Hyaluronate-functionalized hydroxyapatite nanoparticles laden with methotrexate and teriflunomide for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA), an autoimmune inflammatory disorder is currently incurable. Methotrexate and Teriflunomide are routinely prescribed drugs but their uses are limited due to severe hepatotoxicity. Hyaluronic acid (HYA) is a targeting ligand for CD44 receptors overexpressed on inflamed macrophages. The present investigation aimed at design and fabrication of HYA coated hydroxyapatite nanoparticles (HA-NPs) loaded with Methotrexate (MTX) and Teriflunomide (TEF) (HAMT-NPs) to form HYA-HAMT-NPs for the treatment of RA. HYA-HAMT-NPs showed the nanoscale size of 274.9 ± 64 nm along with a zeta potential value of -26.80 ± 6.08 mV. FTIR spectra of HYA and HYA-HAMT-NPs proved the coating of HYA on HYA-HAMT-NPs. HYA-HAMT-NPs showed less cell viability compared to drugs on RAW 264.7 macrophage cells. A biodistribution study by gamma scintigraphy imaging further strengthened the results by revealing significantly higher (p<0.05) percentage radioactivity (76.76%) of HYA-HAMT-NPs in the synovial region. The results obtained by pharmacodynamic studies ensured the better efficacy of HYA-HAMT-NPs in preventing disease progression and promoting articular regeneration. Under hepatotoxicity evaluation, liver histopathology and liver enzyme assay revealed ~29% hepatotoxicity was reduced by HYA-HAMT-NPs when compared to conventional FOLITRAX-10 and AUBAGIO oral treatments. Overall, the results suggest that HYA-HAMT-NP is a promising delivery system to avoid drug-induced hepatotoxicity in RA.

Treatment of sarcoptic and chorioptic mange in an alpaca (Vicugna pacos) herd with a combination of topical amitraz and subcutaneous ivermectin.

Clinical history: An outbreak of intense pruritus and weight loss in a herd of 40 alpacas (Vicugna pacos) in the south-west of France was investigated after the death of 14 adults. One alpaca was referred to a veterinary teaching hospital for diagnosis and treatment but died soon after and one of the dead alpacas was submitted for necropsy. Clinical findings: The remaining alpacas were intensely pruritic with variably severe and extensive alopecia, erythema, lichenification and crusting on the face, ventral abdomen and distal limbs. Superficial skin scrapes from five animals revealed large numbers of Sarcoptes scabiei mites, and less frequent and numerous Chorioptes bovis mites. Coproscopic examinations revealed a median of 1,350 (min 500, max 8800) strongyle epg. The alpaca admitted for treatment was anaemic and hypoalbuminaemic. Skin scrapes revealed copious S. scabiei and C. bovis mites. The two alpacas examined post-mortem had similar skin lesions to those examined on-farm and were cachexic. One had lung lesions attributed to protostrongylid infestation and its liver contained numerous Dicrocoelium spp. adults. Diagnosis: Sarcoptic and chorioptic mange with secondary superficial bacterial skin infection, associated with severe internal parasitism and underfeeding. Treatment and outcome: All 25 alpacas were treated topically with a 3% chlorhexidine shampoo followed by a 0.025% amitraz wash at the initial visit and then 1, 2, 3, 7 and 9 weeks later. A systemic treatment with S/C 500 µg/kg ivermectin was administered at the initial visit and then 2, 7 and 9 weeks later. The alpacas were treated orally with 50 mg/kg praziquantel to control dicrocoeliosis. Nutritional measures, including increased pasture area and supplemental feeding were simultaneously implemented. Pruritus was reduced 1 week after the start of treatment and had resolved after 2 weeks. After 9 weeks, skin lesions were markedly improved. Six months after the initial visit, skin lesions entirely resolved and superficial skin scrapes, taken from half of the animals, were negative for mites. Clinical relevance: This is the first report of the use of two acaricides combined with a chlorhexidine shampoo to successfully treat simultaneous sarcoptic and chorioptic mange in alpacas.

