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author:(Rainer KA roepe)
1.  Plasma pharmacokinetic profile of fluralaner (Bravecto™) and ivermectin following concurrent administration to dogs 
Parasites & Vectors  2015;8:508.
Background
Fluralaner is a novel systemic ectoparasiticide for dogs providing immediate and persistent flea, tick and mite control after a single oral dose. Ivermectin has been used in dogs for heartworm prevention and at off label doses for mite and worm infestations. Ivermectin pharmacokinetics can be influenced by substances affecting the p-glycoprotein transporter, potentially increasing the risk of ivermectin neurotoxicity. This study investigated ivermectin blood plasma pharmacokinetics following concurrent administration with fluralaner.
Findings
Ten Beagle dogs each received a single oral administration of either 56 mg fluralaner (Bravecto™), 0.3 mg ivermectin or 56 mg fluralaner plus 0.3 mg ivermectin/kg body weight. Blood plasma samples were collected at multiple post-treatment time points over a 12-week period for fluralaner and ivermectin plasma concentration analysis.
Ivermectin blood plasma concentration profile and pharmacokinetic parameters Cmax, tmax, AUC∞ and t½ were similar in dogs administered ivermectin only and in dogs administered ivermectin concurrently with fluralaner, and the same was true for fluralaner pharmacokinetic parameters.
Conclusions
Concurrent administration of fluralaner and ivermectin does not alter the pharmacokinetics of either compound. Based on the plasma pharmacokinetic profile and the clinical observations, there is no evident interaction between fluralaner and ivermectin, and co-administration does not increase the risk of ivermectin associated neurotoxicity.
doi:10.1186/s13071-015-1123-8
PMCID: PMC4595236  PMID: 26438338
Fluralaner; Bravecto™; Ivermectin; Dog; Pharmacokinetic; P-glycoprotein; MDR1
2.  Fluralaner activity against life stages of ticks using Rhipicephalus sanguineus and Ornithodoros moubata IN in vitro contact and feeding assays 
Parasites & Vectors  2015;8:90.
Background
Fluralaner is a novel isoxazoline eliciting both acaricidal and insecticidal activity through potent blockage of GABA- and glutamate-gated chloride channels. The aim of the study was to investigate the susceptibility of juvenile stages of common tick species exposed to fluralaner through either contact (Rhipicephalus sanguineus) or contact and feeding routes (Ornithodoros moubata).
Methods
Fluralaner acaricidal activity through both contact and feeding exposure was measured in vitro using two separate testing protocols. Acaricidal contact activity against Rhipicephalus sanguineus life stages was assessed using three minute immersion in fluralaner concentrations between 50 and 0.05 μg/mL (larvae) or between 1000 and 0.2 μg/mL (nymphs and adults). Contact and feeding activity against Ornithodoros moubata nymphs was assessed using fluralaner concentrations between 1000 to 10−4 μg/mL (contact test) and 0.1 to 10−10 μg/mL (feeding test). Activity was assessed 48 hours after exposure and all tests included vehicle and untreated negative control groups.
Results
Fluralaner lethal concentrations (LC50, LC90/95) were defined as concentrations with either 50%, 90% or 95% killing effect in the tested sample population. After contact exposure of R. sanguineus life stages lethal concentrations were (μg/mL): larvae - LC50 0.7, LC90 2.4; nymphs - LC50 1.4, LC90 2.6; and adults - LC50 278, LC90 1973. After exposure of O. moubata nymphs to fluralaner lethal concentrations were (μg/mL): contact exposure - LC50 720, LC95 1133; and feeding exposure- LC50 0.00007, LC95 0.09.
Conclusions
Fluralaner demonstrates potent in vitro acaricidal activity against all life stages of the brown dog tick, R.sanguineus. The testing of fluralaner contact and feeding routes using O. moubata nymphs demonstrates a high acaricidal activity in both exposure routes.
doi:10.1186/s13071-015-0704-x
PMCID: PMC4326483  PMID: 25888750
Rhipicephalus sanguineus; Ornithodoros moubata; Fluralaner; Acaricidal activity; Tick life stages
3.  Onset of activity of fluralaner (BRAVECTO™) against Ctenocephalides felis on dogs 
Parasites & Vectors  2014;7:567.
Background
Fluralaner (Bravecto™) is a novel systemic insecticide and acaricide that provides long persistent antiparasitic activity following a single administration at the minimum dose of 25 mg/kg body weight.
Methods
Three negative controlled, randomized studies were conducted in dogs to evaluate the start to kill (1 study) and the speed of flea kill (2 studies) of fluralaner. All dogs were infested prior to treatment with unfed adult C. felis fleas. Dogs in the treated groups were administered once orally with fluralaner at a minimum dose of 25 mg/kg body weight, while dogs in the control groups were not treated. Separate control and treatment groups were paired at each time point of flea assessment. Flea counts were performed by combing dogs at either 0.5, 1, 2, or 4 hours after fluralaner treatment to measure the start to kill. To evaluate the speed of flea kill over 12 weeks, flea counts were performed by combing dogs at either 4, 8, 12, or 24 hours after fluralaner treatment and then at 4, 8, 12, or 24 hours after each flea re-infestations performed at 4, 8, and 12 weeks following treatment.
Results
In the start to kill study, the fluralaner activity against fleas started already at 1 hour post-treatment (8% numerical efficacy). At 2 and 4 hours post-treatment, the flea reduction was significant with 36.7% and 88% efficacy, respectively.
In the speed of kill studies, the efficacy against fleas after fluralaner treatment was 80.5% at 4 hours and remained ≥ 99.4% at 8, 12 and 24 hours. After flea re-infestations in weeks 4, 8 and 12, the efficacy at 4 hours was 96.8, 91.4, and 33.5%, respectively. Efficacy at 8, 12 and 24 hours after flea re-infestations was 98.0-100% for the 12 weeks of the study. Except for 4 hours after the 12-week flea re-infestation, flea reduction was significant for all time points after flea re-infestation.
Conclusions
Single oral fluralaner administration rapidly eliminates existing flea infestations and provides excellent protection against fleas over 12 weeks following treatment.
doi:10.1186/s13071-014-0567-6
PMCID: PMC4263043  PMID: 25471474
Bravecto™; Chewable tablets; Fluralaner; Onset of activity; Start to kill; Speed of kill; Dog; Flea; Ctenocephalides felis; Efficacy
4.  The speed of kill of fluralaner (Bravecto™) against Ixodes ricinus ticks on dogs 
Parasites & Vectors  2014;7:525.
