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A 16-year-old boy is seen in the emergency
department after he had collapsed after a dental
extraction in which prilocaine hydrochloride 3%
was used as topical anesthesia. His mother tells
the emergency physician that he felt unwell after
the procedure and gradually became more and
more drowsy. The patient is deeply cyanosed
despite a good respiratory effort, a clear airway,
and bilateral breath sounds. Although he initially
responds to vocal commands, his level of
consciousness soon deteriorates. Oxygen
saturation is 60% with the patient breathing room
air. An endotracheal tube is introduced and
assisted ventilation started, but this does not
improve his cyanosis or level of consciousness.
The attending physician is alert to the possible
diagnosis of methemoglobinemia because the
patient is cyanosed, the cyanosis is unresponsive
to ventilation, there is no prior history of
respiratory problems, and the patient had been
exposed to a topical anesthetic that is known to
cause methemoglobinemia.
A blood specimen is drawn and test results
confirm the diagnosis.
Information on methemoglobinemia was obtained
through a literature search using MEDLINE and the fol-
lowing key words: methemoglobinemia, sulfhemoglobine-
mia, cyanosis, and methylene blue.
Methemoglobinemia is a condition characterized by in-
creased quantities of hemoglobin in which the iron of
heme is oxidized to the ferric (Fe
) form. Methemoglo-
bin is useless as an oxygen carrier and thus causes a varying
degree of cyanosis.
The condition may arise as a result of a genetic defect in
red blood cell metabolism or hemoglobin structure, or it
may be acquired following exposure to various oxidant
drugs or toxins.
Genetic defect
Hereditary methemoglobinemia is a rare recessively inher-
ited disorder due to deficiency of an enzyme, called re-
duced nicotinamide adenine dinucleotide (NADH) cyto-
chrome b
reductase. Normal erythrocytes are well
endowed with a system to convert useless methemoglobin
to functional hemoglobin. The major mechanism for this
reductive capacity resides in the soluble NADH cyto-
chrome b
reductase. The gene regulating the synthesis of
cytochrome b
reductase has been localized to chromo-
some 22q13qter, and a number of mutations have been
Hereditary methemoglobinemia due to
NADH cytochrome b
reductase deficiency is classified
into 2 typeserythrocyte (type I) and generalized (type II).
In the type I form, the soluble form of the enzyme is
deficient only in erythrocytes, and cyanosis is the only
Type II hereditary methemoglobinemia is due
to deficiency of the membrane-bound form of the en-
zyme, which is located in the outer mitochondrial mem-
brane and the endoplasmic reticulum of somatic cells.
Type II hereditary methemoglobinemia is a rare disease
characterized by deficiency of the enzyme in all tissues and
manifesting with severe developmental abnormalities, se-
vere mental retardation, and neurologic impairment,
which often lead to premature death.
Heterozygotes with
NADH cytochrome b
reductase deficiency do not usu-
Summary points
Severe methemoglobinemia is a medical emergency,
requiring prompt recognition and appropriate
A good history and high level of suspicion are required
to make the diagnosis
Exposure to medication is the most common cause of
For methemoglobinemia due to drug exposure,
traditional first-line therapy consists of the infusion of
methylene blue
Best Practice
Habib Ur Rehman
Specialist registrar
Department of Medicine
Hull Royal Infirmary
Hull HU3 2JZ
Competing interests:
None declared
West J Med
Volume 175 September 2001 wjm
ally manifest signs of methemoglobinemia. However, un-
der the stress of oxidant drugs, severe cyanosis may de-
velop because of methemoglobinemia. Neurologic
abnormalities do not respond to methylene blue therapy.
There are several abnormal hemoglobin variants asso-
ciated with genetic methemoglobinemia, and these are
designated hemoglobin M. In most of the hemoglobin M,
tyrosine has been substituted for either the proximal or the
distal histidine. This results in reduced capacity of the
enzymatic machinery of the erythrocyte to efficiently re-
duce the iron to the divalent form and thus predisposes to
methemoglobinemia. These hemoglobin variants are as-
sociated with cyanosis, which is present from early life. In
the case of the -chain variants, it is present from birth,
whereas the -chain hemoglobin variants produce cyano-
sis only after the first few months of life as adult hemo-
globin synthesis becomes established. This disorder is in-
herited in an autosomal dominant pattern.
