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Clinical indicators of envenoming and serum levels of venom antigens in patients bitten by Bothrops lanceolatus in Martinique. Research Group on Snake Bites in Martinique.

An enzyme-linked immunosorbent assay was developed to measure venom antigen levels in the serum of 40 patients bitten by Bothrops lanceolatus. The grading system used for the severity of envenomation (grades 1 to 4, minor to major) was predominantly based on the presence of local signs. Serum venom levels increased with the grade of severity (P < 0.001, by Spearman's rank correlation test); they were 6 +/- 6 ng/mL (mean +/- SD) in clinically non-envenomed patients (grade 1, n = 3), 7.6 +/- 11.7 (n = 17), 44.3 +/- 41.8 (n = 17), and 80.3 +/- 34.1 ng/mL (n = 3) in patients diagnosed as grade 2, 3 and 4 respectively. However, venom antigens could not be detected in the serum of 54% of patients who showed clinical signs of envenomation. Most patients diagnosed as grade 2, 3 or 4 were given 20, 40 and 60 mL of a monospecific F(ab')2 antivenom, respectively. Venom concentrations > or = 15 ng/mL were observed in all patients with progressive aggravation of swelling despite the use of early antivenom therapy. No venom was detectable in blood samples taken after completion of serotherapy. All patients recovered. These results confirm the efficacy of both the clinical severity scoring system used and the therapeutic regimen.

Adolescent↗
PubMed2001

Targeted therapy for multiple myeloma.

Multiple myeloma (MM) remains incurable with conventional treatment approaches, and novel biologically based therapies are therefore urgently needed. Targeted therapies are either under development or already undergoing clinical evaluation predicated upon: identifying genetic abnormalities in myeloma cells to enhance chemoradiosensitivity; interrupting growth or triggering apoptotic signaling cascades in tumor cells; treating both the tumor cell and its microenvironment; enhancing allogeneic and autologous antimyeloma immunity; and characterizing new myeloma antigens for serotherapy. These therapies, alone or in combination with conventional treatments, offer great promise to improve the outcome for patients with MM.

Antigens, Neoplasm↗
PubMed2002

Complications of Bothrops, Porthidium, and Bothriechis snakebites in Colombia. A clinical and epidemiological study of 39 cases attended in a university hospital.

The clinical and epidemiological features, as well as complications presented by 39 patients with Bothrops, Porthidium and Bothriechis snakebites, are described. Patients were admitted during 1 year in 25 hospitals of Antioquia and Chocó and then, they were transferred to the Hospital Universitario San Vicente de Paúl in Medellín, 30 of them because of the presence of complications, eight because of lack of antivenoms and another one because of the desire of his relatives. Thirty--one (79.5%) of the patients were male, 13 (33.3%) children, 59% of them were bitten at the lower extremities, the majority (74.4%) by Bothrops asper. Twenty-one (53.8%) of the patients were initially attended by traditional healers and sought medical attention at the local hospitals after 2h in 87.2% of the cases. Edema (100%), hemorrhage (74.4%), blistering (38.5%) and necrosis (38.5%), were the local signs of envenomation, while blood coagulation alteration (79.5%), hematuria (74.4%), gingival bleeding (43.6%), hypovolemic shock (23.1%) and oliguria (23.1%), were the systemic signs of envenomation. The final grade of envenomation was severe in 29 patients (74.4%). Thirty patients (76.9%) had one or more complications of the envenomation: acute renal failure (ARF), 15 (38.5%); soft-tissue infection, 12 (30.8%); central nervous system (CNS) hemorrhage, 5 (12.8%); compartment syndrome, 3 (7.7%); soft--tissue hematomas, 6 (15.4%); and Abruptio placentae, one (2.6%). There were four deaths (10.3%), two from ARF and two from cerebral hemorrhage. Fourteen other patients (35.9%) had sequelae. The onset of serotherapy after 2h of the bite was associated with the occurrence of ARF and CNS hemorrhage (p=0.02), as well as the risk of death and sequelae (RR=2.5).

Adolescent↗
PubMed2002

Intraspecific variability and pharmacokinetic characteristics of Androctonus mauretanicus mauretanicus scorpion venom.

