711
25. Vandenberg BF, Kerber RE. Transesophageal echocardiography and intraoperative monitoring of left ventricular function. Anesthesiology
1990; 73: 799-801. 26. Galvin IF, Black IW, Lee CL, Horton DA. Transesophageal echocardiography in acute aortic transection. Ann Thorac Surg 1991; 51: 310-11. 27. Chan KL, Transesophageal echocardiography for assessing cause of hypotension after cardiac surgery. Am J Cardiol 1988; 62: 1142-43. 28. Oh JK, Seward JB, Khandheria BK, et al. Transesophageal echocardiography in critically ill patients. Am J Cardiol 1990; 66: 1492-95. 29. Black IW, Hopkins AP, Lee LCL, Jacobson BM, Walsh WF. Role of transesophageal echocardiography in the cardioversion of atrial arrhythmias. Circulation 1991; 84 (suppl II): 694. 30. Kronzon I, Tunick PA, Glassman E, Slater J, Schwinger M, Freeberg RS. Transesophageal echocardiography to detect atrial clots in candidates for percutaneous transseptal mitral balloon valvuloplasty.
JACC 1990; 16: 1320-22.
Adhesions and anodynes Chronic pelvic pain in women without gross pelvic disease may have its origin in social, psychological, or physical factors. The social aspects have received scant attention, but the things that nourish the ongoing chronic pain and disability epidemic in industrial workers, usually men, are the common lot of much of womankind-eg, the low self-esteem of a dependent person, a demanding job (especially motherhood), and tension at home.As women struggle to be good earners (often in poorly paid part-time work2), good housewives, and good mothers it would be surprising if a few, with less ability to deal competently with stress than most, did not sometimes react adversely. Personal psychological factors have received more recognition, probably because they are more imaginative and provide an opportunity for voyeurism. Women as well as men have subscribed to the view that a wish for more or a different type of sex may be the underlying problem. Mary Anna Friederich3 believed that, in addition, less directly sexual wishes and fantasies, too threatenting to be allowed to reach consciousness, may sometimes undergo hysterical conversion to conscious pelvic pain. Examples cited include a wish to have been better loved as a child, a desire to desert one’s own children, and a longing to inflict pain on the partner of an ambiguous relationship. Emily Dickinson4 put it another way: The Heart asks Pleasure-firstAnd then-Excuse from PainAnd then-those little Anodynes That deaden sufferingFriederich warned those who would recommend psychological counselling5,6 that, because the patient is unable to tolerate the real cause of her pain, there is no point digging into her psyche for it; and that psychological interpretations are usually resented and rejected by these patients, who prefer simple physical explanations such as "tension" and "congestion". The psychic secrets of the patients reported by Beard et al’ were safe when demonstration of their pelvic varices on the television screen provided them with a somatic cause for their pain. Another little anodyne, used especially when the patient has previously
surgery, is "adhesions". But adhesions differ from tension and congestion in that they are readily amenable to surgical treatment. Peters et al8 recognised that, in the prevailing conservatism regarding the management of chronic pelvic pain in women, there was a danger of a possibly useful surgical procedure being summarily discarded. In a trial conducted at Leiden University in the Netherlands, they studied 48 women with chronic pelvic pain in whom adhesions had been seen on diagnostic laparoscopy. The patients were allocated randomly to receive either expectant treatment or open adhesiolysis via a midline incision, which sometimes needed to be extended above the umbilicus. To allow any placebo effect to wear off, the efficacy of adhesiolysis in combating the patients’ pain was compared with that of conservative management 9-12 months later. No benefit followed adhesiolysis where the adhesions had been few and flimsy; benefit was seen when the adhesions had been dense, vascularised, and attached to bowel. The symptoms in these patients had been characterised by exacerbations of pain accompanied by other features suggestive of small-bowel obstruction. Second-look laparoscopies were not part of the trial protocol. Adhesiolysis has been shown to have a place in the management of chronic pelvic pain in women. However, in most women, in whom the adhesions are not severe and attached to bowel and the symptoms are not suggestive of recurrent subacute intestinal obstruction, a diagnosis of adhesions is probably best used, like that of tension and congestion, to provide little anodynes for the patient’s deeper and more elusive problems, or for her adverse social circumstances.