Exposure to drugs or toxins
The most common cause of methemoglobinemia, as in
this clinical case, is ingestion of or exposure of skin or
mucous membranes to oxidizing agents (see box). Some of
these oxidize hemoglobin directly to form methemo-
globin; others do it indirectly by reducing free oxygen
to the free radical O
, which in turn oxidizes hemoglo-
bin to methemoglobin. Outbreaks of methemoglobine-
mia have occurred due to nitrite poisoning from water
Large amounts of nitric oxide are released in patients
with sepsis. Nitric oxide is converted to methemoglobin
and nitrate. It has been reported that methemoglobin lev-
els are significantly higher in patients with sepsis than in
nonseptic patients.
Methemoglobinemia has been reported in young in-
fants (<6 months) in whom severe metabolic acidosis de-
velops from diarrhea and dehydration.
Young infants
may be particularly susceptible to this complication be-
cause of their low stomach acid production, large number
of nitrite-reducing bacteria, and the relatively easy oxida-
tion of fetal hemoglobin. Small infants have lower eryth-
rocyte levels of cytochrome b reductase.
Higher intestinal
pH of infants may promote the growth of gram-negative
organisms that convert dietary nitrates to nitrites.
Methemoglobinemia has been reported in diarrhea
induced by hypersensitivity to cows milk proteins.
has also been reported in association with renal tubular
This patient has no family history of the disease,
which makes genetic causes unlikely. Structural
alteration of -or-globin chains of hemoglobin
Drugs or toxins that can cause methemoglobinemia*
Benzene derivatives
Bivalent copper
Bismuth subnitrate
Bupivacaine hydrochloride
Dimethyl sulfoxide
Exhaust fumes
Lidocaine hydrochloride
Metoclopramide hydrochloride
Methylene blue
Nitric oxide
Sodium nitroprusside
Phenazopyridine hydrochloride
Prilocaine hydrochloride
Primaquine phosphate
Silver nitrate
Sodium valproate
Smoke inhalation
*Certain drugs are more likely to cause methemoglobinemia than others. These are
dapsone, local anesthetics, phenacetin, and antimalarial drugs. Screening
everybody for methemoglobinemia before exposing them to these drugs is
impractical because of the rarity of the condition and because a growing number of
drugs are implicated in its causation.
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194 wjm Volume 175 September 2001
would have presented early in infancy, and type I
hereditary methemoglobinemia can reasonably
be excluded on the basis that chronic low-grade
cyanosis is the only symptom. The absence of
neurologic signs excludes type II hereditary
methemoglobinemia. The most likely cause of
methemoglobinemia, therefore, is acquired by
exposure to prilocaine hydrochloride.
Methemoglobinemia may be acute or chronic. The physi-
ologic level of methemoglobin in the blood is 0% to 2%.
Methemoglobin concentrations of 10% to 20% are tol-
erated well, but levels above this are often associated with
symptoms. Levels above 70% may cause death. Symp-
toms also depend on the rapidity of its formation. Many
patients with lifelong methemoglobinemia are asymptom-
atic, but patients exposed to drugs and toxins who
abruptly develop the same levels of methemoglobinemia
may be severely symptomatic.
Small infants with methemoglobinemia present with
cyanosis that fails to respond to supplemental oxygen. Cy-
anosis in those with congenital methemoglobinemia usu-
ally appears shortly after birth. Dyspnea, nausea, and
tachycardia occur at methemoglobin levels of 30% or
more. Lethargy, stupor, and deteriorating consciousness
occur as methemoglobin levels approach 55%. Higher
levels may cause cardiac arrhythmias and circulatory fail-
ure. Hemolytic anemia may follow drug-induced methe-
moglobinemia, especially with exposure to dapsone, sul-
fasalazine, or phenacetin. The anemia is characterized by
Heinz bodies (precipitated hemoglobin or globin subunits
due to denaturation of hemoglobin in erythrocytes) and
fragmented red blood cells. Occasionally acute intravas-
cular hemolysis can lead to renal failure. Hemolytic ane-
mia with jaundice may also be a feature of hemoglobin
and hemoglobin M
Hyde Park
abnormal hemo-
globin variants associated with genetic methemoglobine-
mia and identified by where they were discovered.
