HP 818: A centrally acting analgesic with neuroleptic properties

HP 818 (1-benzoyl-6-fluoro-3-(1-methyl-4-piperidinyl)-1H-indazole) exhibits the profile of a potent nonnarcotic analgesic with neuroleptic properties. HP 818 blocks the effects of chemical (phenylquinone), pressure (tail clip), and radiant heat (tail flick) painful stimuli in mice (ED₅₀ values of 0.3, 1.2, and 4.1 mg/kg s.c., respectively). This compound displays antinociceptive activity by the subcutaneous, oral, and intravenous routes of administration. It is also effective in the shock titration assay in squirrel monkeys and in a model of surgically induced pain. The rank order of potency of HP 818 and several other standard compounds in these tests for analgesia was Innovar > fentanyl > HP 818 > codeine > droperidol. In addition to its antinociceptive effects, HP 818 possesses neuroleptic properties. It is active in the climbing mouse, pole climb avoidance, and intracranial self-stimulation assays (ED₅₀ values of 1.8, 1.7, and 2.5 mg/kg i.p., respectively). Moreover, HP 818 inhibits amphetamine- and apomorphine-induced stereotypy, indicative of D₂-dopaminergic blocking properties. HP 818, unlike typical neuroleptic agents, does not induce supersensitivity to the effects of apomorphine when administered chronically in mice. In contrast to the clinical standard neuroleptanalgesic Innovar, HP 818 (1.0–3.0 mg/kg i.v.) produces no significant cardiovascular or respiratory changes in the anesthetized dog. Thus, HP 818 is potentially an effective presurgical medication due to its nonnarcotic analgesic activity and sedative neuroleptic effects, along with its lack of limiting cardiorespiratory side effects.     

Dose-response differences in the ability of ramipril to improve retention in diabetic mice

Ramipril blocks the conversion of angiotensin I to II. The literature indicates that diabetes is often associated with mild impairment of learning and memory. The study reports the effects of ramipril on memory retention in diabetic and non-diabetic mice. Mice were made diabetic by an injection of streptozocin. After overt signs of diabetes were present, diabetic or vehicle-treated mice were partially trained on a footshock active avoidance task. Immediately after training, ramipril (0.5–1.5 mg/kg s.c.) was administered and retention was tested by continuing training one week later until mice avoided footshock on five out of six trails. The results indicate that ramipril enhanced retention of both diabetic and control mice but it required about 5 times as much ramipril in diabetic as control mice to achieve the same effect on retention. Increased sensitivity to angiotensin II may play a role in cognitive impairment in diabetes.     

Distribution of metabotropic glutamate receptor mGluR5 immunoreactivity in rat brain

The receptor mGluR5 is a metabotropic glutamate receptor with messenger RNA abundantly present throughout cortex, hippocampus, and caudate/putamen that is also coupled to phosphatidyl inositide hydrolysis and calcium mobilization. In this study, the distribution of mGluR5 was examined in rat brain by immunocytochemistry. The antibody utilized is highly specific and does not cross react with the most closely related other metabotropic glutamate receptor, as determined by Western blot analysis of nonneuronal cells transfected with metabotropic receptor coding sequences. The receptor mGluR5 is widely expressed with the highest density in olfactory bulb, caudate/putamen, lateral septum, cortex, and hippocampus, as confirmed with both immunocytochemistry and Western blot analysis. Electron microscopic studies in hippocampus and cortex indicate that the labeling is mostly on membranes of dendritic spines and shafts. Light and electron microscopic evidence indicates that some mGluR5 immunoreactivity is located in presynaptic axon terminals, suggesting that mGluR5 may function as a presynaptic receptor.     

Evaluation of Hemoperitoneum Using a Single- vs Multiple-view Ultrasonographic Examination

Objective: To compare the sensitivities, specificities, and accuracies between a single-view ultrasonography (US) technique and a multiple-view technique for identifying hemoperitoneum in multiple-trauma patients.
Methods: Data from a prior prospective study of US for trauma diagnosis at a level I trauma center were retrospectively analyzed. A convenience sample of adult patients (≥ 18 years of age) who had presented with major blunt or penetrating torso trauma and had undergone rapid trauma US examinations to detect hemoperitoneum were reviewed. The US interpretations by emergency physicians had been recorded prior to obtaining other diagnostic tests. Five views were evaluated, including the right intercostal oblique view examining Morison's pouch. Evidence of free intraperitoneal fluid by exploratory laparotomy, CT, or diagnostic peritoneal lavage (DPL) was used as the criterion standard.
Results: Of the 245 patients entered into the study, 37 had free intraperitoneal fluid, confirmed by CT, DPL, or exploratory laparotomy. With the multiple-view technique, US was 87% (95% CI = 71%, 96%) sensitive, 100% (95% CI = 97%, 100%) specific, and 98% (95% CI = 95%, 100%) accurate. The single-view technique, evaluating only Morison's pouch, was 51% (95% CI = 34%, 68%) sensitive, 100% (95% CI = 98%, 100%) specific, and 93% (95%. CI = 89%, 96%) accurate.
Conclusions: An initial trauma US examination using a multiple-view technique is more sensitive than that using a single-view technique for detecting hemoperitoneum in trauma patients.     

