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Biomedical subjects

A Nimrod

Publications and source records attributed to A Nimrod.

At least 19 recordsLinked to original sources
PubMed2005

Synthesis of A/B-ring partial analogs of bruceantin as potential antimalarial agents.

Bruceantin (1), a classical quassinoid with the highest reported antimalarial activity among the quassinoids examined thus far, was selected as a natural product lead for the design of a series of A/B-ring analogs. A viable strategy for the synthesis of the series was developed. The functionalized A-ring and the C-15 ester moiety in bruceantin are incorporated in all designed compounds. The preliminary bioassay results will be discussed in detail.

Animals↗
PubMed2001

Identification and quantitation of 11-nor-delta9-tetrahydrocannabivarin-9-carboxylic acid, a major metabolite of delta9-tetrahydrocannabivarin.

After incubation of delta9-tetrahydrocannabivarin with human hepatocytes, a major metabolic product was detected by gas chromatography-mass spectrometry that showed identical retention time and mass spectrum to the synthetic 11-nor-delta9-tetrahydrocannabivarin-9-carboxylic acid (11-nor-delta9-THCV-9-COOH). Analysis of human urine specimens from marijuana users and plasma samples from Marinol users showed that 11-nor-delta9-THCV-9-COOH was only present in urine specimens of marijuana users. These results supported the conclusion that identification of 11-nor-delta9-THCV-9-COOH in a donor's urine specimen indicates the use or ingestion of cannabis-related product(s) and would not explain the sole use of Marinol.

Chromatography, High Pressure Liquid↗
PubMed1999

Probing the N-5 region of the indoloquinoline alkaloid, cryptolepine for anticryptococcal activity.

N-5 Alkylated analogues of cryptolepine were synthesized and tested for anticryptococcal activity. Evidence provided in this study suggests that the active form of cryptolepine consists of the flat tetracyclic aromatic ring with the methyl group on the N-5 atom. It was also found that changes in the electronic density around the N-5 atom do not appear to affect activity. Steric hindrance of the N-5 substituents seems to decrease activity. Through systematic modification of the N-5 alkyl groups, o-phenylpentyl group was shown to possess the highest potency thus far.

Alkaloids↗
PubMed1999

Evaluation of triage decisions for intensive care admission.

OBJECTIVE: To assess physician decision-making in triage for intensive care and how judgments impact on patient survival. DESIGN: Prospective, descriptive study. SETTING: General intensive care unit, university medical center. INTERVENTIONS: All patients triaged for admission to a general intensive care unit were studied. Information was collected for the patient's age, diagnoses, surgical status, admission purpose, Acute Physiology and Chronic Health Evaluation (APACHE) II score, and mortality. The number of available beds at the time of triage and reasons for refused admission were obtained. MEASUREMENTS AND MAIN RESULTS: Of 382 patients, 290 were admitted, 92 (24%) were refused admission, and 31 were admitted at a later time. Differences between admission diagnoses were found between patients admitted or not admitted (p < .001). Patients refused admission had higher APACHE II scores (15.6+/-1.5 admitted later and 15.8+/-1.4 never admitted) than did admitted patients (12.1+/-.4; p < .001). The frequency of admitting patients decreased when the intensive care unit was full (p < .001). Multivariate analysis revealed that triage to intensive care correlated with age, a full unit, surgical status, and diagnoses. Hospital mortality was lower in admitted (14%) than in refused patients (36% admitted later and 46% never admitted; p < .01) and in admitted patients with APACHE II scores of 11 to 20 (p = .02). The 28-day survival of patients was greater for admitted patients compared with patients never admitted (p = .01). CONCLUSIONS: Physicians triage patients to intensive care based on the number of beds available, the admission diagnosis, severity of disease, age, and operative status. Admitting patients to intensive care is associated with a lower mortality rate, especially in patients with APACHE scores of 11 to 20.

APACHE↗
PubMed1998

Herpes simplex virus-1 and varicella virus infections in familial dysautonomia patients.

