- Email: [email protected]
Miscellaneous drugs
Z. Fastner
51
Miscellaneous drugs
SURGICAL MATERIALS AND MEDICAL APPLIANCES Acrylic b o n e c e m e n t
(SED 9, 796; SEDA-5,
436) A fall in blood pressure during application of acrylic bone cement is a common complication, but the mechanism underlying it is not fully understood. A new hypothesis that the kallikrein-kinin system might be responsible for the hypotension has been advanced by a group of Turkish investigators (1c), and investigated in cats and humans. Twenty patients undergoing total or partial hip replacement using acrylic bone cement were divided into 2 groups of 10 patients each. One group also received aprotinin (Trasylol) in a dose of 1000 KIU/kg as an i.v. infusion during the operation. Whereas in the control patients blood pressure fell from 123 to 79 mm Hg within 30 seconds (P < 0.005), the aprotinin-treated group showed only a slight and entirely insignificant decrease. As aprotinin is an inhibitor of kallikrein, this suggests that the kallikrein-kinin system may indeed be a mediator of hypotension induced by acrylic bone cement. Intrauterine c o n t r a c e p t i v e devices (IUDs)
(SED 9, 799; SEDA-4, 349; SEDA-5, 437) The fact that the IUD contributes to the development of pelvic inflammatory disease (PID) has already been discussed in these volumes. However, attention has usually been focused exclusively upon acute PID in current users. It is therefore useful to note a study undertaken by the Oxford Family Planning Association (2c), in which the investigators found that current users suffer more frequently from the acute form of PID than from the chronic form (1.51 against 0.54 per 1000 woman-years). In ex-users, however, the situation was reversed, with a prevalence of chronic PID (0.95 versus 0.48). Both differences are significant, the
former at P < 0.001 and the latter at the P = 0.05 level. It seems plausible that the chronic disease progresses slowly in some IUD carriers until the symptoms or vague complaints compel removal, and - if the symptoms still persist - the diagnosis is made, often during surgical intervention only. The dispute as to whether calcium deposits on IUDs which have been in situ for a long time predispose to PID infections or not has not yet been settled (36R). Acute PID can run a dramatic course with Staphylococcus aureus septicemia (3 C) or parametritis (4c). PID due to Pseudomonas fluorescens has been described in an IUD carrier (33c). Suture materials (SED 9, 797; SEDA-5, 436) Dacron or tergal thread impregnated with teflon is frequently used in joint and bone surgery, not only for connective tissue fixation but for bone-joint fixation as well, the thread being driven through the bone. A bone reaction in the form of osteolysis had not been described until recently, and now only in a single case. A patient experienced knee pain 7 years after an uneventful operation. In the course of the subsequent 9 months a large osteolytic cavity developed around the thread, involving half the tibial epiphysis. The lesion showed a clear foreign body inflammatory reaction. Although the possibility of infection cannot be completely discarded, intolerance and rejection are more plausible explanations of this unexpected phenomenon; the delayed onset is, however, difficult to explain (5c). Silicone
(SED 9, 798; SEDA-4, 348; SEDA-5,
436) Foreign body reactions to silicone have been reported previously (SEDA-4, 348), but were related to liquid silicone used for augmentation marnmol~lasty. Essentially the
Miscellaneous dmg~
same reaction can occur as a complication of silicone elastomer joint prostheses, nowadays widely used in orthopedic surgery. It is manifested as synovitis and/or lymphadenopathy. Silicone particles from a metacarpophalangeal joint prosthesis can reach the axillary lymph nodes and produce reactive lymphadenopathy. Histologic examination will easily clear the etiology, and will be necessary if neoplastic metastatic adenopathy has to be considered as a differential diagnosis (6 C). Silicone mastopathy has been described previously as a consequence of silicone injections (SEDA-5,436). Besides the usual risk, the history and clinical picture can easily mask unsuspected inflammatory carcinoma, hence delaying the diagnosis and worsening the prognosis (7c). Synthetic fiber hair replacement For the last few years modacrylic fiber hair implantation has been p r o m o t e d by commercial medical establishments. The procedure is extremely expensive and of most dubious safety. In the bald areas, knotted single and multiple modacrylic fibers are sewn deep into the subcuticular fat. Invariably severe complications develop in the form of inflammatory and infected foreign b o d y reactions, requiring antibiotic treatment. Synthetic fibers tunnel through the dermis but no epithelialization occurs. The epidermis contains cysts filled with keratin and on histologic examination shows a typical inflammatory picture. Severe disfiguration is c o m m o n and surgical help very cumbersome, requiring patient removal of at least 70% of the implanted fibers (8 c). The physician-technician who has performed the implantation usually disappears, leaving the victim to his fate. It is obvious that in the present state of affairs, synthetic fiber hair replacement must be condemned and abandoned as constituting quackery and malpractice.
