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Biomedical subjects

D L Tyrrell

Publications and source records attributed to D L Tyrrell.

At least 55 records · Page 3Linked to original sources
PubMed1989

Synthesis of 5-[1-hydroxy(or methoxy)-2-bromo(or chloro)ethyl]-2'-deoxyuridines and related halohydrin analogues with antiviral and cytotoxic activity.

A series of new 5-(1-hydroxy-2-haloethyl)-2'-deoxyuridines (3, 6, 8) were synthesized in 60-70% yields by addition of HOX (X = Br, Cl, I) to the vinyl substituent of the respective 5-vinyl-2'-deoxyuridines (2, 5, 7). Treatment of 3a,b with methanolic sulfuric acid afforded the corresponding 5-(1-methoxy-2-haloethyl)-2'-(deoxyuridines (4a,b). The 5-(1-hydroxy-2-chloroethyl) (3b), 5-(1-methoxy-2-bromoethyl) (4a), 5-(1-hydroxy-2-bromo-2-(ethoxycarbonyl)ethyl) (6a), and 5-(1-hydroxy-2-iodo-2-(ethoxycarbonyl)ethyl) (6b) derivatives exhibited in vitro antiviral activity (ID50 = 0.1-1 microgram/mL range) against herpes simplex virus type 1 (HSV-1). 5-(1-Hydroxy-2-bromo-2-(ethoxycarbonyl)-ethyl)-2'-deoxyuridine (6a) was the most active cytotoxic agent in the in vitro L1210 screen exhibiting an ED50 of 11 micrograms/mL relative to melphalan (ED50 = 0.15 micrograms/mL).

Animals↗
PubMed1989

In vitro and in vivo comparison of the abilities of purine and pyrimidine 2',3'-dideoxynucleosides to inhibit duck hepadnavirus.

Four purine and two pyrimidine 2',3'-dideoxynucleosides were studied for their ability to inhibit duck hepadnavirus replication. The purine 2',3'-dideoxynucleosides were more potent antiviral agents than the pyrimidine 2',3'-dideoxynucleosides. The concentration for 50% inhibition of viral replication (IC50) was determined for each of the effective agents. Two drugs with low IC50s, 2,6-diaminopurine 2',3'-dideoxyriboside and 2',3'-dideoxyadenosine, were chosen for in vivo studies. Animals received 10 mg/kg intramuscularly twice daily. Rapid clearance of hepadnavirus DNA from the sera of the animals was seen as a result of treatment with 2,6-diaminopurine 2',3'-dideoxyriboside; however, treatment with 2',3'-dideoxyadenosine did not clear the virus.

Animals↗
PubMed1989

Synthesis, cytotoxic and antiviral activity of uracils containing 5-(1-hydroxy-2-haloethyl)- and 5-(1-methoxy-2-haloethyl) substituents.

5-(1-Hydroxy-2-haloethyl)- (4), 5-(1-methoxy-2-haloethyl)- (5) and 5-(1-hydroxy-2-methoxyethyl)uracils (6) (see Figure 2 for structures) were synthesized to investigate the effect of the C-5 substituents on cytotoxic and antiviral activity. The bromo compounds (4b and 5b) exhibited greater cytotoxic activity than the chloro or iodo analogues in the in vitro L1210 assay. Replacement of the hydroxyl substituent of 4b (bromo) and 4c (iodo) by a methoxyl substituent (5b-c), or substitution of their halogen substituents by methoxyl (providing 6) increased the potency. However, the cytotoxic activity of all the compounds was weak, the most active (6) producing a 45% decrease in cell survival at a concentration of 50 micrograms/ml, as compared with a 97% decrease when the reference standard (melphalan) was tested at 1 microgram/ml. They were inactive antiviral agents against herpes simplex virus type 1 (HSV-1) infected Vero cells at 10 micrograms/ml; in the same test, the reference standard (acyclovir) exhibited an ID50 of 0.01 micrograms/ml.

Animals↗
PubMed1988

Inhibition of duck hepatitis B virus replication by purine 2',3'-dideoxynucleosides.