Familial dystautonomia (FD) patients are deficient in type C fibers, suggesting that there may be a different pattern of infection and clinical presentation when infected by Herpes simplex virus type 1 (HSV-1) or Varicella-Zoster virus (VZV). These viruses infect and are reactivated in the periphery of the body through type C sensory nerve fibers. HSV-1 infects epithelial cells, penetrates into type C fibers, and migrates to the ganglia to generate latent infection. In reactivation, the viral DNA migrates through type C fibers, infecting the epidermis at the entry site. VZV infects through the respiratory tract, causing systemic viral infection and latency in the ganglia, from which it is reactivated and reaches the skin. The study was carried by clinical questionnaire and by HSV and VZV IgG antibodies on fifty-one FD patients and eighty matched controls. The questionnaire revealed that no FD patient had a history of clinical HSV-1 infection, compared to 15% in the control group (P < 0.05), while 50% FD patients had been infected by varicella, compared to 66% in the VZV control group. However in FD, VZV clinical manifestations were mild in comparison to controls. There was no difference in infection rates for some other viral diseases. HSV-1 antibodies were detected in 24% of the FD patients, compared to 38% in the control group (P < 0.1). VZV antibodies were similar in FD and controls (66%, 63%). We concluded that the rate of HSV infection in FD is low and clinical reactivation is rare. The rate of varicella infection appears to be the same for patients and controls, but in FD the clinical presentation is mild. We suggest that these differences are due to the lack of type C fibers in FD patients.

Adolescent↗
PubMed1997

Recombinant polypeptides derived from the fibrin binding domain of fibronectin are potential agents for the imaging of blood clots.

Thrombus formation in the circulation is accompanied by covalent linkage of fibronectin (FN) through transglutamination of glutamine no. 3 in the fibrin binding amino terminal domain (FBD) of FN. We have exploited this phenomenon for thrombus detection by the employment of radioactively-labelled recombinant polypeptide molecules derived from the 5-finger FBD of human FN. Three recombinant FBD polypeptides, 12 kDa ("2 fingers"), 18.5 kDa ("3 fingers") and 31 kDa FBD ("5 fingers"), were prepared and compared to native FN-derived 31 kDa-FBD with respect to their ability to attach to fibrin clots in vitro and in vivo. The accessibility of Gln-3 in these molecules was demonstrated by the incorporation of stoichiometric amounts of 14C-putrescine in the presence of plasma transglutaminase. Competitive binding experiments to fibrin have indicated that, although the binding affinities of the FBD molecules are lower than that of FN, substantial covalent linkage was obtained in the presence of transglutaminase, and even in the presence of excess FN or heparin. The biological clearance rates of radioactively labelled FBD molecules in rats and rabbits were much higher than those of FN and fibrinogen, thus indicating their potential advantage for use as a diagnostic imaging tool. Of the three molecules, the 12 kDa FBD exhibited the highest rate of clearance. The potential of the 12 kDa and 31 kDa FBDs as imaging agents was examined in a stainless steel coil-induced thrombus model in rats and in a jugular vein thrombus model in rabbits, using either [125I] or [111In]-labelled materials. At 24 h, clot-to-blood ratios ranged between 10 and 22 for [125I]-12 kDa FBD and 40 and 60 for [111In]-12 kDa FBD. In the rat model, heparin did not inhibit the uptake of FBD. Taken together, the results indicate that recombinant 12 kDa FBD is a good candidate for the diagnosis of venous thrombosis.

Animals↗
PubMed1996

Cellular and secretory mechanisms related to delayed radiation-induced microvessel dysfunction in the spinal cord of rats.

