Technologies giving the highest possible yield of safe plasma products, and their appropriate and weighed clinical use, are key factors in national self sufficiency. J LEIKOLA G MYLLYLA

Finnish Red Cross Blood Transfusion Service, 003 10 Helsinki, Finland 1 Cash JD. High potency factor VIII concentrates: value not proved? BAIJ 1991;303:633-4. (14 September.)

SIR, -It is both puzzling and surprising to read that the medical and scientific director of the Scottish National Blood Transfusion Service, Dr John D Cash, is uncertain whether high potency factor VIII is scientifically justified in clinical practice and safe in use with a justifiable costbenefit ratio.' It is puzzling in that Dr Cash ventilates these concerns in public at a time when the Scottish National Blood Transfusion Service has recently announced its intention to market such a product2; and surprising in that the issue is surely one of purity and not of potency. It should be noted that these views are not shared by Bio Products Laboratory, and the laboratory's decision to provide patients in England and Wales with high purity factor VIII was based on its consistent empirical policy to work continually towards increasing the purity, safety, and quality of all products derived from human plasma. Thus Bio Products Laboratory has issued licensed monoclonal antibody purified factor VIII to NHS patients since early this year. With regard to the new high purity factor VIII products, it would be interesting to know what evidence Dr Cash has of "the hasty issue of product licences by medicine control authorities" in the United States and the United Kingdom, and, of course, the promotion of Bio Products Laboratory's high purity factor VIII is limited to its quality profile and its dependence on plasma given by our national voluntary, unremunerated donors. The Scottish National Blood Transfusion Service has followed Bio Products Laboratory's practice by signing a technology agreement with foreign organisations to enable future manufacture of high purity factor VIII in Scotland. The matter of the resultant high cost, ultimately to the tax payer, of supplying to haemophiliac patients high purity factor VIII funded by the public sector is confused in Dr Cash's paper; whether the product is charged to hospitals or distributed without charge, as by the Scottish National Blood Transfusion Service, is immaterial. Both English and Scottish high purity factor VIII products attract royalties for technology licensed from overseas institutions. In deciding to provide NHS patients in England and Wales with a high purity factor VIII Bio Products Laboratory took into consideration the views of expert physicians in haemophilia care and the wishes of their patients. R S LANE

low purity products and in vivo evidence that there is a beneficial influence on depletion of CD4 cells in patients positive for HIV antibody2-4 (K Fukutake et al, XIIth congress of the International Society on Thrombosis and Haemostasis, Amsterdam, 30 June-6 July, 1991). It seems inconsistent to write off this evidence as not substantive while raising the spectre of inhibitor development on the basis of a few limited reports whose importance is far from clear. In my experience, issue of product licences has been far from "hasty." High technology products are rightly subjected to intense scrutiny by all health authorities, and enormous amounts of data on safety and efficacy are demanded before a licence is granted. Apart from the licences granted under the provisions of the National Health Service and Community Care Act 1990, which revoked crown immunity, there is absolutely no evidence that this process has been short circuited to permiit the early release of high purity factor VIII concentrates. It is, of course, true that pharmaceutical development is aimed at product improvement; if this was not so we would still be providing crude thyroid powder-extracts ofbeeftesticles or ovaries and liver extracts, for example-to treat hormone or vitamin deficiencies. Surely Dr Cash is not indicating that such progress is counterproductive and should not proceed until absolute clinical benefit is established. Clinical studies on the various potential benefits of pure factor VIII concentrates are proceeding, but it should also be borne in mind that other benefits may accrue, such as opportunities for alternative and improved delivery systems, as a result of improved purity. Finally, promotion to patients is forbidden by both the code of practice of the Association of the British Pharmaceutical Industry and the Medicines Act. Pharmaceutical companies are most careful regarding potential infringement. People with haemophilia are well informed about their condition and treatments available through information provided by their very active society and the World Federation of Haemophilia. I suggest that this is the source of their information, not direct promotion by manufacturers. Armour Pharmaceutical, Eastbourne, East Sussex BN21 3YG 1 Cash JD. High potency factor VIII concentrates: value not

proved? B._ 1991;303:633-4. (14 September.)

2 Rocino A, Niiraglia E, Mastrullo L, Quirino AA, Ziello L, De Biasi R. Prospective controlled trial of an ultra-pure factor VIII concentrate to evaluate the effects on the immune status of HIV antibody-positive hemophilia patients (preliminary results). Estratto da "Acta Toxicologica et Therapeutica" 1990;

11:49-58. 3 Green D, Deutsche J, Tang M, Goldsmith J. Effect of HIV-I infection on CD4 cells in a hemophilia cohort. Haematologica 1990;75(5): 132-41. 4 Ludlam CA. Effects of alloantigens in blood products on immunity. Semin Hematol 1988;25(suppl 1):3-7.

