Unité des Venins, Institut Pasteur, Paris, Cedex 15, France
(G.R., V.C., B.S., C.B.), and
Laboratoire de Biomathématiques,
Université Paris 5, Faculté des Sciences Pharmaceutiques et
Biologiques, 75006 Paris, France (M.D.)
The mechanisms by which antivenom neutralizes the venom are still
poorly understood. In the present work, we studied the effects of
antivenom, constituted with either F(ab')2 or Fab, on the
processes of absorption and elimination of Vipera aspis
venom in experimentally envenomed rabbits. We first concluded from this
study that during the few hours after intramuscular injection, the
venom rapidly disappeared from the site of injection but did not
immediately reach the vascular system, suggesting that it is partly
absorbed via the lymphatic circulation. Concerning the
elimination process of the venom in the presence of antivenom, we
observed that the elimination of F(ab')2/venom complexes is
slower than that of free venom in the absence of antivenom but faster
than that of free F(ab')2, suggesting that
F(ab')2/venom complexes are eliminated by phagocytosis. The
Fab/venom complexes, on the other hand, are eliminated more slowly than
free Fab. These complexes are not eliminated through the renal route in
agreement with their high molecular weight. In addition, we observed
that the treatment of envenomed rabbits with antivenom made of Fab, but
not F(ab')2, is responsible for an oliguria that could be
responsible for clinical problems.
 |
Introduction |
Immunotherapy
performed with specific Fab fragments is widely used to reverse
digitalis (Smith et al., 1976
) or colchicine (Baud et
al., 1995) intoxications. These immunoglobulin fragments neutralize the toxicity of the toxic compounds by reducing their volume
of distribution due to their ability to form immunocomplexes and by
increasing their elimination through the renal route (Butler et
al., 1977; Sabouraud et al., 1992). Immunotherapy is
also widely used in the case of snake and scorpion envenomations (De
Rezende et al., 1995; Thomas et al., 1996). In
this case, most of the antivenoms are F(ab')2
prepared from horses hyperimmunized against the concerned venoms
(Theakston and Warrell, 1991). However, some authors recommend the use
of immunoaffinity purified sheep Fab (Consroe et al., 1995;
Rawat et al., 1994; Sjostrom et al., 1994), which
proved to be responsible for a lower rate of side effects than horse
F(ab')2 (Hickey et al., 1991; Smith
et al., 1992).
It has been recently shown in clinical and experimental studies
(Karlsonstiber et al., 1997; Rivière et
al., 1997), that specific Fab induce a more transient neutralizing
effect than F(ab')2 on the toxicity of the venom
mainly due to their shorter elimination half-life,
t1/2 = 4.3 hr compared with that of F(ab')2, t1/2 = 18 hr (Meyer et al., 1997). In agreement with the long
duration of snake venom envenomations (Audebert et al.,
1994), these results indicated that Fab fragments have to be reinjected
after a few hours to maintain their neutralizing action, whereas a
single injection of F(ab')2 neutralizes the venom
for a much longer time (up to several days). Thus, the efficacy of
specific venom Fab in treating envenomation is lower than that of
specific colchicine or digitalis Fab in treating intoxications. Moreover, the process of detoxification of the venom with specific Fab
seems to be different than when Fab is directed against digitalis or
colchicine.
In the present report, we examine the mechanisms by which specific
fragments of immunoglobulins [F(ab')2 or Fab]
detoxify the venom. We first determined the mechanism of absorption of the venom injected intramuscularly and the effect of the intravenous injection of antivenom on the venom absorption. We then analyzed the
effects of antivenom on the elimination process of Vipera aspis venom. Finally, we examined the interest of the
intramuscular route for the administration of antivenoms made of
F(ab')2 or Fab.
| |
Methods |
Detection of the venom and of antivenoms.
V.
aspis venom (Latoxan, Rosans, France) was
125I-iodinated according to the method of Fraker
and Speck (1978), as modified by Audebert et al. (1994).
Plasma concentrations of free venom were quantified using
double-sandwich ELISAs as described elsewhere (Rivière et
al., 1997). Briefly, specific V. aspis venom antibodies
from IPSER Europe antivenom were coated onto a microtiter plates (Nunc,
Roskilde, Denmark). After saturation of the wells with
phosphate-buffered saline containing 3% bovine serum albumin, samples
and scale diluted in nonenvenomated rabbit plasma were added to each
well. Antibodies conjugated with peroxidase were then added. After
incubation, the colored reaction was developed using
o-phenylenediamine dichloroamide (2 mg·ml
1) mixed with 0.06% of
H2O2. This procedure
permitted to detect only free venom in plasma. Total venom
concentrations were determined by counting the TCA-precipitable
fraction.
