Biomedical subjects

M D Coleman

Publications and source records attributed to M D Coleman.

At least 19 recordsLinked to original sources

PubMed1997

Studies on the inhibitory effects of analogues of dapsone on neutrophil function in-vitro.

We have compared twelve sulphone analogues of dapsone in terms of inhibition both of zymosan-mediated human neutrophil respiratory burst and inhibition of interleukin-1-stimulated neutrophil adhesion to transformed human umbilical vein endothelial cells. Overall, there was a good correlation between the respective rank orders of compound potency in the two test systems. The most effective compounds in terms of respiratory burst and adherence inhibition were the 2-nitro-4-amino-, 2-hydroxy-4-aminopropyl-, and 2-methoxy-4-aminoethyl- derivatives. In general, potency was inversely associated with lipophilicity; compounds with bulky side-chains, e.g. the 2-methyl-4-aminopentyl, 2-methyl-4-aminohexyl and the 2-hydroxymethyl-4-aminoethyl derivatives, were less potent. A 2-hydroxy-4-amino- derivative was the exception, however, with low lipophilicity and relatively low potency. All of the compounds tested showed comparable or greater inhibition in both the neutrophil-mediated assays compared with dapsone. Some of the compounds might, because of their good tissue penetration and lower toxicity than dapsone, have the potential to undergo further development.

Adult↗

PubMed1996

The effect of acetylation and deacetylation on the disposition of dapsone and monoacetyl dapsone hydroxylamines in human erythrocytes in-vitro.

The fates of both dapsone and monoacetyl hydroxylamine have been studied in terms of acetylation and deacetylation within the human erythrocyte in-vitro. A comparison between the two metabolites showed equipotency in methaemoglobin generation at 15 min, although the monoacetyl derivative was the more rapid haemoglobin oxidizer. Within the erythrocytes, both dapsone and monoacetyl hydroxylamines were found to undergo acetylation, deacetylation and diacetylation. Of the inhibitors of acetylation studied, folate caused an increase in methaemoglobin formation associated with both metabolites, which led to a rise in both acetylated and non-acetylated amine formation. Amethopterin was associated with a rise in hydroxylamine mediated methaemoglobin formation which coincided with a fall in acetylated products. It is possible that the hydroxylamines undergo erythrocytic processes of acetylation and deacetylation before methaemoglobin-mediated reduction to their respective amines.

Acedapsone↗

PubMed1996

Studies on the toxicity of analogues of dapsone in-vitro using rat, human and heterologously expressed metabolizing systems.

Three metabolizing systems (rat, heterologously expressed CYP3A4 and human liver) were used to evaluate 12 analogues of dapsone (4,4'diaminodiphenylsulphone) in-vitro. Methaemoglobin formation in a two-compartment and cytotoxicity in a single-compartment model were studied using human erythrocytes and neutrophils, respectively, as target cells. In the two-compartment system using rat microsomes as a generating system and methaemoglobin as an endpoint, the least potent methaemoglobin formers tested were the 2-methyl-4-propylamino (AXDD14), 2-hydroxy-4-4'amino (ABDD5) derivatives and a sulphone/trimethoprim derivative (K-130). Dapsone itself, a 2-methoxy-4-ethylamino (W10) and a 2-hydroxyl-4-ethylamino compound (ABDD39) were the most toxic. In the single-compartment cytotoxicity test using rat microsomes, AXDD14 was again among the least toxic, as was a 2-methyl 4-cyclopentyl derivative (AXDD17) and surprisingly ABDD39. The most cytotoxic compounds again included dapsone itself as well as two 2-trifluoromethyl derivatives. The only significant methaemoglobin formation and cytotoxicity shown with the heterologously expressed human CYP 3A4 was with AXDD14, which was extensively activated. Interestingly, metabolism of dapsone was low using the expressed CYP 3A4. In the two-compartment system using human liver microsomes, AXDD14, K-130 and ABDD5 were oxidized to a significantly lesser extent compared with dapsone and these preliminary findings indicate that future development of these compounds may be worthwhile.

Animals↗

PubMed1996

Drug-induced methaemoglobinaemia. Treatment issues.

