Impact of antivenom administration on the evolution of cutaneous lesions in loxoscelism: A prospective observational study.

BACKGROUND: Spiders of the genus Loxosceles are distributed throughout tropical and temperate regions worldwide. Loxosceles spp. bites may evolve to necrosis, with or without intravascular hemolysis. There is no consensus regarding the best treatment to prevent necrosis. The objective of this study was to evaluate the factors associated with the development of necrosis and the impact that antivenom administration has on the evolution of cutaneous loxoscelism. METHODOLOGY/PRINCIPAL FINDINGS: This was a prospective observational study carried out at a referral center for envenoming. Over a 6-year period, we included 146 patients with a presumptive or definitive diagnosis of loxoscelism. Depending on the symptom severity, a polyvalent anti-arachnid antivenom was administered or not-in 74 cases (50.7%) and 72 cases (49.3%), respectively. Cutaneous and systemic manifestations were assessed at admission and weekly thereafter. Adverse reactions to the antivenom were also evaluated. Cutaneous loxoscelism was observed in 141 cases (96.6%), and the spider was identified in 29 (19.9%). The mean time from bite to antivenom administration was 41.6 ± 27.4 h. After discharge, 130 patients (90.9%) were treated with corticosteroids, antihistamines and analgesics being prescribed as needed. The probability of developing necrosis was significantly lower among the patients who were admitted earlier, as well as among those who received antivenom (p = 0.0245). Among the 74 patients receiving antivenom, early and delayed adverse reactions occurred in seven (9.5%) and four (5.4%), respectively. Local infection was observed only in three (2.3%) of the 128 patients for whom that information was available. CONCLUSIONS/SIGNIFICANCE: Necrosis after a Loxosceles sp. bite appears to more common when hospital admission is delayed or when antivenom is not administered. In addition, the administration of a polyvalent anti-arachnid antivenom appears to be safe, with a relatively low rate of adverse reactions.

Coexistence of Rhabdomyolysis, Myocarditis and Arrhythmia after Spider Bite: A Case Report.

BACKGROUND: Rhabdomyolysis after spider bite has been reported in a small number of patients, and myocarditis in even fewer. However, arrhythmia associated with latrodectism in children has not been described in the literature to date. CASE SUMMARY: A girl presented approximately 4.5 h after being bitten on the left ankle by a black spider. Two unifocal premature ventricular contractions (PVCs) were observed on the electrocardiogram. In laboratory tests, creatine kinase was elevated. On day 2, levels of troponin, pro-brain and natriuretic peptide were elevated. Electrocardiogram revealed inverted and biphasic T waves. Echocardiography revealed mild left ventricular dilation, mitral and aortic valve regurgitation. Holter electrocardiogram showed PVCs. Her laboratory and echocardiography findings completely normalized after discharge, and no arrhythmia was observed on the Holter electrocardiogram during outpatient follow-up. CONCLUSION: Although spider bites are uncommon, they can cause serious systemic effects. These patients should be evaluated for arrhythmia, rhabdomyolysis and myocarditis.

Rarely, spider bites can cause serious systemic effects, severe morbidity and death. In a small number of patients, spider envenomation causes rhabdomyolysis and myocarditis. In the present case, the elevated troponin and pro-brain natriuretic peptide levels and electrocardiogram/echocardiography findings were consistent with myocarditis, and an increase in creatinine kinase level indicated rhabdomyolysis. In addition, the electrocardiogram and Holter electrocardiogram revealed unifocal premature ventricular contraction. To our knowledge, arrhythmia due to Latrodectus spider bite has not been described in children to date. In addition, this case demonstrates the coexistence of two serious systemic effects, rhabdomyolysis and myocarditis, with full recovery after appropriate treatment.

Stability and Safety of Inhibitor Cystine Knot Peptide, GTx1-15, from the Tarantula Spider Grammostola rosea.

