1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 1. Synthesis and biological properties of alkyl alcohol and statine derivatives

A series of 1,2,4-triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity, which incorporate (1S,2S)-2-amino-1,3-dicyclohexyl-1-hydroxypropane, statine (Sta), and (3S,4S)-4-amino-5-cyclohexyl-3-hydroxy-pentanoic acid (ACHPA) transition-state mimetics, have been prepared. Structure-activity relationships for renin inhibitory activity in the series are consistent with the 2-[8-isobutyl-6-phenyl-1,2,4-triazolo[4,3-a]pyrazin-3-yl]-3-(3 pyridyl)propionic acid moiety 10b acting as a non-peptidic replacement for the P4-P2 (Pro-Phe-His) residues of the natural substrate angiotensinogen. Compounds 12m, 12o and 12q were potent inhibitors of partially purified human renin (IC50 values 1.7, 6.8, and 3.7 nM, respectively), and also effectively lowered blood pressure in anesthetized, sodium depleted marmosets following intravenous administration. On oral administration however, no blood pressure lowering activity could be detected, and absorption studies in bile duct cannulated rats indicate that this may be due primarily to poor oral absorption, rather than rapid biliary excretion. The reason for the observed poor oral activity is not clear, but it seems unlikely that poor aqueous solubility or metabolic instability to gut enzymes are rate-determining, and other factors such as high molecular weight may also be very important.     

Anesthesia and/or Sedation for Pulsed Dye Laser Therapy

One of the most exciting developments in pediatric dermatology has been the use of the flashlamp-pumped, 585-nm, pulsed dye laser for treatment of vascular birthmarks. In many cases the results are miraculous. The increase in self-esteem and happiness of many children and adolescents has been overwhelming; for some, depression has been lifted, stuttering has ceased, social involvement has increased, and antidepressants have been discontinued. There are many success stories to tell.
Despite the remarkable effects of the pulsed dye laser and the medical and psychosocial indications for its use, the issue of pain control remains significant. We have no perfect outpatient pediatric anesthetic. Most methods carry either some risk or, if not hazardous, often are not very effective for controlling pain. Needless to say, a diversity of opinions exist on how to manage discomfort from this treatment modality. Therefore, we thought it would be useful to share the experiences and opinions of several dermatologists who have extensive experience with the pulsed dye laser.     

Hodgkin disease: CT of the thymus

The computed tomography (CT) scans in two groups of patients with Hodgkin disease were reviewed to determine the frequency of thymic enlargement. In 50 CT scans from 50 patients with evidence of thoracic disease on CT scans who were examined for primary staging, the thymus was enlarged in 15 of 50 (30%). Fifty CT scans were obtained from 44 patients at the time of 50 separate episodes of known or suspected relapse. Relapse occurred in the mediastinum in 12 episodes, lung parenchyma in five, and both sites in one. Thymic enlargement thought to be due to involvement by disease was present in seven of 18 (38%). Mediastinal disease was associated with thymic enlargement in all but one patient in whom a thymic cyst developed after radiation therapy. Differentiation of thymic enlargement from enlarged superior mediastinal lymph nodes was easily made in all but two patients. Thymic enlargement in the absence of lymph node enlargement may indicate a different disease, since isolated Hodgkin disease of the thymus is uncommon. Primary thymic tumor should be considered initially, whereas after treatment, rebound hyperplasia of the thymus may be the cause of enlargement.     

Detection of intra-amniotic infection by gas-liquid chromatography.

The use of gas-liquid chromatography to detect short-chain organic acids in the amniotic fluid of patients with amnionitis has been previously described. Most of the studies describe patients in the early third trimester with such infections. The purpose of the current study was to confirm the correlation of infection with increased production of organic acids and to assess the effect of gestational age on the presence of these short-chain fatty acids in the amniotic fluid. Six patients with confirmed chorioamnionitis were used as positive control subjects. Seventy-two patients at various gestational ages from 18 to 42 weeks with negative Gram's stain and culture results from the amniotic fluid were used as negative control subjects. The data revealed an increased production of organic acids, particularly pyruvic, oxalic and succinic, in patients with amnionitis regardless of gestational age. Interestingly, patients with noninfected amniotic fluid also revealed an increase in the concentrations of volatile organic acids between 27 and 32 weeks' gestation. It appears from this study that previous results correlating chorioamnionitis with an increased production of organic acids in the amniotic fluid may have been confounded by gestational age.     

Brainstem neurons projecting to different levels of the spinal cord of the dogfish Scyliorhinus canicula.