Background
Pathogens that are transmitted by ticks to dogs, such as Anaplasma phagocytophilum, Babesia spp., Borrelia burgdorferi sensu latu, and Ehrlichia canis, are an increasing problem in the world. One method to prevent pathogen transmission to dogs is to kill the ticks before transmission occurs. Fluralaner (Bravecto™) is a novel isoxazoline insecticide and acaricide that provides long persistent antiparasitic activity following systemic administration. This study investigated the speed of kill of fluralaner against Ixodes ricinus ticks on dogs.
Methods
A total of 48 dogs were randomized to 8 groups of 6 dogs and each dog was infested with 50 female and 10 male I. ricinus ticks. Two days later (day 0), 4 groups received a single treatment of 25 mg fluralaner/kg body weight as Bravecto™ chewable tablets; the dogs in the other 4 groups were left untreated. Separate control and treatment groups were paired at each time point (4, 8, 12, or 24 hours after treatment) for assessment of tick-killing efficacy. At 4, 8, and 12 weeks after treatment, all dogs were re-infested with 50 female I. ricinus ticks and subsequently assessed for live or dead ticks at either 4, 8, 12, or 24 hours after re-infestation. Efficacy was calculated for each assessment time point by comparison of the treatment group with the respective control group.
Results
Tick-killing efficacy was 89.6% at 4 hours, 97.9% at 8 hours, and 100% at 12 and 24 hours after treatment. Eight hours after re-infestation, efficacy was 96.8%, 83.5%, and 45.8% at 4, 8, and 12 weeks after treatment, respectively. At least 98.1% tick-killing efficacy was demonstrated 12 and 24 hours after re-infestation over the entire 12 week study period.
Conclusions
Fluralaner kills ticks rapidly after treatment at 4 hours, and over its entire 12-week period of efficacy, it achieves an almost complete killing effect within 12 hours after tick infestation. The rapid tick-killing effect together with the long duration of efficacy enables fluralaner to aid in the prevention of tick borne diseases.
doi:10.1186/s13071-014-0525-3
PMCID: PMC4247686  PMID: 25406442
Bravecto™ chewable tablets; Fluralaner; Speed of kill; Dog; Tick; Ixodes ricinus; Tick-borne diseases; Efficacy
5.  Safety of concurrent treatment of dogs with fluralaner (Bravecto™) and milbemycin oxime - praziquantel 
Parasites & Vectors  2014;7:481.
Background
Fluralaner (Bravecto™; Merck/MSD Animal Health) is a novel systemic ectoparasiticide for dogs providing long-acting flea and tick control after a single oral dose. Milbemycin oxime and praziquantel are routinely used to control Dirofilaria immitis and intestinal worm infections in dogs. The safety of concurrent use of fluralaner and a commercially available milbemycin oxime plus praziquantel combination tablet, in particular with regard to gastrointestinal symptoms, was investigated using oral doses at or above the maximum recommended rates.
Findings
Some minor and transient clinical findings were observed during the study period; however, none of these was considered to be related to concurrent treatment with fluralaner and milbemycin oxime plus praziquantel, or to the use of either product alone.
Conclusions
Concurrent treatment with fluralaner, milbemycin oxime and praziquantel is well tolerated in dogs.
doi:10.1186/s13071-014-0481-y
PMCID: PMC4198702  PMID: 25315498
Bravecto™; Fluralaner; Dog; Safety; Milbemycin oxime; Praziquantel
6.  Comparative pharmacokinetics of fluralaner in dogs and cats following single topical or intravenous administration 
Parasites & Vectors  2016;9:296.
Background
Bravecto™ Chewable Tablets for Dogs, containing fluralaner as active ingredient, is an innovative treatment for flea and tick infestations that provides safe, rapid and long acting efficacy after a single oral administration in dogs. Topically applied fluralaner provides similar safe, rapid and long acting efficacy, both in dogs and in cats. The pharmacokinetic profile of fluralaner was evaluated in dogs and in cats following either topical or intravenous administration.
Methods
Twenty four dogs and 24 cats received three different topical doses, with the mid-dose based on the respective minimum recommended dose, and one intravenous dose. Plasma samples were collected for 112 days and fluralaner concentrations were quantified using a validated high performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS) method. Pharmacokinetic parameters were calculated using non-compartmental methods.
Results
In dogs, fluralaner was readily absorbed from the topical administration site into the skin, subjacent tissues and blood. Fluralaner plasma concentrations showed an apparent plateau between ~ day 7 and 63, with individual tmax seen within this time period. After the plasma plateau, concentrations declined slowly and were quantifiable for more than 12 weeks. In cats, fluralaner was readily systemically absorbed from the topical administration site, reaching maximum concentrations (Cmax) in plasma between 3 and 21 days post administration, after which concentrations declined slowly, and were also quantifiable for more than 12 weeks. Systemic exposure, as shown by Cmax and the area under the concentration versus time curve from time 0 to the last measurable concentration (AUC(0→t)) increased proportionally with dose in both species. Following intravenous administration fluralaner showed a relatively high apparent volume of distribution (Vz), a low plasma clearance (Cl), a long terminal half-life (t1/2) and a long mean residence time (MRT); thereby demonstrating a long persistence of fluralaner in both species.
Conclusions
The pharmacokinetic characteristics of fluralaner explain its prolonged activity against fleas and ticks on both dogs and cats after a single topical administration.
doi:10.1186/s13071-016-1564-8
PMCID: PMC4886404  PMID: 27241240
Fluralaner; Dog; Cat; Pharmacokinetics; Bravecto™ Spot-on Solution
7.  A quantitative evaluation of the extent of fluralaner uptake by ticks (Ixodes ricinus, Ixodes scapularis) in fluralaner (BravectoTM) treated vs. untreated dogs using the parameters tick weight and coxal index 
Parasites & Vectors  2015;8:352.
Background
Fluralaner is a new antiparasitic drug that was recently introduced as BravectoTM chewable tablets for the treatment of tick and flea infestations in dogs. Most marketed tick products exert their effect via topical application and contact exposure to the parasite. In contrast, BravectoTM delivers its acaricidal activity through systemic exposure. Tick exposure to fluralaner occurs after attachment to orally treated dogs, which induces a tick-killing effect within 12 h. The fast onset of killing lasts over the entire treatment interval (12 weeks) and suggests that only marginal uptake by ticks is required to induce efficacy. Three laboratory studies were conducted to quantify the extent of uptake by comparison of ticks’ weight and coxal index obtained from BravectoTM-treated and negative-control dogs.
Methods
Three studies were conducted using experimental tick infestation with either Ixodes ricinus or Ixodes scapularis after oral administration of fluralaner to dogs. All studies included a treated (BravectoTM chewable tablets, MSD Animal Health) and a negative control group. Each study had a similar design for assessing vitality and weighing of ticks collected from dogs of both groups. Additionally, in one study the coxal index (I. ricinus) was calculated as a ratio of tick’s ventral coxal gap and dorsal width of scutum. Tick weight data and coxal indices from BravectoTM-treated and negative-control groups were compared via statistical analysis.
