Long-term urinary excretion of methaqualone in a human subject

The urinary excretion rates of methaqualone and of one of its metabolites, 6-hydroxymethaqualone (free and conjugated), were determined in a normal male subject over a 30-day period by stable isotope dilution analysis using field ionization mass spectrometry. The excretion rates for methaqualone were fitted by computer to three-and four-exponential functions. The estimated terminal halflife for the drug was approximately 74 hr. 6-Hydroxymethaqualone excretion in the elimination phase was fitted to a single exponential decay curve. Estimated halflives obtained for the free and total (primarily conjugated) metabolite were 78 and 70 hr, respectively. The apparent difference between the latter two values was not statistically significant. The close similarity between the halflives of methaqualone and 6-hydroxymethaqualone indicates that elimination of these compounds is ratelimited by the same pharmacokinetic process. A similarly long halflife, 50 hr, was estimated in a previous study (5) of another subject in which excretion of the compounds was followed over an 11-day period. These results demonstrate that the half-life of methaqualone can be much longer than has been indicated by relatively short-term investigations.Supported by Contract DADA17-73-C-3063 from the U.S. Army Medical Research and Development Command.     

4α-phorbol 12,13-didecanoate activates cultured mouse dorsal root ganglia neurons independently of TRPV4

Background and Purpose

The Ca²⁺-permeable cation channel TRPV4 is activated by mechanical disturbance of the cell membrane and is implicated in mechanical hyperalgesia. Nerve growth factor (NGF) is increased during inflammation and causes mechanical hyperalgesia. 4α-phorbol 12,13-didecanoate (4αPDD) has been described as a selective TRPV4 agonist. We investigated NGF-induced hyperalgesia in TRPV4 wild-type (+/+) and knockout (–/–) mice, and the increases in [Ca²⁺]_i produced by 4αPDD in cultured mouse dorsal root ganglia neurons following exposure to NGF.

Experimental Approach

Withdrawal thresholds to heat, von Frey hairs and pressure were measured in mice before and after systemic administration of NGF. Changes in intracellular Ca²⁺ concentration were measured by ratiometric imaging with Fura-2 in cultured DRG and trigeminal ganglia (TG) neurons during perfusion of TRPV4 agonists.

Key Results

Administration of NGF caused a significant sensitization to heat and von Frey stimuli in TRPV4 +/+ and –/– mice, but only TRPV4 +/+ mice showed sensitization to noxious pressure. 4αPDD stimulated a dose-dependent increase in [Ca²⁺]_i in neurons from +/+ and –/– mice, with the proportion of responding neurons and magnitude of increase unaffected by the genotype. In contrast, the selective TRPV4 agonist GSK1016790A failed to stimulate an increase in intracellular Ca²⁺ in cultured neurons. Responses to 4αPDD were unaffected by pretreatment with NGF.

Conclusions and Implications

TRPV4 contributes to mechanosensation in vivo, but there is little evidence for functional TRPV4 in cultured DRG and TG neurons. We conclude that 4αPDD activates these neurons independently of TRPV4, so it is not appropriate to refer to 4αPDD as a selective TRPV4 agonist.     

FMS Kinase Inhibitors: Current Status and Future Prospects

FMS, first discovered as the oncogene responsible for Feline McDonough Sarcoma, is a type III receptor tyrosine kinase that binds to the macrophage or monocyte colony‐stimulating factor (M‐CSF or CSF‐1). Signal transduction through that binding results in survival, proliferation, and differentiation of monocyte/macrophage lineage. Overexpression of CSF‐1 and/or FMS has been implicated in a number of disease states such as the growth of metastasis of certain types of cancer, in promoting osteoclast proliferation in bone osteolysis, and many inflammatory disorders. Inhibition of CSF‐1 and/or FMS may help treat these pathological conditions. This article reviews FMS gene, FMS kinase, CSF‐1, IL‐34, and their roles in bone osteolysis, cancer biology, and inflammation. Monoclonal antibodies, FMS crystal structure, and small molecule FMS kinase inhibitors of different chemical scaffolds are also reviewed.     

希—内学习能力测验在中国聋儿中使用的信度和效度

采用经部分修改的希－内学习能力测验（Ｈ－ＮＴＬＡ）量表对全国２１个省、市、自治区１７５８名３－１７岁聋儿逐人测试。样本人群地区分布、家长职业构成与１９９０年全国人口普查资料一致。１７５８名聋儿智商呈现正态分布（ｇ１＝０．０１１Ｐ＞０．０５，ｇ２＝０．０５８Ｐ＞０．０５）。测试员间信度系数０．９８１（Ｎ＝２４），复测信度０．８４１（Ｎ＝１３６），分半信度０．９２７（３－８岁）及０．８５４（９－１７岁）。各分测验得分随年龄增加而增加，小年龄组增加明显，大年龄组增加缓慢。各分测验之间、各分测验和总离差智商之间大多数相关系数有显著统计学意义。智商与学习成绩（语文及数学）相关系数０．２０８（Ｐ＜０．０１Ｎ＝２２４），与教师评语等级相关系数０．４４（Ｐ＜０．０５ｄｆ＝１６），表明经修订的Ｈ－ＮＴＬＡ量表适用于中国听力语言障碍人群进行智力评定。