Acute Dapsone Intoxication: Clinical Findings and Effect of Oral Charcoal and Haemodialysis on Dapsone Elimination

ABSTRACT. Three patients were treated after ingestion of an overdose of dapsone (1–10 g). A considerable acute cyanosis due to methaemoglobinaemia was followed by a late haemolysis within 1–2 weeks. Activated charcoal given orally in multiple doses (20 g × 4/day) shortened the half-life of dapsone to 12.7+0.7 hours, i.e. to about 1/3-1/6 of the preceding control value. The half-life of dapsone was about 10 hours during each of the three 5-hour haemodialysis treatments given to one patient. However, owing to the rebound phenomenon between haemodialyses, the half-life of dapsone from the start of the first to the end of the third haemodialysis was 26 hours. The efficacy of orally administered activated charcoal is fully comparable to that of haemodialysis in increasing the rate of elimination of dapsone and its metabolite monoacetyldapsone. Activated charcoal is cheap, it can be administered anywhere and its administration rarely involves complications.     

Evaluation of drug regimen in lepromatous leprosy--II

A 2 year follow-up study of 4 drug regimen in 45 cases is reported; whereas the combination of Rifampicin and Dapsone had been found to effect clearance of bacteraemia within a week and effect negativity of nasal smears in a shorter period of time, at 2 years the clinical and bacteriological results in the DDS, DDS + Rifampicin, DDS + Thiacetazone + INH, and DDS + Clofazimine regimen were similar. However, on inoculating bacilli obtained from the dartos muscle into the foot-pads of mice, multiplication was found in 1 out of 11 cases on Rifampicin and DDS, whereas 2 out of 9 cases on DDS + Thiacetazone + INH; 2 out of 10 cases on DDS + Clofazimine and 4 out of 8 cases on DDS alone showed multiplication. Therefore at the end of 2 years there was no significant difference in the results of treatment with any of the drug combinations used in the trial. However, the drug combinations have been found to be better than monotherapy with dapsone alone.     

Results of animal experimentation activities at the Institut Marchoux in Bamako (1982-1984)

The Institut Marchoux animal research unit report of activities 1982-1984 shows increasing results in mouse-foods-pads inoculations. Among 17 multibacillary cases, 16 were clinically dapsone-resistant suspected. In 9 cases there was no multiplication; however in 4 cases, multiplication were observed in the untreated controled mice group but no multiplication in dapsone groups. Three cases were fully dapsone-resistant in all concentrations tested. In one case we have detected a partial DDS resistance. No multiplication in the mice group with 10(-2) dapsone dict, but multiplication in 10(-3) and 10(-4) dapsone dict.     

Cardiac toxicity of ajmaline. Comparison of acute voluntary poisoning with complications of the ajmaline test

A comparative and retrospective study of 59 cases of acute voluntary self-poisoning observed at the Toxicology Department of Fernand Widal Hospital, and 15 cases of complications of the Ajmaline test observed in the Cardiology Department of Bichat Hospital showed a similarity in the cardiac effects of high dosage regardless of the mode of administration of the antiarrhythmic. Acute suicidal poisoning in adults or accidental poisoning in children caused toxic effects at doses over more than Ig: they are characterised by their sudden onset after a latent period of 1 to 2 hours and their short duration (no effects after the 12th hour). The ECG changes included:--First degree atrioventricular block (15 p. 100).--Intraventricular conduction defects were observed in almost all cases. They were proportional to the dose taken and were of prognostic interes (no cardiac arrests when the QRS remained less then 0,2 sec).--ST-T wave changes were observed in all patients. They lasted longer and were of no prognostic importance.--Extrasystoles and ventricular tachycardia are nearly always associated with poor hemodynamic tolerance (70 p. 100 of cardiac arrests, compared to only 16 p. 100 in this absence). This intoxication is serious with a mortality of 24 p. 100 of the reported cases and of 9 p. 100 of cases admitted to an Intensive Care Unit.--The complications of the Ajmaline test were similar, the time of apparition being a few minutes instead of a few hours. There were no deaths or serious hemodynamic complications in this series. This is without doubt related to the observation of the contraindications and the fractional administration of the Ajmaline. We conclude that oral Ajmaline, though well tolerated at therapeutic does may cause severe toxic overdose effects. Although its use remains justified in the treatment of arrhythmias, it should not be used for the symptomatic treatment of palpitations and neurovegetative imbalance.     