undergone
1. Weinstein MR. The concept of the disability process. Psychosomatics 1978; 19: 94-97. 2. Pahl RE. Women, work and social change. In: Divisions of labour. Oxford: Blackwell, 1984: 63-85. 3. Friedench MA. Psychological aspects of chronic pelvic pain. In: Clinical obstetrics and gynecology. Hagerstown: Harper and Row, 1976: 399-406. 4. Dickinson E. Poem no 536. In: Hall D, ed. American poetry. London: Faber and Faber, 1969: 72. 5. Pearce S, Knight C, Beard RW. Pelvic pain: a common gynecologic problem. J Psychosom Obstet Gynecol 1982; 1: 12-17. 6. Rocker I. Gynaecological pain. In: Rocker I, ed. Pelvic pain in women. London: Springer-Verlag, 1990: 127-31. 7. Beard RW, Higham JH, Pearce S. Reginald PW. Diagnosis of pelvic varicosities in women with chronic pelvic pain. Lancet 1984; ii: 946-49. 8. Peters AAW, Trimbos-Kemper GCM, Admiral C, Trimbos JB, Hermans J. A randomised clinical trial on the benefit of adhesiolysis in patients with intraperitoneal adhesions and chronic pelvic pain. Br J Obstet Gynaecol 1992; 99: 59-62.
Chlamydial infections: therapeutic options Chlamydiae are intracellular, slow-growing organisms and these characteristics govern antibiotic therapy. A successful antichlamydial agent must have good cell penetration and act on non-dividing as well as dividing cells.
712
Tetracyclines were the treatment of choice for chlamydial infections until lately. Erythromycin has somewhat lower activity in vitro, which correlates with a less satisfactory clinical outcome. With erythromycin, failure rates of up to 37% have been men with urethritis vs 3% for and similar responses have been noted tetracyclines,’ in non-pregnant women with cervicitis. Experience with antibiotic treatment of chlamydial respiratory disease is more limited, but tetracyclines have been recommended in adults and erythromycin in children.2,3,4 Tetracyclines are contraindicated in children, and in pregnant and breast-feeding mothers. Patient acceptability of oral erythromycin is limited by gastrointestinal side-effects. Most chlamydial disease that comes to medical attention is sexually transmitted; Chlamydia trachomatis is now the commonest cause of sexually transmitted disease (STD) in many countries. At least one week’s course of antichlamydial therapy is currently recommended. Longer courses may be needed to eliminate C psittaci, C pneumoniae (previously chlamydia strain TWAR), and pulmonary C trachomatis in neonatal pneumonia. 2,1 Thus there is an urgent need for new therapeutic agents with greater tolerability, favourable dose schedules (preferably a single dose regimen for STD), and greater activity against other genitourinary
recorded
in
pathogens. Azithromycin, a structural analogue of erythromycin and prototype of the new azalide group of antibiotics, is a strong contender. Results of in-vitro studies are generally encouraging.6,7 Girard et al8 showed sustained high tissue levels after single-dose azithromycin, so once daily or even single dosing is feasible. Clinical trials show far fewer gastrointestinal side-effects than with erythromycin or tetracyclines. Microbiological cure rates of 100% and 96% have been achieved in open9 and double-blind1O randomised trials in STD, although no conclusions can be drawn from these studies with respect to late relapses. Roxithromycin, another macrolide, gave satisfactory results in preliminary studies but has not lived up to expectations, its spectrum and activity being similar to erythromycin 11 and with possibly increased risk of toxicity. 12 The role of the newer macrolides in chlamydial chest infection is under investigation. Clarithromycin may be favoured for this purpose because it has the highest in-vitro activity of the compounds so far tested against C pneumoniae.13 Clinical studies of clarithromycin and azithromycin as sole therapy in community-acquired pneumonias are in progress; the cure of 4 patients with chlamydial pneumonia has lately been reported.14 The new quinolone antibiotics have also been studied for activity against Chlamydia species. Theoretical advantages are lethal antichlamydial activity at concentrations attainable in vivo, excellent bioavailability of oral preparations,15 low incidence of
side-effects, and half-life compatible with twice daily administration. Ciprofloxacin showed poor activity against C trachomatis both in vitro16 and in vivo, with late relapse. 17 The high doses used in this study (I g twice daily for 7 days) were associated with many side-effects but no improvement in efficacy. This outcome is disappointing in view of the excellent record of ciprofloxacin against penicillin-resistant and spectinomycin-resistant Neisseria gonorrhoeae and Haemophilus ducreyi (chancroid). Norfloxacin shows little antichlamydial activity in vitro or in vivo." Fleroxacin and enoxacin show moderate activity in vitro,18 but fleroxacin gave variable outcomes in vivo.19 Clinical trial data are not availble for enoxacin. Ofloxacin,16 difloxacin, and temafloxacin2O combine acceptable antichlamydial activity with good activity against N gonorrhoea, including strains resistant to p-lactams. Clinical trials of ofloxacin have shown failure rates of 0% to 19%.16,19 Failures were especially prominent in longer-term studies with follow-up of at least 3 weeks after therapy. Whether relapse was due to poor compliance or lack of efficacy is unclear. The place of quinolones in the treatment of chlamydial disease is unknown. The role of these agents will probably be limited to STD in nonpregnant adults; in view of their potential for inducing arthropathy in laboratory animals, they are considered contraindicated in children and pregnant women. Re-evaluation of older drugs may also prove worthwhile. Rifampicin has excellent antichlamydial activity in vivo and achieves high intracellular concentrations after oral administration. Use of this drug has been restricted by fears that resistance may evolve during therapy. 