ISJ 2: 152-158, 2005 ISSN 1824-307X
Insights into brown spider and loxoscelism
, R Bertoni da Silveira
, W Gremski
, SS Veiga
Department of Cell Biology, Federal University of Paraná, Jardim das Américas, Curitiba, Paraná , Brazil
Catholic University of Paraná, Health and Biological Sciences Institute, Curitiba, Paraná Brazil
Department of Biochemistry, Federal University of São Paulo, São Paulo, Brazil
Accepted December 27, 2005
Loxosceles is a genus of cosmopolitan spiders comprising several species, and popularly known
as brown spiders or brown recluses. Brown spider bites can cause dermonecrotic lesions and
systemic reactions known as loxoscelism. Systemic effects are less common but may be severe or
even fatal in some patients. Systemic manifestations include intravascular hemolysis, disseminated
intravascular coagulation and acute renal failure. A rapid diagnosis and an understanding of the
venom’s molecular activity are crucial for satisfactory treatment. Mechanisms by which venoms exert
their deleterious effects are under investigation, and searches are underway for diagnostic
envenomation assays. Molecular biology is being used to produce quantities of several of the most
important venom molecules and has contributed to the study and understanding of their mechanisms
Key words: brown spider; loxoscelism; venom; recombinant toxins; dermonecrosis
More than 40,000 spider species exist, with
probably 100,000 to be described, but only 3 taxa are
recognized as dangerous, namely Theridiidae,
Loxoscelidae and Ctenidae. Moreover, only the
genera Atrax, Lactrodectus and Loxosceles are
associated with human deaths (Escoubas et al., 2000;
Rash and Hodgson, 2002). Early European tales
during the Middle Ages linked injuries or illness to
spider bites (Schienle et al., 2005). For example the
tarantula bite was associated with a disease
(tarantism) for which the cure was a frenetic dancing
for 3-4 days. This energetic dance, called tarantella, is
now a typical Italian dance (Isbister, 2004). Today, as
a consequence of mistaken diagnoses of spider bites,
scientists are looking for methods to characterize and
identify spider bites and their manifestations as well
as to better understand the biological and molecular
Silvio S. Veiga
Department of Cell Biology, Federal University of Paraná,
Jardim das Américas,81531-990, Curitiba, Paraná,
mechanisms of envenomation.
The genus Loxosceles (variously known as the
brown spider, brown recluse, fiddleback, or gaucho
spiders) is important in these studies because of its
commonness in and around human dwellings. Their
bite is characterized by dermonecrosis and systemic
effects known as loxoscelism (Hogan et al., 2004).
The first case of documented loxoscelism
occurred in 1879 in Tennessee. However, consistent
data traced back about 50 years ago and were
collected in Chile, then other observations were made
in Brazil followed by the United States. These reports
linked brown spider bite with necrotic skin lesions
(Macchiavello, 1947; Atkin et al., 1958; Sams et al.,
2001). Spiders’ habits have caused a close
association with humans, and the number of bites is
increasing and has become a public health problem in
Brazil, Chile and the United States (da Silva et al.,
2004). Most bites occur during sleep or dressing, and
women are bitten more often than men. Thighs, trunk,
hands and arms are more often bitten (Hogan et al.,
Loxosceles spiders are known as violin
(fiddleback) spiders due to a characteristic violin
shape on their cephalothorax (Futrell, 1992). They are
also known as brown spiders because their colour
varies from a pale (L. laeta) to a dark brown (L.
gaucho). Loxosceles body length ranges from 8 to 15
mm with legs measuring from 8 to 30 mm (da Silva et
al., 2004). They are sedentary and nocturnal (Andrade
et al., 1999) with a lifetime of 3 – 7 years (Andrade et
al., 2000). Brown spiders have three pairs of eyes (an
important characteristic useful to identify the genus)
(Vetter and Visscher, 1998). They build irregular,
cottony webs (Futrell, 1992) and normally prefer dead
scavenged prey rather than live preys (Sandidge,
2003). They can survive months without food or water
and withstand temperatures ranging from 8 °C to 43
°C. They are not aggressive and prefer dark dry
places (Futrell, 1992; Málaque et al., 2002; Vetter and
Barger, 2002; da Silva et al., 2004). The sexes
produce venom with differences in volume, toxicity
and compounds proportion (Oliveira et. al., 1999).
Comparative analysis of sex and species in L. laeta
and L. intermedia venom showed some biological
activities (complement-dependent hemolysis and
dermonecrosis) more prominent in venom from female
spiders, especially from L. laeta (Oliveira et al., 2005).