Immunoglobulin fragments [F(ab')2 or Fab] were
detected using double-sandwich enzyme-linked immunosorbent assay as
described previously (Rivière et al., 1997). Rabbit
anti-horse immunoglobulin antibodies were purchased from Biosys
(Compiègne, France). This test was set up to detect free or
complexed immunoglobulin fragments.
Preparation of Fab fragments.
Fab fragments were prepared as
described previously (Rivière et al., 1997). Control
experiments indicated that the proteolytic treatment does not modify
the affinity of the fragments for the venom components. In particular,
first, the protective effects of F(ab')2 and Fab,
determined by premixing with venom and testing the residual toxicity by
lethality assay, were identical. Second, an ELISA performed under
equilibrium conditions indicated that the venom complexation was
identical for F(ab')2 and Fab and that dissociation does not occur after a 1-hr incubation. Because of the
respective molecular weight of F(ab')2 and Fab,
100 and 50 kDa, respectively, the administration of the same quantity
of F(ab')2 or Fab leads to the injection of the
same number of binding sites. The doses of Fab and
F(ab')2 were therefore adjusted according to
their protein concentration.
Purification of specific anti-Vipera venom
F(ab')2 and Fab.
Specific
anti-Vipera venom F(ab')2 or Fab were
purified from IPSER Europe horse serum (Pasteur Mérieux
Sérums et Vaccins, Lyon, France) by immunoaffinity chromatography
on immunosorbent columns coupled with a mixture of V.
aspis, V. berus and V.
ammodytes venoms (Latoxan, Rosans, France), in equal
proportions, after the method of Avrameas and Ternynck (1969). Specific
fragments were eluted with 0.1 M HCl-glycine buffer, pH 3.
Detection of the venom at the site of injection.
The leg
muscles were dissected immediately after the death of the rabbit and
stored at 4°C until used. Muscles were homogenized in
phosphate-buffered saline using successively a Virtis instrument and a
Potter homogenizer. After filtration (cutoff, 100 µm), radioactivity was counted using liquid scintillation spectrometry (LS-6000-SC, Beckman).
Protein content was quantified using the procedure of Folin-Lowry
modified by Markwell et al. (1978). Briefly, a 200-µl
sample was mixed with a solution containing: 2% sodium bicarbonate,
0.4% sodium hydroxide, 0.16% sodium tartrate and 0.004% copper
sulfate (w/v). This mixture was incubated for 10 min at room
temperature, before addition of 60 µl of a 2-fold diluted solution of
Folin and Ciocalteu's Phenol Reagent (Sigma Chemical, St Louis, MO). Absorbance was measured at 660 nm after 45 min. Bovine serum albumin was used as a standard.
Pharmacokinetics.
All pharmacokinetic experiments were
conducted in accordance with the "Principles of Laboratory Animal
Care," as described previously (Rivière et al.,
1997). Briefly, New Zealand rabbits weighing 2.75 to 3 kg (CEGAV, St
Mars-d'Egrenne, France) were placed in metabolism cages that allow the
collection of urine and feces. Food and water were provided ad
libitum. Intravenous injections of the venom were administered in
the marginal vein of the ear over an 8-min period in a volume of 5 ml
of 0.15 M NaCl using a syringe pump (Bioblock, Illkirch, France). We
tested the effects of a high dose of antivenom (125 mg) injected
via the intravenous route 5 hr after an intravenous
injection of venom to study the effects of antivenom on the process of
elimination of the venom.
Intramuscular injections of the venom were performed in the leg in a
final volume of 500 µl of 0.15 M NaCl. Determination of the
pharmacokinetic parameters of Fab injected intramuscularly was done
after an injection performed in the leg in a final volume of 1 ml.
Blood was collected in heparinized tubes and centrifuged at 1500 × g for 15 min to obtain plasma.
Pharmacokinetic analysis of V. aspis venom injected
intravenously was done using the MK-Model software (Biosoft, Cambridge, England). The best-fit line was achieved with the least-squares method
using weighted function
(1/C2obs). We did not insert the
8-min period of infusion in the analysis because of the lack of
experimental points. The choice of a two- or three-compartment model
was decided according to the Schwarz criterion. The total body
clearance (ClT) was determined as equal to D/AUC,
with D being the injected dose, and AUC being the area under the time
vs. concentration curve, from injection to infinity. The
volume of distribution at steady state (Vdss) was
equal to D*AUMC/AUC2 and the mean residence time
was defined as AUMC/AUC, AUMC being the area under the first moment
vs. time curve.