The patient is monitored for evidence of
intravascular hemolysis and acute renal failure.
His urine output, blood cell count, and urea and
electrolyte levels are monitored closely. Any
evidence of hemolysis should alert the physician
so that appropriate treatment can be instituted.
The differential diagnosis of methemoglobinemia in small
infants includes cyanotic congenital heart disease, particu-
larly when right to left shunting is present. Children with
cyanotic congenital heart disease who receive supple-
mental oxygen have a low partial pressure of oxygen
and a low calculated oxygen saturation, but children with
methemoglobinemia have a high partial pressure of oxy-
gen despite cyanosis and normal calculated oxygen
Methemoglobinemia in older children should be dis-
tinguished from sulfhemoglobinemia. Sulfhemoglobine-
mia refers to the incorporation of a sulfur molecule into
the heme moiety. Most drugs, particularly sulfonamides
and phenacetin, that produce methemoglobinemia can
also cause sulfhemoglobinemia, although this condition is
less common than methemoglobinemia.
tend to be milder than in patients with methemoglobine-
mia. The diagnosis is confirmed by elevated levels of sulf-
hemoglobin by either spectrophotometry or gas chroma-
tography-mass spectrometry. Sulfhemoglobinemia does
not respond to methylene blue, and the treatment is sup-
In severe cases, exchange transfusion may be
The potassium cyanide test can distinguish between
methemoglobin and sulfhemoglobin. After the addition of
a few drops of potassium cyanide, methemoglobin turns
bright red, but sulfhemoglobin remains dark brown. This
is due to the binding of methemoglobin to cyanide, form-
ing cyanomethemoglobin, which is bright red in color.
Sulfhemoglobin, on the other hand, is inert and does not
bind cyanide.
A family history is usually helpful in differentiating
methemoglobinemia due to NADH cytochrome b
ductase deficiency from hemoglobin M disease. Cyanosis
in successive generations suggests the presence of hemo-
globin M; normal parents but possibly affected siblings
implies the presence of NADH cytochrome b
Blood containing high concentrations of methemoglobin
appears chocolate brown. Subjects with methemoglobine-
mia may have normal partial pressures of oxygen, despite
life-threatening methemoglobinemia. The oxygen satura-
tion values, measured by a pulse oximeter, are falsely
In methemoglobinemia due to drug exposure, an el-
evated level of methemoglobin is found, but the activity of
NADH cytochrome b
reductase is normal. In hereditary
type II methemoglobinemia, the enzymes activity is less
than 20% of normal. Hemoglobin M may be differenti-
ated from methemoglobin formed from hemoglobin A by
its absorption spectrum in the range of 450 to 750 nm.
Electrophoresis at pH 7.1 is most useful for the separation
of hemoglobin M.
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Volume 175 September 2001 wjm
The course of hereditary methemoglobinemia type I is
benign, but these patients should not be administered oxi-
dant drugs. Treatment may be required for cosmetic rea-
sons or for an inadvertent use of oxidant drugs. Ascorbic
acid, 300 to 600 mg orally daily divided into 3 or 4 doses,
is helpful.
For methemoglobinemia due to drug exposure, tradi-
tional first-line therapy consists of an infusion of methy-
lene blue, whose action depends on the availability of
reduced nicotinamide adenine nucleotide phosphate
(NADPH) within the red blood cells. After an acute ex-
posure to an oxidizing agent, treatment should be consid-
ered when the methemoglobin is 30% in an asymptom-
atic patient and 20% in a symptomatic patient.
with anemia or cardiorespiratory problems should be
treated at lower levels of methemoglobin. Methemoglobi-
nemia due to hemoglobin M does not respond to ascorbic
acid or methylene blue.
Dextrose should be given
because the major source of
NADH in the red blood cells is the catabolism of sugar
through glycolysis. Dextrose is also necessary to form
NADPH through the hexose monophosphate shunt,
which is necessary for methylene blue to be effective.