Loxosceles spiders can be found distributed all
over the world. In North America, the most important
species are L. reclusa, L. deserta, L arizona, L.
rufences (United States and Mexico) and L. laeta
(Canada) (Sams et al., 2001; Vetter and Bush,
2002a). Europe, Africa, Middle East, some parts of
Asia, Israel, and Australia are hosts to some
Loxosceles species (Futrell, 1992; Borkkan et al.,
1995; Young and Pincus, 2001; Nicholson and
In Brazil, seven species have been described but
three are the most implicated in human bites L.
intermedia, L. gaucho and L. laeta (Sezerino et al.,
1998). From 1990 to 1993, the Brazilian Ministry of
Health received 17.781 reports of spiders’ bites, of
which 36 % were due to Loxosceles (Sezerino et al.,
1998). In the metropolitan area of Curitiba, in the state
of Parana (southern Brazil) about 3.000 brown spider
bites are reported annually (Málaque et al., 2002). In
a retrospective study in Florianopolis, in the state of
Santa Catarina, Brazil, 487 suspected cases of brown
spider bites were found, 267 of which fulfilled the
criteria for inclusion in the study (Sezerino et al.,
1998). In 359 cases of loxoscelism between January
1985 and December 1996 at Butantan Intitute, São
Paulo, Brazil, 14 % of patients captured the spiders so
that 28 were classified as L. gaucho, 5 as L. laeta and
18 as non-classified Loxosceles (Málaque et al.,
2002). More bites occur in warmer months (Schenone,
1996). In Curitiba, from 1998 to 2001 the incidence of
Loxosceles bites was 1.4 cases per 1,000 habitants.
Of these, 23 % were in the thigh, 16.7 % in the trunk,
14 % in the arm and 13 % in the lower leg. Only 1 %
of cases were severe (Health Secretary, Curitiba,
Parana, Brazil, 2002).
Pathophysiology of Loxoscelism
Dermonecrosis is the hallmark of loxoscelism
(Fig. 1). Histopathology and clinical data are obtained
from biopsies of human patients after brown spider
bites. Rabbit skin artificially injected with Loxosceles
venom is used for more controlled investigation since
this animal model reproduces human skin lesions that
follow envenomation (Ospedal et al., 2002). Systemic
effects, such as renal failure, are less common and
are usually reproduced in mouse (Luciano et al.,
2004). Observation of human skin biopsies showed an
inflammatory infiltrate, thrombosis, hemorrhage,
dermatitis, erythema, induration of affected area and
liquefactive necrosis of the epidermis and dermis
consistent with pyoderma grangrenosum (Futrell,
1992; Yannias and Winkelmann, 1992). Symptoms in
an experimental study in rabbits showed that after 4 h
oedema, hemorrhage, degeneration of blood vessel
walls, plasma exudation, thrombosis, neutrophil
accumulation in and around blood vessels with an
intensive diapedesis, a diffuse collection of
inflammatory cells (polymorphonuclear leucocytes) in
the dermis, and subcutaneous muscular oedema all
occur. Over the following hours and up to 5 days after
envenomation, the changes progressed to a massive
neutrophil infiltration into the dermis and even into
subcutaneous muscle tissue, destruction of blood
vessels, thrombosis, hemorrhage, myonecrosis, and
coagulative necrosis on the 5
day (Ospedal et al.,
2002). Neutrophil participation and the inflammatory
response seem to be dependent on an endothelial cell
agonist effect triggered by the venom that leads to an
indirect and dysregulated neutrophil activation
involved in dermonecrosis (Patel, 1994).
Envenomation of rabbit skin with L. reclusa venom
after 14 days results in a mixed inflammatory cell
infiltrate, coagulative tissue necrosis, vasculitis and a
dense band of neutrophils bordering the zone of
necrosis (Elston et al., 2000). L. intermedia venom
damaged vessel endothelia, as shown by vessel
instability, endothelium cell vacuolization in biopsies of
rabbit skin (Veiga et al., 2001a; Zanetti et.al., 2002). In
vitro experiments on rabbit aorta endothelium cell
cultures showed cytotoxicity of L. intermedia venom
associated with loss of cell adhesion to the culture
substrate and the shedding of proteoglycans from the
extracellular matrix and cell surface into the medium
(Veiga et al., 2001a). In human umbilical vein
endothelial cell (HUVEC) cultures treated with L.
reclusa venom, agonist activity ensued, inducing
endothelial cell expression of E-selectin and the
release of interleukin (IL)-8 and granulocyte
macrophage colony-stimulating factor, resulting in
dysregulated inflammatory response (Patel et al.,
1994). HUVEC exposed to L. deserta venom produced
IL-8, growth-related oncogene-α and monocyte
chemoattractant protein-1 via an NF-κB- dependent
pathway (Desai et al., 1999; Gomez et al., 1999). L.
deserta venom induces the expression of vascular
endothelial growth factor (VEGF) in human
keratinocytes, suggesting that keratinocyte-derived
VEGF may contribute to vasodilatation, oedema and
erythema in brown spider envenomation (Desai et al.,
2000). Primary cultures of keratinocytes exposed to
100 ng/ml of L. gaucho venom release tumour
necrosis factor (TNF)-α into the medium after 6 h
(Málaque et al., 1999).