Inhibitor cystine knot (ICK) peptides are knotted peptides with three intramolecular disulfide bonds that affect several types of ion channels. Some are proteolytically stable and are promising scaffolds for drug development. GTx1-15 is an ICK peptide that inhibits the voltage-dependent calcium channel Cav3.1 and the voltage-dependent sodium channels Nav1.3 and Nav1.7. As a model molecule to develop an ICK peptide drug, we investigated several important pharmaceutical characteristics of GTx1-15. The stability of GTx1-15 in rat and human blood plasma was examined, and no GTx1-15 degradation was observed in either rat or human blood plasma for 24 h in vitro. GTx1-15 in blood circulation was detected for several hours after intravenous and intramuscular administration, indicating high stability in plasma. The thermal stability of GTx1-15 as examined by high thermal incubation and protein thermal shift assays indicated that GTx1-15 possesses high heat stability. The cytotoxicity and immunogenicity of GTx1-15 were examined using the human monocytic leukemia cell line THP-1. GTx1-15 showed no cytotoxicity or immunogenicity even at high concentrations. These results indicate that GTx1-15 itself is suitable for peptide drug development and as a peptide library scaffold.

Skin Necrosis, Diffuse Urticaria, and Cellulitis Due to Presumed Loxosceles Spider Bite.

The clinical manifestations of a recluse spider bite range from local erythema to necrotic skin reactions; bites rarely lead to a systemic disease known as viscerocutaneous loxoscelism. A 29-y-old female patient was admitted to the emergency department with a wound, swelling, and pain on her left leg and a rash on her whole body as a result of a spider bite. On physical examination, a round, hard, black, irregularly shaped necrotic area was found in the bite zone on the lower posterior part of the left thigh, as were lesions in the form of erythematous papules around the area. There was a color change around the lesion, extending from posterior to medial of the thigh, and a papule on a diffuse erythematous surface on the trunk and arms. At follow-up, the necrotic area had become more apparent. After approximately 1 mo, the necrotic area was surgically debrided and a flap was formed on the necrotic tissue area. In this article, a case that was thought to be caused by a Loxosceles spider bite and which started with erythema, progressed to lymphangitis, cellulitis, and severe necrosis, and was surgically debrided, was evaluated in light of the clinical findings and previously reported cases of verified loxoscelism. In patients with a history suggestive of a bite and with these clinical findings, the diagnosis of a bite by Loxosceles spp. should be carefully considered based on clinical and epidemiologic findings.

Spider venom-derived peptide induces hyperalgesia in Nav1.7 knockout mice by activating Nav1.9 channels.

The sodium channels Nav1.7, Nav1.8 and Nav1.9 are critical for pain perception in peripheral nociceptors. Loss of function of Nav1.7 leads to congenital insensitivity to pain in humans. Here we show that the spider peptide toxin called HpTx1, first identified as an inhibitor of Kv4.2, restores nociception in Nav1.7 knockout (Nav1.7-KO) mice by enhancing the excitability of dorsal root ganglion neurons. HpTx1 inhibits Nav1.7 and activates Nav1.9 but does not affect Nav1.8. This toxin produces pain in wild-type (WT) and Nav1.7-KO mice, and attenuates nociception in Nav1.9-KO mice, but has no effect in Nav1.8-KO mice. These data indicate that HpTx1-induced hypersensitivity is mediated by Nav1.9 activation and offers pharmacological insight into the relationship of the three Nav channels in pain signalling.

Loxoscelism: Advances and Challenges in the Design of Antibody Fragments with Therapeutic Potential.

Envenoming due to Loxosceles spider bites still remains a neglected disease of particular medical concern in the Americas. To date, there is no consensus for the treatment of envenomed patients, yet horse polyclonal antivenoms are usually infused to patients with identified severe medical conditions. It is widely known that venom proteins in the 30-35 kDa range with sphingomyelinase D (SMasesD) activity, reproduce most of the toxic effects observed in loxoscelism. Hence, we believe that monoclonal antibody fragments targeting such toxins might pose an alternative safe and effective treatment. In the present study, starting from the monoclonal antibody LimAb7, previously shown to target SMasesD from the venom of L. intermedia and neutralize its dermonecrotic activity, we designed humanized antibody V-domains, then produced and purified as recombinant single-chain antibody fragments (scFvs). These molecules were characterized in terms of humanness, structural stability, antigen-binding activity, and venom-neutralizing potential. Throughout this process, we identified some blocking points that can impact the Abs antigen-binding activity and neutralizing capacity. In silico analysis of the antigen/antibody amino acid interactions also contributed to a better understanding of the antibody's neutralization mechanism and led to reformatting the humanized antibody fragment which, ultimately, recovered the functional characteristics for efficient in vitro venom neutralization.