Results
Ticks collected from BravectoTM-treated dogs weighed significantly less (p ≤ 0.0108) than ticks collected from negative-control dogs, and their coxal index was also significantly lower (p < 0.0001). The difference in tick weights was demonstrated irrespective of the tick species investigated (I. ricinus, I. scapularis). At some assessments the mean tick weights of BravectoTM-treated dogs were significantly lower than those of unfed pre-infestation (baseline) ticks. The demonstrated tick-killing efficacy was in the range of 94.6 – 100 %.
Conclusions
Tick weights and coxal indices confirm that a minimal uptake results in a sufficient exposure of ticks to fluralaner (BravectoTM) and consequently in a potent acaricidal effect.
doi:10.1186/s13071-015-0963-6
PMCID: PMC4488133  PMID: 26123249
BravectoTM chewable tablets; Fluralaner; Dog; Tick weight; Coxal index; Ixodes ricinus; Ixodes scapularis; Efficacy
8.  Prevention of transmission of Babesia canis by Dermacentor reticulatus ticks to dogs treated orally with fluralaner chewable tablets (Bravecto™) 
Parasites & Vectors  2015;8:305.
Background
The preventive effect of fluralaner chewable tablets (Bravecto™) against transmission of Babesia canis by Dermacentor reticulatus ticks was evaluated.
Methods
Sixteen dogs, tested negative for B. canis by PCR and IFAT, were allocated to two study groups. On day 0, dogs in one group (n = 8) were treated once orally with a fluralaner chewable tablet according to label recommendations and dogs in the control group (n = 8) remained untreated. On days 2, 28, 56, 70 and 84, dogs were infested with 50 (±4) B. canis infected D. reticulatus ticks with tick in situ thumb counts 48 ± 4 h post-infestation. Prior to each infestation, the D. reticulatus ticks were confirmed to harbour B. canis by PCR analysis. On day 90, ticks were counted and removed from all dogs. Efficacy against ticks was calculated for each assessment time point. After treatment, all dogs were physically examined in conjunction with blood collection for PCR every 7 days, blood samples for IFAT were collected every 14 days and the dog’s rectal body temperature was measured thrice weekly. From dogs displaying symptoms of babesiosis or were PCR positive, a blood smear was taken, and, if positive, dogs were rescue treated and replaced with a replacement dog. The preventive effect was evaluated by comparing infected dogs in the treated group with infected dogs in the untreated control group.
Results
All control dogs became infected with B. canis, as confirmed by PCR and IFAT. None of the 8 treated dogs became infected with B. canis, as IFAT and PCR were negative throughout the study until day 112. Fluralaner chewable tablet was 100 % effective against ticks on days 4, 30, 58, and 90 and an efficacy of 99.6 % and 99.2 % was achieved on day 72 and day 86 after treatment, respectively. Over the 12-week study duration, a 100 % preventive effect against B. canis transmission was demonstrated.
Conclusions
A single oral administration of fluralaner chewable tablets effectively prevented the transmission of B. canis by infected D. reticulatus ticks over a 12-week period.
doi:10.1186/s13071-015-0923-1
PMCID: PMC4465614  PMID: 26040319
Bravecto™; Babesia canis; Babesiosis; Chewable tablets; Fluralaner; Dermacentor reticulatus; Dog; Efficacy; Preventive effect; Tick; Tick-borne disease; Transmission blocking
9.  Safety of fluralaner chewable tablets (BravectoTM), a novel systemic antiparasitic drug, in dogs after oral administration 
Parasites & Vectors  2014;7:87.
Background
Fluralaner is a novel systemic insecticide and acaricide that provides long acting efficacy in dogs after a single oral treatment. This study investigated the safety of oral administration of fluralaner in chewable tablets to dogs at the highest recommended treatment dose and at multiples of this dose.
Methods
Thirty-two (16 male and 16 female) healthy 8-week old Beagle dogs weighing 2.0 - 3.6 kg at first administration were included in the study. Fluralaner was administered on three occasions at 8-week intervals at doses of up to 56, 168, and 280 mg fluralaner/kg body weight, equivalent to 1, 3, and 5 times the highest recommended treatment dose of fluralaner; sham dosed dogs served as controls.
During the study, all dogs were clinically observed, and their health was carefully monitored including body weight development, food consumption and measurement of hematology, coagulation, clinical chemistry (including measurement of levels of ACTH and C-reactive protein) and urinalysis. Following euthanasia of the dogs, complete gross post mortem examination, including organ weight determination, and histopathological examination of multiple tissues were conducted.
Results
There were no clinical findings related to fluralaner treatment. Statistically significant differences between the treated groups and the control group were observed for some clinical pathology parameters and organ weights; none of these findings were considered to be of clinical relevance.
Conclusions
Oral administration of fluralaner at the highest recommended treatment dose (56 mg/kg) at 8-week intervals is well tolerated and has a safety margin of more than five in healthy dogs eight weeks of age or older and weighing at least 2 kg.
doi:10.1186/1756-3305-7-87
PMCID: PMC3975339  PMID: 24606886
Fluralaner; Dog; Safety; Bravecto™
10.  Pharmacokinetics of fluralaner in dogs following a single oral or intravenous administration 
Parasites & Vectors  2014;7:85.
Background
Fluralaner is a novel systemic insecticide and acaricide. The purpose of these studies was to investigate the pharmacokinetic properties of fluralaner in Beagle dogs following single oral or intravenous (i.v.) administration.
Methods
Following the oral administration of 12.5, 25 or 50 mg fluralaner/kg body weight (BW), formulated as chewable tablets or i.v. administration of 12.5 mg fluralaner/kg BW, formulated as i.v. solution to 24 Beagles, plasma samples were collected until 112 days after treatment. Plasma concentrations of fluralaner were measured using HPLC-MS/MS. Pharmacokinetic parameters were calculated by non-compartmental methods.
Results
After oral administration, maximum plasma concentrations (Cmax) were reached within 1 day on average. Fluralaner was quantifiable in plasma for up to 112 days after single oral and i.v. treatment. The apparent half-life of fluralaner was 12–15 days and the mean residence time was 15–20 days. The apparent volume of distribution of fluralaner was 3.1 L/kg, and clearance was 0.14 L/kg/day.
Conclusions
Fluralaner is readily absorbed after single-dose oral administration, and has a long elimination half-life, long mean residence time, relatively high apparent volume of distribution, and low clearance. These pharmacokinetic characteristics help to explain the prolonged activity of fluralaner against fleas and ticks on dogs after a single oral dose.
doi:10.1186/1756-3305-7-85
PMCID: PMC3975451  PMID: 24606874
Fluralaner; Pharmacokinetics; Dog; Oral; Intravenous
11.  Safety of fluralaner, a novel systemic antiparasitic drug, in MDR1(-/-) Collies after oral administration 
Parasites & Vectors  2014;7:86.