Mice injected with L. reclusa venom developed
local hemorrhage after 6 h accompanied by blistering
of the ear skin (Sunderkötter et al., 2001).
Fig. 1 Cellular and molecular aspects of brown spider and loxoscelism. (A) Loxosceles intermedia (brown spider)
male. (B) L. intermedia (brown spider) female. (C) SDS-PAGE 3-20 % venom profile stained by Coomassie blue
dye. (D) Dermonecrotic lesion on rabbit skin after 24 h post-L. intermedia venom (10 µg) exposure. Arrowhead
indicates the site of venom injection with characteristic black and white eschar named marble plate. Black arrow
points an erythema surrounding the lesion and white arrow shows the gravitational spreading of lesion (a hallmark
of dermonecrotic loxoscelism). (E) Microscopical view of dermonecrotic lesion showing inflammatory leukocytes
accumulated in the connective tissue (arrowhead) and disorganization of collagen fiber and oedema (black arrow)
(magnification 400X). The inset shows inflammatory cells of the infiltrate represented by neutrophils (white arrow)
Histopathology showed a vasculitis reaction 2 h
after exposure. The microscopical analysis of some
mouse organs injected with different doses of L.
intermedia venom revealed remarkable kidney
alterations. Acute tubular necrosis accompanied by
deposition of eosinophilic material inside the proximal
and distal renal tubules was seen in several nephrons
(Tambourgi et.al., 1998). Mouse kidneys, treated with
L. intermedia venom showed hyalinisation and
erythrocytes in the Bowman’s space, glomerular
collapse, tubular epithelial cell cytotoxicity and
deposition of eosinophilic material within the tubular
lumen (Luciano et al., 2004). Confocal microscopy
observations of double staining immunofluorescence
against type IV collagen or laminin and L. intermedia
venom showed that toxins deposit and bind along the
tubular and glomerular basement membrane of mice
kidneys. Ultrastructural observations showed
glomerular epithelial and endothelial cell cytotoxicity,
the collapse and destruction of glomerular basement
membrane and tubular epithelial cell degeneration.
The basement membrane is a target for brown spider
venom, as shown administrating L. intermedia venom
to murine tumor Engelbreth-Holm-Swarm (EHS),
which is rich in basement membrane molecules. L.
intermedia venom degraded and fragmented the
basement membrane (Veiga et.al., 2000a). Venom
displays hydrolytic activity for entactin and heparan
sulphate proteoglycan, two important constituents of
basement membranes, while having no apparent
activity on purified type IV collagen and laminin (Veiga
et al., 2000a, 2001a,b).
In the bone marrow and peripheral blood cells, L.
intermedia initially causes a decrease in the number
of nucleated red cells, bone-marrow depression of
megakariocytes with thrombocytopenia in peripheral
blood and decrease of platelet count (da Silva et al.,
2003). Neutropenia in peripheral blood and low
neutrophil counts were observed as consequence of
bone-marrow depletion, which may reflect an
extensive neutrophil influx to the tissues. Eosinophils
are apparently unaffected.
Brown spider venom toxins
L. intermedia and L. laeta have different protein
patterns of glycosylation and the same is between
sexes of the same species (Oliveira et al., 2005).
Hemolytic and dermonecrotic activities have been
described for L. similes venom. Sphingomyelinase D
molecules, with molecular mass ranging from 30 to 35
kDa and having hemolytic, necrotic and platelet
aggregation activity were found in L. reclusa, L.
rufescens, L. gaucho, L. laeta and L. intermedia
venoms (Futrell 1992; Barbaro et al., 1994; Mota and
Barbaro, 1995; Tambourgi et al., 1995; Barbaro et al.,
1996a,b, 1997). Three sphingomyelinase D isoforms
were purified from L. boneti venom (Lb1, Lb2 and
Lb3). Only Lb1 and Lb2 had dermonecrotic activity
(Ramos-Cerrillo et al., 2004). An alkaline phosphatase
was described in L. reclusa venom (Futrell, 1992).
