Letters to the Editor

(Aust Prescr 1996;19:59-62)

Letters, which may not necessarily be published in full, should be restricted to not more than 250 words. When relevant, comment on the letter is sought from the author. Due to production schedules, it is normally not possible to publish letters received in response to material appearing in a particular issue earlier than the second or third subsequent issue.

The new antidepressants

Editor, - We enjoyed reading the informative article on 'The new antidepressants' by Associate Professor J.W.G. Tiller (Aust Prescr 1995;18:92-6). We were also pleased to note that attention was drawn to the potential for interactions with drugs which interfere with the metabolic pathways of the various antidepressants. Unfortunately, some of the information with regard to hepatic metabolism was incorrect.

Moclobemide is metabolised by cytochrome P450 2C19 (CYP2C19)¹, not by cytochrome P450 2D6 (CYP2D6) as was stated. Confusion may have arisen because moclobemide does inhibit the metabolism of those drugs dependent on CYP2D6 for their elimination.² Interactions are therefore possible.

With regard to the selective serotonin reuptake inhibitors (SSRIs), the article correctly stated that they may inhibit CYP2D6 and hence elevate plasma concentrations of drugs metabolised by this pathway, such as the tricyclic antidepressants. However, Table 1, which listed drugs metabolised by CYP2D6, was incorrect in a number of ways. It omitted many drugs known to be metabolised by the pathway, but included several that are not: theophylline, warfarin, prednisone and felodopine are all metabolised by other cytochrome P450s. Once again the confusion may have been due to the fact that metabolism of these drugs may indeed be inhibited by the SSRIs which inhibit several different P450s.³

Full information on the metabolic pathways of the SSRIs themselves is not yet available. Paroxetine is predominantly, and fluoxetine partially, metabolised by CYP2D6, but the enzymes that predominantly metabolise fluoxetine and sertraline have not been established. If these are members of other P450 families, there would be potential for a range of possible interactions.

Your readers should be aware that full information about pathways of metabolism and potential for interactions is not always available when new drugs are marketed. Care should always be taken when prescribing in combination with other medications.

J. Hoskins, A. Gross and G. Shenfield Department of Clinical Pharmacology Royal North Shore Hospital St Leonards, N.S.W.

R E F E R E N C E S
1. Gram LF, Guentert TW, Grange S, Vistisen K, Brosen K. Moclobemide, the substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6 and CYP1A2: a panel study. Clin Pharmacol Ther 1995;57:670-7.

2. Gram LF, Brosen K. Moclobemide treatment causes a substantial rise in the sparteine metabolic ratio. Danish University Antidepressant Group. Br J Clin Pharmacol 1993;35:649-52.

3. DeVane CL. Pharmacokinetics of the newer antidepressants: clinical relevance. Am J Med 1994;97(6A Suppl):13S-23S.

Editor, - Australian Prescriber vol. 18 no. 4 has some excellent articles which I enjoyed reading and which are very useful for our undergraduate medical students.

I wish to draw to your attention the article by Professor Tiller on new antidepressants and, in particular, his Table 1 on page 93. This Table, which is headed 'Some drugs, metabolised by the cytochrome P450 2D6 hepatic microsomes, which may have clinically significant interactions with SSRI antidepressants', lists 7 drugs. It is my understanding that neither theophylline, warfarin, prednisone or felodipine are metabolised by cytochrome P450 2D6, but rather by other cytochrome P450 isoforms.

Associate Professor A. Somogyi Department of Clinical and Experimental Pharmacology University of Adelaide Adelaide, S.A.

Associate Professor J. Tiller, the author of the article, comments:
Drs Hoskins, Gross and Shenfield and Associate Professor Somogyi highlight the important issue that full information about pathways of metabolism and the potential for interaction is not always available when new drugs are marketed. This knowledge is gained over time. I thank them for providing data on metabolism and interactions with antidepressants which update and correct some data in my paper.

Management of acid peptic disease

Editor, - I refer to Professor Richard Smallwood's article 'The management of acid peptic disease' (Aust Prescr 1995;18:97-9).

Respectfully I disagree with Professor Smallwood's view that 'Barium studies are seldom (my emphasis) definitive and probably most helpful in locations where endoscopy is not readily available'. I find the first half of his sentence completely unacceptable and indefensible, and the second half discriminatory.

