Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition.

Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and Leishmania infantum, is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential to treat this neglected tropical disease. The compound series was discovered by repurposing hits from a screen against the related parasite Trypanosoma cruzi Subsequent optimization of the chemical series resulted in the development of a potent cidal compound with activity against a range of clinically relevant L. donovani and L. infantum isolates. Compound 8 demonstrates promising pharmacokinetic properties and impressive in vivo efficacy in our mouse model of infection comparable with those of the current oral antileishmanial miltefosine. Detailed mode of action studies confirm that this compound acts principally by inhibition of the chymotrypsin-like activity catalyzed by the ß5 subunit of the L. donovani proteasome. High-resolution cryo-EM structures of apo and compound 8-bound Leishmania tarentolae 20S proteasome reveal a previously undiscovered inhibitor site that lies between the ß4 and ß5 proteasome subunits. This induced pocket exploits ß4 residues that are divergent between humans and kinetoplastid parasites and is consistent with all of our experimental and mutagenesis data. As a result of these comprehensive studies and due to a favorable developability and safety profile, compound 8 is being advanced toward human clinical trials.

Preventing tick attachment to dogs using essential oils.

Preventing tick bites using repellents could make a valuable contribution to an integrated tick management programme for dogs. Here, the ability of a range of essential oils or active ingredients of commercially available repellents, to abolish the orientation and taxis of the tick Ixodes ricinus towards sebum extracted from dog hair was examined in laboratory bioassays. Substantial differences between oils were observed, but turmeric oil was both able to prevent a climbing response by ticks and had a longer residual activity than other oils. A blanket-drag field assay was then used to compare the attachment of ticks to blankets impregnated with one of: turmeric oil, DEET (positive control), orange-oil or excipient only (negative controls). In total, 899 ticks were counted, with an average of 23.3 (SD ±â€¯21.3) ticks per blanket drag for excipient-only (n = 16), 26.9 (SD ±â€¯28.6) for orange oil (n = 16), 2.6 (SD ±â€¯2.0) for turmeric oil (n = 16) and 3.4 (SD ±â€¯3.7) for DEET (n = 16). Finally, in a participatory in vivo trial, tick acquisition by 15 untreated control dogs was compared with 24 dogs sprayed with turmeric-oil and 16 dogs sprayed with orange oil (both 2.5% v/v diluted in water with a 1% coco glucoside excipient) before each walk in known tick infested areas. The percentage of dogs with ticks attached to the legs or belly of dogs sprayed with turmeric oil suspension (15% ±â€¯19.4%) was significantly lower than that of ticks attached to the same areas of dogs sprayed with orange oil suspension (85% ±â€¯19.4%) and unsprayed dogs (73% ±â€¯26.2%) (P < 0.05). The data indicate that turmeric-oil may form a valuable component of a tick management programme for domestic dogs.

Maggot-therapy in veterinary medicine.

Maggot-therapy is the application of disinfected fly larvae to chronic wounds to debride the wound bed of necrotic tissue, reduce bacterial contamination and enhance the formation of healthy granulation tissue. Interest in the use of maggot-therapy in human medicine is growing as a result of the prevalence of antibiotic resistant bacteria. Maggot therapy, however, is used relatively little in veterinary medicine. Nevertheless, concern over antibiotic resistance and the increase in demand for organic husbandry and residue-free meat and milk, suggest that it is an option which merits further consideration.

Spiritual care of families in the intensive care unit.

OBJECTIVES: There is growing recognition of the importance of spiritual care as a quality domain for critically ill patients and their families, but there is a paucity of research to guide quality improvement in this area. Our goals were to: 1) determine whether intensive care unit (ICU) family members who rate an item about their spiritual care are different from family members who skip the item or rate the item as "not applicable" and 2) identify potential determinants of higher family satisfaction with spiritual care in the ICU. DESIGN: Cross-sectional study, using data from a cluster randomized trial aimed at improving end-of-life care in the ICU. SETTING: ICUs in ten Seattle-area hospitals. SUBJECTS: A total of 356 family members of patients dying during an ICU stay or within 24 hrs of ICU discharge. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Family members were surveyed about spiritual care in the ICU. Chart abstractors obtained clinical variables including end-of-life care processes and family conference data. The 259 of 356 family members (73%) who rated their spiritual care were slightly younger than family members who did not rate this aspect of care (p = .001). Multiple regression revealed family members were more satisfied with spiritual care if a pastor or spiritual advisor was involved in the last 24 hrs of the patient's life (p = .007). In addition, there was a strong association between satisfaction with spiritual care and satisfaction with the total ICU experience (p < .001). Ratings of spiritual care were not associated with any other demographic or clinical variables. CONCLUSIONS: These findings suggest that for patients dying in the ICU, clinicians should assess each family's spiritual needs and consult a spiritual advisor if desired by the family. Further research is needed to develop a comprehensive approach to ICU care that meets not only physical and psychosocial but also spiritual needs of patients and their families.