19 The newer rifamycin derivative, rifabutin, does not seem to select for resistant mutants and may be more useful in chlamydial disease.21 Penicillins have an incomplete inhibitory effect on chlamydiae in vitro,22 and poor cell penetration. They have repeatedly been shown not to eradicate C trachomatis when used alone for mixed infections with Ngonorrhoeae. However, studies with amoxycillin and ampicillin esters with enhanced bioavailability after oral administration have given encouraging results, with cure rates matching those of erythromycin therapy. 2324 Although concern has been expressed over the potential for suppression rather than eradication of infection with j3-Iactam antibiotics,19 they merit further investigation as alternatives to erythromycin for infection in pregnancy. 1. Sanders LL
Jr, Harrison HR, Washington AE. Treatment of sexually transmitted Chlamydia infections. JAMA 1986; 255: 1750-56. 2. Bowie WR, Holmes KK. Chlamydia trachomatis. In: Mandel GL, Douglas RG, Bennett JE, eds. Principles and practice of infectious diseases, 3rd ed. New York: Churchill Livingstone: 1990: 1426-40. 3. Schaffner W. Chlamydiapsittaci. In: Mandel GL, Douglas, RG, Bennett JE, eds. Principles and practice of infectious diseases, 3rd ed. New York: Churchill Livingstone, 1990: 1440-43. 4. Kuo C, Grayston JT. In vitro drug susceptibility of Chlamydia sp strain TWAR. Antimicrob Agents Chemother 1988; 32: 257-58.
713
5. Grayston JT. Chlamydia pneumoniae, strain TWAR. In: Bowie WR, Caldwell HD, Jonas RP, et al, eds. Chlamydial infections. Proceedings of the 7th International Symposium on Human Chlamydial Infections, 1991. Harrison Hot Springs, Canada. Cambridge: Cambridge University Press, 1991: 389-401. 6. Scieux C, Bianchi A, Chapprey B, Vassias I, Perol Y. In vitro activity of azithromycin against Chlamydia trachomatis. J Antimicrob Chemother 1990; 25 (suppl A): 7-10. 7. Slaney L, Chubb H, Ronald A, Brunham R. In vitro activity of anthromycin, erythromycin" ciprofloxacin and norfloxacin against Neisseria gonorrhoea, Haemophilus ducreyi and Chlamydia trachomatis. J Antimicrob Chemother 1990; 25 (suppl A): 1-5. 8. Girard AE, Girard D, English AR, Gootz TD, Cimochowski CR, Faiella JA. Pharmacokinetic and in vivo studies with azithromycin (CPnew macrolide with an extended half-life and excellent tissue distribution. Antimicrob Agents Chemother 1987; 31: 1948-54. 9. Lassus A. Comparative studies of azithromycin in skin and soft tissue infections and sexually transmitted infections by Neisseria and Chlamydia species. J Antimicrob Chemother 1990; 25 (suppl A): 115-21. 10. Steingrimsson O, Olafsson JH, Thorarinsson H, Ryan RW, Johnson RB, Tilton RC. Azithromycin in the treatment of sexually transmitted disease. J Antimicrob chemother 1990; 25 (suppl A): 109-14. 11. Bowie WR, Shaw CE, Chan DGW, Black WA. In vitro activity of Ro 15-8074, Ro 195247, A-56268 and roxithromycin against Neisseria gonorrhoeae and Chlamydia trachomatis. Antimicrob Agents Chemother
62,993), a
1987; 31: 470-72. 12. Villa P, Sassnalla D, Careda M, Bartosek I. Toxicity, uptake and subcellular distribution in rat hepatocytes of roxithromycin, a new
semisynthetic macrolide, and erythromycin base. Antimicrob Agents Chemother 1988; 32: 1541-46. 13. Chirgwin K, Roblin PM, Hammerschlag MR. In vitro susceptiblities of Chlamydia pneumoniae (Chlamydia sp strain TWAR). Antimicrob Agents Chemother 1989; 33: 1634-35. 14. Schonwald S, Skerk V, Petricevic I, Car V, Majerus-Misic L, Gunjaca M. Comparison of three day and five day courses of azithromycin in the treatment of atypical pneumonia. Eur J Clin Micro Infect Dis 1991; 10: 877-80. 15. Kucers A, Bennett N McK. The use of antibiotics. 4th ed. London: Heinemann, 1987: 1254-57. 16. Oriel JD. Use of quinolones in chlamydial infection. Rev Infect Dis 1989; 11 (suppl 5): S1273-76. 17. Hooton TM, Rogers EM, Medina TG, et al. Ciprofloxacin compared with doxycycline for nongonococcal urethritis: ineffectiveness against Chlamydia trachomatis due to relapsing infection. JAMA 1990; 264: 1418-21. 18. Maeda H, Fujii A, Nakata K, Arakawa S, Kamidono S. In vitro activities of T-3262, NY-198, fleroxacin (AM-833; RO 23-6240), and other new quinolone agents against clinically isolated Chlamydia trachomatis strains. Antimicrob Agents Chemother 1988; 32: 1080-81. 19. Toomey KE, Barnes RC. Treatment of Chlamydia trachomatis genital infection. Rev Infect Dis 1990; 12 (suppl 6): S645-55. 