Background
Fluralaner is a novel systemic ectoparasiticide for dogs providing long-acting flea- and tick-control after a single oral dose. This study investigated the safety of oral administration of fluralaner at 3 times the highest expected clinical dose to Multi Drug Resistance Protein 1 (MDR1(-/-)) gene defect Collies.
Methods
Sixteen Collies homozygous for the MDR1 deletion mutation were included in the study. Eight Collies received fluralaner chewable tablets once at a dose of 168 mg/kg; eight sham dosed Collies served as controls. All Collies were clinically observed until 28 days following treatment.
Results
No adverse events were observed subsequent to fluralaner treatment of MDR1(-/-) Collies at three times the highest expected clinical dose.
Conclusions
Fluralaner chewable tablets are well tolerated in MDR1(-/-) Collies following oral administration.
doi:10.1186/1756-3305-7-86
PMCID: PMC3975640  PMID: 24602342
Fluralaner; Bravecto™; Dog; Safety; MDR1
12.  The effect of food on the pharmacokinetics of oral fluralaner in dogs 
Parasites & Vectors  2014;7:84.
Background
Fluralaner is a novel systemic ectoparasiticide for dogs providing long-acting flea- and tick-control after a single oral dose. The pharmacokinetics of orally administered drugs may be influenced by feeding. This study investigated the influence of concurrent feeding on fluralaner pharmacokinetics.
Methods
Twelve fasted or fed beagles received a single oral administration of 25 mg fluralaner/kg body weight in a chewable tablet. Plasma samples were collected at multiple post-treatment time points for fluralaner concentration analysis. Clinical observations were performed on all dogs at regular intervals throughout the study.
Results
Fluralaner was readily absorbed in fasted and fed dogs administered at a dose of 25 mg/kg BW with a similar mean tmax for both groups. In fed dogs, AUC and Cmax were increased compared to fasted dogs by a factor of 2.5 and 2.1 respectively. The difference in AUC and Cmax between the fed and fasted groups was statistically significant. No adverse events were observed following oral fluralaner administration to fasted and fed dogs.
Conclusions
Fluralaner is absorbed to a considerable extent in fasted and fed dogs. Administration of fluralaner chewable tablets with food significantly increases bioavailability.
doi:10.1186/1756-3305-7-84
PMCID: PMC3975707  PMID: 24598049
Fluralaner; Dog; Pharmacokinetics; Food effect; Fasted
13.  A randomized, blinded, controlled and multi-centered field study comparing the efficacy and safety of Bravecto™ (fluralaner) against Frontline™ (fipronil) in flea- and tick-infested dogs 
Parasites & Vectors  2014;7:83.
Background
Fluralaner, a new molecular entity of the isoxazoline class, has potent insecticidal and acaricidal activity and can be safely administered orally to dogs.
Methods
A randomized, investigator-blinded, multi-centered field study compared the flea- and tick-control efficacy for dogs over a 12-week period with either a single oral dose of Bravecto™ (fluralaner) formulated as a chewable tablet or with three sequential topical Frontline™ (fipronil) treatments. Individual dogs were the experimental unit for ticks and households were the experimental unit for fleas. A total of 108 tick-infested dogs were treated with Bravecto™ (fluralaner) and 54 tick-infested dogs were treated with Frontline™ (fipronil). Dogs in 115 flea-infested households received Bravecto™ (fluralaner) and dogs in 61 flea-infested households received Frontline™ (fipronil). Flea and tick counts were conducted on all dogs at weeks 2, 4, 8, and 12 following initial treatment and efficacy was calculated as the mean percent reduction in tick or flea count at each time point compared with the mean pretreatment initiation count for each treatment group. Additionally, the percentages of tick-free and flea-free households were determined.
Results
At weeks 2, 4, 8, and 12, Bravecto™ (fluralaner) flea-control efficacy in treated households was 99.2%, 99.8%, 99.8%, and 99.9% respectively, while Frontline™ (fipronil) efficacy was 94.1%, 93.0%, 96.0%, and 97.3%, respectively. Bravecto™ (fluralaner) tick-control efficacy on treated dogs at weeks 2, 4, 8, and 12 was 99.9%, 99.9%, 99.7%, and 100%, respectively, and Frontline™ (fipronil) tick efficacy was 97.6%, 93.8%, 100%, and 100%, respectively. Of dogs showing clinical flea allergy dermatitis (FAD) signs at the study start, 85.7% in the Bravecto™ (fluralaner)-treated group and 55.6% in the Frontline™ (fipronil)-treated group were evaluated at each time point as showing no clinical signs of FAD until study completion.
Conclusions
Bravecto™ (fluralaner) administered once orally to dogs in a chewable tablet was highly effective for 12 weeks against fleas and ticks on privately-owned dogs and was significantly non-inferior (ticks) and superior (fleas) in comparison with topical Frontline™ (fipronil) administered 3 times sequentially.
doi:10.1186/1756-3305-7-83
PMCID: PMC3975895  PMID: 24593931
Fleas; Ticks; Bravecto™ (fluralaner); Isoxazoline; Frontline™ (fipronil); Efficacy; Field study; Dog
14.  Efficacy of fluralaner against Otodectes cynotis infestations in dogs and cats 
Parasites & Vectors  2017;10:30.
Background
The efficacy of fluralaner for the treatment of Otodectes cynotis infestations in dogs and cats was evaluated after oral (dogs) or topical administration (dogs and cats).
Twenty-four dogs and sixteen cats were experimentally infested with O. cynotis and randomly allocated to equal sized groups (n = 8/group). Dog groups were treated once, either orally with fluralaner at a minimum dose of 25 mg/kg body weight, topically with fluralaner at a dose of 25 mg/kg body weight or topically with saline solution (control). Cat groups were treated once, either topically with fluralaner at a dose of 40 mg/kg body weight or topically with saline solution. Ears of all animals were examined otoscopically for live visible mites and the amount of debris and cerumen before, and 14 and 28 days after treatment. Twenty-eight days after treatment, animals were sedated and both ears were flushed to obtain the total number of live mites per animal. The efficacy was calculated, based on the results of the ear flushing, by comparing mean live mite counts in the fluralaner treated groups versus the saline solution treated group.
