Antiarrhythmic and Electrophysiological Effects In-vivo of the Major Metabolite of Org 7797 Found in Canine and Rodent Liver Homogenate Preparations

Org 20781, the major metabolite of Org 7797 found in in-vitro experiments was examined for antiarrhythmic and electrophysiological effects in-vivo. Org 20781 (0·5–2·0 mg kg^?1 i.v.) inhibited the development of early ischaemia-induced arrhythmias in rats, suppressed spontaneous ventricular tachycardia (VT) in conscious dogs with 24-h old infarcts, and prevented electrical induction of VT in dogs with 5–6-day old infarcts, actions associated with slowing of conduction at all levels of the myocardium. Cardiac refractory periods were only modestly prolonged whilst repolarization was unchanged. Peak plasma levels of the parent compound (infused to total doses of 2–4mg kg^?1) associated with suppression of late arrhythmias were 6–18 μm, whilst the mean plasma elimination half-life (in normal dogs) was 107 min. It was concluded that the major metabolite has a similar antiarrhythmic and electrophysiological profile to the parent compound, is at least half as potent and may contribute to the therapeutic effects of Org 7797 administration.     

Geriatric trauma: resource use and patient outcomes.

INTRODUCTION: Elderly patients who suffer trauma have a higher mortality and use disproportionately more trauma resources than younger patients. To compare these 2 groups and determine the outcomes and characteristics of elderly patients, we reviewed patients in these 2 groups admitted and treated in our tertiary care provincial trauma centre. METHODS: From the provincial trauma registry we selected a cohort of 40 geriatric patients (group 1) (> or = 65 yr of age) with an ISS of 16 or more who were admitted to and spent time in our trauma service for more than 48 hours and compared them with a similar randomly selected cohort of 44 patients (group 2) aged 20-30 years. Family physicians were contacted for follow-up of these patients 2 years after discharge. We considered length of hospital stay, complications, disposition of the patients and use of consultation services. RESULTS: Patients in group 1 had a mean age of 72.1 years (range from 65-98 yr) and a mean ISS of 27.3 (range from 17-50). Patients in group 2 had a mean age of 26.3 years (range from 22-29 yr) and a mean ISS of 26.3 (range from 17-54). Hospital stay was significantly longer in the group 1: 34.5 days (95% confidence interval [CI]: 24-44 d) versus 21.6 days (95% CI: 15-28 d). More elderly patients experienced complications (35 v. 13, p < 0.001) and required medical consultations (35 v. 26, p < 0.001). In-hospital death rates were 8% (3 of 40) and 4% (2 of 44) respectively (p = 0.3). Fewer geriatric patients could be discharged home (35% [14 of 40] v. 27% [22 of 44], p = 0.056) or to rehabilitation facilities (28% [11 of 40] v. 34% [15 of 44], p = 0.3). Five geriatric patients were discharged to nursing homes (p = 0.007). Of the geriatric patients discharged to rehabilitation facilities or home, 75% were independent 2 years after discharge. CONCLUSIONS: Aggressive care for geriatric trauma patients is warranted, and resources should be directed toward rehabilitation. Based on our findings, we expect that creating a directed care pathway for these patients, targetting complications and earlier discharge, will further improve their outcomes.     

Collateral sensitivity to nitrosoureas in multidrug-resistant cells selected with verapamil.

We have examined the effects of the nitrosoureas, streptozotocin (STZ) and 1,3-bis(chloroethyl)-1-nitrosourea (BCNU), on a human multiple myeloma cell line, RPMI 8226, and its drug-resistant variants. Cell lines selected for doxorubicin (DOX) resistance alone displayed a STZ and BCNU cytotoxicity profile similar to that of the parent cell line. In contrast, two of the drug-resistant variants selected with DOX plus verapamil, an agent which inhibits P-glycoprotein-mediated multidrug resistance, displayed a collateral sensitivity to STZ and BCNU. Verapamil was included in the selection protocol because it has been shown to inhibit the P-glycoprotein-mediated multidrug resistance phenotype and is now in clinical trials as a chemosensitizing agent. The collateral sensitivity to these nitrosoureas seen in the DOX plus verapamil-selected cell lines is due to the functional loss of a DNA repair molecule, O6-Methylguanine DNA methyltransferase (MGMT). The functional loss of MGMT is secondary to the loss of MGMT gene expression. The loss of MGMT gene expression is not due to loss or gross rearrangement of the MGMT-coding region. If this selection pressure applied in vitro reflects the in vivo situation, then new chemotherapeutic strategies may be devised to exploit this phenomenon. These cell lines will serve as useful models for delineating mechanisms which govern MGMT expression.     

Exacerbation of lymphocytic choriomeningitis in mice treated with the inducible nitric oxide synthase inhibitor aminoguanidine

To elucidate the possible involvement of the inducible nitric oxide synthase (iNOS) and NO in the development of lymphocytic choriomeningitis (LCM), the consequences of inhibition of iNOS by the inhibitor aminoguanidine was examined in mice following intracerebral infection with LCM virus (LCMV). Aminoguanidine administration to mice infected with LCMV completely blocked increased plasma nitrate/nitrite levels and led to increased proinflammatory cytokine gene expression at early stages of lesion development in the brain, enhanced clinical severity and decreased survival time. The levels of LCMV recovered from the brain of aminoguanidine treated mice did not differ from those in infected control mice. These findings argue against either an anti-viral or pathogenic role of NO in LCM but rather suggest a possible protective action of this mediator.     

Efficacy of the dorsal pedal bypass for limb salvage in diabetic patients: short-term observations

Limbs of diabetic patients with distal tibial disease are frequently considered unreconstructible; however, when studied with intraarterial digital subtraction angiography, the dorsal pedal artery is frequently found to be patent. We have reviewed our recent experience with 96 patients, 94% of whom had diabetes and had 97 bypasses placed to the dorsal pedal artery. All procedures were for limb salvage. Superimposed infection was present in 42.3%. In 92 instances where intraarterial digital subtraction angiography successfully visualized the dorsal pedal artery, 91 bypasses were placed. In 12 other cases where the dorsal pedal artery was not visualized by intraarterial digital subtraction angiography but audible with the continuous-wave Doppler, bypasses were completed successfully in six. All procedures were performed with vein. Inflow was taken from the femoral artery in 48, popliteal artery in 45, tibial artery in 2, and from a femoral tibial graft in 2. Perioperative mortality was 1.92%. Actuarial graft patency, limb salvage, and patient survival were 82%, 87%, and 80%, respectively at 18 months. We conclude that bypass grafting to the dorsal pedal artery can be reliably performed with acceptable short-term results. An attempt should always be made to visualize the foot vessels angiographically, especially in diabetic patients, so that this valuable option in arterial reconstruction will not be overlooked.     

Phaeohyphomycosis caused by Bipolaris spicifera: An informative case

A case of phaeohyphomycosis caused by Bipolaris spicifera involving the brain and sinuses is presented. The patient survived following surgery and ketoconazole therapy, which successfully treated both the sinus and the brain infections.     

Bilateral aberrant internal carotid arteries.

This case report represents the first well-documented case of aberrant internal carotid arteries in both middle ears. CT and DSA can establish the diagnosis before surgical intervention. Aberrant internal carotid artery represents a rare finding in the differential diagnosis of middle ear masses. Most patients manifest either vertigo, tinnitus, or a variable hearing loss. Clinical findings include a red or blue mass behind the eardrum that may or may not be pulsatile. The otolaryngologist should be aware that this potential landmine may be obscured by serous otitis media. Once suspected, the mass should be evaluated by radiographic studies before surgical intervention.