The pharmacokinetic parameters of the F(ab')2 or
Fab complexes were determined as follows. Immunopurified antivenoms (1 mg) were injected intravenously 5 hr after intravenous injection of 250 µg·kg1 of V. aspis venom.
The delay of 5 hr was chosen to allow complete distribution of the
venom based on the pharmacokinetic parameters obtained using ELISA
quantification. Immunoglobulin fragments concentrations were determined
using ELISA as described above. The noncompartmental method was used to
analyze the pharmacokinetics of the complexes of
F(ab')2 or Fab with venom components. The AUC of
the total venom from injection of antivenom to infinity (AUC5
) was calculated using the
log-trapezoidal rule from time zero to the last experimental point and
from the last experimental point to infinity by extrapolation using
C/
, C being the concentration measured at the last experimental
point and being the terminal slope.
Statistics.
All measurements are expressed as mean ± S.E.M. The mean values were calculated from at least three independent
experiments. The significance of the data was analyzed by the
two-tailed unpaired or paired Student's t test. When
multiple comparisons were done, we used one-way analysis of variance
followed by Dunnett's or Bonferroni's procedure. The level of
significance was set at P < .05.
| |
Results |
Pharmacokinetics of V. aspis venom.
We first
determined the pharmacokinetic parameters of 125I
radiolabeled V. aspis venom after intravenous injection in
rabbits. For this purpose, we quantified the concentrations of plasma
venom by two methods: ELISA and radioactivity (fig.
1). With ELISA, the decrease in venom
concentration could be fitted with a biexponential decline, indicating
that the venom was distributed into two compartments with a terminal
half-life of 14.2 hr, in agreement with the value determined by
Audebert et al. (1994) with the same method. However, when
the venom concentrations were determined by counting the radioactivity,
we observed a triexponential decline, with a higher terminal half-life
of 27.2 hr, significantly different from that determined by ELISA
(P < .05). In fact, all pharmacokinetic parameters (terminal
half-life, Vdss and ClT)
differed statistically between the two methods of venom quantification
(table 1). Such a difference, which has
already been reported in a study where the venom was injected
via the intramuscular route (Rivière et
al., 1997), suggests a differential detection of some venom
proteins by ELISA and by radioactivity. In fact, Audebert et
al. (1994) have shown that all the venom proteins are not
125I-iodinated with the same specific
radioactivity and that they do not respond to ELISA with the same
intensity. On the other hand, it has been shown that iodination of
low-molecular-weight proteins (<80 kDa) could alter their
pharmacokinetics (Bauer et al., 1996; Kuo et al.,
1997). These differences, however, have no consequence on the further
interpretation of the results obtained in this investigation because
the two methods have been used independently to measure the extent of
redistribution or the pharmacokinetics of immune complexes in different
conditions. Moreover, when these data sets are considered together,
they yield a useful and complementary picture of the concentration-time
curves.
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Fig. 1.
Pharmacokinetics of 250 µg·kg1 of
radioactive V. aspis venom after an i.v. injection.
Concentrations of plasma venom were quantified either by ELISA
(-- --) or radioactivity (- - - -). Curves were drawn
using pharmacokinetic parameters obtained by model-dependent analysis.
Experimental values are the means ± S.E.M. of 5 independent
experiments.
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|
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TABLE 1
Pharmacokinetic parameters of Vipera aspis venom after
intravenous injection of 250 µg · kg1
Venom concentrations were determined by ELISA or radioactivity. Results
are expressed as mean ± S.E.M. of five independent experiments.
|
|
Influence of specific F(ab')2 or Fab
antibodies on the pharmacokinetics of V. aspis venom.
We first tested the effects of 125 mg of immunoglobulin fragments
[F(ab')2 or Fab] injected intravenously 5 hr
after an intravenous injection of 250 µg·kg1 of V. aspis venom on
the pharmacokinetic of the venom. In the case of
F(ab')2, no free venom was detectable by ELISA up
to 72 hr after venom administration (fig.