Hyaluronidase (32.5 kDa) was found in L. refescens
and L. reclusa (Futrell, 1992; Young and Pincus,
2001). L. deserta, L. gaucho, L. intermedia, L. laeta
and L. reclusa venoms contained an enzyme of
similar molecular size (44 kDa), which digested
hyaluronic acid (Barbaro et al., 2005). A 5’-
ribonucleotide phosphohydrolase was found in L.
reclusa venom (Futrell 1992). Loxnecrogin A (31.4
kDa) and Loxnecrogin B (31.6 kDa) with necrotic
activity on rabbit skin were found in L. gaucho venom
(Cunha et al., 2003). L. intermedia has a range of
proteases described in its venom: Loxolysin A (20-28
kDa) with fibronectinolytic and fibrinogenolytic activity;
Loxolysin B (32-35 kDa) with gelatinolytic activity
(Feitosa et al., 1998); a serin protease (85 kDa) with
gelatinolytic activity (Veiga et.al., 2000b) and
proteases able to hydrolyse entactin, heparan
sulphate proteoglican and basement membrane
(Veiga et al., 2000b, 2001a,b). L. rufescens also has a
broad molecular range of caseinolytic, gelatinolytic
and fibrogenolytic metalloproteases (Young and
Pincus, 2001). To test whether proteases in L.
intermedia venom were due to natural constitution and
not a digest fluid contamination, da Silveira et al.,
(2002) compared the proteolytic activity of the venom
obtained directly from venom glands with that
obtained by electroshock. Both protein profiles
showed very similar electrophoretic and enzymatic
At present, a new generation of molecules
developed through cloning techniques is under study.
L. intermedia LiD1 recombinant protein (31.4 kDa) is a
sphingomyelinase D family molecule without
dermonecrotic activity but with antigenic activity
(Kalapothakis et al., 2002). L. laeta recombinant
protein (33 kDa) is a sphingomyelinase isoform able to
degrade sphingomyelin (Pedrosa et al., 2002). This
recombinant protein induced complement
susceptibility, release of glycophorins and had
dermonecrotic activity. L. intermedia recombinant
protein (LiRecDT, 34 kDa) has dermonecrotic activity
and was able to directly induce nephrotoxicity in mice
(Chaim et al., 2005). L. laeta recombinant
phospholipase D generated lysophosphatidic acid and
was hemolytic (Lee and Lynch, 2005).
Clinical features, diagnosis and treatment of
brown spider bites
Diagnosis of loxoscelism is rarely based on spider
identification and therefore clinical features,
epidemiological and historical findings must be well
known (Wright et al., 1997; Vetter, 1999; Málaque et
al., 2002). Lesion recovery improves once the patient
is treated. However, brown recluse bites have been
misdiagnosed in North America because they
occurred in regions of non-endemicity (Vetter, 1999;
Nishioka, 2001; Vetter and Barger, 2002; Vetter and
Bush, 2002a,b; Vetter et al., 2003). A typical necrotic
skin lesion begins soon after the spider bites the
victim, followed by gravitational spreading (da Silva et
al., 2004). The bite is painless, hence the patient is
often unaware that he has been bitten (Futrell, 1992),
and the delay between the bite and when the victim
pursues help makes the treatment less effective. From
mild to severe pain begins 2-8 h after the bite. At the
bite a small puncture wound may appear, associated
with transient erythema with itching and swelling and
mild to severe tenderness (Futrell, 1992; da Silva et
al., 2004). Blebs or blisters appear (12-24 h), may
become hemorrhagic, and surrounded by a halo of
ischemic tissue. In the following days, necrotized
lesions become a dull blue-violet, the area of the
gravitational spread turns blue, and the size of the
blue area increases. Within three to seven days an
eschar may form, after which the lesion hardens. The
eschar may drop off leaving an ulcer that may require
a skin graft (Schenone, 1996; Sezerino et al., 1998;
Málaque et al., 2002; da Silva et al., 2004).
Success of therapy depends upon a correct and
rapid diagnosis, the volume of the venom injected, and
the patient susceptibility to the venom (Futrell, 1992;
da Silva et al., 2004). Phentolamine, heparin, topical
nitro-glycerine, cyproheptadine and hyperbaric
oxygenation have been used for therapy, but the
efficacy of these therapies is inconclusive and their
use is not recommended (Futrell, 1992; Wendell,
2003; da Silva et al., 2004). The established therapy is
dapsone, acetylsalicylic acid (aspirin), antibiotics
(erythromycin and cephalosporin), ice and elevation,
avoidance of strenuous activity and heat and, when
necessary, surgery. Early surgical excision has not
been shown to be effective and often delays healing
(Futrell, 1992; Merigian and Blaho, 1996; Goddard,
1998, Monteiro et al., 2002; da Silva et al., 2004).
Serum anti-Loxosceles venom is used only in severe
cases and effectiveness is doubtful especially against
local manifestation. Systemic envenomation studies in
animals and humans have demonstrated that
antivenom neutralizes the deleterious effects of the
venom and reduces paediatric mortality (Isbister et al.,
2003). Effectiveness of antivenom to prevent
dermonecrotic lesions seems to be time dependent
and usually patient looks for medical help 4 h after the
bite when lesions is already established (Ospedal et
al., 2002; Nicholson and Graudins, 2003). Some local
and systemic noxious activities of the venom are
attributed to proteolytic toxins that degrade fibrinogen,
fibronectin, entactin and heparan sulphate
proteoglycan and disrupt basement membrane
structures, thereby causing local hemorrhage,
gravitational spreading, disseminated intravascular
coagulation and renal failure (Feitosa, et al., 1998;
Veiga et al., 1999, 2000b, 2001a,b; Luciano et al.,
2004; Chaim et al., 2005).
