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R J Nash

Publications and source records attributed to R J Nash.

At least 37 records · Page 2Linked to original sources
PubMed1997

Specific alpha-galactosidase inhibitors, N-methylcalystegines--structure/activity relationships of calystegines from Lycium chinense.

An examination of the roots of Lycium chinense (Solanaceae) has resulted in the discovery of 14 calystegines, a cycloheptane bearing an amino group and three hydroxyl groups, and two polyhydroxylated piperidine alkaloids. Calystegines A7 and B5, in addition to the previously known calystegines A3, A5, A6, B1, B2, B3, B4, C1, C2 and N1, were isolated and determined as 1alpha,2beta,4alpha-trihydroxy-nortropane and 1alpha,2alpha,4alpha,7alpha-tetrahydroxy-nort ropane, respectively. L. chinense also had two polyhydroxytropanes bearing a methyl group on the nitrogen atom, unlike the previously reported nortropane alkaloids. They were established as N-methylcalystegines B2 and C1, and their N-methyl groups were found to be axially oriented from NOE experiments. 1Beta-amino-3beta,4beta,5alpha-trihydroxycyclohepta ne was also present in L. chinense and may be a biosynthetic precursor of the calystegines that occur in this plant. Two polyhydroxypiperidine alkaloids, fagomine and 6-deoxyfagomine, were isolated. Calystegine B2 is a potent competitive inhibitor of almond beta-glucosidase (Ki = 1.9 microM) and coffee bean alpha-galactosidase (Ki = 0.86 microM), while N-methylcalystegine B2 was a more potent competitive inhibitor of the latter enzyme (Ki = 0.47 microM) than the parent compound but showed a marked lack of inhibitory activities towards most other glycosidases. Since this compound is a very specific inhibitor of alpha-galactosidase and inhibits rat liver lysosomal alpha-galactosidase with a Ki of 1.8 microM, it may provide a useful experimental model for the lysosomal storage disorder, Fabry's disease. The addition of a hydroxyl group at C6exo, as in calystegines B1 and C1, enhances the inhibitory potential towards beta-glucosidase and beta-galactosidase but markedly lowers or abolishes inhibition towards alpha-galactosidase. Hence, the N-methylation of calystegine C1 did not enhance its inhibition of alpha-galactosidase. The chemical N-methylation of calystegines A3 and B4 markedly enhanced inhibition of coffee bean alpha-galactosidase, with Ki values of 5.2 microM and 36 microM, respectively, but almost eliminated their inhibitory potential towards beta-glucosidase and trehalase, respectively. Thus, methylation of the nitrogen atom significantly altered the specificity of the inhibitors.

Animals↗
PubMed1997

Stability of a perturbed Leslie model.

A small perturbation introduced in the stochastic Leslie model leads to a long-lived stable population in a region or parameter space where the stochastic model predicts the demise of the population. This somewhat surprising result is understood by considering a related model with a density-dependent sex ratio which exhibits similar features.

Birth Rate↗
PubMed1997

Homonojirimycin and N-methyl-homonojirimycin inhibit N-linked oligosaccharide processing.

Homonojirimycin (HNJ) and N-methylhomonojirimycin (MHNJ) were tested as inhibitors of the purified glycoprotein processing enzymes, glucosidase I and glucosidase II. MHNJ was a reasonably good inhibitor of glucosidase I (Ki = 1 x 10(-6) M) and was about three times as effective on this enzyme as was HNJ. On the other hand, HNJ inhibited glucosidase II with a Ki of about 1 x 10(-6) M, whereas MHNJ was three times less effective (Ki = 3 x 10(-5) M). However, the butyl derivative of HNJ had very low activity toward these two processing glucosidases. HNJ and its methyl derivative were also tested in vivo using influenza virus-infected MDCK cells, and measuring the inhibition of N-linked oligosaccharide processing of the viral envelope glycoproteins. With 100 micrograms/ml of MHNJ in the medium, essentially all of the N-linked oligosaccharide chains of the virus were of the "high-mannose" type with the major structure being characterized as Glc3Man9(GlcNAc)2. Similar results were obtained with HNJ although this compound was less effective in vivo as well as in vitro. These results are in keeping with these inhibitors being effective at the glucosidase I step. Both inhibitors were also tested in MDCK cell cultures to determine whether they affected the in vivo synthesis of proteins, or of lipid-linked saccharides. In contrast to deoxynojirimycin, which has been reported to inhibit the formation of lipid-linked saccharides, no effects were seen on either the incorporation of mannose into lipid-linked saccharides or the incorporation of leucine into protein.

