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Biomedical subjects

A Sjoerdsma

Publications and source records attributed to A Sjoerdsma.

At least 19 recordsLinked to original sources
PubMed1992

Cure of murine Trypanosoma brucei rhodesiense infections with an S-adenosylmethionine decarboxylase inhibitor.

The compound 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxyadenosine (MDL73811), a potent inhibitor of S-adenosylmethionine decarboxylase, was effective in mice against six of eight clinical isolates of Trypanosoma brucei rhodesiense, the causative agent of East African sleeping sickness. In combination with the ornithine decarboxylase inhibitor DL-alpha-difluoromethylornithine (DFMO; Ornidyl), MDL73811 acted synergistically to cure seven of eight infections. MDL73811 was effective when given singly at 50 to 100 mg/kg of body weight per day for 7 days (osmotic pumps). In combination with subcurative DFMO levels (0.25 to 1.0% in drinking water for 7 days), the curative MDL73811 dose could be lowered to 25 or 50 mg/kg, depending on the isolate. Oral administration of the MDL73811-DFMO combination was also effective in an acute infection and in a long-term central nervous system model of Trypansoma brucei brucei infection. These data indicate that MDL73811 may be effective therapeutically in drug-refractory and late-stage East African trypanosomiasis.

Adenosylmethionine Decarboxylase↗
PubMed1991

Participation of T-lymphocytes in the curative effect of a novel synthetic polyamine analogue, N,N'-bis[3-(ethylamino)propyl]-1,7-heptanediamine, against L1210 leukemia in vivo.

We have recently established that combination therapy with N,N'-bis[3-(ethylamino)propyl]-1,7-heptanediamine (BEPH), a synthetic polyamine analogue, and N,N'-bis-2,3-butadieneyl-putrescine, a polyamine oxidase inhibitor, eradicated L1210 leukemia in mice and induced resistance to a subsequent L1210 challenge. We now demonstrate that BEPH treatment alone, given on a more frequent schedule (5 mg/kg, day 3, 4, 5) or at a higher dose (10 mg/kg, day 3, 4), cures 100% of L1210 leukemic mice. These treated animals were subsequently immune to a second challenge with L1210 tumor cells. However, mice cured with BEPH did not reject P388 leukemic cells, although their mean survival time was slightly prolonged. In an in vivo tumor neutralization assay, splenocytes from cured mice and L1210 cells were injected into naive mice; 80% did not develop L1210 leukemia. Coculturing lymphocytes from cured mice with L1210 cells in vitro generated a potent tumor-specific cytolytic response against L1210 target cells, whereas lymphocytes from naive mice did not generate any significant cytolytic activity. Both the in vitro and in vivo activities were completely eliminated by pretreating the splenic lymphocyte population with anti-Thy-1.2 monoclonal antibodies and complement, indicating T-cells as the effector population. In T-cell-deficient nude mice BEPH treatment was not curative, increasing survival time by approximately 2-fold. We conclude from these studies that T-cell-mediated immunity plays a pivotal role in the mechanism by which synthetic polyamine analogues, such as BEPH, prevent neoplastic growth.

Animals↗
PubMed1991

Antimalarial polyamine analogues.

A series of novel tetraamines of the general formula RNH(CH2)xNH(CH2)yNH(CH2)xNHR was synthesized and examined for activity against growth of Plasmodium falciparum in vitro. Within the series, dibenzyl analogues (R = benzyl) were found to be the most effective growth inhibitors, with IC50 values of about 10(-6) M. Further modifications of the tetraamine provided the optimum chain length for antimalarial activity of y = 7, x = 3. Compound 8 (MDL 27,695) with the structure y = 7, x = 3, R = benzyl, in combination with the ornithine decarboxylase inhibitor alpha-(difluoromethyl)ornithine, resulted in radical cures when tested against experimental Plasmodium berghei infections in mice. The structure-activity relationships of the series are discussed.

Animals↗
PubMed1990

Clinical relevance of measuring GABA concentrations in cerebrospinal fluid.

Determination of GABA concentrations in human cerebrospinal fluid can be used to assess GABAergic activity in the central nervous system. As CSF free GABA concentrations may vary with age, sex, CSF fraction, and collection and storage conditions, careful attention to these factors are necessary to allow interpretation of results. Longitudinal studies to investigate the influence of pharmacological agents on CSF GABA have proven especially useful to define clinical biochemical activity and have been utilized to attribute the anti-epileptic action of vigabatrin, a selective inhibitor of GABA-transaminase, to its effects on brain GABA metabolism.

4-Aminobutyrate Transaminase↗
PubMed1990

Inhibition of glycoprotein processing and HIV replication by castanospermine analogues.