V a g i n a l t a m p o n s and t o x i c s h o c k syndrome The toxic shock syndrome (TSS) is a relatively new clinical entity described ini-
427 tially by Todd in 1978, although many physicians will recall having seen similar clinical pictures in the past. Although TS8 is nowadays almost exclusively associated with the use o f internal vaginal tampons, one must remember that TSS is by no means a monopoly o f women, let alone menstruating tampon users. One recent report (9 R ) relates to 7 children (aged 8 - 1 7 ) , 3 o f them boys. However, the fact is that attention is largely focused on menstruating tampon users, in whom TSS has been so frequently seen that the American Center for Diseases Control initiated close monitoring o f a l l cases reported (1oR). It would be beyond the scope o f this review to describe once more the clinical features o f TSS; only the essential epidemiologic facts will be discussed. For some time it was thought that TSS as a result o f tampon use was limited to the USA, but soon the reports began to f l o w in from other countries, including the UK (11 C, 12c), N e w Zealand (13 C) and the Netherlands (14c). Two well-documented clinical epidemiologic studies (9 r 15 C) were published, seeking to elucidate the essential conditions leading to the manifestation o f TSS. 95% o f all patients with TSS are women. In 98~o o f these women the disease begins during the menstrual period and in 98% o f the patients Staphylococcus aureus was isolated from the vaginal swab. Staphylococcus aureus was o f phage group I, but was in no case isolated from the blood. It is obvious that shock was produced not by bacteriemia but by epidermal toxin. Only some 8~o o f healthy controls harbored Staphylococcus aureus vaginally. This unexpected ailment did not fail to take its toll, lethality probably attaining 1 0 - 1 5 % o f cases (1 7R, 18R). Since Staphylococcus contamination - both vaginal and extravaginal - can and usually does occur without clinical consequences, let alone dramatical ones, all attention was focused upon the obvious link with vaginal tampons. This connection seemed to be particularly specific in that one special brand (Rely tampons) appeared to produce a greater number o f cases than others. As a consequence the producer, Proctor & Gamble, withdrew R e l y from the market, although other brands o f tampons had also been incriminated. It is important to realize that many o f the surviving patients had several recurrences
Z. Fasmer
428 during several subsequent periods (up to 5), every following one being less severe in its clinical course (11 r 13C). Insertion o f a contraceptive diaphragm could trigger the onset o f TSS, even at times other than menstruation. The pathogenesis o f TSS is not fully understood. It is certain that the tampons were not contaminated, and thus cannot be considered as the direct cause o f the ailment, but rather as a trigger for the course o f events leading to TSS. It seems most plausible that the toxin produced by Staphylococcus aureus accumulates in the tampon and is absorbed either directly from the vagina or by reflux o f menstrual blood through the Fallopian tubes into the peritoneal cavity. In favor o f this hypothesis one could quote the observation that a number o f cases o f TSS occurred in women leaving the tampon in situ for a long period, even up to 3 days. It is difficult to say why from 1978 onwards the incidence o f TSS increased. Highly absorbent tampons may be one factor, but obviously not the only one. It is clear that several factors have to coincide to produce TSS, e.g. the presence o f highly virulent Staphylococcus in the vagina, and conditions favoring their increased growth or colonization, e.g. a tampon saturated with menstrual blood. In our present state o f knowledge we have to recognize that a risk, however remote ( 1 0 - 1 5 per 100,000 menstruating women per year) exists, and is triggered by vaginal tampons. It even seems that poor hygienic habits (leaving tampons in situ for several days) are not a sine qua non, as TSS was described in women changing their tampons regularly. The practical question is whether this remote risk has to be accepted, in other words, whether the use o f vaginal tampons is justified. The answer is difficult to give, but as epidemiologic data have failed to define clear and reliable ways to avoid the risk, caution is mandatory. Good hygienic habits are no guarantee against this ailment and mass screening for virulent vaginal staphylococci is certainly not feasible. Certainly, women who have previously had febrile attacks during menstrual periods must use tampons with utmost restraint or abandon them completely in favor o f old-fashioned external tampons.
MISCELLANEOUS ORGANIC COMPOUNDS
Aristolochic acid As of June, 1981, the German Federal Ministry of Health took measures to withdraw drugs containing aristolochic acid from the market. The decision was based on the findings of a carcinogenic potential in a 3m o n t h toxicity study in rats. At doses of 10 mg/kg/day per os aristolochic acid induced malignant papillomatous lesions of the stomach in all the animals sacrificed at the end of the dosage period. Animals allowed to survive free of treatment for a further 4 months were found to have multiple carcinomatous lesions. Sites most frequently involved were the duodenum, mesentery, liver, kidney, bladder, lungs, thoracic cavity, diaphragm and skin. It is unusual for any compound to prove so potent with respect to carcinogenicity as this, inducing within a short period widespread malignant lesions which continue to develop rapidly after the withdrawal of the stimulus. Aristolochic acid is claimed to promote phagocytosis and to have immunostimulant activity. Extracts of aristolochiaceae have traditionally been used as a bitter; no proven medical applications seem to exist. Of the 240 drug products on the German market with this component only those with extreme homeopathic dilutions will be allowed to remain on sale (39, 40). It is not k n o w n to what extent aristolochic acid is used outside Germany, but herbal components of this type are often present in products of cosmetic or tonic nature and sold outside ordinary pharmaceutical channels.
Cinnamic aldehyde Contact leukoderma simulating vitiligo is known to occur after skin exposure to certain catechols and phenols. Recently, a similar case was reported in a young woman using toothpaste containing cinnamic aldehyde. The patient noted that perioral foam formed during toothbrushing resulted in slight transient irritation, and that depigmentation was developing in the area concerned. Patch-testing revealed that cinnamic aldehyde was responsible, and the perioral depigmentation cleared after another brand of
429
Miscellaneous drugs
toothpaste, without cinnamic aldehyde, was substituted (19C).
