldn’t continue using these products if they didn’t work", he said. Dr Richard Gorman of Maryland Poison Control Center said that in 1990 about 7% of poisonings were related to agents containing anithistamines. He pointed out that care should be taken in making antihistamines readily available since there is no antidote for an overdose. Dr Carl Peck, director of the Center for Drug Evaluation and Research at FDA, said that "FDA would not allow any drug to remain on the market that was either ineffective or unsafe. Antihistamines are known to be effective for allergies. Evaluations of the effectiveness of antihistamines in the common cold were undertaken in the late 1970s and evaluated by the agency in the early 1980s. And a tentative conclusion was published in 1985 which was the basis for the current marketing. The FDA is, however, undertaking a review and will come to a final conclusion in the near future".
Syed
Rizwanuddin Ahmad
Medicine and the Law Cosmetic surgery for
(and had retired in 1974). A writ was issued in December, 1987, claiming not that the surgery had been negligently performed but that the surgeon had been negligent in embarking on the series of procedures. The plaintiff only obtained experts’ reports to support her case in February, 1989. She had consulted solicitors some years before, though later than 1978, when the usual 3-year period after she had achieved the then age of majority had expired. 1989
portwine stain
The decision to remove a portwine stain from the face of a
5-year-old girl-which required thirteen operations, ending in 1974 when she was 17-was held to be negligent by Mr Justice Henry, in a 1991 case recently reported. The judge awarded damages on the basis that in 1962, when the operations began and in 1963, by which time there was no turning back, no responsible body of opinion would have approved such a course. The stain should have been left alone to be covered by make-up when the child became older. The case raises two important issues, one legal and the other more clinical. Should the claim have been heard, almost 30 years after the first operation, and is it ever appropriate to try to remove by surgery a portwine stain from the face of a young child? The defendants had resisted trial on the basis that the claim was too late (statute barred). The delay had effectively deprived the defendant health authority from being able to call the surgeon as a witness. He had had a stroke in January,
An expert medical report at that time had been unfavourable but a year later the patient saw a television programme on medical accidents and was put in touch with the Association of Victims of Medical Accidents (AVMA), which recommended a solicitor. Even then matters progressed slowly. However, the judge recognised that the plaintiff had been going through a difficult time in 1982, with the birth of a severely handicapped baby, followed by a divorce, and he felt that he should use his discretion to allow the action to continue. This treatment had blighted the plaintiffs childhood, and affected her whole life, the judge said. "I do not find her personally blameworthy in not having commenced this action by the time she was 21.... Is it then equitable that she must, in all the circumstances, put up with not having a claim so important to her investigated by the court? Only a belief that a fair trial would not now be possible would have driven me to such a conclusion." The judge said that there was a large measure of agreement between the experts, including the fact that none of them would have operated in this case. An expert called by the plaintiff said that "The management of portwine stains is influenced by the fact that the lesion is quite benign and does not have to be removed because of any danger to life. The quality of the skin in portwine stains is usually excellent". When the surgeon who did the operations saw the child there had been no lumps, growths, or bleeding and no interference with function. The contemporary notes and photographs showed that, and the series of skin grafts was for cosmetic reasons alone. The final result was far from that envisaged by the plaintiff and her parents. As the plaintiff’sexpert’s report put it, the whole process had "not been successful in that some of the portwine stain remains and the skin grafts used to resurface the defects are rather irregular and unsightly. Further plastic surgical treatment is unlikely to be of much benefit". The experts agreed that the patchwork effect of the skin grafts and the number of operations were unavoidable once surgery had been decided on. The outcome was, in the defendant expert’s view, "a predictable disappointment", and it was common ground that the surgeon should have discussed the predictability of a disappointing outcome with the parents. It was clear from his letter to the referring general practitioner that he contemplated surgery from the start. There had been no real dialogue with the parents, and they had found him daunting and deferred to his judgment. The judge was satisfied that the surgeon would not have dwelt on the risks but would have told the parents in general terms what he hoped to achieve, and their recollection was that their daughter would be beautiful though some scarring would be visible in cold weather. The judge had no doubt that the course of operations had had a devastating effect on the child who had been teased and bullied at school, responding aggressively and thus becoming yet more isolated. Her suffering had been borne in the belief of a substantial improvement which could never have been. The judge found it difficult to arrive at a sum to award for pain, suffering, and loss of amenity. Old cases in relation to scarring, when scaled up with reference to the _
1046
retail
price index,
came to
surprisingly high figures in the judge’s
of the 1991 scale of damage. That said, the award of only £ 30 000 looks very low to me. context
Doughtyv North Staffordshire Health Authority. [1992] (Queen’s Bench Division, Henry J, April 9, 1991.)