1-Deoxynojirimycin↗
PubMed1997

The effects of calystegines isolated from edible fruits and vegetables on mammalian liver glycosidases.

The polyhydroxylated nortropane alkaloids called calystegines occur in many plants of the Convolvulaceae, Solanaceae, and Moraceae families. Certain of these alkaloids exhibit potent inhibitory activities against glycosidases and the recently demonstrated occurrence of calystegines in the leaves, skins, and sprouts of potatoes (Solanum tuberosum), and in the leaves of the eggplant (S. melongena), has raised concerns regarding the safety of these vegetables in the human diet. We have surveyed the occurrence of calystegines in edible fruits and vegetables of the families Convolvulaceae, Solanaceae, and Moraceae by GC-MS. Calystegines A3, B1, B2, and C1 were detected in all the edible fruits and vegetables tested; sweet and chili peppers, potatoes, eggplants, tomatoes, Physalis fruits, sweet potatoes, and mulberries. Calystegines B1 and C1 were potent competitive inhibitors of the bovine, human, and rat beta-glucosidase activities, with Ki values of 150, 10, and 1.9 microM, respectively for B1 and 15, 1.5, and 1 microM, respectively, for C1. Calystegine B2 was a strong competitive inhibitor of the alpha-galactosidase activity in all the livers. Human beta-xylosidase was inhibited by all four nortropanes, with calystegine C1 having a Ki of 0.13 microM. Calystegines A3 and B2 selectively inhibited the rat liver beta-glucosidase activity. The potent inhibition of mammalian beta-glucosidase and alpha-galactosidase activities in vitro raises the possibility of toxicity in humans consuming large amounts of plants that contain these compounds.

Animals↗
PubMed1996

Calystegine B4, a novel trehalase inhibitor from Scopolia japonica.

GLC-MS analysis has been developed for screening plants of the family Solanaceae for new calystegines. GLC-MS analyses of the extract of Scopolia japonica showed the presence of a new tetrahydroxy-nor-tropane alkaloid in addition to the known calystegines A3, A5, B1, B2, B3, and C1. We gave this new alkaloid the trivial name calystegine B4. The structure of calystegine B4 was determined as 1 alpha, 2 beta, 3 alpha, 4 alpha-tetrahydroxy-nor-tropane from a variety of NMR spectral data. Calystegines B1, B2, and C1 are potent competitive inhibitors with Ki values ranging from 10(-6) to 10(-7) M for almond beta-glucosidase, while calystegine B4 inhibited this enzyme in a competitive manner, with a Ki value of 7.3 microM. Calystegine B2 is also a potent inhibitor of green coffee bean alpha-galactosidase, whereas calystegine B4 exhibited no significant activity for this enzyme. Among rat intestinal glycosidases, only trehalase was potently inhibited by calystegine B4, with an IC50 value of 9.8 microM. Furthermore, calystegine B4 potently inhibited pig kidney trehalase in a competitive manner, with a Ki value of 1.2 microM, but it was almost inactive against yeast and fungal trehalases.

Alkaloids↗
PubMed1995

Antiviral activity and metabolism of the castanospermine derivative MDL 28,574, in cells infected with herpes simplex virus type 2.

The 6-O-butanoyl derivative of castanospermine (MDL 28,574: BUCAST), an inhibitor of glycoprotein processing, blocked the growth of herpes simplex virus type-2 with the effect markedly enhanced by exposure of cells to the compound pre- as well as post-infection. The effectiveness of the derivative corresponded to an increased uptake with greatest accumulation after virus infection. Gas chromatography/mass spectrometry identified the predominant component in MDL 28,574 treated cells as castanospermine, an inhibitor of alpha-glucosidase 1. The effects of this compound on the synthesis of viral glycoprotein, gB, was determined with the increased molecular weight of the mannose-rich precursor evidence for the modulation of glycoprotein processing.

