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J L Morris

Publications and source records attributed to J L Morris.

At least 73 records · Page 4Linked to original sources
PubMed1992

Evaluation of the antiviral activity of anthraquinones, anthrones and anthraquinone derivatives against human cytomegalovirus.

A number of anthraquinones, anthrones and anthraquinone derivatives were evaluated for antiviral activity against human cytomegalovirus (HCMV) as well as for cytotoxicity. Of those compounds evaluated, quinalizarin, emodin, rhein, hypericin, protohypericin, alizarin, emodin bianthrone and emodin anthrone showed antiviral activity against a normal laboratory HCMV strain, AD-169. When tested against a ganciclovir-resistant strain of HCMV, the EC50 values for quinalizarin, rhein and alizarin were superior to the values obtained for the AD-169 strain of HCMV. These results suggest that these compounds will be useful as prototypes for synthesizing a class of anti-HCMV drugs that are effective against ganciclovir-sensitive and -resistant strains of HCMV.

Anthracenes↗
PubMed1992

Treatment of murine cytomegalovirus infections in severe combined immunodeficient mice with ganciclovir, (S)-1-[3-hydroxy-2-(phosphonylmethoxy)propyl]cytosine, interferon, and bropirimine.

Severe combined immunodeficient (SCID) mice were found to be highly susceptible to murine cytomegalovirus (MCMV) infection. Treatment of infected mice with ganciclovir (12.5, 25, and 50 mg/kg of body weight for 10 days) starting 24 h after virus challenge resulted in delays in death by 2 to 8 days, and no animals survived the infection. (S)-1-[3-Hydroxy-2-(phosphonylmethoxy)propyl]cytosine (HPMPC) was much more potent, with doses of 1, 3.2, and 10 mg/kg/day (for 10 days) increasing the mean survival time by 15 to 30 days. Twenty-day treatments with HPMPC starting 5 days after virus inoculation increased the mean survival time by 24 to 32 days, with once-weekly (50-mg/kg) treatments being equivalent to daily (10-mg/kg) treatments. Delays in the development of liver, lung, and spleen virus titers in ganciclovir- and HPMPC-treated groups correlated with extensions in the mean survival times relative to the survival times of the placebo controls. The two compounds were approximately equally toxic to uninfected BALB/c mice treated for 10 days, causing 80 to 100% mortality after a dose of 150 mg/kg and 0% mortality after a dose of 75 mg/kg. Thus, the relative therapeutic index of HPMPC was 50-fold greater than that of ganciclovir. Recombinant alpha interferon delta 4 alpha 1/alpha 2 (1 x 10(4) and 5 x 10(4) units per mouse per day) and bropirimine (100 and 300 mg/kg/day) provided no protection from the lethal MCMV infection. The severe combined immunodeficient mouse MCMV infection is an important new model that will permit chemotherapy regimens to be studied over several months.

Animals↗
PubMed1992

Stimulation of N-methyl-D-aspartate receptor-mediated calcium entry into dissociated neurons by reduced and oxidized glutathione.

The effects of GSH (gamma-glutamylcysteinylglycine) and GSSG on intracellular calcium levels ([Ca2+]i) were investigated using fura-2-loaded dissociated brain cells from newborn rat pups. Both produced concentration-dependent increases in [Ca2+]i (EC50 values of 914.3 +/- 190.5 and 583.0 +/- 97.2 microM for GSH and GSSG, respectively), similar to that observed with N-methyl-D-aspartate (NMDA) and other agonists at the NMDA receptor. Maximum response (expressed as percentage change in [Ca2+]i relative to basal) was significantly greater for GSSG (37.5 +/- 1.6%) than for GSH (25.3 +/- 1.6%). The response to both agents was prevented or reversed by competitive (100 microM) (-)-2-amino-5- phosphonovalerate and noncompetitive (400 nM) MK-801 or 1.0 mM Mg2+ antagonists of NMDA receptor-mediated calcium entry, even at concentrations of GSH and GSSG normally producing maximal response. The idea that these effects are mediated, at least in part, by interaction with the NMDA receptor was supported by the effects of GSH and GSSG on the binding of the NMDA receptor ligand [3H]CGP-39653 to membranes isolated from hippocampal and cortical homogenates. Both GSH and GSSG displaced bound [3H]CGP-39653, with IC50 values of 0.93 +/- 0.18 and 11.02 +/- 1.22 microM, respectively, and produced an increase in the apparent Kd of binding (control, 8.92 +/- 0.83 nM, and GSH, 13.31 +/- 1.19 nM; control, 11.59 +/- 0.35 nM, and GSSG, 18.73 +/- 0.66 nM). However, both also produced modest reductions in Bmax (control, 1265 +/- 69 fmol/mg of protein, and GSH, 901 +/- 73 fmol/mg of protein; control, 1068 +/- 30 fmol/mg of protein, and GSSG, 730 +/- 18 fmol/mg of protein) and Hill slopes (GSH, 0.66 +/- 0.02; GSSG, 0.62 +/- 0.04). This suggests complex kinetics for the interaction of GSH and GSSG with the NMDA receptor. Taken together, the results suggest the potential for modulation of the NMDA receptor complex by GSH and GSSG.