Latrodectus Facies After Latrodectus Hesperus Envenomation in a Pediatric Patient.

BACKGROUND: Black widow spider (Latrodectus spp) envenomation represents the most medically significant spider envenomation in the United States, prompting more than 2500 calls to poison centers annually. The female spider, which is responsible for symptomatic envenomations, is classically described as a shiny black spider with a red hourglass-shaped marking on the ventral abdomen. Clinical features of envenomation include painful muscle cramping, abdominal pain, and autonomic disturbances, such as tachycardia, hypertension, and diaphoresis. "Latrodectus facies" or "facies latrodectismica" is an additional distinctive but rarely described clinical finding characterized by periorbital edema, lacrimation, and blepharospasm. CASE REPORT: A 6-year-old female developed the typical clinical features of Latrodectus envenomation after being found in bed with a Western black widow spider (Latrodectus hesperus) with no ventral marking. She initially improved with opioid analgesia, but 6 h later her symptoms worsened again, and concurrent with this worsening she developed Latrodectus facies. She received additional opioid analgesia and all her symptoms resolved within 24 h. Her mother provided informed and written consent for the acquisition and publication of the facial photographs presented. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: A high degree of clinical suspicion is necessary to correctly diagnose Latrodectus envenomation, especially when the spider escapes unnoticed or in young children in whom the bite is not witnessed. To our knowledge, Latrodectus facies has not been reported previously in a young child, and recognition of this finding will aid clinicians in limiting unnecessary interventions and administering appropriate therapy.

[Experience in visceral cutaneous and cutaneous loxoscelism of hospital management: clinical, evolution and therapeutic proposal]. / Experiencia en loxoscelismo cutáneo y cutáneo visceral de manejo hospitalario: clínica, evolución y propuesta terapéutica.

BACKGROUND: Loxoscelism is a common pathology in our environment with a broad spectrum of differential diagnoses and presentations, with potentially serious complications, even to the point of death. To date, there is no standard treatment for these patients. AIM: To describe the clinical manifestations, main complications, therapeutic management, and evolution of loxoscelism in an inpatient setting from a tertiary hospital in Chile. METHODS: All patients consulting and hospitalized in the hospital of the Pontificia Universidad Católica de Chile with diagnosis of loxoscelism between 2014 to 2017 and evaluated by dermatologist were included. Review of clinical files, including symptoms, images, laboratory parameters and treatment. RESULTS: We evaluated seventeen inpatient with loxoscelism, whose presentation responds to the national epidemiological pattern. Most cases were managed with antibiotics, systemic corticosteroids, antihistamines, and dapsone. From these, 11.8% corresponded to viscerocutaneous loxoscelism, successfully managed with supportive measures, systemic corticosteroids and antihistamines. Fifty-nine percent healed their cutaneous lesions after one month of treatment, with slight residual scarring or post inflammatory hyperpigmentation, without associated mortality in our series. DISCUSSION: Most cases of cutaneous loxoscelism presented excellent response and rapid resolution of the disease after combined therapy with systemic corticosteroids, antibiotics and dapsone, suggesting that the use of these therapies could stop the progression of cutaneous necrosis and prevent complications associated with loxoscelism.

Experiencia en loxoscelismo cutáneo y cutáneo visceral de manejo hospitalario: clínica, evolución y propuesta terapéutica / Experience in visceral cutaneous and cutaneous loxoscelism of hospital management: clinical, evolution and therapeutic proposal