We evaluated the degree of venom toxicity and protein content of several specimens of Androctonus mauretanicus mauretanicus. The quantity of protein of individual venom obtained after manual extraction from 31 different scorpions varied from a minimum of 0.15 mg to a maximum of 1.53 mg. We determined the venom toxicity, in mice, by estimating the number of LD(50)s of 20 scorpions chosen randomly among the 31 scorpions. It ranged from less than 40 LD(50)s to a maximum of 272 LD(50)s. The correlation between protein content and venom lethality is not systematic. We also determined the pharmacokinetics of the venom and its specific anti-venom in rabbits to compare their distribution and elimination properties. After a subcutaneous injection, high concentrations of venom were measured by ELISA in the vascular space rapidly after the injection (T(max) = 0.5 h). The terminal half-life was 2.8 h, close the one determined after intravenous injection (t(1/2beta) = 3.2 h). The total volume of distribution (Vd(ss) or Vd(beta)) was between 317 and 380 ml/kg. The total body clearance was 82 ml/kg/h. For scorpion anti-venom, the terminal half-life, after intravenous injection, was 20.25 h; the volume of distribution was 83 ml/kg and the total body clearance was 3 ml/kg/h. After intramuscular administration, T(max) was reached at 36 h. The results show that venom lethality varies from specimen to specimen and that pharmacokinetic parameters of venom and anti-venom are totally different. This must be taken under consideration in anti-venom production (anti-venom titre) as well as in therapeutic protocols (dose, injection route) to improve serotherapy.

Animals↗
PubMed1997

Time factor in the detection of circulating whole venom and crotoxin and efficacy of antivenom therapy in patients envenomed by Crotalus durissus.

Thirty-seven patients envenomed by Crotalus durissus were classified into three groups according to the interval between the bite and hospital admission (delta T): group 1 (n = 14, delta T < 4 hr), group 2 (n = 14, delta T > 4 hr < 8 hr) and group 3 (n = 9, delta T > 8 hr). Venous blood from these patients was sampled for biochemical and hematological analysis and for whole venom, crotoxin and antivenom enzyme-linked immunosorbent assays before antivenom treatment (T0) and at 1 hr (T1), 6 hr (T6), 12 hr (T12) and 24 hr (T24) after the start of antivenom therapy. The patients were treated with 100-200 ml (10-20 ampules) of C. durissus antivenom. Whole venom and crotoxin were detected in 13 (92.8%) and 11 (78.6%) of 14 group 1 patients, respectively, in 11 (78.6%) and six (42.9%) of 14 group 2 patients, respectively, and in two (22.2%) and one (11.1%) of nine group 3 patients, respectively, before antivenom treatment. Data from this study show that whole venom and crotoxin were not detected in most of patients when the time elapsed between the bite and hospital admission was greater than 8 hr, and crotoxin was not detected in most of the patients who were admitted to the hospital at times ranging from 4 to 8 hr after the snakebite. Plasma whole venom, crotoxin and antivenom levels measured over time in these patients show the efficacy of antivenom treatment, since circulating venom and crotoxin were no longer detected 1 hr after antivenom therapy and high antivenom titers persisted for at least 24 hr after serotherapy.

Adolescent↗
PubMed1998

Inhibitory effect of habu antivenom on fibrinopeptide A release induced by Trimeresurus flavoviridis crude venom.

The correlation between the clotting activity of crude venom and concentration of fibrinopeptide A (FPA) released by the crude venom in rabbit plasma was evaluated and expressed as the coefficient of correlation (r = 0.850). The venom-induced FPA release was inhibited by habu antivenom. For such inhibition of FPA release, the correlation between the concentration of habu antivenom (Y) and that of crude venom (X) could be expressed by the equation Y = 7.115 + 0.709X. An absence of venom-induced FPA release in rabbit plasma had suggested that the clotting activity of crude venom could be neutralized by the habu antivenom. It is suggested that determinations of the FPA level in the plasma are effective in providing an indication of the reliability for serotherapy using habu antivenom.

Animals↗
PubMed1998

Immunotherapy for scorpion envenoming in Brazil.

