Neuroprotective effects of vinpocetine, as a phosphodiesterase 1 inhibitor, on long-term potentiation in a rat model of Alzheimer's disease.

BACKGROUND: Vinpocetine (Vin) is known as a phosphodiesterase 1 inhibitor (PDE1-I) drug with multilateral effects, including antioxidant and anti-inflammatory activity. In this research, we investigated the neuroprotective and therapeutic effects of Vin through hippocampal synaptic plasticity on a rat's model of Alzheimer's disease (AD) induced by an intracerebroventricular (ICV) injection of beta-amyloid (Aß). METHODS: Sixty adult male Wistar rats were randomly divided into six groups: 1. control, 2. sham, 3. Aß, 4. pretreatment (Vin + Aß): Vin (4 mg/kg, gavage) for 30 days and then, inducing an AD model by an ICV injection of Aß(1-42), 5. treatment (Aß + Vin): inducing an AD model and then receiving Vin for 30 days by gavage, and 7. pretreatment + treatment (Vin + Aß + Vin): receiving Vin by gavage for 30 days before and 30 days after the induction of an AD model. After these procedures, via stereotaxic surgery, the stimulating electrodes were placed at the perforant pathway (PP) and the recording electrodes were implanted in the dentate gyrus. RESULTS: Excitatory postsynaptic potential (EPSP) slope and population spike (PS) amplitude in the Aß group meaningfully diminished compared to the control group after the induction of long-term potentiation (LTP). CONCLUSIONS: Vin could significantly prevent the Aß effects on LTP. It can be concluded that pretreatment and treatment with Vin can be neuroprotective against harmful consequences of Aß on hippocampal synaptic plasticity.

A case of Spider bite localized to the eyelid.

Loxosceles Spiders have a worldwide distribution and are considered one of the most medically important groups of Spiders. The venom from Spiders of the genus Loxosceles, the most famous being Loxosceles reclusa (brown recluse Spider), can promote severe local and systemic damages. This report describes a girl presenting with a Spider bite over her right upper eyelid.

Brown recluse spider bite to the upper lip.

Brown recluse spiders are predominantly found in south central United States. Their bites usually cause mild self-limiting reactions, although localized tissue necrosis and rare systemic, potentially fatal, envenomations are known to occur. Herein, we report an atypical presentation of a brown recluse bite in a 20 year old female who was admitted to the intensive care unit due to angioedema and cellulitis. We photographically document the bite site for twenty-four hours following envenomation. She received glucocorticoids, antihistamines, antibiotics and dapsone while hospitalized and was subsequently discharged with complete resolution of symptoms without the development of tissue necrosis or scarring.

Acute generalized exanthematous pustulosis and Coombs-positive hemolytic anemia in a child following Loxosceles reclusa envenomation.

Previously reported cases of acute generalized exanthematous pustulosis secondary to brown recluse spider bite have been questioned due to lack of identification of the spider or because of the concomitant administration of antibiotics. We report a 9-year-old boy who arrived at the emergency department with a confirmed Loxosceles reclusa bite to the neck. On the third day of hospitalization, he developed hundreds of monomorphous, sterile pustules, initially in intertriginous areas. The eruption disseminated and was followed by pinpoint desquamation typical for acute generalized exanthematous pustulosis. During this he also developed late onset Coombs-positive hemolytic anemia and systemic loxoscelism. Sphingomyelinase in Loxosceles venom induces the production of interleukin-8 and granulocyte-macrophage colony-stimulating factor, cytokines involved in the pathogenesis of acute generalized exanthematous pustulosis, providing a mechanism by which Loxosceles reclusa bite may trigger acute generalized exanthematous pustulosis. We suggest that this case adds Loxosceles envenomation to the spectrum of agents that can trigger acute generalized exanthematous pustulosis.

A rare cause of severe periorbital edema and dermonecrotic ulcer of the eyelid in a child: brown recluse spider bite.

Spider bites are a worldwide problem. Brown recluse spider bites can lead to severe local or systemic clinical effects, such as edema, necrotic ulcer, rashes, fever, chills, nausea, vomiting, malaise, arthralgia, myalgia, hemolysis, leukocytosis, disseminated intravascular coagulation, renal failure, and death. Eyelid bites from brown recluse spiders are rare. We report a child with severe facial edema and a dermonecrotic ulcer on the eyelid. Upon laboratory examination, leukocytosis with a significant left shift was detected. The patient was treated with antibiotics, systemic corticosteroid and conservative therapy that included saline compresses and ocular lubrication. No surgical excision was required. Vision was not impaired. A dermonecrotic ulcer is a severe complication of brown recluse spider bites. Since the diagnosis is difficult, clinical and epidemiological findings and a detailed history are important for an accurate diagnosis.