In normal erythrocytes, small quantities of methaemoglobin are formed constantly and are continuously reduced, almost entirely by the reduced nicotine adenine dinucleotide (NADH) diaphorase system, rather than the reduced nicotine adenine dinucleotide phosphate (NADPH) diaphorase system. Methaemoglobinaemias are usually the result of xenobiotics, either those that may directly oxidise haemoglobin or those that require metabolic activation to an oxidising species. The most clinically relevant direct methaemoglobin formers include local anaesthetics (such as benzocaine and, to a much lesser extent, prilocaine) as well as amyl nitrite and isobutyl nitrite, which have become drugs of abuse. Indirect, or metabolically activated, methaemoglobin formation by dapsone and primaquine may cause adverse reactions. The clinical consequences of methaemoglobinaemia are related to the blood level of methaemoglobin; dyspnoea, nausea and tachycardia occur at methaemoglobin levels of > or = 30%, while lethargy, stupor and deteriorating consciousness occur as methaemoglobin levels approach 55%. Higher levels may cause cardiac arrhythmias, circulatory failure and neurological depression, while levels of 70% are usually fatal. Cyanosis accompanied by a lack of responsiveness to 100% oxygen indicates a diagnosis of methaemoglobinaemia, which should be confirmed using a CO-oximeter. Pulse oximeters do not detect methaemoglobin and may give a misleading impression of patient oxygenation. Methaemoglobinaemia is treated with intravenous methylene blue (methyl-thioninium chloride; ;1 to 2 mg/kg of a 1% solution). If the patient does not respond, perhaps because of glucose-6-phosphate dehydrogenase (G6PD) deficiency or continued presence of toxin, admission to an intensive care unit and exchange transfusion may be required. Dapsone-mediated chronic methaemoglobin formation can be reduced by coadministration of cimetidine to aid patient tolerance. Increasing knowledge and awareness of drug-mediated acute methaemoglobinaemia among physicians should lead to prompt diagnosis and treatment of this potentially life-threatening condition.

Humans↗

PubMed1995

Dapsone toxicity: some current perspectives.

1. Dapsone is a potent anti-inflammatory and anti-parasitic compound, which is metabolised by cytochrome P-450 to hydroxylamines, which in turn cause methaemoglobinaemia and haemolysis. However, during the process of methaemoglobin formation, erythrocytes are capable of detoxifying the hydroxylamine to the parent drug, which may either reach the tissues to exert a therapeutic effect or return to the liver and be re-oxidised in a form of systemic cycling. This glutathione-dependent effect, combined with the un-ionised state of the drug at physiological pH, may contribute to its efficacy. 2. Paradoxically, other aspects of the glutathione-dependent cycling of the hydroxylamine metabolite may contribute to the major adverse reaction of the drug, agranulocytosis. Erythrocytes exposed to the metabolite and repeatedly washed may still release the hydroxylamine in sufficient concentration to kill mononuclear leucocytes in vitro. Thus, erythrocytes may be a conduit for the hydroxylamine to reach the bone marrow to covalently bind to granulocyte precursors, which may trigger an immune response in certain individuals and may lead to the potentially fatal eradication of granulocytes from the circulation. 3. Attempts to increase patient tolerance to dapsone have been most successful using a metabolic inhibitor to reduce hepatic oxidation of the drug to the hydroxylamine. Methaemoglobin formation in the presence of cimetidine was maintained at 30% below control levels for almost 3 mo, and patients' reported side effects such as headache and lethargy were significantly reduced. 4. As clinical application of new and safer dapsone analogues is years away, the use of cimetidine provides an immediate route to increasing patient compliance during dapsone therapy, especially in those maintained on dapsone dosages in excess of 200 mg/day.

Agranulocytosis↗

PubMed1995

Dapsone-induced motor peripheral neuropathy in pemphigus foliaceus.

We describe a case of pemphigus foliaceus complicated by dapsone-induced motor peripheral neuropathy. This idiosyncratic dapsone side-effect, which is rare other than in leprosy patients, was noteworthy for both its rapid onset, occurring within a month of commencing treatment, and its profound and prolonged nature.

Adult↗

PubMed1994

Reduction of dapsone hydroxylamine to dapsone during methaemoglobin formation in human erythrocytes in vitro. III: Effect of diabetes.

