Imidazopyridines: towards novel hypnotic and anxiolytic drugs.
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Animals↗
Biomedical subjects
J Allen
Publications and source records attributed to J Allen.
Effects of vasodilators on isolated human uteroplacental arteries.
The effects of the vasodilator drugs hydralazine, labetalol, prazosin, and nitrendipine were studied on responses to K+ (124 mmol/L), noradrenaline, vasopressin, and angiotensin II in small human maternal intramyometrial arteries and on responses to K+, prostaglandin (PG) F2 alpha, and angiotensin II in fetal stem villous arteries. The vessels were dissected from biopsy specimens obtained during term cesareans and mounted in organ baths. Hydralazine failed to inhibit responses to any of the agonists tested in the fetal and maternal arteries. Labetalol and prazosin decreased responses to noradrenaline but did not affect contractions induced by the other agonists in maternal arteries. In fetal arteries, which did not respond to noradrenaline, no effects of labetalol and prazosin were found. Nitrendipine inhibited responses to all the agonists tested in maternal arteries. In fetal preparations, the drug decreased responses to K+ and PGF2 alpha but did not affect contractions induced by angiotensin II. Vasodilator drugs applied for treatment of pregnancy-induced hypertension show differential effects on human maternal and fetal uteroplacental arteries, depending on their mode of action and the agonists responsible for the contractile activation in these vessels.
Angiotensin II↗
Binding of [3H]ifenprodil, a novel NMDA antagonist, to a polyamine-sensitive site in the rat cerebral cortex.
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Animals↗
Seasonal independence of low prolactin concentration and high spontaneous eye blink rates in unipolar and bipolar II seasonal affective disorder.
Twenty-four subjects with seasonal affective disorder (SAD: bipolar II, n = 14; unipolar, n = 10) and 20 normal controls were assessed for early follicular basal serum prolactin (PRL) concentration in winter and summer. Luteal basal PRL concentration was assessed in winter. The PRL values represented the mean of three values derived during a 45-minute period. A subset of 17 subjects with SAD and 11 controls were also assessed for spontaneous eye blinking via a polygraphic recording in winter and summer. In winter, compared with controls, subjects with SAD were characterized by significantly lower follicular (10.1 vs 4.5 micrograms/L, respectively) and luteal (14.4 vs 7.4 micrograms/L, respectively) PRL values and by significantly higher eye blink rates (30 vs 61 blinks per 3 minutes, respectively). In summer, controls and subjects with SAD showed similar significant differences in follicular PRL values (9.3 vs 3.9 micrograms/L, respectively) and eye blink rates (25 vs 67 blinks per 3 minutes, respectively). No significant differences in PRL values or eye blink rates were found between the bipolar II and unipolar forms of SAD in either season. Results were discussed in terms of dopamine functioning.
Adult↗
Cytogenetic analyses of mice exposed to dichloromethane.
Chromosome damage was studied in female B6C3F1 mice exposed to dichloromethane (DCM) by subcutaneous or inhalation treatments. No increase in the frequency of either sister chromatid exchanges (SCEs) or chromosome aberrations (CAs) in bone marrow cells was observed after a single subcutaneous injection of 2,500 or 5,000 mg/kg DCM. Inhalation exposure to DCM for 10 days at concentrations of 4,000 or 8,000 ppm resulted in significant increases in frequencies of SCEs in lung cells and peripheral blood lymphocytes, CAs in lung and bone marrow cells, and micronuclei (MN) in peripheral blood erythrocytes. Lung cell CAs and blood erythrocyte MN reached frequencies of approximately two times control levels. Following a 3-month inhalation exposure to 2,000 ppm DCM, mice showed small but significant increases in lung cell SCEs and peripheral blood erythrocyte MN. These findings suggest that genotoxicity may play a role in the carcinogenicity of DCM in the lungs of B6C3F1 female mice.
Administration, Inhalation↗
Effect of pancreas allografts on the ultrastructure of sciatic nerves in diabetic rats.