Animals↗
PubMed1995

The effect of oral treatment with 6-O-butanoyl castanospermine (MDL 28,574) in the murine zosteriform model of HSV-1 infection.

Oral treatment of mice, cutaneously infected with herpes simplex virus type 1 (HSV-1) (strain SC16), with the alpha-glucosidase 1 inhibitor 6-O-butanoyl castanospermine (MDL 28,574) produced a significant delay in lesion development and reduced the amount of virus recovered from the brain. Virus load in the brains of mice, whose treatment started 2 days prior to infection, was reduced approximately 100-fold when compared to untreated controls. Treatment initiated at the time of infection, while less effective than pre-treatment, nevertheless reduced virus recovery from the brain by 10-fold. Consistent with its antiviral activity, orally administered MDL 28,574 was rapidly incorporated by brain tissue and mice fed with compound over extended periods maintained relatively high levels of drug at this site.

Acyclovir↗
PubMed1992

Phenylethylamine and piperidine alkaloids in aloe species.

Of the approximately 300 species of ALOE (Liliaceae) native to Africa and Arabia, leaf extracts of 224 species have been examined chromatographically for alkaloids using ninhydrin, Dragendorff's reagent, nitroprusside, and iodoplatinate as revealing agents. From these, 48 (21%) species contained compounds giving a strong colorimetric reaction with at least one of these reagents. Tyramine derivatives were identified in 18 species and piperidine derivatives in a further 6 species. The other coloured zones remain unidentified but often appeared to represent common amino acids. Some taxonomic correlations are suggested. The presence of the toxic hemlock alkaloids in aloes readily available for potential medicinal use by local inhabitants sounds a note of caution against the unthinking use of these otherwise useful plants.

Journal Article↗
PubMed1992

Implications of the study population in the early evaluation of anticholinesterase inhibitors for Alzheimer's disease.

OBJECTIVE: Velnacrine testing for tolerance and safety in both normal elderly subjects and patients with Alzheimer's disease (AD) is reviewed to illustrate the importance of Phase I trials in the target group as more predictive of safety and tolerance for subsequent multicenter trials than those conducted in healthy elderly subjects. DESIGN: Both a single-dose and a randomized, double-blind, placebo-controlled, ascending, multiple-dose study were performed with healthy, elderly men. In the multiple-dose study, the subjects were randomized to four groups of 14, with 10 subjects receiving velnacrine and 4 receiving placebo. The doses were velnacrine 25 (group 1), 50 (group 2), and 100 mg (group 3), respectively, administered twice daily; group 4 received 100 mg three times daily for 28 days. Blood and urine were collected serially for the pharmacokinetic assessment. With AD patients, 24 subjects were randomly assigned to receive either placebo or velnacrine for 10 days in a double-blind, sequential escalation study in a hospital setting. There were three groups of 8 subjects. Six patients in each group received velnacrine and 2 placebo. The three groups received respective dosages of 450, 300, and 225 mg/d three times daily. Adverse events were closely monitored and recorded. PATIENTS/PARTICIPANTS: The multiple-dose test in healthy elderly men included 56 men, aged 60-74 years. Rigorous screening for any potential complications that could affect absorption, distribution, metabolism, or excretion preceded patient entry in the AD patient study. Patients with a history of major psychiatric, neurologic, and cardiovascular disorders were excluded. The patients ranged in age from 56 to 89 years, and were equally distributed between gender. INTERVENTION: Velnacrine was administered in various doses. MAIN OUTCOME MEASURES: We emphasize the extreme adverse effects encountered in the AD patient group compared with the healthy group. Plasma concentrations of velnacrine over time in both groups are given, as well as the drug's half-life and excretion rates. RESULTS: The tolerable dosage predicted by studies performed in healthy elderly subjects was 300 mg/d. This dosage was not tolerable among the AD patients. A dosage as high as 450 mg/d resulted in a tonic seizure in one patient. The predicted dosage of 300 mg/d produced an adverse effect profile in AD patients that included dizziness, nausea and/or vomiting, headaches, and severe diarrhea. AD patients tolerated a dosage of 225 mg/d. CONCLUSIONS: A velnacrine dosage of 300 mg/d that was tolerated in healthy elderly subjects was not tolerated by AD patients.

