[Toxic retinopathy caused by veterinary antiparasitic closantel: a case report].

A 32-year-old female patient presented with bilateral vision loss for 2 months following her intake of various antiparasitic drugs, including closantel, a veterinary drug, for a self-perceived intraocular parasitic infection. Swept-source optical coherence tomography revealed diffuse hyperreflectivity between the outer nuclear layer and the retinal pigment epithelium, as well as the largely indistinguishable outer retinal layers. This case was clinically diagnosed with veterinary closantel-induced toxic retinopathy and had a poor visual prognosis after nerve nutrition and circulation improvement therapy due to the long duration of the disease.

Closantel retinal toxicity: Recovery from severe vision loss after corticosteroid therapy.

PURPOSE: To present a relatively rare case of retinal toxicity and consequent severe vision loss due to Closantel ingestion. CASE REPORT: A 37-year-old female presented with sudden painless decrease vision in both eyes. She had no previous history of medical disease and denied any trauma. The patient had accidentally ingested Closantel a few days prior to presentation. Closantel is a veterinary anti-helminthic drug used mainly in livestock. Best corrected visual acuity (BCVA) at presentation was 20/200 bilaterally. There was no relative afferent pupillary defect (RAPD) and red saturation test was normal. Macular optical coherence tomography (OCT) revealed disruption in the outer retinal layer and ellipsoid zone in both eyes. A diagnosis of retinal toxicity due to Closantel was made and the patient was started on 1 mg/kg oral prednisolone acetate. On the 45th day after presentation, her BCVA had improved to 20/20 bilaterally. CONCLUSION: Closantel is a potentially toxic drug causing destruction of the neurosensory retina and visual disturbances. We suggest eye-care personnel awareness regarding the risk of Closantel-induced retinal toxicity and prompt treatment with systemic steroids should be considered.

Repositioning of Anthelmintic Drugs for the Treatment of Cancers of the Digestive System.

Tumors of the digestive system, when combined together, account for more new cases and deaths per year than tumors arising in any other system of the body and their incidence continues to increase. Despite major efforts aimed at discovering and validating novel and effective drugs against these malignancies, the process of developing such drugs remains lengthy and costly, with high attrition rates. Drug repositioning (also known as drug repurposing), that is, the process of finding new uses for approved drugs, has been gaining popularity in oncological drug development as it provides the opportunity to expedite promising anti-cancer agents into clinical trials. Among the drugs considered for repurposing in oncology, compounds belonging to some classes of anthelmintics-a group of agents acting against infections caused by parasitic worms (helminths) that colonize the mammalian intestine-have shown pronounced anti-tumor activities and attracted particular attention due to their ability to target key oncogenic signal transduction pathways. In this review, we summarize and discuss the available experimental and clinical evidence about the use of anthelmintic drugs for the treatment of cancers of the digestive system.

Urine retention in cattle putatively associated with injection of an ivermectin and closantel anthelmintic formulation into the ischiorectal fossa.

CASE HISTORY: A group of 39, 19-22-month-old Friesian bulls were administered an ivermectin/closantel anthelmintic via intended S/C injection in the ischiorectal fossa on 15 June 2017 (Day 0). Over the next 50 days, 22 affected bulls presented various degrees of anorexia, abdominal pain and urine dribbling. Seventeen bulls were examined by transrectal ultrasonography which revealed urinary bladder distension in all 17, and peritoneal fluid accumulation in some. Overall, eight bulls died or were subjected to euthanasia. On-farm postmortem examination of three bulls revealed urinary bladder rupture. CLINICAL FINDINGS: On Day 50 one affected live bull was admitted to Massey University for further investigation. This bull continuously dribbled urine and had an overtly distended urinary bladder as determined by rectal palpation and ultrasonography. PATHOLOGICAL FINDINGS: Postmortem examination of this bull revealed a markedly distended urinary bladder, massive subcapsular and pericapsular renal oedema with retroperitoneal fluid accumulation, minimal hydronephrosis and no evidence of mechanical urinary outflow obstruction. The right ischiorectal fossa contained multifocal areas of tissue fibrosis that extended into areas innervated by the distal cutaneous branch of the pudendal nerve and the pelvic nerve. Histopathological changes consisted of extensive fibrosis, myonecrosis and neurodegeneration, and evidence of granulation tissue and inflammation at the putative injection site and in surrounding tissues. DIAGNOSIS: A local inflammatory reaction at the presumed injection site together with localised peripheral neurodegeneration and myelopathy may have led to detrusor-sphincter dyssynergia causing urine retention. CLINICAL RELEVANCE: These cases of urine retention and bladder rupture in cattle were of putative iatrogenic origin. Veterinarians should be aware of this rare complication after S/C injections in the ischiorectal fossa.