20. Segreti J, Kessler HA, Kapell KS, Trenholme GM. In vitro activitites of temafloxacin (A-62254) and four other antibiotics against Chlamydia trachomatis. Antimicrob Agents Chemother 1989; 33: 118-19. 21. Treharne JD, Yearsley PJ, Ballard RC. In vitro studies of Chlamydia trachomatis susceptibility and resistance to rifampin and rifabutin. Antimicrob Agents Chemother 1989; 33: 1393-94. 22. Lee CK, Bowie WR, Alexander ER. In vitro assays of the efficiency of antimicrobial agents in controlling Chlamydia trachomatis propagation. Antimicrob Agents Chemother 1978; 13: 441-45. 23. Crombleholme J, Schachter J, Grossman M, Landers DV, Sweet RL. Amoxycillin therapy for Chlamydia trachomatis in pregnancy. Obstet Gynecol 1990; 75: 752-56. 24. Cramers M, Kaspersen P, From E, Moller BR. Pivampicillin compared with erythromycin for treating women with genital Chlamydia trachomatis infection. Genitourin Med 1988; 64: 247-48.
Is aluminium
a
dementing ion?
Three years ago Martyn et al,l writing in The Lancet, stated that "aluminium in drinking water is either dissolved or readily brought into solution and its bioavailability may therefore be much higher than aluminium from other sources". Time and more clinical and epidemiological studies, it was said in an accompanying editorial, would decide whether this statement was correct.
Has there been any
progress?
Aluminium is generally found as a relatively insoluble aluminosilicate, which comprises 8% of the earth’s crust by weight.3 Daily intake in man is 20-5 mg from ingestion4 (0-5 mg with 1500 ml of fluid and 20 mg with 1 kg of food) and 10 pg by inhalation.5 Overall, the body guards against aluminium and efficiently excretes it; silicic acid and fluoride are protective, but acidity facilitates absorption.6The result is a total body burden of less than 50 mg, although there is increased accumulation with age in lung, bone, and brain.3Occupational health studies suggest a storage mechanism that varies with exposure.7 Aluminium undoubtedly causes dialysis dementia (DD). This encephalopathy8 is characterised by
speech disturbance, seizures, progressive cognitive changes, and death within one year. The high aluminium concentrations in DD apparently do not cause the amyloid plaques and neurofibrillary tangles typically seen in Alzheimer’s disease (at).4Although DD can be fatal, the condition may respond to restriction of ingested aluminium or to chelating agents.9 The putative association between aluminium and AD is complex and controversial and a distinction must be made between aetiology and pathogenesis. Moreover, the dose and response to aluminium in DD different. In DD the brain succumbs acutely high doses of the metal in those with renal failure whereas in AD lengthy exposure to low doses may cause slow death of ageing brains. Nevertheless, the differences between animal models, DD, and AD are much debated. Impaired cholinergic activity, plaques, and tangles are not seen in the first two;10and high aluminium concentrations are not seen in the latter." Although DD may be reversed by dietary restriction and chelation, these only slow the progress of AD. 12 It is clear that aluminium is somewhat increased in Alzheimer brains, especially in amyloid plaques and neurofibrillary tangles, but this finding is not consistent4 and may vary by laboratory. It has been suggested, following the discovery of a mutant gene on chromosome 21 in early onset AD, that the aluminium may be associated with a pathogenic pathway. Abnormal beta-amyloid precursor protein (APP) metabolism leads to beta amyloid deposition, tau phosphorylation, paired helical filament formation, and then death.44 The only recent clinical study of aluminium and dementia is the chelation research of McLachlan et al.12 There have been several direct or statistical epidemiology studies, some of which have examined aluminium and dementia or cognitive impairment with air or skin contact as vectors. Sjogren" reported an association between duration of exposure and self-reported memory disorder and depression; and Rifat,14 in the Northern Ontario Miners study, where men had been previously exposed to aluminium powder as a prophylaxis against silicosis, took this approach further with objective testing. There was no excess of neurological disorder but there was
and AD
are so
to
significantly
more
cognitive impairment compared
25. Vandenberg BF, Kerber RE. Transesophageal echocardiography and intraoperative monitoring of left ventricular function. Anesthesiology
1990; 73: 799-801. 26. Galvin IF, Black IW, Lee CL, Horton DA. Transesophageal echocardiography in acute aortic transection. Ann Thorac Surg 1991; 51: 310-11. 27. Chan KL, Transesophageal echocardiography for assessing cause of hypotension after cardiac surgery. Am J Cardiol 1988; 62: 1142-43. 28. Oh JK, Seward JB, Khandheria BK, et al. Transesophageal echocardiography in critically ill patients. Am J Cardiol 1990; 66: 1492-95. 29. Black IW, Hopkins AP, Lee LCL, Jacobson BM, Walsh WF. Role of transesophageal echocardiography in the cardioversion of atrial arrhythmias. Circulation 1991; 84 (suppl II): 694. 30. Kronzon I, Tunick PA, Glassman E, Slater J, Schwinger M, Freeberg RS. Transesophageal echocardiography to detect atrial clots in candidates for percutaneous transseptal mitral balloon valvuloplasty.