Methylene blue is an oxidant; its metabolic product
leukomethylene blue is the reducing agent. Therefore,
large doses of methylene blue may result in higher levels of
methylene blue rather than the leukomethylene blue,
which will result in hemolysis and, paradoxically, methe-
moglobinemia in patients with glucose-6-phosphate dehy-
drogenase (G6PD) deficiency.
Patients with G6PD
deficiency also may not produce sufficient NADPH to
reduce methylene blue to leukomethylene blue; thus,
methylene blue therapy may be ineffective in these
Some drugs, such as dapsone, benzocaine, and aniline,
produce a rebound methemoglobinemia, in which met-
hemoglobin levels increase 4 to 12 hours after successful
methylene blue therapy.
N-Acetylcysteine, cimetidine, and ketoconazole are ex-
perimental therapies in the treatment of methemoglobi-
nemia that have shown some promising results.
change transfusion is reserved for patients in whom
methylene blue therapy is ineffective.
The patient is treated with intravenous methylene
blue and dextrose infusion, with a good response.
His cyanosis and blood oxygenation improve, as
does his consciousness level. His urine output is
monitored, and a close eye is kept on his
biochemistry. Blood tests are repeated after 24
hours for evidence of hemolysis and rebound
methemoglobinemia. His G6PD status is
ascertained and found to be normal. He does not
show any evidence of hemolysis or renal
impairment and makes a complete recovery.
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... The concentration level between 10% and 20% is associated with symptoms. 15 MetHb is classified into two types that are congenital and acquired. There are two forms of congenital MetHb, type I and II. ...
... 16 Examples of medications causing MetHb include chloroquine, dapsone and bupivacaine. 15 It has been reported that a 6-week-old infant presented to the hospital with a 2-day history of diarrhoea, poor feeding and lethargy. The initial pH was acidotic with a methaemoglobin of 29%. ...
A 4-week-old boy presented to the hospital with symptoms of diarrhoea and vomiting initially thought to be due to cow’s milk allergy. He was discharged with extensively hydrolysed formula. The patient represented with worsening of symptoms with metabolic acidosis and was screened and treated for sepsis. However, his condition deteriorated further and he developed methaemoglobinaemia. He was transferred to the high dependency unit and was given two doses of methylene blue. Further investigations were carried out, including rapid trio exome sequencing, which identified a homozygous pathogenic Peptidase D (PEPD) variant (c.978G>A, p.(Trp326*)). This was consistent with a diagnosis of prolidase deficiency.
Methemoglobin (MetHb) is a form of hemoglobin in which iron in Hb is in an oxidized form (ferric) instead of ferrous, making it difficult to bind with oxygen. Usually, MetHb is present in small quantities (<1%) in humans, but once MetHb increases beyond 3%, the condition is known as methemoglobinemia. It can be further classified into hereditary and acquired. Hereditary forms are a rare cause of hypoxia and cyanosis. Only a few cases have been reported worldwide. Here, we present a case of a 33-year-old female with congenital methemoglobinemia who remains relatively healthy in spite of her underlying condition. This case report focuses on knowledge sharing and practical aspects of managing patients with congenital methemoglobinemia.
Statement of the problem: Methemoglobinemia is a potentially life-threatening rare medical condition, which refers to an increase in the level of oxidized form of hemoglobin (methemoglobin). Excessive replacement of hemoglobin with methemoglobin leads to functional hypoxia and even fatal conditions. Purpose: The aim of this study was to evaluate the effect of two common local anesthetic agents namely lidocaine and articaine administered for hemostasis during surgery on methemoglobin level. Materials and method: This prospective cohort study was conducted from January 2017 to December 2019. Demographic data including age, gender, and weight of patients were collected. Sixty patients were randomly divided into three groups (n=20) regarding the local anesthetic agent administered for hemostasis during surgery as lidocaine group (group 1), articaine group (group 2), and control group (no local anesthetic; group 3). The patients were candidates for orthognathic surgery, reconstruction of the maxillary and mandibular atrophic ridges with autogenous grafts, and reconstruction of maxillofacial fractures. The methemoglobin level was measured before surgery and six hours after the initiation of surgery. Results: The mean age and weight of patients were not significantly different among the three groups (p= 0.891 and p= 0.416, respectively). No significant differences were observed among the three groups regarding the gender distribution (p= 0.343) or type of surgery (p= 0.990). Statistical analysis did not show any significant difference in the mean baseline methemoglobin level among the three groups (p= 0.109). Although the mean methemoglobin values increased in the three groups, paired sample t-test did not show any significant change in the values at six hours after the initiation of surgery compared with baseline in any of the three groups (p= 0.083 for group 1, p= 0.096 for group 2, and p= 0.104 for group 3). Conclusion: The results demonstrated that administration of lidocaine and articaine plus epinephrine for hemostasis during general anesthesia are equally safe.