Target animal safety testing of an oral salicylanilide suspension, oxyclozanide, for the treatment of fascioliasis in bovine in China.

The aim of this study was to determine the potential toxicity risk of an oxyclozanide suspension to the target animal, bovine. In this experiment, 32 Simmental beef cattle were fattened and fed a full-price diet without antimicrobial agents. The test cattle were divided into 4 groups, which were treated with 0, 1, 3, and 5 times the recommended dosage through continuous intermittent oral administration at intervals of 2 days. The body weight of the cattle was recorded before and after the experiment, and the weight changes were calculated. The safety of the drugs was evaluated by weight gain, observation of clinical toxicity, haematology, clinical chemistry and histopathology. The results showed that the cattle had different degrees of diarrhoea, loss of appetite and depression after administration. The results of clinicopathology had no significant effect. The results of pathological examination showed that there was a certain degree of damage in the 5 times recommended dose group. The recommended dose was safe to use. Thus, the recommended dose should be given by a single oral administration to ensure the safe use of this drug in the clinic.

Does closantel in therapeutic doses display thyroid hormone-like activity in sheep?

The aim of this study was to define the thyroid hormone-like activity of closantel in sheep by measuring some blood parameters that are known to be influenced by thyroid hormones triiodothyronine (T3) and thyroxine (T4). Our hypothesis was that, if closantel possesses thyroid hormone-like activity, its use under in vivo conditions will result in changes similar to those in hyperthyroidism. The study was conducted in 20 Jezersko-Solchava breed sheep. Blood sampling was performed before and 10 days after routine anthelmintic treatment with closantel. Complete blood count, plasma cholesterol, triglycerides, protein, and albumin levels, as well as those of serum T3 and T4, were compared before and 10 days after closantel administration. This routine anthelmintic treatment of sheep with closantel did not significantly influence hematological parameters, thyroid hormone levels, or most of the biochemical parameters. No evidence was found for thyroid hormone-like activity of closantel in sheep. However, significantly (P < 0.01) elevated levels of plasma triglycerides were present 10 days after closantel administration.

Salicylanilide ester prodrugs as potential antimicrobial agents--a review.

Salicylanilides have been a subject of interest in medicinal chemistry as a group with a wide range of biological activities. The antibacterial (including antimycobacterial) and antifungal activities have come to be viewed as very significant. The synthesis of new prodrugs to counter a number of problematic properties of salicylanilides is a current trend. This article brings together the known basic facts about these prodrugs, particularly about the different mechanisms of the antimicrobial action of salicylanilides, including salicylanilide toxicity and undesired effects. The largest part of this group consists of antimicrobial salicylanilide esters with different organic acids, e.g. acetates, carbamates, esters with N-protected amino acids, and mutual antibacterial compounds with known antibacterial agents (ß-lactames and linezolid), with the activity and structure-activity relationships of these compounds being of particular interest. This review summarizes the activity of salicylanilides as potential virulence inhibitors attributable to a blockade of the type III secretion pathway. Many salicylanilide ester derivatives have been demonstrated an effective and promising treatment against pathogenic fungi and bacteria (especially against Gram-positive, tuberculous and atypical mycobacterial strains), including strains such as methicillin-resistant Staphylococcus aureus and isoniazid-resistant mycobacteria which are resistant to one or more clinically used drugs.

Polioencephalomalacia associated with closantel overdosage in a goat.

This report describes clinical and pathological findings associated with closantel (a halogenated salicylanilide anthelmintic) overdosage in a 3-year-old goat. The clinical signs included blindness, incoordination, ataxia, depression of the palpebral and pupillary reflexes, and recumbency. No gross lesions were noted in tissue or organs at necropsy, but microscopic lesions were seen in nervous tissue and hepatic cells. Polioencephalomalacia was clearly evident. Bilaterally symmetrical status spongiosus of the white matter of the brain, bilateral laminar necrosis, microcavitations, ischaemic cell change and severe degeneration of the cerebellum were seen in nervous tissue. Fatty change and hydropic degeneration in the liver and hepato-cellular degeneration were observed histologically.

