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PubMed1991

Therapeutic effects of leflunomide, a new antirheumatic drug, on glomerulonephritis induced by the antibasement membrane antibody in rats.

Leflunomide is a new antirheumatic drug. It was evaluated, in comparison with azathioprine (AZA) and methylprednisolone acetate (MPA), for its therapeutic effects on the glomerulonephritis induced in rats by rabbit antiserum against the rat glomerular basement membrane. Its effect on body weight was also determined. Leflunomide (2 and 10 mg/kg/day, po), AZA (20 mg/kg/day, po), and MPA (2 mg/kg/day, sc) were administered for 28 days from 5 days after the intravenous injection of the rabbit antiserum. Leflunomide at both doses significantly decreased the urinary total protein, plasma total cholesterol, and plasma fibrinogen. On the other hand, neither AZA nor MPA affected the parameters except that they tended to reduce the urinary total protein. All three compounds decreased the plasma rat anti-rabbit IgG titer. Histologically, leflunomide at the high dose showed apparent therapeutic effects on the glomerulonephritis, as judged by light and electron microscopy and by immunofluorescence; the lesions were improved and deposits of rat IgG and C3 along the glomerular capillary wall decreased to a great extent. AZA and MPA exerted no therapeutic effects on the histological parameters except that MPA tended to reduce rat IgG and C3 deposits. Body weights increased favorably and slightly during leflunomide and AZA administration, respectively, but decreased during MPA treatment. Thus, leflunomide had more potent therapeutic effects on glomerulonephritis and less side effects than the already marketed drugs, suggesting that the compound is highly effective in improving immunologically mediated forms of glomerulonephritis, including membranous glomerulonephritis, at their early stages.

Animals↗
PubMed1998

Cell cycle perturbations in acute myeloid leukemia samples following in vitro exposures to therapeutic agents.

Cell cycle checkpoints establish the timing and strength of arrest, repair and apoptosis responses to damaging treatments. We designed flow cytometric assays to measure cell cycle arrest and apoptosis in acute myeloid leukemia (AML) samples treated in vitro with relevant therapeutic agents so as to functionally characterize checkpoints in these samples and to ask if checkpoint abnormalities are common in AML and contribute to therapeutic failures. We show here that cell cycle responses to daunomycin (DNR), cytosine arabinoside (ARA-C) and gamma irradiation (RAD) were reproducibly treatment agent- and dose-dependent and distinct in different myeloid cell lines. DNR treatments differentially induced cell accumulations in the gap 2 and mitosis (G2/M) phases of the cell cycle and/or in the gap 1 (G1) phase, as did RAD, while ARA-C induced accumulations in the DNA synthesis (S) phase or in the G1 phase. Flow cytometric gates were devised to exclude lymphocytes and mature neutrophils in analyses of primary myeloid cell samples. Cell subsets in bone marrow samples from normal donors were thus enriched for myeloid constituents and used as normal myeloid cell controls. Proliferating cell nuclear antigen (PCNA) immunostaining was used to further identify actively dividing cell subpopulations in primary cell samples. AML samples were similarly analyzed and the majority showed lower DNA synthesis cell cycle phase (S) fractions and lower PCNA-positive fractions than normal myeloid cells, suggesting that AMLs are generally less proliferative in these culture conditions. Exceptional AML samples with high S phase fractions had cytogenetic abnormalities associated with poor prognosis. Most AML samples mounted weak cell cycle responses relative to normal myeloid cells, while a minority showed robust, agent-specific cell cycle arrests. This non-responsiveness was not simply associated with lower cycling indices-neither the response patterns nor the degrees of response were correlated with untreated S phase fractions or with PCNA-positive fractions. Cell cycle responses were also not associated with clinical parameters including patient age, FAB class, or white blood cell count, nor with immunophenotypic features including CD34 status, nor with specific cytogenetic markers. This suggests that functional cell cycle response assays could provide unique diagnostic information in AML. These assays might also have prognostic value as ARA-C induced G1 arrests and DNR-specific G2/M arrests tended to be associated with failure to achieve clinical remission. In addition, G1 arrests after ARA-C and G2/M accumulations after DNR treatments tended to be more robust in samples that had previously been shown to be more highly immunopositive for bcl-2 expression. This data suggests that the association of bcl-2 expression with particular cell cycle responses to therapeutic agents may contribute to the association of bcl-2 with poor clinical responses in AML. These data provide the basis for further laboratory studies aimed at examining specific cell cycle arrests as mechanisms of therapeutic resistance and prospective studies aimed at rigorously assessing the prognostic utility of in vitro assays of checkpoint function.

