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Biomedical subjects

P J Schechter

Publications and source records attributed to P J Schechter.

At least 19 recordsLinked to original sources
PubMed1994

Complement activation and hemodynamic changes following intravenous administration of phosphorothioate oligonucleotides in the monkey.

Rapid intravenous infusion of GEM 91, a 25-mer phosphorothioate oligonucleotide complementary to the gag site of HIV, in the monkey produces transient decreases in peripheral total WBC and neutrophil counts, hemoconcentration, and a brief increase followed by a prolonged decrease in arterial blood pressure. These changes are preceded by and are likely mediated by activation of C5 complement. These effects are dose and infusion rate dependent and can be avoided by administering GEM 91 by slow intravenous infusion. Similar hemodynamic effects are produced with rapid intravenous infusion of other phosphorothioate oligonucleotides varying in length from 20- to 33-mer, and are, therefore, not sequence specific but a property of this chemical structure.

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

Review: Normal and abnormal central nervous system GABA metabolism in childhood.

The metabolism and function of central nervous system GABA is briefly reviewed. Hereditary disorders of the GABA metabolism presenting in childhood are discussed with particular emphasis on the recently identified succinic semialdehyde dehydrogenase deficiency and GABA-transaminase deficiency, and on diseases associated with low CSF GABA which await further unravelling. Low CSF GABA concentrations are not always associated with convulsions. A separate section is devoted to the CSF as a tool in the diagnosis of these disorders. Finally, we present a few diagnostic and therapeutic guidelines.

Amino Acid Metabolism, Inborn Errors↗
PubMed1989

[African trypanosomiasis in children treated with eflornithine. A case].

We report the case of a 14-year old African girl presenting with late-stage African T. gambiense trypanosomiasis. She was treated with eflornithine, an ornithine decarboxylase inhibitor which is a key enzyme in the biosynthesis of polyamine. Polyamines are essential to the multiplication of trypanosomes. Two treatment courses were necessary to achieve an apparent cure after one year; however, a longer follow up will be required to confirm whether or not the cure is permanent. Determination of drug concentrations in plasma and cerebrospinal fluid was performed during the second treatment course. Side-effects were easily controlled.

Adolescent↗
PubMed1989

Clinical pharmacology of vigabatrin.

1. Upon oral administration vigabatrin is rapidly absorbed. Plasma elimination half-life ranges between 5 and 7 h in normal volunteers. Vigabatrin is eliminated primarily via the kidneys with about 65% of the administered dose found unchanged in the urine within 24 h. Kinetics are dose-linear within the range of usual therapeutic doses. 2. At therapeutic doses in man vigabatrin produces dose-related increases in CSF concentrations of free and total GABA, homocarnosine (the GABA-histidine dipeptide) and beta-alanine. These biochemical changes are consistent with an inhibition of GABA-transaminase activity in brain. 3. Thus, with systemic availability upon oral administration and biochemical activity in the CNS, the prerequisites for potential uses of vigabatrin in neurological disorders have been demonstrated in clinical pharmacological studies.

4-Aminobutyrate Transaminase↗
PubMed1989

The effect of different vigabatrin treatment regimens on CSF biochemistry and seizure control in epileptic patients.

1. Vigabatrin, 50 mg kg-1, was administered orally as add-on therapy to 11 patients with drug-resistant complex partial epilepsy as a single dose, then once every third day for 2 months, every other day for 2 months and daily for 1 month. 2. Lumbar punctures were carried out prior to treatment and at the end of each dosage regimen and cerebrospinal fluid (CSF) evaluated for concentrations of free and total GABA, homocarnosine (GABA-histidine dipeptide), homovanillic acid (HVA), 5-hydroxyindole acetic acid (5-HIAA) and vigabatrin. 3. Each regimen resulted in significant increases in CSF concentrations of free and total GABA and homocarnosine compared with the immediately preceding regimen. 4. CSF concentrations of HVA significantly increased after a single vigabatrin dose but returned to pre-treatment levels with subsequent dosing schedules. In contrast, 5-HIAA concentrations also increased with the single dose but were significantly decreased, compared with pre-treatment values, following alternate day and daily vigabatrin administration. 5. Seizure frequency progressively decreased with decreasing dosing interval. Daily vigabatrin administration was associated with greater than 50% decrease in seizures in 8 of the 10 patients treated.

Adult↗
PubMed1989

Cerebrospinal fluid parameters in healthy volunteers during serial lumbar punctures.

Lumbar punctures were performed on four occasions over a 5-day period (8:30 a.m. on days 1, 3, and 5; 2:30 p.m. on day 2) on 10 normal volunteers (five of each sex; mean age, 27.7 years) to assess, with repeated sampling, the day-to-day variation of selected CSF parameters. Two subjects abstained from the lumbar puncture on day 5 due to headache after the third puncture. Lumbar CSF was analyzed for concentrations of free and total gamma-aminobutyric acid (GABA), homocarnosine, homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), total protein, albumin, and immunoglobulin (Ig)G. No significant concentration differences were found between the afternoon and next morning samples. No differences were found in concentrations of free GABA, total GABA, homocarnosine, 5-HIAA, or albumin across the study. In contrast, HVA concentrations significantly increased by day 5, whereas total protein and IgG decreased during the study. The most likely explanation for these changes involves the known concentration gradients in the CSF column.

