Disposition of etofibrate, clofibric and nicotinic acid esters, and their products in dogs

Etofibrate, the ethylene glycol diester of clofibric and nicotinic acids, on intravenous infusion into dogs, has a terminal half-life of 2 min. The intermediate half-esters, the nicotinate and the clofibrate, have respective terminal half-lives of 4.6 and 1.7 min and appear fleetingly when etofibrate is administered. In contrast to the 42-h terminal half-life of clofibric acid, the other final transformation product, nicotinic acid, shows saturable or dose-dependent pharmacokinetics in dogs that conform to the Michaelis-Menten equation with a terminal half-life of 4.4 min at low concentrations (less than 6.9 microM/kg). Three distinct metabolites of nicotinic acid can be identified and assayed chromatographically in the urine. The partition properties were similar to nicotinic acid. Nicotinic acid is excreted 30% unchanged into urine with a renal clearance of 70 mL/min in 27-kg dogs.     

Multiple myeloma masquerading as metastatic breast cancer

Two women are described in whom, on the basis of prior therapy for breast cancer and the presence of painful, lytic bone lesions, an initial diagnosis of metastatic breast cancer was made. Further evaluation established the diagnosis of multiple myeloma in both patients. Neither had evidence of recurrent breast cancer. These cases indicate that women with a history of breast cancer in whom lytic bone lesions develop without evidence of extraskeletal metastases should have the diagnosis of multiple myeloma excluded.     

Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis

Among 141 consecutive patients with neuro-psychiatric abnormalities due to cobalamin deficiency, we found that 40 (28 percent) had no anemia or macrocytosis. The hematocrit was normal in 34, the mean cell volume was normal in 25, and both tests were normal in 19. Characteristic features in such patients included paresthesia, sensory loss, ataxia, dementia, and psychiatric disorders; longstanding neurologic symptoms without anemia; normal white-cell and platelet counts and serum bilirubin and lactate dehydrogenase levels; and markedly elevated serum concentrations of methylmalonic acid and total homocysteine. Serum cobalamin levels were above 150 pmol per liter (200 pg per milliliter) in 2 patients, between 75 and 150 pmol per liter (100 and 200 pg per milliliter) in 16, and below 75 pmol per liter (100 pg per milliliter) in only 22. Except for one patient who died during the first week of treatment, every patient in this group benefited from cobalamin therapy. Responses included improvement in neuropsychiatric abnormalities (39 of 39), improvement (often within the normal range) in one or more hematologic findings (36 of 39), and a decrease of more than 50 percent in levels of serum methylmalonic acid, total homocysteine, or both (31 of 31). We conclude that neuropsychiatric disorders due to cobalamin deficiency occur commonly in the absence of anemia or an elevated mean cell volume and that measurements of serum methylmalonic acid and total homocysteine both before and after treatment are useful in the diagnosis of these patients.     

Effect of CGS-8216 on high-dose flurazepam convulsive threshold

Flurazepam, a clinically proven and widely accepted sedative hypnotic, has been shown by a number of investigators to produce convulsions at toxic doses. In the present study, CGS-8216, a benzodiazepine receptor antagonist, reduced the dose of flurazepam required to produce convulsions. This suggests that the convulsant action of FLZ is exerted at a site other than the benzodiazepine receptor.     

Effects of aromatase inhibitors, aminoglutethimide, and 4-hydroxyandrostenedione on cyclic rats and rats with 7,12-dimethylbenz(a)anthracene-induced mammary tumors

4-Hydroxyandrostenedione (4-OHA) is a more potent and specific inhibitor of aromatase (estrogen synthetase) than aminoglutethimide (AG). The two inhibitors were compared in rats with 7,12-dimethylbenz(a)anthracene-induced, hormone-dependent tumors and in normal cyclic rats treated for 4 and 2 weeks, respectively. Ovarian estradiol levels and aromatase activities were not consistently reduced, and tumors regressed in only two of eight rats treated with AG. In animals treated with 4-OHA or 4-OHA:AG, the total tumor volume, estradiol levels, and aromatase activity decreased by greater than 70%. Ovarian weights and plasma luteinizing hormone (LH) levels were also reduced by 4-OHA but increased by AG. Uterine weights were not altered by AG treatment but were increased by 4-OHA. Similar but more consistent results were obtained with these treatments in normal, cyclic rats. In ovariectomized rats, AG had no effect, whereas 4-OHA decreased LH levels and increased uterine weights. The results suggest that, although AG reduces ovarian estrogen secretion by aromatase inhibition, this may lead to an increase in LH secretion. Increased LH may promote ovarian growth and aromatase synthesis, counteracting the inhibitory action of AG to some extent. 4-OHA which inactivates aromatase may also prevent new enzyme synthesis by directly inhibiting gonadotropins. This would result in more effective reduction in ovarian estrogen production by 4-OHA than AG during long-term treatment.     