There are numerous excellent text books and scientific articles devoted to the particular and special ability to demonstrate gastrointestinal disorders conclusively with double contrast barium swallow and meal. This investigation, properly conducted with modern apparatus and techniques by an experienced gastrointestinal radiologist, will give similar results to those obtained at endoscopy in almost all clinically significant causes of dyspepsia.

There are a number of recent articles in the radiological literature¹,²,³, confirming the value of double contrast barium meal in the specific diagnosis of Helicobacter pylori infection. This examination, when combined with non -invasive breath and serum testing, obviates the need for invasive endoscopy in this particular disorder.

In my opinion, the Health Insurance Commission, other third party payers and, no doubt, the NHMRC would welcome any reduction in costs, without significant loss of diagnostic efficacy, by the reintroduction of referred barium studies in place of self-referred endoscopy. As pointed out by Gelfand4 'if endoscopy had been performed for decades and radiological examinations had become available subsequently with their relative cheapness, negligible mortality and morbidity, minimal discomfort and high accuracy, then it is likely that radiology would be recommended as the desirable initial examination of the gastrointestinal tract'.

Gerald T. Davies Radiologist St Georges, S.A.

R E F E R E N C E S
1. Glick SN. Duodenal ulcer. Radiol Clin North Am 1994;32:1259-74.

2. Levine MS, Rubesin SE. The Helicobacter pylori revolution: radiologic perspective. Radiology 1995;195:593-6.

3. Sohn J, Levine MS, Furth EE, Laufer I, Rubesin SE, Herlinger H, et al. Helicobacter pylori gastritis: radiographic findings. Radiology 1995;195:763-7.

4. Gelfand DW, Ott DJ, Munitz HA, Chen YM. Radiology and endoscopy: a radiologic viewpoint [editorial]. Ann Intern Med 1984;101:550-2.

Chloramphenicol for conjunctivitis

Editor, - Dr J.P. O'Brien's letter to the editor regarding the use of chloramphenicol for conjunctivitis ('Letters' Aust Prescr 1996;19:4-5) prompts me to write. That letter quotes from an editorial1 which refers to a letter2 published in the U.S.A.

In 1982 a fatal case of aplastic anaemia was reported after the use of topical chloramphenicol.3 Since then a national registry has collected 22 cases of various blood dyscrasias, ranging from aplastic anaemia to pancytopenia. Only 7 cases were fully investigated and reported in the literature. It has taken 13 years to collect this handful of cases. Given the lack of full investigation, possibly two-thirds of the cases may not be causally related, yet the inference remains. The published reports cluster around the original case report.

If chloramphenicol is so widely used locally, given the lack of other suitable and efficacious agents, why are we not seeing the problems of aplastic anaemia or blood dyscrasias reported overseas? It may reflect difficulties in reporting adverse drug reactions, but it also suggests that a problem has been highlighted where none exists. Given recent changes in informed consent guidelines, it would be timely to resolve this issue. If the Adverse Drug Reactions
Advisory Committee is aware of local cases, perhaps it should be seeking to have chloramphenicol banned altogether. If they are not, then the warnings in current prescribing information should be amended.

T.J.P. Hodson Eye Surgeon and Physician Mount Gambier, S.A.

R E F E R E N C E S
1. Doona M, Walsh JB. Use of chloramphenicol as topical eye medication: time to cry halt? [editorial]. Br Med J 1995;310:1217-8.

2. Fraunfelder FT, Morgan RL, Yunis AA. Blood dyscrasias and topical ophthalmic chloramphenicol [letter]. Am J Ophthalmol 1993;115:
812-3.

3. Fraunfelder FT, Bagby CG Jr, Kelly DJ. Fatal aplastic anemia following topical administration of ophthalmic chloramphenicol. Am J Ophthalmol 1982;93:356-60.

The Editor comments:
The Adverse Drug Reactions Advisory Committee has received 8 reports of aplastic anaemia in association with chloramphenicol since it began collecting data in 1972. Only 3 cases involved topical formulations and, as all these patients were taking other drugs, there are no reports of aplastic anaemia due to chloramphenicol eye drops or ointment alone. As over a million prescriptions are written every year for these formulations, the risk of aplastic anaemia must be negligible, if it exists at all. In view of this controversy, the Therapeutic Goods Administration plans to review the product information of the chloramphenicol preparations.