Acute Disease↗
PubMed2000

Therapeutic targeting of human immunodeficiency virus type-1 latency: current clinical realities and future scientific possibilities.

Factors affecting HIV-1 latency present formidable obstacles for therapeutic intervention. As these obstacles have become a clinical reality, even with the use of potent anti-retroviral regimens, the need for novel therapeutic strategies specifically targeting HIV-1 latency is evident. However, therapeutic targeting of HIV-1 latency requires an understanding of the mechanisms regulating viral quiescence and activation. These mechanisms have been partially delineated using chronically infected cell models and, clearly, HIV-1 activation from latency involves several key viral and cellular components. Among these distinctive therapeutic targets, cellular factors involved in HIV-1 transcription especially warrant further consideration for rational drug design. Exploring the scientific possibilities of new therapies targeting HIV-1 latency may hold new promise of eventual HIV-1 eradication.

Antiviral Agents↗
PubMed2001

Molecular vehicle for target-mediated delivery of therapeutics and diagnostics.

Selective targeting of therapeutic and diagnostic agents improves their efficacy and minimizes potentially adverse side effects. Existing methods for selective targeting are based on chemical conjugation of therapeutics and diagnostics, or their carriers, to cell-specific targeting molecules (e.g., growth factors, antibodies). These methods are limited by potential damage to targeting molecules that can be inflicted by the conjugation procedure. In addition, conjugation procedures have to be developed on a case-by-case basis. In order to avoid these problems we have developed a new approach to constructing molecular vehicles for target-mediated delivery of therapeutics and diagnostics. In this approach, the targeting molecule is expressed as a fusion protein containing a recognition tag. The recognition tag is defined as a peptide or protein that can bind non-covalently another peptide or protein (adapter). In turn, the adapter is chemically conjugated to a carrier of therapeutics or diagnostics. The assembled molecular delivery vehicle contains a carrier-adapter conjugate bound non-covalently to a recognition tag fused to the targeting protein. The advantages of this technology are: (i) no chemical modification of targeting molecules, and (ii) universal, 'off-the-shelf' carrier-adapter constructs that can be combined with different fusion targeting proteins. To obtain a proof-of-principle we have constructed VEGF fusion proteins containing a 15-aa S-peptide fragment of RNase A as a recognition tag. Using the S-protein fragment of RNase A as an adapter and polyethylenimine as a DNA carrier we have achieved selective gene delivery to cells overexpressing VEGFR-2.

Animals↗
PubMed2000

Cellular transplants as sources for therapeutic agents.

Soluble factors normally produced by cells of the human body are of increasing importance as potential therapeutic agents. Although considerable progress has been made in understanding the etiology and pathogenesis of disease, in developing animal models and newer experimental therapeutics, few discoveries have been translated into clinically effective ways of delivering the multiple therapeutic agents obtained from living mammalian cells. This review examines the use of transplanted cells as alternatives to conventional delivery systems to deliver a variety of protein based therapeutic agents. The chapter begins with a set of questions to establish the complexity and challenges of this form of drug delivery. The following section focuses the discussion on our understanding of genetic engineering, tissue engineering, and some areas of developmental biology as they relate to the development of this nascent field. Much of the discussion has a neuro/endocrine emphasis. The chapter ends by listing the basic ingredients needed to push the use of transplanted cells toward medical practice and some general comments about future developments.

Animals↗
PubMed2003

Bispecific antibody conjugates in therapeutics.