Disodium Disuccinate Astaxanthin (CardaxTM): Antioxidant and Antiinflammatory Cardioprotection

Disodium disuccinate astaxanthin (Cardax^TM, DDA) has cardioprotective effects in the rat, rabbit, and canine models of experimental infarction. It is highly effective by parenteral administration in subchronic and acute dosing regimens. Unpublished data in rats suggest that oral cardioprotection is also readily achievable. DDA‐induced myocardial salvage in the canine can reach 100% with a 4‐day subchronic dosing regimen. At a single i.v. dose DDA is cardioprotective, when given 2 h before experimental coronary occlusion, but the protection is on the average two‐thirds of that achieved with the subchronic regimen in dogs. In conscious animals DDA has no effects on hemodynamic parameters. The primary mechanism of cardioprotection appears to be antioxidant activity involving direct scavenging of superoxide anion, the lynchpin radical in ischemia‐reperfusion injury. In addition, modulation of serum complement activity, as well as the reduction in the levels of C‐reactive protein (CRP) and the membrane attack complex (MAC) in infarcted tissue suggest a significant antiinflammatory component in the mechanism of cardioprotective action of DDA. Stoichiometric binding of the meso‐form of the compound to human serum albumin (HSA) has been demonstrated in vitro. This binding capacity overcomes the supramolecular assembly of the compound in aqueous solution, which by itself improves the stability and shelf life of aqueous formulations. Non‐esterified astaxanthin readily enters cardiac tissue after either oral or parenteral administration, providing a reservoir of a cardioprotective agent with a significant half‐life due to favorable ADME in mammals. Due to the well‐documented safety profile of non‐esterified astaxanthin in humans, disodium disuccinate astaxanthin may well find clinical utility in cardiovascular indications in humans following successful completion of preclinical and clinical pharmacology and toxicology studies.     

The development of type I and type II benzodiazepine receptors in the mouse cortex and cerebellum

The postnatal development of benzodiazepine (BDZ) receptors was monitored in Heterogeneous Stock (HS) mice, and the BDZ receptors were characterized and categorized into Type I and Type II receptors. When the number of 3H-Flu binding sites (Bmax) was assessed at weekly intervals after the birth of the animal, the number of sites in both the cortex and cerebellum increased significantly if the data was expressed as fmol/mg tissue. On the other hand, no significant change in 3H-Flu binding sites was evidenced in the cortex, and the number of 3H-Flu binding sites in the cerebellum decreased during postnatal development if Bmax values were expressed as fmole/mg protein. When receptor binding data was analyzed for the presence of Type I and Type II BDZ receptors, the changes in KD values for 3H-Flu binding development could be accounted for by changes in relative proportions of Type I and Type II receptors present in the cortex and cerebellum during the maturation process. Type II receptors predominated in both cortex and cerebellum at birth, and Type I receptors proliferated primarily during the first two weeks of postnatal life. In the cortex of adult mice there were approximately equal numbers of Type I and Type II BDZ receptors. In the cerebellum of adult mice, computer assisted analysis of binding data could not distinguish the presence of two distinct BDZ binding sites. However, Hill coefficients and overall binding constants determined from data on CL-218,872 displacement of 3H-Flu binding to cerebellar membranes indicated that cerebellar tissue from adult mice did contain a heterogeneous array of BDZ receptors.     

The efficacy of treatment for children with developmental speech and language delay/disorder: a meta-analysis.

A meta-analysis was carried out of interventions for children with primary developmental speech and language delays/disorders. The data were categorized depending on the control group used in the study (no treatment, general stimulation, or routine speech and language therapy) and were considered in terms of the effects of intervention on expressive and receptive phonology, syntax, and vocabulary. The outcomes used in the analysis were dependent on the aims of the study; only the primary effects of intervention are considered in this review. These were investigated at the level of the target of therapy, measures of overall linguistic development, and broader measures of linguistic functioning taken from parent report or language samples. Thirty-six articles reporting 33 different trials were found. Of these articles, 25 provided sufficient information for use in the meta-analyses; however, only 13 of these, spanning 25 years, were considered to be sufficiently similar to be combined. The results indicated that speech and language therapy might be effective for children with phonological or expressive vocabulary difficulties. There was mixed evidence concerning the effectiveness of intervention for children with expressive syntax difficulties and little evidence available considering the effectiveness of intervention for children with receptive language difficulties. No significant differences were found between interventions administered by trained parents and those administered by clinicians. The review identified longer duration (>8 weeks) of therapy as being a potential factor in good clinical outcomes. A number of gaps in the evidence base are identified.     

A biomechanical study of human lateral ankle ligaments and autogenous reconstructive grafts

The purpose of this study was to investigate the biomechanical behavior of human anterior talofibular and calcaneofibular ligaments, as well as peroneus brevis, split peroneus brevis, and toe extensor tendon grafts. This article represents the first published data comparing the most frequently injured ankle ligaments to the most commonly used autogenous reconstructive grafts. Twenty fresh human ankles provided the bone-ligament-bone and tendon graft specimens for biomechanical testing on a Minneapolis Testing System. Protocol consisted of cyclic loading at physiologic deflections, followed by several load-deflection tests at varying velocities, followed by a final extremely rapid load to failure test. The load-deflection data for all ligaments and tendons demonstrated nonlinearity and strain rate dependence. The maximum load to failure for the anterior talofibular ligament was the lowest of all specimens tested, while its strain to failure was the highest. The loads to failure of the peroneus brevis and split peroneus tendons were significantly greater than the anterior talofibular ligament and approximately equal to the calcaneofibular ligament. Strains to failure for all tendons were significantly less than ligament strains. The high strain to failure of the anterior talofibular ligament demonstrates its physiologic function of allowing increased ankle plantar flexion-internal rotation, while its low load to failure shows its propensity for injury. The greater strength of the tendon grafts explains the success of most reconstructive procedures in reestablishing stability in chronic ankle sprains; at the same time, the data presented suggest that those surgical procedures sacrificing the entire peroneus brevis tendon are unnecessary.(ABSTRACT TRUNCATED AT 250 WORDS)