746
low-grade MALT lymphoma and reactive lymphoma infiltrates in the presence of Hpylori associated gastritis. The initial results show that eradication can be used in differential diagnosis. The lymphoid infiltrates seen in H pylori induced gastritis regress within 4 weeks of eradication of H pylori, and endoscopic findings return to normal within the same period of time. By contrast, no such regression, endoscopic or histological, occurs in MALT lymphomas. Institute of Pathology, 8580 Bayreuth, Germany
MANFRED STOLTE
Zukerberg LR, Ferry JA, Southern JF, Harris NL. Lymphoid infiltrates of the stomach. Evaluation of histologic criteria for the diagnosis of low-grade gastric lymphoma on endoscopic biopsy specimens. Am J Surg Pathol 1990; 14: 1087-99. 2. Stolte M, Eidt S. The diagnosis of early gastric lymphoma. Z Gastroenterol 1991; 29: 1.
6-10.
M, Eidt S. Lymphoid follicles in the antral mucosa: Campylobacter pylori. J Clin Pathol 1989; 42: 1269-71.
3. Stolte
immune response
to
basophils could be disrupted. Proteolysis of cell-bound IgE in, for example, the skin of people with atopic dermatitis, could ameloriate the immediate inflammatory response, but not necessarily the delayed response: patch-testing of individuals with atopy to D pteronyssinus extracts produces a form of delayed-type hypersensitivity reaction.’ Depending on relative concentrations of immunoglobulins and allergenic enzymes present, proteolysis may either enhance immediate hypersensitivity reactions or downgrade them. Several mite enzymes are known to be allergenic.5Our results add to the evidence suggesting a role for the enzymatic activity of mite allergens in mechanisms of allergenic disease. Department of Zoology, University of Glasgow, Glasgow G12 8QQ, UK Scottish Parasite Diagnostic Department of Bacteriology,
M. Laboratory,
Stobhill Hospital, Glasgow
Proteolysis of human IgG by house dust mite allergens SIR,—It has been shown in vitro that the house dust mite allergen Der p I from Dermatophagoides pteronyssinus can increase permeability of the bronchial epithelium, putatively by enzymatic digestion.1 Der p I is a cysteine proteinase with an aminoacid sequence similar to that of papain.2 These findings led us to investigate whether an extract of D pteronyssinus, like papain, could digest human immunoglobulin. We incubated Cohn-fractionated human IgG (5 mg/ml) in a waterbath at 37°C for 7 h or 24 h with an extract of D pteronyssinus, enriched in Der p I by affinity chromatography (2’5 mg protein/ml), or papain (1 mg/ml), in the presence of edetic acid (20 mmol/1) to inhibit metalloproteinase activity and of cysteine (1 mol/1) and dithiothreitol (1 mmol/1) to activate cysteine proteinase. Iodoacetamide (75 mmol/1) was added post incubation to inhibit further proteolysis. The peptide fragments of the digests were separated with SDS-polyacrylamide gel electrophoresis.3IgG without Der p I or papain was a negative control (lane 2). Evidence for the digestion of IgG by the house dust mite extract can clearly be seen in the figure (lanes 3 and 4). The bands on the gel are not mite extract: it stains very faintly at the dilution used. The series of IgG fragments produced with D pteronyssinus extract and papain seemed to be identical, indicating that an enzyme in the mite with activity similar to papain caused the proteolysis. Although the digestion products need to be better characterised and the active component(s) in the mite extract identified, one candidate enzyme is Der p 1. If proteolysis of IgG or other antibody isotypes by mite allergens takes place in vivo, IgG blocking of IgE-binding to mast cells and
SDS-polyacrylamide gel electrophoresis of human IgG. Digested with Der p I-enriched house dust mite extract for 7 h (lane 3) and 24 h (lane 4), and with papain for 7 h (lane 5) and 24 h (lane 6), lane 2, intact IgG negative control
J. COLLOFF
H. V. SMITH C. W. HOWE
