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Biomedical subjects

M Moran

Publications and source records attributed to M Moran.

At least 91 records · Page 5Linked to original sources
PubMed1991

Tobacco smoking increases square-wave jerks during pursuit eye movements.

Smooth-pursuit eye-movement (SPEM) abnormalities have been consistently observed in schizophrenia. The SPEM changes in schizophrenia are not thought to be an artifact of voluntary attention or medication, although a number of nondisease factors are known to affect SPEM. However, cigarette smoking has recently been reported to deteriorate SPEM in both smokers and nonsmokers. This finding is particularly relevant to schizophrenia, because schizophrenic patients smoke cigarettes considerably more than do normals, and none of the previous studies in this patient group have controlled for smoking. The current study was initiated to examine the effects of smoking on a number of oculomotor measures, including SPEM in smoker and nonsmoker normal volunteers. The results of this study suggest that cigarette smoking induces or significantly increases square-wave jerks, especially during smooth pursuit in normals. However, the effect is small and the global qualitative SPEM score is not affected. Other eye movements such as latencies for reflex and volitional saccades and saccadic distractibility are also unaffected by smoking. No differences were apparent between chronic smokers and nonsmokers under nonsmoking conditions in any of the eye-movement measures.

Adult↗
PubMed1991

End-systolic regional wall stress-length and stress-shortening relations in an experimental model of normal, ischemic and reperfused myocardium.

Assessment of left ventricular function is influenced by a number of hemodynamic factors. The purpose of this study was to evaluate the end-systolic regional wall stress-dimension relation in a series of 25 mongrel dogs. In Group A (n = 18) the regional wall stress-velocity of circumferential fiber shortening relation was measured before and after three interventions: volume infusion, metoprolol infusion and dobutamine infusion. The electrocardiogram, left ventricular pressure and its first derivative (dP/dt), arterial pressure and echocardiograms were recorded at baseline and after phenylephrine administration (to increase afterload). For each dog values for regional wall stress were plotted against the velocity of circumferential fiber shortening. For all dogs the relations were inversely linear (r = -0.65 to -0.98). Volume infusion increased end-diastolic volume (p less than 0.05) without shifting the slope or intercept of the relation, indicating its independence from preload. Dobutamine caused a shift in the intercept to the right but no change in slope and metoprolol shifted the relation to the left without altering the slope. The effect of ischemia and reperfusion on the end-systolic regional wall stress-length relation was examined in Group B (n = 7), at baseline, after 5 min of mid-left anterior descending coronary artery occlusion and after 10 min of reperfusion. Afterload was increased by hydraulic aortic occlusion. Regional wall stress was lowest at baseline, highest during ischemia and intermediate after reperfusion (100.2 +/- 32.1, 193.5 +/- 81.5, 141.9 +/- 67.6 kdyn/cm2, respectively, p less than 0.001). The end-systolic regional wall stress-length relation was linear during baseline, ischemia and reperfusion (r = 0.96, 0.95, 0.98, respectively, p less than 0.05). Ischemia caused an increase in the slope and a shift in the intercept to the right compared with baseline. Reperfusion represented an incomplete return toward baseline. This study demonstrates that the regional wall stress-velocity of circumferential fiber shortening relation is linear, independent of preload, incorporates afterload and is sensitive to changes in contractility. In addition, the regional wall stress-length relation can be measured in a nonhomogeneously contracting left ventricle and is predictably altered by ischemia and reperfusion. This relation may prove useful to determine whether alterations in regional systolic function result from changes in local load or contractility in the left ventricle with a regional wall motion abnormality.

Animals↗
PubMed1991

Amocarzine investigated as oral onchocercacidal drug in 272 adult male patients from Guatemala. Results from three dose regimens spread over three days.