2-Amino-5-phosphonovalerate↗
PubMed1992

Long-acting carbidopa-levodopa in the management of moderate and advanced Parkinson's disease.

Parkinson's disease patients treated chronically with levodopa often develop fluctuations in motor response. Motor fluctuations can be attributed in part to oscillating plasma levodopa concentrations. A controlled-release formulation containing 200 mg of levodopa and 50 mg of carbidopa provides superior plasma levodopa profiles compared with the standard preparation. A multicenter, double-blind trial involving 202 patients with fluctuating motor response found controlled-release carbidopa-levodopa to be safe and tolerable, with improved efficacy compared with the standard formulation. Long-term exposure to the controlled-release formulation, at least for a period of 3 years, does not appear to be associated with any increase in the incidence of adverse side effects.

Carbidopa↗
PubMed1991

Pertussis toxin attenuates postsynaptic actions of neuropeptide Y on the guinea-pig uterine artery.

The mechanisms by which neuropeptide Y (NPY) mediates its postsynaptic actions on the guinea-pig uterine artery, were investigated by incubating arterial segments in culture medium containing pertussis toxin (PTX). Arteries were incubated with 0, 0.25 or 1 microgram.ml-1 PTX for 24 or 48 h. Arterial segments incubated in culture medium without PTX showed the three postsynaptic responses to NPY which were reported previously in uncultured arteries: NPY further contracted segments which were precontracted with prostaglandin F2 alpha; NPY reduced the maximum relaxations produced by vasoactive intestinal peptide (VIP); and NPY produced a rightward shift in the VIP concentration-response curves. PTX attenuated the three actions of NPY on the uterine artery to different degrees. PTX also reduced the magnitude of contractions produced by prostaglandin F2 alpha, but did not affect contractions produced by 0.126 M KCl, or relaxations produced by VIP in the absence of NPY. These data indicate that all postsynaptic actions of NPY on the uterine artery, and contractions produced by prostaglandin F2 alpha, are at least partly mediated by pertussis toxin-sensitive GTP-binding proteins. It is not clear whether these multiple actions of NPY are mediated by one, or more than one, GTP-binding protein.

Animals↗
PubMed1991

Roles of neuropeptide Y and noradrenaline in sympathetic neurotransmission to the thoracic vena cava and aorta of guinea-pigs.

The roles of neuropeptide Y (NPY) and noradrenaline (NA) in sympathetic neurotransmission to large arteries and veins were studied in vitro using the thoracic portions of the aorta and inferior vena cava from guinea-pigs. Both vessels are densely innervated by axons containing NA and NPY. Repetitive transmural stimulation at 2-30 Hz produced contractions of the aorta, which were abolished by prazosin. NPY did not have significant postsynaptic or presynaptic effects on vascular tone of the aorta. Transmural stimulation of the vena cava produced long-lasting contractions which were enhanced by alpha- and beta-adrenoceptor antagonists, and were blocked by guanethidine. Precontracted venae cavae responded to sympathetic stimulation with beta-adrenoceptor-mediated relaxation, followed by contraction. alpha-Adrenoceptor blockade delayed the onset of neurogenic contractions. NPY was a potent contractile agent of the vena cava (EC50 approximately 1.5 x 10(-8) M). A high concentration (3 x 10(-6) M) of NPY, or the specific NPY Y1 receptor agonist, [Leu31, Pro34]NPY, caused parallel, and reversible, desensitization of contractions produced by sympathetic nerve stimulation, and by low concentrations of exogenous NPY. This provides good evidence that NPY is the mediator of the non-adrenergic sympathetic contractions of the vena cava. Furthermore, these results demonstrate that differential location or coupling of postsynaptic receptors for NA and NPY in the aorta and vena cava, leads to differential participation by these substances in sympathetic vasomotor responses. This is likely to be related to the different functions of these two parts of the systemic circulation.