Primary hepatocyte cultures from duck hepatitis B virus (DHBV) infected ducklings were used to evaluate the antiviral activity of purine and pyrimidine 2',3'-dideoxynucleosides. The purine 2',3'-dideoxynucleosides were very effective inhibitors of hepadnavirus replication, whereas the pyrimidine dideoxynucleosides were not. 2',3'-Dideoxyguanosine and 2,6-diaminopurine 2',3'-dideoxyriboside (ddDAPR) were the most effective antiviral agents studied. ddDAPR given intramuscularly twice daily at 10 mg/kg rapidly cleared DHBV-DNA from the sera of persistently infected ducklings but this effect was not permanent.

Animals↗
PubMed1988

Herpes simplex virus infection of the hand. Clinical features and management.

Herpes simplex virus (HSV) infection of the hand occurs predominantly in three different population groups. Young adults with a recurrent HSV II infection of the hand account for the majority of cases. A prodromal phase of up to 72 hours and a recurrence of seven to 10 days' duration occasionally associated with lymphangitis, lymphadenopathy, and lymphedema are characteristic. HSV I infection of the hand classically occurs in children with herpetic stomatitis and in health care workers infected during patient care delivery. In health care workers, the infection may last 21 to 28 days and be associated with severe pain and lymphangitis. Recurrences appear uncommon in HSV I infections. Primary infection is usually managed conservatively. Vesicle drainage for pain relief and antiviral therapy with acyclovir may be of value. For recurrent infections, acyclovir, 800 mg orally, twice daily, initiated during the prodrome in an open study of eight patients appeared effective in aborting the attack. Evaluation of long-term suppression in recurrent HSV infection of the hand is in progress.

Acyclovir↗
PubMed1988

An extracorporeal model of biofilm-adherent bacterial microcolony colonization for the study of peritonitis in continuous ambulatory peritoneal dialysis.

We have developed an extracorporeal system for investigating in vitro the biofilm-adherent bacterial microcolonies (BABM) that grow on Tenckhoff catheters (TC), to study peritonitis in patients undergoing continuous ambulatory peritoneal dialysis (CAPD). A modified Robbins' device, attached to sampling plugs with TC discs and connected to the dialysate via a peristaltic pump, is run for 24 h; scrapings from pairs of TC discs are processed for assessment of viable BABM, one of each pair for culture by routine microbiology techniques and the other for examination by scanning and transmission electron microscopy (EM). No colonization was noted with fresh dialysis solutions and spent dialysates from patients without clinical peritonits; but, when bacterial suspensions were added to aliquots of the same dialysates, BABM were noted on both culture and EM. In a study of 4 patients on CAPD treatment, who had clinically evident peritonitis, routine cultures of spent dialysate were positive in only 2, but BABM were found in cultures and EM preparations of disc scrapings in all 4 cases. We conclude from these preliminary findings that this extracorporeal system is reliable, and well suited for studying the role of BABM in CAPD-associated peritonitis in vitro.

Bacterial Adhesion↗
PubMed1988

The in vitro evaluation of nucleoside analogues as probes for use in the noninvasive diagnosis of herpes simplex encephalitis.

1-(2-Deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU) and the 5-iodo (FIRU), 5-bromo (FBrRU), 5-chloro (FClRU) and 5-fluoro (FFRU) analogues of 1-(2-deoxy-2-fluoro-beta-D-ribofuranosyl)uracil were examined in four in vitro tests designed to evaluate their potential as radiopharmaceuticals in a non-invasive diagnostic test for herpes simplex encephalitis (HSE). The tests involved, (a) cellular uptake studies--which showed that all five nucleosides are selectively trapped in rabbit kidney cells infected with herpes simplex virus, type I, which codes for its own thymidine kinase; (b) incubation studies--which showed that, in human platelets, FIAU, FIRU and FFRU are not degraded by thymidine phosphorylase (an enzyme which catalyzes the glycosidic bond cleavage of physiological nucleosides); (c) a transport study, using mouse erythrocytes--which indicated that all five nucleosides have good affinity for a NBMPR-sensitive nucleoside transporter, with inhibition constants (Ki values in the range of 0.177-0.41; and (d) determination of octanol/water partition coefficients--which (log P = -0.14 to -1.67) indicated that FIAU is the most lipophilic of the five compounds studied, and may therefore cross the blood-brain barrier most readily. We conclude from the results that FIAU is the most promising compound for further evaluation in HSE animal models. The combination of tests described in this study provide a useful screening protocol for evaluation of other nucleoside analogues of potential use in a diagnostic test for HSE.