3 Med LR 81.
Diana Brahams
Conference Hormones and cell death Tissue necrosis is often equated with cell death and can take place after injuries due to complement attack, severe hypoxia, hyperthermia, lytic viral infection, or exposure to toxins, for example. The final common path of these insults is to increase membrane permeability to Na’, K +, Ca2+, and Mg2+, thus severely compromising cell water balance. However, cell death also occurs in healthy tissues as a physiologically regulated process, sometimes called programmed cell death or apoptosis. This subject was the focus of a symposium at the British Endocrine Societies’ meeting on March 23-26 in Harrogate, UK. Apoptosis encompasses cell death occurring as part of normal organised tissue reactions in embryogenesis, metamorphosis, endocrine-dependent tissue atrophy, and normal cell turnover. It is characterised by cytoplasmic shrinkage, loss of cell contents, chromatin condensation, cell fragmentation, and phagocytosis. Dr Andrew Wyllie (Edinburgh), one of the first investigators to study this process, said that only two molecular events in apoptosis are well defined: sustained increase in intracellular free Ca2+, associated with activation of a Ca2+ and Mg2dependent endonuclease; and expression of sugar residues on the cell membrane to allow recognition, and hence promote phagocytosis of the cell. The molecular process controlling and coordinating these precisely regulated reactions have remained obscure but are now being unravelled by the use of new techniques. Dr Christine Dive (Manchester) described how flow cytometry allowed an understanding of the tempoal correlation of events during apoptosis. An increase in intracellular Ca 2concentrations is followed by changes in pH and gene expression. What regulates this sequence of events? The answer seems to be growth factors and hormones. But instead of asking why cells need these factors to live, investigators have now focused on why cells die without them. If cells are deprived of growth factors and hormones, they produce proteins that ultimately cause cell death. Dr Gerard Evan (London) described how hormones and growth factors stimulate proto-oncogene expression in target cells. Some proto-oncogenes encode proteins that localise to the cell nucleus and are rapidly induced when quiescent cells are stimulated by mitogenic growth factors. The protein products of such "nuclear oncogenes" are probably transcription factors that serve to regulate expression of genes mediating and controlling molecular processes of proliferation and differentiation. The c-fos and c-jun proto-oncogene products comprise the dimeric AP-11 transcription factor that specifically recognises the DNA motif TGACTCA. Abrupt and transient expression of both c-fos and c-jun is induced in many cell types by many stimuli-for instance, differentiation signals, neural stimulation, and physical damage. Expression of AP-1 has been shown to follow several stimuli that cause apoptosis in various cell types. Presumably, AP-1 is part of a general T
transcription pathway that mediates long-term genetic changes of various kinds depending on the particular cellular context in which it is expressed. The c-myc proto-oncogene is also rapidly induced by mitogens. However, unlike c-fos and c-jun, expression of c-myc in normal cells is continuously dependent on the presence of mitogens; the removal of these mitogens causes rapid loss of both c-myc mRNA and protein because both have extremely short biological half lives. The c-myc protein product is a nuclear phosphoprotein that binds the DNA motif CACGTG. It is not known which genes are regulated by c-myc or to what biological end. Because down-regulation of c-myc expression takes place so rapidly in response to mitogen removal, it may be a signal for growth arrest in cells. To test this hypothesis, Evan and colleagues constructed untransformed fibroblasts and keratinocytes that contain a de-regulated c-myc, and that are refractory to down-regulation by growth-arresting signals. When such cells are deprived of mitogens, they fail to go into growth arrest. At this stage cells are usually faced with two choices-to divide or to die. Curiously, in cultures of these deregulated, mitogen-deprived cells, massive apoptosis ensues. Thus, c-myc induces proliferation only if cells have access to mitogens; if they do not, then apoptosis is activated in a large proportion of cells. These observations suggest that c-myc may have a general role in regulating the cell’s decision as to whether to proliferate or die. Evan suggested that choice is determined by the presence or absence of mitogens. The path from c-myc activation to cell death is "gated" by factors such as insulin-like growth factor-1. When insulin-like growth factor 1 is present, the death pathway is blocked. In the presence of mitogens, the cell is pushed towards cell proliferation. In the absence of exogenous
or
endogenous mitogens,
c-myc
expression can
also lead to cell death. The steps from c-myc to cell elimination remain to be defined but proto-oncogene expression is linked to phosphatidyl inositol hydrolysis and a subsequent increase in intracellular calcium. The clinical importance of apoptosis is now becoming clearer. Apoptosis occurs not only as part of normal physiological and developmental processes but also in malignant tumours, either spontaneously or when induced by radiation or cytotoxic drugs. Prof John Isaacs (Baltimore) described how apoptosis might be used as a therapeutic target for breast and prostate cancer. Metastatic cancers are usually heterogeneous and contain both hormonedependent and hormone-independent cancer cells. Oestrogen ablation for breast cancer and androgen ablation for prostate cancer are rarely curative, since such treatment does not eliminate hormone-independent cells. Effective therapy against these hormone-independent cells is required. Hormone-dependent cancer cells undergo classic apoptosis after appropriate hormonal ablation, exhibiting sustained increases in intracellular free Ca2’ and activation of a Ca2+ and Mg2+ dependent endonuclease. Hormoneindependent cancer cells do not exhibit the sustained rise in Ca2+ after hormonal ablation and do not enter the apoptosis pathway. A new approach to treat hormone-independent breast and prostate cancer cells would be the use of therapeutic agents to induce a sustained increase in free intracellular Ca 21Isaacs’ studies have shown that if an increase in calcium is sustained, even in hormoneindependent cancer cells, Ca2+ and Mg2’dependent endonuclease is activated and apoptosis results. Department of Clinical Chemistry, University of Birmingham
Ann
Logan