Biotechnological products from brown spider
Recently developed technologies are being used
to produce biotechnological products from Loxosceles
venom. ARACHnase (Hemostasis Diagnosis
International Co., Denver, CO, USA), normal plasma
containing L. reclusa venom, mimics a lupus
anticoagulant and may provide a positive control for
anticoagulant testing (McGlasson et al., 1993). An
antiserum against venoms of L. gaucho, Phoneutria
nigriventer, Tityus serrulatus, and Tityus bahiensis
that reacts with L. intermedia and L. laeta toxins is
produced by The Butantan Institute, São Paulo, Brazil.
The CCPI (Production Center of Immunobiologic
Products, Parana, Brazil) has also produced
antiserum using L. intermedia venom that is able to
neutralize some activities of Loxosceles venom. L.
laeta antiserum is produced by the National Institute
of Health (Peru) (da Silva et al., 2004). These antisera
have all been used as bioproducts for serum therapy
(Roodt et al., 2002; Barbaro et al., 1994; 1996a;
Health Secretary, Curitiba, Parana, Brazil). Guilherme
et al. (2001) produced monoclonal antibodies
recognising L. gaucho venom toxins, which were able
to neutralize the dermonecrotic effect and lethal
activities of this species venom but not those of
Monoclonal and polyclonal antibodies are not
only powerful tools for neutralizing the effects of
venom; they are also useful for research. They can be
used to purify toxins from venom by affinity
chromatography. They can be used on location of
specific toxins on cell and tissue treated with venom
toxins. Immunofluorescence techniques such as
confocal microscopy and flow cytometry are modern
techniques based on antibody specific binding.
In contrast to the collection of snake venom,
spiders provide very little venom, which limits the
ability to study spider venom toxins. Protein cloning
techniques are helping to solve this problem. After
cloning it is possible to have milligrams of the same
protein thereby improving the quality of research work
and allowing more controlled experimental studies.
Today several spider venom recombinant proteins are
under investigation most of which are in the
sphingomyelinase protein family (Kalapothakis et al.,
2002; Pedrosa et al., 2002; Chaim et al., 2005).
Toxins from Loxosceles spiders are a group of
proteins with a great range of different activities. Each
toxin may be used to investigate molecular and
cellular effects of venom. Also each of these proteins
is a putative molecular model for drug design and to
develop knowledge on some effects not yet fully
understood such as the inflammatory reaction of
dermonecrosis and platelet aggregation.
This work was supported by CNPq, CAPES,
Fundação Araucária and Secretaria de Estado de
Ciência, Tecnologia e Ensino Superior do Parana,
Andrade RMG, Oliveira KC, Giusti AL, Silva WD, Tambourgi
DV. Ontogenetic development of Loxosceles intermedia
spider venom. Toxicon 37: 627-632, 1999.
Andrade RMG, Lourenço WR, Tambourgi DV. Comparison of
the fertility between Loxosceles intermedia and
Loxosceles laeta spiders. J. Arachnol. 28: 245-247,
Atkin JA, Wingo CW, Sodeman WA, Flynn JE. Necrotic
arachnidism. Am. J. Trop. Med. 7: 165-184, 1958.
Barbaro KC, Eickstedt VRD, Mota I. Antigenic cross-reactivity
of venoms from medically important Loxosceles
(Araneae) species in Brazil. Toxicon 32: 113-120, 1994.
Barbaro KC, Ferreira ML, Cardoso DF, Eickstedt VRD, Mota
I. Identification and neutralization of biological activities
in venoms of Loxosceles spiders. Braz. J. Med. Biol.
Res. 29: 1491-1497, 1996a.
Barbaro KC, Souza MV, Morhy L, Eickstedt VRD, Mota I.
Compared chemical properties of dermonecrotic and
lethal toxins from spiders of genus Loxosceles
(Araneae). J. Protein Chem. 15: 337-343, 1996b.
Barbaro KC, Ferreira ML, Cardoso DF, Souza MV, Morhy L,
Eickstedt VRD, Mota I. Study of Loxosceles spider
venom. J. Ven. Anim. Toxins 3: 232, 1997.
Barbaro KC, Knysak I, Martins R, Hogan C, Winkel K.
Enzymatic characterization, antigenic cross-reactivity
and neutralization of dermonecrotic activity of five
Loxosceles spider venoms of medical importance in the
Americas. Toxicon 45: 489-499, 2005.