Animals↗
PubMed1988

Liposomes for targeted delivery of radioiodinated IVdU and 3-CH3-IVdU for non-invasive detection of herpes simplex virus encephalitis in mice.

Liposomal encapsulation of radioiodinated anti-herpes nucleosides was undertaken to reduce metabolic inactivation and increase blood-brain barrier penetration of the nucleosides, and so provide formulations suitable for use in the non-invasive scintigraphic diagnosis of herpes simplex encephalitis (HSE). The nucleosides investigated were [125I]-IVdU and its more lipophilic 3-methyl derivative, and they were encapsulated in phosphatidylcholine:cholesterol:sulfatide liposomes with an efficiency of 4.4% and 1.7% respectively. The encapsulation of IVdU reduced in vitro phosphorolysis (by 31% in serum at 25 degrees C over 3 hr as compared with non-encapsulated IVdU), and markedly increased in vivo stability (fifty-fold greater than that of free drug). In normal mice, higher radioactivity levels were observed in most tissues and there was prolonged, constant blood and brain uptake. Biodistribution of liposomal IVdU in herpes simplex virus (HSV) infected animals was similar, but somewhat lower concentrations were attained. Liposomal encapsulation of [125I]-3-CH3-IVdU produced less dramatic changes in tissue distribution in either healthy or HSV infected mice, as compared with the non-encapsulated drug. Whilst, in HSV infected mice, liposomal encapsulation of both drugs caused increased uptake by spleen, liver and lung, the uptake by brain was still too low for detection by whole-body scintigraphy.

Animals↗
PubMed1988

Synthesis and antiviral activity of IVFRU, a potential probe for the non-invasive diagnosis of herpes simplex encephalitis.

Synthesis of (E)-5-(2-iodovinyl)-1-(2-deoxy-2-fluoro-beta-D-ribofuranosyl)uracil (IVFRU; 4a), and its [125I] and [131I] derivatives (4b and 4c) are described. Compared with IVDU, IVFRU had comparable antiviral activity (MIC50 = 0.01-0.1 microgram/ml), and a greater ethanol/water partition coefficient; its affinity for the murine erythrocyte nucleoside transporter system was greater than that of 2'-deoxyuridine. The [125I] derivative (4b) was selectively trapped within rabbit kidney cells (27.9 and 41.2% at 4 and 24 hr, respectively) infected in vitro by thymidine kinase-positive (TK+) herpes simplex virus (HSV-1), but not within either HSV (TK-) or mock-infected cells where uptake was less than 1%. It was resistant to glycosidic bond cleavage by pyrimidine nucleoside phosphorylases, but underwent catabolism to an unidentified metabolite and iodide during in vivo plasma and urinary excretion studies in mice. We conclude that the [123I] derivative of IVFRU warrants further evaluation as a non-invasive radiopharmaceutical agent for the diagnosis of herpes simplex encephalitis (HSE), and that IVFRU warrants further evaluation as an antiviral agent.

Animals↗
PubMed1988

Paramyxovirus membrane protein augments the antibody response to actin in mice.

The production of anti-actin antibodies has been studied in mice. Not one of 10 mice immunized with native actin produced anti-actin antibodies, whereas seven out of 10 mice immunized with actin mixed with paramyxovirus membrane (M) protein produced a high titre of antibodies to actin. The enhancement of anti-actin antibody production by M protein is specific to actin since antibodies to protein purified derivatives (PPD) or gelatin were not enhanced by M protein. The enhanced anti-actin antibodies depended upon the interaction of actin and M protein since injection of M protein and actin in separate sites failed to produce anti-actin antibodies. Five Balb/c nude mice immunized with actin and M protein failed to produce anti-actin antibodies suggesting that cell-mediated immune response is also required for this response.