The fate of dapsone hydroxylamine has been investigated in diabetic and normal human erythrocytes. In erythrocytes from four type 1 (insulin dependent) diabetic subjects, there was a significant decrease in dapsone hydroxylamine-mediated methaemoglobin formation compared with cells drawn from normal individuals (P < 0.01). However, the ability of the diabetic cells to detoxify the hydroxylamine to dapsone was not correspondingly reduced and was not different to normal cells. The initial rate of the accelerating effect of diethyl dithiocarbamate (DDC) on hydroxylamine-mediated methaemoglobin and dapsone formation was significantly reduced in diabetic compared with normal cells. There was no significant difference in hydroxylamine-dependent methaemoglobin formation between diabetic erythrocytes pretreated with either statil or sorbinil and untreated diabetic cells. Dapsone recovery in diabetic erythrocytes incubated with statil was not significantly different from statil-free incubations. However, in the presence of sorbinil, there was a marked reduction in dapsone formation at all four time points, (P < 0.001 at 15 min). Mean measured levels of glutathione did not differ significantly between the normal (380 +/- 30.9 mg/L; N = 8) and diabetic (349 +/- 58.7 mg/L; N = 8) volunteers. In summary, although diabetic erythrocytes were less sensitive to the effect of dapsone hydroxylamine-mediated methaemoglobin formation in comparison with normal cells, glutathione-dependent hydroxylamine reduction to dapsone was unaffected.

Dapsone↗

PubMed1994

Reduction of dapsone hydroxylamine to dapsone during methaemoglobin formation in human erythrocytes in vitro. IV: Implications for the development of agranulocytosis.

We have studied the efflux of dapsone hydroxylamine from normal and diabetic erythrocytes by the use of a two-compartment (1 and 2) in vitro dialysis system, in order to model the in vivo blood supply to the bone marrow. When both types of erythrocytes were dialysed against mononuclear leucocytes, the hydroxylamine crossed the membrane and caused significantly greater white cell death compared with dialysis of leucocytes against untreated erythrocytes. However, in the case of both normal and diabetic cells, the presence of the glutathione depletor diethyl maleate (DEM) caused a marked reduction in movement of hydroxylamine from compartment 1 to 2. Diethyl dithiocarbamate (DDC), a methaemoglobin accelerant, caused a marked reduction in movement of hydroxylamine from erythrocytes (diabetic and normal) in compartment 1 to 2 which led to a significant reduction in white cell death compared with the absence of DDC (18.3 +/- 5.5 vs 34.8 +/- 8.1%, P < 0.05). Dapsone recovery from compartment 1 rose significantly in the presence of DDC compared with control in both erythrocyte types. In contrast, recovery of dapsone from normal erythrocytes incubated in compartment 1 was significantly reduced by the presence of DEM compared with control, although there was no difference between control and DEM-treated diabetic cells. Dapsone analysis in compartment 2 revealed a significant increase in dapsone recovery in both diabetic (11.3 +/- 1.1%) and normal (11.9 +/- 1.1%) erythrocytes in the presence of DDC compared with diabetic (3.3 +/- 0.4%) and normal control (4.8 +/- 2.0%, P < 0.001). The presence of DEM in compartment 1 caused a significant fall in dapsone recovery in compartment 2 (3.7 +/- 0.26) compared with control (4.7 +/- 0.36%, P < 0.05). Hence, dapsone hydroxylamine is capable of leeching out of normal and diabetic erythrocytes, traversing a semipermeable membrane and causing toxicity to human mononucleocyte cells in vitro. This process may be one of the first stages in immune-mediated agranulocytosis.

Agranulocytosis↗

PubMed1993

Reduction of dapsone hydroxylamine to dapsone during methaemoglobin formation in human erythrocytes in vitro--II. Movement of dapsone across a semipermeable membrane into erythrocytes and plasma.