Neurons in the brain that project to different levels of the spinal cord in the dogfish Scyliorhinus canicula have been identified by retrograde labelling with horseradish peroxidase. Injections have been made at four different levels, namely, cervical (segments 3-6), pectoral (segments 16-18), pelvic (segments 34-36) and caudal (segments 60-80). Labelled neurons were located in the diencephalon, mesencephalon and rhombencephalon. Twenty nuclei contained labelled cells following cervical injections. Fourteen of these contained labelled cells following pectoral injections as did nine following pelvic injections and only seven after caudal injections. Of the three diencephalic nuclei projecting to the cord only nucleus thalamus ventralis pars medialis projected further than cervical regions. From the mesencephalon, the tectospinal projection, which arises from tectal and tectotegmental regions, reaches only as far as the cervical cord. The reticulospinal system, arising from cell groups in both the mesencephalon and rhombencephalon, provides the major descending pathway and reaches the most caudal levels. From the octaval region a vestibulospinal pathway arises from nucleus octavus magnocellularis, to reach all levels of the cord, and from nucleus octavus descendens, to project only as far as the pectoral cord. Other rhombencephalic cell groups--the trigeminal nuclei and nuclei B, F and G--project at least as far as the pectoral cord. We conclude that few brainstem nuclei can directly affect the whole spinal cord, whereas many nuclei may have an impact on its most rostral regions; here we have found labelled spinal interneurons with long descending axons that reach the most caudal cord levels.     

Axial tissue diffusion can account for the disparity between current models of hepatic elimination for lipophilic drugs

An assumption of previous models of hepatic elimination is that there is negligible axial diffusion in the liver. We show, by construction of a stochastic model and analysis of published data, that compounds which are readily diffusible and partitioned into hepatocytes may undergo axial tissue diffusion. The compounds most likely to be affected by axial tissue diffusion are the lipophilic drugs for which the cell membranes provide little resistance and which are highly extracted, thereby creating steep concentration gradients along the sinusoid at steady state. This phenomenon greatly modifies the availability of the compound under conditions of altered hepatic blood flow and protein binding. For moderately diffusible compounds, these relationships are similar to those predicted by the simplistic venous-equilibrium model. Hence, the paradoxical ability of the venous-equilibrium model to describe the steady-state kinetics of lipophilic drugs such as lidocaine, meperidine, and propranolol may be finally resolved. The effects of axial tissue diffusion and vascular dispersion on hepatic availability of drugs are compared. Vascular dispersion is of major importance to the availability of poorly diffusible compounds, whereas axial tissue diffusion becomes increasingly dominant for highly diffusive and partitioned substances.This study was supported by the National Health and Medical Research Council of Australia.     

Autoimmune diseases in pregnancy.

Autoimmune diseases are a significant problem in women of reproductive age. This article reviews some of the more common autoimmune disorders and discusses their diagnosis and management during pregnancy. The effects of the autoimmune disorder on pregnancy and the effects of pregnancy on the course of the autoimmune disorder are also discussed with an emphasis on the implications for clinical management.     

Solitary bronchioloalveolar carcinoma: CT criteria

The computed tomographic (CT) scans of 30 patients with solitary bronchioloalveolar carcinoma were reviewed. Common features at CT included the peripheral or subpleural location of a pulmonary mass (25 cases), pseudocavitation (18 cases), heterogeneous attenuation (17 cases), irregular margins forming a star pattern (22 cases), and pleural tags (21 cases). Using these CT criteria, four independent observers attempted to identify cases of bronchioloalveolar carcinoma from a larger sample of lung cancers and benign lesions by categorizing a series of test cases into four probability categories. Although the bronchioloalveolar carcinomas were correctly ranked in the two highest probability categories 75% of the time (in 45 of 60 cases), there was considerable overlap with other lung lesions, particularly with adenocarcinoma and large cell undifferentiated carcinoma. However, even though the typical features of bronchioloalveolar carcinoma are not invariable or highly specific, they are characteristic enough to suggest the diagnosis.     

Return to training and competition after deep venous calf thrombosis.

A 25-yr-old female triathlete presented with 4 d of increasing left calf pain that started 1 d after an elective termination of pregnancy during the eighth week of gestation. She had been training with running, bicycling, and swimming but did not recall any injury to the calf muscle. Deep venous thrombosis of the calf and popliteal veins was diagnosed, and she was treated with intravenous heparin and oral warfarin anticoagulation. Her major concern was return to training and competition. A protocol was developed based on experience with less active patients and animal studies to allow a progressive return to training activities over 5 wk, followed by running in the sixth week. After release from the hospital, she accelerated the return-to-training protocol and progressed to running within 3 wk. She developed the post-phlebitic syndrome that resolved within 2 yr. The diagnosis and treatment of deep venous thrombosis are reviewed, with specific attention to the needs of athletic patients.     

Maturational changes in retinal excitatory amino acid receptors

The appearance, kinetics and pharmacological properties of receptors for n-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), kainate (KA), L-glutamate (Glu) and L-aspartate (Asp) was investigated using 3H-ligand binding during the development of chick embryo retina. Receptors for AMPA are maximally concentrated at embryonic day 7 (ED 7) and decline 50% in subsequent days; L-Glu receptors are low until ED 11, and the same is true for Asp and NMDA receptors which increase at ED 14 and 18 respectively. All receptors studied underwent an increase in pharmacological specificity, whereas only AMPA-receptors showed an important change in affinity during ontogeny. Results demonstrate that receptors for excitatory amino acids in the retina suffer maturational changes and suggest that while NMDA and aspartate could interact with the same receptor, AMPA and glutamate seem to bind to different sites.