Resumen Introducción: El loxoscelismo es una patología frecuente en nuestro medio con un amplio espectro de presentaciones y diagnósticos diferenciales, con complicaciones potencialmente graves, e incluso con riesgo de muerte. A la fecha no existe un tratamiento estándar para estos pacientes. Objetivo: Describir las manifestaciones clínicas, principales complicaciones, manejo terapéutico y evolución de pacientes internados por loxoscelismo en un hospital terciario en Chile. Pacientes y Método: Se analizaron todos los pacientes consultantes e internados por loxoscelismo en el Hospital Clínico de la Pontificia Universidad Católica de Chile entre los años 2014 y 2017, evaluados en interconsulta por Dermatología. Revisión de los registros clínicos incluyendo semiología, imágenes, informes de laboratorio y tratamientos efectuados. Resultados: Se registraron 17 casos de loxoscelismo de manejo hospitalario, cuya presentación responde al patrón epidemiológico nacional. La mayoría de los casos fue manejada con antimicrobianos, corticosteroides sistémicos, antihistamínicos y dapsona. De ellos, 11,8% correspondieron a loxoscelismo cutáneo visceral, manejados exitosamente con medidas de soporte, corticosteroides sistémicos y antihistamínicos. El 59% presentó resolución de las lesiones al mes de tratamiento, con cicatriz residual leve o hiperpigmentación postinflamatoria, sin mortalidad en nuestra serie. Discusión: La mayoría de los casos de loxoscelismo cutáneo presentó excelente respuesta y rápida resolución del cuadro tras el tratamiento asociado de corticosteroides sistémicos, antimicrobianos y dapsona, sugiriendo que el uso de estas terapias podría detener la progresión de la necrosis cutánea y prevenir las complicaciones asociadas al loxoscelismo.

Background: Loxoscelism is a common pathology in our environment with a broad spectrum of differential diagnoses and presentations, with potentially serious complications, even to the point of death. To date, there is no standard treatment for these patients. Aim: To describe the clinical manifestations, main complications, therapeutic management, and evolution of loxoscelism in an inpatient setting from a tertiary hospital in Chile. Methods: All patients consulting and hospitalized in the hospital of the Pontificia Universidad Católica de Chile with diagnosis of loxoscelism between 2014 to 2017 and evaluated by dermatologist were included. Review of clinical files, including symptoms, images, laboratory parameters and treatment. Results: We evaluated seventeen inpatient with loxoscelism, whose presentation responds to the national epidemiological pattern. Most cases were managed with antibiotics, systemic corticosteroids, antihistamines, and dapsone. From these, 11.8% corresponded to viscerocutaneous loxoscelism, successfully managed with supportive measures, systemic corticosteroids and antihistamines. Fifty-nine percent healed their cutaneous lesions after one month of treatment, with slight residual scarring or post inflammatory hyperpigmentation, without associated mortality in our series. Discussion: Most cases of cutaneous loxoscelism presented excellent response and rapid resolution of the disease after combined therapy with systemic corticosteroids, antibiotics and dapsone, suggesting that the use of these therapies could stop the progression of cutaneous necrosis and prevent complications associated with loxoscelism.

Loxoscelismo cutáneo y cutáneovisceral. Reporte de 4 casos / Cutaneus and viscerocutaneous loxoscelism. Repor of 4 cases

La mordedura por araña del género Loxosceles produce dermonecrosis en el sitio de la lesión y complicaciones sistémicas secundarias a reacciones enzimáticas de su veneno, lo que aumenta la tasa de mortalidad. El objetivo es reportar cuatro casos de loxoscelismo atendidos en el hospital General San Juan de Dios, donde los pacientes tuvieron una evolución satisfactoria a pesar de la inexistencia del antiveneno como manejo ideal de la toxicidad (AU)

Yellow sac spider (Cheiracanthium punctorium) bites in Slovenia: case series and review.

In Central Europe, reports of human envenomation by Cheiracanthium punctorium, commonly known as the yellow sac spider, are sporadic, despite the fact that this species is widespread in Europe. However, in recent years, C. punctorium has been repeatedly described globally in medical and toxicological literature. Its venom was found to possess insecticidal, haemolytic, cytotoxic, and membrane-damaging activities. Its bite is often very painful, frequently associated with local and transient cutaneous and neurotoxic effects, but sometimes also with systemic symptoms which require medical help. The main objective of this article is to introduce more details about C. punctorium, the clinical manifestations and circumstances of its bite, the characteristics of its venom and proposed clinical management. The authors provide case reports of patients bitten by C. punctorium during the 10-year observational period. All patients presented in this article showed generally mild clinical manifestations and recovered completely without sequelae. No further treatment in terms of hospital surveillance or specific clinical measures was necessary in any of the reported cases.

Antinociceptive effect of a novel armed spider peptide Tx3-5 in pathological pain models in mice.