PURPOSE: This study aimed to investigate long-term, radiation-induced changes in microvessel permeability, the profile of the vasoactive mediators endothelin and nitric oxide, and the response of specific cell systems in the irradiated spinal cord of rats. METHODS AND MATERIALS: The thoracolumbar spinal cords of Fischer rats were irradiated to a dose of 15 Gy, and the rats were sacrificed at various times afterward. Endothelin levels and nitric oxide-synthase (NOS) activity were assayed in extracts of spinal cords. Microvascular permeability and the effect of treatment with recombinant human manganese superoxide dismutase (r-hMnSOD) were assessed quantitatively. Immunohistochemistry evaluated astrocytes, microglia, vascular basal membrane, and neurofilaments. RESULTS: None of the rats developed neurologic dysfunction. Endothelin levels were significantly reduced at 18 h after irradiation and markedly attenuated after 10 days (p < 0.007). Thereafter, endothelin levels returned to normal values at 56 days after radiation and escalated to markedly high levels after 120 and 180 days (p < 0.002). NOS activity remained very low throughout the period of follow-up and failed to counterbalance the shifts in endothelin levels. Treatment with r-hMnSOD had no effect on normal vascular permeability but it abolished the abnormally increased permeability measured at 18 h after radiation and again after 120 and 180 days. Standard microscopic evaluation failed to reveal abnormalities in the irradiated spinal cord, but immunohistochemical staining showed a progressive increase in the number of microglial cells per field after 120 and 180 days (p < 0003). A similar increase in the number of astrocytic cells per field was noted after more than 180 days, but an earlier short lasting peak was also noted at 14 days after radiation. No abnormalities were found in blood vessel configuration, density, diameter, and basal membrane staining, or in the neurofilaments. CONCLUSION: Marked imbalance in the regulatory function of endothelium-derived mediators of the vascular tone is present after radiation therapy probably inducing chronic vasoconstriction. This imbalance favors localized procoagulation that may enhance the consequent loss of function measured as increased permeability. Microglial proliferation may account for continuous release of superoxide that may enhance disruption of normal permeability. The latter is corrected by SOD treatment. Astrocytic proliferation may present a response to the mitogenic effect of endothelin and to microglial-derived paracrine effect of cytokines.

Animals↗
PubMed1996

Successful treatment of radiation-induced fibrosis using Cu/Zn-SOD and Mn-SOD: an experimental study.

PURPOSE: To establish how far liposomal copper/zinc superoxide dismutase (Cu/Zn-SOD) and manganese superoxide dismutase (Mn-SOD), respectively, reduce radiation-induced fibrosis (RIF), using a well-characterized pig model of RIF permitting the design of a controlled laboratory experiment. METHODS AND MATERIALS: In this model of acute localized gamma irradiation simulating accidental overexposure in humans, three groups of five large white pigs were irradiated using a collimated 192Ir source to deliver a single dose of 160 Gy onto the skin surface (100%) of the outer side of the thigh. A well-defined block of subcutaneous fibrosis involving skin and skeletal muscle developed 6 months after irradiation. One experimental group of five pigs was then injected i.m. with 10 mg/10 kg b.wt. of Cu/Zn-SOD, twice a week for 3 weeks, and another experimental group of five was injected with 10 mg/10 kg b.wt. of Mn-SOD, three times a week for 3 weeks. Five irradiated control pigs were injected with physiological serum. Animals were assessed for changes in the density of the palpated fibrotic block and in the dimensions of the projected cutaneous surface. Block depth was determined by ultrasound. Physical and sonographic findings were confirmed by autopsy 12-14 weeks after completing SOD injections. The density, length, width, and depth of the fibrotic block, and the areas and volume of its projected cutaneous surface were compared before treatment, 1, 3, and 6 weeks thereafter, and at autopsy, 12-14 weeks after treatment ended. RESULTS: The experimental animals exhibited no change in behavior and no abnormal clinical or anatomic signs. Whether they were given Cu/Zn- or Mn-SOD, significant and roughly equivalent softening and shrinking of the fibrotic block were noted in all treated animals between the first week after treatment ended and autopsy, when mean regression was 45% for length and width, 30% for depth, and 70% for area and volume. Histologic examination showed completely normal muscle and subcutaneous tissue surrounding the residual scar. This replacement of scar tissue by normal tissue in experimental animals and the 50% decrease in the linear dimensions of the scar were comparable to the results obtained in previous clinical studies and highly significant compared to the clinical and autopsy results for the control animals. CONCLUSIONS: Our results are striking and comparable to the results obtained in our previous clinical study after liposomal Cu/Zn-SOD treatment. To our knowledge, this is the first time that two agents have been shown to reverse the radiation-induced fibrotic process in experimental animals and to permit the regeneration of normal tissue in a zone of well-established postirradiation fibrosis.