Dapsone syndrome in Vanuatu: a high incidence during multidrug treatment (MDT) of leprosy.

Side-effects of leprosy treatment with dapsone are said to be uncommon, with drug allergy occurring in only one of every several hundred patients treated with dapsone. The dapsone or sulphone syndrome (DDS) has been recognized since the earliest days of sulphone therapy but until recently its incidence had been decreasing. In Vanuatu, during the years 1988-1991, nine leprosy patients have developed the dapsone syndrome, four of whom have died. During the last 4 years only 37 patients were started on treatment, which is an incidence of the dapsone syndrome of 24% with a fatality rate of 11%. All the patients were being given multi-drug treatment (MDT) of daily dapsone (100 mg) and clofazimine (50 mg) and monthly rifampicin (600 mg) and clofazimine (300 mg). There has been speculation that the increased incidence of what was previously described as a rare reaction is due to the use of MDT, and the reasons for this are discussed. We feel the increase in the number of reactions in Vanuatu since starting MDT is probably due to the high starting dose of 100 mg of dapsone, possibly enhanced by the combination with clofazimine and rifampicin and a genetic susceptibility of the Melanesian population.     

Monitoring self administration of dapsone by patients

The Urinary DDS/Creatinine ratios in the supervised in-patients and out-patients attending the C.L.T. & R.I., clinic were compared. The subjects of this study were receiving dapsone at the daily dosage of 25, 50 and 100 mg or bi-weekly dosage of 25, 50, 75, 100 and 200 mgs. The mean urinary DDS/Creatinine ratios from out-patients were significantly lower than those of the in-patients in both dosage schedules of treatment and suggest that a certain percentage of out-patients have been irregular in the intake of dapsone in the period immediately prior to the collection of urine specimens. The estimated percentage of gross irregularity of intake is markedly higher in the bi-weekly as compared with the daily dosage schedule. The gross irregularity of intake was particularly marked in the higher dosage groups such as 100 mg daily or bi-weekly and 200 mg bi-weekly. The implications of the findings are discussed.     

Oral aluminium phosphide poisoning in Indian children.

Aluminium phosphide, due to its low cost, easy availability and highly toxic nature, is emerging as a common self-poisoning agent in adults. In children, besides accidental ingestion, it is usually given by their parents who themselves have taken it with suicidal intentions. Seven such cases in children are reported. Since prevention is the only logical approach there is an urgent need to take appropriate steps to prevent further loss of lives.     

Sulfone-resistance of Mycobacterium leprae--monotherapy with diaminodiphenylsulfone--the value of triple-drug combinations

While the emergence of drug resistance in Mycobacterium leprae was foreseen and known for a long time, it is now presented as a tragedy jeopardizing leprosy control through monotherapy. This resistance has been mainly reported in the United States. It is not observed in other parts of the world. In our opinion, the unfavorable observations made at present result from an incorrect implementation of dapsone (DDS) therapy in the patients, resulting in low sulfone blood levels, as a consequence of the use of complex disubstituted sulfones, insufficient daily dapsone dosages, irregular or noncompliance to treatment, premature interruption of treatment, etc. Two measures are required in order to prevent the emergence of primary or secondary resistance to dapsone in M. leprae. First, it is necessary to go back to the previous regimen of 200 mg dapsone daily in an adult. It yields the "maximum tolerated effective dosage." It should never have been rejected in favor of 100 mg daily as currently recommended at the moment. The second measure is the implementation of multiple drug therapy (MDT), using concurrently DDS in association with rifampin and clofazimine. This is a logical and rational approach, at least from a theoretical point of view. However, MDT is most unfortunately quite expensive and therefore inapplicable in most countries with high prevalence, since they are poor and underdeveloped. Implementation of MDT also raises great problems, since dosages have to be strictly adhered to in order to prevent a potentially catastrophic emergence of multiple drug resistance in M. leprae.     