We have used an in vitro two-compartment model, to investigate the ability of dapsone, formed by erythrocyte-mediated detoxification of its hydroxylamine metabolite, to escape the cells and cross a semi-permeable membrane into both plasma and other erythrocytes. Both diethyl dithiocarbamate (DDC) treated and untreated erythrocytes were incubated with dapsone hydroxylamine and dialysed against either fresh cells or plasma. Methaemoglobin was predominantly detectable in compartment A although the presence of low levels of methaemoglobin in compartment B indicated that the hydroxylamine itself had crossed the membrane. In contrast to methaemoglobin disposition, recovery of dapsone was higher (P < 0.05) in compartment B compared with A for all three treatment groups at 30 and 60 min, but not at the remaining time points. Regression analysis of the cumulative recovery of dapsone over 150 min in all three treatment groups for both compartments A and B showed correlation coefficients close to unity. In compartment A, analysis of the mean slopes of the regression lines indicated that, overall, significantly more dapsone was recovered from group 1 (erythrocytes, hydroxylamine and DDC dialysed against untreated red cells) compared with group 3 (erythrocytes and hydroxylamine dialysed against plasma) (0.22 +/- 0.05 vs 0.09 +/- 0.005; P < 0.025). Also in compartment A, significantly more dapsone was recovered from group 2 (erythrocytes and hydroxylamine dialysed against untreated red cells) compared with group 3 (erythrocytes and hydroxylamine dialysed against plasma: 0.16 +/- 0.02 vs 0.09 +/- 0.005). In compartment B, dapsone recovery was significantly greater in group 1 (erythrocytes, hydroxylamine and DDC dialysed against untreated red cells; slope of regression line: 0.59 +/- 0.05) compared with group 2 (erythrocytes and hydroxylamine dialysed against untreated red cells; slope of line: 0.28 +/- 0.02, P < 0.005). In addition, dapsone recovery was significantly greater in group 1 (0.59 +/- 0.05) compared with group 3 (erythrocytes and hydroxylamine dialysed against plasma; 0.21 +/- 0.02, P < 0.005). Dialysis of erythrocytes with dapsone itself over 120 min caused no detectable methaemoglobin formation. The process of erythrocyte-mediated dapsone formation from its hydroxylamine may feasibly occur in vivo and contribute to the systemic persistence and therapeutic effect of dapsone.

Cell Membrane Permeability↗

PubMed1993

Reduction of dapsone hydroxylamine to dapsone during methaemoglobin formation in human erythrocytes in vitro.

The fate of the toxic metabolite of dapsone, dapsone hydroxylamine, has been studied in the human red cell. Twice-washed red cells were incubated at 37 degrees with dapsone hydroxylamine: at 3 and 5 min, 27.0 +/- 2.2 and 33.2 +/- 2.7% of the haemoglobin had been converted to methaemoglobin, leading to a maximum at 45 min (45 +/- 1.8%). HPLC analysis revealed that parent amine was produced from dapsone hydroxylamine during methaemoglobin formation in the red cells. At 3 min, conversion of dapsone hydroxylamine to dapsone reached 7.0 +/- 3.9% leading to a maximum at 30 min (18.1 +/- 3.7%). There was a linear relationship between hydroxylamine-dependent methaemoglobin formation and conversion of hydroxylamine to dapsone (r = 0.97). At 4 degrees, methaemoglobin and dapsone formation was greatly retarded, and did not exceed 10%. Co-incubation of diethyl dithiocarbamate (DDC) with dapsone hydroxylamine and red cells led to a marked increase in methaemoglobin formation (61.4 +/- 3.4%) compared with hydroxylamine and red cells alone (45.0 +/- 1.8%, P < 0.001) at 45 min, and conversion of dapsone hydroxylamine to dapsone was almost doubled at 45 min (35.7 +/- 5.3%) compared with hydroxylamine and red cells (18.1 +/- 2.5%). A linear relationship between methaemoglobin formation and dapsone formation (r = 0.96) was also shown to occur in the presence of DDC. Incubation of red cells with DDC and dapsone hydroxylamine caused a significantly greater reduction in glutathione levels (98.3 +/- 1.6%) compared with red cells and dapsone hydroxylamine alone (84.8 +/- 2.7%) at 5 min (P < 0.001), although there was no significant difference between the groups at 15 min (96.9 +/- 2.6 vs 98.1 +/- 2.2%). Intra-erythrocytic glutathione was then depleted by 75 +/- 3.4%, by pretreatment with diethyl maleate (6 mM), and these cells in the presence of the hydroxylamine showed a significant fall in both methaemoglobin generation (29.7 +/- 1.2 vs 35.0 +/- 1.7%) and parent amine formation (11.1 +/- 0.2 vs 16.5 +/- 1.1%) compared with untreated red cells at 45 min. It is possible that a cycle exists between hepatic oxidation of dapsone to its hydroxylamine and reduction to the amine within the red cell, which may lead to re-oxidation by hepatic cytochrome P450. This process may contribute to the persistence of the drug in vivo.