Bispecific monoclonal antibodies have drawn considerable attention from the research community due to their unique structure against two different antigens. The two-arm structure of bsMAb allows researchers to place a therapeutic agent on one arm while allowing the other to specifically target the disease site. The therapeutic agent can be a drug, toxin, enzyme, DNA, radionuclide, etc. Furthermore, bsMAb may redirect the cytotoxicity of immune effector cells towards the diseased cells or induce a systemic immune response against the target. BsMAb holds great promise for numerous therapeutic needs in the light of: (1) recent breakthroughs in recombinant DNA technology, (2) the increased number of identified disease targets as the result of the completion of human genomic map project, and (3) a better understanding of the mechanism of human immune system. This review focuses on therapeutic applications and production of bsMAb while providing the up-to-date clinical trial information.

Antibodies, Bispecific↗
PubMed2004

[Therapeutic options for patients with localized prostatic carcinoma: our experience with 454 patients].

OBJECTIVES: To evaluate the influence of different therapeutic options on progression-free survival (PFS), overall survival (OS) and specific survival (SS) in a cohort of 454 patients with localized prostatic carcinoma, taking into account different prognostic factors, and to compare our results to those reported in the world literature. MATERIAL AND METHODS: Between 1983 and 2000 we have diagnosed 706 new cases of prostatic carcinoma and 454 were clinically localized tumors. The different therapeutic options employed in our series of patients have been: follow-up (FU) (103 patients); radical prostatectomy (RP) (108 patients); radiotherapy without hormonal blockade (RT) (148 patients); and hormonal blockade (HB) (95 patients). We have determined the PFS, the OS and the SS for each group of patients and compared them in patients with different prognostic factors at the time of diagnosis, including age, PSA levels, Gleason's grading and TNM staging. We have also analysed the influence of the tumor progression on the OS. The mean follow-up time has been 5.6 years (range: 0.1-19.2; median: 5.2). RESULTS: For PFS: the disease progressed in 145 patients (32%) and the PFS at 5 and 10 years has been 77% and 67% for FU; 61% and 50% for RP; 63% and 25% for RT; and 73% and 67% for HB, respectively. The differences between RT and RP were not statistically significant. For the subgroup of patients with PSA levels <10 and Gleason <8 the differences between FU, RP and RT did not reach statistical significance. For OS: 126 patients of our series died (28%) and the OS at 5 and 10 years has been 80% and 61% for FU; 90% and 76% for RP; 85% and 67% for RT; and 64% and 32% for HB, respectively. We have found no significant differences between FU, RP and RT. For SS: 31 patients of our series died of disease (6.8%). The SS at 5 and 10 years has been 100% and 94% for FU; 98% and 98% for RP; 97% and 88% for RT; and 83% and 77% for HB, respectively. We have found no significant differences in the OS between patients with disease progression and without disease progression treated with FU, RP and RT. CONCLUSIONS: Determination of PSA levels has allowed diagnosis of prostatic carcinomas in early stages of disease; however, our results and those reported in the literature cannot define which is the best therapeutic option in these patients. We should offer the patients individualized information both in the phase of early diagnosis and of therapeutic decisions.

Adenocarcinoma↗
PubMedDate not supplied

[Efficacy, tolerability and therapeutic benefit of etodolac (Lodine 200) in rheumatologic practice].

Efficacy, safety and therapeutic benefit of etodolac (Lodine 200) in rheumatological practice. An open clinical trial performed by 974 rheumatologists enabled an evaluation of efficacy, safety and therapeutic benefit of etodolac (Lodine 200) on 4,947 patients with rheumatoid arthritis, ankylosing spondylitis and osteoarthritis of the lower limbs; the initial dosage was 600 mg/d (for 2 weeks), then 400 to 600 mg/d (for 2 to 4 weeks, according to the indication). Efficacy, assessed by classical items for NSAID's, was shown to be excellent to good by 61-77 p. 100 of patients, according to the indication. 7.7 p. 100 of patients only dropped out for lack of efficacy. 20.4 p. 100 of patients developed adverse effect(s) (AE), but the relationship between etodolac and AE was assessed "possible" or "probable" only for 9.6 p. 100 of patients; this figure should be compared to the 7.6 p. 100 of patients who dropped out for AE and to the 92 p. 100 of patients who assessed the global safety as "excellent or good". The therapeutic benefit was estimated very favorable: 75 p. 100 of patients felt better than at the beginning of the study, 64.5 p. 100 of patients wished to continue the treatment and the (mean) benefit-risk ratio assessed with a logarithm scale (-1 to +1), ranged from 0.45 to 0.6 according to the indication. Therefore, this trial confirmed the good efficacy and safety profile of etodolac on a large scale in normal clinical practice in France, following assessments during controlled trials. It also permitted to perfect new items of evaluation for NSAID's, in particular for therapeutic benefit.