Photocontact dermatitis and chloracne: two major occupational and environmental skin diseases induced by different actions of halogenated chemicals.

Among occupational and environmental disorders, contact or photocontact dermatitis and an acneiform eruption are two major skin disorders. Photocontact dermatitis was historically caused by various halogenated salicylanilides, while the acne is induced by halogenated aromatic hydrocarbons and thus called chloracne. Therefore, it should be noted that halogenated chemical compounds are important causative agents in the occupational and environmental medicine. In photocontact dermatitis, photoconjugation of epidermal cells with a photohaptenic halogenated chemical is the initial step. Langerhans cells serve as antigen-presenting cells and T cells sensitized by photoantigen-bearing Langerhans cells induce this photosensitivity. On the other hand, in chloracne, halogeneted hydrocarbons render keratinocytes of the outer root sheath and sebaceous duct hyperplastic. The dilated infundibulum of most hair follicles is then filled with comedone that consist of many accumulated layers of keratinized cells and sebum. Therefore, halogenated chemicals exhibit different actions, i.e. the induction of an immunologic consequence and the modulation of keratinocyte biology. These two conditions also provide good experimental models for investigating dermatology.

Spectrum of cross-photosensitization in 18 consecutive patients with contact photoallergy to ketoprofen: associated photoallergies to non-benzophenone-containing molecules.

Contact photoallergy to ketoprofen gels has been widely reported, and cross-sensitivity reactions with other compounds, such as tiaprofenic acid, fenofibrate and benzophenones, are well known. However, positive photopatch tests to other different non-benzophenone-related compounds have recently been observed. We report the results of photopatch testing in patients with contact photoallergy to ketoprofen and discuss the spectrum of cross-sensitization to ketoprofen. 18 consecutive patients with a history of photocontact dermatitis from ketoprofen were investigated. Patch and photopatch tests were performed. As expected, we observed positive photopatch tests to Ketum* gel and ketoprofen 2.5% in petrolatum in all patients (100%). However, it was remarkable to note positive photopatch tests to other unexpected and non-relevant allergens, including fentichlor (67%), tetrachlorosalicylanilide (28%), triclosan (17%), tribromsalan (11%) and bithionol (11%), with no clinical relevance. Interestingly, these agents belong to the family of halogenated salicylanilides and related compounds, which have been forbidden in Europe since the 1970s. Our results raise the question of hyper-photosusceptibility to non-relevant allergens induced by photosensitivity to ketoprofen. The mechanism may involve the high photoreactivity induced by the association of a benzene ring with an oxygen group.

[Photocontact dermatitis due to ketoprofen and photosensitization to tetrachlorosalicylanide and to Fenticlor(R)]. / Photoallergie au kétoprofène et photosensibilisations au tétrachlorosalicylanide et au Fenticlor(R).

BACKGROUND: Photoallergy to ketoprofen and cross reactivity of ketoprofen with diphenylketones are well known; here are some cases of photoreaction to ketoprofen and unusual substances. PATIENTS AND METHODS: Eleven photoallergic to ketoprofen patients were photo patch tested with Ketum(R), ketoprofen, oxybenzone, tiaprofenic acid, fenofibrate, and also chlorphenesin, sunscreen series, and photobiologists series (without lichen mix and benzocaine). We performed tests at day 0, we irradiated them with UVA at day 2, and control series remained closed. We performed readings at day 3 and 4 according to ICDRG's recommendations. RESULTS: Nine tested patients had positive reactions to the irradiated tests with no expected allergens: fenticlor (9 cases), halogenated salicylanilides (4 cases), dibenzoylmethane (3 cases) and cinnamate (1 case). DISCUSSION: The mechanism of these unusual photosensitizations is discussed. These cases show that it is important to test sunscreen series and photobiologists series in patients photoallergic to ketoprofen.

Closantel intoxication in a dog.

A case of overdosage with closantel, a salicynalide derivative, in a dog is described. The dog received 6 times the recommended dosage. Closantel induced optic neuritis, retinal degeneration, partial deafness, hepatotoxicosis and myopathy. Only the blindness was irreversible. The therapy included albumin administration to reduce the acute toxicity of closantel.