Adrenergic alpha-Antagonists↗
PubMed1991

Long-term evaluation of Sinemet CR in parkinsonian patients with motor fluctuations.

The safety and efficacy of Sinemet CR, a controlled-release formulation of carbidopa/levodopa, were investigated in a three year, open-label trial involving 18 parkinsonian patients with fluctuating motor response. The average daily levodopa dosing frequency did not change significantly during long-term treatment. Efficacy measures generally revealed a gradual progression of parkinsonian disability. Patient diaries of motor fluctuations revealed relative stability of time "on" but with a tendency toward increased time "on with dyskinesias" over the 36 month follow-up period. There were no adverse laboratory results deemed to be related to Sinemet CR and no unexpected side effects were observed.

Aged↗
PubMed1991

Spatial contrast sensitivity is reduced in bilateral Parkinson's disease.

We studied the contrast sensitivity functions of 41 patients with idiopathic Parkinson's disease (PD) with a wide range of parkinsonian symptomatology (Hoehn and Yahr stages 1 to 4) and 22 age-matched control subjects in a parametric design. Results demonstrated reduced contrast sensitivity in PD patients but only in those patients who had progressed beyond Hoehn and Yahr stage 1. Furthermore, there were deficits in contrast sensitivity related to the severity of PD.

Aged↗
PubMed1990

Sympathetic noradrenergic neurons containing dynorphin but not neuropeptide Y innervate small cutaneous blood vessels of guinea-pigs.

We have used double-labelling immunofluorescence techniques and retrograde axonal transport of Fast Blue to characterize three populations of sympathetic noradrenergic neurons innervating blood vessels in the hairless skin of the ears and paws of guinea-pigs. Each population of neurons innervated a specific level of the vascular bed, and had a distinctive content of neuropeptides. Sympathetic noradrenergic neurons innervating large distributing arteries contained immunoreactivity to neuropeptide Y. Neurons innervating smaller cutaneous arteries contained immunoreactivity to prodynorphin-derived peptides in addition to neuropeptide Y. Finally, sympathetic neurons innervating the smallest arterioles, and arterio-venous anastomoses, contained immunoreactivity to prodynorphin-derived peptides, but had no detectable neuropeptide Y. Although the major form of dynorphin immunoreactivity in perivascular sympathetic axons was dynorphin A(1-8), immunoreactivity to both dynorphin A(1-8) and dynorphin A(1-17) occurred in the cell bodies of these neurons, suggesting that dynorphin A is processed during axonal transport to the terminals. The perivascular sympathetic neurons containing prodynorphin-derived peptides but not neuropeptide Y are most likely to be involved in the regulation of thermoregulatory cutaneous vascular circuits.

Adrenergic Fibers↗
PubMed1989

Multicentric reticulohistiocytosis: response to alkylating agents in six patients.