Results
A single topical treatment of cats with fluralaner reduced the mean mite counts by 100% (P < 0.001) at 28 days after treatment. Similarly, a single oral or topical treatment of dogs with fluralaner reduced the mean mite counts by 99.8% (P < 0.001) at 28 days after treatment. Cats treated topically with fluralaner had no mites visible during otoscopic examination at either 14 or 28 days after treatment. All dogs treated orally or topically with fluralaner had no mites visible during otoscopic examination at 28 days after treatment. At 14 days after treatment, only 1–2 mites were visible in three dogs (oral treatment: 2 dogs, topical treatment: 1 dog). All fluralaner-treated animals showed improvement in the amount of cerumen exudation compared with observations performed before treatment. No treatment related adverse events were observed in any dogs or cats enrolled in these studies.
Conclusions
In this study, fluralaner administered topically to cats and orally or topically to dogs was highly effective against Otodectes cynotis mite infestations.
doi:10.1186/s13071-016-1954-y
PMCID: PMC5240227  PMID: 28093080
Bravecto™; Bravecto™ spot-on solution; Cat; Chewable tablets; Dog; Ear mite; Efficacy; Fluralaner; Oral; Otodectes cynotis; Otocariosis; Topical
15.  Pericardial Tamponade in an Adult Suffering from Acute Mumps Infection 
Case Reports in Medicine  2016;2016:7980936.
Here, we report a case of a 51-year-old man with acute pericardial tamponade requiring emergency pericardiocentesis after he suffered from sore throat, headache, malaise, and sweats for two weeks. Serological analyses revealed increased mumps IgM and IgG indicating an acute mumps infection whereas other bacterial and viral infections were excluded. In addition, MRI revealed atypical swelling of the left submandibular gland. Whereas mumps has become a rare entity in children due to comprehensive vaccination regimens in western civilizations, our case highlights mumps as an important differential diagnosis also in adults, where the virus can induce life-threatening complications such as pericardial tamponade.
doi:10.1155/2016/7980936
PMCID: PMC5080511  PMID: 27818687
16.  Efficacy of fluralaner administered either orally or topically for the treatment of naturally acquired Sarcoptes scabiei var. canis infestation in dogs 
Parasites & Vectors  2016;9:392.
Background
The efficacy of fluralaner, formulated as a chewable tablet (Bravecto™) or topical solution (Bravecto™ Spot-on Solution), was evaluated against naturally acquired Sarcoptes scabiei var. canis infestation in dogs.
Methods
The study was performed in privately-owned dogs naturally infested with S. scabiei var. canis. All dogs living in the same household as the infested dog were enrolled into one of 3 groups (2 fluralaner treated and 1 negative control). All dogs within one household were administered the same treatment, with one dog per household included in further observations and assessments. In total, 29 dogs confirmed positive for sarcoptic mange were included. On Day 0, all dogs in group 1 (n = 9) were treated once orally with fluralaner at a minimum dose of 25 mg/kg body weight; all dogs in group 2 (n = 11) were treated once topically with fluralaner at a dose of 25 mg/kg body weight; and dogs in group 3 (n = 9) were treated once topically with saline solution. Sarcoptes scabiei var. canis mites on each dog were counted before treatment and at 4 weeks after treatment in deep skin scrapings (~4 cm2) from 5 different body areas. Clinical signs of infestation (i.e. erythematous papules; casts, scales and crusts; body areas with hair loss) and pruritus were recorded at the same time points.
Results
Single oral or topical treatment with fluralaner resulted in a 100 % reduction in mite counts post-treatment (group 1: P = 0.0009 and group 2: P = 0.0011). Resolution of clinical signs at four weeks post-treatment was variable, with improvement observed for erythematous papules, casts and crusts, and pruritus. All fluralaner treated dogs showed an improvement in overall hair re-growth compared with pre-treatment observations.
Conclusion
Fluralaner administered either orally or topically to naturally infested dogs eliminates Sarcoptes scabiei var. canis mites and improves clinical signs over a 4-week observation period.
doi:10.1186/s13071-016-1670-7
PMCID: PMC4937584  PMID: 27387742
Bravecto™; Bravecto™ Spot-on Solution; Chewable tablets; Fluralaner; Efficacy; Dog; Oral; Sarcoptes scabiei var. canis; Topical; Mange; Mites
18.  Safety of concurrent treatment of cats with fluralaner and emodepsid–praziquantel 
Parasites & Vectors  2016;9:322.
Background
Fluralaner is a novel systemic ectoparasiticide for cats providing immediate and persistent flea- and tick-control after a single topical dose. Emodepsid and praziquantel are routinely used to control intestinal worm infections in cats. The safety of concurrent use of fluralaner and a commercially available emodepsid-praziquantel combination topical solution was investigated using topical administrations at the maximum recommended dose rates.
Findings
Few mild and transient clinical findings like erythema at the administration site and single incidences of salivation or vomiting were observed. All of which were consistent with the individual product leaflets. There were no findings suggesting an increased safety risk associated with the concurrent treatment of cats with fluralaner and emodepsid-praziquantel.
Conclusions
Concurrent treatment with fluralaner, emodepsid and praziquantel is well tolerated in cats.
doi:10.1186/s13071-016-1618-y
PMCID: PMC4896020  PMID: 27267592
Cat; Fluralaner; Bravecto™; Emodepsid; Praziquantel; Profender™; Safety
19.  Efficacy of fluralaner spot-on solution against induced infestations with Rhipicephalus sanguineus on dogs 
Parasites & Vectors  2016;9:276.
Background
The efficacy of fluralaner spot-on solution administered once topically against induced infestations with Rhipicephalus sanguineus was evaluated in dogs over a 12-week post-treatment period.
Methods
Six negative-controlled studies were conducted, involving a total of 112 adult dogs (57 mixed breed, 47 Beagles, eight Labradors). In each study, dogs were randomized to two groups of eight to ten dogs each. On day 0, dogs in each treated group were topically administered fluralaner spot-on solution once at a dose of 25 mg/kg body weight, while dogs in each control group were not treated. Two days before treatment, and on days 28, 56 and 84 after treatment, all dogs were infested with approximately 50 unfed, adult Rh. sanguineus ticks (sex ratio 1:1). Ticks were removed and counted on days 2, 30 (4 weeks), 58 (8 weeks), and 86 (12 weeks) after treatment to assess efficacy.
Results
Efficacy against ticks 2 days after treatment was 91.1 % (study 1), 98.4 % (study 2), 100 % (study 3), 97.6 % (study 4), 99.6 % (study 5), and 99.8 % (study 6). At all other assessment time points, tick efficacy was 95.4–100 %. Tick reduction in all treatment groups was significant at all assessment time points (P < 0.0001).