It was unexpected that cinnamic aldehyde would produce this action, since its aromatic ring is not hydroxylated, as are other catechols and phenols with depigmentating effects. Moreover, leukoderma in an allergic patch is unusual. As cinnamic aldehyde is contained in some sunburn creams, looking for depigmentation could be rewarding, as patchy depigmentation may tend to be ascribed to the sunburn itself rather than to the remedy used to prevent it.
Dimethylsulfoxide(DMSO) (SED 9, 238-9; SEDA-4, 351; SEDA-5, 440) Although still controversial, DMSO continues to be widely used in a host o f ailments, despite official restrictions in most countries even on its experimental use (as in the UK), or its approval for limited indications only (e.g. interstitial cystitis in the USA) (20 e, 21"). Despite widespread use and extensive publicity for what are claimed to be dramatic therapeutic effects (more than 1000 publications), effectiveness and safety o f DMSO have generally remained unclear; a few studies only were performed in such a way as to permit reliable conclusions (2Or). DMSO is used currently inter alia, and probably quite validly, for the cryopreservation o f bone marrow concentrate, e.g. in concentrations o f 10%. In a case recently reported, a man o f 54 receiving an autologous bone marrow infusion for acute myeloblastic leukemia developed an acute reaction to the infusion, with pyrexia, facial congestion, vomiting, rigors, tachycardia and collapse. The symptoms subsided with due treatment and 2 days after this he was again treated with the infusion, from which the DMSO had in the meantime been removed, without complications (22c). Whilst this case suggests the involvement o f DMSO in the acute reaction, it does not prove it, in view o f the fact that one was dealing here with a seriously ill patient receiving both antibiotics and cytostatic agents.
The most heavily debated indication for DMSO use the treatment o f arthritis - has begun to lose favor among rheumatologists, as the effect on an inflamed joint has never been shown and only an analgesic effect was demonstrable, probably through interference with nerve conductivity (23R). As a potent osmotic agent, however, DMSO is enjoying popularity as adjuvant in the treatment o f cerebral edema. Besides local use on the skin and eyes, often as an excipient to aid penetration o f another substance, DMSO is also used intravenously as a 1 0 - 4 0 % solution and orally. Since DMSO penetrates quickly through the tissues, no great differences between its effects with different administration forms are to be expected (24r), though it may potentiate the effect o f drugs administered simultaneously (25r). In local use on the skin in high concentrations ( 9 0 - 1 0 0 % ) D M S O can cause irritation, but when the concentration is somewhat lower (70%), the irritation seems to be much less. Only one fatality was reported, due to a hypersensitivity reaction (23R). Short-term use o f low doses did not produce ocular side effects in humans (2OR). It is intravenous use which obviously poses the biggest problems. Recent publications indicate that Lv. administration produces transient systemic hemolysis with hemoglobinurla but without gross hematuria. The hemolysis is dose-dependent and appears within several minutes after 2 0 - 4 0 % infusions, while after a 10% infusion slight pink coloration o f the urine has been observed in some patients. A t the same time hematocrit, hemoglobin and serum haptoglobin fell, while serum free hemoglobin, bilirubin and LDH rose (22 C, 26 C, 27c). Renal function was unaffected and indeed seemed to be improved in patients with amyloid-induced renal failure (28r). The efficacy o f DMSO in most conditions is not proven, whilst its risks (especially in i.v. use) are real ones. Even the above-mentioned apparent innocuity as regards renal function must be taken with caution, as the kidney can be damaged by handling higher amounts o f hemoglobin after hemolysis. Its use, except perhaps as an excipient and in tissue preservation, should therefore be abandoned until more information is available. -
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Disulfirarn (SED 9, 802; SEDA-4, 351; SEDA-5, 440) A child with numerous congenital abnormalities as well as retarded physical growth and mental development was born to a mother who had been taking 400 mg/day disulfiram at the time of conception and perhaps for some weeks afterwards. The case appeared typical of the 'fetal alcohol syndrome' which has been thought to be due to acetaldehyde rather than to alcohol itself. In the circumstances, the authors of the paper in question felt the possibility should be raised that disulfiram had, by arresting the metabolism of alcohol at the aldehyde stage, accentuated the induction of the syndrome (34c). Toxic liver damage has in the course of the years been reported some 10 times with disulfiram; a recent case from Sweden relates to a female non-alcoholic who had been receiving disulfiram for reasons other than alcoholism (35C). Besides systemic reactions, disulfiram is reported to produce skin reactions if alcohol is used externally in the form of cosmetic lotions and shampoos. The reaction usually consists of a pruritic rash persisting for about half an hour after local application of an alcohol-containing solution. Due to the transient nature of the effect the vast majority of these cases probably remain unreported (29cr).
Elsinore pills (Helsing~r-piller) The Elsinore pill is a magistral preparation which since 1974 has gained some popularity in Denmark and perhaps elsewhere as a slimming remedy. It contains phenobarbital, ephedrine chloride, caffeine, antacids and vitamins. Its adverse reactions are generally what one would expect, with the added complication that the physician faced with such a reaction may not be aware that the patient is using this preparation or may not know its composition. Serup has recently described a case of severe drug rash in a woman taking this product. Administration of prednisone tablets in doses up to 75 mg daily proved necessary to control the condition. After recovery, a renewed severe skin rash of the exfoliative erythrodermal type occurred 1 - 2 days after accidental exposure to ephedrine nose drops.