STUDY OBJECTIVE: To determine the efficacy of alkylating agents in multicentric reticulohistiocytosis. DESIGN: Open consecutive case series. SETTING: Tertiary-care referral clinic. PATIENTS: Six patients with skin-biopsy-proven multicentric reticulohistiocytosis. All had skin nodules and polyarthritis. INTERVENTION: Five patients received cyclophosphamide (dose range, 1.25 to 2.2 mg/kg body weight) and one patient received chlorambucil (0.1 mg/kg). Therapy was administered from 6 to 24 months. MEASUREMENTS AND MAIN RESULTS: In five patients treated with cyclophosphamide a response was seen within 4 months. Four patients eventually had a complete remission and one had almost a complete remission. The four patients in complete remission had cyclophosphamide therapy discontinued after 6, 12, 16, and 18 months. Three of the four patients remained in complete remission off therapy at 6, 6, and 22 months, whereas one had a recurrence after 6 months. The one patient given chlorambucil went into a complete remission and stopped treatment after 12 months. He remained in complete remission 32 months after stopping medication. CONCLUSION: Our experience with patients with aggressive multicentric reticulohistiocytosis shows that alkylation therapy is warranted. We conclude that a response to an alkylating agent may be expected. Whether after treatment for 6 to 18 months most patients may be able to discontinue the drug and remain in remission has yet to be shown. The rarity of multicentric reticulohistiocytosis precludes the possibility of a double-blind study.

Adult↗
PubMed1989

Galanin-like immunoreactivity in sympathetic and parasympathetic neurons of the toad Bufo marinus.

Immunoreactivity (IR) to galanin (GAL) was detected in a wide range of peripheral autonomic neurons in the toad Bufo marinus. Forty percent of adrenergic nerve cell bodies in paravertebral sympathetic ganglia had GAL-IR in addition to neuropeptide Y (NPY)-IR. Some of these neurons projected to systemic arteries. GAL-IR was localized in parasympathetic neurons supplying the heart, lung, pulmonary artery, bladder, rectum and tongue. Eighty-two percent of intracardiac vagal nerve cell bodies had both GAL-IR and somatostatin (SOM)-IR. GAL-IR and SOM-IR were also co-localized in cholinergic post-ganglionic vagal neurons supplying the lung musculature and the pulmonary artery, and in neurons intrinsic to the bladder. Many postganglionic glossopharyngeal neurons in the tongue contained both GAL-IR and vasoactive intestinal peptide (VIP)-IR. Therefore, in Bufo marinus, a GAL-like peptide, in combination with other peptides or with adrenaline or acetylcholine, may be involved in neurotransmission in several different functional classes of autonomic neurons.

Adrenergic Fibers↗
PubMed1989

Aging does not alter cytosolic calcium levels of cortical synaptosomes in Fischer 344 rats.

Several lines of experimental evidence support an association between altered Ca2+ regulation and aging. It has been supposed that free cytosolic Ca2+ concentrations ([Ca2+]i) may decrease or increase in aged animals. In this study, both resting and KCl-stimulated [Ca2+]i were measured in purified cortical synaptosomes from young (3 mo.), middle-aged (12 mo.), and old (24 mo.) Fischer 344 rats. Two additional groups of rats were included, one middle-aged and one old which were trained on a treadmill for 6 months prior to experimentation. The [Ca2+]i was determined using the fluorescent Ca2+ chelator fura-2. Net KCl-dependent changes (delta K) in [Ca2+]i were determined by the difference between stimulatory (100 microM Ca2+/60 mM KCl) and resting (100 microM Ca2+/5 mM KCl buffer) conditions among the 3 age groups. Significant increases in [Ca2+]i were observed in each age group upon depolarization with 60 mM KCl. However, there were no significant age-dependent differences in either resting [Ca2+]i or KCl-stimulated [Ca2+]i.

Aging↗
PubMed1989

Analogues of vasoactive intestinal peptide (VIP) contract the guinea-pig uterine artery but do not antagonize VIP-induced relaxations.

Guinea-pig vasoactive intestinal peptide (gpVIP-(1-28] in the concentration range 3 x 10(-9)-3 x 10(-7) mol.1-1 relaxed precontracted segments of the guinea-pig uterine artery. Porcine VIP-(10-28) (pVIP-(10-28], [4-Cl-D-Phe6,Leu17]VIP, or [N-Ac-Tyr1, D-Phe2]GRF-(1-29)-NH2 did not antagonize VIP-induced relaxations of the artery, but high concentrations of the two VIP analogues produced large, transient contractions of the artery. In some preparations 10(-5) mol.1-1 gpVIP-(1-28) also caused transient arterial contractions. These data indicate the presence of two distinct receptors for VIP on the guinea-pig uterine artery, mediating opposite effects on vascular tone.