Aged↗
PubMed1991

Evaluation of HP 029 (velnacrine maleate) in Alzheimer's disease.

HP 029 (1,2,3,4-tetrahydro-9-aminoacridin-1-ol-maleate) is a cholinesterase inhibitor and one of a series of compounds synthesized at Hoechst-Roussel Pharmaceuticals Inc. (HRPI) as a potential therapeutic agent for senile dementia of the Alzheimer type (SDAT). An ongoing clinical development program for HP 029 (velnacrine maleate) reflects a rational, traditional progression from therapeutic concept through clinical evaluation. Prior to the initiation of outpatient studies, sufficient data had been obtained from normal volunteers and hospitalized patients to support the following conclusions: the pharmacokinetic profile of HP 029 in young and elderly normal men is predictable; tolerance and safety data for HP 029 using normal volunteers poorly correlates with experience in patients with SDAT; patients with SDAT exhibit marked intersubject variability in tolerance within a suspected therapeutic dose range; mandatory endpoints for drug discontinuation for outpatients can be reliably established in an inpatient environment. Subsequently, Protocol 201 was initiated as a multicenter, multistage investigation of HP 029 in patients with probable SDAT (NINCDS-ADRDA criteria). A dose-ranging component determined patient eligibility for a subsequent dose-replication phase based upon explicit safety and efficacy criteria defined within protocol. One a priori specified interim analysis was conducted by the sponsor (HRPI) for administrative purposes after completing approximately 50% of the planned sample (September 1989). Results suggested that (1) beneficial effects of HP 029 existed on key and secondary measures for the approximately 30% of enrolled patients; (2) interim results would provide an accurate reflection of the results at the conclusion of the study (1991); (3) HP 029-induced hepatocellular injury appeared to be a reversible, predominantly dose-related event; and (4) cholinergically mediated adverse events are infrequent and clinically inconsequential at dosages less than or equal to 225 mg/day. Post hoc hypotheses based on the interim dataset suggest that: (1) carry-over effects of HP 029 exist within a dose-ranging/dose-replication paradigm that militate against the utility of an "enriched population" design; (2) beneficial effects are more robust on initial exposure to HP 029 with effects discerned on both memory and arousal; (3) patient characteristics associated with toxicity or response are not identified; (4) dosage reduction in subsequent efficacy trials may reduce hepatocellular injury and yield clinically unimportant differences in overall efficacy results.

Aged↗
PubMed1990

Synthesis of the enantiomers of 6-epicastanospermine and 1,6-diepicastanospermine from D- and L-gulonolactone.

The synthesis of the enantiomers of 6-epicastanospermine and of 1,6-diepicastanospermine from the enantiomeric gulonolactones is reported and the structure of the former is established as (1S,6R,7R,8R,8aR)-1,6,7,8-tetrahydroxyoctahydroindolizine. The inhibitory activities of the diastereomers against the amyloglucosidase-catalysed hydrolysis of p-nitrophenyl alpha-D-glucopyranoside were investigated, and the effects of 6-epicastanospermine and of 1,6-diepicastanospermine on 14 human liver glycosidases are reported.

Glycoside Hydrolases↗
PubMed1990

The structural basis of the inhibition of human glycosidases by castanospermine analogues.

A series of epimers and deoxy derivatives of castanospermine has been synthesized to investigate the contribution of the different chiral centres to the specificity and potency of inhibition of human liver glycosidases. Castanospermine inhibits all forms of alpha- and beta-D-glucosidases, but alteration to any of the five chiral centres in castanospermine markedly decreases the inhibition. 6-Epicastanospermine, which is related to D-pyranomannose in the same way as castanospermine is to D-pyranoglucose, does not inhibit lysosomal (acidic) alpha-mannosidase, but is a good inhibitor of the cytosolic or neutral alpha-mannosidase. Conversely, 1-deoxy-6-epicastanospermine inhibits acidic alpha-mannosidase strongly, but not the neutral alpha-mannosidase. An explanation of this different inhibition based on preferential recognition of different configurations of mannose by the different forms of alpha-mannosidase is postulated. All derivatives of 6-epicastanospermine also have the minimum structural feature for the inhibition of alpha-L-fucosidase, but those with a beta-anomeric substituent do not inhibit the enzyme, or do so very weakly. 1-Deoxy-6,8a-diepicastanospermine, which has four chiral centres identical with alpha-L-fucose, is, however, a potent inhibitor of alpha-L-fucosidase (Ki 1.3 microM).