JACC 1990; 16: 1320-22.
Adhesions and anodynes Chronic pelvic pain in women without gross pelvic disease may have its origin in social, psychological, or physical factors. The social aspects have received scant attention, but the things that nourish the ongoing chronic pain and disability epidemic in industrial workers, usually men, are the common lot of much of womankind-eg, the low self-esteem of a dependent person, a demanding job (especially motherhood), and tension at home.As women struggle to be good earners (often in poorly paid part-time work2), good housewives, and good mothers it would be surprising if a few, with less ability to deal competently with stress than most, did not sometimes react adversely. Personal psychological factors have received more recognition, probably because they are more imaginative and provide an opportunity for voyeurism. Women as well as men have subscribed to the view that a wish for more or a different type of sex may be the underlying problem. Mary Anna Friederich3 believed that, in addition, less directly sexual wishes and fantasies, too threatenting to be allowed to reach consciousness, may sometimes undergo hysterical conversion to conscious pelvic pain. Examples cited include a wish to have been better loved as a child, a desire to desert one’s own children, and a longing to inflict pain on the partner of an ambiguous relationship. Emily Dickinson4 put it another way: The Heart asks Pleasure-firstAnd then-Excuse from PainAnd then-those little Anodynes That deaden sufferingFriederich warned those who would recommend psychological counselling5,6 that, because the patient is unable to tolerate the real cause of her pain, there is no point digging into her psyche for it; and that psychological interpretations are usually resented and rejected by these patients, who prefer simple physical explanations such as "tension" and "congestion". The psychic secrets of the patients reported by Beard et al’ were safe when demonstration of their pelvic varices on the television screen provided them with a somatic cause for their pain. Another little anodyne, used especially when the patient has previously
surgery, is "adhesions". But adhesions differ from tension and congestion in that they are readily amenable to surgical treatment. Peters et al8 recognised that, in the prevailing conservatism regarding the management of chronic pelvic pain in women, there was a danger of a possibly useful surgical procedure being summarily discarded. In a trial conducted at Leiden University in the Netherlands, they studied 48 women with chronic pelvic pain in whom adhesions had been seen on diagnostic laparoscopy. The patients were allocated randomly to receive either expectant treatment or open adhesiolysis via a midline incision, which sometimes needed to be extended above the umbilicus. To allow any placebo effect to wear off, the efficacy of adhesiolysis in combating the patients’ pain was compared with that of conservative management 9-12 months later. No benefit followed adhesiolysis where the adhesions had been few and flimsy; benefit was seen when the adhesions had been dense, vascularised, and attached to bowel. The symptoms in these patients had been characterised by exacerbations of pain accompanied by other features suggestive of small-bowel obstruction. Second-look laparoscopies were not part of the trial protocol. Adhesiolysis has been shown to have a place in the management of chronic pelvic pain in women. However, in most women, in whom the adhesions are not severe and attached to bowel and the symptoms are not suggestive of recurrent subacute intestinal obstruction, a diagnosis of adhesions is probably best used, like that of tension and congestion, to provide little anodynes for the patient’s deeper and more elusive problems, or for her adverse social circumstances.
