relative to noradrenaline were determined in native and cell-based assays using human recombinant a 1 -ARs; they acted as selective a 1A/1L -AR full and partial agonists, respectively. In anaesthetized micropigs and rabbits, amidephrine and Ro 115-1240 produced non-selective, dose-dependent increases in intraurethral and arterial blood pressures but the magnitude of the pressure increases evoked by Ro 115-1240 were about a third of those with amidephrine. In conscious micropigs both agents produced dose-dependent increases in urethral tension. Again, the magnitude of the urethral response to Ro 115-1240 was about a third of that with amidephrine. More importantly, only amidephrine produced dose-dependent increases in blood pressure and decreases in heart rate. Ro 115-1240 produced a maximum increase in urethral tension with no effect on blood pressure or heart rate. CONCLUSIONThese results show that by combining selectivity for the a 1A/1L -AR subtype with a reduction in intrinsic agonist efficacy, Ro 115-1240 has reduced haemodynamic effects while retaining to some degree the contractile effects on urethral smooth muscle. These studies indicate that Ro 115-1240 may be useful as a novel treatment for SUI. KEYWORDSstress urinary incontinence, a -adrenoceptor, urethral smooth muscle, blood pressure OBJECTIVETo describe the preclinical pharmacology of Ro 115-1240, a peripherally acting selective a 1A/1L -adrenoceptor (AR) partial agonist, compared with the a 1A/1L -AR full agonist amidephrine, as AR agonists have some utility in the treatment of stress urinary incontinence (SUI) but are limited by undesirable cardiovascular and central nervous system side-effects. RESULTSIn radioligand-binding studies Ro 115-1240 had greater affinity for a 1A than for a 1B and a 1D subtypes. The potency and intrinsic activity of amidephrine and Ro 115-1240

The goal of rapid medical assessment (RMA) is to estimate the general health of a patient during an emergency room or a doctor's office visit, or even while the patient is at home. Currently the devices used during RMA are typically "all-in-one" vital signs monitors. They require time, effort and expertise to attach various sensors to the body. A device optimized for RMA should instead require little effort or expertise to operate and be able to rapidly obtain and consolidate as much information as possible. MouthLab is a battery powered hand-held device intended to acquire and evaluate many measurements such as non-invasive blood sugar, saliva and respiratory biochemistry. Our initial prototype acquires standard vital signs: pulse rate (PR), breathing rate (BR), temperature (T), blood oxygen saturation (SpO2), blood pressure (BP), and a three-lead electrocardiogram. In our clinical study we tested the device performance against the measurements obtained with a standard patient monitor. 52 people participated in the study. The measurement errors were as follows: PR: -1.7 ± 3.5 BPM, BR: 0.4 ± 2.4 BPM, T: -0.4 ± 1.24 °F, SpO2: -0.6 ± 1.7%. BP systolic: -1.8 ± 12 mmHg, BP diastolic: 0.6 ± 8 mmHg. We have shown that RMA can be easily performed non-invasively by patients with no prior training.

Many of the pathophysiological effects of endotoxin (ETX) can be mimicked by the administration of platelet activating factor (PAF), and the latter has been implicated as a possible mediator of the derangements seen in endotoxic shock. In this investigation, two new potent PAF antagonists, bepafant (WEB-2170) and L-659,989, were studied for their effects in experimental endotoxic and septic shock in rats. Pretreatment with the PAF antagonists, 15 min prior to the iv administration of Escherichia coli endotoxin (ETX), was found to be highly effective in decreasing the mortality caused by the lipopolysaccharide. The antagonists were less effective in reducing mortality when given as post-treatment 15 min after ETX, and were ineffective when post-treatment was delayed until 30 min after ETX. Administration of ETX caused manifestations of disseminated intravascular coagulation (DIC), including thrombocytopenia, prolongation of prothrombin time (PT) and partial thromboplastin time (PIT), hypofibrinogenemia, elevation of serum fibrin(ogen) degradation products (FDP), and gastrointestinal hemorrhage. With the exception of the thrombocytopenia, the PAF antagonists reduced or abolished all of the hematological manifestations of DIC caused by ETX. Septic shock was produced by ligation and puncture of the cecum in rats. The PAF antagonists, given as two iv doses (an initial 2.0 mg/kg dose administered 1.5 or 2.5 h after cecal puncture and a second dose given 5 h later), significantly reduced the cumulative 24-h mortality. These results provide added evidence of the importance of PAF and DIC in the pathophysiology of ETX and suggest that PAF antagonists may be useful in the clinical management of septicemia/endotoxemia. o 1993 Wlley-Liss, tnc.

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