Metabolism of haloperidol to pyridinium species in patients receiving high doses intravenously: is HPTP an intermediate?

The metabolism of haloperidol (HP) to the potentially neurotoxic pyridinium species, HPP+ and RHPP+, has been demonstrated in humans. In vitro studies in microsomes harvested from various animal species indicate that the tetrahydropyridines, HPTP and RHPTP, could be intermediates in this pathway. However, this has not yet been demonstrated in vivo in humans. In this study, plasma and urine collected from eight critically ill patients treated with high doses of intravenous HP were analyzed for HPTP and RHPTP using HPLC with electrochemical detection. However, neither HPTP nor RHPTP were detected despite plasma concentrations of HP and RHP higher than any previously reported. HPP+ and RHPP+ were both present in the urine in high concentrations and accounted for 1.1 +/- 0.5% and 5.3 +/- 3.6%, respectively, of the administered dose of HP. The apparent elimination half-lives of HPP+ and RHPP+ were 67.3 +/- 11.0 hr and 63.3 +/- 11.6 hr, respectively. The absence of HPTP and RHPTP in plasma and urine suggests that in humans these tetrahydropyridines either are insignificant intermediates in the metabolism of HP in vivo or are present only transiently at their site of formation and are not released into the circulation.     

Endothelial dysfunction and nitrogen monoxide (NO; nitric oxide)

Emotion processing deficits may have an important effect on the quality of life of Alzheimer's disease (AD) patients and their families, yet there are few studies in this area and little is known about the cause of such deficits in AD. This study sought to determine if some AD patients have a disruption in a specific right hemisphere emotion processing system, and to determine if the processing of emotional facial expression is more vulnerable to the pathology of AD than is the perception of emotional prosody. It was specifically hypothesized that patients with greater right hemisphere dysfunction (low spatial AD patients) would be impaired on emotion processing tasks relative to those with predominantly left hemisphere dysfunction (low verbal AD patients). Both groups showed impairment on emotion processing tasks but for different reasons. The low verbal patients performed poorly on the affect processing measures because they had difficulty comprehending and/or remembering the task instructions. In contrast, low spatial AD patients have emotion processing deficits that are independent of language and/or memory and may be due to a more general visuoperceptual deficit that affects the perception of static but not dynamic affective stimuli.     

Prospective study of bacteremia rate after elastic band ligation and sclerotherapy of esophageal varices in patients with hepatosplenic schistosomiasis

Bone scintigraphy was performed in a 69-year-old male patient with adult T-cell leukemia suffering from right lower limb pain. Numerous sites of increased uptake were seen in the skull, left clavicle, bilateral humeri, bilateral radii and right femur and tibia. Bone radiographs showed multiple osteolytic lesions, most of which corresponded to the abnormal deposits on the bone scans with 740 MBq of 99mTc-hydroxymethylene diphosphonate. This pattern is rarely reported, but bone involvement of adult T-cell leukemia is not uncommon. Bone involvement was remarkable on the appendicular skeleton when compared with common metastatic bone tumors. Bone scintigraphy may be useful in detecting bone involvement in adult T-cell leukemia.     

Effect of maturation and aging on material and ultrasonographic properties of equine superficial digital flexor tendon

Results of studies in human beings and other species have indicated that aging significantly influences the strength, modulus of elasticity, and energy storage ability of tendon. We wanted to determine the effects of aging on the material and ultrasonographic properties of equine superficial digital flexor (SDF) tendon. Ultrasonographic measurements of left forelimb SDF tendon cross-sectional area and mean echogenicity were made in 23 standing horses ranging in age from 2 to 23 years. All horses had not been in work for a minimum of 6 months prior to the study. After euthanasia, left forelimb bone-muscle-tendon-bone specimens were mounted in a materials testing system. The SDF tendon was cyclically loaded sinusoidally 100 times at 0.5 Hz from 1.5 to 5.0% strain, then was submitted to 10-minute creep-and-stress relaxation tests. Modulus of elasticity, load at 3% strain, and creep-and-stress relaxation were determined for each specimen. A significant positive correlation was found between elastic modulus and age. Correlation was not found between age and SDF tendon cross-sectional area or mean echogenicity. When 2-year-old horses were compared with older horses, the latter had tendons with a significantly (P = 0.007) greater modulus of elasticity. The authors conclude that increasing age through maturity is associated with a corresponding increase in equine SDF tendon elastic modulus.     

Factors affecting revision rate after continent ileostomy

Our aim was to determine factors that may predispose to malfunction of a continent ileostomy. Among 299 patients who underwent continent ileostomy and were followed up for at least one year, the need for revision of the ileostomy was compared by sex, age, type of initial operation, and type of revision. Revision was required less often in females, younger patients, and patients undergoing proctocolectomy and continent ileostomy. However, the rate of subsequent revision was similar after the two types of repair (repair of old valve vs construction of new valve). Constructing a continent ileostomy in stages is not necessary; patients undergoing proctocolectomy and continent ileostomy required fewer revisions than did those who had a Brooke ileostomy prior to their continent ileostomy. Moreover, a malfunctioning valve should be revised rather than a new one created; revision was technically simpler and gave comparable results.     