The venom of the Brazilian armed spider Phoneutria nigriventer is a rich source of biologically active peptides that have potential as analgesic drugs. In this study, we investigated the analgesic and adverse effects of peptide 3-5 (Tx3-5), purified from P. nigriventer venom, in several mouse models of pain. Tx3-5 was administered by intrathecal injection to mice selected as models of postoperative (plantar incision), neuropathic (partial sciatic nerve ligation) and cancer-related pain (inoculation with melanoma cells) in animals that were either sensitive or tolerant to morphine. Intrathecal administration of Tx3-5 (3-300 fmol/site) in mice could either prevent or reverse postoperative nociception, with a 50 % inhibitory dose (ID50) of 16.6 (3.2-87.2) fmol/site and a maximum inhibition of 87 ± 10 % at a dose of 30 fmol/site. Its effect was prevented by the selective activator of L-type calcium channel Bay-K8644 (10 µg/site). Tx3-5 (30 fmol/site) also produced a partial antinociceptive effect in a neuropathic pain model (inhibition of 67 ± 10 %). Additionally, treatment with Tx3-5 (30 fmol/site) nearly abolished cancer-related nociception with similar efficacy in both morphine-sensitive and morphine-tolerant mice (96 ± 7 and 100 % inhibition, respectively). Notably, Tx3-5 did not produce visible adverse effects at doses that produced antinociception and presented a TD50 of 1125 (893-1418) fmol/site. Finally, Tx3-5 did not alter the normal mechanical or thermal sensitivity of the animals or cause immunogenicity. Our results suggest that Tx3-5 is a strong drug candidate for the treatment of painful conditions.

Systemic lupus erythematosus flare triggered by a spider bite.

Systemic lupus erythematosus is a chronic autoimmune disease with a relapsing and remitting course characterized by disease flares. Flares are a major cause of hospitalization, morbidity and mortality in patients with systemic lupus erythematosus. Some triggers for these exacerbations have been identified, including infections, vaccines, pregnancy, environmental factors such as weather, stress and drugs. We report a patient who presented with a lupus flare with predominantly mucocutaneous, serosal and cardiac involvement after being bitten by a spider and we present the possible mechanisms by which the venom elicited such a reaction. To the best of our knowledge, this is the first such case reported in the literature.

Characterization of the antinociceptive effect of PhTx3-4, a toxin from Phoneutria nigriventer, in models of thermal, chemical and incisional pain in mice.

Venom-derived peptides constitute a unique source of drug prototypes for the pain management. Many of them can modulate voltage-gated calcium channels that are central in the processing of pain sensation. PhTx3-4 is a peptide isolated from Phoneutria nigriventer venom, which blocks high voltage-activated calcium channels with low specificity, thereby leading to neuroprotection in models of ischemia in vitro. The aim of the present work was evaluating the potential of intrathecal PhTx3-4 in the reversal of different nociceptive states in mice, furthermore assessing the potential of PhTx3-4 in triggering motor side effects. We found that bellow 100 pmol/site, PhTx3-4 did not cause major motor side effects. By comparison, ω-conotoxin MVIIA and ω-conotoxin MVIIC triggered motor side effects at the doses of 10 and 100 pmol/site, respectively. Also, PhTx3-4 (30 pmol/site) caused no significant alterations in the forced locomotor activity test (rotarod) and in the exploratory activity test (versamax). In a model of inflammatory persistent pain (formalin test), PhTx3-4 reversed nociceptive behavior both pre or post-administered, although this effect was observed only at the inflammatory phase of the test and not at the neurogenic phase. Comparatively, ω-conotoxin MVIIC was effective only when post-administered in the formalin test. Nonetheless, PhTx3-4 treatment was devoid of action in acute nociceptive thermal model (hotplate test), whereas morphine showed efficacy in this test. Efficacy of PhTx3-4 in the formalin test was associated with inhibition of formalin-induced glutamate release in the cerebrospinal fluid. PhTx3-4, but not ω-conotoxin MVIIC, reversed NMDA-induced nociceptive behavior indicating a putative role of PhTx3-4 at ionotropic glutamate receptors. Finally, we observed efficacy of PhTx3-4 in ameliorating mechanical hypersensitivity induced by paw incision, a post-operative and more clinically relevant pain model. Taken together, our data show that PhTx3-4 possesses antinociceptive effect in different models of pain in mice, suggesting that this toxin may serve as drug prototype for pain control.