In a long-term study using cyclosporin-A (Cy-A) as immunosuppressant in a dose of 10 mg/kg/day, pancreas-duodenum was transplanted from Brown-Norway donors to alloxan-diabetic Lewis rats (n = 190). The pancreas transplants (PT) were performed after 1, 3, 6, 9, 12, and 15 months of diabetes. Recipient rats were sacrificed between 3 and 12 months of graft retainment. The mean axonal cross-sectional area and relative percentage of small, medium, and large myelinated fibers was evaluated. Also studied were unmyelinated fiber, ovoid body, and glycogen inclusion densities. Control rats consisted of non-diabetic rats (n = 36), similar rats receiving Cy-A (n = 42), diabetic rats (n = 103), and diabetic rats receiving Cy-A (n = 45). It was found that PT had a beneficial effect on the axonal cross-sectional area of myelinated nerves, the relative percentage of the various sizes of nerve fibers, and the ovoid body density, especially so in early diabetes. The effects in late diabetes were less spectacular. PT did not prove beneficial to the glycogen inclusion and unmyelinated fiber densities.
Animals↗
Effect of pancreatic allografts on vascular basement membrane thickness in the diabetic rat.
Diabetic Lewis rats received pancreaticoduodenum allotransplants from Brown-Norway donors. Cyclosporine A (Cy-A) was used in a dose of 10 mg/kg/day for immunosuppression. These transplanted rats (n = 190) were compared with nondiabetic Lewis rats (n = 36), nondiabetic Lewis rats receiving 10 mg/kg/day Cy-A (n = 42), diabetic rats (n = 103), and diabetic rats receiving 10 mg/kg/day Cy-A (n = 45). The percentage area of periodic acid-Schiff (PAS) positive basement membrane (BM) of rectus muscle microvasculature was compared in each of the groups. It was found that the percentage area of PAS positive BM increased markedly over 15 months of uncontrolled diabetes. Cy-A did not have a significant effect on either normal or diabetic skeletal muscle vascular BM. Rats with established diabetes showed some reversal in the percentage area of PAS positive BM, when pancreas transplantation was performed at 9, 12, and 15 months of diabetes. Pancreas transplantation may appear beneficial even after the development of BM thickening of skeletal muscle vascular BM.
Abdominal Muscles↗
Ventricular stroke work loss: validation of a method of quantifying the severity of aortic stenosis and derivation of an orifice formula.
Because aortic stenosis results in the loss of left ventricular stroke work (due to resistance to flow through the valve and turbulence in the aorta), the percentage of stroke work that is lost may reflect the severity of stenosis. This index can be calculated from pressure data alone. The relation between percent stroke work loss and anatomic aortic valve orifice area (measured by planimetry from videotape) was investigated in a pulsatile flow model. Thirteen valves were studied (nine human aortic valves obtained at necropsy and four bioprosthetic valves) at stroke volumes of 40 to 100 ml, giving 57 data points. Valve area ranged from 0.3 to 2.8 cm2 and mean systolic pressure gradient from 3 to 84 mm Hg. Percent stroke work loss, calculated as mean systolic pressure gradient divided by mean ventricular systolic pressure x 100%, ranged from 7 to 68%. It was closely related to anatomic orifice area with an inverse exponential relation and was not significantly related to flow (r = -0.15). An orifice formula was derived that predicted anatomic orifice area with a 95% confidence interval of +/- 0.5 cm2 (orifice area [cm2] = 4.82 [2.39 x log percent stroke work loss], r = -0.94, SEE = 0.029). These results support the clinical use of percent stroke work loss as an easily obtained index of the severity of aortic stenosis.
Aortic Valve↗
Flexible ureteropyeloscopy in the diagnosis of benign essential hematuria.
Benign essential hematuria is an uncommon syndrome that constitutes a dilemma in diagnosis for the urologist. We studied 32 patients with flexible ureteropyeloscopy. Previous studies included renal arteriography, computerized tomography, ultrasound and urinary cytology. The entire intrarenal collecting system was inspected in 28 of the 32 patients and discrete lesions were found in 16. The most common finding was a hemangioma on a renal papilla in 11 patients. A discrete lesion was treated in 12 patients with successful results in 11. Nonspecific abnormalities were found in 9 patients and attempts at treatment of these lesions in 4 were unsuccessful. No lesion was found in 5 patients. Flexible ureteropyeloscopy offers a minimally invasive approach for the diagnosis of unilateral gross hematuria. Treatment of solitary small discrete lesions was highly successful.
Adolescent↗
Selectivity for omega-receptor subtypes as a strategy for the development of anxiolytic drugs.
