Variation of the aryl substituent on the piperazine ring within the 4-(piperazin-1-yl)-2,6-di(pyrrolidin-1-yl)pyrimidine scaffold unveils potent, non-competitive inhibitors of the inflammatory caspases.

The inflammatory caspases (caspase-1, -4 and -5) are potential therapeutic targets for autoimmune and inflammatory diseases due to their involvement in the immune response upon inflammasome formation. A series of small molecules based on the 4-(piperazin-1-yl)-2,6-di(pyrrolidin-1-yl)pyrimidine scaffold were synthesized with varying substituents on the piperazine ring. Several compounds were pan-selective inhibitors of the inflammatory caspases, caspase-1, -4 and -5, with the ethylbenzene derivative CK-1-41 displaying low nanomolar Ki values across this family of caspases. Three analogs were nearly 10 fold selective for caspase-5 over caspase-1 and -4. The compounds display non-competitive, time dependent inhibition profiles. To our knowledge, this series is the first example of small molecule inhibitors of all three inflammatory caspases.

Incidence, characteristics and management of pain in one operational area of medical emergency teams.

BACKGROUND: Experience of pain associated with both chronic as well as acute medical conditions is a main cause for call for ambulance. The aim of this study was to establish both frequency and characteristics of pain reported by patients treated in pre-hospital environment in a single operational area. The supplementary goal was an analysis of methods of pain alleviation applied by medical personnel in the above described scenario. METHODS: The written documentation of 6 months of year 2009 provided by doctor-manned as well as paramedic-only ambulances operating in Tatra county, Malopolska, Poland was analyzed. RESULTS: Medical personnel inquired about pain experienced in 57.4% of cases, 10-point numerical rating scale was used in 22.3% of patients. Pain was reported by 43.8% of patients, the most frequent reasons of experienced pain were trauma and cardiovascular diseases. In almost half of the cases pain was referred to the areas of chest and abdomen. Non-traumatic pain was reported by 47.7% of patients, post-traumatic in 41.3% of cases, 11% of subjects reported ischemic chest pain. 42.3% of pain-reporting patients received some form of analgesia, yet only 3% of subjects in this group received opiates. Personnel of paramedic-only ambulances tended to use pain intensity scale more often (P < 0.01), yet administered pain alleviating drugs noticeably less often than the doctor-manned teams (P < 0.01). CONCLUSION: The use of pain alleviating drugs, opiates especially, was inadequate in proportion to frequency and intensity of pain reported by patients. General, nation-wide standards of pain measurement and treatment in pre-hospital rescue are suggested as a means to improve the efficacy of pain reduction treatment.