Conclusions
A single topical administration of fluralaner spot-on solution provides a high level of therapeutic and persistent efficacy against Rh. sanguineus ticks over the subsequent 12 weeks.
doi:10.1186/s13071-016-1523-4
PMCID: PMC4886405  PMID: 27241176
Bravecto™ Spot-on Solution; Dog; Efficacy; Fluralaner; Rhipicephalus sanguineus; Tick
20.  The effect of water and shampooing on the efficacy of fluralaner spot-on solution against Ixodes ricinus and Ctenocephalides felis infestations in dogs 
Parasites & Vectors  2016;9:233.
Background
Fluralaner spot-on solution provides immediate and persistent efficacy against tick and flea infestations in dogs and cats for 12-weeks following topical administration. The active ingredient fluralaner is distributed systemically following transdermal absorption. Therefore, this study tested the hypothesis whether water-immersion or shampooing of dogs following administration of fluralaner spot-on solution has an impact on subsequent tick and flea efficacy.
Methods
Thirty-two Beagle dogs were allocated to four study groups of 8 dogs each. On day 0, dogs in the 2 treatment groups received topical administration of fluralaner (Bravecto™ spot-on solution) according to label instructions. Dogs in the 2 corresponding control groups remained untreated. On days 3, 21, 49, and 77 dogs in one treatment group and control group were water-immersed for 2–5 min, while dogs in the other treatment group and control group were shampooed 6–8 min with a commercial foaming micro-emulsion, unscented product. On days 4, 28, 56, and 84 all dogs were co-infested with 50 ± 2 female and 10 ± 2 male Ixodes ricinus and 100 ± 4 Ctenocephalides felis, with tick and flea removal and counts 48 ± 2 h post-infestation. Efficacy against ticks and fleas was calculated for each assessment time point.
Results
No treatment-related adverse event was observed in any of the 16 dogs treated with fluralaner spot-on solution during the study.
Efficacy against ticks at each assessment time point was between 99.7 and 100 % in the water-immersed group and between 99.2 and 100 % in the shampooed group. Efficacy against fleas was 100 % at each assessment time point as well in the water-immersed as the shampooed group. Tick and flea reduction in both treatment groups was significant at all assessment time points (p < 0.0001).
Conclusions
Neither water-immersion nor shampooing after single topical administration of fluralaner spot-on solution had an impact on the excellent tick and flea efficacy over the 12-week recommended re-treatment interval.
doi:10.1186/s13071-016-1367-y
PMCID: PMC4886437  PMID: 27241021
Bathing; Bravecto™ spot-on solution; Fluralaner; Dog; Flea; Ctenocephalides felis; Efficacy; Water-immersion; Shampooing; Tick; Ixodes ricinus
21.  Prevention of transmission of Babesia canis by Dermacentor reticulatus ticks to dogs after topical administration of fluralaner spot-on solution 
Parasites & Vectors  2016;9:234.
Background
The preventive effect of fluralaner spot-on solution against transmission of Babesia canis by Dermacentor reticulatus ticks was evaluated.
Findings
Sixteen dogs, tested negative for B. canis by polymerase chain reaction (PCR) and immunofluorescence assay test (IFAT), were allocated to two study groups. On day 0, dogs in one group (n = 8) were treated once topically with fluralaner spot-on solution (Bravecto™ Spot-on Solution) according to label recommendations and dogs in the control group (n = 8) remained untreated. On days 2, 28, 56, 70 and 84, all dogs were infested with 50 (±4) D. reticulatus ticks harbouring B. canis, with tick in situ thumb counts 48 ± 4 h after each infestation. On day 90, ticks were removed from all dogs and counted. Prior to each infestation, the presence of B. canis in the respective tick batch was confirmed by PCR, and 12–16 % of ticks were found to be infected with B. canis. Efficacy against ticks was 99.5 and 99.3 % on days 4 and 58 after treatment, respectively and 100 % on all other days. Replacement dogs were included for any B. canis infected control dog (in total 19). All control dogs (n = 27) became infected with B. canis, as confirmed by PCR, performed every 7 days, and by IFAT, performed every 14 days after treatment. None of the eight treated dogs became infected with B. canis, as they were tested negative by PCR and IFAT throughout the study until day 112. By comparing infected dogs in the treated group with infected dogs in the untreated control group, a 100 % preventive effect against B. canis transmission was demonstrated.
Conclusions
A single topical administration of fluralaner spot-on solution effectively prevented the transmission of B. canis by infected D. reticulatus ticks over a 12-week period.
doi:10.1186/s13071-016-1481-x
PMCID: PMC4886439  PMID: 27241120
Bravecto™ Spot-on Solution; Babesia canis; Babesiosis; Fluralaner; Dermacentor reticulatus; Dog; Efficacy; Prevention of transmission; Spot-on
22.  Safety of the concurrent treatment of dogs with Bravecto™ (fluralaner) and Scalibor™ protectorband (deltamethrin) 
Parasites & Vectors  2014;7:105.
Background
Bravecto™ (fluralaner; MSD Animal Health) is a novel systemic ectoparasiticide for dogs providing long-acting flea- and tick-control after a single oral dose. Scalibor™ Protectorband (deltamethrin; MSD Animal Health) is a collar often used to reduce sandfly feeding for leishmaniasis prevention. This study investigated the safety of the concurrent use of BravectoTM and ScaliborTM Protectorband at the recommended dosage regimens.
Findings
Throughout the study period of 24 weeks, there were no clinical findings related to the concurrent treatment with Bravecto™ in dogs fitted with Scalibor™ Protectorband at the recommended dosage regimen.
Conclusions
Concurrent treatment with Bravecto™ in dogs fitted with Scalibor™ Protectorband is well tolerated.