The clinical investigations with three types of a three days regimen of amocarzine permitted to adjust the fixed dosing to the body weight related dosing and subsequently the administration of amocarzine from fasting state to drug intake after food. The main objective to reach a dose with predictable and sustained absorption was achieved, and this in turn proved to be onchocercacidal and safe. A combined clinicopharmacokinetic study showed enhancement and consistency of amocarzine absorption after food. Quantitative assessment of the urinary excretion confirmed the presence of the N-oxide metabolite, which qualitatively was visible by a urine colorimetry. This assay proved useful for drug monitoring. Ultrasonography of onchocercal skin nodules detected changes within the nodules following amocarzine therapy. Histology after nodul-ectomy at four months post-therapy showed that 57% of the female worms were dead, 24% necrobiotic, and 19% alive; male worms were more necrobiotic. Skin microfilariae were reduced within one week to about 10% of the initial level and after one year they remained at about 20%. Skin punch biopsies on day 5 showed that most microfilariae were dead or moribund. Ocular reduction of microfilariae was also observed, although it was slower than in the skin. The visual acuity improved within the one year's observation time. Ocular and clinical tolerability was good, with one exception of neurological disturbance, which was fully reversible. Sequential testing of the liver function showed average values within the normal range. In conclusion, a repeat low dose regimen of amocarzine (3 mg/kg twice daily post-prandially for three consecutive days) was well absorbed with predictable plasma levels, macro- and microfilaricidal with good local and systemic tolerability in patients with moderate to heavy onchocerciasis. Amorcarzine is recommended for further clinical investigations, particularly in females and juveniles. Urine colorimetry and nodular ultrasonography are recommended for optional monitoring of amocarzine.

Administration, Oral↗
PubMed1991

Onchocercacidal effect of three drug regimens of amocarzine in 148 patients of two races and both sexes from Esmeraldas, Ecuador.

The objective of this multidisciplinary clinical investigation was to test whether amocarzine was absorbed effectively and safely in patients of two races and either sex infected with Onchocerca volvulus while living in the holoendemic area of Esmeraldas Province, Ecuador. The prerequisite for a systemic onchocercacidal effect is the regular absorption of orally administered amocarzine. Single dosing after overnight fasting proved to produce irregular absorption of amocarzine, although some microfilaricidal effect was achieved. A pilot study with repeated low dose and postprandial administration of amocarzine showed a regular and predictable absorption with acceptable tolerability and a microfilaricidal effect lasting up to one year post-therapy. Since amocarzine and its major N-oxide metabolite are coloured agents, urine colorimetry was used to assess the urinary excretion of the N-oxide qualitatively. For the postprandial drug regimens plasma concentrations of amocarzine and its metabolite were determined at two selected time points in patients of two races and either sex; the results showed no major differences. Excision of onchocercal nodules was performed four months post-therapy. The pooled results of the histologic analysis of 100 patients with the same drug regimen read under blinded condition showed that 65% of the adult female worms were dead, 20% necrobiotic and 15% alive. The male worms were fewer and mainly necrobiotic. Control worm populations in Esmeraldas without chemotherapy showed that on the average 81.5% were alive and 18.5% dead. Amocarzine was also microfilaricidal producing a reduction of skin dwelling microfilariae to about 10% of the initial value within the first week after start of therapy and lasting for half a year at a 20% level. The reduction of ocular microfilarial was slower and reached 35-40% after one year. The general tolerability was acceptable to good. Reversible dermal reactions were usually mild and peaked as a rash in 57% of the patients on day 6. No prohibitive ocular intolerance was observed. Mild and reversible dizziness peaked on day 4 in 74% of patients. A positive reversible Romberg sign was found in 12 patients on day 4. Amocarzine, the first oral micro- and macrofilaricidal agent administered as a low dose repeat regimen (3 mg/kg twice daily and postprandial for three consecutive days) can be recommended for oral onchocercacidal therapy in adult patients. Clinical trials in juveniles should be encouraged.

Absorption↗
PubMed1991

Microfilaricidal effect of amocarzine in skin punch biopsies of patients with onchocerciasis from Latin America.