The estimated number of prescriptions dispensed for chloramphenicol eye drops and eye ointment in the community (as supplied by the Drug Utilization Sub -Committee of the Pharmaceutical Benefits Advisory Committee) is:

Year	Prescriptions
1990	1,327,720
1991	1,200,307
1992	1,279,483
1993	1,289,381
1994	1,371,386

Current concepts in wound dressings

Editor, - In the article 'Current concepts in wound dressings' (Aust Prescr 1996;19:11-3) by P.G. Hayward and W.A. Morrison, no mention is made of that cheap agent hydrogen peroxide in wound debridement. I find it quite useful. What do the authors think of it?

Peter C. Stephenson General Practitioner Narangba, Qld

The authors of the article, Drs P.G. Hayward and
W.A. Morrison, comment:

We too use peroxide as a cleansing agent during surgical debridement. It has the added advantage of being relatively haemostatic. However, it has limited in vivo activity against Gram positive bacteria and so other antiseptic agents are probably superior where antiseptic activity is required in the cleansing of surface wounds.

Dental implications - management of the post-infarct patient

Editor, - In writing on the dental implications of the management of the post-infarct patient (Aust Prescr 1996;19:13), Dr R. Woods appears to have selectively quoted from his reference1 regarding antibiotics and warfarin. He states 'If antibiotics are employed, dentists should be aware that some antibiotics may inhibit the action of warfarin.' This is true for rifampicin, nafcillin, dicloxacillin1 and griseofulvin.2 Dr Woods has not mentioned that Buckley and Dawson1 also reported potentiation of warfarin by erythromycin, metronidazole, chloramphenicol, quinolones, trimethoprim/sulfamethoxazole, sulfonamides, the imidazole antifungals, some cephalosporins and high intravenous dose penicillin. This latter group includes antibiotics more likely to be prescribed by dentists as the former drugs are not on the Schedule of Pharmaceutical Benefits for dentists.³ Antibiotic potentiation of warfarin has also been referred to in the dental literature.^4,5

A recent review concluded there was probable potentiation of warfarin by paracetamol and by dextropropoxyphene6, and potentiation by aspirin was referred to by Buckley and Dawson.1 These are common drugs in dentistry. Given the number of patients on long-term anticoagulants, Dr Woods may care to elaborate on these important interactions.

Dentists should be mindful of both potentiation and inhibition of warfarin. The former is a potential dental emergency with respect to haemorrhage, the latter a potential medical emergency. I feel the evidence would lead dentists to be more concerned about potentiation of warfarin rather than inhibition and suspect this is by far the more likely problem that dentists may cause or have cause to deal with.

Rod Marshall Periodontist Lecturer in Periodontology Faculty of Dentistry University of Queensland Brisbane, Qld

R E F E R E N C E S
1. Buckley NA, Dawson AH. Drug interactions with warfarin. Med J Aust 1992;157:479-83.

2. Okino K, Weibert RT. Warfarin-griseofulvin interaction. Drug Intell Clin Pharm 1986;20:291-3.

3. Commonwealth Department of Health and Family Services. Pharmaceutical benefits for dental use. In: Schedule of pharmaceutical benefits. Canberra:Australian Government Publishing Service, 1996:137-58.

4. Wood GD, Deeble T. Warfarin: dangers with antibiotics. Dent Update 1993;20:350, 352-3.

5. Wood GD. Antibiotic prescribing and warfarin enhancement [letter]. Br Dent J 1993;175:241.

6. Wells PS, Holbrook AM, Crowther NR, Hirsh J. Interactions of warfarin with drugs and food. Ann Intern Med 1994;121:676-83.  

Dr R.G. Woods, the author of the article, comments:
I appreciate the interest expressed by Dr R. Marshall and his comments. Dr Marshall is quite correct regarding the effects of antibiotics on the action of warfarin in the drug regimens of post-infarct patients.