Animals↗
PubMed1989

Noradrenergic and peptidergic innervation of the extrinsic vessels and microcirculation of the rat cremaster muscle.

The noradrenergic and peptidergic innervation of the extrinsic vessels and microcirculation of the rat cremaster muscle was examined. Catecholamine-containing nerves were identified histochemically by glyoxylic acid-induced fluorescence and tyrosine hydroxylase immunoreactivity (TH-IR). The extrinsic pudic-epigastric artery and vein as well as the entire intramuscular arteriolar network was innervated by noradrenergic axons. The capillaries and intramuscular venules of the cremaster muscle were devoid of a noradrenergic innervation. Immunohistochemical double-labeling demonstrated that most, if not all, of the TH-IR axons also possessed neuropeptide Y immunoreactivity (NPY-IR), implying colocalization of the norepinephrine and NPY in the perivascular nerves. No vasoactive intestinal peptide immunoreactivity (VIP-IR) was found, except for occasional VIP-IR axons associated with the pudic-epigastric artery. Substance P immunoreactive (SP-IR) axons formed a sparse plexus around the arteries and larger arterioles. Calcitonin gene-related peptide immunoreactivity (CGRP-IR) had a similar distribution to the SP-IR axons. CGRP-IR was also observed in axons alongside some smaller arterioles and capillaries. The extrinsic vessels and intramuscular arteriolar network of the rat cremaster muscle are innervated by noradrenergic axons which contain NPY and by presumed sensory nerves containing SP and/or CGRP. Both types of nerves may contribute to regulation of microvascular function.

Adrenergic Fibers↗
PubMed1989

Co-localization and plasticity of transmitters in peripheral autonomic and sensory neurons.

Immunohistochemical studies have shown that most peripheral autonomic and sensory ganglia are heterogeneous, consisting of several populations of neurons which can be distinguished by their content of peptide and non-peptide transmitters, and transmitter-associated enzymes. Many neurons contain several different potential transmitters, especially neuropeptides. Some neuropeptides have been localized in more than one population of autonomic and sensory neurons. However, the peptide often occurs together with a distinctive combination of additional transmitters in each neuronal class. The precise combination of transmitters found in any individual neuron is highly correlated with the peripheral target of the neuron. This indicates that immunohistochemically defined neuronal populations represent distinct functional classes of neurons. In an increasing number of cases, many of the potential transmitters contained in a particular neuron have been shown to be released from the nerve terminals, and to contribute to presynaptic or postsynaptic effects of nerve activation. Despite this association between the combination of potential transmitters contained in a neuron, and the function of the neuron, not all transmitters or transmitter-associated enzymes are expressed equally at all times in the life of a neuron: the levels of some substances change dramatically during development; some are detected only after experimental alteration of the environment of the developing or mature neurons. Taken together, these results indicate that, during development, pathway-specific information influences the differentiation of peripheral autonomic and sensory neurons. Furthermore, the expression of neuropeptides and transmitter-associated enzymes in a particular neuron appears to be under continuous regulation. These phenomena demonstrate the complexity and precision involved in development and maintenance of the peripheral autonomic and sensory nervous systems.

Animals↗
PubMed1989

Multicenter controlled study of Sinemet CR vs Sinemet (25/100) in advanced Parkinson's disease.

Controlled-release carbidopa/levodopa 50/200 (Sinemet CR) and standard carbidopa/levodopa (Sinemet 25/100) were compared in a multicenter double-blind trial involving 202 patients with advanced Parkinson's disease and motor response fluctuations. Treatment with Sinemet CR significantly reduced daily "off" time. According to both physician and patient global ratings, patients showed significant improvements with Sinemet CR compared to treatment with standard Sinemet. Patients preferred Sinemet CR treatment by a ratio of approximately 2 to 1. Daily dosing frequency was 33% less with Sinemet CR, while daily intake of levodopa required was increased by 25%. The safety profiles of the 2 formulations were similar. We conclude that Sinemet CR is superior to standard Sinemet for many patients with advanced Parkinson's disease, although it does not solve the problem of fluctuating motor performance.

Aged↗