Skin punch biopsies were performed in 54 selected patients with onchocerciasis participating in a clinical trial with amocarzine (CGP 6140) in Ecuador and Guatemala. Skin snipping for counting microfilariae of Onchocerca volvulus was done before treatment (day 0) and day 4 and 8 following start of the therapy which consisted of 3 mg/kg amocarzine postprandially twice daily for three consecutive days. The mean microfilarial skin density has been reduced by 45% on day 4 and 95% on day 8. Skin punch biopsies were taken on day 5, within 1 cm from the snip site on the iliac crest. Histopathologic examination revealed that the vast majority of the microfilariae in the upper as well as in the deeper dermis were degenerated or necrotic, surrounded often (57%) by minute foci of fibrinoid change of the collagen. There was usually slight, less frequently moderate eosinophilic, lympho-plasmocytic and initial histocytic inflammatory reaction in the vicinity. Microfilariae were frequently (69%) found at the dermal-epidermal junction and in the epidermis. Occasionally (7%) intra-epidermal microabscesses were noted. Microfilariae were detected also in the lumen of some dermal lymphatic vessels. Therefore it is concluded that amocarzine showed marked microfilaricidal effects in the skin of patients with onchocerciasis as evidenced histologically by mainly destroyed or moribund microfilariae which induced a mild to moderate inflammatory cell reaction.

Adult↗
PubMed1991

Longterm follow-up of onchocerciasis patients in Latin America after treatment and retreatment with amocarzine. Preliminary results.

Amocarzine has been reported to have onchocercacidal effects. Four months posttherapy the majority of adult worms were dead or moribund. The effect of skin microfilariae lasted up to one year as reflected by markedly reduced microfilaridermia. Since the duration of the onchocercacidal effect of amocarzine beyond one year was unknown and since such an effect may influence the planning of future control strategies, efforts were made to follow-up the already treated amocarzine patients for a second year. The present study from Latin America showed that various amocarzine drug regimens produced a prolonged reduction of microfilaridermia at the end of the second year following the initial therapy, the best levels were about 7-17% of the initial parasite load in the skin for some three days amocarzine regimens. Such an effect occurring in a transmission area of onchocerciasis in Latin America provides additional, although indirect, evidence of a macrofilaricidal effect of amocarzine. Similar experiences of a prolonged amocarzine effect on skin microfilariae has also been observed in West Africa (Ghana, Mali). Preliminary results of retreatment schedules at the start of the third year post-initial therapy showed that simplified postprandial dose regimen of one or two days were well tolerated. It is premature at the time of this report to judge upon their ultimate efficacy, but they had significantly reduced levels of moderate microfilaridermia.

Animals↗
PubMed1990

Prevention of acute graft rejection by the prostaglandin E1 analogue misoprostol in renal-transplant recipients treated with cyclosporine and prednisone.

Prostaglandins of the E series have been shown to have immunosuppressive properties. To study the effects of the prostaglandin E1 analogue misoprostol on renal function and graft rejection after transplantation, we conducted a randomized, double-blind, placebo-controlled trial in 77 renal-allograft recipients. The subjects received misoprostol (200 micrograms four times daily by mouth; n = 38) or placebo (n = 39) for the first 12 weeks after transplantation, in addition to standard immunosuppression with cyclosporine and prednisone. They were then observed for an additional four weeks after the drug or placebo was discontinued. Treatment with misoprostol was associated with a significant improvement in renal function as judged by the mean (+/- SEM) serum creatinine concentration (128 +/- 7 vs. 158 +/- 11 mumol per liter after 12 weeks; P = 0.03) and creatinine clearance (84 +/- 6 vs. 69 +/- 5 ml per minute per 1.73 m2 of body-surface area; P = 0.05). There was a significant reduction in the incidence of acute rejection in the group treated with misoprostol as compared with the placebo group (10 of 38 vs. 20 of 39; P = 0.02), and there was less need for rehospitalization after transplantation (4 +/- 1 days with misoprostol vs. 10 +/- 2 days for placebo; P = 0.03). Although blood levels of cyclosporine did not differ significantly between the groups, they tended to be higher in the misoprostol group, as did the incidence of acute nephrotoxicity due to cyclosporine (13 of 38 vs. 8 of 39). Infectious complications tended to be fewer in the misoprostol-treated group (14 of 38 vs. 21 of 39). We conclude that misoprostol improves renal function and safely reduces the incidence of acute rejection in renal-transplant recipients treated concurrently with cyclosporine and prednisone.