Inhibitors of glycoprotein processing enzymes have been shown to have activity against HIV. Several analogues of the known glucosidase I inhibitor, castanospermine (CAST), were synthesized and evaluated for their inhibitory effect on glucosidases and for antiviral activity against Moloney murine leukemia virus (MOLV) and HIV-1. The most effective analogue was 6-O-butanoyl CAST (B-CAST, MDL 28,574) with an IC50 of 0.05 micrograms/mL against MOLV. A correlation between inhibition of glucosidase I and MOLV replication was observed. This analogue was further evaluated against HIV-induced syncytial formation in HeLa T4+ cells and against productive infection in JM cells infected with HIV 1 (GB8 strain). B-CAST showed an IC50 of 0.3 micrograms/mL in the HeLa T4+ assay, compared to CAST at 11 micrograms/mL. The compound also was more potent (IC50:0.15 micrograms/mL) than CAST (4-6 micrograms/mL) in JM cells. The antiretroviral activity of B-CAST was further confirmed in Friend leukemia virus (FLV) infection in mice. B-CAST showed equivalent activity to AZT and was more potent than CAST in inhibiting FLV-induced splenomegaly in mice. The data presented herein suggest the potential of these novel glucosidase inhibitors as anti-HIV agents.

Animals↗
PubMed1990

Suppression of both antimony-susceptible and antimony-resistant Leishmania donovani by a bis(benzyl)polyamine analog.

It was recently demonstrated that a bis(benzyl)polyamine analog (MDL 27695; N,N'-bis(3-[(phenylmethyl)amino]propyl)-1,7-diaminoheptane) possessed potent antimalarial activity in vitro and in vivo (A. J. Bitonti, J. A. Dumont, T. L. Bush, M. L. Edwards, D. M. Stemerick, P. P. McCann, and A. Sjoerdsma, Proc. Natl. Acad. Sci. USA 86:651-655, 1989). We now report that MDL 27695 also has potent antileishmanial activity, eliminating 77 to 100% of Leishmania donovani amastigotes from mouse peritoneal macrophages in vitro at 1 microM. Administration of 15 mg of MDL 27695 per kg three times per day for 5 days to L. donovani-infected mice suppressed parasite burdens in liver, spleen, and bone marrow by 83 to 96, 90, and 87%, respectively, and by 99.9% in livers of mice given the same dose two times per day for 10 days. Liver parasites were suppressed 74% in L. donovani-infected hamsters treated three times per day for 4 days with 5 mg of MDL 27695 per kg. The 50% effective doses for MDL 27695 were 2.5 mg/kg in mice and about 1 mg/kg in hamsters. In hamsters, MDL 27695 was equally effective against both antimony-susceptible and antimony-resistant L. donovani, suggesting a different mechanism of action for the two types of drugs. Coadministration of N1,N4-bis(butadienyl)-butanediamine (MDL 72527) to mice to inhibit host polyamine oxidase, and hence the formation of oxidative metabolites of MDL 27695, did not affect the antileishmanial activity of MDL 27695. Thus, the mechanism of action of MDL 27695 does not appear to be related to its oxidation to toxic metabolites but may involve interference with DNA and RNA syntheses as found previously in Plasmodium falciparum (Bitonti et al., Proc. Natl. Acad. Sci. USA 86:651-655, 1989).

Animals↗
PubMed1990

Cure of Trypanosoma brucei brucei and Trypanosoma brucei rhodesiense infections in mice with an irreversible inhibitor of S-adenosylmethionine decarboxylase.

A structural analog, 5'-([(Z)-4-amino-2-butenyl]methylamino)-5'-deoxy adenosine (MDL 73811), of decarboxy S-adenosyl-L-methionine, the product of the reaction catalyzed by S-adenosyl-L-methionine (AdoMet) decarboxylase (DC), was found to inhibit Trypanosoma brucei brucei AdoMet DC. The inhibition was time dependent (tau 50, 0.3 min), exhibited pseudo-first-order kinetics (Ki, 1.5 microM), and was apparently irreversible. The natural substrate of the reaction, AdoMet, protected the enzyme from inactivation, suggesting that MDL 73811 was directed at the enzyme active site and was probably catalytically activated. Administration of MDL 73811 to T. b. brucei-infected rats resulted in rapid inhibition of AdoMet DC activity, a decrease in spermidine, and an increase in putrescine in the trypanosomes isolated from treated rats. Treatment of T. b. brucei-infected mice with MDL 73811 (20 mg/kg of body weight intraperitoneally twice daily for 4 days) resulted in cures of the trypanosome infections. Additionally, drug-resistant T. brucei rhodesiense infections in mice were cured by either a combination of MDL 73811 (50 mg/kg intraperitoneally three times per day for 5 days) and relatively low oral doses of alpha-difluoromethylornithine or MDL 73811 (50 mg/kg per day for 7 days) administered alone in implanted miniosmotic pumps. These data suggest that MDL 73811 and, perhaps, other inhibitors of AdoMet DC have potential for therapeutic use in various forms of African trypanosomiasis.