2A). This indicates that all the venom
antigens were immunocomplexed. Moreover, the AUC value, determined for
radioactive (free and immunocomplexed) venom from the time of antivenom
injection to infinity (AUC5), was
considerably higher than that calculated in the absence of antivenom (14,600 ± 450 compared with 3300 ± 300 ng·hr1·ml1·kg1,
respectively, P < .05). In contrast to this experiment performed with F(ab')2, free venom could be detected after
an injection of 125 mg of Fab under the same conditions (fig. 2B): the
concentration of free venom measured by ELISA immediately after
immunotherapy with Fab was ~10 ng·ml1.
The AUC5 value was higher than that
without antivenom (5000 ± 450 compared with 3300 ± 300 ng·hr1·ml1·kg1,
respectively, P < .05) but significantly (P < .05) lower
than that after the injection of F(ab')2
(5000 ± 450 and 14,600 ± 650 ng·hr1·ml1·kg1,
respectively).
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Fig. 2.
Effect of an i.v. injection of 125 mg of
F(ab')2 (A) or Fab (B) injected 5 h (arrows) after an i.v.
injection of 250 µg·kg1 of V. aspis venom.
Total venom concentrations (----) and free venom concentrations
(----) were determined up to 72 hr. Experimental values are the
means ± S.E.M. of 5 independent experiments.
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|
When V. aspis venom is injected via the
intramuscular route, the venom components undergo a slow resorption for
up to 72 hr, with an apparent terminal half-life of ~30 hr (Audebert
et al., 1994), and we have shown (Rivière et
al., 1997) that an intravenous injection of antivenom
[F(ab')2 or Fab] induced a substantial redistribution of the venom from the extravascular compartment to the
vascular space. This phenomenon did not occur or was very modest when
the venom was injected intravenously (fig. 2). This could be explained
by the fact that the Vdss was higher when the venom was injected intramuscularly (Vdss = 2 liter·kg1) than when it was
intravenously injected (table 1). Thus, we investigated the origin of
the venom that appears in the vascular space during the redistribution
process observed after immunotherapy in the case of an intramuscular
injection of the venom. When we assayed the venom at the site of
injection immediately after an intramuscular injection of 750 µg·kg1 of V. aspis venom,
we detected 70 ng of venom/mg of total muscle protein; this value
decreased to 2.9 and 1 ng·mg1 after 7 and 30 hr, respectively. When the intramuscular injection of the venom
was followed 7 hr later by an intravenous injection of 125 mg of IPSER
Europe antivenom, the venom concentration observed at the site of
injection after 30 hr was not significantly different (0.75 ng·mg1).
Pharmacokinetics of F(ab')2/or Fab/venom
complexes.
To study the elimination process of immune complexes
formed between antivenom and venom, we immunopurified immunoglobulin fragments [F(ab')2 or Fab]. It is known that
most antivenoms contain both venom-specific immunoglobulins (or
fragments of immunoglobulins) and nonspecific immunoglobulins. In the
case of IPSER Europe antivenom, 20% of the
F(ab')2 of the antivenom preparation is able to
bind venom antigens (data not shown). Thus, the use of commercial
antivenom to determine the pharmacokinetic parameters of the
F(ab')2/or Fab/venom complexes is inappropriate
because the nonspecific immunoglobulin fragments will not be complexed
with the venom antigens. We therefore immunopurified Fab or
F(ab')2, as described in Methods, to perform these studies. Rabbits were injected intravenously with 250 µg·kg1 V. aspis venom and 5 hr later with 1 mg of purified fragments [Fab or
F(ab')2]rabbit (fig.
3). In these experimental conditions, the
venom is in excess, as shown by the presence of free venom detected
throughout the experiment, and all the immunoglobulin fragments
[F(ab')2 or Fab] are complexed with venom
components, as indicated by the absence of free specific fragments
[F(ab')2 and Fab], so a specific ELISA directed
to horse F(ab')2 or Fab will quantify only immune
complexes. Fab/venom and F(ab')2/venom complexes
are eliminated with similar elimination half-lives, but the mean
residence time of Fab/venom complexes is shorter than that of
F(ab')2/venom complexes (table
2). On the other hand, the injection of 1 mg of Fab, but not of F(ab')2, in envenomed rabbits greatly reduced the volume of urine collected during the first
24 hr of the experiment: 5 ± 5 ml of urine instead of 64 ± 24 ml in the case of rabbits that received venom but not antivenom (P < .05). At subsequent periods, the volumes of collected urine were not statistically different with or without antivenom. It is
important to remember that this phenomenon did not occur with venom-specific F(ab')2.