The names omega 1-, omega 2-, and omega 3-receptor subtypes have recently been proposed to replace the nomenclature of BZ1, BZ2 and BZp receptors in order to avoid a nomenclature exclusively linked to the benzodiazepine (BZ) structure or to a regional localization. The multiplicity of pharmacological actions of currently available anxiolytics may be due to their lack of selectivity for omega-receptor subtypes. The idea that a receptor-subtype selective drug will offer a more specific therapeutic profile is widely accepted. In the field of preferential anxiolytic or hypnotic drugs, imidazopyridines represent a new chemical and therapeutic class possessing selectivity for omega-receptor subtypes. Of these, alpidem (6-chloro-2-(4-chloro-phenyl)-N,N-dipropylimid-azo[1,2-a] pyridine-3-acetamide) behaves preferentially as an anxiolytic drug in both animal models and man. Receptor-binding studies using alpidem either as a displacer or as a radioligand indicate that the compound has a high affinity for omega 1- and for omega 3- but not for omega 2-receptors. In the human brain, the binding of [3H]-alpidem to omega 1- and omega 3-receptors occurs with a Kd of 1.67 nM and 0.33 nM respectively. The binding of [3H]-alpidem to omega 1-receptors in the rat cerebral cortex with a Kd of 1.5 nM is enhanced by GABA, and in contrast to anxiolytics of the benzodiazepine type, is unaffected by chloride ions and pentobarbital. In conclusion, the affinity of alpidem for the omega 1-receptor is allosterically influenced by the activation of the GABAA receptor but not by other components of the same receptor complex.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Cell death induced in a murine mastocytoma by 42-47 degrees C heating in vitro: evidence that the form of death changes from apoptosis to necrosis above a critical heat load.
The pathogenesis of heat-induced cell death is controversial. Categorizing the death occurring after various heat loads as either apoptosis or necrosis might help to elucidate this problem, since it has been shown that these two processes differ in their mode of initiation as well as in their morphological and biochemical features. Log-phase cultures of mastocytoma P-815 x 2.1 were heated at temperatures ranging from 42 to 47 degrees C for 30 min. After 42 degrees C heating a slight increase in apoptosis was observed morphologically. However, after heating at 43, 43.5 and 44 degrees C, there was marked enhancement of apoptosis, and electrophoresis of DNA showed characteristic internucleosomal cleavage. With heating at 45 degrees C both apoptosis and necrosis were enhanced, whereas at 46 and 47 degrees C only necrosis was produced. DNA extracted from the 46 and 47 degrees C cultures showed virtually no degradation, which contrasts with the random DNA breakdown observed in necrosis produced by other types of injury; lysosomal enzymes released during heat-induced necrosis may be inactivated at the higher temperatures. It is suggested that apoptosis following heating may be triggered either by a limited increase in cytosolic calcium levels resulting from mild membrane changes or by DNA damage. Necrosis, on the other hand, is likely to be a consequence of severe membrane disruption.
Animals↗
Chronic animal testing of new cardiac pacing electrodes.
To evaluate the electrical performance of new electrode technologies, 24 leads containing either carbon coated porous titanium (BIOPORE, (Intermedics, Inc., Freeport, TX], iridium oxide (IROX), or iridium oxide coated with polyethylene glycol (IROX-PEG) electrodes (eight of each) were implanted into the ventricles of 12 canines. Stimulation threshold data was measured at regular intervals for 24 weeks. Low acute values were observed for all leads (0.32 +/- .13 V at 0.6 msec pulse width), but the IROX-PEG electrode demonstrated lower subchronic, peak, and chronic values. Compared to implant, the IROX-PEG electrodes' stimulation thresholds rose only 0.23 V when chronic conditions occurred. There were no significant differences between the electrodes in pacing impedance or R wave amplitude measurements. We conclude that both IROX and IROX-PEG technologies represent a promising approach to the design of more efficient cardiac pacing leads.
Animals↗
Purification and characterization of a Bacteroides loeschei adhesin that interacts with procaryotic and eucaryotic cells.