Purpose There is an increased number of reports being published on rasburicase-induced methemoglobinemia recently. We aimed to identify and critically evaluate all the descriptive studies that described the rasburicase-induced methemoglobinemia, its treatment approach, and their outcomes. Methodology PubMed, Scopus and grey literature databases were searched from inception to January 2022 using search terms “rasburicase” and “methemoglobinemia” without any language and date restriction. A bibliographic search was also done to find additional studies. Only descriptive studies on Rasburicase-induced methemoglobinemia were included for our review. Two contributors worked independently on study selection, data abstraction, and quality assessment, and any disagreements were resolved by consensus or discussion with a third reviewer. Result A total of 24 reports including 27 patients (23 male, 3 female patients, and 1 study did not specify the gender of the patient) aged from 5 to 75 years were included in the review. Immediate withdrawal of the drug and administering methylene blue, ascorbic acid, blood transfusion, and supportive oxygen therapy are the cornerstone in the management of rasburicase-induced methemoglobinemia. Conclusion Rasburicase administration should be followed by careful monitoring of patients for any severe complication and treat it as early as possible appropriately. In a patient who presents with rasburicase-induced haemolysis or methemoglobinemia, it is often important to expect a diagnosis of G6PD deficiency unless otherwise confirmed and to avoid administering methylene blue, even though the patient is from a low-risk ethnicity for G6PDD.
Full-text available
A 63-year-old male patient underwent coronary artery bypass surgery under cardiopulmonary bypass. Preoperative test results were all normal. During surgery, sudden methemoglobinemia developed after the intravenous administration of lidocaine which was used to prevent arrhythmias. In the intensive care unit, methylene blue was given to the patient and an extracorporeal membrane oxygenator was used to correct deep hypotension and worsening hemodynamic parameters. However, the patient died from multiorgan failure secondary to hypoxia. In conclusion, many factors may play a role in the etiology of methemoglobinemia. Treatment options are limited. Methylene blue is used as an effective method in the treatment. Lidocaine is one of the most common drugs used in the practice of cardiology and cardiovascular surgery. Therefore, the possibility of developing methemoglobinemia should be always kept in mind.
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Background Methemoglobin is the reduced form of haemoglobin that is normally found in the blood in levels < 1%. Methemoglobinemia can occur as a congenital or acquired disease. Two types of recessive congenital methaemoglobinemia (RCM) are caused by the NADH-dependent cytochrome b5 reductase enzyme deficiency of the CYB5R3 gene. RCM-I is characterized by higher methaemoglobin levels (> 2 g/dL), causing only cyanosis, whereas RCM-II is associated with cyanosis with neurological impairment. Methods Routine haematological investigations were done by standard method. The methaemoglobin level was evaluated by the potassium ferricyanide assay. NADH-cytochrome b5 reductase (cytb5r) enzyme activities were measured by standard methods, and molecular analysis was performed by polymerase chain reaction (PCR) followed by DNA sequencing. The interpretation of mutation effect and the molecular modeling were performed by using specific software DEEP VIEW SWISS-PDB VIEWER and Pymol molecular graphics program. Results The present study discovered three novel homozygous pathogenic variants of CYB5R3 causing RCM I and II in four unrelated Indian patients. In patient-1 and patient-2 of RCM type I caused due to novel c.175C>T (p.Arg59Cys) and other reported c.469T>C (p.Phe157Ser) missense pathogenic variants respectively, whereas patient-3 and patient-4 presented with the RCM type II are related to developmental delay with cyanosis since birth due to a novel homozygous (g.25679_25679delA) splice-site deletion and novel homozygous c.824_825insC (p.Pro278ThrfsTer367) single nucleotide insertion. The CYB5R3 transcript levels were estimated by qRT-PCR in the splice-site deletion, which was 0.33fold of normal healthy control. The insertion of nucleotide C resulted in a frameshift of termination codon are associated with neurological impairment. Conclusions Molecular diagnosis of RCM can help to conduct genetic counselling for novel mutations and, subsequently, prenatal diagnosis of high-risk genetic disorders.