High-dose vecuronium neuromuscular block: a comparison of arrhythmias and onset of block during sufentanil anaesthesia

This study compared the heamodynamic effects of sufentanil with those observed following concomitant sufentanil and highdose vecuronium administration to determine whether vecuronium induces bradyarrhythmias. Sixty coronary artery bypass patients were stratified into beta blocker (n = 30) or non-beta blocker (n = 30) groups and following induction with sufentanil (9 ± 3 μg · kg^?1) and midazolam (0.07 ± 0.04 mg · kg^?1), received either succinylcholine 1 mg · kg^?1 (SxCh), vecuronium 0.3 mg · kg^?1 (Vec 0.3), or vecuronium 0.5 mg · kg^?1 (Vec 0.5). Using a Holter ECG monitor, bradyarrhythmias were classified as mild (HR 46–50), moderate (HR 40–45) or severe (HR < 40). In the pre-induction period, there were no differences in the incidence of mild, moderate or severe bradyarrhythmias among the SxCh, Vec 0.3 or Vec 0.5 groups, in either the beta blocker or non-beta blocker groups. Following induction, there were similar reductions in mean heart rate and mean arterial pressure in all three muscle relaxant groups in both the beta and the non-beta blocker groups; however, there was no difference in the incidence of mild, moderate or severe bradyarrhythmias among the SxCh, Vec 0.3 or Vec 0.5 groups. The Vec 0.5 beta blocker group had a higher incidence of mild bradyarrhythmias (32 ± 36%) than the Vec 0.5 non-beta blocker group (2 ± 3% P = 0.017). Using EMG recording, the onset time of maximal neuromuscular block for the Vec 0.3 group (108 ± 17 sec) was longer (P < 0.05) than the SxCh (76 ±21 sec) and Vec 0.5 (82 ± 13 sec) groups, which were similar. We conclude: (i) vecuronium does not affect HR or the incidence of bradyarrhythmias following sufentanil administration and that the observed reduction in HR and mean arterial pressure were due to sufentanil administration, (ii) vecuronium (0.5 mg · kg^?1) provides an onset time of neuromuscular block similar to SxCh, and (iii) patients taking beta blockers preoperatively are more prone to develop bradyarrhythmias during sufentanil administration.     

Healthy lungs tolerate repetitive collapse and reopening during short periods of mechanical ventilation

The possible occurrence of lung damage if alveolar units are allowed to collapse and reopen breath by breath during mechanical ventilation with normal tidal volumes was investigated. Anaesthetised, paralysed, open chest rabbits were subjected to either intrathoracic negative (NEEP; n=6) or positive (PEEP; n=6) end-expiratory pressure during volume controlled mechanical ventilation. Both experimental settings were preceded by a 30 min control period and followed by a 30 min recovery period during which a PEEP of 0.2 kPa was maintained. Pao₂ and pulmonary compliance deteriorated significantly in the NEEP group during the experimental period and compared to ventilation with PEEP. Partial restoration of lung mechanics and blood gases was achieved during the recovery period. After an alveolar recruitment manoeuvre, this recovery was complete. Lung clearance studied by depositing an aerosol of technetium-99m-labelled diethylenetriamine pentaacetate (^99mTc-DTPA) in the alveoli, was significantly faster during ventilation with NEEP compared to the PEEP group ( P =0.0002) as well as the control period ( P = 0.0029). It did not recover completely during the recovery period but remained significantly faster. light microscopic histology was normal in both groups with no evidence of inflammation or epithelial disruption. We conclude that previously healthy rabbit lungs show only a transient disturbance of lung mechanics and blood gases with repetitive collapse and re-expansion. The integrity of the alveolar rnicrostructure is preserved. The disturbance in the alveolo-capillary permeability persists and may indicate surfactant related alveolo-capillary barrier dysfunction.     

CAG repeat number governs the development rate of pathology in Huntington's disease

We compared the number of CAG repeats, the age at death, and the severity of neuropathology in 89 Huntington's disease brains. We found a linear correlation between the CAG repeat number and the quotient of the degree of atrophy in the striatum (the brain region most severely affected in Huntington's disease) divided by age at death, with an intercept at 35.5 repeats. The largest CAG repeat length, therefore, at which no pathology is expected to develop is 35.5. These results imply that striatal damage in Huntington's disease is almost entirely a lineaar function of the length of the polyglutamine stretch beyond 35.5 glutamines multiplied by the age of the patient. Thus, it is predicted that the pathological process develops linearly from birth. Analysis of other measures of striatal function could test this hypothesis and might determine when treatment for CAG repeat diseases should start.