Efficacy and safety of antiscabietic agents: A systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Many drugs have been used to treat scabies, but it is unclear which of them is the most efficacious. OBJECTIVE: To evaluate the comparative efficacy and safety of antiscabietic agents. METHODS: A systematic review of randomized controlled trials was conducted. Direct and network meta-analyses were applied to 13 antiscabietic agents on 3 outcomes (cure, persistent itching, and adverse events). Their probability of having highest efficacy and safety was estimated and ranked. RESULTS: A network meta-analysis of 52 trials including 9917 patients indicated that permethrin (the reference treatment) had a significantly higher cure rate than sulfur, malathion, lindane, crotamiton, and benzyl benzoate. Combination permethrin plus oral ivermectin had a nonsignificantly higher cure rate than permethrin. Combination permethrin plus oral ivermectin was ranked highest in terms of cure, topical ivermectin in terms of persistent itching, and synergized pyrethrins in terms of adverse events. On the basis of clustered ranking, permethrin, oral ivermectin, and synergized pyrethrins seemed to retain balance between cure and adverse events. LIMITATIONS: There are small numbers of trials and patients in some comparisons and a high risk of bias in some trials. CONCLUSION: There is no 1 treatment that ranked highest in all aspects. Physicians should consider the drug's efficacy and safety profiles, along with ease of administration.

Teriflunomide Modulates Vascular Permeability and Microglial Activation after Experimental Traumatic Brain Injury.

Despite intensive research and clinical trials with numerous therapeutic treatments, traumatic brain injury (TBI) is a serious public health problem in the United States. There is no effective FDA-approved treatment to reduce morbidity and mortality associated with TBI. Inflammation plays a pivotal role in the pathogenesis of TBI. We looked to re-purpose existing drugs that reduce immune activation without broad immunosuppression. Teriflunomide, an FDA-approved drug, has been shown to modulate immunological responses outside of its ability to inhibit pyrimidine synthesis in rapidly proliferating cells. In this study, we tested the efficacy of teriflunomide to treat two different injury intensities in rat models of TBI. Our results show that teriflunomide restores blood-brain barrier integrity, decreases inflammation, and increases neurogenesis in the subgranular zone of the hippocampus. While we were unable to detect neurocognitive effects of treatment on memory and special learning abilities after treatment, a 2-week treatment following injury was sufficient to reduce neuroinflammation up to 120 days later.

Teriflunomide (Aubagio®) for the treatment of multiple sclerosis.

Teriflunomide (Aubagio®) is a once-daily oral immunomodulatory disease modifying therapy (DMT) presently approved in several regions, including Europe, North America, Latin America and Australia, for the treatment of relapsing forms of multiple sclerosis (RMS; RRMS). The therapeutic mode of action of teriflunomide in MS continues to be investigated. This review summarizes the main efficacy and safety results of the clinical trial program leading to teriflunomide's approval, highlights a number of practical clinical considerations, and overviews its presumed therapeutic mode of action (MOA) based on pharmacokinetic and pharmacodynamic observations and the growing body of teriflunomide-related in vitro, pre-clinical (animal model), and in vivo human studies.

Teriflunomide for the treatment of multiple sclerosis.

Several novel oral agents are emerging for use in multiple sclerosis (MS). Among these oral agents, teriflunomide is showing promise with respect to clinical efficacy and safety in relapsing MS patients. In this review, the authors clarify the role of teriflunomide in the context of current and emerging MS treatment options by summarizing salient points on the use of teriflunomide in MS, with a discussion of teriflunomide's development, pharmacologic properties, preclinical and clinical trials, and safety and tolerability.

Anti pruritic effects of topical crotamiton, capsaicin, and a corticosteroid on pruritogen-induced scratching behavior.

Itch accompanies various skin diseases. As a number of mediators other than histamine can be involved in the itch sensation, H1 receptor antagonists are not necessarily effective in treating itch. External application of antipruritic drugs is occasionally used as an alternative therapy for pruritic skin conditions, such as pruritus on primary non-diseased, non-inflamed skin. Even so, the actual effects of these drugs on the itch sensation have yet to be studied in detail. To verify the antipruritic effects of crotamiton, capsaicin, and a corticosteroid on the itch sensation, we examined the inhibitory effects of these drugs on various pruritogen-induced scratching behaviors in mice. Topical application of 10% crotamiton moderately inhibited histamine-, serotonin-, and PAR-2 agonist-induced scratching behaviors. Topical capsaicin (0.025%) also exerted a moderate suppressive effect on histamine-, substance P-, and PAR-2 agonist-induced itch responses. Notably, topical corticosteroid (0.05% clobetasol propionate) remarkably inhibited the scratching behaviors induced by all of the pruritogenic agents tested. Therapeutic effects of capsaicin on substance P-induced pruritus did not seem to be mediated by desensitization of the TRPV1 (+) C fibers and/or by altered responsiveness of the mast cells. In addition, the antipruritic effects of crotamiton and corticosteroid appear to be, at least partly, associated with a TRPV1-independent pathway. This study examined the itch responses to pruritogens and demonstrated the mode of action of the externally applied antipruritic drugs.