undergone
1. Weinstein MR. The concept of the disability process. Psychosomatics 1978; 19: 94-97. 2. Pahl RE. Women, work and social change. In: Divisions of labour. Oxford: Blackwell, 1984: 63-85. 3. Friedench MA. Psychological aspects of chronic pelvic pain. In: Clinical obstetrics and gynecology. Hagerstown: Harper and Row, 1976: 399-406. 4. Dickinson E. Poem no 536. In: Hall D, ed. American poetry. London: Faber and Faber, 1969: 72. 5. Pearce S, Knight C, Beard RW. Pelvic pain: a common gynecologic problem. J Psychosom Obstet Gynecol 1982; 1: 12-17. 6. Rocker I. Gynaecological pain. In: Rocker I, ed. Pelvic pain in women. London: Springer-Verlag, 1990: 127-31. 7. Beard RW, Higham JH, Pearce S. Reginald PW. Diagnosis of pelvic varicosities in women with chronic pelvic pain. Lancet 1984; ii: 946-49. 8. Peters AAW, Trimbos-Kemper GCM, Admiral C, Trimbos JB, Hermans J. A randomised clinical trial on the benefit of adhesiolysis in patients with intraperitoneal adhesions and chronic pelvic pain. Br J Obstet Gynaecol 1992; 99: 59-62.
Chlamydial infections: therapeutic options Chlamydiae are intracellular, slow-growing organisms and these characteristics govern antibiotic therapy. A successful antichlamydial agent must have good cell penetration and act on non-dividing as well as dividing cells.
712
Tetracyclines were the treatment of choice for chlamydial infections until lately. Erythromycin has somewhat lower activity in vitro, which correlates with a less satisfactory clinical outcome. With erythromycin, failure rates of up to 37% have been men with urethritis vs 3% for and similar responses have been noted tetracyclines,’ in non-pregnant women with cervicitis. Experience with antibiotic treatment of chlamydial respiratory disease is more limited, but tetracyclines have been recommended in adults and erythromycin in children.2,3,4 Tetracyclines are contraindicated in children, and in pregnant and breast-feeding mothers. Patient acceptability of oral erythromycin is limited by gastrointestinal side-effects. Most chlamydial disease that comes to medical attention is sexually transmitted; Chlamydia trachomatis is now the commonest cause of sexually transmitted disease (STD) in many countries. At least one week’s course of antichlamydial therapy is currently recommended. Longer courses may be needed to eliminate C psittaci, C pneumoniae (previously chlamydia strain TWAR), and pulmonary C trachomatis in neonatal pneumonia. 2,1 Thus there is an urgent need for new therapeutic agents with greater tolerability, favourable dose schedules (preferably a single dose regimen for STD), and greater activity against other genitourinary
recorded
in
pathogens. Azithromycin, a structural analogue of erythromycin and prototype of the new azalide group of antibiotics, is a strong contender. Results of in-vitro studies are generally encouraging.6,7 Girard et al8 showed sustained high tissue levels after single-dose azithromycin, so once daily or even single dosing is feasible. Clinical trials show far fewer gastrointestinal side-effects than with erythromycin or tetracyclines. Microbiological cure rates of 100% and 96% have been achieved in open9 and double-blind1O randomised trials in STD, although no conclusions can be drawn from these studies with respect to late relapses. Roxithromycin, another macrolide, gave satisfactory results in preliminary studies but has not lived up to expectations, its spectrum and activity being similar to erythromycin 11 and with possibly increased risk of toxicity. 12 The role of the newer macrolides in chlamydial chest infection is under investigation. Clarithromycin may be favoured for this purpose because it has the highest in-vitro activity of the compounds so far tested against C pneumoniae.13 Clinical studies of clarithromycin and azithromycin as sole therapy in community-acquired pneumonias are in progress; the cure of 4 patients with chlamydial pneumonia has lately been reported.14 The new quinolone antibiotics have also been studied for activity against Chlamydia species. Theoretical advantages are lethal antichlamydial activity at concentrations attainable in vivo, excellent bioavailability of oral preparations,15 low incidence of