The adhesin of Bacteroides loeschei PK1295 that mediates coaggregation with Streptococcus sanguis 34 and hemagglutination of erythrocytes was purified to electrophoretic homogeneity. The lectinlike protein has an estimated native Mr of 450,000 and consists of six subunits of identical molecular weight (Mr 75,000). The purified adhesin appears to be a basic protein with a pI between 7.4 and 8.0. Amino acid and N-terminal sequence analyses were carried out with the purified protein. These indicated that the protein contains a large number of Asx and Glx residues as well as basic amino acid residues. The binding site of the pure adhesin retained its native configuration during purification. When preincubated with streptococcal partner cells at pH 4.6, the adhesin prevented B. loeschei cells from coaggregating with the streptococci. An adhesin preparation adjusted to a pH of 6.8 rapidly agglutinated both streptococci and neuraminidase-treated erythrocytes. Galactosides inhibited the agglutination reactions.
Adhesins, Bacterial↗
Segmenting blood donors by their perceptions and awareness about blood donation.
A battery of 26 items was used to assess blood donors' perceptions on donor eligibility, blood testing, and notification procedures. An analysis of these items from a mail survey of 392 California blood donors resulted in the identification of four clusters of differing perceptions regarding four aspects of the blood collection process. Three of the four segments identified exhibited moderate to strong degrees of skepticism regarding blood donation. Implications for the continued encouragement and maintenance of donor pools are discussed.
Awareness↗
Interdisciplinary approach to assessing the health risk of air toxic chemicals: an overview.
To assist the regulatory branch of the Environmental Protection Agency in addressing the risk assessment of air toxics, the Health Effects Research Laboratory initiated a comprehensive inhalation toxicology program to provide key health effects data missing from the current data base. A priority ranking of chemicals based on the potential for substantial human exposure and the need for health effects data was developed to identify candidate chemicals for toxicological research. The major goal of the program is to evaluate the concentration-response from acute, intermittent and subchronic inhalation exposures to developmental, genetic, hepatic, immunologic, neurologic, pulmonary and reproductive toxicity in a manner that provides data for the regulatory health assessment of air toxic chemicals. Extrapolation and dosimetry research is also conducted to improve the basis for human risk assessment. Determination of biological endpoints to be examined will be decided on a compound-by-compound basis, depending on the physical, chemical and structural characteristics of the chemical and evaluation of the existing health data base. Although the main emphasis is on inhalation as the primary route of exposure, some of the laboratories will compare inhalation to other routes, such as oral, to better understand the influence of route of exposure and hence the potential applicability of existing health data. Acute and intermittent exposures will be done for all compounds. Upon evaluation of the acute results, a decision will be made as to whether subchronic studies are needed. Endpoints that show unusual sensitivity may be investigated in greater detail. The total length of exposure will vary from 1 to 21 days. The daily length of exposure will range from 1 to 8 hr. If adverse effects are observed at ambient levels, the time to recovery after exposure will be investigated.
Administration, Inhalation↗
When you give phenytoin i.v.
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Extravasation of Diagnostic and Therapeutic Materi↗
Patient classification in the postanesthesia care unit.
A patient classification system is an attempt to measure the intensity of the necessary nursing care or the amount of nursing time required to meet the individual patient's needs. A classification system qualifies and quantifies the nursing workload. To compare or match the patient census and minutes of nursing time with the number of nurse caregivers is insufficient. Severity of illness, age of the patent, and other factors must also be considered when time and effort are distributed to assure quality care.
Age Factors↗
Expression of Hox-2.4 homeobox gene directed by proviral insertion in a myeloid leukemia.
The presence of an altered Hox-2.4 gene in the WEHI3B murine myeloid leukemia suggests that homeobox genes may contribute to neoplasia. A survey of 31 leukemia cell lines of the myeloid, lymphoid and erythroid lineages revealed that Hox-2.4 was expressed only in WEHI3B and the pre-B lymphoid line 70Z/3, in which no DNA rearrangement was observed. To clarify the WEHI3B alteration and normal Hox-2.4 structure, we have sequenced near full length cDNA clones from WEHI3B and 70Z/3, and the 5' portion of the normal Hox-2.4 gene. A WEHI3B cDNA clone demonstrates that an intracisternal A-particle (IAP) provirus has inserted within the first exon of the gene and generated a Hox-2.4 mRNA with a 5' sequence derived from the IAP long terminal repeat. A remarkable degree of similarity found between the amino acid sequences of Hox-2.4 and Hox-3.1, which reside on different chromosomes, supports the notion that an ancient homeobox gene cluster has been duplicated and dispersed early in vertebrate evolution.
Amino Acid Sequence↗