Using the ELISA we have shown that in rats subcutaneously injected with Tityus serrulatus scorpion venom there is a fast absorption rate, a fast and high distribution of venom to tissues, a great affinity of the venom for the tissues and a slow elimination half-life. Because of these experimental data, i.v. immunotherapy should be given to patients stung by scorpions as soon as possible after hospital admission. The severity of scorpion envenoming is related to plasma venom concentration (ELISA). The high levels of plasma scorpion venom antigens (ELISA) were cleared 1 h after the infusion of antivenom (5-30 ml of Fab2 fragment) and high concentrations of circulating antivenom persisted for at least 24 h, confirming the efficacy of immunotherapy to neutralise circulating venom. Some symptoms (e.g. local pain and vomiting) decreased 1 h after the starting of immunotherapy, whereas the other symptoms disappeared from 12-48 h later. Using our tripartite approach of treating scorpion envenoming (symptomatic measures, support of vital functions and serotherapy), the mortality rate was very low (0.28%).

Animals↗
PubMed1998

Pharmacokinetics of 125I-labelled IgG, F(ab')2 and Fab fractions of scorpion and snake antivenins: merits and potential for therapeutic use.

The immunoglobulin fractions IgG, F(ab')2 and Fab of scorpion and snake antivenoms possess pharmacokinetic characteristics that are significantly different from their respective venoms. The venoms (and their toxins) are several fold faster in their distribution into the tissues than any of the immunoglobulin fraction. In rabbits, F(ab')2 possessed the fastest disposition rate constants and the longest distribution half lives. In the physiologically based pharmacokinetic experiments carried out in mice F(ab')2 possessed the highest Cp(max), smallest AUC and the shortest t1/2beta in the different tissues while Fab had values in between IgG and F(ab')2. Rescue experiments in anaesthetized rats challenged with lethal doses of venoms or toxins and infused with border-line neutralizing doses of antivenoms, showed that rats infused with F(ab')2 completely recovered, those infused with IgG partially rescued and none of the rats infused with Fab survived. It is concluded that F(ab')2 of scorpion and snake antivenoms possess pharmacokinetic characteristics that render it the most suitable for use in serotherapy of scorpion and snake envenoming.

Animals↗
PubMed1998

Neutralization of local tissue damage induced by Bothrops asper (terciopelo) snake venom.

Local tissue damage represents a serious consequence of Bothrops asper envenomations. It encompasses a complex series of alterations, including myonecrosis, dermonecrosis, hemorrhage and edema. Due to its rapid development it is difficult to neutralize by antivenoms, especially if there is a delay in serotherapy. Experimental studies with this venom and the polyvalent (Crotalinae) antivenom produced in Costa Rica indicate that antivenom is effective in neutralizing these toxic activities when incubated with the venom prior to injection. However, if venom and antivenom are injected independently in mice, neutralization of these effects is only partial. Moreover, neutralization is not complete even if homologous or heterologous antibodies are present in the circulation before venom is injected. Despite differences in their pharmacokinetic profiles, equine whole IgG and F(ab')2 antivenoms show similar efficacy in the neutralization of edema, hemorrhage and myonecrosis induced by B. asper venom, suggesting that the use of antivenoms made of antibody fragments may not improve neutralization of these effects. This is due, at least in part, to the fact that microvessel disruption by venom components favors a similar antibody concentration in the affected tissues. Recent advances in the development of neutralizing substances of rapid diffusion, that could be injected locally in the field, may contribute to the neutralization of metalloproteinases and phospholipases A2. In addition, the rapid administration of antivenoms with high antibody titers against locally-acting toxins is very important in the treatment of these effects.

Animals↗
PubMed1986

Monoclonal antibodies in cancer treatment: where do we stand after 10 years?

Monoclonal antibodies (MoAbs) with specificity to tumour-associated antigens have become increasingly available during the past years. Presently, they are being applied in various in vitro diagnostic assays. They have contributed to the knowledge of cancer biology to a large extent. The understanding of cell surface characteristics and antigenic phenotype of tumours has in particular influenced the approach in the treatment of leukemias and lymphomas. From successful tumour localization in patients by gamma-emitting radio-labelled MoAbs it became clear, that these proteins offer a unique possibility to target therapeutic agents to tumour sites. The mere administration of MoAbs did not result in sufficient clinical benefit, but with proper precautions high doses of murine antibody were well tolerated. In order to use MoAbs as a carrier system, various toxins, cytostatic drugs, or radionuclides have been conjugated to these proteins. Thus far, specific problems were encountered not only associated with the immunoconjugate itself, but also to its fate in the patient. With regard to the substantial knowledge on the use of MoAbs in vivo obtained from animal tumour models, immunoscintigraphy in patients, and phase I serotherapy trials, we will undoubtedly determine the optimal conditions required for a conjugated anti-tumour agent to achieve enhanced cytotoxicity without increased side-effects. Preliminary results with high doses of 131I-labelled MoAbs in patients having tumour lesions expressing relevant antigens encourage further studies with immunoconjugates in cancer treatment. While much work needs to be done to further define the role of MoAbs as a new treatment modality in malignancies, this area of immunotherapy deserves great emphasis for the development of effective conjugates for future patients.