Alkaloids↗
PubMed1990

Clinical safety, tolerance, and plasma levels of the oral anticholinesterase 1,2,3,4-tetrahydro-9-aminoacridin-1-oL-maleate (HP 029) in Alzheimer's disease: preliminary findings.

HP 029 (1,2,3,4-tetrahydro-9-aminoacridin-1-oL-maleate), an oral anticholinesterase, enhances memory in rodents and may be useful in treating Alzheimer's disease (AD). To assess adverse events in relation to dosage and plasma drug levels, 24 hospitalized AD subjects were randomly assigned to receive placebo or HP 029 for 10 days in a double-blind, sequential escalation study. Maximum daily dosages were 450 mg (group 1), 300 mg (group 2), and 225 mg (group 3), divided into three doses per day. The group 1 trial was discontinued on day 5 because one subject, 6 hours following the second of three scheduled 150-mg doses, had a tonic seizure after protracted vomiting and hyperventilation; adverse events in other patients included nausea, vomiting, abdominal cramps, diarrhea, dizziness, and syncope. Adverse events were generally less severe in group 2, but only two of six HP 029 subjects could complete the trial at 300 mg/day. All group 3 subjects completed the trial at 225 mg/day with drug related, mild adverse events (nausea, vomiting, lacrimation, rhinorrhea) in only two subjects. Although mean plasma drug levels were related to adverse events across dosage groups, they did not adequately predict the occurrence or severity of adverse events in individual subjects. The 225 mg/day dose appears to be safe for use in multicenter outpatient trials of HP 029 efficacy in AD. Further patient studies are ongoing to determine the relation of specific subject characteristics to the metabolic profile of HP 029 and biological response.

Administration, Oral↗
PubMed1990

Sugar-shaped alkaloids.

A range of simple, natural chemicals almost unknown 20 years ago are now being used to advance research in cancer, AIDS, diabetes, immunology and plant-insect recognition. These alkaloids of the pyrrolidine, piperidine, pyrrolizidine and indolizidine classes resemble sugar molecules in the arrangement of hydroxyl substituents and are often potent and specific glycosidase inhibitors.

Alkaloids↗
PubMed1988

Loss of cytomegalovirus infectivity after treatment with castanospermine or related plant alkaloids correlates with aberrant glycoprotein synthesis.

Many plants contain polyhydroxyalkaloids which are potent inhibitors of glucosidases, enzymes involved in oligosaccharide trimming. These are important in determining the final configuration of specific glycoproteins. Human cytomegalovirus (CMV) encodes a number of glycoproteins, some of which ultimately reside in the outer envelope of the mature virion and are important for virus infectivity. Treatment with three polyhydroxyalkaloids, castanospermine (CAST), deoxynojirimycin (DNJ) and 2R,5R-dihydroxymethyl-3R,4R-dihydroxypyrrolidine (DMDP) blocked the growth of infectious virus, as determined by yield reduction and plaque reduction assays. However, in the presence of CAST, CMV infected cells continued to shed virions into the extracellular medium, as determined by electron microscopy. Envelope glycoproteins of virions produced after treatment with CAST (2.5 mM) were immunoprecipitated with a monoclonal antibody (F5) specific for the gcI family of glycoproteins. Analysis by PAGE-SDS showed an absence of gcI complex 2 (gp52 disulphide-linked to gp130) with a proportional increase in gcI complex 1 (gp52 disulphide-linked to gp95). The results indicated that gp130 alone, or linked to gp52, was important for CMV infectivity. As well as being potential targets for antiviral agents against CMV, inhibitors of glycoprotein trimming reactions may define components of the virion surface important for infectivity.

Alkaloids↗
PubMed1986

Inhibition of mammalian digestive disaccharidases by polyhydroxy alkaloids.

Several polyhydroxy alkaloids, including the eight presently known to occur in plants, have been compared as inhibitors of mouse gut digestive disaccharidases. The indolizidine castanospermine inhibited all activities tested, but others showed a selectivity which could be of value in studies of carbohydrate digestion and errors of metabolism.

Alkaloids↗