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Fig. 3.
Pharmacokinetics of F(ab')2-venom (A)
and Fab-venom (B) complexes. One milligram of specific immunoglobulin
fragments was injected 5 hr after an i.v. injection of 250 µg·kg1 of V. aspis venom. Experimental
values are the means ± S.E.M. of independent experiments.
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TABLE 2
Pharmacokinetic parameters of specific immunoglobulin fragments
complexed with Vipera aspis venom
Results are expressed as mean ± S.E.M. of five independent
experiments.
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|
Pharmacokinetic of Fab fragments injected
intramuscularly.
When 10 mg of Fab was injected into nonenvenomed
rabbits via the intramuscular route, the time-dependent
change in plasma concentration of Fab showed two phases (fig.
4): an absorption phase followed by an
elimination phase characterized by an apparent terminal half-life of
13.2 ± 0.3 hr. The elimination of intramuscularly injected Fab
thus occurs faster than that of F(ab')2
(t1/2 = 59.6 hr; Pépin
et al., 1995). Moreover, it has been shown that F(ab')2 is absorbed more slowly than Fab, with an
observed Tmax of 48 hr for
F(ab')2 (Pépin et al., 1995) and
12 hr for Fab.
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Fig. 4.
Pharmacokinetics of 10 mg of Fab injected
via the intramuscular route. Experimental values are the
means ± S.E.M. of independent experiments.
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| |
Discussion |
The injection of a high dose of antivenom (125 mg), composed of
either F(ab')2 or Fab, 5 hr after an intravenous
administration of V. aspis venom increased the
AUC5 of the venom complexed to the
antibodies and detected by radioactivity and decreased the plasma
concentration of noncomplexed venom. The immunocomplexation of the
venom in plasma was complete (free venom was undetectable) with
F(ab')2, whereas it was not in the case of Fab.
This cannot be attributed to a weaker neutralizing capacity of Fab
compared with F(ab')2. On the other hand, the
larger Vdss calculated for Fab than for
F(ab')2 (Rivière et al., 1997)
is related to a lower Fab concentration in plasma responsible for the
lower immunocomplexation of the venom. The phenomenon of
immunocomplexation with specific Fab is well understood in the case of
intoxications by colchicine (Cano et al., 1995), digitalis
(Smith et al., 1976) and phencyclidine (Valentine et
al., 1994). The injection of Fab induces a redistribution of the
drug from the extravascular compartment (where it exerts its toxicity)
to the vascular space (where it is neutralized). In the case of
intravenously injected V. aspis venom, the administration of
a high dose of specific immunoglobulin fragments did not induce the
marked redistribution observed with these low-molecular-weight toxins
(colchicine, digitalis, phencyclidine). This might be explained by the
fact that the Vdss values of colchicine, digitalis and phencyclidine are very large, >3
liter·kg1 (Sabouraud et al.,
1992; Timsina and Hewick, 1992; McClurkan et al., 1993),
allowing a marked redistribution when brought back in the vascular
space by the Fab, whereas the Vdss value of the venom injected by the intravenous route is rather small (725 or 400 ml·kg1, using ELISA or radioactivity
quantification, respectively) and close to the vascular volume, not
allowing the antibodies to cause a significant redistribution of the
venom.
Surprisingly, Rivière et al. (1997) reported that the
intravenous injection of antivenom induces a larger redistribution of
the venom when the venom is injected via the intramuscular route instead of the intravenous route. This is in good correlation with the Vdss value of the venom, which is higher
when injected via the intramuscular route than the
intravenous one. Audebert et al. (1994) showed that the
resorption of intramuscularly injected viper venom is a slow process,
developing up to 72 hr, which could suggest that the venom was
sequestered at the site of injection during this time. However, we
observed that at 7 hr after its intramuscular injection, all the venom
had disappeared from the site of injection, whereas only 25% of the
venom has reached the vascular space (Audebert et al.,
1994). This suggests that during the first hours after the
intramuscular envenomation, most of the venom has been absorbed in the
lymphatic circulation, but it is not yet significantly released in the
vascular compartment. In agreement with this conclusion, it has been
observed that V. aspis venom causes an important vascular
extravasation and edema to appear at the site of injection during the
first hours after snake bite (Sorkine et al., 1995), which
might be responsible for a 4- to 9-fold increase in the flow rate of
lymph (Ikomi and Schmid-Schonbein, 1996). In this context, the large
increase in the venom concentrations observed in the vascular space
after intravenous administration is simply explained by the fact that antibodies [F(ab')2 or Fab] could induce a
redistribution of the venom from the lymphatic compartment to the
vascular space rather than displacing it from the site of injection.