Adenosylmethionine Decarboxylase↗
PubMed1989

Bis(benzyl)polyamine analogs inhibit the growth of chloroquine-resistant human malaria parasites (Plasmodium falciparum) in vitro and in combination with alpha-difluoromethylornithine cure murine malaria.

A number of bis(benzyl)polyamine analogs were found to be potent inhibitors of both chloroquine-resistant and chloroquine-sensitive strains of the human malaria parasite Plasmodium falciparum in vitro (IC50 values = 0.2-14 microM). Administration of one of the compounds, MDL 27695, which is N,N'-bis(3-[(phenylmethyl)amino]propyl)-1,7-diaminoheptane (C6H5CH2NH(CH2)3NH(CH2)7NH(CH2)3NHCH2C6H5), at 10-15 mg/kg i.p. three times per day for 3 days in combination with 2% alpha-difluoromethylornithine (DFMO; eflornithine) in drinking water effected cures of 47/54 mice infected with Plasmodium berghei. Cured mice were found to be immune upon rechallenge with the same P. berghei strain 4 months after the initial infection and drug-induced cure. MDL 27695 rapidly inhibited the incorporation of [3H]hypoxanthine into P. falciparum RNA and DNA, whereas the incorporation of [3H]isoleucine was not affected until much later. We conclude, therefore, that the major cytotoxic event may be direct binding of MDL 27695 to DNA with subsequent disruption of macromolecular biosynthesis and cell death. These compounds offer a lead in the search for new agents for chemotherapy of malaria.

Animals↗
PubMed1988

Reversal of chloroquine resistance in malaria parasite Plasmodium falciparum by desipramine.

Desipramine and several other tricyclic antidepressant drugs reverse chloroquine resistance in Plasmodium falciparum in vitro at concentrations observed in the plasma of human patients treated for depression. Reversal of resistance is associated with increased chloroquine accumulation in the parasite, probably because of inhibition of a putative chloroquine efflux pump. When owl monkeys (Aotus lemurinus lemurinus) infected with chloroquine-resistant Plasmodium falciparum were treated with chloroquine plus desipramine, their parasitemias were rapidly suppressed. Desipramine was found to be one of the most effective compounds yet described for the reversal of chloroquine resistance both in vitro and in vivo.

Animals↗
PubMed1988

African sleeping sickness in the United States. Successful treatment with eflornithine.

The traditional treatment of African sleeping sickness (trypanosomiasis) with central nervous system involvement is an organic arsenical compound, melarsoprol, which is associated with severe and even life-threatening side effects. A polyamine biosynthesis inhibitor, eflornithine (chemical name, DL-alpha-difluoromethylornithine, supplied as monohydrochloride monohydrate), was used to treat a 3 1/2-year-old child with newly diagnosed severe trypanosomiasis that had been acquired more than two years previously in Zaire or the Congo. Treatment consisted of 300 to 400 mg/kg/d of eflornithine by continuous intravenous infusion for 25 days followed by 300 mg/kg/d of eflornithine by mouth divided in four equal doses daily for 17 days. The child's recovery was dramatic, with eradication of blood and cerebrospinal fluid parasites in the first week. Cerebrospinal fluid pleocytosis resolved completely. Her generalized adenopathy and fever gradually resolved. Severe ataxia, inability to walk or to change posture on her own, marked language regression, and lethargy all improved during and after her therapy. The drug was well tolerated; the only noted adverse effect was transient thrombocytopenia during the fourth week of therapy. Eflornithine was a safe and effective agent for treatment of trypanosomiasis with central nervous system involvement in this child.

Animals↗
PubMed1988

Design and early clinical evaluation of selective inhibitors of monoamine oxidase.