Animals↗
PubMed2001

[Treatment of lithiasis in horseshoe kidney with extracorporeal shock-wave lithotripsy].

UNLABELLED: The horseshoe kidney is the most frequent renal anomaly. As a consequence of impaired urinary drainage, urolithiasis is present in 20% of the cases. Indications for extracorporeal shock wave lithotripsy (ESWL) in the treatment of patients with anomalous kidneys is still the subject of controversy. OBJECTIVE: To evaluate ESWL efficacy in the treatment for lithiasis in horseshoe kidney. MATERIAL AND METHODS: Between april 1988 and december 1999 a total of 32 symptomatic lithiasis in 30 patients with horseshoe kidneys were managed by 65 sessions with ESWL. Until march 1999 a Dornier HM-4 electrohydraulic lithotripter was used. Posteriorly, two treatments was performed with an electromagnetic Dornier Lithotripter S. These procedures have been performed without anaesthesia or sedation for the Dornier HM-4 equipment. Analgesia with Meperidine was used for the Dornier Lithotripter S. Diuresis was not forced during or after treatment with diuretics or serotherapy. Treatments was conducted in an outpatient clinic in all cases. RESULTS: Treatment/lithiasis rate was 2.03. Following treatment 16 patients (54%) were stone-free by X-ray, 9 patients (30%) had residual fragments and in 5 patients (16%) no sign of stone disintegration was observed. Open surgery was performed in three of this patients. Better results was achieved in stones located in the renal pelvis and stone size is 10 mm or less. Clinical evolution: free of symptoms in 20 patients; chronic vague flank pain in 5 patients and acute renal colic with or without hematuria in 5 patients. No major complication was observed in our compilation. CONCLUSIONS: These results suggest that ESWL is the method of primary choice in the treatment for small lithiasis (10 mm or less) in horseshoe kidney.

Adult↗
PubMed2004

[Effect of a campaign to promote breast-feeding among women in the province of Malaga who had their babies by caesarean section].

OBJECTIVE: To determine whether an intervention to foster breast-feeding did actually increase it and how long it lasted in nursing mothers who gave birth through caesarean section. DESIGN: Evaluation of a community intervention. SETTING: Mother-and-Child Hospital in Málaga. PARTICIPANTS: Sample of 152 pregnant women who delivered their baby by caesarean section, 76 in 1996 and 76 in 1998. INTERVENTIONS: During 1997, activities to promote breast-feeding were organised in the health district. These included workshops aimed at primary care and specialist professionals, public events to promote breast-feeding (public feeds, photography competitions, media comment, etc), accords with institutions (university, nursing college inter al) and changes in the health services (improvement of services to new mothers and neonates; co-ordination between primary and hospital care). MAIN MEASUREMENTS AND RESULTS: In 1996, only 28% of women who started feeding did so with serotherapy. In 1998 this became 85% (P<.0005). Length of breast-feeding also increased significantly (P<.215). There was greater involvement of nursing, though it was not statistically significant (P<.06), moving from 40% in 1996 to 65.2% in 1998. CONCLUSIONS: The campaign showed its efficacy as a method of promotion of breast-feeding, on achieving an earlier start in breast-feeding, longer duration of it and greater involvement of nurses. Practical applications included changes in hospital routines, professional training, working out of strategies and specific records for the ongoing assessment of breast-feeding.

Breast Feeding↗
PubMed1993

[A fatal case of viper bite in an adult in France].

Vipera bites in France are supposed to be benign. We report here, the case of a snake bite with fatal outcome due to hypoxemia and shock, occurring in a young woman without previous disease. This case could lead to reevaluate the indication of antivenomous serotherapy in the severe envenomations. However the tolerance of the new serums has to the confirmed.