The in Vitro Action of Dapsone and its Derivatives on Normal and G6PD-deficient Red Cells

S ummary . In an attempt to define the mechanism of dapsone-induced haemolysis the in vitro action of dapsone (4,4', diaminodiphenylsulphone) and some of its derivatives on normal and G6PD-deficient red cells has been investigated. Dapsone, its N' acetyl- and hydroxy-derivatives have no measurable effect on metabolism, haemoglobin or the membrane in either normal or G6PD-deficient red cells. 4, hydroxylamino-4' aminodiphenylsulphone (HADS) and 4, hydroxylamino-4' acetaminodiphenylsulphone (HMDS) have oxidant effects on red cells. Both of these compounds readily form methaemoglobin but in normal red cells higher levels of methaemoglobin are achieved with HMDS than with HADS. With both compounds less methaemoglobin is formed in glucose-deprived or in G6PD-deficient red cells. In normal red cells hexose monophosphate pathway (HMP) activity is increased, HADS being a more potent stimulus than HMDS. It is suggested that methaemoglobin formation is dependent upon the recycling of these compounds via the HMP.
Normal red cells incubated with the two hydroxylamine compounds did not show any change in reduced glutathione (GSH), globin or the membrane, apart from increased sensitivity to peroxide lysis. G6PD-deficient red cells, on the other hand, did lose GSH rapidly and underwent increased autohaemolysis. The mechanism of these effects is discussed.
Some, but not all, of the in vivo effects of dapsone can be reproduced by the hydroxylamine derivatives in vitro. It is concluded that either some other derivatives are involved or that the effect of long exposure to these oxidant compounds in vivo is different.     

Massive pulmonary arteriovenous fistula in the newborn.

Although pulmonary arteriovenous fistula as a cause of cyanosis is well recognized, most of the reported cases occur in older children and adults, and its importance as a correctable lesion in the newborn is often overlooked. The details of two babies who presented with cyanosis in the first few days of life are presented to emphasize that this eminently treatable lesion may need to be managed as an emergency.     

Intravenous immunoglobulin given to lymphoma patients with recurrent haemolytic transfusion reactions after transfusion of compatible blood

Accelerated destruction of red cells after transfusion of compatible blood has been reported in both sickle cell disease (SCD) and non-SCD patients. We report three patients with lymphoma, all of whom had recurrent haemolytic transfusion reactions after receiving compatible red cell units. The direct antiglobulin test (DAT) was negative and there were no detectable red cell alloantibodies in either pre-transfusion or post-transfusion samples. As there was no evidence of red cell antibody-mediated haemolysis and response to oral steroids, a trial of intravenous immunoglobulin (IVIg) was given. Immediate cessation of haemolysis with sustained haemoglobin level was achieved in all cases. The response to IVIg in these cases suggests that IVIg should be tried when recurrent non-antibody mediated haemolytic transfusion reactions occur in patients with a lymphoid malignancy.     

Intravenous immunoglobulin given to lymphoma patients with recurrent haemolytic transfusion reactions after transfusion of compatible blood

Accelerated destruction of red cells after transfusion of compatible blood has been reported in both sickle cell disease (SCD) and non-SCD patients. We report three patients with lymphoma, all of whom had recurrent haemolytic transfusion reactions after receiving compatible red cell units. The direct antiglobulin test (DAT) was negative and there were no detectable red cell alloantibodies in either pre-transfusion or post-transfusion samples. As there was no evidence of red cell antibody-mediated haemolysis and response to oral steroids, a trial of intravenous immunoglobulin (IVIg) was given. Immediate cessation of haemolysis with sustained haemoglobin level was achieved in all cases. The response to IVIg in these cases suggests that IVIg should be tried when recurrent non-antibody mediated haemolytic transfusion reactions occur in patients with a lymphoid malignancy.     