1. Selective inhibitors of the monoamine oxidase (MAO) isoenzymes, types A and B, are of potential therapeutic utility. Brain selectivity would overcome the risk of tyramine interactions which have been shown to occur with selective MAO-A but not MAO-B inhibitors. 2. (E)-3-Fluoroallylamines of general structure, FHC = C(R)CH2NH2 have been designed as enzyme-activated, irreversible inhibitors of these enzymes. Two compounds, MDL 72145 (R = 3,4 dimethoxyphenyl) and MDL 72974 (R = 4-fluorophenethyl), are selective and irreversible inhibitors of MAO type B which in vivo show high inhibitory potency against the rat brain enzyme (ED50 0.35 and 0.18 mg/kg p.o., respectively). In animals, these inhibitors do not potentiate the cardiovascular effects of tyramine and have no amphetamine-like effects. However, they do potentiate the central effects of L-Dopa and prevent the neurotoxic effects of MPTP in both mice and monkeys. 3. In early clinical studies, MDL 72145 has been shown to be a potent, long-acting inhibitor of MAO type B. Doses of 16 mg per patient totally inhibit platelet enzyme without potentiating the cardiovascular effects of oral tyramine. Compounds of this type should prove useful in Parkinson's disease. 4. Selective inhibition of brain MAO-A can be achieved by using the bioprecursor amino acid MDL 72394 (E-beta-fluoromethylene-m-tyrosine). This amino acid is decarboxylated by aromatic L-amino acid decarboxylase (AADC) to liberate MDL 72392 (R = 3-hydroxyphenyl), a potent irreversible inhibitor of MAO-A. Combination of MDL 72394 with a peripherally selective inhibitor of AADC (e.g., carbidopa) restricts MAO inhibition to the brain. Consequently, under these conditions, there is a greatly reduced propensity to potentiate the cardiovascular effects of tyramine. 5. This has been confirmed in human volunteers; MDL 72394 (8 mg), combined with carbidopa, substantially decreased urinary MHPG and plasma DHPG concentrations with minimal potentiation of the cardiovascular effects of i.v. tyramine. These results predict that such therapy has potential in the treatment of affective disorders.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1988

A multicenter, open study of the non-sedating antihistamine, terfenadine (Seldane), in the maintenance therapy of seasonal allergic rhinitis.

A multicenter open study was conducted throughout the 1984 fall pollen season to assess the possible development of tolerance or loss of efficacy to terfenadine in the maintenance therapy of patients with seasonal pollinosis. Patients with proven allergic pollinosis were entered into a 1-week initial treatment period taking terfenadine 60 mg bid and only those who responded to the initial treatment with "moderate" to "complete" relief continued on terfenadine throughout a 4 to 11-week pollen season for evaluation of continued efficacy. A total of 179 patients from five study centers were enrolled in the initial treatment period and 154 (86%) responded to terfenadine with "moderate" to "complete" relief of symptoms. Of these 154 patients who continued terfenadine treatment, approximately 90% of the patients maintained the same degree of relief throughout the pollen season. All symptoms of seasonal pollinosis including nasal congestion improved significantly the first day of treatment. This improvement in symptoms continued during the first week and remained unabated throughout the pollen season. The incidence of adverse events was low with sedation being reported by only 2.8% of patients at some time point during the study. It is concluded that terfenadine is a safe and effective non-sedating antihistamine in the maintenance therapy of seasonal allergic pollinosis and that tolerance is not noted during continued administration.

Adult↗
PubMed1987

Antiretroviral activity of castanospermine and deoxynojirimycin, specific inhibitors of glycoprotein processing.

The objective of this study was to investigate the antiretroviral activity of specific inhibitors of glycosidases and mannosidases that are involved in N-linked oligosaccharide processing of glycoproteins. Castanospermine and 1-deoxynojirimycin, potent inhibitors of glucosidases I and II, showed significant activity against Moloney murine leukemia virus (IC50: 1.2 microgram/ml). Deoxymannojirimycin and swainsonine, inhibitors of mannosidase I and II, respectively, did not show any activity. These observations suggest that removal of the outermost glucose residue from high mannose asparagine-linked oligosaccharide may be essential for the replication of mouse leukemia virus. The relative nontoxic nature of these inhibitors and a novel mechanism of action suggest a potential for compounds of this type as chemopreventive and therapeutic agents in the treatment of acquired immune deficiency syndrome (AIDS).

1-Deoxynojirimycin↗
PubMed1987

Difluoromethylornithine, an effective new treatment of Gambian trypanosomiasis. Results in five patients.

Recent studies have shown DL-alpha-difluoromethylornithine (eflornithine), an inhibitor of polyamine biosynthesis, to be curative in various Trypanosoma species infections of laboratory animals. Five patients are described with Gambian trypanosomiasis treated in Belgium with difluoromethylornithine, using various intravenous and oral dosage schedules. Three patients had late-stage and two had early-stage disease. Difluoromethylornithine treatment was associated with clearing of parasites from blood within one to four days, a trend towards normalization of all altered biologic values associated with the disease, and marked amelioration of clinical symptoms. Side effects of difluoromethylornithine, including loose stools in three patients and both anemia, and a decrease in auditory acuity in one patient, were mild, transient, and never required interruption of drug treatment. The presence of difluoromethylornithine in cerebrospinal fluid, determined in three patients, demonstrated that difluoromethylornithine penetrates into the central nervous system. In three patients, follow-up of at least 24 months after treatment demonstrated a continued healthy state without evidence of relapse. These promising, albeit preliminary, results of difluoromethylornithine therapy, even in patients with central nervous system involvement, indicate that extended clinical trials are warranted to determine the optimal dosage regimen in patients with early- and late-stage disease.

Adult↗