Animals↗
PubMed1996

Enhancement of recombinant tissue-type plasminogen activator thrombolysis with a selective factor Xa inhibitor derived from the leech Hirudo medicinalis: comparison with heparin and hirudin in a rabbit thrombosis model.

OBJECTIVE: To compare the efficacy of Yagin, a factor Xa inhibitor derived from the leech Hirudo medicinalis, with those of heparin and hirudin as adjuncts to recombinant tissue-type plasminogen activator (rTPA) thrombolysis in a rabbit thrombosis model. METHODS: Thirty-one animals were allocated randomly to three groups, all administered four boluses of 0.25 mg/kg rTPA every 10 min for 30 min, 17 mg/kg aspirin intravenously, and heparin (as a 100 IU/kg bolus followed by infusion of 50 IU/kg heparin per h), hirudin (as a 2 mg/kg bolus followed by infusion of 1 mg/kg hirudin per h), or Yagin (as an 80 micrograms/kg bolus followed by infusion of 43 micrograms/kg Yagin per h). RESULTS: Administration of Yagin was associated with a significant acceleration of the reflow time, this time being 14.5 +/- 1.2 min with Yagin, 25.8 +/- 5.2 min with heparin (P < 0.0001, versus Yagin), and 28.7 +/- 16.0 min with hirudin (P = 0.012, versus Yagin). Overall patency did not differ significantly among the three groups. CONCLUSIONS: At the indicated single doses, inhibition of factor Xa by a relatively low concentration of Yagin was found to be superior than that with either heparin or hirudin for accelerating rTPA thrombolysis.

Animals↗
PubMed1996

Inhibitory effects of recombinant manganese superoxide dismutase on influenza virus infections in mice.

The oxygen free-radical scavenger recombinant human manganese superoxide dismutase (MnSOD) was studied for its effects on influenza virus infections in mice when used alone and in combination with ribavirin. Mice challenged with influenza A/NWS/33 (H1N1) virus were treated parenterally in doses of 25, 50, and 100 mg/kg of body weight per day every 8 h for 5 days beginning at 48 h post-virus exposure. An increase in mean day to death, lessened decline in arterial oxygen saturation, and reduced lung consolidation and lung virus titers occurred in the treated animals. To determine the influence of viral challenge, experiments were run in which mice were infected with a 100 or 75% lethal dose of virus and were treated intravenously once daily for 5 days beginning 96 h after virus exposure. Weak inhibition of the mortality rate was seen in mice receiving the high viral challenge, whereas significant inhibition occurred in the animals infected with the lower viral challenge, indicating that MnSOD effects are virus dose dependent. To determine if treatment with small-particle aerosol would render an antiviral effect, infected mice were treated by this route for 1 h daily for 5 days beginning 72 h after virus exposure. A dose-responsive disease inhibition was seen. An infection induced by influenza B/Hong Kong/5/72 virus in mice was mildly inhibited by intravenous MnSOD treatment as seen by increased mean day to death, lessened arterial oxygen saturation decline, and lowered lung consolidation. MnSOD was well tolerated in all experiments. A combination of MnSOD and ribavirin, each administered with small-particle aerosol, resulted in a generally mild improvement of the disease induced by the influenza A virus compared with use of either material alone.

Animals↗
PubMed1996

Sodium hyaluronate as a tool in strabismus surgery in rabbits.

BACKGROUND AND OBJECTIVE: The authors tested whether coating tissue with sodium hyaluronate (Na-HA) reduced postoperative adhesions and accelerated the healing process in strabismus surgery. MATERIALS AND METHODS: The surgical technique was tested during recession and resection operations performed on 30 rabbits and was compared with the use of NaCl 0.9%. Clinical, biomicroscopic examinations were performed on postoperative days 1, 2, 7, and 30 and histopathologic examinations were performed on postoperative days 2, 7, and 30. RESULTS: Clinically, there were no statistically significant differences between the study group and the control group. Also, there were no statistically significant differences between the two groups for most of the histopathologic criteria; however, new vessel formation was smaller with Na-HA than without it. Statistical significance was defined as P < .05. CONCLUSION: The authors found no significant positive effect of Na-HA on postoperative healing in rabbits.