CA, Holgate ST, Robinson C, Thompson PJ, Stewart GA. Effect of mite allergen on permeability of bronchial mucosa. Lancet 1990; 336: 1132. 2. Simpson RJ, Nice EC, Montz RL, Stewart GA. Structural studies on the allergen Der p I from the house dust mite Dermatophagoides pteronyssinus: similarity with cysteine proteinases Protein Seq Data Anal 1989; 2: 17-21. 3. Colloff MJ, Howe CW, McSharry C, Smith HV. Characterization of IgE antibody binding profiles of sera from patients with atopic dermatitis to allergens of the domestic mites Dermatophagoides pteronyssinus and Euroglyphus maynei, using enhanced chemiluminescent immunoblotting. Int Archs Allergy Appl Immunol (in press). 4. Mitchell EB, Crow J, Rowntree S, Webster AD, Platts-Mills TAE. Cutaneous basophil hypersensiuvity to inhalent allergens in atopic dermatitis patients: elicitation of delayed responses containing basophils following local transfer of immune serum but not IgE antibody. J Invest Dermatol 1984; 83: 290-95. 5. Stewart GA, Thompson PJ, Simpson RJ. Protease antigens from housedust mite 1. Herbert
Lancet 1989; ii: 154-55; 415.
Calcitonin in painful diabetic neuropathy SiR,—Zieleniewski1 described the analgesic effects of salmon calcitonin nasal spray in a woman with painful diabetic neuropathy. We have examined the use of this substance in ten insulin-treated diabetic patients. Their clinical and metabolic characteristics are summarised in the table. All had painful diabetic neuropathy of the legs, and vibratory perception threshold was above the upper limit of normal adjusted for age. They were being treated with analgesic or non-steroidal, antiinflammatory drugs, with poor results. Before entering the study, they stopped treatment for neuropathy and were specifically asked not to take aspirin or other analgesic drugs during the whole period of observation. Afterwards, the ten diabetics were given calcitonin (calcitonin nasal spray, Sandoz, Basel, Switzerland) 100 IU daily and placebo (also supplied by Sandoz) according to a randomised, double-blind procedure: the active treatment (calcitonin) and placebo each lasted for 2 weeks and were separated by a 2-week wash-out period. The patients who received calcitonin first took placebo later and vice versa. The patients were asked to grade severity of neuropathic symptoms of pain (burning, deep ache, tenderness) with a visual analogue scale graded from 0 to 10 (0 = no symptoms, 10 = very severe). At baseline the mean value was 6-6 (SD 1’3), it fell to 41 (2-7) after calcitonin. This resulted in complete relief of symptoms in three diabetics and in a 50% improvement in a fourth. No relevant changes in the visual score were found after placebo. Vibratory perception threshold did not show any change after calcitonin or placebo. Polyneuropathies affecting the peripheral nervous system are common complications of diabetes mellitus Treatment is palliative or supportive. The long list of drugs proposed for this distressing condition is still unsatisfactory. We think that there are several reasons why calcitonin should be tried when the usual analgesic drugs have failed to control pain. First, according to our results, which need to be confirmed, at least 30% of diabetics can have near-complete relief of symptoms. Second, the analgesic response, if any, is seen after only 2 weeks of treatment; prolonged treatment does not seem to augment the percentage of responders. Third, in the four diabetics who had good results on calcitonin, pain reappeared 3 to 7 days after stopping treatment. Lastly, the
747
CLINICAL AND METABOLIC FEATURES OF 10 DIABETICS (3 MALE, 7 FEMALE) WITH PAINFUL NEUROPATHY
Drug interactions in use of dapsone for Pneumocystis carinii prophylaxis SIR,-Dapsone is emerging as an important alternative agent for prophylaxis of Pneumocystis carinii pneumonia (PCP). Preliminary
*Mean of plasma glucose values measured every 2 h &dag er;1 µg/I 331 pmol/I †1µg/l=331pmol BMI =body mass mdex
(day) and
every 4 h
(mght).
