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180. In vitroandin vivoantiviral (RNA) evaluation of orotidine 5′-monophosphate decarboxylase inhibitors and analogues including 6-azauridine-5′-(ethyl methoxyalaninyl)phosphate (a 5′-monophosphate prodrug)

Author

Gabrielsen, B., primary, Kirsi, J. J., additional, Kwong, C. D., additional, Carter, D. A., additional, Krauth, C. A., additional, Hanna, L. K., additional, Huggins, J. W., additional, Monath, T. P., additional, Kefauver, D. F., additional, Blough, H. A., additional, Rankin, J. T., additional, Bartz, C. M., additional, Huffman, J. H., additional, Smee, D. F., additional, Sidwell, R. W., additional, Shannon, W. M., additional, and Secrist, J. A., additional

Published
1994
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184. Lipophilic Antifolates as Agents against Opportunistic Infections. 1. Agents Superior to Trimetrexate and Piritrexim against Toxoplasma gondii and Pneumocystis carinii in in Vitro Evaluations<SUP>1,2</SUP><BBR RID="jm950760yb00001"><BBR RID="jm950760yb00002">

Author

Piper, J. R., Johnson, C. A., Krauth, C. A., Carter, R. L., Hosmer, C. A., Queener, S. F., Borotz, S. E., and Pfefferkorn, E. R.

Abstract

2,4-Diaminopteridines (21 compounds) and 2,4-diamino-5-methyl-5-deazapteridines (34 compounds) along with three 2,4-diamino-5-unsubstituted-5-deazapteridines and four 2,4-diaminoquinazolines, each with an aryl group attached to the 6-position of the heterocyclic moiety through a two-atom bridge (either CH2NH, CH2N(CH3), CH2S, or CH2CH2), were synthesized and evaluated as inhibitors of the growth of Toxoplasma gondii in culture and as inhibitors of dihydrofolate reductase enzymes from T. gondii, Pneumocystis carinii, and rat liver. Exceptionally high levels of combined potency and selectivity as growth inhibitors of T. gondii and as inhibitors of the microbial enzymes relative to the mammalian enzyme were found among the 5-methyl-5-deazapteridines but not for the other heterocyclic types. Thirty of the 34 5-methyl-5-deaza compounds gave growth inhibition IC50 values lower than that of pyrimethamine (0.4 μM) with 14 compounds below 0.1 μM, values that compare favorably with those for piritrexim and trimetrexate (both near 0.02 μM). As inhibitors of T. gondii DHFR, all but three of the 34 5-methyl-5-deaza compounds gave IC50 values in the order of magnitude with those of piritrexim (0.017 μM) and trimetrexate (0.010 μM), and 17 compounds of this group gave IC50 values versus P. carinii DHFR similarly comparable with those of piritrexim (0.031 μM) and trimetrexate (0.042 μM). Thirteen of these congeners gave both T. gondii growth inhibition and DHFR inhibition IC50 values of 0.10 μM or less, thus indicating facile penetration of the cell membrane. Eleven of these inhibitors of both T. gondii growth and DHFR have selectivity ratios (IC50 rat liver divided by IC50 T. gondii) of 5 or greater for the parasite DHFR. The highest selectivity ratio of nearly 100 belongs to the 5-methyl-5-deaza compound whose 6-substituent is CH2CH2C6H3(OCH3)2-2,5. This compound is over 103-fold more selective for T. gondii DHFR than bridge homologue piritrexim (selectivity ratio 0.088), a compound now in clinical trials. The candidate with CH2NHC6H3(CH3)2-2,5 in the 6-position gave the highest P. carinii DHFR selectivity ratio of 4.0, which is about 60-fold more selective than trimetrexate (0.071) and 80-fold more selective than piritrexim (0.048) toward this enzyme. The 10 best compounds with respect to potency and selectivity includes six compounds bearing 2,5-disubstituted phenyl groups in the side chain (with little, if any, difference in effects of methyl, methoxy, or ethoxy), two side chains bearing 1-naphthyl groups, and two with 5,6,7,8-tetrahydro-1-naphthyl groups. Bridge groups represented in the 10 choice compounds are CH2NH, CH2N(CH3), CH2CH2, and CH2S. The high levels of both potency and selectivity among these agents suggest that in vivo studies now underway may lead to agents that could replace trimetrexate and piritrexim in treatment of toxoplasmosis and P. carinii pneumonia.