doi:10.1186/1756-3305-7-105
PMCID: PMC3972964  PMID: 24646450
BravectoTM; Fluralaner; Dog; Safety; Scalibor™; Deltamethrin
23.  Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications 
Todd Milne, G. | Sandner, Peter | Lincoln, Kathleen A. | Harrison, Paul C. | Chen, Hongxing | Wang, Hong | Clifford, Holly | Qian, Hu Sheng | Wong, Diane | Sarko, Chris | Fryer, Ryan | Richman, Jeremy | Reinhart, Glenn A. | Boustany, Carine M. | Pullen, Steven S. | Andresen, Henriette | Moltzau, Lise Román | Cataliotti, Alessandro | Levy, Finn Olav | Lukowski, Robert | Frankenreiter, Sandra | Friebe, Andreas | Calamaras, Timothy | Baumgartner, Robert | McLaughlin, Angela | Aronovitz, Mark | Baur, Wendy | Wang, Guang-Rong | Kapur, Navin | Karas, Richard | Blanton, Robert | Hell, Stefan | Waldman, Scott A. | Lin, Jieru E. | Colon-Gonzalez, Francheska | Kim, Gilbert W. | Blomain, Erik S. | Merlino, Dante | Snook, Adam | Erdmann, Jeanette | Wobst, Jana | Kessler, Thorsten | Schunkert, Heribert | Walter, Ulrich | Pagel, Oliver | Walter, Elena | Gambaryan, Stepan | Smolenski, Albert | Jurk, Kerstin | Zahedi, Rene | Klinger, James R. | Benza, Raymond L. | Corris, Paul A. | Langleben, David | Naeije, Robert | Simonneau, Gérald | Meier, Christian | Colorado, Pablo | Chang, Mi Kyung | Busse, Dennis | Hoeper, Marius M. | Masferrer, Jaime L. | Jacobson, Sarah | Liu, Guang | Sarno, Renee | Bernier, Sylvie | Zhang, Ping | Todd Milne, G. | Flores-Costa, Roger | Currie, Mark | Hall, Katherine | Möhrle, Dorit | Reimann, Katrin | Wolter, Steffen | Wolters, Markus | Mergia, Evanthia | Eichert, Nicole | Geisler, Hyun-Soon | Ruth, Peter | Friebe, Andreas | Feil, Robert | Zimmermann, Ulrike | Koesling, Doris | Knipper, Marlies | Rüttiger, Lukas | Tanaka, Yasutake | Okamoto, Atsuko | Nojiri, Takashi | Kumazoe, Motofumi | Tokudome, Takeshi | Miura, Koichi | Hino, Jun | Hosoda, Hiroshi | Miyazato, Mikiya | Kangawa, Kenji | Kapil, Vikas | Ahluwalia, Amrita | Paolocci, Nazareno | Eaton, Philip | Campbell, James C. | Henning, Philipp | Franz, Eugen | Sankaran, Banumathi | Herberg, Friedrich W. | Kim, Choel | Wittwer, M. | Luo, Q. | Kaila, V. | Dames, S. A. | Tobin, Andrew | Alam, Mahmood | Rudyk, Olena | Krasemann, Susanne | Hartmann, Kristin | Prysyazhna, Oleksandra | Zhang, Min | Zhao, Lan | Weiss, Astrid | Schermuly, Ralph | Eaton, Philip | Moyes, Amie J. | Chu, Sandy M. | Baliga, Reshma S. | Hobbs, Adrian J. | Michalakis, Stylianos | Mühlfriedel, Regine | Schön, Christian | Fischer, Dominik M. | Wilhelm, Barbara | Zobor, Ditta | Kohl, Susanne | Peters, Tobias | Zrenner, Eberhart | Bartz-Schmidt, Karl Ulrich | Ueffing, Marius | Wissinger, Bernd | Seeliger, Mathias | Biel, Martin | Ranek, Mark J. | Kokkonen, Kristen M. | Lee, Dong I. | Holewinski, Ronald J. | Agrawal, Vineet | Virus, Cornelia | Stevens, Donté A. | Sasaki, Masayuki | Zhang, Huaqun | Mannion, Mathew M. | Rainer, Peter P. | Page, Richard C. | Schisler, Jonathan C. | Van Eyk, Jennifer E. | Willis, Monte S. | Kass, David A. | Zaccolo, Manuela | Russwurm, Michael | Giesen, Jan | Russwurm, Corina | Füchtbauer, Ernst-Martin | Koesling, Doris | Bork, Nadja I. | Nikolaev, Viacheslav O. | Agulló, Luis | Floor, Martin | Villà-Freixa, Jordi | Manfra, Ornella | Calamera, Gaia | Surdo, Nicoletta C. | Meier, Silja | Froese, Alexander | Nikolaev, Viacheslav O. | Zaccolo, Manuela | Levy, Finn Olav | Andressen, Kjetil Wessel | Aue, Annemarie | Schwiering, Fabian | Groneberg, Dieter | Friebe, Andreas | Bajraktari, Gzona | Burhenne, Jürgen | Haefeli, Walter E. | Weiss, Johanna | Beck, Katharina | Voussen, Barbara | Vincent, Alexander | Parsons, Sean P. | Huizinga, Jan D. | Friebe, Andreas | Mónica, Fabiola Zakia | Seto, Edward | Murad, Ferid | Bian, Ka | Burgoyne, Joseph R. | Prysyazhna, Oleksandra | Richards, Daniel | Eaton, Philip | Calamera, Gaia | Bjørnerem, Marianne | Ulsund, Andrea Hembre | Kim, Jeong Joo | Kim, Choel | Levy, Finn Olav | Andressen, Kjetil Wessel | Donzelli, Sonia | Goetz, Mara | Schmidt, Kjestine | Wolters, Markus | Stathopoulou, Konstantina | Prysyazhna, Oleksandra | Scotcher, Jenna | Dees, Christian | Subramanian, Hariharan | Butt, Elke | Kamynina, Alisa | Bruce King, S. | Nikolaev, Viacheslav O. | de Witt, Cor | Leichert, Lars I. | Feil, Robert | Eaton, Philip | Cuello, Friederike | Dobrowinski, Hyazinth | Lehners, Moritz | Schmidt, Michael Paolillo Hannes | Feil, Robert | Feil, Susanne | Wen, Lai | Wolters, Markus | Thunemann, Martin | Schmidt, Kjestine | Olbrich, Marcus | Langer, Harald | Gawaz, Meinrad | Friebe, Andreas | de Wit, Cor | Feil, Robert | Franz, Eugen | Kim, Jeong Joo | Bertinetti, Daniela | Kim, Choel | Herberg, Friedrich W. | Ghofrani, Hossein-Ardeschir | Grimminger, Friedrich | Grünig, Ekkehard | Huang, Yigao | Jansa, Pavel | Jing, Zhi Cheng | Kilpatrick, David | Langleben, David | Rosenkranz, Stephan | Menezes, Flavia | Fritsch, Arno | Nikkho, Sylvia | Frey, Reiner | Humbert, Marc | Groneberg, Dieter | Aue, Annemarie | Schwiering, Fabian | Friebe, Andreas | Harloff, Manuela | Reinders, Joerg | Schlossmann, Jens | Jung, Joon | Wales, Jessica A. | Chen, Cheng-Yu | Breci, Linda | Weichsel, Andrzej | Bernier, Sylvie G. | Solinga, Robert | Sheppeck, James E. | Renhowe, Paul A. | Montfort, William R. | Qin, Liying | Sung, Ying-Ju | Casteel, Darren | Kim, Choel | Kollau, Alexander | Neubauer, Andrea | Schrammel, Astrid | Russwurm, Michael | Koesling, Doris | Mayer, Bernd | Kumazoe, Motofumi | Takai, Mika | Takeuchi, Chieri | Kadomatsu, Mai | Hiroi, Shun | Takamatsu, Kanako | Nojiri, Takashi | Kangawa, Kenji | Tachibana, Hirofumi | Opelt, Marissa | Eroglu, Emrah | Waldeck-Weiermair, Markus | Russwurm, Michael | Koesling, Doris | Malli, Roland | Graier, Wolfgang F. | Fassett, John T. | Schrammel, Astrid | Mayer, Bernd | Sollie, Selene J. | Moltzau, Lise Román | Hernandez-Valladares, Maria | Berven, Frode | Levy, Finn Olav | Andressen, Kjetil W. | Nojiri, Takashi | Tokudome, Takeshi | Kumazoe, Motofumi | Arai, Miki | Suzuki, Yutaka | Miura, Koichi | Hino, Jun | Hosoda, Hiroshi | Miyazato, Mikiya | Okumura, Meinoshin | Kawaoka, Shinpei | Kangawa, Kenji | Peters, Stefanie | Schmidt, Hannes | Selin Kenet, B. | Nies, Sarah Helena | Frank, Katharina | Wen, Lai | Rathjen, Fritz G. | Feil, Robert | Petrova, Olga N. | Lamarre, Isabelle | Négrerie, Michel | Robinson, Jerid W. | Egbert, Jeremy R. | Davydova, Julia | Jaffe, Laurinda A. | Potter, Lincoln R. | Robinson, Jerid W. | Blixt, Nicholas | Shuhaibar, Leia C. | Warren, Gordon L. | Mansky, Kim C. | Jaffe, Laurinda A. | Potter, Lincoln R. | Romoli, Simone | Bauch, Tobias | Dröbner, Karoline | Eitner, Frank | Ruppert, Mihály | Radovits, Tamás | Korkmaz-Icöz, Sevil | Li, Shiliang | Hegedűs, Péter | Loganathan, Sivakanan | Németh, Balázs Tamás | Oláh, Attila | Mátyás, Csaba | Benke, Kálmán | Merkely, Béla | Karck, Matthias | Szabó, Gábor | Scheib, Ulrike | Broser, Matthias | Mukherjee, Shatanik | Stehfest, Katja | Gee, Christine E. | Körschen, Heinz G. | Oertner, Thomas G. | Hegemann, Peter | Schmidt, Hannes | Dickey, Deborah M. | Dumoulin, Alexandre | Kühn, Ralf | Jaffe, Laurinda | Potter, Lincoln R. | Rathjen, Fritz G. | Schobesberger, Sophie | Wright, Peter | Poulet, Claire | Mansfield, Catherine | Friebe, Andreas | Harding, Sian E. | Nikolaev, Viacheslav O. | Gorelik, Julia | Kollau, Alexander | Opelt, Marissa | Wölkart, Gerald | Gorren, Antonius C. F. | Russwurm, Michael | Koesling, Doris | Schrammel, Astrid | Mayer, Bernd | Schwaerzer, Gerburg K. | Casteel, Darren E. | Dalton, Nancy D. | Gu, Yusu | Zhuang, Shunhui | Milewicz, Dianna M. | Peterson, Kirk L. | Pilz, Renate | Schwiering, Fabian | Aue, Annemarie | Groneberg, Dieter | Friebe, Andreas | Argyriou, Aikaterini I. | Makrynitsa, Garyfalia | Alexandropoulos, Ioannis I. | Stamopoulou, Andriana | Bantzi, Marina | Giannis, Athanassios | Topouzis, Stavros | Papapetropoulos, Andreas | Spyroulias, Georgios A. | Stuehr, Dennis J. | Ghosh, Arnab | Dai, Yue | Misra, Saurav | Tchernychev, Boris | Jung, Joon | Liu, Guang | Silos-Santiago, Inmaculada | Hannig, Gerhard | Dao, Vu Thao-Vi | Deile, Martin | Nedvetsky, Pavel I. | Güldner, Andreas | Ibarra-Alvarado, César | Gödecke, Axel | Schmidt, Harald H. H. W. | Vachaviolos, Angelos | Gerling, Andrea | Thunemann, Martin | Lutz, Stefan Z. | Häring, Hans-Ulrich | Krüger, Marcel A. | Pichler, Bernd J. | Shipston, Michael J. | Feil, Susanne | Feil, Robert | Vandenwijngaert, Sara | Ledsky, Clara D. | Agha, Obiajulu | Hu, Dongjian | Domian, Ibrahim J. | Buys, Emmanuel S. | Newton-Cheh, Christopher | Bloch, Donald B. | Voussen, Barbara | Beck, Katharina | Mauro, Nadine | Keppler, Jonas | Friebe, Andreas | Ferreira, Wilson A. | Chweih, Hanan | Brito, Pamela L. | Almeida, Camila B. | Penteado, Carla F. F. | Saad, Sara S. O. | Costa, Fernando F. | Frenette, Paul S. | Brockschnieder, Damian | Stasch, Johannes-Peter | Sandner, Peter | Conran, Nicola | Zimmer, Daniel P. | Tobin, Jenny | Shea, Courtney | Sarno, Renee | Long, Kimberly | Jacobson, Sarah | Tang, Kim | Germano, Peter | Wakefield, James | Banijamali, Ali | Im, G-Yoon Jamie | Sheppeck, James E. | Profy, Albert T. | Todd Milne, G. | Currie, Mark G. | Masferrer, Jaime L.
BMC Pharmacology & Toxicology  2017;18(Suppl 1):64.
doi:10.1186/s40360-017-0170-5
PMCID: PMC5667593  PMID: 29035170
24.  Does Osmotic Stress Affect Natural Product Expression in Fungi? 
Marine Drugs  2017;15(8):254.
The discovery of new natural products from fungi isolated from the marine environment has increased dramatically over the last few decades, leading to the identification of over 1000 new metabolites. However, most of the reported marine-derived species appear to be terrestrial in origin yet at the same time, facultatively halo- or osmotolerant. An unanswered question regarding the apparent chemical productivity of marine-derived fungi is whether the common practice of fermenting strains in seawater contributes to enhanced secondary metabolism? To answer this question, a terrestrial isolate of Aspergillus aculeatus was fermented in osmotic and saline stress conditions in parallel across multiple sites. The ex-type strain of A. aculeatus was obtained from three different culture collections. Site-to-site variations in metabolite expression were observed, suggesting that subculturing of the same strain and subtle variations in experimental protocols can have pronounced effects upon metabolite expression. Replicated experiments at individual sites indicated that secondary metabolite production was divergent between osmotic and saline treatments. Titers of some metabolites increased or decreased in response to increasing osmolite (salt or glycerol) concentrations. Furthermore, in some cases, the expression of some secondary metabolites in relation to osmotic and saline stress was attributed to specific sources of the ex-type strains.
doi:10.3390/md15080254
PMCID: PMC5577608  PMID: 28805714
fungi; metabolite expression; LC-MS; metabolome; osmotic stress

Results 1-24 (24)