drug is safe, easy to use, and does not negatively affect carbohydrate metabolism in diabetes.3 The high cost of calcitonin nasal spray is balanced by the consideration that diabetic patients with painful neuropathy are fortunately few and present, to a great extent, after
negative and disappointing experiences with other drugs. Diabetic Clinic, San Rita, Taranto
ANTONIO QUATRARO ARCANGELO MINEI
Department of Geriatrics and Metabolic Diseases, First Faculty of Medicine, University of Naples, Naples, Italy
NICOLETTA DE ROSA DARIO GIUGLIANO
1 Zieleniewski W. Calcitonin nasal spray for painful diabetic neuropathy. Lancet 1990; 336: 449. 2. Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of 4400 patients observed between 1947 and 1973. Diabetes Metab 1977, 3: 97-107. 3. Grugliano D, Passariello N, Sgambato S, D’Onofrio F. Calcitomn in diabetes. Lancet 1980; i: 653.
Uteroplacental flow velocity waveforms after CVS SIR,—Like Dr Quintero and colleagues (Jan 18, p 193), we have also speculated about a vascular aetiology for the limb and oromandibular defects described after chorionic villous sampling (CVS).l,2 Are there demonstrable changes in uteroplacental flowvelocity waveforms after the procedure? We postulated that in the umbilical artery such changes might result from showers of emboli and in the uterine arteries from trauma-induced uterine contractions. We investigated 23 women having transabdominal CVS for prenatal diagnosis. Uterine, arcuate, and umbilical artery flowvelocity waveforms were measured before and within 20 min of the procedure with pulsed wave doppler.3,4There were no differences: Artery
Right uterine Left uterine
Right arcuate Left arcuate Umbilical *Mean
Before CVS*
234(0-7) 2-16 (0-65) 1. 42 (0-60) 122 (0-48) 2-99 (0-44)
After CVS* 2-31 2’14 1 ’37
(0-71) (0-53) (0-63) 1-21(047) 3-08 (0-49)
(SD) pulsatility indices
These data do not support a change in blood flow as the cause of putative ischaemia but are compatible with an embolic event. Emboli are probably rare in clinical practice and unless very large would probably not affect flow-velocity waveforms.
data suggest a success rate of 82-98 %.1-3 The dose that best balances toxicity with efficacy has yet to be determined. We wish to draw Lancet readers’ attention to potential pharmacokinetic interactions that may affect the efficacy of this sulphone. Rifampicin, a drug often prescribed for the HIV-infected patient, decreases the plasma half-life of dapsone by 22-83%, probably by enhancing hepatic clearance by induction of microsomal enzymes, and reduced levels of dapsone in nerve and skin (by a factor of 7 to 10) have been reported when daily doses of dapsone 100 mg and rifampicin 600 mg were used together.4 In studies of the efficacy of combination therapy in leprosy, this interaction was not clinically important.5,6 However, the high dose of dapsone (50-100 mg daily) and its potent activity against the leprosy bacillus may account for the excellent clinical outcome. Although the in-vivo minimum inhibitory concentration (MIC) of dapsone for P carinii is not known, the MIC in cell culture is 0 1-10 µg/ml.7 Since blood concentrations of dapsone are 0 1-7-0 µg/ml with a dose of 200 mg per day, the concurrent use of rifampicin could lead to prolonged subtherapeutic concentrations of dapsone and to therapeutic failure. The use of this combination may be especially problematic with intermittent or weekly dapsone administration. We are