side-effects, and half-life compatible with twice daily administration. Ciprofloxacin showed poor activity against C trachomatis both in vitro16 and in vivo, with late relapse. 17 The high doses used in this study (I g twice daily for 7 days) were associated with many side-effects but no improvement in efficacy. This outcome is disappointing in view of the excellent record of ciprofloxacin against penicillin-resistant and spectinomycin-resistant Neisseria gonorrhoeae and Haemophilus ducreyi (chancroid). Norfloxacin shows little antichlamydial activity in vitro or in vivo." Fleroxacin and enoxacin show moderate activity in vitro,18 but fleroxacin gave variable outcomes in vivo.19 Clinical trial data are not availble for enoxacin. Ofloxacin,16 difloxacin, and temafloxacin2O combine acceptable antichlamydial activity with good activity against N gonorrhoea, including strains resistant to p-lactams. Clinical trials of ofloxacin have shown failure rates of 0% to 19%.16,19 Failures were especially prominent in longer-term studies with follow-up of at least 3 weeks after therapy. Whether relapse was due to poor compliance or lack of efficacy is unclear. The place of quinolones in the treatment of chlamydial disease is unknown. The role of these agents will probably be limited to STD in nonpregnant adults; in view of their potential for inducing arthropathy in laboratory animals, they are considered contraindicated in children and pregnant women. Re-evaluation of older drugs may also prove worthwhile. Rifampicin has excellent antichlamydial activity in vivo and achieves high intracellular concentrations after oral administration. Use of this drug has been restricted by fears that resistance may evolve during therapy. 19 The newer rifamycin derivative, rifabutin, does not seem to select for resistant mutants and may be more useful in chlamydial disease.21 Penicillins have an incomplete inhibitory effect on chlamydiae in vitro,22 and poor cell penetration. They have repeatedly been shown not to eradicate C trachomatis when used alone for mixed infections with Ngonorrhoeae. However, studies with amoxycillin and ampicillin esters with enhanced bioavailability after oral administration have given encouraging results, with cure rates matching those of erythromycin therapy. 2324 Although concern has been expressed over the potential for suppression rather than eradication of infection with j3-Iactam antibiotics,19 they merit further investigation as alternatives to erythromycin for infection in pregnancy. 1. Sanders LL
Jr, Harrison HR, Washington AE. Treatment of sexually transmitted Chlamydia infections. JAMA 1986; 255: 1750-56. 2. Bowie WR, Holmes KK. Chlamydia trachomatis. In: Mandel GL, Douglas RG, Bennett JE, eds. Principles and practice of infectious diseases, 3rd ed. New York: Churchill Livingstone: 1990: 1426-40. 3. Schaffner W. Chlamydiapsittaci. In: Mandel GL, Douglas, RG, Bennett JE, eds. Principles and practice of infectious diseases, 3rd ed. New York: Churchill Livingstone, 1990: 1440-43. 4. Kuo C, Grayston JT. In vitro drug susceptibility of Chlamydia sp strain TWAR. Antimicrob Agents Chemother 1988; 32: 257-58.
713
5. Grayston JT. Chlamydia pneumoniae, strain TWAR. In: Bowie WR, Caldwell HD, Jonas RP, et al, eds. Chlamydial infections. Proceedings of the 7th International Symposium on Human Chlamydial Infections, 1991. Harrison Hot Springs, Canada. Cambridge: Cambridge University Press, 1991: 389-401. 6. Scieux C, Bianchi A, Chapprey B, Vassias I, Perol Y. In vitro activity of azithromycin against Chlamydia trachomatis. J Antimicrob Chemother 1990; 25 (suppl A): 7-10. 7. Slaney L, Chubb H, Ronald A, Brunham R. In vitro activity of anthromycin, erythromycin" ciprofloxacin and norfloxacin against Neisseria gonorrhoea, Haemophilus ducreyi and Chlamydia trachomatis. J Antimicrob Chemother 1990; 25 (suppl A): 1-5. 8. Girard AE, Girard D, English AR, Gootz TD, Cimochowski CR, Faiella JA. Pharmacokinetic and in vivo studies with azithromycin (CPnew macrolide with an extended half-life and excellent tissue distribution. Antimicrob Agents Chemother 1987; 31: 1948-54. 9. Lassus A. Comparative studies of azithromycin in skin and soft tissue infections and sexually transmitted infections by Neisseria and Chlamydia species. J Antimicrob Chemother 1990; 25 (suppl A): 115-21. 10. Steingrimsson O, Olafsson JH, Thorarinsson H, Ryan RW, Johnson RB, Tilton RC. Azithromycin in the treatment of sexually transmitted disease. J Antimicrob chemother 1990; 25 (suppl A): 109-14. 11. Bowie WR, Shaw CE, Chan DGW, Black WA. In vitro activity of Ro 15-8074, Ro 195247, A-56268 and roxithromycin against Neisseria gonorrhoeae and Chlamydia trachomatis. Antimicrob Agents Chemother
62,993), a
1987; 31: 470-72. 12. Villa P, Sassnalla D, Careda M, Bartosek I. Toxicity, uptake and subcellular distribution in rat hepatocytes of roxithromycin, a new