Dapsone↗

PubMed1993

Lack of interaction between sulphasalazine and cimetidine in patients with rheumatoid arthritis.

The interaction between sulphasalazine and cimetidine has been studied, a drug combination which is quite likely in view of the higher incidence of peptic ulceration in patients with RA. Nine patients with RA on sulphasalazine (group I) were given cimetidine 400 mg three times daily and followed up for 18 weeks. In addition, five patients on sulphasalazine alone (group II), who served as a control group, were also followed up in the same manner as group I. Monitoring included assessment of disease activity and haematological variables, and measurement of plasma and urinary levels of sulphapyridine and its metabolites. There was no significant change in either the haematological parameters or sulphapyridine pharmacokinetics upon administration of cimetidine. We therefore conclude that cimetidine may be safely used in patients with RA who are being treated with sulphasalazine.

Adult↗

PubMed1993

Dapsone: modes of action, toxicity and possible strategies for increasing patient tolerance.

Dapsone is useful in the treatment of a number of inflammatory conditions which are characterized by neutrophil infiltration. It is the drug of choice for suppression of the symptoms of dermatitis herpetiformis, as it inhibits the process by which neutrophils leave the circulation and migrate to lesional sites. It also prevents the tissue destruction normally caused by the neutrophils' respiratory burst. Although dapsone can cause a number of serious idiosyncratic reactions, such as agranulocytosis, tolerance of the drug at higher doses is more usually determined by its haematological side-effects of methaemoglobinaemia and haemolysis. These effects are due entirely to the hepatic N-hydroxylation of dapsone to a hydroxylamine metabolite, some of which escapes from the liver and rapidly enters red cells. Attempts have been made to counteract the haemotoxic effects of the metabolite by the use of antioxidants such as vitamins E and C. Recently, the co-administration of a metabolic inhibitor such as cimetidine has been shown to reduce significantly dapsone-dependent methaemoglobinaemia, without any change in drug efficacy. It remains to be seen if this approach will be adopted clinically, to improve patient tolerance of high dapsone dosage.

Dapsone↗

PubMed1992

The use of cimetidine to reduce dapsone-dependent methaemoglobinaemia in dermatitis herpetiformis patients.

1. We have attempted to reduce dapsone-dependent methaemoglobinaemia formation in six dermatitis herpetiformis patients stabilised on dapsone by the co-administration of cimetidine. 2. In comparison with control, i.e. dapsone alone, methaemoglobinaemia due to dapsone fell by 27.3 +/- 6.7% and 26.6 +/- 5.6% the first and second weeks after commencement of cimetidine administration. The normally cyanotic appearance of the patient on the highest dose of dapsone (350 mg day-1), underwent marked improvement. 3. There was a significant increase in the trough plasma concentration of dapsone (2.8 +/- 0.8 x 10(-5)% dose ml-1) at day 21 in the presence of cimetidine compared with control (day 7, 1.9 +/- 0.6 x 10(-5)% dose ml-1, P less than 0.01). During the period of the study, dapsone-mediated control of the dermatitis herpetiformis in all six patients was unchanged. 4. Trough plasma concentrations of monoacetyl dapsone were significantly increased (P less than 0.05) at day 21 (1.9 +/- 1.0 x 10(-5)% dose ml-1) compared with day 7 (1.6 +/- 0.9 x 10(-5)% dose ml-1:control). 5. Over a 12 h period, 20.6 +/- 8.9% (day 0) of a dose of dapsone was detectable in urine as dapsone hydroxylamine. Significantly less dapsone hydroxylamine was recovered from urine at day 14 (15.0 +/- 8.4) in the presence of cimetidine, compared with day 0 (control: P less than 0.05). 6. The co-administration of cimetidine may be of value in increasing patient tolerance to dapsone, a widely used, effective, but comparatively toxic drug.