Actins↗
PubMed1987

Increased frequency of Epstein-Barr virus excretion in patients with new daily persistent headaches.

In a case-control study 27 (84%) of 32 patients with new daily persistent headaches (NDPH) and 8 (25%) of 32 controls had evidence of Epstein-Barr virus (EBV) "active" infection, as demonstrated by EBV excretion and/or early antigen titre above 1:32. 20 (62%) patients and 4 (12%) controls were excreting EBV in the oropharynx, as determined by a dot hybridisation assay. The mean titre of IgG antibodies to early antigen was significantly higher in patients than controls. EBV reactivation may be important in the pathogenesis of NDPH. Alternatively, patients with NDPH may be unusually prone to EBV reactivation.

Adolescent↗
PubMed1987

Effect of acyclovir on the uptake of 131I-labelled 1-(2'fluoro-2'-deoxy-beta-D-arabinofuranosyl)-5-iodouracil in herpes infected cells.

Selective uptake of nucleoside analogues by herpes simplex virus infected cells may serve as the basis for a specific non-invasive diagnostic test for herpes simplex encephalitis. We have examined the effect of acyclovir on the selective uptake of [131I] 1-(2'-fluoro-2'-deoxy-beta-D-arabinofuranosyl)-5-iodouracil in herpes simplex virus infected primary rabbit kidney cells. Infected cells treated with acyclovir continued to concentrate [131I] 1-(2'-fluoro-2'-deoxy-beta-D-arabinofuranosyl)-5-iodouracil for up to 24 h after the addition of the antiviral agent. These results indicated that therapy with acyclovir for as long as 24 h would not prevent the selective trapping of nucleoside analogues. This has important implications for the use of nucleoside analogues in diagnostic brain scans to detect herpes simplex encephalitis.

Acyclovir↗
PubMed1987

Clinical course of recurrent genital herpes and treatment with foscarnet cream: results of a Canadian multicenter trial.

Clinic-initiated topical treatment of recurrent genital herpes with foscarnet cream (concentration, 0.3% in men and 1% in women) was compared with a placebo in a Canadian multicenter trial involving 309 patients. Culture-positive episodes of herpes took significantly longer to heal than did the others. Lesions in men were larger and lasted longer but were less symptomatic than those in women. Foscarnet did not statistically improve the times to healing or the loss of symptoms overall but did result in a higher proportion of symptom-free individuals after one day of treatment. Foscarnet-treated patients had a reduced duration of shedding of virus, and this was significant for men. These clinical benefits do not, however, warrant general use of this agent for established lesions. Earlier, prodromal treatment might have been more effective, but patient-initiated studies include a greater proportion of culture-negative (shorter) episodes that often make results difficult to interpret.

Administration, Topical↗
PubMed1987

DNA-DNA dot hybridization to detect Epstein-Barr virus in throat washings.

To compare the abilities of the nucleic acid dot hybridization assay and the cord blood lymphocyte transformation assay to detect Epstein-Barr virus (EBV), we examined throat washings from healthy control subjects (nine EBV-seronegative and 51 EBV-seropositive), patients with acute infectious mononucleosis, and renal transplant recipients. The dot hybridization assay detected EBV excretion in four (8%) of the EBV-seropositive controls; three of these four were also positive by the lymphocyte transformation assay. Throat washings from seven (87.5%) of eight patients with acute infectious mononucleosis were positive by both assays. EBV was present in throat washings from 13 (50%) of 26 renal transplant recipients. For specimens stored at -70 C for less than four months, the dot hybridization assay had a sensitivity of 90% and a specificity of 98% when compared with the lymphocyte transformation assay. The dot hybridization assay is a rapid, sensitive, and specific test that can be performed on readily available clinical specimens.

Antibodies, Viral↗