Adult↗
PubMed1998

[The discovery of anaphylaxis: 19 days after an anodyne account of toxicology, it is shown that immunity is perhaps pathogenic].

While studying the toxicology of various coelenteres fishing filament poisons, Charles Richet and Paul Portier observed cases of rapid death which had no correlation with the injected doses. In dogs, death only occurred in those which, more than 15 days beforehand, had withstood well an injection more concentrated or identical to the later fatal one. The authors created the neologism 'anaphylaxis' which signifies 'non-protection'. Thus, it appeared that an immune response could be pathological. This discovery opened the subject area of immunopathology at a period of time when, in contrast, vaccination and serotherapy researches were prominent.

Anaphylaxis↗
PubMed2002

[Botulism: the agent, mode of action of the botulinum neurotoxins, forms of acquisition, treatment and prevention].

The botulinum neurotoxins are produced by anaerobic, spore-forming bacteria belonging to the Clostridium genus. They are synthesised as a single chain protein (150 kDa), which is not or weakly active. The active form results from a proteolysis cleaving the precursor in a light chain (about 50 kDa) and a heavy chain (about 100 kDa), which are linked by a disulfide bridge. The heavy chain is involved in the recognition of a specific neuronal surface receptor and mediates the internalization of the light chain into the cytosol. The light chain is responsible for the intracellular activity. It catalyses the proteolysis of SNARE proteins, which are involved in the exocytosis of synaptic vesicles containing acetylcholine. Hence, the release of acetylcholine at the neuromuscular junction is blocked, leading to a flaccid paralysis. Human botulism, usually type A, B or E, is associated with intoxination, ingestion of preformed toxin in food, with digestive toxi-infection, mainly in newborns (infant botulism), or with wound contamination (wound botulism). The treatment of botulism is usually symptomatic. The specific treatment is based on the serotherapy or on the use of purified specific antibodies. The vaccination against botulism is efficient. However, since the botulinum neurotoxins are widely used for the treatment of numerous dystonias, a generalised vaccination is not conceivable.

Bacterial Vaccines↗
PubMed1988

Reshaping human antibodies for therapy.

A human IgGI antibody has been reshaped for serotherapy in humans by introducing the six hypervariable regions from the heavy- and light-chain variable domains of a rat antibody directed against human lymphocytes. The reshaped human antibody is as effective as the rat antibody in complement and is more effective in cell-mediated lysis of human lymphocytes.

Amino Acid Sequence↗
PubMed1997

Retargeting serum immunoglobulin with bispecific diabodies.

Monospecific antibody fragments produced in bacteria lack the Fc portion of antibodies, and are therefore unable to recruit natural effector functions. We describe the use of a bispecific antibody fragment (diabody) to recruit the whole spectrum of antibody effector functions by retargeting serum immunoglobulin (Ig). One arm of the diabody was directed against the target antigen, and the other against the serum Ig. The bispecific diabodies were able to recruit complement, induce mononuclear phagocyte respiratory burst and phagocytosis, and promote synergistic cytotoxicity towards colon carcinoma cells in conjunction with CD8+ T-cells. Further, by virtue of binding to serum Ig their half-life (beta-phase) was increased fivefold compared to a control diabody of the same molecular weight. Such bispecific diabodies may provide an attractive alternative to monoclonal antibodies for serotherapy.

Animals↗
PubMed2004

An efficient method to make human monoclonal antibodies from memory B cells: potent neutralization of SARS coronavirus.

Passive serotherapy can confer immediate protection against microbial infection, but methods to rapidly generate human neutralizing monoclonal antibodies are not yet available. We have developed an improved method for Epstein-Barr virus transformation of human B cells. We used this method to analyze the memory repertoire of a patient who recovered from severe acute respiratory syndrome coronavirus (SARS-CoV) infection and to isolate monoclonal antibodies specific for different viral proteins, including 35 antibodies with in vitro neutralizing activity ranging from 10(-8)M to 10(-11)M. One such antibody confers protection in vivo in a mouse model of SARS-CoV infection. These results show that it is possible to interrogate the memory repertoire of immune donors to rapidly and efficiently isolate neutralizing antibodies that have been selected in the course of natural infection.

Adult↗