not aware of such an interaction between pentamidine or cotrimoxazole and rifampicin. Preliminary data indicate failure of dapsone prophylaxis when used concomitantly with didanosine (ddl), which is given with a citrate-phosphate buffer to facilitate absorption at a pH of 7 to 8.8 Dapsone requires an acidic gastric environment for absorption, and until further information is available, physicians should also be cautious about giving medications that may increase gastric pH concurrently with dapsone. Hypochlorhydria is common in patients with AIDS;9 hypochlorhydria is associated with decreased absorption ofketoconazole10 and the same may be true for dapsone. Publications on dapsone for PCP prophylaxis have not mentioned these interactions. In designing protocols for dapsone prophylaxis against PCP and in evaluating individual treatment failures, these interactions must be considered. Department of Medicine, Division of Infectious Diseases, New York Medical College, Valhalla, NY 10595, USA
HAROLD W. HOROWITZ ULRICH P. JORDE GARY P. WORMSER
CR, Sandland AM, Mijch A, Simpson JM. Primary dapsone chemoprophylaxis for Pneumocystis carinii pneumonia in immunocompromised patients infected with the human immunodeficiency virus. Med J Aust 1989; 151:
1. Lucas
30-33. 2. Hughes WT,
Kennedy W, Dugdale M, et al. Prevention of Pneumocystis carinii pneumonitis in AIDS patients with weekly dapsone. Lancet 1990; 336: 1066. 3. Lee BL, Medina I, Benowitz NL, et al. Dapsone, trimethoprim, and sulfamethoxazole plasma levels during treatment of Pneumocystis pneumonia in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1989; 110: 606-11. 4. Peters JH, Murray JF, Gordon GR, et al. Effect of rifampicin on the disposition of dapsone in Malaysian leprosy patients. Fed Proc 1977; 36: 996 (abstr). 5. Girdhar BK, Sreevatsa, Desikan KV. Intermittent rifampicin therapy in lepromatous leprosy. Lepr (India) 1980; 52: 89-96. 6. Yawalkar SJ, McDougall AC, Languillon J, et al. Once monthly rifampicin plus daily dapsone in initial treatment of lepromatous leprosy. Lancet 1982; i: 1199-02. 7. Cushion MT, Stanforth D, Linke JM, et al. Method of testing the susceptibility of Pneumocystis carinii to antimicrobial agents in vitro. Antimicrob Ag Chemother 1985, 26: 796-801.
LJ, Jacobus DP, et al. Failure of prophylaxis with dapsone patients taking dideoxyinosine. N Engl J Med 1991; 325: 737. 9. Lake-Bakaar G, Quadros E, Beidas S, et al. Gastric secretory failure in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1988; 109: 502-04. 10 Lake-Bakaar G, Wiston T, Lake-Bakaar D, et al. Gastropathy and ketoconazole malabsorption in the acquired immunodeficiency syndrome (AIDS) Ann Intern Med 1988; 109: 471-73. 8. Metroka CE, Laubenstein
University of Leeds, Academic Unit of Obstetrics and Gynaecology, St James’s University Hospital, Leeds LS9 7TF, UK
B. Y. JIANG J. G. THORNTON M. D. GRIFFITH-JONES R. J. LILFORD
1. Firth HV Severe limb abnormalities after chorionic sampling at 56-66 days gestation. Lancet 1991; 337: 762-63. 2 Lilford RJ The rise and fall of chononic villus sampling. Br MedJ 1991, 303: 936-37. 3. Jurkovic D, Jauniaux E, Kurjak A, Hustin J, Cambell S, Nicolaides KH. Transvaginal color doppler assessment of the uteroplacental circulation in early pregnancy. Obstet Gynecol 1991; 77: 365-69. 4. Arduini D, Rizzo G. Umbilical artery velocity waveforms in early pregnancy: a transvaginal color doppler study. J Clin Ultrasound 1991; 19: 335-39.