Fatal sodium nitrite poisonings are unusual in the forensic setting. Suicide by poisoning includes drug overdose, the inhalation of toxic gasses, and poisoning from pesticides and chemical substances. Sodium nitrite is an inorganic compound usually seen as a crystalline powder that is very water soluble. Sodium nitrite is used mostly in the food industry (as a preservative) and in medical field (as an antidote to cyanide poisoning), and if ingested in large enough amounts, it can be fatal.The ingestion of sodium nitrite can cause severe methemoglobinemia, which is a metabolic disorder characterized by an inability of hemoglobin (which gets oxidized into methemoglobin) to bind (and therefore carry) oxygen. Severe cases of this condition, if not treated, can be fatal.We describe a case of fatal self-poisoning with sodium nitrite; in particular, the article focuses on the autoptic and toxicological investigations that enabled the correct diagnosis to be established.
Sickle cell disease (SCD) is an inherited medical condition where sickled red blood cells cause vaso-occlusive crises. One major complication of SCD is priapism, defined as an erection of the penis lasting over four hours beyond sexual stimulation or orgasm. SCD priapism is caused by sickled erythrocytes obstructing venous outflow and can lead to permanent erectile dysfunction. This article reviews the pathology, physiology, and management of SCD priapism, including potential novel therapeutic agents.
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Methemoglobinemia (MetHb) can be a deadly condition at certain levels, presenting in a fulminant form of cyanosis or disguising itself with vague symptoms. Methemoglobinemia is an altered state of the body's hemoglobin, which can be congenital or acquired. We report a case of a 62-year-old male who presented with altered mental status and hypoxia after consuming "Jungle Juice", raising concern for methemoglobinemia. A diagnosis of methemoglobinemia was confirmed with arterial blood gas and guidance from New York State poison control. The patient was adequately treated with the antidote methylene blue with a resolution of symptoms. We highlight that methemoglobinemia can present itself in various forms and that early recognition and treatment can prevent fatal outcomes.
Methemoglobinemia occurs as iron in heme is oxidized to its ferric state, resulting in a decreased ability of hemoglobin to bind and release oxygen. Rasburicase is a recombinant urate-oxidase enzyme used in the prevention of tumor lysis syndrome. Methemoglobinemia can occur as a rare complication of treatment with rasburicase, primarily in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Methylene blue, an agent used for treating methemoglobinemia, should be avoided in patients with G6PD deficiency. In patients with G6PD deficiency, methylene blue is inadequately reduced to its active form, which then causes the methylene blue to further the oxidize the hemoglobin to methemoglobin that can result in hemolysis.
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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.
The activity of glutathione peroxidase (GSH Px), glucose-6-phosphate dehydrogenase (G-6-PD), hexokinase, and glutamic oxaloacetic transaminase (EGOT) was measured in 78 blood samples. GSH Px activity was not found to correlate with hexokinase or EGOT activity, indicating that it was not a strongly age-dependent enzyme. Although modest elevations of GSH Px activity were observed in the red cells of patients with a variety of hematologic disorders, the most consistent and striking increases in activity were observed in G-6-PD-deficient subjects.
It has long been recognized that certain ordinarily salutary drugs may produce an acute hemolytic anemia in some susceptible individuals. The 8-aminoquinoline antimalarial, pamaquine (plasmoquine), was such a medication. It was the investigation of the hemolytic effect of pamaquine and its derivatives which led to the recognition that hereditary red cell enzyme deficiencies could produce hemolytic disease.