Rash appears to be a frequent problem with this product in Denmark, and it has been suggested that an interaction between phenobarbital and ephedrine may provide an explanation for this fact (37Cr). Hematoporphyrin Hematoporphyrin is a synthetic porphyrin not occurring in nature. It has been sold since about 1949 in France, and perhaps elsewhere, as a parenteral antidepressant drug, under names which include Hematon, Novitan and Hemodonin. Its value is controversial. In the course of 2 years, Leroy et al. observed no less than 23 cases of photosensitization to this drug, all in women of middle age, and in the majority of cases localized around the injection site. They also point out that the drug can cause disfiguring residual pigmentation and may perhaps derange porphyrin metabolism (38 C).
Intravenous fluids (additives and excipients) Local reactions to i.v. injections, even of short duration (several minutes), depend greatly o n the composition of the solvent, as shown in a study using i.v. diazepam in 3 different solution fluids. In a series of 200 patients, 3 formulations were used. One third received Stesolid (solvent propylene glycol), another third Stesolid ML (solvent Cremophor EL), and the remainder Diazemuls (solvent soybean oil emulsified in water according to the techniques used in the production of Intralipid for i.v. nutrition). The differences were striking, as is evident from Table 1. The third formulation therefore seems highly superior, especially as Cremophor EL has sometimes led to severe anaphylactic reactions (30Cr), particularly when used in parenteral anesthetics (SED 9,802).
Table 1. Differences in reaction to 3 i.v. formulations
Stesolid Stesolid MR
Diazemuls
Pain
Thrombophlebitis
78% 38%
49% 9%
I%
4%
431
Miscellaneous drugs Phenol
Phenol is present in numerous injectable drugs, and it is sometimes forgotten that it can, when given in small doses internally, have unexpected effects of its own. Bowling et al. have described how a surgical emergency case began to void green urine, a finding which was at first unexplained but which persisted for 2 days. The urine was positive for phenol and it was then realized that the patient had been treated parenterally with cimetidine (each 2 ml vial of which con-
tained 10 mg o f phenol), and promethazine (containing 5 mg of phenol per ml). The discoloration was still present 12 hours after the last cimetidine dose (3 le). Placebo
Adverse effects reported by patients taking placebo were reviewed in SEDA-1 (p. 384). A further extensive review in German can be recommended (32R), particularly since it provides a thorough discussion of factors influencing the placebo reaction.
REFERENCES 1. Arac, S.S., Ercan, Z.S. and Tiirker, R.K. (1980): Prevention by aprotinin of the hypotension due to acrylic cement implantation into the bone. Curt. ther. Res., 28,554. 2. Vessey, M.P., Yeates, D., Flavel, R. and McPherson, K. (1981): Pelvic inflammatory disease and the intrauterine device: findings in a large cohort study. Brit. med. J., 282, 855. 3. Geddes, A.M. (1980): Staphylococcal septieaemia after insertion of an intrauterine contraceptive device. Brit. reed. J., 281, 1639. 4. Verhoeven, A. (1981): Parametritis door een IUD. Ned. 7". Geneesk., 125,319. 5. Vives, P., De Lestang, M., Dorde, T. and Gaffuri, J.G. (1980): R~action ost~olytique tardive massive autour de Iris transosseux. Rev. Chir. orthop., 66, 394. 6. Kixcher, T. (1980): Silicone lymphadenopathy. A complication of silicone elastomer finger joint prostheses. Hum. Pathol. , 11,240. 7. Lewis, C. M. (1980): Inflammatory carcinoma of the breast following silicone injections. Plast. reconstr. Surg. , 66,134. 8. Lepaw, M.I. (1980): Therapy and histopathology of complications from synthetic fiber implants for hair replacement. J. Amer. Acad. Dermatoi., 3, 195. 9. Davis, J. P., Chesney, P. J., Wand, P. J. and La Venture, M. (1980): Toxic shock syndrome. New Engl. J. Med., 303, 1429. 10. Editorial (1980): Update on toxic shock syndrome. FDA Drug Bull., 10, 17. 11. Medical student (1980): Toxic shock and tampons. Brit. med. J., 281, 1426. 12. Holt, P. (1980): Tampon-associated shock syndrome. Brit. med. J., 281, 1321. 13. Lea, S. and Ellis-Pegler, R.B. (1980): Toxic shock and tampons. Brit. med. J. , 281, 1639. 14. Van Ketel, R.J. (1981): Tamponziekte in Nederland. Ned. T. Geneesk., 125, 93. 15. Shands, K. N., Schmid, G. P., Dan, B. B. et al. (1980): Toxic shock syndrome in menstruating women. New Engl. Y. Med. , 303, 1436. 16. De Geus, J.P. (1981): Het toxische-shock-
syndroom ('tamponziekte'). Ned. T. Geneesk., 125, 95. 17. Glasgow, L. A. (1980): Staphylococcal infection in the toxic-shock syndrome. New Engl. J. Med., 303, 1473. 18. Editorial (1980): Toxic shock and tampons. Brit. med. J. , 281, 1161. 19. Mathias, C. G. T., Maibach, H. I. and Conant, M.A. (1980): Perioral leukoderma simulating vitiligo from use of a toothpaste containing cinnamic aldehyde. Arch. Dermatol. , 116, 1172. 20. Finkel, M.J. (1980): Dimethyl suifoxide. J. Amer. med. Ass., 244, 2767. 21. Griffin, J.P. (1981): Letter to the Editor. DMSO. Lancet, 1, 41. 22. O'Donnel, J.R., Bumett, A. K., Sheehan, T. et al. (1981): Safety of dimethylsulfoxide. Lancet, I, 498. 23. Bennett, C.C. (1980): Dimethyl sulfoxide. J. Amer. med. Ass., 244, 2768. 24. Greenfield, C. (1981): Dimethylsulfoxide toxicity. Lancet, I, 276. 25. Van Rijswijk, M.H. (1981): Dimethylsulfoxide. Lancet, I, 41. 26. Muther, R. S. and Bennett, W. M. (1980): Effects of dimethyl sulfoxide on renal function in man. J. Amer. med. Ass., 244, 2081. 27. Yellowlees, P., Greenfield, C. and McIntyre, N. (1980): Dimethylsulphoxide-induced toxicity. Lancet, II, 1004. 28. Knott, L. J. (1980): Safety of intravenous dimethylsuifoxide. Lancet, II, 1299. 29. Stoll, D. and King Jr., L.E. (1980): Disulfiram-alcohol skin reaction to beer-containing shampoo. J. Amer. med. Ass., 244, 2045. 30. Schou Olesen, A. and Hiittel, M. S. (1980): Local reactions to i.v. diazepam in three different formulations. Brit. J. Anaesth. , 52, 609. 31. Bowling, P., Belliveau, R. R. and Butler, T. J. (1981): Intravenous medications and green urine. J. Amer. med. Ass., 246, 216. 32. Piechowiak, H. (1981): Die namenlose Pille. Schweiz. med. Wschr., 111, 1222. 33. Foulon, W., Naessens, A., Lauwers, S. et al.