Adult↗
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

Pharmacokinetics of vigabatrin: implications of creatinine clearance.

The pharmacokinetics of both enantiomers of vigabatrin after a single oral dose in healthy young subjects (mean creatinine clearance 120 ml/min) were compared with kinetics in two groups of elderly subjects, one group aged 60 to 75 years (mean creatinine clearance 86 ml/min) and one group aged 76 to 97 years (mean creatinine clearance 30 ml/min). At a dose of 1500 mg, the group with the eldest subjects and the lowest creatinine clearance values showed mean increases of 3.3-fold in the time to reach the maximum concentration, 2.7-fold in the maximum concentration, and 9.8-fold in the AUC; a twofold prolongation of the t1/2; and reduced urinary excretion of the biologically and pharmacologically active S(+)-enantiomer. Changes in the intermediate group were qualitatively similar but quantitatively less. Parallel observations were made for the inactive R(-)-enantiomer. Most of these changes can be related to decreased renal clearance of vigabatrin. No interference of either enantiomer in the renal clearance of the other was noted. A nonlinear relationship between renal clearance and creatinine clearance for both enantiomers is suggested. Knowledge of the patient's renal function and an appropriate dose adjustment will minimize side effects during vigabatrin therapy, especially in elderly patients.

Administration, Oral↗
PubMed1988

[Treatment of human trypanosomiasis caused by Trypanosoma brucei gambiense using alpha-difluoromethylornithine. Results in 7 patients].

Alpha-difluoromethylornithine (DFMO, eflornithine) is a specific irreversible inhibitor of ornithine decarboxylase, shown to be curative in various Trypanosoma species infections of animals. In the present open study, the efficiency of DFMO was assessed in 7 patients (4 Africans, 3 Europeans) with Trypanosoma brucei gambiense (Tbg) infection, 4 in the advanced stage and 3 in the early phase of the disease. Treatment with DFMO at initial dosages ranging 300-500 mg/kg/day administered IV (except 1 case) for 10-15 days, followed by 200-300 mg/kg/day per os for 28-69 days was associated with clearing of trypanosomes from blood within 1-4 days, a trend towards normalisation or full normalisation of all altered biological values characterizing the disease and disappearance of clinical symptoms. Side effects of DFMO, including loose stools (5 cases), anemia (3 cases) and decreased hearing (1 case), were mild and transient requiring no treatment or interruption of the drug, except in one case. Pharmacokinetic studies carried out in 4 patients, demonstrate penetration of the drug into CNS. In 6 cases, no evidence of relapse was found at 24 months posttreatment follow-up indicating that DFMO can be curative in early and late-stage of Tbg sleeping sickness. In 1 case, no relapse could be detected after a follow-up of 6 months. Further studies are needed to confirm our encouraging results and to determine the optimal regimens of DFMO for the cure of the early and late-stage of sleeping sickness.

Adult↗
PubMed1987

Difluoromethylornithine for arseno-resistant Trypanosoma brucei gambiense sleeping sickness.

26 patients with arseno-resistant Trypanosoma brucei gambiense trypanosomiasis were treated with difluoromethylornithine (eflornithine), an inhibitor of ornithine decarboxylase, given intravenously, then orally. There was rapid disappearance of trypanosomes in the cerebrospinal fluid (CSF), gradual decrease of CSF lymphocytosis, and parallel improvement in central nervous system status. Side-effects, including diarrhoea, anaemia, and hair loss, were common but tolerable and reversible. 5 patients died during or shortly after treatment. None of the 21 patients who completed therapy has had a relapse during the 6-30 month follow-up.

Administration, Oral↗
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↗
PubMed1987

Decarboxylated-S-adenosylmethionine excretion: a biochemical marker of ornithine decarboxylase inhibition by alpha-difluoromethylornithine.

In an attempt to define a biochemical marker of ornithine decarboxylase inhibition in humans, alpha-difluoromethylornithine hydrochloride (DFMO), an irreversible ornithine decarboxylase inhibitor, was infused i.v. in seven cancer patients over 10-day courses at doses of 10-90 g/day and 24-h urinary excretion of polyamines and decarboxylated-S-adenosylmethionine was determined before, during, and after treatment. DFMO produces marked increases in urinary decarboxylated-S-adenosylmethionine excretion, up to 84 times pretreatment values. This response appears to be time dependent, requiring several days to reach a maximum and lasting at least 4-5 days after stopping DFMO. In contrast, urinary excretion of the polyamines putrescine, cadaverine, spermidine, N1-monoacetylspermidine, N8-monoacetylspermidine, and spermine, were not consistently altered by DFMO. We conclude that urinary excretion of decarboxylated-S-adenosylmethionine represents a valid biochemical indicator of ornithine decarboxylase inhibition in humans, whereas urinary polyamines are of no value.