1In erythrocytes of man and rabbits methylene blue catalysis is limited by the following factors at the pH optimum 7.5; primarily by the cellular concentration of NADP+, next by that of glucose-6-P. Possible further limiting steps are glucose-6-phosphate dehydrogenase, phosphogluconate dehydrogenase and reduced-NADP dehydrogenase.2Calculation of the intracellular NADP+ concentration with the two-substrate equation for the glucose-6-phosphate dehydrogenase-reaction does not yield reasonable results. The existence of inhibiting factors of the methylene blue catalysis is postulated. Their amount is presumably lower in intact cells as compared with hemolysates.3There is no pH dependence of the glucose-6-P concentration in presence of methylene blue. There exists a competition between the oxidative pentose-phosphate-pathway and the Embden-Meyerhof pathway, in which the phosphofructokinase plays a key role.4The proportions of the two pathways at different pH values are calculated from data on oxygen and glucose consumption. At pH values below 7.6 glucose is utilized practically exclusively via the oxidative pentose phosphate pathway, whereas the Embden-Meyerhof pathway is inhibited. At pH 8.2 the participation of the oxidative pentose-phosphate pathway amounts to 40% of the total glucose utilization, while the Embden-Meyerhof pathway is little if any reduced as compared to cells without methylene blue.5With increased degree of oxidation of the pyridine nucleotides there occur decreases in the levels of hexose- and triose-phosphates. With these changes and the decreased flow to lactate an increased formation of 2,3-diphosphoglycerate occurs.
This fifth edition is a timely and welcome one because of recent management changes in the treatment of acute poisoning. The routine use of syrup of ipecac as the primary household emetic has been supplanted by immediately calling the Poison Control Center, which may then recommend ipecac or, more likely, other measures and actions. General management of poisoning and overdoses is more important than the use of specific antidotes. Nevertheless, important antidotes or antagonists are still useful and recommended for special situations. Each chapter ends with an in-depth discussion of the relevant antidotes for the particular type of poison. I particularly enjoyed the historical account of the "birth" of the Poison Control Center concept and movement, since I was a member of the first Accident Prevention Committee of the American Academy of Pediatrics when it made the survey of its 3000 members in 1952 seeking the most prevalent childhood accident.
A Japanese man with cytochrome b5 reductase (b5R) deficiency in various blood cell lineages (red cells, platelets, and lymphocytes) and in cultured fibroblasts demonstrated congenital methemoglobinemia associated with mental and neurological retardation, and various skeletal anomalies, such as spondylosis deformans and finger joint deformations, which have never been described in association with this enzyme deficiency. Cytochrome b5 reductase deficiency was most severe in red cells (0.3-4%) and less marked in platelets (13-27%), lymphocytes (18-31%), and fibroblasts (50%). The present case appears to be a new variant of cytochrome b5 reductase deficiency (b5RKurashiki).
1. We have utilized a two compartment system in which two teflon chambers are separated by a semi-permeable membrane in order to investigate the role of metabolism in dapsone-induced methaemoglobinaemia. Compartment A contained a drug metabolizing system (microsomes prepared from human liver +/- NADPH), whilst compartment B contained target cells (human red cells). 2. Incubation of dapsone (1-100 microM) with human liver microsomes (2 mg protein) and NADPH (1 mM) in compartment A (final volume 500 microliters) led to a concentration-dependent increase in the methaemoglobinaemia (15.4-18.9% at 100 microM) compared with control (2.3 +/- 0.4%) detected in the red cells within compartment B. In the absence of NADPH dapsone had no effect. 3. Of the putative dapsone metabolites investigated, only dapsone-hydroxylamine caused methaemoglobin formation in the absence of NADPH (40.6 +/- 6.3% with 100 microM). However, methaemoglobin was also detected when monoacetyl-dapsone, 4-amino-4'-nitro-diphenylsulphone and 4-aminoacetyl-4'-nitro-diphenylsulphone were incubated with human liver microsomes in the presence of NADPH. 4 Dapsone-dependent methaemoglobin formation was inhibited by addition of ketoconazole (1-1000 microM) to compartment A, with IC50 values of 285 and 806 microM for the two liver microsomal samples studied. In contrast, methaemoglobin formation was not inhibited by cimetidine or a number of drugs pharmacologically-related to dapsone. The presence of glutathione or ascorbate (500 microM) did not alter the level of methaemoglobin observed.