Treatment of rosacea.

A range of treatment options are available in rosacea, which include several topical (mainly metronidazole, azelaic acid, other antibiotics, sulfur, retinoids) and oral drugs (mainly tetracyclines, metronidazole, macrolides). In some cases, the first choice is a systemic therapy because patients may have sensitive skin and topical medications can be irritant. Isotretinoin can be used in resistant cases of rosacea. Unfortunately, the majority of studies on rosacea treatments are at high or unclear risk of bias. A recent Cochrane review found that only topical metronidazole, azelaic acid, and oral doxycycline (40 mg) had some evidence to support their effectiveness in moderate to severe rosacea and concluded that further well-designed, adequately-powered randomised controlled trials are required. In our practice, we evaluate our patients for the presence of two possible triggers, Helicobacter pylori infection and small intestinal bacterial overgrowth. When they are present we use adapted antibiotic protocols. If not, we use oral metronidazole or oral tetracycline to treat papulopustolar rosacea. We also look for Demodex folliculorum infestation. When Demodex concentration is higher than 5/cm(2) we use topical crotamiton 10% or metronidazole.

Acaricidal efficacy against cattle ticks and acute oral toxicity of Lippia javanica (Burm F.) Spreng.

In search for low-cost, safe and environmentally benign plant-based alternatives to commercial pesticides, the efficacy of Lippia javanica aqueous leaf extracts in controlling ticks on cattle, acute oral toxicity in mice and phytochemistry were evaluated. L. javanica aqueous leaf extracts at 10% and 20% w/v were effective at controlling cattle ticks but not as good as an amitraz-based acaricide Tickbuster. However, they can provide an effective tick control option where synthetic products are unavailable or unaffordable, particularly in remote parts of southern Africa. Peripheral blood samples collected showed no haemoparasites in treated cattle implying that animals did not suffer from clinical tick-borne diseases. The leaf aqueous extracts of L. javanica were tested for toxicity in BALB/c mice. While anecdotal evidence suggests L. javanica has low mammalian toxicity, within 48 h all mice fed with the L. javanica leaf aqueous extract at 12.5-37.5% v/v were lethargic, and overall mortality was 37.5% (n = 24). Thus, despite their apparent safety, water extracts of L. javanica leaves may have deleterious health implications on humans and animals if consumed at very high doses. Many compounds have been identified from L. javanica including an array of phenolic glycosides, flavonoids and essential oils but none of these are known to have acute toxic properties.

Evaluation of the efficacy and safety of a novel formulation of metaflumizone plus amitraz in dogs naturally infested with fleas and ticks in Europe.

The efficacy and safety of a novel spot-on formulation of metaflumizone plus amitraz (ProMeris/ProMeris Duo for Dogs, Fort Dodge Animal Health, Overland Park, KS) was assessed in dogs naturally infested with ticks and/or fleas in a multiregional, clinical field study. Nineteen veterinary clinics in Germany and 11 clinics in France enrolled patients to the study. One hundred eighty one dogs with tick infestation and 170 dogs with flea infestation (plus three dogs harboring both ticks and fleas) qualified as primary patients and were randomly allocated to one of two treatments in a ratio of approximately 2:1 for metaflumizone plus amitraz (minimum dosage of 20 plus 20mg/kg) or fipronil (at the recommended label rate). Clinical examinations and baseline parasite counts were performed on Day 0 prior to treatment. Tick and/or flea counts and safety evaluations were repeated at intervals of about 2 weeks for 8 weeks. Both products resulted in consistent reductions in tick numbers (>81%) throughout the study, with metaflumizone plus amitraz giving consistently higher reductions in tick numbers. The efficacy against tick count compared with Day 0 was 97.6%, 93.5%, 89% and 94% at Day 14, 28, 42 and 56, respectively, for metaflumizone plus amitraz. The corresponding efficacies for fipronil were 86.3%, 81.1%, 84.8% and 86.1%. Within groups, the tick reduction was highly significant (P<0.0001) compared to baseline at all observation periods. Both treatments resulted in consistent (>89%) and highly significant (P<0.0001) reductions in flea numbers relative to the baseline counts throughout the study, although fipronil resulted in numerically higher reductions on each count day. The efficacy against fleas compared to baseline was 91.8%, 88.7%, 91.5% and 92.0% at Day 14, 28, 42 and 56, respectively, for metaflumizone plus amitraz. The corresponding efficacies for fipronil were 98.2%, 96.3%, 95.9% and 96.7%. Metaflumizone plus amitraz was highly effective in controlling existing infestations of fleas and ticks on dogs and was effective against reinfestation for at least 56 days. Metaflumizone plus amitraz showed a good tolerance profile in dogs.