Aged↗
PubMed1987

Cerebrospinal fluid GABA and homocarnosine concentrations in patients with Friedreich's ataxia, Parkinson's disease, and Huntington's chorea.

Free and total gamma-aminobutyric acid (GABA) and homocarnosine concentrations were measured in the lumbar cerebrospinal fluid (CSF) of patients with Friedreich's ataxia, Huntington's chorea, and Parkinson's disease (with and without levodopa treatment), and compared with those determined in control subjects. Values found in Friedreich's ataxia or Parkinson's disease were not significantly different from those in controls. Unexpectedly, in Huntington patients, known to have a characteristic decrease in GABA concentrations in specific brain areas, CSF concentrations of total GABA and homocarnosine were significantly higher, whereas free GABA was not different from controls. These findings indicate that the measurement of CSF GABA and homocarnosine in patients with CNS degenerative diseases should be interpreted cautiously.

Adult↗
PubMed1987

Treatment of acute myeloid leukemia and blastic phase of chronic myeloid leukemia with combined eflornithine (alpha difluoromethylornithine) and methylglyoxal-bis-guanyl hydrazone (methyl-GAG).

A combined eflornithine-MGBG treatment was studied in patients with acute myeloid leukemia (AML) or blastic transformation of chronic myeloid leukemia (BT CML). The first ten patients (5 AML, 5 BT CML) received i.v. or p.o. eflornithine 6 g m-2 day-1 and i.v. MGBG 500 mg/m2 once a week. The duration of treatment was 5-37 days (median 15) with one to five MGBG infusions (median 2). The results were complete response (CR) in one patient, partial response (PR) in four, minimal response (MR) in one and failure (F) in four. Pronounced side effects, including severe mucositis, gastrointestinal disturbances and skin infiltration, were observed in eight patients. As the four PRs were achieved in patients with BT CML, it was decided also to study ten patients with this indication. In attempts to decrease the incidence and severity of unwanted effects, lower doses of eflornithine-MGBG were used, i.e., eflornithine 4 g m-2 day-1 and MGBG 200 mg m-2 once a week. The duration of treatment was 9-110 days (median 46), with 2-14 MGBG infusions (median 6). Responses observed were CR in two patients (in one of whom it was only transient), transient PR in two, transient MR in four, and F in two. Treatment at lower doses was better tolerated, thus allowing a longer duration of treatment. Five of ten patients had moderate or severe gastrointestinal disturbances and one patient had a severe subjective hearing loss. The eflornithine-MGBG combination may prove to be a useful alternative treatment for AML and BT CML, but comparative trials will ultimately be necessary for a more definitive assessment of the combination.

Adult↗
PubMed1987

Phase I-II clinical trial with alpha-difluoromethylornithine--an inhibitor of polyamine biosynthesis.

Alpha-difluoromethylornithine (DFMO) is an enzyme-activated, irreversible inhibitor of ornithine decarboxylase, the first enzyme in the synthesis of the polyamines putrescine, spermidine and spermine. DFMO has been shown to have a cytostatic and cytotoxic effect against various human tumor cell lines. The present study was designed to evaluate the toxicity and efficacy of this compound when administered orally at a dose of 1.7 g/m sq. t.i.d. added to conventional chemotherapy to 38 patients with carcinoma of the breast, stomach, prostate, female genital organs or metastatic carcinoma of unknown origin. A control group of 32 patients with similar malignancies received conventional chemotherapy only. Gastrointestinal, hematologic and biochemical abnormalities caused by DFMO were negligible. Reasonable ototoxicity was the major toxic effect caused by DFMO and resulted in discontinuation of therapy in 6 of 38 patients (15.8%). No differences in disease progression were seen between those patients receiving DFMO plus conventional chemotherapy and those receiving only conventional chemotherapy.

Aged↗
PubMed1987

Treatment of human late stage gambiense trypanosomiasis with alpha-difluoromethylornithine (eflornithine): efficacy and tolerance in 14 cases in Côte d'Ivoire.

alpha-Difluoromethylornithine (DFMO; eflornithine), an inhibitor of polyamine biosynthesis, was used to treat 14 patients with late stage gambiense sleeping sickness, 12 cases having been previously treated with and considered refractory to melarsoprol. alpha-Difluoromethylornithine was administered intravenously at a dose of 400 mg/kg/day for 14 days followed by oral treatment, 300 mg/kg/day, for 21-28 days. In all patients treatment was associated with rapid disappearance of trypanosomes from body fluids (in several cases within 24 hr) and decreased cerebrospinal fluid white blood cell counts. In all but one patient, who died of a pulmonary infection during treatment, alpha-difluoromethylornithine produced a dramatic reversal of clinical signs and symptoms of the disease. Determination of drug concentrations in serum and cerebrospinal fluid of 5 patients demonstrated that alpha-difluoromethylornithine diffuses into the central nervous system with cerebrospinal fluid levels representing up to 51% of corresponding serum concentrations. Diarrhea, abdominal pain, and anemia were the most frequent side effects associated with therapy, but were reversible and did not necessitate discontinuation of treatment. Four patients have been followed for more than 2 years post-treatment without evidence of relapse.

Administration, Oral↗