Published
1996

185. In vitroand in vivoantiviral (RNA) evaluation of orotidine 5′-monophosphate decarboxylase inhibitors and analogues including 6-azauridine-5′-(ethyl methoxyalaninyl)phosphate (a 5′-monophosphate prodrug)

Author

Gabrielsen, B., Kirsi, J. J., Kwong, C. D., Carter, D. A., Krauth, C. A., Hanna, L. K., Huggins, J. W., Monath, T. P., Kefauver, D. F., Blough, H. A., Rankin, J. T., Bartz, C. M., Huffman, J. H., Smee, D. F., Sidwell, R. W., Shannon, W. M., and Secrist, J. A.

Abstract

A series of 29 pyrimidines comprising analogues of 6-azauridine (e.g. 2- and 4-thio-6-azauridine), 6-substituted uridines (including several known inhibitors of orotidine 5′-monophosphate decarboxylase, ODCase, e.g. pyrazofurin), and 6-azauridine-5′-(ethyl methoxyalaninyl) phosphate (a potential prodrug of 6-AU-5′-MP) were synthesized and evaluated in vitroand in vivoagainst five RNA viruses: Japanese encephalitis (JE), yellow fever (YF), sandfly fever (SF), Punta Tora (PT) and Venezuelan equine encephalomyelitis (VEE) viruses. 2-Thio-6-azauridine demonstrated the best In vitroactivity against all five viruses. However, in vivoactivity was not observed in JE-, PT- and VEE-infected mice. The phosphate prodrug of 6-azauridine was significantly more effective than the parent compound in the PT virus mouse model. Optimum in vivodose/route/schedule was determined for pyrazofurin in PT-virus-infected mice.

Published
1994
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198. Case management for the treatment of patients with major depression in general practices – rationale, design and conduct of a cluster randomized controlled trial – PRoMPT (Primary care Monitoring for depressive Patient's Trial) [ISRCTN66386086] – Study protocol

Author

Krauth Christian, Rosemann Thomas, Beyer Martin, Wendt-Hermainski Heike, Peitz Monika, Torge Marion, Gensichen Jochen, Raspe Heiner, Aldenhoff Josef B, and Gerlach Ferdinand M

Subjects
Public aspects of medicine, RA1-1270
Abstract

Abstract Background Depression is a disorder with high prevalence in primary health care and a significant burden of illness. The delivery of health care for depression, as well as other chronic illnesses, has been criticized for several reasons and new strategies to address the needs of these illnesses have been advocated. Case management is a patient-centered approach which has shown efficacy in the treatment of depression in highly organized Health Maintenance Organization (HMO) settings and which might also be effective in other, less structured settings. Methods/Design PRoMPT (PRimary care Monitoring for depressive Patients Trial) is a cluster randomised controlled trial with General Practice (GP) as the unit of randomisation. The aim of the study is to evaluate a GP applied case-management for patients with major depressive disorder. 70 GPs were randomised either to intervention group or to control group with the control group delivering usual care. Each GP will include 10 patients suffering from major depressive disorder according to the DSM-IV criteria. The intervention group will receive treatment based on standardized guidelines and monthly telephone monitoring from a trained practice nurse. The nurse investigates the patient's status concerning the MDD criteria, his adherence to GPs prescriptions, possible side effects of medication, and treatment goal attainment. The control group receives usual care – including recommended guidelines. Main outcome measure is the cumulative score of the section depressive disorders (PHQ-9) from the German version of the Prime MD Patient Health Questionnaire (PHQ-D). Secondary outcome measures are the Beck-Depression-Inventory, self-reported adherence (adapted from Moriskey) and the SF-36. In addition, data are collected about patients' satisfaction (EUROPEP-tool), medication, health care utilization, comorbidity, suicide attempts and days out of work. The study comprises three assessment times: baseline (T0) , follow-up after 6 months (T1) and follow-up after 12 months (T2). Discussion Depression is now recognized as a disorder with a high prevalence in primary care but with insufficient treatment response. Case management seems to be a promising intervention which has the potential to bridge the gap of the usually time-limited and fragmented provision of care. Case management has been proven to be effective in several studies but its application in the private general medical practice setting remains unclear.

Published
2005
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