The matter of drug interactions with warfarin is summarised in Goodman and Gilman.¹

'The list of drugs and other factors that may affect the action of oral anticoagulants is prodigious and expanding. Any substance or condition is potentially dangerous if it alters (1) the uptake or metabolism of the oral anticoagulant or vitamin K; (2) the synthesis, function, or clearance of any factor or cell involved in hemostasis or fibrinolysis; or (3) the integrity of any epithelial surface.'

Coagulation for those on warfarin is unpredictable. It is usual for the INR to be checked regularly and frequently.

Whether to alter coagulation therapy in anticipation of dental treatment is a decision based on clinical judgment, which should be taken jointly by the medical practitioner managing the case and the dentist. Considerations will include the nature of the proposed treatment, its urgency and the possible consequences of a changed anticoagulant regimen.

R E F E R E N C E
1. Majerus PW, Broze GJ Jr, Miletich JP, Tollefsen DM. Anticoagulant, thrombolytic and antiplatelet drugs. In: Goodman Gilman A, Rall TW, Nies AS, Taylor P, editors. Goodman and Gilman's the pharmacological basis of therapeutics. 8th ed. New York: Pergamon Press, 1990:
1311-31.

Attention deficit hyperactivity disorder

Editor, - We were most concerned to read Dr Hazell's statement ('Letters' Aust Prescr 1996;19:5) that 'The important take home message ... is that clinicians, educators and parents should not expect conduct or learning problems to respond to stimulants in the absence of ADHD'. This comment perpetuates the myth that a response to stimulant medication confirms the diagnosis of ADHD. Medications which alter the balance of neurotransmitters in the brain modify symptoms, not diagnoses. Stimulants, like most centrally-acting medications, do not obey any particular diagnosis-therapy couplings. As there is considerable overlap in symptom complexes between the various disruptive behaviour syndromes of children, as well as with other emotional disturbances, there is no logical basis for assuming that the effects of stimulants are married to any particular diagnosis. In fact, it has been shown that even 'normal' children often demonstrate improvements in cognitive performance and behaviour when given stimulants.¹ These somewhat unpalatable truths strike at the very heart of the on-going debate regarding the reasonable and proper use
of these medications.

Certainly, there is now a large body of research evidence that the majority of children with ADHD display clinically significant and often dramatic improvements in impulse control, sustained attention, task completion, compliance and social acceptability when treated with stimulants. However, children with other related problems may also show response. We feel it is important that discussion be informed by what is known from the literature rather than biased by misinformation.

Dr Daryl Efron Dr Rick Jarman Paediatricians Centre for Community Child Health & Ambulatory Paediatrics Royal Children's Hospital Melbourne, Vic.

R E F E R E N C E
1. Rapoport JL, Buchsbaum MS, Zamin TP, et al. Dextroamphetamine: cognitive and behavioral effects in normal prepubertal boys. Science 1978;199:560-3.

Dr P. Hazell, the author of the article on attention deficit hyperactivity disorder (Aust Prescr 1995;18:60-3), comments:
Drs Efron and Jarman have inferred from my comments in a previous letter that I consider stimulant responsiveness to validate the diagnosis of ADHD. This is not my view, and such a view could hardly be sustained in the presence of the significant placebo response seen in samples of children with ADHD. However, I am grateful to the correspondents for raising the question of whether children with behavioural or academic problems in the absence of ADHD may derive clinically significant benefit from treatment with stimulants, since this has prompted me to look further into the issue.

Treatment studies of children without comorbid ADHD are rare, but one inpatient study of 22 conduct-disordered adolescent males (15 of whom were reported not to have comorbid ADHD) found a greater decrease in aggressiveness in response to methylphenidate than to placebo.1 The authors cautioned that there was improvement in only some aspects of the conduct problems, but the findings do suggest a treatment effect independent of ADHD. In the light of these findings, I accept that the specific comment I made, at least in relation to conduct disorder, should be tempered. I have not been successful in locating any treatment study that demonstrates an effect on learning disorder or disability independent of effects on ADHD symptoms. Perhaps the readership can help me with this.

R E F E R E N C E
1. Brown RT, Jaffe SL, Silverstein J, Magee H. Methylphenidate and hospitalized adolescents with conduct disorder: dose effects on classroom behaviour, academic performance, and impulsivity. J Youth Adolescence 1991;20:501-18