Erythrokinetic Studies in Myelofibrosis: Their Significance for Prognosis

S ummary . Eighty-three patients with myelofibrosis have been studied by erythrokinetics and have been followed up until death or for at least 12 months. Because of a large plasma volume the venous haematocrit gives only a poor idea of the red blood cell volume. The red cell survival was reduced in the majority of cases but significant haemolysis was rare. The amount of haemolysis of autologous and isologous red cells was similar, suggesting an extra-corpuscular origin for the haemolysis. Plasma iron turnover was always increased, sometimes markedly, but red cell iron incorporation was reduced in 70% of cases, indicating ineffective erythropoiesis. Surface counting showed an absence on diminution of sacral iron fixation and a rapid and marked splenic uptake in more than 90% of the cases; uptake of iron by the liver occurred in half the cases, usually not very high; iron release from the spleen was absent or reduced in 67% of the cases.
The degree of ineffective erythropoiesis as measured by radio-iron incorporation and release by the spleen, the amount of haemolysis, and the red cell volume were strongly correlated with prognosis. These factors enabled a more precise prediction to be made of the clinical outcome in the 2 years following the study, than the clincal data alone. A prospective study might show whether erythrokinetic studies are also useful in determining the choice of treatment.     

Rosetting, phagocytosis and immune red cell damage

Observations on rosette formation of red blood cells sensitized with a known number of IgG1 or IgG3 polyclonal or monoclonal anti-Rh(D) antibodies with monocytes, lymphocytes and granulocytes have provided further evidence for the essential role of monocytes/macrophages in red cell destruction. The rosette test with monocytes and the monocyte-monolayer assay (MMA) have confirmed, on a quantitative basis, the greater binding ability of IgG3 than of IgG1 antibodies and that the rate of interaction with red cells increases in proportion to the level of their sensitization. These observations have suggested that the MMA may reflect haemolysis in vivo. It has appeared that the MMA is suitable for assessing haemolysis in many cases of haemolytic disease of the newborn, in autoimmune haemolytic anaemia and in patients with alloantibodies to be transfused. Since in individual cases a clear correlation between the MMA results and haemolysis in vivo was not observed, the factors which may influence such discrepancies are discussed.     

Polymorphic acetylation of the antibacterials, sulfamethazine and dapsone, in South Indian subjects.

A group of South Indian subjects was studied for their capacities to acetylate sulfamethazine (SMZ) and dapsone (DDS) and to clear DDS from the circulation. An apparent trimodal distribution of acetylator phenotypes was found in 49 subjects (51% slow, 12% intermediate, and 37% rapid acetylators) from measurements of the percentage acetylation of SMZ in 6-hour plasma samples after administration of 10 mg SMZ/kg. The intermediate phenotype was not discernible from either the percentage acetylation of SMZ in urine (collected concurrently with the plasma after SMZ) or that of DDS in plasma after the ingestion of 50 mg DDS by the same subjects. The latter two measurements yielded a bimodal distribution of 59% slow and 41% rapid acetylators, nearly identical to earlier reported distributions of isoniazid inactivator phenotypes in larger numbers of South Indian tuberculosis patients. In the current group, acetylation of DDS and SMZ was positively correlated. The half-time of disappearance (T 1/2) of DDS, an expression of the rate of clearance from the plasma, ranged from 13 to 40 hours. No correlation was found between the subject's capacity to acetylate DDS and the T 1/2 value for DDS. These results were generally consistent with earlier observations made during similar studies of American and Filipino subjects.     

A second case of multidrug-resistant Mycobacterium leprae isolated from a Japanese patient with relapsed lepromatous leprosy

Emergence of drug resistant strains of Mycobacterium leprae was reported soon after the introduction of dapsone (diamino-diphenyl sulphone, DDS) for leprosy treatment (6, 10, 11). Three cases of multidrug-resistant strains of M. leprae have been reported recently (2, 8, 9, 13). In order to prevent multiple drug resistant strains of M. leprae from developing, current leprosy control strategies are based on early detection of cases and treatment with multidrug therapy (MDT) as recommended by the World Health Organization (WHO). We report here the identification of a multidrug-resistant strain of M. leprae from a patient who received inadequate therapy for leprosy. The drug resistant profile of the isolated strain was confirmed by the mouse footpad method and the identification of mutations in genes previously shown to be associated with resistance to each drug was made.     

