Rapamycin (RAPA) is a potent immunosuppressant. Several reports indicate that the drug can act at the late G1 stage of the lymphocyte activation. We studied the effect of RAPA on the expression of an immediate early phase gene c-jun, which plays a pivotal role in cell activation. The results showed that RAPA could inhibit PHA-induced c-jun expression by human T cells. This strongly suggests that there exists a mechanism for RAPA to interact with the lymphocyte activation cascade at a very early stage. We also demonstrated that in T cells a Na+/K+ ATPase inhibitor, ouabain, could induce a late (16 h poststimulation) c-jun expression, which was sensitive to cyclosporin A (CsA) but not to RAPA. This suggests that c-jun's role is probably not restricted to the early phase of lymphocyte activation.

Blotting, Northern↗

PubMed1993

Plasma concentrations of bupivacaine after brachial plexus administration of liposome-associated and plain solutions to rabbits.

Bupivacaine has been associated to multilamellar liposomes with the aim of altering circulating plasma concentrations after injection into the rabbit brachial plexus. Plasma concentrations of bupivacaine have been compared after administration of free drug (BP) or bupivacaine associated to multilamellar liposomes (BP-MLV) made of phosphatidylcholine and cholesterol (molar ratio 4:3). Under light general anaesthesia, one group of six rabbits received an axillary injection of 2.5 mg BP (1 ml, 0.25%), and a second received the same dose of BP-MLV. In both groups 3H bupivacaine was used as a marker. The brachial plexus was located using a nerve stimulator. Injection of the anaesthetic solutions invariably prevented the motor response of the paw. The arterial plasma concentrations of bupivacaine were determined after 5 to 240 min and after 24 hr by beta counting. In the MLV population, additional measurements were performed after 48 and 72 hr. The two plasma curves showed a plateau (0.2 microgram.ml-1) which was reached after five minutes in the BP group and after 90 min using BP-MLV. In the BP-MLV group, the plasma concentrations of bupivacaine were lower during the first ten minutes (P < 0.05), and higher after 24 hr (P < 0.05). Radioactivity decreased between 4 and 24 hr in the BP group and between one and two days in the BP-MLV population. It is concluded that elevated plasma drug concentrations were maintained for longer with BP-MLV than with BP. This could prolong the action of the local anaesthetic through a slow release.

Animals↗

PubMed1993

Enhancement of thrombolysis by external ultrasound.

The purpose of our study was to assess the efficacy of external ultrasound to enhance in vitro thrombolysis with urokinase or streptokinase. One-hour-, 1-day-, 4-day-, and 6-day-old human blood thrombi (n = 366) were incubated in normal saline solution with three different concentrations of streptokinase (50, 250, and 2000 mu/ml) or urokinase (200, 2000, and 5000 mu/ml). Thrombi were exposed to pulsed ultrasound of 1 MHz at 1.0, 1.5 and 2.2 W/cm2 at different exposure times. The combination of ultrasound (2.2 W/cm2, 30 min) and urokinase or streptokinase enhanced lysis rate by an average of 25% compared with lysis with thrombolytic agents alone (p < 0.05). The enhancement was greater at higher ultrasound power outputs (2.2 W/cm2 > 1.5 W/cm2 > 1.0 W/cm2). At higher-power outputs there was no increase of temperature in the solution containing the thrombus. The extent of lysis was higher with longer ultrasound exposure time and with fresh thrombi. These data suggest that use of external ultrasound has the potential to increase both efficacy and rate of thrombolysis.

Combined Modality Therapy↗

PubMed1993

The presence of mast cells in the human endometrium pre- and post-insertion of intrauterine devices.

A study of the density of mast cells in the human endometrium was carried out on biopsy specimens prepared for light microscopy in 87 cases with three types of IUDs (stainless steel ring SS-type, copper Cu-T 220 and LNG-IUD levonorgestrel-releasing device) pre- and post-insertion. The results revealed that, in general, there was an increase of mast cells after 3 to 24 months' use of IUD, independent of type (p < 0.01 when compared with the pre-insertion value). The increase in number of mast cells was most prominent in women having used the Cu-T220 IUD for 24 months (p < 0.05 when compared with the SS-IUD and p < 0.01 when compared with the LNG-IUD). The difference between the SS-IUD and the LNG-IUD as to the number of mast cells was not significant. No significant difference was found between the "bleeders" and "non-bleeders" in any of the three types of IUDs. It is noteworthy that patients using the Cu-T220-IUD had the highest percentage of patients with abnormal bleeding (> 50%) and that this group also had the highest density of mast cells per mm2 after 24 months' use. Although no significant difference with regard to the density of mast cells could be found between the "bleeders" and the "non-bleeders" in the present study, the number of "bleeders" of the three study groups is usually small and sometimes this number does not allow an adequate statistical analysis for comparison. Further investigations, involving larger number of IUD users, may yield a better understanding with regard to the potential relationship between the number of bleeding episodes and the density of mast cells in the human endometrium.