in
Seasonal variation in presentation of
Pneumocystis carinii pneumonia SIR,-We have noted variations in the number of HIV-positive patients presenting to our unit with Pneumocystis carinii pneumonia at different times of the year. We retrospectively reviewed the numbers of patients with pneumocystis pneumonia presenting to
low-grade MALT lymphoma and reactive lymphoma infiltrates in the presence of Hpylori associated gastritis. The initial results show that eradication can be used in differential diagnosis. The lymphoid infiltrates seen in H pylori induced gastritis regress within 4 weeks of eradication of H pylori, and endoscopic findings return to normal within the same period of time. By contrast, no such regression, endoscopic or histological, occurs in MALT lymphomas. Institute of Pathology, 8580 Bayreuth, Germany
MANFRED STOLTE
Zukerberg LR, Ferry JA, Southern JF, Harris NL. Lymphoid infiltrates of the stomach. Evaluation of histologic criteria for the diagnosis of low-grade gastric lymphoma on endoscopic biopsy specimens. Am J Surg Pathol 1990; 14: 1087-99. 2. Stolte M, Eidt S. The diagnosis of early gastric lymphoma. Z Gastroenterol 1991; 29: 1.
6-10.
M, Eidt S. Lymphoid follicles in the antral mucosa: Campylobacter pylori. J Clin Pathol 1989; 42: 1269-71.
3. Stolte
immune response
to
basophils could be disrupted. Proteolysis of cell-bound IgE in, for example, the skin of people with atopic dermatitis, could ameloriate the immediate inflammatory response, but not necessarily the delayed response: patch-testing of individuals with atopy to D pteronyssinus extracts produces a form of delayed-type hypersensitivity reaction.’ Depending on relative concentrations of immunoglobulins and allergenic enzymes present, proteolysis may either enhance immediate hypersensitivity reactions or downgrade them. Several mite enzymes are known to be allergenic.5Our results add to the evidence suggesting a role for the enzymatic activity of mite allergens in mechanisms of allergenic disease. Department of Zoology, University of Glasgow, Glasgow G12 8QQ, UK Scottish Parasite Diagnostic Department of Bacteriology,
M. Laboratory,
Stobhill Hospital, Glasgow
Proteolysis of human IgG by house dust mite allergens SIR,—It has been shown in vitro that the house dust mite allergen Der p I from Dermatophagoides pteronyssinus can increase permeability of the bronchial epithelium, putatively by enzymatic digestion.1 Der p I is a cysteine proteinase with an aminoacid sequence similar to that of papain.2 These findings led us to investigate whether an extract of D pteronyssinus, like papain, could digest human immunoglobulin. We incubated Cohn-fractionated human IgG (5 mg/ml) in a waterbath at 37°C for 7 h or 24 h with an extract of D pteronyssinus, enriched in Der p I by affinity chromatography (2’5 mg protein/ml), or papain (1 mg/ml), in the presence of edetic acid (20 mmol/1) to inhibit metalloproteinase activity and of cysteine (1 mol/1) and dithiothreitol (1 mmol/1) to activate cysteine proteinase. Iodoacetamide (75 mmol/1) was added post incubation to inhibit further proteolysis. The peptide fragments of the digests were separated with SDS-polyacrylamide gel electrophoresis.3IgG without Der p I or papain was a negative control (lane 2). Evidence for the digestion of IgG by the house dust mite extract can clearly be seen in the figure (lanes 3 and 4). The bands on the gel are not mite extract: it stains very faintly at the dilution used. The series of IgG fragments produced with D pteronyssinus extract and papain seemed to be identical, indicating that an enzyme in the mite with activity similar to papain caused the proteolysis. Although the digestion products need to be better characterised and the active component(s) in the mite extract identified, one candidate enzyme is Der p 1. If proteolysis of IgG or other antibody isotypes by mite allergens takes place in vivo, IgG blocking of IgE-binding to mast cells and
SDS-polyacrylamide gel electrophoresis of human IgG. Digested with Der p I-enriched house dust mite extract for 7 h (lane 3) and 24 h (lane 4), and with papain for 7 h (lane 5) and 24 h (lane 6), lane 2, intact IgG negative control