Brown recluse spider (Loxosceles reclusa) envenomation leading to acute hemolytic anemia in six adolescents.

Loxosceles reclusa (brown recluse spider) bites often cause local envenomation reactions; however, acute hemolysis from systemic loxoscelism is rare. To highlight this important diagnostic consideration for unexplained hemolysis in areas endemic for brown recluse spiders, we report on 6 adolescents with acute hemolytic anemia from presumed L reclusa bites.

Loxoscelism and negative pressure wound therapy (vacuum-assisted closure): an experimental study.

Brown recluse spider (Loxosceles) bites cause lesions ranging from chronic necrotic ulcers to acute life-threatening sepsis. Based on our experience in treating acute and chronic wounds with negative pressure, we postulated that vacuum-assisted closure (VAC) would be valuable in this application. Chester pigs were procured and injected with purified brown recluse spider venom, 1 µl of venom in two anterior sites and 0·1 µl of venom in two posterior sites on their dorsum. For each concentration of venom, treatment consisted of either VAC or dry, non adherent dressings (control group). Each day, the wounds were inspected and measured. For wounds receiving 1·0 µl of venom, the control wounds decreased in surface area to 50% of initial size after 7 days and none had healed, whereas VAC-treated wounds were less than 50% after 48 hours and completely healed and reepithelialised after 8 days. Wounds with 0·1 µl of venom had 50% reduction after 5 days with no complete healing for control wounds, and the VAC wounds were 50% after 48 hours and all had closed and reepithelialised after 5 days. Our experimental study showed an accelerated healing time in the animals treated with the VAC as compared with controls.

Diagnosis of loxoscelism in two Turkish patients confirmed with an enzyme-linked immunosorbent assay (ELISA) and non-invasive tissue sampling.

Confirmed envenomations due to Loxosceles reclusa have not been previously documented in Turkey, to our knowledge. This brief report describes two Turkish patients with suspected envenomation by Loxosceles spider bites on the eyelids. Material obtained by swabbing the lesions with gauze was tested using a venom-specific enzyme-linked immunosorbent assay (ELISA). Both patients tested positive for the presence of Loxosceles venom.

Efficacy and tolerability of vardenafil in men with mild depression and erectile dysfunction: the depression-related improvement with vardenafil for erectile response study.

OBJECTIVE: Erectile dysfunction and depression are highly associated. Previous studies have shown benefits of phosphodiesterase-5 inhibitor treatment for erectile dysfunction associated with antidepressant therapy or subsyndromal depression. The present study assessed the safety and efficacy of vardenafil in men with erectile dysfunction and untreated mild depression. METHOD: In this 12-week, multicenter, randomized, flexible-dose, parallel-group, double-blind study, 280 men with erectile dysfunction for at least 6 months and untreated mild major depression received placebo or vardenafil, 10 mg/day, for 4 weeks, with the option to titrate to 5 mg/day or 20 mg/day after each of two consecutive 4-week intervals. Endpoints included International Index of Erectile Function erectile function domain and 17-item Hamilton Depression Rating Scale (HAM-D) scores. RESULTS: Vardenafil produced statistically significant and clinically meaningful improvement in all erectile function parameters. The International Index of Erectile Function erectile function domain score was 22.9 with vardenafil compared to 14.9 with placebo. The HAM-D score was lower in the vardenafil group (7.9) than in the placebo group (10.1). Treatment with vardenafil was the most important predictor for return to normal erectile function. Improvement in International Index of Erectile Function erectile function domain score was the most important predictor of remission in depressive symptoms. CONCLUSIONS: Vardenafil was well tolerated and highly efficacious in men with erectile dysfunction and untreated mild major depression. Significant improvements in erectile function and depression were observed in patients treated with vardenafil versus placebo. Erectile dysfunction treatment should be considered a component of therapy for men with depression and erectile dysfunction.

Pulmonary hypertension: inhaled nitric oxide, sildenafil and natriuretic peptides.