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432 (1981):
Pelvic inflammatory disease due to
Pseudomonas fluorescens in patients wearing an intrauterine device. Lancet, II, 358. 34. Gardner, R. J. M. and Clarkson, J. E. (1981): Exacerbation of fetal alcohol syndrome or a direct effect? N.Z. meR J., 3, 184. 35. Kristensen, M. E. (1981): Toxic hepatitis induced by disulfiram in a non-alcoholic. Acta. reed. scand., 209, 335. 36. Anon. (1981): Calcium deposits on 1UDs may play role in infections. J. Amer. reed. Ass., 245, 1625. 37. Serup, J. (1981): Eksfofiativ erythrodermi efter Helsing~r-piller og accidentel provokation -
med efedrin-naesedr~ber. Ugeskr. Laeg., 143, 1660. 38. Leroy, D., le Maitre, M., Marteret, P. et al. (1981): Accidents de photosensibilisation apr~s injection intramusculaire d'h~matoporphyrine. A propos de 23 cas. Ann. ~Dermatol. Vdn$rdol. (Paris), 108, 95. 39. Anon. (1981): Drugs containing aristolochic acid withdrawn from F.R.G. market. Circular issued by WHO, Geneva, 19 august 1981. 40. Anon. (1981): BGA verbietet aristolochias~urehaltige Arzneimittel. Dtsch. Apoth. Ztg, 121, 1330.
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Miscellaneous drugs
SURGICAL MATERIALS AND MEDICAL APPLIANCES Acrylic b o n e c e m e n t
(SED 9, 796; SEDA-5,
436) A fall in blood pressure during application of acrylic bone cement is a common complication, but the mechanism underlying it is not fully understood. A new hypothesis that the kallikrein-kinin system might be responsible for the hypotension has been advanced by a group of Turkish investigators (1c), and investigated in cats and humans. Twenty patients undergoing total or partial hip replacement using acrylic bone cement were divided into 2 groups of 10 patients each. One group also received aprotinin (Trasylol) in a dose of 1000 KIU/kg as an i.v. infusion during the operation. Whereas in the control patients blood pressure fell from 123 to 79 mm Hg within 30 seconds (P < 0.005), the aprotinin-treated group showed only a slight and entirely insignificant decrease. As aprotinin is an inhibitor of kallikrein, this suggests that the kallikrein-kinin system may indeed be a mediator of hypotension induced by acrylic bone cement. Intrauterine c o n t r a c e p t i v e devices (IUDs)
(SED 9, 799; SEDA-4, 349; SEDA-5, 437) The fact that the IUD contributes to the development of pelvic inflammatory disease (PID) has already been discussed in these volumes. However, attention has usually been focused exclusively upon acute PID in current users. It is therefore useful to note a study undertaken by the Oxford Family Planning Association (2c), in which the investigators found that current users suffer more frequently from the acute form of PID than from the chronic form (1.51 against 0.54 per 1000 woman-years). In ex-users, however, the situation was reversed, with a prevalence of chronic PID (0.95 versus 0.48). Both differences are significant, the
former at P < 0.001 and the latter at the P = 0.05 level. It seems plausible that the chronic disease progresses slowly in some IUD carriers until the symptoms or vague complaints compel removal, and - if the symptoms still persist - the diagnosis is made, often during surgical intervention only. The dispute as to whether calcium deposits on IUDs which have been in situ for a long time predispose to PID infections or not has not yet been settled (36R). Acute PID can run a dramatic course with Staphylococcus aureus septicemia (3 C) or parametritis (4c). PID due to Pseudomonas fluorescens has been described in an IUD carrier (33c). Suture materials (SED 9, 797; SEDA-5, 436) Dacron or tergal thread impregnated with teflon is frequently used in joint and bone surgery, not only for connective tissue fixation but for bone-joint fixation as well, the thread being driven through the bone. A bone reaction in the form of osteolysis had not been described until recently, and now only in a single case. A patient experienced knee pain 7 years after an uneventful operation. In the course of the subsequent 9 months a large osteolytic cavity developed around the thread, involving half the tibial epiphysis. The lesion showed a clear foreign body inflammatory reaction. Although the possibility of infection cannot be completely discarded, intolerance and rejection are more plausible explanations of this unexpected phenomenon; the delayed onset is, however, difficult to explain (5c). Silicone
(SED 9, 798; SEDA-4, 348; SEDA-5,
436) Foreign body reactions to silicone have been reported previously (SEDA-4, 348), but were related to liquid silicone used for augmentation marnmol~lasty. Essentially the
Miscellaneous dmg~