J. COLLOFF
H. V. SMITH C. W. HOWE
CA, Holgate ST, Robinson C, Thompson PJ, Stewart GA. Effect of mite allergen on permeability of bronchial mucosa. Lancet 1990; 336: 1132. 2. Simpson RJ, Nice EC, Montz RL, Stewart GA. Structural studies on the allergen Der p I from the house dust mite Dermatophagoides pteronyssinus: similarity with cysteine proteinases Protein Seq Data Anal 1989; 2: 17-21. 3. Colloff MJ, Howe CW, McSharry C, Smith HV. Characterization of IgE antibody binding profiles of sera from patients with atopic dermatitis to allergens of the domestic mites Dermatophagoides pteronyssinus and Euroglyphus maynei, using enhanced chemiluminescent immunoblotting. Int Archs Allergy Appl Immunol (in press). 4. Mitchell EB, Crow J, Rowntree S, Webster AD, Platts-Mills TAE. Cutaneous basophil hypersensiuvity to inhalent allergens in atopic dermatitis patients: elicitation of delayed responses containing basophils following local transfer of immune serum but not IgE antibody. J Invest Dermatol 1984; 83: 290-95. 5. Stewart GA, Thompson PJ, Simpson RJ. Protease antigens from housedust mite 1. Herbert
Lancet 1989; ii: 154-55; 415.
Calcitonin in painful diabetic neuropathy SiR,—Zieleniewski1 described the analgesic effects of salmon calcitonin nasal spray in a woman with painful diabetic neuropathy. We have examined the use of this substance in ten insulin-treated diabetic patients. Their clinical and metabolic characteristics are summarised in the table. All had painful diabetic neuropathy of the legs, and vibratory perception threshold was above the upper limit of normal adjusted for age. They were being treated with analgesic or non-steroidal, antiinflammatory drugs, with poor results. Before entering the study, they stopped treatment for neuropathy and were specifically asked not to take aspirin or other analgesic drugs during the whole period of observation. Afterwards, the ten diabetics were given calcitonin (calcitonin nasal spray, Sandoz, Basel, Switzerland) 100 IU daily and placebo (also supplied by Sandoz) according to a randomised, double-blind procedure: the active treatment (calcitonin) and placebo each lasted for 2 weeks and were separated by a 2-week wash-out period. The patients who received calcitonin first took placebo later and vice versa. The patients were asked to grade severity of neuropathic symptoms of pain (burning, deep ache, tenderness) with a visual analogue scale graded from 0 to 10 (0 = no symptoms, 10 = very severe). At baseline the mean value was 6-6 (SD 1’3), it fell to 41 (2-7) after calcitonin. This resulted in complete relief of symptoms in three diabetics and in a 50% improvement in a fourth. No relevant changes in the visual score were found after placebo. Vibratory perception threshold did not show any change after calcitonin or placebo. Polyneuropathies affecting the peripheral nervous system are common complications of diabetes mellitus Treatment is palliative or supportive. The long list of drugs proposed for this distressing condition is still unsatisfactory. We think that there are several reasons why calcitonin should be tried when the usual analgesic drugs have failed to control pain. First, according to our results, which need to be confirmed, at least 30% of diabetics can have near-complete relief of symptoms. Second, the analgesic response, if any, is seen after only 2 weeks of treatment; prolonged treatment does not seem to augment the percentage of responders. Third, in the four diabetics who had good results on calcitonin, pain reappeared 3 to 7 days after stopping treatment. Lastly, the
747
CLINICAL AND METABOLIC FEATURES OF 10 DIABETICS (3 MALE, 7 FEMALE) WITH PAINFUL NEUROPATHY
Drug interactions in use of dapsone for Pneumocystis carinii prophylaxis SIR,-Dapsone is emerging as an important alternative agent for prophylaxis of Pneumocystis carinii pneumonia (PCP). Preliminary
*Mean of plasma glucose values measured every 2 h &dag er;1 µg/I 331 pmol/I †1µg/l=331pmol BMI =body mass mdex
(day) and
every 4 h
(mght).