The transmission rate of the lacI transgene from the Big Blue mouse

Since transgenic mice are being used to analyze somatic and germinal mutation rates in vivo, it is of interest to know to what extent these mice are normal or abnormal in any way. During experiments designed to compare the mutational response of the transgene and an endogenous gene, Big Blue mice hemizygous for the transgene were bred to create a hybrid mouse in which the comparisons could be made. The fraction of these mice that inherited the transgene was 37% rather than the Mendelian expectation of 50%.     

Comparison of the characteristics and density of dopamine-1 receptors in membranes from different arteries using [3H]SCH23390 binding

By using radioreceptor binding techniques and [3H]SCH23390 as a ligand, a comparative study was performed on the pharmacological properties and the density of dopamine-1 (D1) receptors in different vascular systems. [3H]SCH23390 was specifically bound to membranes from rabbit renal, mesenteric and pulmonary, but not femoral, arteries. The binding was saturable and in a manner consistent with the labeling of D1 receptors. The Kd value and Hill coefficient (nH) were similar in all three arteries with no statistically significant differences (p > 0.05) among them, indicating a homogenous binding site with a single class of high affinity. In competitive binding tests, the selective D1 antagonist and agonist inhibited the binding much more potently than the D2 antagonist, indicating a pharmacological characteristic of D1 receptors. The Bmax values, however, differed considerably among these arteries, with the value being the largest in the renal artery and smallest in the pulmonary artery. These findings are indicative of the existence of D1 receptor sites with identical properties but diverse density in different vascular beds, which underlies the relative functional importance of the receptors in regulating local blood flow in distinct vessels.     

Supracondylar femoral fractures in the frail elderly. Fractures in need of treatment

The investigators of this study reviewed 112 consecutive frail elderly patients with supracondylar femoral fractures to evaluate primarily functional outcomes to optimize initial treatment of these challenging patients. A high 1-year mortality rate (22%) and significant decrease in function and quality of life occurred in frail elderly patients who sustained supracondylar femoral fractures. No statistical relationship could be found among preinjury function, age, cognitive function, type of fracture, treatment, and overall results. Nine percent of patients required late above-knee amputation in the involved extremity because of displacement of the fracture or infection or both. Optimal treatment for this type of patient remains elusive. Primary above-knee amputation may be the preferred treatment in patients who are this severely affected.     

Pharmacokinetics and pharmacodynamics of recombinant human interleukin-12 in male rhesus monkeys

The pharmacokinetics and pharmacodynamics of recombinant human interleukin-12 (rHuIL-12) were investigated in male rhesus monkeys. The monkeys received a 40-min i.v. infusion of 42.5 micrograms/kg of recombinant human interleukin-12 on day 1 followed by a s.c. injection of the same dose on day 5. Serum samples were collected at appropriate time points and assayed for interleukin (IL-12) by an IL-12 capture bioassay, interferon (IFN-gamma) by an IFN-gamma enzyme-linked immunosorbent assay, and neopterin by a neopterin radioimmunoassay. After i.v. infusion, the systemic clearance rate of this protein was very slow (average, 3 ml/hr/kg). The volume of distribution at steady state ranged from 59 to 90 ml/kg. After the s.c. dose, the mean Cmax was 61 ng/ml and the mean Tmax was 18 hr. The absolute bioavailability was moderate (20-30%) after s.c. injection. By compartmental analysis, by using a two-compartment model the T 1/2 lambda 1 ranged from 0.2 to 5 hr and the T 1/2 lambda 2 ranged from 13 to 19 hr. When determining the percentage of the area of the serum concentration-time curve, per phase, > 85% of the protein was found in the lambda 2 phase. We selected IFN-gamma as one of the pharmacodynamic markers to study because it is produced by T-lymphocytes and natural killer cells in response to IL-12. In addition, once IFN-gamma is produced, it primes macrophages for tumor killing that in turn secrete neopterin. We show that within 24 to 48 hr after the i.v. dose, IFN-gamma concentrations are elevated in these monkeys (average, 300 pg/ml).(ABSTRACT TRUNCATED AT 250 WORDS)     

Ultrasound velocity, through bone predicts incident vertebral deformity

Seminal plasma zinc (SP Zn) determinations were undertaken in 22 patients suspected of having chronic bacterial prostatitis and in 12 normal subjects free from prostatic infection. Of the 20 patients with positive Staphylococcus culture 17 (85%) showed the same bacterial growth in urethral urine with no significant difference in colony counts (P > 0.005). Mean SP Zn concentration in seminal plasma of 20 patients (164.69 +/- 122.25 mg/ml) was not significantly different in comparison with the control group (168.47 +/- 123.01 mg/ml) (P = 0.755). Mean SP Zn concentration of 3 (15%) patients (156.95 +/- 98.44 mg/ml), with staphylococcal infection bacteriologically localized to the prostate was not significantly different from those of the control group (P = 0.77). We believe that assays of SP Zn content might aid in the confirmation of the role of Staphylococcus in the aetiology of chronic prostatis in larger patient groups.