Effects of RM-beta-CD on sublingual bioavailability of Delta9-tetrahydrocannabinol in rabbits.

The purpose of the present study was to develop novel cyclodextrin-containing sublingual formulations of cannabinoids. Complexation of model cannabinoids, Delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD), with randomly methylated beta-cyclodextrin (RM-beta-CD) and hydroxypropyl-beta-cyclodextrin (HP-beta-CD), were studied by the phase-solubility method. Due to better complexation efficiency, RM-beta-CD was selected for further studies. Solid THC/RM-beta-CD and CBD/RM-beta-CD complexes were prepared by freeze-drying. The dissolutions of both THC and CBD in the presence and absence of RM-beta-CD were determined. THC was selected for in vivo studies: the pharmacokinetics of THC after both sublingual and oral administrations of ethanolic THC and THC/RM-beta-CD complex solutions were studied in rabbits. The aqueous solubility of CBD and THC increased as a function of CD concentration, showing A(L)- and A(P)-type diagrams for HP-beta-CD and RM-beta-CD, respectively. Dissolution rates of THC/RM-beta-CD and CBD/RM-beta-CD complexes were significantly (p < 0.05) higher than those of plain THC and plain CBD, respectively. The absolute bioavailability (F) of THC decreased in the following order: sublingual THC/RM-beta-CD solution (F = 12.1+/-1.4%; mean+/-S.D.; n = 4) > oral THC/RM-beta-CD solution (F = 4.0+/-6.0%) > or = sublingual ethanolic THC solution (F = 3.8+/-2.8%) > oral ethanolic THC solution (F = 1.3+/-1.4%). These results demonstrate that RM-beta-CD increases both the aqueous solubility and dissolution rate of these cannabinoids, making the development of novel sublingual formulation possible. These results also suggest that the sublingual administration of a THC/RM-beta-CD complex substantially increases the bioavailability of THC in rabbits.     

Mivacurium When Precedent by Pancuronium Becomes a Long-acting Muscle Relaxant

Background: To ensure rapid recovery of neuromuscular block, it might be useful to administer a short-acting relaxant after a long-acting one. Therefore, the interaction between pancuronium and mivacurium was investigated when mivacurium was administered during the recovery from pancuronium block.

Methods: After written informed consent, 41 adult patients were studied during propofol/alfentanil/nitrous oxide/oxygen anesthesia. Neuromuscular function was monitored using an electromyographic (EMG) method. After a stable EMG calibration response, cumulative doses of pancuronium were given to establish a 95% neuromuscular block. In the control group, an ED95 dose of 100 micro gram/kg mivacurium was administered instead of pancuronium. When the EMG response after pancuronium or mivacurium had recovered to 25% of the baseline, a single randomized intravenous bolus dose of 10 or 70 micro gram/kg mivacurium was given. Thereafter, spontaneous recovery of the neuromuscular function was recorded.

Results: The time from pancuronium until T1 25% EMG recovery was 38 +/-12 min (mean+/-SD). The respective times after 10 or 70 micro gram/kg mivacurium were 28+/-8 and 54+/-7 min in the pancuronium group or 3+/-1 (n = 3) and 10+/-4 min in the mivacurium group (P = 0.0001). Times to 95% EMG recovery after 10 or 70 micro gram/kg mivacurium were 77+/-14 and 97+/-16 min in the pancuronium group and 11+/-3 and 20+/-7 min in the mivacurium group, respectively (P < 0.0001). Recovery indexes after 10 or 70 micro gram/kg mivacurium were 26+/-4 and 22+/- 6 min in the pancuronium group or 7+/-3 (n = 3) and 5+/- 2 min in the mivacurium group, respectively (P < 0.0001). Times from the administration of 10 or 70 micro gram/kg mivacurium until train-of-four ratio 0.7 were 94+/-16 and 111+/-14 min in the pancuronium group and 12+/-4 and 22+/-8 min in the mivacurium group, respectively (P < 0.0001).     