Adult↗

PubMed1993

Assessment of lidocaine metabolite formation in comparison with other quantitative liver function tests.

In clinical practice, the seriousness of liver disease is assessed based on the combined information from clinical examination, routine biochemical tests, and liver histology. Recently, the assessment of hepatic lidocaine metabolism has been proposed as a quantitative liver function test offering valuable additional information. To evaluate whether this new liver function test reflects the combined clinical assessment, we prospectively measured lidocaine metabolism in 111 patients with well characterized liver disease. In addition, lidocaine test results were compared with the aminopyrine breath test and the galactose elimination capacity. Lidocaine (1 mg/kg) was injected i.v. and serum concentrations of its main metabolite monoethylglycinexylidide were determined after 15 min. The results varied widely and the means (+/- S.D.) were similar among patients with mild liver disease (46 +/- 23 ng/ml), but significantly (P < 0.05) lower among patients with Child class A cirrhosis (19 +/- 11 ng/ml) or Child class B or C cirrhosis (21 +/- 19 ng/ml). The [13C]aminopyrine breath test, however, gave a better discrimination among patients with increasing severity of liver disease than lidocaine metabolite formation. The galactose elimination capacity finally best separated patients with mild liver disease from those with cirrhosis. The correlations between any two of the different quantitative liver function tests were weak (R2 consistently < 0.2). We conclude that lidocaine metabolite formation, like other quantitative liver function tests that are based on the microsomal metabolism of model compounds, quantitates a very particular enzymatic reaction which may not be representative for the functional reserve of the entire organ.

Adolescent↗

PubMed1993

Long-term in vivo effects of rapamycin on humoral and cellular immune responses in the rat.

Rapamycin (RAPA) is a strong immunosuppressant and is able to prevent allograft rejection in animal models. We have demonstrated that RAPA could strongly inhibit in vitro immunoglobulin (Ig) production by human lymphocytes. The present study investigated the long-term in vivo effect of RAPA on humoral and cellular immune responses, and the effect of RAPA on accelerated rejection. It was shown that RAPA strongly inhibited antigen (Ag) specific antibody (AB) production (i.e. cytotoxic Ab to donor lymphocytes and Ab to tetanus toxoid) during the period of drug administration. The accelerated rejection of cardiac allografts in presensitized animals was alleviated by RAPA administration. These results suggest the potential application of RAPA in treatment of presensitized candidates for organ transplantation. A little more than two months after the drug withdrawal, the rats were basically competent in Ab response to further Ag challenges. When tested 4 months after the RAPA-treatment, the rats showed uncompromised cardiac allograft rejection, and the cellular immune response in vitro according to mixed lymphocyte reaction (MLR) and mitogen-stimulated proliferation were not hampered. Such results suggest that the immune system can return to normal status without sequelae after discontinuation of RAPA.

Animals↗

PubMed1993

A pharmacological comparison of citalopram, a bicyclic serotonin selective uptake inhibitor, with traditional tricyclic antidepressants.

Major depressive disorder is a very common and a very serious illness that not only disrupts the lives of the people with the condition but also the lives of their families. Effective identification and treatment of those with this disease would greatly improve the lives of a very sizeable proportion of the people of the world. Numerous drugs have been introduced since the 1950s that have proven to be useful in the therapy of major depressive disorder patients but these compounds typically have unwanted side effects due to their actions on many different aspects of brain function. Citalopram, one of the more recently developed antidepressant drugs, is a selective inhibitor of the transport of the neurotransmitter serotonin into nerve terminals and other cells that accumulate serotonin. Citalopram does not affect the uptake of other neurotransmitters nor does it have affinity for the receptors of any neurotransmitter. It is as effective therapeutically as the older antidepressants but it produces considerably fewer side effects than the traditional antidepressants such as amitriptyline. Citalopram appears to have minimal effects on the cardiovascular system and to be one of the few antidepressants to be eliminated to any extent by the kidneys. These characteristics may be an advantage in treating elderly patients with major depressive disorder, or those patients unable to tolerate the anti-cholinergic side effects of the traditional antidepressants.