Herida por picadura de loxosceles tratada con una matriz sintética de polímeros: nueva perspectiva en la cura avanzada de heridas complejas / Loxoceles bite wound treatment with synthetic polymer matrix

El loxoscelismo es un cuadro tóxico producido por el veneno que inoculan con su mordedura las arañas del género Loxosceles («arañas de rincón»). Puede presentarse bajo dos formas clínicas: loxoscelismo cutáneo y loxoscelismo cutáneo-visceral. En España se encuentra la especie Loxosceles rufescens, a la que se le han atribuido casos de loxoscelismo cutáneo. El loxoscelismo cutáneo se inicia con prurito, posteriormente dolor intenso y evoluciona hacia una forma necrosante más grave o bien a una forma edematosa, de mejor pronóstico, como el caso que exponemos a continuación. El diagnóstico es clínico. El tratamiento sistémico consiste en analgésicos, antihistamínicos, corticoides, antibióticos de amplio espectro y dapsona en casos graves. El tratamiento local se basa en la limpieza y el desbridamiento de la lesión y curas avanzadas para heridas complejas. No es infrecuente que requieran injerto cutáneo. El caso que exponemos es el de una joven de 18 años que sufrió la picadura o mordedura de una loxosceles en el dorso del pie y que desarrolló una necrosis de tejidos profundos en la zona. Presentó complicaciones sistémicas como leucocitosis y fiebre y también infección local y celulitis, por lo que requirió tratamiento sistémico e ingreso hospitalario y curas de terapéutica avanzada. Finalmente se ha conseguido la recuperación de la integridad cutánea en 84 días (AU)

Loxocelism is a toxic condition produces by the venom inoculated by the bit of the recluse spider (genus Loxosceles). In can appear in two clinical forms: cutaneous loxocelism and viscerocutaneous loxocelim. The species Loxoceles rufescens, found in Spain, is responsible of cases of cutaneous loxocelism. Cutaneous loxocelism starts with an itch, later giving rise to intense pain, and it later takes either a more or less severe necrotic form or an edematous form. The latter, with a better prognosis, is the one we focus on here. The diagnosis is clinical. The systemic treatment consists in analgesics, antihistamines, corticosteroids, broad-spectrum antibiotics, and dapsone in severe cases. The local treatment is based on the cleaning and debridement of the wound, and in advanced treatments for complex wounds. It is not uncommon that such wounds require skin grafting. We present the case of an 18-year female bitten by a loxosceles on the dorsal area of the foot. She developed a deep tissue necrosis in the area. She presented systemic complications such as leucocitosis, fever, local infection and cellulitis. Systemic treatment and hospitalization were required, as well as advanced therapeutic care. Finally, cutaneous integrity was restored after 84 days (AU)

Huwentoxin-XVI, an analgesic, highly reversible mammalian N-type calcium channel antagonist from Chinese tarantula Ornithoctonus huwena.

N-type calcium channels play important roles in the control of neurotransmission release and transmission of pain signals to the central nervous system. Their selective inhibitors are believed to be potential drugs for treating chronic pain. In this study, a novel neurotoxin named Huwentoxin-XVI (HWTX-XVI) specific for N-type calcium channels was purified and characterized from the venom of Chinese tarantula Ornithoctonus huwena. HWTX-XVI is composed of 39 amino acid residues including six cysteines that constitute three disulfide bridges. HWTX-XVI could almost completely block the twitch response of rat vas deferens to low-frequency electrical stimulation. Electrophysiological assay indicated that HWTX-XVI specifically inhibited N-type calcium channels in rat dorsal root ganglion cells (IC50 ∼60 nM). The inhibitory effect of HWTX-XVI on N-type calcium channel currents was dose-dependent and similar to that of CTx-GVIA and CTx-MVIIA. However, the three peptides exhibited markedly different degrees of reversibility after block. The toxin had no effect on voltage-gated T-type calcium channels, potassium channels or sodium channels. Intraperitoneal injection of the toxin HWTX-XVI to rats elicited significant analgesic responses to formalin-induced inflammation pain. Toxin treatment also changed withdrawal latency in hot plate tests. Intriguingly, we found that intramuscular injection of the toxin reduced mechanical allodynia induced by incisional injury in Von Frey test. Thus, our findings suggest that the analgesic potency of HWTX-XVI and its greater reversibility could contribute to the design of a novel potential analgesic agent with high potency and low side effects.