Sarcoptic mange in three alpacas treated successfully with amitraz.

Sarcoptic mange is a serious skin disease in alpacas that can result in high morbidity and even mortality. Three alpacas were presented with sarcoptic mange that had previously failed to respond to repeated topical applications of eprinomectin, and an injection of doramectin. They were moderately to severely pruritic, had extensive lesions of alopecia, erythema, scaling and crusting, and had lost weight. As no drug is currently licensed for the treatment of sarcoptic mange in alpacas in the UK, they were treated with a topical solution of amitraz (50 mL in 10 L) after initial bathing with antibacterial or keratolytic shampoos. The clinical signs completely resolved with no relapse over a 10-month follow-up period. In this small group of alpacas, amitraz was an effective and well-tolerated treatment for sarcoptic mange.

[Alcoholic extract of lemongrass (Cymbopogon citratus) on the control of Boophilus microplus in cattle]. / Extrato alcoólico de Capim-cidreira (Cymbopogon citratus) no controle do Boophilus microplus em bovinos.

The objective of this study was to determine the effect of lemongrass (Cymbopogon citratus) alcoholic extracts on the control of Boophilus microplus in naturally infested Holstein cows. Twelve animals were allocated in three groups of four animals. Group 1 was treated with amitraz at 0.025%, Group 2 was treated with lemongrass extracts at 1.36% and Group 3 with the same product at 2.72% of the plant. Engorged ticks were evaluated on animals with length superior to 4.0 mm, before (mean of days -3, -2, -1) and at 1, 2, 3, 4, 5, 6, 7 and 14 days after treatment. The mean efficacy of amitraz was 97.93%. Lemongrass extract at 2.72% reduced tick infestation by 40.3, 46.6 and 41.5% on day 3, 7 and 14 post-treatment, respectively.

[A case of very serious Sarcoptes mange in alpacas (Lama pacos)]. / Een geval van ernstige Sarcoptes-schurft bij alpaca's (Lama pacos).

After the diagnosis sarcoptic mange in four alpaca's (Lama pacos) we have tried to control this infection. Despite three treatments with doramectin, three with ivermectin, four with amitraz and two with diazinon we were unable to get the animals free of Sarcoptes mites and their condition deteriorated. One animal died six month after the first treatment. The three remaining animals were euthanized one month thereafter.

Interventions for treating scabies.

BACKGROUND: Scabies is a common public health problem with an estimated global prevalence of 300 million. Infestation can cause considerable discomfort and intense itching. Severe adverse effects have been reported for some drugs used to treat scabies. OBJECTIVES: The objective of this review is to assess the effects and toxicity of topical and systemic drug treatment for scabies. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials Register, MEDLINE, EMBASE, military records, traditional medicine databases. We also contacted international specialist centres and drug manufacturers. SELECTION CRITERIA: Randomised controlled trials of any drug treatment for scabies. Tolerability and toxicity were sought in any study of humans taking any drug treatments for scabies. DATA COLLECTION AND ANALYSIS: Two reviewers assessed trial quality and extracted data. MAIN RESULTS: Thirteen trials were included (nine compared drug treatments, two compared treatment regimens, one compared the drug vehicle, and one was a community intervention). In one small trial, ivermectin was associated with a significant higher clinical cure rate at seven days when compared with placebo. Permethrin appeared to be more effective than crotamiton for clinical and parasitic cure rates. Permethrin appeared to be better than lindane for clinical cure rates in two small trials, but had no advantage in the largest trial (test for heterogeneity P < 0.001). Permethrin also appeared more effective in reducing itch persistence than lindane. There appeared to be no difference in clinical cure rates between crotamiton and lindane or benzyl benzoate and sulphur. Two trials assessed: the effectiveness of oral versus topical treatment (ivermectin versus benzyl benzoate and ivermectin ); single trial assessed treatment vehicle (pork fat versus cold cream); and mass community treatment (ivermectin), but all were too small to demonstrate an effect. No randomised trials of malathion were identified. Serious adverse drug reactions (including death and convulsions), most notably to lindane, permethrin and ivermectin, have been reported elsewhere. REVIEWER'S CONCLUSIONS: The evidence that permethrin is more effective than lindane is inconsistent. Lindane, permethrin, and ivermectin appear to be associated with rare but serious drug reactions although this is not derived from trial data. More research is needed on the safety and effectiveness of ivermectin and malathion compared to permethrin, on community management, and on different regimens and vehicles for topical treatment.