Borkkan J, Gross E, Lubin Y, Oryan I. An outbreak of
venomous spider bites in a citrus grove. Am. J. Trop.
Med. Hyg. 52: 228-230, 1995.
Chaim OM, Sade YB, da Silveira RB, Toma L, Kalapothakis
E, Cháves-Olórtegui C, Mangili OC, Gremski W, Dietrich
CP, Nader HB, Veiga SS. Brown spider dermonecrotic
toxin directly induces nephrotoxicity. Toxicol. App.
Pharmacol. 2006 (in press).
Cohen N, Sarafian DA, Alon I, Gorelik O, Zaidenstein R
Simantov R, Blatt A, Litinsky I, Modai D, Golik A.
Dermonecrotic loxoscelism in the Mediterranean region.
J. Toxicol. Cut. Ocul. Toxicol. 18: 75-83, 1999.
Cunha RB, Barbaro KC, Muramatsu D, Portaro FCV, Fontes
W, Sousa MV. Purification and characterization of
Loxnecrogin, a dermonecrotic toxin from Loxosceles
gaucho brown spider venom. J. Prot. Chem. 22: 135-
da Silva PH, Hashimoto Y, Santos FA, Mangili OC, Gremski
W, Veiga SS. Hematological cell findings in bone
marrow and peripheral blood of rabbits after
experimental acute exposure to Loxosceles intermedia
(brown spider) venom. Toxicon 42: 155-161, 2003.
da Silva PH, da Silveira RB, Appel MH, Mangili OC, Gremski
W, Veiga SS. Brown spider and loxoscelism. Toxicon
44: 693-709, 2004.
da Silveira RB, Filho JFS, Mangili OC, Veiga SS, Gremski W,
Nader HB, Dietrich CP. Identification of proteases in the
extract of venom glands from brown spiders. Toxicon
40: 815-822, 2002.
Desai A, Miller,MJ, Gomez HF, Warren JS, Loxosceles
deserta spider venom induces NF-κB-dependent
chemokine production by endothelial cells. Clin. Toxicol.
37: 447-456, 1999.
Desai A, Lankford HA, Warren JS. Loxosceles deserta spider
venom induces the expression of vascular endothelial
growth factor (VEGF) in keratinocytes. Inflammation 24:
Elston DM, Eggers JS, Schmidt WE, Storrow AB, Doe RH,
McGlasson D, Fischer JR. Histological findings after
brown recluse spider envenomation. Am. J.
Dermatopathol. 22: 242-246, 2000.
Escoubas P, Diochot S, Corzo G. Structure and
pharmacology of spider venom neurotoxins. Biochimie
82: 893-907, 2000.
Feitosa L, Gremski W, Veiga SS, Elias MCQB, Graner E,
Mangili OC, Brentani RR. Detection and
characterization of metalloproteinases with gelatinolytic,
fibronectinolytic and fibrinogenolytic activities in brown
spider (Loxosceles intermedia) venom. Toxicon 36:
Futrell J. Loxocelism. Am. J. Med. Sci. 304: 261-267, 1992.
Goddard J. Loxoscelism. N. Engl. J. Med. 339: 1944-1945,
Gomez HF, Miller MJ, Desai A, Warren JS. Loxosceles
spider venom induces the production of alpha and beta
chemokines: implications for the pathogenesis of
dermonecrotic arachnidism. Inflammation 23: 207-2015,
Guilherme P, Fernandes I, Barbaro KC. Neutralization of
dermonecrotic and lethal activities and differences
among 32-35kDa toxins of medically important
Loxosceles spider venoms in Brazil revealed by
monoclonal antibodies. Toxicon 39: 1333-1342, 2001.
Hogan C, Barbaro KC, Winkel K. Loxoscelism: old obstacles,
new directions. Ann. Emerg. Med. 44: 608-624, 2004.
Isbister Gk, Graudins A, White J, Warrell D. Antivenom
treatment in arachnidism. J. Toxicol. Clin. Toxicol. 41:
Isbister GK. Necrotic arachnidism: the mythology of a
modern plague. Lancet 364: 549-553, 2004.
Isbister GK, Vetter RS. Loxoscelism and necrotic
arachnidism: More myths and minor corrections. Ann.
Emerg. Med. 46: 205-206, 2005.
Kalapothakis E, Araujo SC, Castro CS, Mendes TM, Gomez
MV, Mangili OC, Gubert IC, Chavez-Olórtegui C.