same reaction can occur as a complication of silicone elastomer joint prostheses, nowadays widely used in orthopedic surgery. It is manifested as synovitis and/or lymphadenopathy. Silicone particles from a metacarpophalangeal joint prosthesis can reach the axillary lymph nodes and produce reactive lymphadenopathy. Histologic examination will easily clear the etiology, and will be necessary if neoplastic metastatic adenopathy has to be considered as a differential diagnosis (6 C). Silicone mastopathy has been described previously as a consequence of silicone injections (SEDA-5,436). Besides the usual risk, the history and clinical picture can easily mask unsuspected inflammatory carcinoma, hence delaying the diagnosis and worsening the prognosis (7c). Synthetic fiber hair replacement For the last few years modacrylic fiber hair implantation has been p r o m o t e d by commercial medical establishments. The procedure is extremely expensive and of most dubious safety. In the bald areas, knotted single and multiple modacrylic fibers are sewn deep into the subcuticular fat. Invariably severe complications develop in the form of inflammatory and infected foreign b o d y reactions, requiring antibiotic treatment. Synthetic fibers tunnel through the dermis but no epithelialization occurs. The epidermis contains cysts filled with keratin and on histologic examination shows a typical inflammatory picture. Severe disfiguration is c o m m o n and surgical help very cumbersome, requiring patient removal of at least 70% of the implanted fibers (8 c). The physician-technician who has performed the implantation usually disappears, leaving the victim to his fate. It is obvious that in the present state of affairs, synthetic fiber hair replacement must be condemned and abandoned as constituting quackery and malpractice.
V a g i n a l t a m p o n s and t o x i c s h o c k syndrome The toxic shock syndrome (TSS) is a relatively new clinical entity described ini-
427 tially by Todd in 1978, although many physicians will recall having seen similar clinical pictures in the past. Although TS8 is nowadays almost exclusively associated with the use o f internal vaginal tampons, one must remember that TSS is by no means a monopoly o f women, let alone menstruating tampon users. One recent report (9 R ) relates to 7 children (aged 8 - 1 7 ) , 3 o f them boys. However, the fact is that attention is largely focused on menstruating tampon users, in whom TSS has been so frequently seen that the American Center for Diseases Control initiated close monitoring o f a l l cases reported (1oR). It would be beyond the scope o f this review to describe once more the clinical features o f TSS; only the essential epidemiologic facts will be discussed. For some time it was thought that TSS as a result o f tampon use was limited to the USA, but soon the reports began to f l o w in from other countries, including the UK (11 C, 12c), N e w Zealand (13 C) and the Netherlands (14c). Two well-documented clinical epidemiologic studies (9 r 15 C) were published, seeking to elucidate the essential conditions leading to the manifestation o f TSS. 95% o f all patients with TSS are women. In 98~o o f these women the disease begins during the menstrual period and in 98% o f the patients Staphylococcus aureus was isolated from the vaginal swab. Staphylococcus aureus was o f phage group I, but was in no case isolated from the blood. It is obvious that shock was produced not by bacteriemia but by epidermal toxin. Only some 8~o o f healthy controls harbored Staphylococcus aureus vaginally. This unexpected ailment did not fail to take its toll, lethality probably attaining 1 0 - 1 5 % o f cases (1 7R, 18R). Since Staphylococcus contamination - both vaginal and extravaginal - can and usually does occur without clinical consequences, let alone dramatical ones, all attention was focused upon the obvious link with vaginal tampons. This connection seemed to be particularly specific in that one special brand (Rely tampons) appeared to produce a greater number o f cases than others. As a consequence the producer, Proctor & Gamble, withdrew R e l y from the market, although other brands o f tampons had also been incriminated. It is important to realize that many o f the surviving patients had several recurrences
Z. Fasmer
428 during several subsequent periods (up to 5), every following one being less severe in its clinical course (11 r 13C). Insertion o f a contraceptive diaphragm could trigger the onset o f TSS, even at times other than menstruation. The pathogenesis o f TSS is not fully understood. It is certain that the tampons were not contaminated, and thus cannot be considered as the direct cause o f the ailment, but rather as a trigger for the course o f events leading to TSS. It seems most plausible that the toxin produced by Staphylococcus aureus accumulates in the tampon and is absorbed either directly from the vagina or by reflux o f menstrual blood through the Fallopian tubes into the peritoneal cavity. In favor o f this hypothesis one could quote the observation that a number o f cases o f TSS occurred in women leaving the tampon in situ for a long period, even up to 3 days. It is difficult to say why from 1978 onwards the incidence o f TSS increased. Highly absorbent tampons may be one factor, but obviously not the only one. It is clear that several factors have to coincide to produce TSS, e.g. the presence o f highly virulent Staphylococcus in the vagina, and conditions favoring their increased growth or colonization, e.g. a tampon saturated with menstrual blood. In our present state o f knowledge we have to recognize that a risk, however remote ( 1 0 - 1 5 per 100,000 menstruating women per year) exists, and is triggered by vaginal tampons. It even seems that poor hygienic habits (leaving tampons in situ for several days) are not a sine qua non, as TSS was described in women changing their tampons regularly. The practical question is whether this remote risk has to be accepted, in other words, whether the use o f vaginal tampons is justified. The answer is difficult to give, but as epidemiologic data have failed to define clear and reliable ways to avoid the risk, caution is mandatory. Good hygienic habits are no guarantee against this ailment and mass screening for virulent vaginal staphylococci is certainly not feasible. Certainly, women who have previously had febrile attacks during menstrual periods must use tampons with utmost restraint or abandon them completely in favor o f old-fashioned external tampons.