Animals↗
PubMed1993

Studies on fibronectin and its domains. I. Novel recombinant cell-binding domain of fibronectin--a modulator of human platelet functions.

The DNA sequences encoding for two proteins of the cell-binding domain (CBD) of human fibronectin (FN), namely a 33-kDa protein (aa 1329-1722) and a 40-kDa (aa 1380-1851) protein, were cloned and expressed in Escherichia coli. The interactions of the resulting rCBD proteins, refolded and purified to homogeneity, with human platelets were studied in comparison with those of the pentapeptide GRGDS. The binding of both the 33-kDa and the 40-kDa proteins to washed platelets appeared to be dependent upon platelet activation. In the case of the 33-kDa protein, binding to stimulated platelets was shown to be saturable, with Kd = 2 microM (thrombin as agonist). Moreover, both the 33-kDa and the 40-kDa proteins inhibited fibrinogen binding (at 0.1 microM) to ADP- or thrombin-stimulated platelets with IC50 values in the same concentration range. Binding seemed therefore to occur mainly at the GPIIb/IIIa receptor, and accordingly monoclonal antibodies against this receptor prevented up to 85% of the binding of the 33-kDa protein to platelets. With most stimuli the 33-kDa and the 40-kDa proteins inhibited platelet aggregation at concentrations 15- to 25-fold lower than those required by GRGDS and, in the case of the 33-kDa protein, this was shown to occur in either platelet-rich plasma, washed platelets, or whole blood. The 33-kDa protein also inhibited platelet aggregation and thromboxane A2 (TXA2) generation on the subendothelial extracellular matrix, whereas the GRGDS peptide inhibited only matrix-induced platelet aggregation, but not TXA2 formation. Furthermore, the 33-kDa protein, which is derived from the human FN CBD, seemed to be highly selective, since it inhibited the aggregation of platelets from primates only, and not from other animals tested. Finally, the 33-kDa protein did not promote fibroblast cell attachment, as was observed for both whole FN and the 40-kDa protein, thus displaying a selectivity toward platelets. In conclusion, the unique properties of the 33-kDa protein, and, in particular, its special affinity directed only toward activated primate platelets, seem to hold a promising potential for the further development of an antithrombotic agent.

3T3 Cells↗
PubMed1992

Superoxide dismutase inhibits radiation-induced lung injury in hamsters.

An animal model of pulmonary radiation-induced lung injury was established in the hamster and the effects of pretreatment with recombinant human CuZn superoxide dismutase (SOD) on the development of the lesion were evaluated. Hamsters exposed to a single irradiation dose of 2000 cGy delivered to the thorax were treated with 150 mg/kg body weight of SOD or an equivalent volume of saline intraperitoneally 75 min and subcutaneously 5 min before receiving irradiation. At 4, 8, and 16 weeks following irradiation, pulmonary injury was evaluated by the grading of morphologic changes semiquantitatively, measurement of lung hydroxyproline content, and analysis of bronchoalveolar lavage fluid for total and differential cell counts and total protein concentration. Radiation-induced lung injury in saline-pretreated animals was documented at 16 weeks by histologic morphology and increased protein in bronchoalveolar lavage fluid. SOD protected against radiation-induced pulmonary injury as indicated by the absence of severe histopathologic changes and prevention of elevation in bronchoalveolar lavage protein levels. The beneficial effects of SOD in preventing radiation-induced pulmonary toxicity suggests that this recombinant enzyme may play a role in protection against radiation-induced pulmonary injury in humans.

Animals↗
PubMed1992

Absorption, distribution, metabolism, and excretion of bacteria-derived hyaluronic acid in rats and rabbits.