Adult↗

PubMed1992

Inhibition of dapsone-induced methaemoglobinaemia by cimetidine in the presence of trimethoprim in the rat.

Administration of dapsone in combination with trimethoprim and cimetidine to male rats resulted in a marked decrease (P less than 0.05) in measured methaemoglobin levels (46.2 +/- 24% Met Hb h) compared with administration of dapsone alone (124.5 +/- 24.4% Met Hb h). The elimination half-life of dapsone (814 +/- 351 min) was more than doubled in the presence of trimethoprim and cimetidine compared with control (355 +/- 160 min, P less than 0.05). However, there were no significant differences in AUC and clearance when dapsone was administered in combination with trimethoprim and cimetidine compared with dapsone alone. Co-administration of trimethoprim with dapsone in the absence of cimetidine did not affect either methaemoglobin formation, AUCs, half-lives, or clearance values of dapsone compared with control. There was a threefold increase in the AUC of trimethoprim (6296 +/- 2249 micrograms min mL-1) in the presence of dapsone compared with trimethoprim alone (2122 +/- 552 micrograms min mL-1). There was also a corresponding decrease in the clearance of trimethoprim in the presence of dapsone compared with control (19.1 +/- 6.9 vs 60.8 +/- 21.0 mL min-1). However, there was no change in the elimination half-life of trimethoprim between the two experimental groups (273 +/- 120 vs 292 +/- 54 min). The AUC of trimethoprim increased more than threefold in the presence of cimetidine (7100 +/- 1501 micrograms min mL-1) compared with trimethoprim alone (2122 +/- 552 micrograms min mL-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗

PubMed1991

Direct and metabolism-dependent toxicity of sulphasalazine and its principal metabolites towards human erythrocytes and leucocytes.

1. The role of metabolites in sulphasalazine-mediated toxicity has been investigated in vitro by the use of human red blood cells and mononuclear leucocytes as target cells, with methaemoglobin formation and cytotoxicity respectively, being the defined toxic end-points. 2. Of the metabolites of sulphasalazine investigated, only sulphapyridine was bioactivated by human liver microsomes in the presence of NADPH to a metabolite which caused marked methaemoglobinaemia and a small, but statistically significant degree of mononuclear leucocyte cell death. 3. Methaemoglobinaemia was inhibited by ketoconazole but not by ascorbic acid (100 microM), glutathione (500 microM) and N-acetylcysteine (50 microM). In contrast, ascorbic acid and the thiols afforded complete protection for mononuclear leucocytes. 4. Sulphapyridine (100 microM) was converted in vitro to a metabolite (metabolite conversion 6.8 +/- 0.3%), the retention time of which on h.p.l.c. corresponded to synthetic sulphapyridine hydroxylamine. The half-life of sulphapyridine hydroxylamine in phosphate buffer (pH 7.4) was found to be 8.1 min. 5. In the absence of microsomes and NADPH, sulphapyridine hydroxylamine caused a concentration-dependent (10-500 microM) increase in methaemoglobinaemia (2.9%-24.4%) and cytotoxicity (5.4%-51.4%), whereas sulphasalazine, sulphapyridine, 5-hydroxy sulphapyridine and 5-aminosalicylic acid had no effect.

Acetylcysteine↗

PubMed1991

The effect of preincubation with cimetidine on the N-hydroxylation of dapsone by human liver microsomes.

We have examined the ability of cimetidine to inhibit the oxidative metabolism and hence haemotoxicity of dapsone in vitro, using a two compartment system in which two Teflon chambers are separated by a semi-permeable membrane. Compartment A contained a drug metabolizing system (microsomes prepared from human or rat liver +/- NADPH), whilst compartment B contained human red cells. Preincubation (30 min) of human liver microsomes with cimetidine (0-1000 microM) and NADPH prior to the addition of dapsone (100 microM) and NADPH (1 mM) resulted in a concentration-dependent decrease in the concentrations of dapsone hydroxylamine (from 179 +/- 47 to 40 +/- 6 ng) in compartment B. This reduction of hydroxylamine metabolite was reflected in the concentration-dependent reduction in methaemoglobin measured (from 7.1 +/- 0.7 to 3.5 +/- 1.5%) in parallel experiments. Preincubation of microsomes with cimetidine in the absence of NADPH had no effect. The effect of cimetidine pretreatment on dapsone-dependent methaemoglobin was confirmed using microsomes prepared from a further three sources of human liver, as well as from rat liver.