Adult↗
PubMed1990

Phosphorylation of GAP and GAP-associated proteins by transforming and mitogenic tyrosine kinases.

The critical pathways through which protein-tyrosine kinases induce cellular proliferation and malignant transformation are not well defined. As microinjection of antibodies against p21ras can block the biological effects of both normal and oncogenic tyrosine kinases, it is likely that they require functional p21ras to transmit their mitogenic signals. No biochemical link has been established, however, between tyrosine kinases and p21ras. We have identified a non-catalytic domain of cytoplasmic tyrosine kinases, SH2, that regulates the activity and specificity of the kinase domain. The presence of two adjacent SH2 domains in the p21ras GTPase-activating protein (GAP) indicates that GAP might interact directly with tyrosine kinases. Here we show that GAP, and two co-precipitating proteins of relative molecular masses 62,000 and 190,000 (p62 and p190) are phosphorylated on tyrosine in cells that have been transformed by cytoplasmic and receptor-like tyrosine kinases. The phosphorylation of these polypeptides correlates with transformation in cells expressing inducible forms of the v-src or v-fps encoded tyrosine kinases. Furthermore, GAP, p62 and p190 are also rapidly phosphorylated on tyrosine in fibroblasts stimulated with epidermal growth factor. Our results suggest a mechanism by which tyrosine kinases might modify p21ras function, and implicate GAP and its associated proteins as targets of both oncoproteins and normal growth factor receptors with tyrosine kinase activity. These data support the idea that SH2 sequences direct the interactions of cytoplasmic proteins involved in signal transduction.

Animals↗
PubMed1990

Coronary hemodynamic effects of atrial natriuretic peptide in humans.

Studies of the effects of atrial natriuretic peptide on the coronary circulation have yielded conflicting results in animals and have not been fully investigated in human subjects. To further characterize the direct coronary hemodynamic actions of atrial natriuretic peptide in humans and to assess the safety of its administration in patients with coronary artery disease, incremental doses of synthetic atrial natriuretic peptide and nitroglycerin were infused into the left coronary artery in 14 patients, 11 of whom had coronary artery disease. Both agents caused dose-related increases in total coronary sinus blood flow. The largest dose of atrial natriuretic peptide given to all patients (100 micrograms) increased mean coronary sinus blood flow from 127 +/- 7 to 149 +/- 9 ml/min (p less than 0.05) and decreased coronary vascular resistance from 0.93 +/- 0.07 to 0.81 +/- 0.05 mm Hg/ml per min (p less than 0.05); mean arterial blood pressure and heart rate were not affected by this dose of atrial natriuretic peptide. The greatest changes in coronary sinus blood flow (+25%) and coronary vascular resistance (-18%) after atrial natriuretic peptide administration occurred in the patients with coronary artery disease and no other associated cardiovascular disease. The maximal effects of atrial natriuretic peptide were similar to those of nitroglycerin, and no untoward effects were observed. Thus, atrial natriuretic peptide is a direct coronary vasodilator in humans. Its maximal dose effects are similar to those of nitroglycerin and were well tolerated in this small group of patients. The physiologic importance and therapeutic potential of atrial natriuretic peptide in patients with coronary artery disease merit further investigation.

Atrial Natriuretic Factor↗
PubMed1990

Prostaglandin deficiency.