The feasibility of using bacteria-derived hyaluronate solution as a viscous aid for anterior chamber surgery was examined by studying the pharmacokinetic behavior and metabolic fate of 14C-labelled material, following administration to rats and rabbits. Intravenously-administered HA disappeared rapidly from the blood of rabbits and rats with a mean t1/2 of 5.3 and 3.7 min, respectively. The labelled material has concomittantly accumulated in the liver, where it was digested to oligomeric sugar subunits; these were further utilized metabolically either for energy generation or for incorporation into new high molecular weight species. Metabolic cage studies has indicated that most of the 14C-HA label administered intravenously to rats was excreted as CO2 via the respiration within 24h, while a smaller portion was excreted in the urine. The disposition of viscous 14C-HA administered into the anterior eye chamber of rabbits was slow and followed first-order kinetics with a t1/2 of 10.5h. No degradation occurred in the aqueous humour. Low blood levels of 14C-labeled material were found during 72h after intra-ocular administration. The results indicate that the absorption, distribution, metabolism and excretion of bacteria-derived HA is similar to those of the currently used ophthalmic surgery HA aids extracted from rooster combs.

Absorption↗
PubMed1991

Protective effects of human recombinant MnSOD in adjuvant arthritis and bleomycin-induced lung fibrosis.

We have previously shown that human recombinant methionyl manganese superoxide dismutase (MnSOD) is more efficient than CuZnSOD as an anti-inflammatory agent in a model of acute inflammation (Carrageenan-induced paw edema). This effect was attributed to the prolonged half-life of MnSOD in blood (t1/2 = 6 h vs. 10 min, respectively). In the present study, the two enzymes were compared in terms of their effectiveness in two systems: (1) Adjuvant-induced arthritis in rats, which is considered to be a model for the chronic situation of rheumatoid arthritis and (2) Bleomycin-induced lung fibrosis, which is a chronic situation believed to be mediated by oxygen free radicals. Rats inflicted with adjuvant arthritis were treated during the period of maximal joint swelling (Days 15-21 after adjuvant injection) with MnSOD or CuZnSOD (12 to 50 mg/kg, i.p. daily). MnSOD administration resulted in a 50-75% reduction of paw swelling, as well as inhibition of the elevation of serum globulins. A similar treatment with CuZnSOD gave merely marginal effects. In the second system, lung fibrosis was induced in rats by intratracheal administration of bleomycin. MnSOD (50 mg/kg, s.c.), administered 2 h before and then 2 and 4 days after bleomycin, markedly inhibited lung fibrosis, as evident from lung weight and collagen content measured by the 3rd week. By contrast, CuZnSOD administration did not give a significant effect. The results indicate that MnSOD is superior to CuZnSOD in the treatment of chronic inflammatory processes. In addition, they lend further support to the involvement of oxygen free radicals in bleomycin toxicity.

Arthritis, Experimental↗
PubMed1991

Recombinant human superoxide dismutases: production and potential therapeutical uses.

In many pathological situations, tissue damage is caused by cellular generation of superoxide free radicals (O2-). These active species are generated during post-ischemic reperfusion of organs, in hyperoxic tissue, during acute and chronic inflammation and during exposure to ionizing radiation. Exogenous superoxide dismutase (SOD) was shown to significantly prevent such damage. The genes for human cytosolic Cu/ZnSOD and mitochondrial MnSOD were cloned and introduced into an E. coli expression system. The proteins were expressed in high yields and purified to homogeneity, yielding pharmaceutical-grade materials. These enzymes were used in a variety of in vivo animal models for the demonstration of their protective effects against oxidative damage. Comparative pharmacokinetic studies in rats have revealed that the half-life of Cu/ZnSOD was 6-10 min., while that of MnSOD was 5-6 hours, thus indicating that MnSOD may be superior to Cu/ZnSOD for the treatment of chronic diseases. Indeed, MnSOD was found to be effective as an anti-inflammatory agent in the rat carrageenan induced paw edema acute inflammation model. Both enzymes were also effective in ameliorating post-irradiation damage in mice exposed to whole-body or localized chest X-ray radiation.

Animals↗