Molecular cloning, expression and immunological
properties of LiD1, a protein from the dermonecrotic
family of Loxosceles intermedia spider venom. Toxicon
40: 1691-1699, 2002
Lee S, Lynch KR. Brown recluse spider (Loxosceles reclusa )
venom phospholipase D (PLD) generates
lysophosphatidic acid (LPA). Biochem. J. 391: 317-323,
Luciano MN, Silva PH, Chaim OM, Santos VL, Franco CRC,
Soares MFS, Zanata SM, Mangili OC, Gremski W,
Veiga SS. Experimental evidence for a direct
cytotoxicity of Loxosceles intermedia (brown spider)
venom on renal tissue. J. Histochem. Cytochem. 52:
Macchiavello A. Cutaneous arachnidism or gangrenous spot
of Chile. Pub. Health Trop. Med. 22: 425-466, 1947.
Málaque CMS, Ori M, Santos SA, Andrade DR. Production
of TNF-α by primary cultures of human keratinocytes
challenged with Loxosceles gaucho venom. Rev. Inst.
Med. Trop. S. Paulo, 41, 1999.
Málaque CMS, Castro-Valencia JE, Cardoso JLC, França
FOS, Bárbaro KC, Fan HW. Clinical and
epidemiological features of definitive and presumed
loxoscelism in São Paulo, Brazil. Rev. Inst. Med. Trop.
S. Paulo, 44, 2002.
McGlasson DL, Babcock JL, Berg L, Triplett DA.
ARACHnase. An evaluation of a positive control for
platelet neutralization procedure testing with seven
commercial activated partial thromboplastin time
reagents. Am. J. Pathol. 100: 576-578, 1993.
Merigian KS, Blaho R. Envenomation from brown recluse
spider: review of mechanism and treatment options. Am.
J. Ther. 10: 724-734, 1996.
Monteiro CLB, Rubel R, Cogo LL, Mangili OC, Gremski W
Veiga SS. Isolation and identification of Clostridium
perfringens in the venom and fangs of Loxosceles
intermedia (brown spider): enhancement of the
dermonecrotic lesion in loxoscelism. Toxicon 40: 409-
Mota I, Barbaro KC. Biological and biochemical properties of
venom from medically important Loxosceles (Araneae)
species in Brazil. J. Toxicol. Tox. Rev. 14: 401-421,
Nicholson GM, Graudins A. Antivenoms for treatment of
spider envenomation. J. Toxicol. Tox. Rev. 22: 35-59,
Nishioka SA. Misdiagnosis of brown recluse spider bite.
West. J. Med. 174: 240, 2001.
Oliveira KC, Andrade RMG, Giusti AL, Silva WD, Tambourgi
DV. Sex-linked variation of Loxosceles intermedia spider
venoms. Toxicon 37: 217-221, 1999.
Oliveira KC, Andrade RMG, Piazza RMF, Ferreira JMC, van
den Berg CW, Tambourgi DV. Variations in Loxosceles
spider venom composition and toxicity contribute to the
severity of envenomation. Toxicon 45: 421-429, 2005.
Ospedal KZ, Appel MH, Neto JF, Mangili OC, Veiga SS,
Gremski W. Histopathological findings in rabbits after
experimental acute exposure to the Loxosceles
intermedia (brown spider) venom. Int. J. Exp. Pathol. 84:
Patel KD, Modur V, Zimmerman GA. The necrotic venom of
the brown recluse spider induces dysregulated
endothelial cell-dependent neutrophil activation:
differential induction of GM-CSF, IL-8, and E-selectin
expression. J. Clin. Invest. 94: 631-642, 1994.
Pedrosa MFF, Azevedo ILMJ, Andrade RMG, Berg CW,
Ramos CRR, Ho PL, Tambourgi DV. Molecular cloning
and expression of functional dermonecrotic and
haemolytic factor from Loxosceles laeta venom.
Biochem. Bioph. Res. Commun. 298: 638-645, 2002.
Ramos-Cerrillo B, Olvera A, Odell GV, Zamudio F, Paniagua-
Solis J, Alagón A, Stock RP. Genetic and enzymatic
characterization of sphingomyelinase D isoforms from
the North American fiddleback spiders Loxosceles
boneti and Loxosceles recluse. Toxicon 44: 507-514,
Roodt AR, Salomon, OD, Lloveras SC, Orduna TA. Poisoning
by spiders of Loxosceles genus. Medicina 62: 83-94,
Rash LD, Hodgson WC. Pharmacology and biochemistry of
spider venoms. Toxicon 40: 225-254, 2002.
Sams HH, Dunnick CA, Smith ML, King LE. Necrotic
arachnidism. J. Am. Acad. Dermatol. 44: 561-537, 2001.
Sandidge JS. Arachnology: scavenging by brown recluse
spiders. Nature 426: 30, 2003
Schenone H. Diagnosis in 1348 patients which consulted for
a probable spider bite or insect sting. Bol. Chil. Parasitol.
51: 20-27, 1996.
Schienle A, Schäfer A Walter B, Stark R, Vaitl D. Brain
activation of spider phobics towards disorder-relevant,
generally disgust- and fear-inducing pictures. Neurosci.