Healthy cells from virtually all tissues synthesize a variety of prostaglandins, autacoids which can significantly alter cellular functions. An absolute or relative deficiency of prostaglandins has now been demonstrated in many diseases or clinical conditions. These include 'natural' disorders such as peptic ulcer disease and diabetes mellitus. These also include 'acquired' or iatrogenic conditions such as cyclosporine nephrotoxicity and the gastropathy induced by nonsteroidal anti-inflammatory drugs. We believe that the diversity of the disorders associated with prostaglandin deficiency may be wider and of greater pathogenetic importance than is currently recognized. We propose: 1) that prostaglandin deficiency will be demonstrated in many abnormalities which are now described as of uncertain etiology; and 2) that adverse effects from many commonly prescribed drugs may also be related to an unrecognized and unfavorable alteration in prostaglandin synthesis, disposal, or activity.

Humans↗
PubMed1990

The immunosuppressive properties of new oral prostaglandin E1 analogs.

Prostaglandins play an important role in cell-mediated immune responses. Their clinical use has been limited by poor oral bioavailability, short half-lives, and significant toxicity profiles. We studied the immunosuppressive properties of new, synthetic, prostaglandin E1 (PGE1) methyl ester analogs (misoprostol, enisoprost) with oral bioavailability using an allogeneic in vitro immunoassay. Our results show that the PGE1 analogs suppress alloproliferative responses and supplement the immunosuppressive activity of cyclosporine and methylprednisolone. Moreover, we demonstrate that addition of recombinant interleukin-2 to the PGE1 analogs restores alloimmune responsiveness and the expression of surface class II antigen and IL-2 receptors on responder lymphocytes. These studies, together with preliminary in vivo data in rodents and man, suggest that the new synthetic oral PGE1 analogs may provide therapeutic efficacy in clinical transplantation and a variety of immunologically mediated diseases.

Administration, Oral↗
PubMed1990

Immunosuppressive effect of misoprostol: a new synthetic prostaglandin E1 analogue.

Prostaglandins are reported to play an important regulatory role in cell-mediated immunity. The immunosuppressive properties of a new synthetic oral prostaglandin E1 analogue, misoprostol, were studied in vivo in a rat heterotopic cardiac allograft model, and in vitro in mixed lymphocyte reaction. The results show that parenteral misoprostol, alone or in combination with low dose cyclosporin immunosuppressive therapy, significantly prolonged cardiac allograft survival compared with appropriate controls. Oral misoprostol alone in this model did not allow for measurable cardiac allograft prolongation. In vitro misoprostol demonstrated significant dose-response inhibition of the mixed lymphocyte culture assay. It is concluded that new prostaglandin E1 analogues with oral bioavailability may have important applications to clinical transplantation in man, and may be cyclosporin sparing.

Administration, Oral↗
PubMed1990

Effects of oral prostaglandins on indomethacin-induced renal failure in patients with cirrhosis and ascites.

Nonsteroidal antiinflammatory drugs (NSAID), such as indomethacin, reduce production of renal prostaglandins and markedly impair renal function in patients with cirrhosis and ascites. To determine if simultaneous administration of oral prostaglandin analogs minimizes the renal impairment, 10 patients received indomethacin and either misoprostol or placebo in a double-blind, crossover study. Indomethacin reduced urinary sodium from 23 +/- 9 to 8 +/- 4 microEq/min in 4 hours. Misoprostol with indomethacin tended to prevent the fall in urinary sodium (from 35 +/- 15 to 46 +/- 21 microEq/min at 4 hours), but sodium excretion fell to the same level in both groups by 8 hours (6 +/- 3 microEq/min). Indomethacin reduced creatinine clearance in 4 hours by 49%; misoprostol plus indomethacin reduced creatinine clearance by only 34%. Misoprostol tended to minimize or delay the nephrotoxic effects of indomethacin, suggesting that more potent prostaglandin analogs may prevent the renal impairment induced by NSAID.

Administration, Oral↗