Antidepressive Agents, Tricyclic↗

PubMed1993

Reversal of ongoing heart, kidney, and pancreas allograft rejection and suppression of accelerated heart allograft rejection in the rat by rapamycin.

Rapamycin was examined for its effects on reversal of ongoing rejection of heart, kidney, and pancreas allografts and on suppression of accelerated heart allograft rejection in the rat. A 14-day continuous intravenous infusion of RAPA by an osmotic pump at 0.02, 0.08, and 0.8 mg/kg/day to WFu recipients, starting 4 days postoperation, significantly protected the BUF heart allografts with a mean survival time (MST) +/- 1 SD of 33.2 +/- 19.8 (p < 0.001), 48.2 +/- 14.8 (p < 0.001), and 107.0 +/- 86.3 (p < 0.001) days, respectively, as compared with 7.2 +/- 0.8 days in vehicle-treated controls. Combination of low dose RAPA (0.02 mg/kg or 0.08 mg/kg) and low dose CsA (2 mg/kg) achieved significantly longer cardiac allograft survival than RAPA or CsA alone. RAPA's effect in reversing ongoing rejection of renal and pancreatic allografts was also significant. The BUF kidney and pancreas in WFu recipients treated with a 14-day course of RAPA (0.8 mg/kg/day starting 4 days postoperation) had an MST of 44.7 +/- 15.9 (p < 0.001) and 46.4 +/- 12.5 (p < 0.001), while in vehicle-treated controls, the grafts were rejected within 10 days. RAPA could also suppress accelerated cardiac allograft rejection. Hyperimmunized WFu recipients were treated with two 14-day courses of continuous i.v. RAPA at 0.8 mg/kg/day before and after BUF heart allografting. Significantly longer survival of the grafts (25.5 +/- 3.7 days, p < 0.001) was achieved compared with that of the vehicle-treated controls (3.8 +/- 1.0 days). One-course RAPA treatment before or after heart transplantation was considerably less effective. RAPA was also shown to prevent the increase of serum IgG levels and to inhibit the production of specific cytotoxic Ab in the rat receiving repetitive immunizations. Such effects presumably contribute to the inhibition of the accelerated rejection. The results of this study suggest that RAPA is potentially useful in treatment of ongoing as well as accelerated allograft rejection.

Animals↗

PubMed1993

Thermodynamics and transport properties of n-butane computed by molecular dynamics using a rigid interaction model.

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Journal Article↗

PubMed1993

Anti-CD28 antibody- and IL-4-induced human T cell proliferation is sensitive to rapamycin.

Rapamycin (RAPA) is a potent immunosuppressant. In this study we investigated the effect of RAPA on T cell proliferation triggered by various stimuli in an in vitro human model. The proliferation of T cells stimulated via an alternative pathway using phorbol myristate acetate (PMA) and anti-CD28 antibody (alpha CD28) in the absence of antigen-presenting cells (APC) was strongly inhibited by RAPA. T cell proliferation provoked via a combination of CD3/TCR and CD28 pathways using anti-CD3 antibody (alpha CD3) plus alpha CD28 was also inhibited by RAPA in the presence of APC. The mitogen (phytohaemagglutinin (PHA) or alpha CD3)-induced up-regulation of expression of the IL-2 receptor alpha chain (IL-2R alpha) and the IL-4 receptor (IL-4R) was sensitive to RAPA. This suggests that RAPA's interference with the IL-2 and IL-4 autocrine loops during T cell activation might contribute to RAPA's overall immunosuppressive effect. We have further demonstrated in a two-stage culture system that RAPA strongly inhibited IL-4-stimulated proliferation of T cells, the latter being either pretreated with alpha CD3 in the presence of APC, or with PMA plus alpha CD28 in the absence of APC. The result suggests that the Ca++ influx during the pretreatment is not obligatory for T cells to achieve IL-4 responsiveness. The results also indicate that RAPA's antiproliferative effect on IL-4-stimulated T cells is not contingent on the various mechanisms of cell priming. Therefore, RAPA's major target is probably at the second stage after the priming. Our study has extended current knowledge about the effect of RAPA on human T cells.

Antibodies, Monoclonal↗