The effect of pirenzepine on gastric emptying and salivary flow rate: constraints on the use of saliva paracetamol concentrations for the determination of paracetamol pharmacokinetics.

1. The effects of pirenzepine on gastric emptying, salivary flow and saliva paracetamol concentrations were investigated in healthy volunteers. 2. Pirenzepine significantly reduced the area under the saliva flow-time curves (7.29 +/- 3.30 g min-1 h without pirenzepine; 4.19 +/- 2.59 g min-1 h with pirenzepine, P less than 0.01). Pirenzepine had no significant effect on plasma paracetamol Cmax (17.5 +/- 7.8 micrograms ml-1 without pirenzepine; 12.6 +/- 7.7 micrograms ml-1 with pirenzepine), plasma tmax (0.2 h (0.2-0.8 h) without pirenzepine; (0.2 h 0.2-0.8 h) with pirenzepine) and plasma AUC(0.6 h) (32.3 +/- 7.2 micrograms ml-1 h without pirenzepine; 30.3 +/- 6.5 micrograms ml-1 h with pirenzepine). 3. Mean ratios of saliva:plasma paracetamol AUC (1.06 +/- 0.24 without pirenzepine; 1.84 +/- 0.48 with pirenzepine, P less than 0.001) and saliva:plasma paracetamol Cmax (1.7 +/- 1.0 without pirenzepine; 6.5 +/- 2.7 with pirenzepine, P less than 0.01) were significantly increased by pirenzepine pretreatment, but there was a poor correlation between the percentage change in the area under the saliva flow-time curve and the percentage change in saliva paracetamol AUC (r = 0.47, P = 0.21). 4. The findings suggest that a) pirenzepine is a more selective antagonist of the muscarinic receptors in salivary glands than those in gastric smooth muscle and b) caution is required when using saliva paracetamol concentrations to determine the pharmacokinetics of the drug in the presence of other agents which may influence salivary flow rate.     

Autogenous bone grafting for severe angular deformity in total knee arthroplasty

Fourteen patients with severe angular knee deformities (range, 30 degrees varus to 35 degrees valgus) had total knee arthroplasty using autogenous bone graft to the tibia. Twelve knees had osteoarthritis, one rheumatoid arthritis, and one gouty arthritis. The preoperative knee motion averaged -5 degrees of extension to 80 degrees of flexion and the average motion arc was 70 degrees. All tibial defects were greater than 25% of the tibial component support surface and more than 10 mm deep. Twelve knees were reconstructed with Insall-Burstein posterior stabilized total condylar knee implants and two knees, with severe preoperative ligamentous instability, with the constrained Total Condylar III implant. Postoperative rehabilitation was routine, and weight bearing was begun, on average, on the third postoperative day. The follow-up period averaged 4.1 years (range, 2-7.3 years). Radiographic analysis revealed no change in knee or component alignment compared with immediate postoperative position. All grafts consolidated without evidence of collapse, resorption, or prosthetic subsidence. All patients had good or excellent clinical results (Hospital for Special Surgery Knee Rating Scale). The average postoperative arc of motion was 90 degrees. There were no infections and no need for implant removal. The technique developed by the senior author (T.P.S.) utilizes bone resected from the distal femur during knee arthroplasty. An oblique planar cancellous surface is created on the recipient side, and coaptation of cancellous distal femoral graft surface to this recipient bed is ensured by vitallium screw fixation. The proximal tibia is reconstituted by the graft, and subchondral femoral bone after shaping of the graft forms the tibial periphery.     

Androgen receptor YAC transgenic mice carrying CAG 45 alleles show trinucleotide repeat instability

X-linked spinal and bulbar muscular atrophy (SBMA) is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene. Disease-associated alleles (37-66 CAGs) change in length when transmitted from parents to offspring, with a significantly greater tendency to shift size when inherited paternally. As transgenic mice carrying human AR cDNAs with 45 and 66 CAG repeats do not display repeat instability, we attempted to model trinucleotide repeat instability by generating transgenic mice with yeast artificial chromosomes (YACs) carrying AR CAG repeat expansions in their genomic context. Studies of independent lines of AR YAC transgenic mice with CAG 45 alleles reveal intergenerational instability at an overall rate of approximately 10%. We also find that the 45 CAG repeat tracts are significantly more unstable with maternal transmission and as the transmitting mother ages. Of all the CAG/CTG repeat transgenic mice produced to date the AR YAC CAG 45 mice are unstable with the smallest trinucleotide repeat mutations, suggesting that the length threshold for repeat instability in the mouse may be lowered by including the appropriate flanking human DNA sequences. By sequence-tagged site content analysis and long range mapping we determined that one unstable transgenic line has integrated an approximately 70 kb segment of the AR locus due to fragmentation of the AR YAC. Identification of the cis - acting elements that permit CAG tract instability and the trans -acting factors that modulate repeat instability in the AR YAC CAG 45 mice may provide insights into the molecular basis of trinucleotide repeat instability in humans.