MISCELLANEOUS ORGANIC COMPOUNDS
Aristolochic acid As of June, 1981, the German Federal Ministry of Health took measures to withdraw drugs containing aristolochic acid from the market. The decision was based on the findings of a carcinogenic potential in a 3m o n t h toxicity study in rats. At doses of 10 mg/kg/day per os aristolochic acid induced malignant papillomatous lesions of the stomach in all the animals sacrificed at the end of the dosage period. Animals allowed to survive free of treatment for a further 4 months were found to have multiple carcinomatous lesions. Sites most frequently involved were the duodenum, mesentery, liver, kidney, bladder, lungs, thoracic cavity, diaphragm and skin. It is unusual for any compound to prove so potent with respect to carcinogenicity as this, inducing within a short period widespread malignant lesions which continue to develop rapidly after the withdrawal of the stimulus. Aristolochic acid is claimed to promote phagocytosis and to have immunostimulant activity. Extracts of aristolochiaceae have traditionally been used as a bitter; no proven medical applications seem to exist. Of the 240 drug products on the German market with this component only those with extreme homeopathic dilutions will be allowed to remain on sale (39, 40). It is not k n o w n to what extent aristolochic acid is used outside Germany, but herbal components of this type are often present in products of cosmetic or tonic nature and sold outside ordinary pharmaceutical channels.
Cinnamic aldehyde Contact leukoderma simulating vitiligo is known to occur after skin exposure to certain catechols and phenols. Recently, a similar case was reported in a young woman using toothpaste containing cinnamic aldehyde. The patient noted that perioral foam formed during toothbrushing resulted in slight transient irritation, and that depigmentation was developing in the area concerned. Patch-testing revealed that cinnamic aldehyde was responsible, and the perioral depigmentation cleared after another brand of
429
Miscellaneous drugs
toothpaste, without cinnamic aldehyde, was substituted (19C).
It was unexpected that cinnamic aldehyde would produce this action, since its aromatic ring is not hydroxylated, as are other catechols and phenols with depigmentating effects. Moreover, leukoderma in an allergic patch is unusual. As cinnamic aldehyde is contained in some sunburn creams, looking for depigmentation could be rewarding, as patchy depigmentation may tend to be ascribed to the sunburn itself rather than to the remedy used to prevent it.
Dimethylsulfoxide(DMSO) (SED 9, 238-9; SEDA-4, 351; SEDA-5, 440) Although still controversial, DMSO continues to be widely used in a host o f ailments, despite official restrictions in most countries even on its experimental use (as in the UK), or its approval for limited indications only (e.g. interstitial cystitis in the USA) (20 e, 21"). Despite widespread use and extensive publicity for what are claimed to be dramatic therapeutic effects (more than 1000 publications), effectiveness and safety o f DMSO have generally remained unclear; a few studies only were performed in such a way as to permit reliable conclusions (2Or). DMSO is used currently inter alia, and probably quite validly, for the cryopreservation o f bone marrow concentrate, e.g. in concentrations o f 10%. In a case recently reported, a man o f 54 receiving an autologous bone marrow infusion for acute myeloblastic leukemia developed an acute reaction to the infusion, with pyrexia, facial congestion, vomiting, rigors, tachycardia and collapse. The symptoms subsided with due treatment and 2 days after this he was again treated with the infusion, from which the DMSO had in the meantime been removed, without complications (22c). Whilst this case suggests the involvement o f DMSO in the acute reaction, it does not prove it, in view o f the fact that one was dealing here with a seriously ill patient receiving both antibiotics and cytostatic agents.