Indeed, these two compartments are closely connected (Garlick and
Renkin, 1970). Interestingly, the absorption of the venom
via the lymphatic system was suggested a long time ago by
Barnes and Trueta (1941) in the case of the venom of Notechis
scutatus.
As previously reported, F(ab')2 and Fab differ in
their effects on the pharmacokinetics of V. aspis venom
(Rivière et al., 1997). Although
F(ab')2 causes a complete and durable
neutralization of the venom, the action of Fab is much more transient.
It is thus interesting to examine whether this might be due to
differences in the kinetics of elimination of
F(ab')2/venom and Fab/venom complexes. In both
cases, the pharmacokinetic parameters determined for
F(ab')2 or Fab complexed with venom differed from
those obtained respectively for noncomplexed immunoglobulin fragments
(Rivière et al., 1997). In the case of
F(ab')2, the terminal half-life of
F(ab')2/venom complexes was shorter than that
calculated for free fragments, and ClT and
Vdss were larger (table 2), as easily explained
considering that these immune complexes are large and undergo
phagocytosis. On the other hand, in the case of Fab, the terminal
half-life of Fab/venom complexes is significantly longer than that of
free Fab, whereas ClT and
Vdss are smaller, most probably because the
Fab/venom complexes are soluble and therefore cannot be eliminated by
phagocytosis. This is also different from the colchicine/Fab complexes,
which are eliminated with the same terminal half-life as free Fab
(Sabouraud et al., 1992). Thus, the elimination process of
the Fab/toxin complexes seems to be different when immunotherapy is
performed against high-molecular-weight components, as in the case of
viper venom or small drugs like colchicine or digitalis. This is
certainly due to the fact that Fab/venom complexes cannot be eliminated
by the renal route because of their high molecular weight, whereas
individual constituents (free Fab, free venom antigens or drugs) and
Fab complexes made with small drugs as colchicine or digitalis have a
molecular weight smaller than the filtration threshold of the renal
glomeruli and are rapidly eliminated in urine (Sabouraud et
al., 1992). On the other hand, although the
F(ab')2/venom and Fab/venom complexes have
similar terminal half-lives (31.5 and 25.6 hr, respectively), it cannot
be concluded that they have the same route of elimination.
The renal toxicity of Fab fragments is still controversial. Some
authors reported that transient oliguria and increased serum creatinine
occurred only after the injection of very high doses of nonspecific
human Fab (3-5 g·kg1) in dogs (Keyler
et al., 1991). On the other hand, Moran et al. (1994), reported that injection of 2 mg·kg1 digoxin-specific sheep Fab
fragments in rats induced marked renal toxicity (urine volume and
creatinine clearance were decreased by 30%). In the case of the Fab
fragment from IPSER Europe antivenom, we did not determine creatinine
clearance but observed a substantial reduction in the volume of urine
in envenomed rabbits during the 24 hr after immunotherapy with Fab but
not with F(ab')2. The renal toxicity of Fab
fragments thus seems to depend on their complexation with the venom
component and might vary with their species origin (human, sheep or
horse) or with the experimental animal (dog, rat or rabbit). In this
context, it has been recently shown in a clinical study (Dart et
al., 1997) that injection of specific crotalid ovine Fab (up to
9 g per patient) did not induce renal toxicity.
Specific Fab fragments proved to be very effective in the treatment of
colchicine and digitalis intoxications (Smith et al., 1976;
Baud et al., 1995). Their use, instead of
F(ab')2, also has been recommended because of
their lower incidence of adverse reactions (Hickey et al.,
1991; Smith et al., 1992). However, specific Fab appeared
much less effective than F(ab')2 in treating viper envenomations when the immunotherapy is performed by intravenous injection (Rivière et al., 1997; Karlsonstiber
et al., 1997). The present study emphasizes this conclusion.
Because of their faster resorption, Fab might be of value when
intravenous injection of antivenom made of
F(ab')2 is not feasible. However, the renal toxicity that we observed in experimentally envenomed rabbits treated
with Fab, but not with F(ab')2, implies that
further investigations must be performed to clarify this point before
recommending the use of snake antivenoms made of Fab in humans.
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Abstract
Introduction