Phosphodiesterase-5 (PDE5) inhibitors and other agents that modulate intracellular cGMP are now emerging as promising, safe, and easy to administer therapies for pulmonary hypertension, with relatively few side effects. Recent studies have shown that PDE5 inhibitors are potent acute pulmonary vasodilators in experimental models that partially reverse established pulmonary arterial hypertension and blunt chronic pulmonary hypertension. In addition, studies on animals reveal that PDE5 inhibitors work in concert with nitric oxide and/or natriuretic peptide levels by enhancing intracellular cGMP and cGMP-mediated vasodilator effects. Further, the combination of PDE5 inhibitors and agents that increase cGMP or cAMP also yields additive beneficial effects on pulmonary hemodynamics in patients with pulmonary arterial hypertension.

Aural involvement in loxoscelism: case report and literature review.

An 11-year-old male presented with fever, rash, and a necrotic lesion on the lobule of the left ear. The lesion became tender and formed an eschar over 4 days. The patient developed leukocytosis, hemolytic anemia, and proteinuria, and was diagnosed with systemic loxoscelism from a brown recluse spider bite. He was managed with supportive therapy and improved in 4 days. Loxoscelism is a clinical diagnosis which should be suspected in an otherwise healthy patient with a necrotic wound, particulary in the endemic Southern and Midwestern United States. Physicians should be aware of this disease entity and its complications.

Inhibitory effects of flavonoids on phosphodiesterase isozymes from guinea pig and their structure-activity relationships.

The structure-activity relationships of flavonoids with regard to their inhibitory effects on phosphodiesterase (PDE) isozymes are little known. The activities of PDE1-5 were measured by a two-step procedure using cAMP with [(3)H]-cAMP or cGMP with [(3)H]-cGMP as substrates. In the present results, PDE1, 5, 2, and 4 isozymes were partially purified from guinea pig lungs in that order, and PDE3 was from the heart. The IC(50) values of PDE1-5 were greater than those reported previously for the reference drugs, vinpocetin, EHNA, milrinone, Ro 20-1724, and zaprinast, by 5-, 5-, 7-, 5-, and 3-fold, respectively. As shown in Table 2, luteolin revealed non-selective inhibition of PDE1-5 with IC(50) values in a range of 10-20 microM, as did genistein except with a low potency on PDE5. Daidzein, an inactive analogue of genistein in tyrosine kinase inhibition, showed selective inhibition of PDE3 with an IC(50) value of around 30 microM, as did eriodictyol with an IC(50) value of around 50 microM. Hesperetin and prunetin exhibited more-selective inhibition of PDE4 with IC(50) values of around 30 and 60 microM, respectively. Luteolin-7-glucoside exhibited dual inhibition of PDE2/PDE4 with an IC(50) value of around 40 microM. Diosmetin more-selectively inhibited PDE2 (IC(50) of 4.8 microM) than PDE1, PDE4, or PDE5. However, biochanin A more-selectively inhibited PDE4 (IC(50) of 8.5 microM) than PDE1 or PDE2. Apigenin inhibited PDE1-3 with IC(50) values of around 10-25 microM. Myricetin inhibited PDE1-4 with IC(50) values of around 10-40 microM. The same was true for quercetin, but we rather consider that it more-selectively inhibited PDE3 and PDE4 (IC(50) of < 10 microM). In conclusion, it is possible to synthesize useful drugs through elucidating the structure-activity relationships of flavonoids with respect to inhibition of PDE isozymes at concentrations used in this in vitro study.

Isolation and identification of Clostridium perfringens in the venom and fangs of Loxosceles intermedia (brown spider): enhancement of the dermonecrotic lesion in loxoscelism.

Loxoscelism or the envenoming by the brown spiders (Loxosceles genus spiders), may produce extensive dermonecrosis and hemorrhage at the bite site and, eventually, systemic reactions that may be lethal. Isolation and identification of many different bacteria, among them Clostridium perfringens, of great medical importance due to its involvement in dermonecrotizing and systemic conditions, was carried out from the venomous apparatus (fangs and venom) of spiders obtained directly from nature, through microbiological cultures in aerobic and anaerobic conditions. Working with Loxosceles intermedia venom (alone) and with the venom conjugated with Clostridium perfringens using rabbits as experimental models for dermonecrosis, allowed for the observation that venom and anaerobic bacteria conjugated resulted in a striking increase of the dermonecrotic picture when compared to venom alone, suggesting a role for Clostridium perfringens in the severe dermonecrotic picture of these patients and opening the possibility for the association of antibiotic therapy in treating loxoscelism.