semisynthetic macrolide, and erythromycin base. Antimicrob Agents Chemother 1988; 32: 1541-46. 13. Chirgwin K, Roblin PM, Hammerschlag MR. In vitro susceptiblities of Chlamydia pneumoniae (Chlamydia sp strain TWAR). Antimicrob Agents Chemother 1989; 33: 1634-35. 14. Schonwald S, Skerk V, Petricevic I, Car V, Majerus-Misic L, Gunjaca M. Comparison of three day and five day courses of azithromycin in the treatment of atypical pneumonia. Eur J Clin Micro Infect Dis 1991; 10: 877-80. 15. Kucers A, Bennett N McK. The use of antibiotics. 4th ed. London: Heinemann, 1987: 1254-57. 16. Oriel JD. Use of quinolones in chlamydial infection. Rev Infect Dis 1989; 11 (suppl 5): S1273-76. 17. Hooton TM, Rogers EM, Medina TG, et al. Ciprofloxacin compared with doxycycline for nongonococcal urethritis: ineffectiveness against Chlamydia trachomatis due to relapsing infection. JAMA 1990; 264: 1418-21. 18. Maeda H, Fujii A, Nakata K, Arakawa S, Kamidono S. In vitro activities of T-3262, NY-198, fleroxacin (AM-833; RO 23-6240), and other new quinolone agents against clinically isolated Chlamydia trachomatis strains. Antimicrob Agents Chemother 1988; 32: 1080-81. 19. Toomey KE, Barnes RC. Treatment of Chlamydia trachomatis genital infection. Rev Infect Dis 1990; 12 (suppl 6): S645-55. 20. Segreti J, Kessler HA, Kapell KS, Trenholme GM. In vitro activitites of temafloxacin (A-62254) and four other antibiotics against Chlamydia trachomatis. Antimicrob Agents Chemother 1989; 33: 118-19. 21. Treharne JD, Yearsley PJ, Ballard RC. In vitro studies of Chlamydia trachomatis susceptibility and resistance to rifampin and rifabutin. Antimicrob Agents Chemother 1989; 33: 1393-94. 22. Lee CK, Bowie WR, Alexander ER. In vitro assays of the efficiency of antimicrobial agents in controlling Chlamydia trachomatis propagation. Antimicrob Agents Chemother 1978; 13: 441-45. 23. Crombleholme J, Schachter J, Grossman M, Landers DV, Sweet RL. Amoxycillin therapy for Chlamydia trachomatis in pregnancy. Obstet Gynecol 1990; 75: 752-56. 24. Cramers M, Kaspersen P, From E, Moller BR. Pivampicillin compared with erythromycin for treating women with genital Chlamydia trachomatis infection. Genitourin Med 1988; 64: 247-48.
Is aluminium
a
dementing ion?
Three years ago Martyn et al,l writing in The Lancet, stated that "aluminium in drinking water is either dissolved or readily brought into solution and its bioavailability may therefore be much higher than aluminium from other sources". Time and more clinical and epidemiological studies, it was said in an accompanying editorial, would decide whether this statement was correct.
Has there been any
progress?
Aluminium is generally found as a relatively insoluble aluminosilicate, which comprises 8% of the earth’s crust by weight.3 Daily intake in man is 20-5 mg from ingestion4 (0-5 mg with 1500 ml of fluid and 20 mg with 1 kg of food) and 10 pg by inhalation.5 Overall, the body guards against aluminium and efficiently excretes it; silicic acid and fluoride are protective, but acidity facilitates absorption.6The result is a total body burden of less than 50 mg, although there is increased accumulation with age in lung, bone, and brain.3Occupational health studies suggest a storage mechanism that varies with exposure.7 Aluminium undoubtedly causes dialysis dementia (DD). This encephalopathy8 is characterised by
speech disturbance, seizures, progressive cognitive changes, and death within one year. The high aluminium concentrations in DD apparently do not cause the amyloid plaques and neurofibrillary tangles typically seen in Alzheimer’s disease (at).4Although DD can be fatal, the condition may respond to restriction of ingested aluminium or to chelating agents.9 The putative association between aluminium and AD is complex and controversial and a distinction must be made between aetiology and pathogenesis. Moreover, the dose and response to aluminium in DD different. In DD the brain succumbs acutely high doses of the metal in those with renal failure whereas in AD lengthy exposure to low doses may cause slow death of ageing brains. Nevertheless, the differences between animal models, DD, and AD are much debated. Impaired cholinergic activity, plaques, and tangles are not seen in the first two;10and high aluminium concentrations are not seen in the latter." Although DD may be reversed by dietary restriction and chelation, these only slow the progress of AD. 12 It is clear that aluminium is somewhat increased in Alzheimer brains, especially in amyloid plaques and neurofibrillary tangles, but this finding is not consistent4 and may vary by laboratory. It has been suggested, following the discovery of a mutant gene on chromosome 21 in early onset AD, that the aluminium may be associated with a pathogenic pathway. Abnormal beta-amyloid precursor protein (APP) metabolism leads to beta amyloid deposition, tau phosphorylation, paired helical filament formation, and then death.44 The only recent clinical study of aluminium and dementia is the chelation research of McLachlan et al.12 There have been several direct or statistical epidemiology studies, some of which have examined aluminium and dementia or cognitive impairment with air or skin contact as vectors. Sjogren" reported an association between duration of exposure and self-reported memory disorder and depression; and Rifat,14 in the Northern Ontario Miners study, where men had been previously exposed to aluminium powder as a prophylaxis against silicosis, took this approach further with objective testing. There was no excess of neurological disorder but there was
and AD
are so
to
significantly
more
cognitive impairment compared