Testicular infarction following ethanol embolization of a renal neoplasm

A case of infarction of the left testis secondary to transcatheter embolization of a malignant left renal tumor with absolute ethanol is presented. The mechanism producing this complication was due to the anomalous nature of the left testicular artery, originating from the left renal artery distal to the site of the balloon occlusion catheter. The importance of this anomaly is discussed and the literature reviewed.     

Radiographic diagnosis of biceps tendinitis

The radiographic findings and arthrographic image of the intertubercular groove and the biceps tendon were analysed in 143 patients with chronic shoulder pain. Forty-eight patients had been operated on, and of these 33 had tendinitis, caused by attrition in a narrow intertubercular groove in 17 cases, by medial dislocation of the biceps tendon in 11 cases, and by impingement associated with rupture of the rotator cuff in five cases. Plain radiographs revealed degenerative changes in the walls of the groove in half of the patients with biceps tendinitis. A shallow groove was seen in cases of medial dislocation of the biceps tendon, but also in many with a normal tendon. The arthrogram, however, showed whether a shallow groove was associated with dislocation of the tendon. In patients with attrition tendinitis the groove had a depth of 4.8 mm or more or an inclination of the medial wall of 58° or more.

Radiographic measurements of the dimensions of the intertubercular groove may provide valuable information on the state of the biceps tendon.     

Bacterial infection in under school age children with expiratory difficulty

Serological evidence of bacterial infection was prospectively studied in less than 6 years old patients during 188 acute episodes of expiratory difficulty requiring hospital treatment. Such evidence indicated by antibody or antigen assays was found in 40 patients (21%). Streptococcus pneumoniae was identified in 25 cases; antigenemia was found in 10, antigenuria in 2 and seroconversion in 14 cases. Seroconversion to nontypable Haemophilus influenzae was found in 9 and to Branhamella catarrhalis in 2 cases. Seroconversion to Chlamydia spp. was demonstrated in 8 patients, but specific tests for C. trachomatis were negative. C-reactive protein was over 40 mg/L in 35 patients (19%); serological evidence of bacterial infection was present in 14 and absent in 21 of them. Thus, either serological evidence of bacterial infection or an elevated C-reactive protein was found in 61 of the 188 cases (32%). We conclude that bacterial infection is commonly associated with acute wheezing in children under school age. We suggest that bacterial, as well as viral, infections may trigger an acute obstructive attack in children with reactive airways.     

Changes in the oral health of adolescents treated by the Finnish public dental services between the ages of 13 and 15 years

Oral cavity health was monitored in 2422 young people aged 13–15 years attending four health centres in Finland between 1992 and 1995. Assessments were made in terms of DMF, D and CPITN indices at clinical examinations. Of those who had no carious teeth at the initial examination, 60% did not develop cavities during the whole period, whereas half of those who had at least two carious teeth at the initial examination developed at least three new carious teeth The treatment time needed by the latter accounted for half of the total time expended by the researchers until the end of the period. Costs can be saved or new patients brought into the dental care system by reorganizing the treatment of the patients who suffer from abundant caries and by reducing the resources devoted to the treatment of healthy patients.     

The neural restrictive silencer element can act as both a repressor and enhancer of L1 cell adhesion molecule gene expression during postnatal development

The cell adhesion molecule L1 mediates axonal guidance during neural development and mutations in its gene result in severe neurological defects. In previous studies, we identified the promoter for the L1 gene and showed that a neural restrictive silencer element (NRSE) was critical for preventing ectopic expression of L1 during early embryonic development. In the present study, we have investigated the role of the NRSE in the regulation of L1 expression during postnatal development. In gel mobility shift experiments, the NRSE formed DNA–protein complexes with nuclear extracts prepared from the brains of postnatal mice. To examine the influence of the NRSE on postnatal patterns of L1 expression in vivo, we compared the expression of two lacZ transgene constructs, one containing the native L1 gene regulatory sequences (L1lacZ) and another (L1lacZΔN) lacking the NRSE. Newborn mice carrying the L1lacZΔN showed enhanced β-galactosidase expression relative to L1lacZ in the brain and ectopic expression in nonneural tissues. In contrast to L1lacZ mice, however, L1lacZΔN mice showed an unexpected loss, during postnatal development and in the adult, of β-galactosidase expression in several neural structures, including the neural retina, cerebellum, cortex, striatum, and hippocampus. These data support the conclusion that the NRSE not only plays a role in the silencing of L1 expression in nonneural tissues during early development but also can function as a silencer and an enhancer of L1 expression in the nervous system of postnatal and adult animals.     