Adolescent↗

PubMed1991

An investigation into the haematological toxicity of structural analogues of dapsone in-vivo and in-vitro.

With microsomes prepared from a single human liver, 4,4'-diaminodiphenyl sulphone (DDS), 4-acetyl-4-aminodiphenyl sulphone (MADDS), 4-acetyl-4-aminodiphenyl thioether (MADDT) and 4,4'-diacetyldiphenyl thioether (DADDT) caused significantly greater methaemoglobin formation compared with control. In-vitro in the rat, the pattern of toxicity was slightly different:DADDT was not haemotoxic, whilst 3,4'-diaminodiphenyl sulphone (3,4'DDS) and 3,3'-diaminodiphenyl sulphone (3,3'DDS) as well as DDS, MADDS and MADDT were significantly greater than control. 4,4' Acetyl diphenyl sulphone (DADDS), 4,4' diaminodiphenyl thioether (DDT), 4,4'-diaminodiphenyl ether (DDE) and 4,4' diaminooctofluorodiphenyl sulphone (F8DDS) did not cause significant methaemoglobinaemia in either human or rat liver microsomes. DDS, MADDS, and MADDT were not significantly different in haemotoxicity generation in-vitro in the presence of human microsomes. In the rat in-vitro, DDS, MADDS, and 3,4'DDS did not differ significantly in red cell toxicity, and were the most potent methaemoglobin formers. The 3,3'DDS and MADDT derivatives were both significantly less toxic compared with DDS. None of the compounds tested caused haemoglobin oxidation in the absence of NADPH in-vitro. In the whole rat, DDS, MADDS and MADDT caused significantly higher levels of methaemoglobin compared with control. None of the remaining compounds caused methaemoglobin formation which was significantly greater than control. DDS and MADDS were the most potent methaemoglobin formers tested, in-vivo and in-vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1991

Inhibition of dapsone-induced methaemoglobinaemia by cimetidine in the rat during chronic dapsone administration.

Dapsone undergoes N-acetylation to monoacetyl dapsone as well as N-hydroxylation to a hydroxylamine which is responsible for the haemotoxicity (i.e. methaemoglobinaemia; Met Hb) of the drug. Since dapsone is always given chronically, we have investigated the ability of cimetidine to inhibit Met Hb formation caused by repeated dapsone administration. The drug was given (i.p.) to four groups (n = 6 per group) of male Wistar rats, 300-360 g. Group I received 10 mg kg-1 at 1, 24, 48 and 72 h. Group II received 10 mg kg-1 at 1, 8, 24, 32, 48, 56, 72 and 80 h. Groups III and IV received the drug as for groups I and II, respectively, as well as cimetidine (50 mg kg-1) 1 h before each dose of dapsone. Twice daily dapsone administration (Group II) resulted in a significantly greater (P less than 0.05) Met Hb AUC (757 +/- 135 vs 584 +/- 115% Met Hb h), dapsone AUC (140 +/- 17.5 vs 113 +/- 13.0 micrograms h mL-1) and monoacetyl dapsone AUC (48.2 +/- 18.3 vs 10.8 +/- 4.6 micrograms h mL-1) compared with a single daily dapsone dose (group I). The administration of cimetidine before the once daily dose of dapsone (group III) resulted in a significant (P less than 0.05) fall in Met Hb (302 +/- 179 vs 584 +/- 115% Met Hb h) and an increase in both the dapsone (151 +/- 22.2 vs 113 +/- 13.0 micrograms h mL-1) and monoacetyl dapsone AUC values (33.6 +/- 5.8 vs 10.8 +/- 4.0 micrograms h mL-1) compared with a single daily dose of dapsone (group I).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