drug is safe, easy to use, and does not negatively affect carbohydrate metabolism in diabetes.3 The high cost of calcitonin nasal spray is balanced by the consideration that diabetic patients with painful neuropathy are fortunately few and present, to a great extent, after
negative and disappointing experiences with other drugs. Diabetic Clinic, San Rita, Taranto
ANTONIO QUATRARO ARCANGELO MINEI
Department of Geriatrics and Metabolic Diseases, First Faculty of Medicine, University of Naples, Naples, Italy
NICOLETTA DE ROSA DARIO GIUGLIANO
1 Zieleniewski W. Calcitonin nasal spray for painful diabetic neuropathy. Lancet 1990; 336: 449. 2. Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of 4400 patients observed between 1947 and 1973. Diabetes Metab 1977, 3: 97-107. 3. Grugliano D, Passariello N, Sgambato S, D’Onofrio F. Calcitomn in diabetes. Lancet 1980; i: 653.
Uteroplacental flow velocity waveforms after CVS SIR,—Like Dr Quintero and colleagues (Jan 18, p 193), we have also speculated about a vascular aetiology for the limb and oromandibular defects described after chorionic villous sampling (CVS).l,2 Are there demonstrable changes in uteroplacental flowvelocity waveforms after the procedure? We postulated that in the umbilical artery such changes might result from showers of emboli and in the uterine arteries from trauma-induced uterine contractions. We investigated 23 women having transabdominal CVS for prenatal diagnosis. Uterine, arcuate, and umbilical artery flowvelocity waveforms were measured before and within 20 min of the procedure with pulsed wave doppler.3,4There were no differences: Artery
Right uterine Left uterine
Right arcuate Left arcuate Umbilical *Mean
Before CVS*
234(0-7) 2-16 (0-65) 1. 42 (0-60) 122 (0-48) 2-99 (0-44)
After CVS* 2-31 2’14 1 ’37
(0-71) (0-53) (0-63) 1-21(047) 3-08 (0-49)
(SD) pulsatility indices
These data do not support a change in blood flow as the cause of putative ischaemia but are compatible with an embolic event. Emboli are probably rare in clinical practice and unless very large would probably not affect flow-velocity waveforms.
data suggest a success rate of 82-98 %.1-3 The dose that best balances toxicity with efficacy has yet to be determined. We wish to draw Lancet readers’ attention to potential pharmacokinetic interactions that may affect the efficacy of this sulphone. Rifampicin, a drug often prescribed for the HIV-infected patient, decreases the plasma half-life of dapsone by 22-83%, probably by enhancing hepatic clearance by induction of microsomal enzymes, and reduced levels of dapsone in nerve and skin (by a factor of 7 to 10) have been reported when daily doses of dapsone 100 mg and rifampicin 600 mg were used together.4 In studies of the efficacy of combination therapy in leprosy, this interaction was not clinically important.5,6 However, the high dose of dapsone (50-100 mg daily) and its potent activity against the leprosy bacillus may account for the excellent clinical outcome. Although the in-vivo minimum inhibitory concentration (MIC) of dapsone for P carinii is not known, the MIC in cell culture is 0 1-10 µg/ml.7 Since blood concentrations of dapsone are 0 1-7-0 µg/ml with a dose of 200 mg per day, the concurrent use of rifampicin could lead to prolonged subtherapeutic concentrations of dapsone and to therapeutic failure. The use of this combination may be especially problematic with intermittent or weekly dapsone administration. We are not aware of such an interaction between pentamidine or cotrimoxazole and rifampicin. Preliminary data indicate failure of dapsone prophylaxis when used concomitantly