Selective Acceleration of Auditory Processing in Chronic Alcoholics during Abstinence

Simultaneous auditory processing between the hemispheres was studied with a whole-head magnetometer in 13 abstinent chronic alcoholics and 10 healthy control subjects. Auditory stimuli were presented monaurally with interstimulus intervals of 0.5 and 2.5 sec in different blocks. The N100m response, which contributes to stimulus detection, was significantly accelerated in the hemisphere ipsilateral to the ear stimulated in abstinent alcoholics. The MMNm response reflecting automatic stimulus-change detection peaked earlier in alcoholics, and the ipsilateral N100m latency correlated significantly with the abstinence duration. These results suggest that auditory processing is accelerated in the auditory cortex ipsilateral to the stimulated ear in chronic abstinent alcoholics and that the accelerated processing is at least partly reversible. This may be caused by the hyperexcitation in the brain related to the ethanol withdrawal.     

Myocardial energy metabolism and functional recovery in coronary bypass surgery: A comparative study between continuous retrograde warm and mild hypothermic blood cardioplegia

The optimal temperature for delivery of continuous retrograde blood cardioplegia is not known. Twenty-two patients admitted to the hospital for elective coronary artery bypass grafting were randomized into the warm (37°) and mild hypothermic (28°C) cardioplegia groups. Changes in myocardial energy metabolism during cardiopulmonary bypass, postoperative efflux of the creatine kinase MB isoform (CK-MB), functional hemodynamic recovery, and postoperative complications were followed. During aortic cross-clamp, the average oxygen consumption was higher in the warm than in the mild hypothermic group (3.4±0.4 vs 2.4±0.3 ml/minute,p=0.06), as was the average transcardiac (outflow-inflow) pCO₂-difference (1.1±0.1 vs 0.7±0.1 kPa,p=0.02). The average transcardiac pH-difference during aortic cross-clamp was lower in the warm group (–0.08±0.01 vs –0.06±0.01 U,p=0.02), reflecting more profound tissue acidosis. In accordance with this, warm hearts produced more lactate, especially towards the end of the aortic cross-clamp period (p=0.001). The net efflux of adenosine and its degradation products was more prominent during warm than during mild hypothermic cardioplegia (p=0.016), indicating less degradation of high energy adenylates in the hypothermic group. The functional hemodynamic recovery during the first postoperative day was similar in both patient groups, although the myocardial injury estimated as postoperative leakage of CK-MB was less extensive in the hypothermic group (p=0.011). There were no major differences in the postoperative complications between the study groups. We conclude that continuous retrograde mild hypothermic blood cardioplegia offers better myocardial protection during coronary bypass surgery than does continuous retrograde warm cardioplegia. The clinical significance of this should be tested in a larger series of patients, especially those with recent myocardial infarction, unstable angina, or severely depressed left ventricular function.This study was supported by grants from the Finnish Foundation for Cardiovascular Research and the Finnish Angiology FoundationPresented at the 37th Annual World Congress International College of Angiology     

Titanium implants and lateral forces. An experimental study with sheep.

The purpose of this study was to investigate the resistance of titanium implants to horizontal forces in a sheep model. Twenty implants were inserted into the foreheads of 5 sheep, 4 implants on each animal. After a healing period of 3 months, abutments were mounted on the implants. After a further healing period of 3 weeks, the implants were loaded with a horizontal pull of orthodontic elastics. The force varied between 250 and 350 grams. The duration of loading was 3 months. After the loading period the animals were sacrificed and the forehead bones with implants were fixed in formalin and evaluated histologically. In the histological specimens no signs of infection or bone loss were found around the implants. The results of the present study encourage the use of titanium implants also in cases where constant lateral forces are present.