Severe immune haemolysis after standard doses of Penicillin

Summary Penicillin causes immune haemolytic anaemia by the 'drug-adsorption' mechanism and typically occurs after prolonged exposure to large doses of the drug. Withdrawal of the drug is associated with improved red cell survival and gradual cessation of haemolysis. Although this complication is uncommon, it can be potentially serious. An unusual case is described herein. The patient was exposed to a short course (9 days) of standard dose penicillin but suffered acute severe haemolysis about 1 week after cessation of therapy. A high titre anti-penicillin antibody (1 : 512) not cross-reacting with cephalosporins, was demonstrated. The delay in the development of immune haemolysis vis-à-vis penicillin therapy may be due to the patient being immunologically naive to the drug. Penicillin may persist for weeks in circulation, coating red cells and providing continued antigenic stimulation for the development of anti-penicillin antibody.     

Increasing US mortality due to accidental poisoning: the role of the baby boom cohort

Aims In this study we examine whether the recent, sharp increase in mortality in the United States due to accidental poisoning since 2000 is the result of the aging of the baby boom cohort or, instead, a historical trend apparent among decedents of all ages. Design We conducted an age–period–cohort analysis using data from the US Vital Statistics and the US Census covering the period 1968–2007. Setting and participants The United States population aged 15–64 years. Measurements Cause of death and demographic data as recorded on death certificates. Findings The increase in mortality due to accidental poisoning since the year 2000 stems primarily from a historical period effect across all ages for whites, but results in large part from a rate spike in the baby boom cohort among blacks. For all demographic groups baby boomers had higher odds of death due to accidental poisoning than the cohorts that came before and after them. Historical influences acting across all ages led to an increase in accidental poisoning mortality that was almost 10‐fold for whites and threefold for blacks over the study period. Conclusions While the recent, sharp increase in accidental poisoning mortality stems in part from the aging of the baby boom cohort, substantially more of the increase results from influences unique to recent years that have affected all age groups. These results point to the need to bolster overdose prevention programs and policies as the historical increase in accidental poisoning mortality appears to continue unabated.     

Hereditary ovalocytosis with compensated haemolysis

Summary. The clinical and laboratory phenotype of compensated haemolysis in a patient with hereditary ovalocytosis is reported. Clinical presentation was intermittent jaundice and abdominal pain due to pigment gall stones. Haematological analysis revealed an absolute reticulocytosis with an otherwise normal full blood count and biochemical evidence of haemolysis. Variable results were observed with blood grouping reagents. The patient's red cells were stomatocytic ovalocytic, rigid, resistant to malarial parasite invasion, defective in anion transport, and had the characteristic two linked mutations in the red cell band 3 gene.     

Use of intravenous immunoglobulin and intravenous methylprednisolone in hyperhaemolysis syndrome in sickle cell disease

Hyperhaemolysis syndrome (HS), a syndrome in which there is destruction of both donor and recipient red cells after transfusion, is well recognised in patients with sickle cell disease and beta-thalassaemia. It has also been reported in a patient with myelofibrosis. In acute forms of HS, evidence of red cell antibody-mediated haemolysis is lacking, and it has been proposed that the transfused and the patient's own red blood cells were destroyed by hyperactive macrophages. Continuation of transfusion may be lethal as this can further exacerbate haemolysis. We report two cases of HS successfully treated with IVIg and IV methylprednisolone. The cessation of haemolysis following administration of IVIg and IV methylprednisolone supports the view that hyperactive macrophages contribute to the RBC destruction. IVIg and methylprednisolone appear to have a synergistic effect on suppressing the activity of macrophages.