Medically unexplained physical symptoms

I Cash JD. High potency factor V111 concentrates: value not

SIR,-Dr Richard Mayou is right to say that patients "often complain of feeling frustrated at being told that results ofinvestigations are negative but not receiving any convincing explanation of persistent distressing symptoms."' He does not, however, sufficiently emphasise the need to make a clear positive diagnosis which would be the basis of such an explanation, and he is right that "preoccupation with traditional psychiatric diagnostic categories may have hindered understanding." It is usually possible, however, to make a diagnosis, as in the following example. "This 45 year old patient's pain in the left side of the face for the past three months results from ischaemia in persistently clenching jaw muscles

proved? BM7 1991;303:633-4. (14 September.)

SIR,-Dr John D Cash's article discussing the value of high potency factor VIII concentrates contains several inaccurate suggestions that cannot pass unchallenged. ' At least 12 published papers have reported immunological abnormalities in people with haemophilia who have received repeated treatments with clotting factor concentrates of low purity over several years. There is also growing evidence, mainly in vitro, that high purity concentrates are less immunosuppressive than the older,



Department of Psychiatry, Royal London Hospital Medical College, London El 2AD I Mayou R. Medically unexplained physical symptoms. BMJ7

1991;303:534-5. (7 September.)


Bio Products Laboratory, Elstree, Hertfordshire WD6 3BX

2 Vive I'alliance. Bloodletter 1991;48:1.

(bruxism). The pain is unilateral because the bite is asymmetric. The patient has always been rather tense and anxious, and the basis for the present symptoms is a rise in the level of his anxiety in the past three months as evidenced by other features of this such as sleeplessness, palpitations, and frequency of micturition. The reason for this increase in his anxiety is . " Most symptoms of the kind under discussion that come to psychiatrists are the somatic manifestations of anxiety. The common causes of anxiety in my regular outpatient clinics are major emotional conflicts or personal disasters in about half of cases and, in the remaining half, the use of alcohol, often not in what may be called "alcoholic" amounts, or the continuing use of benzodiazepine drugs. Dr Mayou uses the terms unexplained, nonspecific, and atypical. These say what the disorder is not but not what it is. The atypical facial pain in the example above is absolutely typical of numerous patients with a disorder that is far commoner than trigeminal neuralgia, the disorder of which this pain is supposed to be atypical. The pain in the chest after myocardial infarction which Dr Mayou refers to as atypical is typical of the pain in many such patients and almost certainly arises in contracting chest muscles resulting from fear, as evidenced by the fact that it is commonly associated with other symptoms of muscular contraction such as tension headaches, tightness in the neck, or aching in the shoulders. How can you give symptomatic treatment if you do not know the pathogenesis, and how can you reassure if you do not know what is wrong but only the negative results of a series of investigations? Of course these patients are difficult to treat as long as they remain diagnostic puzzles. It is, however, perfectly possible as a rule to make a sufficiently precise statement about the disorder to allow some worthwhile intervention to be made and so to relieve the patient.

Use of thalidomide in leprosy SIR,-Despite Dr M F R Waters's reassurance' neither the most recent report from the World Health Organisation's expert committee on leprosy,2 nor the most recent review3 contains any reference to thalidomide neuropathy. We should be told if the manufacturers, Chemie-Grunenthal, Andrulis Research Corporation, and Interbras, which are currently supplying thalidomide, include a warning about its neuropathic side effects. Even the very existence of the side effect was aggressively denied in 1976 by the then Secretary of State for Health and Social Security, Dr David Owen: supporting the use of thalidomide in leprosy treatment, he wrote to Jack Ashley MP, stating, "You will also wish to know that Sir Ludwig Gutmmann among others is satisfied that allegations of neurotoxicity are unfounded and has given evidence to this effect." Even if the high figure for nodular prurigo is excluded, neuropathy occurred in 15 out of 60,4 three out of nine,5 and two out of six6 patients given the drug for other disorders, making the cited frequency of 0 5% much too low. ' In patients other than patients with leprosy given the drug careful, frequent clinical examinations are routinely carried out and are supplemented by electrophysiological testing, enabling early detection of neuropathy. Stopping the drug at this stage offers the best chance of recovery. Even when the treatment has been successful, as in life threatening graft versus host disease, the drug has had to be withdrawn


26 OCTOBER 1991

Medically unexplained physical symptoms.

Technologies giving the highest possible yield of safe plasma products, and their appropriate and weighed clinical use, are key factors in national se...
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