γ-Carbolines: a novel class of cannabinoid agonists with high aqueous solubility and restricted CNS penetration.

An oral, peripherally restricted CB1/CB2 agonist could provide an interesting approach to treat chronic pain by harnessing the analgesic properties of cannabinoids but without the well-known central side effects. γ-Carbolines are a novel class of potent mixed CB1/CB2 agonists characterized by attractive physicochemical properties including high aqueous solubility. Optimization of the series has led to the discovery of 29, which has oral activity in a rat inflammatory pain model and limited brain exposure at analgesic doses, consistent with a lower risk of CNS-mediated tolerability issues.

Discovery of P2X3 selective antagonists for the treatment of chronic pain.

Purinergic receptor P2X3 has been linked to analgesia in a number of pre-clinical models of pain, and is expressed in the human pain perception pathway. Only few P2X3-selective antagonists have been reported to date. This Letter describes the SAR and in vivo analgesic profile of a novel scaffold of selective P2X3 antagonists.

Novel benzimidazole derivatives as selective CB2 agonists.

The preparation and evaluation of a novel class of CB2 agonists based on a benzimidazole moiety are reported. They showed binding affinities up to 1nM towards the CB2 receptor with partial to full agonist potencies. They also demonstrated good to excellent selectivity (>1000-fold) over the CB1 receptor.

[Feasibility and safety evaluation of retrograde inserting of ureteric catheter via flexible cystoscope].

OBJECTIVE: To introduce a method of retrograde ureteric catheter placement via flexible cystoscope , and to evaluate the feasibility and safety of this method. METHODS: 112 patients, 62 males and 50 females undergoing retrograde ureteropyelography by 2 same physicians in cooperation were randomly divided into two equal groups with 31 males and 25 females each: one group via flexible cystoscope and the other group via rigid cystoscope. The catheterizing time, visual analogue scale (VAS) pain score, gross hematuria rate, and fever rate were compared between these 2 groups. RESULTS: Fifty-five patients underwent ureteric catheter placement successfully via flexible cystoscope (98%, 55/56), while 53 cases were technically successful by rigid cystoscope (95%, 53/56). The inserting time in women patients of the flexible cystoscopy group was (7.6 +/- 1.8) min, significantly shorter than that of the men [(8.0 +/- 1.8) min, P < 0.05]. The inserting time in women patients of the rigid cystoscopy group was (7.4 +/- 1.5) min, significantly shorter than that of the men [(8.2 +/- 1.2) min, P < 0.05]. However, there were not significant differences in the inserting times in both men and women between these 2 groups (both P > 0.05). The VAS pain scores in men and women of the flexible cystoscope group were 3. 5 and 2. 3 respectively, both significantly lower than those of the rigid cystoscopy group (7.2 and 3.3 respectively, both P < 0.05). The gross hematuria rate of the flexible cystoscope group was 8.6% (5/56), significantly lower than that of the rigid cystoscopy group (25.0%, 14/56, P < 0.05). Four patients had a fever after flexible cystoscopy while 6 cases did after rigid cystoscopy, however, without significant difference between these 2 groups (P > 0.05). CONCLUSIONS: Retrograde placement of ureteric catheter via flexible cystoscope is safe and reliable as rigid cystoscopy. Meanwhile, inserting ureteric catheter via flexible cystoscope causes the patients less pain and less chance of hematuria.

Multiple organ dysfunction syndrome due to ingestion of fish gall bladder.

OBJECTIVE: To investigate changes in renal function, urine N-acetyl-beta-D-glucosaminidase enzyme (N-AG),liver function, myocardial enzymes, the pathology of renal damage and the mechanism of acute renal failure (ARF) associated with fish gall bladder poisoning. METHODS: Eleven patients with acute fish gall bladder poisoning were consecutively admitted to our hospital from September 1997 to October 1999. Renal function, urine N-AG enzyme, liver function, and myocardial enzymes were assayed before and after treatment. One patient consented to a kidney biopsy and the pathology of renal damage was observed under light and electron microscopes. RESULTS: All patients had multiple organ dysfunction syndrome (MODS) and 11 patients suffered from ARF. Ten patients had liver dysfunction, ten patients had poisonous myocarditis, and 8 patients had gastrointestinal dysfunction. Renal function, urine N-AG enzyme, liver function, and myocardial enzymes were significantly improved after treatment compared with those of before treatment (P < 0.05). Kidney biopsy showed that the main damage site was the proximal renal tubule. All eleven patients recovered and were discharged from the hospital. CONCLUSIONS: Ingestion of fish gall bladder leads to kidney damage, as well as liver, heart and gastrointestinal tract injury. The mechanism of acute renal function failure is the serious tubular damage, confirming the location of kidney damage. Necrosis of the proximal tubules plays an important role in the development of ARF. Immediate hemodialysis is the most effective treatment.

[Change of nuclear factor-kappaB activity in early burn injury and its significance].

OBJECTIVE: To study the change of nuclear factor-kappaB(NF-kappaB) activity in the blood leukocytes of rats in the early period after severe burn injury and its significance. METHODS: To examine the change of NF-kappaB activity in leukocytes of blood of rats in the early period(48 hours) after severe burn injury to show its relation with tumor necrosis factor-alpha(TNF-alpha) and intercellular adhesion molecule-1(ICAM-1). RESULTS: The activity of NF-kappaB after burn injury was increased than that was before burn injury, and reached the peak at the 12 hours. TNF-alpha, ICAM-1 and polymorphonuclear neutrophilic leucocytes(PMN) in plasma had the similar changeable patterns, and NF-kappaB had the positive correlation with TNF-alpha, ICAM-1 and PMN. CONCLUSION: The activity of NF-kappaB is increased in blood leukocytes in the early period after severe burn injury. It may play an important role in systemic inflammatory response syndrome(SIRS) and multiple organ dysfunction syndrome(MODS) after burn injury.

Practical synthesis of quinoxalinones via palladium-catalyzed intramolecular N-arylations.

A practical and highly efficient route to the synthesis of pharmaceutically interesting quinoxalinone scaffolds is reported. The key step involves an intramolecular palladium-catalyzed N-arylation under microwave irradiation. The developed methodology tolerates a variety of bromoanilides to afford a diverse collection of bicyclic and polycyclic quinoxalinones in high yield.

Total synthesis of A-315675: a potent inhibitor of influenza neuraminidase.

A concise, stereocontrolled, and practical synthesis of a neuraminidase inhibitor consisting of a highly functionalized D-proline scaffold is described. Key features involve a stereocontrolled addition of a propiolate ester to a chiral nonracemic nitrone derived originally from D-serine and the manipulation of acyclic and cyclic motifs en route to the target in 12.8% overall yield over 22 steps. Several crystalline intermediates were suitable for single-crystal X-ray analysis.