Direct correlation between diffusion of Loxosceles reclusa venom and extent of dermal inflammation.

OBJECTIVES: Envenomation by Loxosceles species (brown recluse) spiders results in large dermal inflammatory lesions. Venom-induced dermal inflammation occurs indirectly via soluble mediators of inflammation. This study aimed to explore whether the anatomic extent of dermonecrotic arachnidism is due to the cascade of soluble proinflammatory mediators elicited by venom deposited at the bite site, or due to diffusion of the venom per se. METHODS: Three New Zealand white rabbits received intradermal L. reclusa venom (3-microg) injections in the flank. At the time of maximum dermal inflammation (24 hr), paired 4-mm dermal biopsies were obtained in 2-cm intervals extending 0 to 12 cm from the inoculation site. Normal dermal tissue was obtained from the opposite flank to serve as a negative control. One biopsy sample from each interval was homogenized and assayed for myeloperoxidase (MPO) activity and for the presence of venom via an enzyme immunoassay (EIA). The other paired dermal biopsy was sectioned, and examined for the presence of polymorphonuclear neutrophils (PMNs) by microscopy. Lesional areas were measured using digital images imported into imaging software. RESULTS: Mean +/- SD lesional diameter 24 hours post inoculation measured 9.18 +/- 0.64 cm. Venom was detected in biopsies 0 to 10 cm from the injection site. As expected, the highest venom concentrations were measured at the inoculation site (4.28 +/- 3.9 ng/4 mm). In addition, PMNs and MPO were detected up to 8 and 10 cm from the inoculation site, respectively. Neither PMNs nor MPO was detected in tissue absent of venom (kappa = 0.88, p < 0.001). CONCLUSIONS: Loxosceles venom diffuses from the envenomation site. The extent of dermal inflammation mirrors the extent of Loxosceles venom diffusion. This observation implies that the venom itself defines the extent and magnitude of tissue injury following Loxosceles envenomation.

Tetracycline and penicillin resistant Clostridium perfringens isolated from the fangs and venom glands of Loxosceles laeta: its implications in loxoscelism treatment.

The venom of Loxosceles spiders produces severe dermonecrotic damage, intravascular hemolysis, systemic alterations and risk of death. Clostridium perfringens is present in the microbial flora of the fangs and venom glands of Loxosceles intermedia. Its inoculation with the venom may infect the wound site and exacerbate the dermonecrotic damage. This anaerobic bacterium is widely distributed in nature and capable of damage with similar characteristics and severity to the spider venom. In this study we isolated and characterized species of Clostridium from the fangs and venom glands of Loxosceles laeta, including C. perfringens. The sensitivity patterns of different isolates of C. perfringens were evaluated by minimum inhibitory concentration against penicillin, ampicillin, erythromycin, gentamicin, chloramphenicol, clindamycin and tetracycline, under anaerobic conditions, using the method of microdilution in broth. Strain C. perfringens H28 showed resistance to penicillin, ampicillin, tetracycline and chloramphenicol. Resistance to penicillin and ampicillin was mediated by beta-lactamase. In vivo evaluation of dermonecrosis in rabbits using L. laeta venom co-inoculated with isolate C. perfringens H28 produced an increase in the area of dermonecrotic lesions in the presence of penicillin and tetracycline, but not with gentamicin. Antibiotic therapy Loxosceles poisoning should be re-evaluated, considering the existence of multi-resistant strains of C. perfringens.

The brown spider Loxosceles laeta: source of the remedy Tarentula cubensis?

The homeopathic remedy Tarentula cubensis (Cuban tarantula), used in homeopathy to treat abscesses with burning pains, gangrene, septicaemia, toxaemia, has been grouped by homeopathic authorities with either the mygalomorph or wolf spiders. The original specimen used for preparation of the mother tincture was decomposed, leaving the spider's exact identity in doubt. Investigation of the toxicological and clinical literature, compared with homeopathic materia medica, reveals the brown spider, Loxosceles laeta, indigenous to South America but present also in Mid- and North America, as a more likely source. Venoms of spiders of the genus Loxosceles cause severe necrotic arachnidism, as well as, in some cases, a life-threatening systemic reaction marked by renal failure, disseminated intravascular coagulation, thrombocytopeania, coma and convulsions.