The most heavily debated indication for DMSO use the treatment o f arthritis - has begun to lose favor among rheumatologists, as the effect on an inflamed joint has never been shown and only an analgesic effect was demonstrable, probably through interference with nerve conductivity (23R). As a potent osmotic agent, however, DMSO is enjoying popularity as adjuvant in the treatment o f cerebral edema. Besides local use on the skin and eyes, often as an excipient to aid penetration o f another substance, DMSO is also used intravenously as a 1 0 - 4 0 % solution and orally. Since DMSO penetrates quickly through the tissues, no great differences between its effects with different administration forms are to be expected (24r), though it may potentiate the effect o f drugs administered simultaneously (25r). In local use on the skin in high concentrations ( 9 0 - 1 0 0 % ) D M S O can cause irritation, but when the concentration is somewhat lower (70%), the irritation seems to be much less. Only one fatality was reported, due to a hypersensitivity reaction (23R). Short-term use o f low doses did not produce ocular side effects in humans (2OR). It is intravenous use which obviously poses the biggest problems. Recent publications indicate that Lv. administration produces transient systemic hemolysis with hemoglobinurla but without gross hematuria. The hemolysis is dose-dependent and appears within several minutes after 2 0 - 4 0 % infusions, while after a 10% infusion slight pink coloration o f the urine has been observed in some patients. A t the same time hematocrit, hemoglobin and serum haptoglobin fell, while serum free hemoglobin, bilirubin and LDH rose (22 C, 26 C, 27c). Renal function was unaffected and indeed seemed to be improved in patients with amyloid-induced renal failure (28r). The efficacy o f DMSO in most conditions is not proven, whilst its risks (especially in i.v. use) are real ones. Even the above-mentioned apparent innocuity as regards renal function must be taken with caution, as the kidney can be damaged by handling higher amounts o f hemoglobin after hemolysis. Its use, except perhaps as an excipient and in tissue preservation, should therefore be abandoned until more information is available. -
Z Fastner
430
Disulfirarn (SED 9, 802; SEDA-4, 351; SEDA-5, 440) A child with numerous congenital abnormalities as well as retarded physical growth and mental development was born to a mother who had been taking 400 mg/day disulfiram at the time of conception and perhaps for some weeks afterwards. The case appeared typical of the 'fetal alcohol syndrome' which has been thought to be due to acetaldehyde rather than to alcohol itself. In the circumstances, the authors of the paper in question felt the possibility should be raised that disulfiram had, by arresting the metabolism of alcohol at the aldehyde stage, accentuated the induction of the syndrome (34c). Toxic liver damage has in the course of the years been reported some 10 times with disulfiram; a recent case from Sweden relates to a female non-alcoholic who had been receiving disulfiram for reasons other than alcoholism (35C). Besides systemic reactions, disulfiram is reported to produce skin reactions if alcohol is used externally in the form of cosmetic lotions and shampoos. The reaction usually consists of a pruritic rash persisting for about half an hour after local application of an alcohol-containing solution. Due to the transient nature of the effect the vast majority of these cases probably remain unreported (29cr).
Elsinore pills (Helsing~r-piller) The Elsinore pill is a magistral preparation which since 1974 has gained some popularity in Denmark and perhaps elsewhere as a slimming remedy. It contains phenobarbital, ephedrine chloride, caffeine, antacids and vitamins. Its adverse reactions are generally what one would expect, with the added complication that the physician faced with such a reaction may not be aware that the patient is using this preparation or may not know its composition. Serup has recently described a case of severe drug rash in a woman taking this product. Administration of prednisone tablets in doses up to 75 mg daily proved necessary to control the condition. After recovery, a renewed severe skin rash of the exfoliative erythrodermal type occurred 1 - 2 days after accidental exposure to ephedrine nose drops.
Rash appears to be a frequent problem with this product in Denmark, and it has been suggested that an interaction between phenobarbital and ephedrine may provide an explanation for this fact (37Cr). Hematoporphyrin Hematoporphyrin is a synthetic porphyrin not occurring in nature. It has been sold since about 1949 in France, and perhaps elsewhere, as a parenteral antidepressant drug, under names which include Hematon, Novitan and Hemodonin. Its value is controversial. In the course of 2 years, Leroy et al. observed no less than 23 cases of photosensitization to this drug, all in women of middle age, and in the majority of cases localized around the injection site. They also point out that the drug can cause disfiguring residual pigmentation and may perhaps derange porphyrin metabolism (38 C).
Intravenous fluids (additives and excipients) Local reactions to i.v. injections, even of short duration (several minutes), depend greatly o n the composition of the solvent, as shown in a study using i.v. diazepam in 3 different solution fluids. In a series of 200 patients, 3 formulations were used. One third received Stesolid (solvent propylene glycol), another third Stesolid ML (solvent Cremophor EL), and the remainder Diazemuls (solvent soybean oil emulsified in water according to the techniques used in the production of Intralipid for i.v. nutrition). The differences were striking, as is evident from Table 1. The third formulation therefore seems highly superior, especially as Cremophor EL has sometimes led to severe anaphylactic reactions (30Cr), particularly when used in parenteral anesthetics (SED 9,802).
Table 1. Differences in reaction to 3 i.v. formulations
Stesolid Stesolid MR
Diazemuls
Pain
Thrombophlebitis
78% 38%
49% 9%
I%
4%
431
Miscellaneous drugs Phenol
Phenol is present in numerous injectable drugs, and it is sometimes forgotten that it can, when given in small doses internally, have unexpected effects of its own. Bowling et al. have described how a surgical emergency case began to void green urine, a finding which was at first unexplained but which persisted for 2 days. The urine was positive for phenol and it was then realized that the patient had been treated parenterally with cimetidine (each 2 ml vial of which con-
tained 10 mg o f phenol), and promethazine (containing 5 mg of phenol per ml). The discoloration was still present 12 hours after the last cimetidine dose (3 le). Placebo
Adverse effects reported by patients taking placebo were reviewed in SEDA-1 (p. 384). A further extensive review in German can be recommended (32R), particularly since it provides a thorough discussion of factors influencing the placebo reaction.
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