with didanosine (ddl), which is given with a citrate-phosphate buffer to facilitate absorption at a pH of 7 to 8.8 Dapsone requires an acidic gastric environment for absorption, and until further information is available, physicians should also be cautious about giving medications that may increase gastric pH concurrently with dapsone. Hypochlorhydria is common in patients with AIDS;9 hypochlorhydria is associated with decreased absorption ofketoconazole10 and the same may be true for dapsone. Publications on dapsone for PCP prophylaxis have not mentioned these interactions. In designing protocols for dapsone prophylaxis against PCP and in evaluating individual treatment failures, these interactions must be considered. Department of Medicine, Division of Infectious Diseases, New York Medical College, Valhalla, NY 10595, USA
HAROLD W. HOROWITZ ULRICH P. JORDE GARY P. WORMSER
CR, Sandland AM, Mijch A, Simpson JM. Primary dapsone chemoprophylaxis for Pneumocystis carinii pneumonia in immunocompromised patients infected with the human immunodeficiency virus. Med J Aust 1989; 151:
1. Lucas
30-33. 2. Hughes WT,
Kennedy W, Dugdale M, et al. Prevention of Pneumocystis carinii pneumonitis in AIDS patients with weekly dapsone. Lancet 1990; 336: 1066. 3. Lee BL, Medina I, Benowitz NL, et al. Dapsone, trimethoprim, and sulfamethoxazole plasma levels during treatment of Pneumocystis pneumonia in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1989; 110: 606-11. 4. Peters JH, Murray JF, Gordon GR, et al. Effect of rifampicin on the disposition of dapsone in Malaysian leprosy patients. Fed Proc 1977; 36: 996 (abstr). 5. Girdhar BK, Sreevatsa, Desikan KV. Intermittent rifampicin therapy in lepromatous leprosy. Lepr (India) 1980; 52: 89-96. 6. Yawalkar SJ, McDougall AC, Languillon J, et al. Once monthly rifampicin plus daily dapsone in initial treatment of lepromatous leprosy. Lancet 1982; i: 1199-02. 7. Cushion MT, Stanforth D, Linke JM, et al. Method of testing the susceptibility of Pneumocystis carinii to antimicrobial agents in vitro. Antimicrob Ag Chemother 1985, 26: 796-801.
LJ, Jacobus DP, et al. Failure of prophylaxis with dapsone patients taking dideoxyinosine. N Engl J Med 1991; 325: 737. 9. Lake-Bakaar G, Quadros E, Beidas S, et al. Gastric secretory failure in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1988; 109: 502-04. 10 Lake-Bakaar G, Wiston T, Lake-Bakaar D, et al. Gastropathy and ketoconazole malabsorption in the acquired immunodeficiency syndrome (AIDS) Ann Intern Med 1988; 109: 471-73. 8. Metroka CE, Laubenstein
University of Leeds, Academic Unit of Obstetrics and Gynaecology, St James’s University Hospital, Leeds LS9 7TF, UK
B. Y. JIANG J. G. THORNTON M. D. GRIFFITH-JONES R. J. LILFORD
1. Firth HV Severe limb abnormalities after chorionic sampling at 56-66 days gestation. Lancet 1991; 337: 762-63. 2 Lilford RJ The rise and fall of chononic villus sampling. Br MedJ 1991, 303: 936-37. 3. Jurkovic D, Jauniaux E, Kurjak A, Hustin J, Cambell S, Nicolaides KH. Transvaginal color doppler assessment of the uteroplacental circulation in early pregnancy. Obstet Gynecol 1991; 77: 365-69. 4. Arduini D, Rizzo G. Umbilical artery velocity waveforms in early pregnancy: a transvaginal color doppler study. J Clin Ultrasound 1991; 19: 335-39.
in
Seasonal variation in presentation of
Pneumocystis carinii pneumonia SIR,-We have noted variations in the number of HIV-positive patients presenting to our unit with Pneumocystis carinii pneumonia at different times of the year. We retrospectively reviewed the numbers of patients with pneumocystis pneumonia presenting to