Lett. 388: 1-6, 2005.
Sezerino UM, Zannin M, Coelho LK, Gonçalves J, Grando M,
Mattosinho SG, Cardoso JLC, Eickstedt VR, França
FOS, Bárbaro KC, Fan HW. A clinical and
epidemiological study of Loxosceles spider envenoming
in Santa Catarina, Brazil. Trans. R. Soc. Trop. Med.
Hyg. 92: 546-548, 1998.
Sunderkötter C, Seeliger S, Schönlau F, Roth J, Hallmann R,
Luger TA, Sorg C, Kolde G. Different pathway leading to
cutaneous leukocytoclastic vasculitis in mice. Exp.
Dermatol. 10: 391-404, 2001.
Tambourgi DV, Magnoli FC, Eickstedt VRD, Benedetti ZC,
Petricevich VL, Silva WD. Incorporation of 35kDa
purified protein from Loxosceles intermedia spider
venom transforms human erythrocytes into activators of
autologous complement alternative pathway. J.
Immunol. 155: 4459-4466, 1995.
Tambourgi DV, Petricevich VL, Magnoli FC, Assaf SLMR,
Mancar S, Silva WD. Endotoxemic-like shock induced
by Loxosceles spider venoms: pathological changes
and putative mediators. Toxicon 36: 391-403, 1998.
Veiga SS Gremski W, Santos VLP, Feitosa L, Mangili OC,
Nader HB, Dietrich CP, Brentani RR. Oligosaccharide
residues of Loxosceles intermedia (brown spider)
venom proteins: dependence on glycosylation for
dermonecrotic activity. Toxicon 37: 587-607 1999.
Veiga SS, Feitosa L. Santos VLP, Souza GA, Ribeiro AS,
Mangili OC, Porcionatto MA, Nader HB, Dietrich CP,
Brentani RR, Gremski W. Effect of brown spider venom
on basement membrane structures. Histochem. J. 32:
Veiga SS, da Silveira RB, Dreyfuss JL, Haoach J, Pereira
AM, Mangili OC, Gremski W. Identification of high
molecular weight serine-proteases in Loxosceles
intermedia (brown spider) venom. Toxicon 38: 825-839,
Veiga SS, Zanetti VC, Franco CRC, Trindade ES,
Porcionatto MA, Mangili OC, Gremski W, Dietrich CP,
Nader HB. In vivo and in vitro cytotoxicity of brown
spider venom for blood vessel endothelial cells. Throm.
Res. 102: 229-237, 2001a.
Veiga SS, Zaneti VC, Braz A, Mangili OC, Gremski W.
Extracellular matrix molecules as target for brown spider
venom toxins. Braz. J. Med. Biol. Res. 34: 843-850,
Vetter RS. Identifying and misidentifying the brown recluse
spider. Dermatol. Online J. 5: 7, 1999.
Vetter RS, Barger DK. An infestation of 2,055 brown recluse
spiders (Araneae:Sicariidae) and no envenomation in a
Kansas home: implications for bite diagnoses in
nonendemic areas. J. Med. Entomol. 39: 948-951, 2002.
Vetter RS, Bush SP. Reports of presumptive brown recluse
spider reinforce improbable diagnosis in region of North
America where the spider is not endemic. Clin. Inf. Dis.
35: 442-445, 2002a.
Vetter RS, Bush SP. The diagnosis of brown recluse spider
bite is overused for dermonecrotic wounds of uncertain
etiology. Ann. Emerg. Med. 39: 544-546, 2002b.
Vetter RS, Cushing PE, Crawford RL, Royce LA. Diagnoses
of brown recluse spider bites (loxoscelism) greatly
outnumber actual verifications of spider in four western
American states. Toxicon 42: 413-418, 2003.
Vetter RS, Visscher PK. Bites and stings of medically
important venomous arthopods. Int. J. Dermatol. 37:
Wendell RP. Brown recluse spiders: a review to help guide
physicians in nonendemic areas. South. Med. J. 96:
Wright SW, Wrenn KD, Murray L, Seger D. Clinical
presentation and outcome of brown spider bite. Ann.
Emerg. Med. 30: 28-32, 1997.
Yannias JA, Winkelmann RK. Persistent painful plaque due
to a brown recluse spider bite. Cutis 50: 273-275, 1992.
Young AR, Pincus SJ. Comparison of enzymatic activity from
three species of necrotising arachnids in Australia:
Loxosceles rufescens, Badumma insignis and Lampona
cylindrata. Toxicon 39: 391-400, 2001.
Zanetti VC, da Silveira RB, Dreyfuss JL, Haoach J, Mangili
OC, Veiga SS, Gremski W. Morphological and
biochemical evidence of blood vessel damage and
fibrinogenolysis triggered by brown spider venom. Blood
Coag. Fibrin. 13: 135-148, 2002.