A new animal model for contact dermatitis: the hairless guinea pig.

Allergic and irritant contact reactions were evaluated in the recently identified hairless guinea pig, Crl:IAF(HA)BR, a mutant from the Hartley strain. The cutaneous changes were observed macro- and microscopically. The irritant contact dermatitis was induced by croton oil, 2,4-dinitrochlorobenzene (DNCB), or anthralin. Both hairless and hairy guinea pigs developed similar reactions to these chemicals. The density of the epidermal Langerhans cells (LC) of hairless guinea pigs was significantly higher than that in the hairy strain. Allergic contact sensitization was easily induced with DNCB. Photoallergic contact sensitization was also induced with tetrachlorosalicylanilide (TCSA) but not with tribromosalicylanilide (TBS). However, by administration of cyclophosphamide before sensitization, positive photocontact responses were seen with TBS. These results indicate that hairless guinea pigs can be used as animal models for investigation of immunologic and nonimmunologic contact reactions.

Genetic control of contact photosensitivity to tetrachlorosalicylanilide. I. Preferential activation of suppressor T cells in low responder H-2k mice.

The genetic control of contact photosensitivity (CPS) to 3,3',4',5-tetrachlorosalicylanilide (TCSA) was studied in H-2- and IgH-congenic mice. The H-2 complex was found to play a major role in determining the pattern of responsiveness, whereas the effect of the Igh locus on the response was not apparent. The H-2k haplotype was closely associated with low responders, whereas mice with the H-2b,d alleles were high responders. The responsiveness of the H-2k strains was converted from low to high levels by treatment with cyclophosphamide (CY) before photosensitization. Transfer of spleen cells from photosensitized H-2k mice showed a suppressive effect on the development of the CPS reaction of syngeneic recipients pretreated with CY. These spleen cells contained antigen-specific CD4+, CD8- suppressor T cells (Ts) that functioned in the induction phase of CPS. The in vitro proliferation of immune lymph node T cells pulsed with photohapten-coupled cells plus peritoneal adherent cells was suppressed by the addition of anti-I-A monoclonal antibody in both H-2d and H-2k strains, suggesting that the I-A molecule are responsible for inducing the positive immune response. On the other hand, such proliferation was significantly enhanced by the addition of anti-I-E alpha antibody in H-2k, but not H-2d, mice. This implies that the low responsiveness of CPS in the H-2k strain is due to the preferential activation of Ts via I-Ek molecules. The present observation further supports the important role of the I-E molecule in the suppressor circuit of CPS to TCSA.

Persistent light reaction. Successful treatment with cyclosporin A.

A 53-year-old male patient who had suffered for several years from severe persistent light reaction possibly due to tribromsalan photosensitivity was treated with cyclosporin A after long-term low-dose administration of corticosteroids which had to be discontinued. PUVA therapy was impracticable due to the extraordinarily high UVA sensitivity. When cyclosporin A blood concentrations between 100 and 200 ng/ml were reached, the patient was nearly free from symptoms; the excellent clinical response was also documented by phototesting performed prior to and during therapy. Cyclosporin A may be a valuable therapeutic alternative to systemic corticosteroids for severe cases of persistent light reaction which cannot be controlled by photoprotective measures.

[Photosensitivity in human pathology: mechanisms and clinical aspects]. / La photosensibilité en pathologie humaine: mécanismes et aspects cliniques.

Photosensitivity diseases are reviewed. The pathogenesis of photodermatoses is not completely elucidated, especially because the photosensitizing agents are rarely identified. In exogenous photosensitization, the chemical agent (chromophore) is most often identified, reaching the skin either via topical contact or by systemic administration (drugs). Concepts of phototoxicity (photochemical reaction) and photo-allergy (photo-immunologic reaction) explain the clinical aspects. Dermatoses with photosensitivity are divided into three groups: photo-aggravated dermatoses (solar herpes, lupus erythematosus), photosensitivity caused by protective system defect (xeroderma pigmentosum), and photosensitivity caused by metabolic defects (porphyrias, pellagra). Idiopathic photodermatoses (unknown chromophore) are triggered by solar exposure (systemic photo-allergens would serve as mediators): 'benign estival polymorphous light eruption', polymorphous light eruptions, persistent light reactor, solar urticaria.