Interventions for treating scabies.

BACKGROUND: Scabies is a common public health problem with an estimated prevalence of 300 million. Infestation can cause considerable discomfort and intense itching. Severe adverse effects have been reported for some drugs used to treat scabies. OBJECTIVES: The objective of this review is to assess the effects and toxicity of topical and systemic drug treatment for scabies. SEARCH STRATEGY: We searched the Cochrane Infectious Diseases Group trials register, the Cochrane Controlled Trials Register, Medline, Embase, military records, traditional medicine databases. We also contacted international specialist centres and drug manufacturers. SELECTION CRITERIA: Randomised controlled trials of any drug treatment for scabies. Tolerability and toxicity were sought in any study of humans taking any drug treatments for scabies. DATA COLLECTION AND ANALYSIS: Two reviewers assessed trial quality and extracted data. MAIN RESULTS: Eleven trials were included (7 compared drug treatments, 2 compared treatment regimes, 1 compared the drug vehicle and 1 was a community intervention). Compared with placebo in one small trial, ivermectin was associated with a significant higher clinical cure rate at seven days. Permethrin appeared to be more effective than crotamiton for clinical and parasitic cure rates. Permethrin appeared to be better than gamma benzene hexachloride for clinical cure rates in two small trials but had no advantage in the largest trial (test for heterogeneity p< 0.001). Permethrin also appeared more effective in reducing itch persistance than gamma benzene hexachloride. There appeared to be no difference in clinical cure rates between crotamiton and gamma benzene hexachloride. Single trials assessed: the effectiveness of oral versus topical treatment (ivermectin versus benzyl benzoate); treatment vehicle (pork fat versus cold cream); and mass community treatment (ivermectin) but were too small to demonstrate an effect. No randomised trials of malathion were identified. Serious adverse drug reactions (including death and convulsions) have been reported in other studies of scabies drugs, most notably gamma benzene hexachoride and ivermectin. REVIEWER'S CONCLUSIONS: The evidence that permethrin is more effective than gamma benzene hexachloride is inconsistent. Permethrin appears to have less potential serious drugs reactions than gamma benzene hexachloride although this is not derived from trial data. More research is needed of the safety and effectiveness of ivermectin and malathion compared to permethrin, on community management, and on different regimes and vehicles for topical treatment.

Efficacy of amitraz (Taktic 12.5% EC) as a dip for the control of Boophilus microplus (Canestrini) (Acari: Ixodidae) on cattle.

Four groups of cattle infested with Boophilus microplus (Canestrini) were each dipped in a different concentration of amitraz diluted from a 12.5% EC formulation to determine the efficacy and performance of the product in an 11,400 l dipping vat. Except for the period when heifers were dipped, animals were restrained in stanchions placed individually inside 3.3 x 3.3 m2 stalls within an open-sided barn. The amitraz in the vat was stabilized with hydrated lime to maintain a pH of ca. 12. Analyses of vat samples showed that concentrations of amitraz in the vat were 7.6 to 13% lower than the targeted concentrations of 0.010, 0.015, 0.020, and 0.025% active ingredient (AI) for dilutions prepared according to instructions on the manufacturer's label. The large quantity of hydrated lime added to the vat (10 kg/1000 l) interfered with the HPLC analysis of vat samples. Therapeutic efficacy of each of the four observed concentrations (0.0088, 0.0131, 0.0174, and 0.0231% AI) of amitraz was excellent (> 99% control). However, the rapid detachment of all ticks from an animal within a few hours after treatment with amitraz, that has been frequently observed, was not pronounced in the present study. Only 47% of the B. microplus detached in the first 4 h post-treatment, and 84% detached within the first 24 h. All of the treatments, except the lowest concentration, provided protection of cattle against re-infestation by B. microplus larvae for 14 days post-treatment. Possibly as a result of the formation of a compact layer of lime and amitraz on the bottom after the vat was undisturbed for six weeks, intense agitation was required to re-suspend the active ingredient.

Effect of a herbal compound for treatment of sarcoptic mange infestations on dogs.

Charmil gel, a herbal product was tried against Sarcoptes scabei var canis on dogs and its efficacy was compared with that of amitraz. Mite scrapings examined at scheduled intervals after the topical application of Charmil gel caused complete recovery after 14 days in severe infestation and 7 to 10 days in mild to moderate infestations with regrowth of hair on Day 28 post-treatment. No adverse reactions were observed except mild irritation and restlessness, which persisted for a few hours soon after application.