Adult↗
PubMed2002

A molecular basis of the therapeutic and psychoactive properties of cannabis (delta9-tetrahydrocannabinol).

All of the therapeutic properties of marihuana (analgesic, antiemetic, appetite stimulant, antiglaucoma) have been duplicated by the tetrahydrocannabinol (THC) molecule or its synthetic derivatives. Today, the molecular mechanisms of action of these compounds have led to a general understanding of the pharmacological effects of marihuana and of its therapeutic properties. These mechanisms involve the specific binding of THC to the 7-transmembrane (7TM) domain G protein-linked receptor, a molecular switch which regulates signal transduction in the cell membrane. The natural ligand of the 7TM receptor is an eicosanoid, arachidonylethanolamide (AEA), generated in the membrane and derived from arachidonic acid. THC acts as a substitute ligand to the 7TM receptor site of AEA. THC would deregulate the physiological function of the 7TM receptor and of its ligand AEA. As a result, the therapeutic effects of the drug may not be separated from its adverse psychoactive and cardiovascular effects. The binding of THC to the 7TM receptor site of AEA induces allosteric changes in the receptor sites of neurotransmitter and opiates resulting in variable interactions and pharmacological responses. The pharmacokinetics of THC with its prolonged storage in fat and its slow release result in variable and delayed pharmacological response, which precludes precise dosing to achieve timely therapeutic effects. The experimental use of THC and of its synthetic analogues, agonists, and antagonists has provided novel information in the nature of molecular signaling in the cell membrane. As a result, the relationships between allosteric receptor responsiveness, molecular configuration of proteins, and physiological regulation of cellular and organ function may be further investigated.

Animals↗
PubMed1985

Therapeutic uses of trace elements.

The properties of trace elements which feature in their therapeutic activity are: binding to macromolecules (enzymes, nucleic acids, etc.) with disturbance of biological function, and interaction with other elements. These properties, particularly the binding to large molecules, are far from specific, an observation which is reflected in the very wide range of diseases in which trace elements are employed. While metal compounds have been administered for several centuries, the scientific basis for treatment with trace elements began with the use of gold compounds, initially in patients with tuberculosis and later those with rheumatoid arthritis. Although many other drugs have been developed, some of which also include metal complexes, gold has retained an important position in the treatment of this condition. The gold-induced effects upon the immunological aspects of RA are also observed in other conditions with autoimmune involvement. The antineoplastic potential of metal complexes will be further exploited by the development of less toxic compounds--of platinum and possibly also of other metals. At the same time there are improvements in the protocols for administration which increase the range of cancers responding to treatment. Perturbation of gastrointestinal activity represents another area where trace elements have an important therapeutic role, both in the control of intraluminal acidity and in the adjustment of nutrient availability. A fourth significant area of trace element therapeutics involves the central nervous system where the use of lithium has provided spectacular results in the treatment of affective and other disorders. With a very wide range of other conditions in which they are employed, therapeutic uses provide somewhat unusual illustrations of the importance of trace elements in human disease.

Arthritis, Rheumatoid↗
PubMed1998

Placental anatomy, fetal demise and therapeutic intervention in monochorionic twins and the transfusion syndrome: new hypotheses.

OBJECTIVE: Monochorionic twins with circulatory sharing have an incompletely understood response to acute hemodynamic events. We relate placental vascular anatomy with, first, the response to (a) acute fetal demise and (b) laser interrupted placental anastomoses and, second, the efficacy of current and possibly future therapeutic interventions in twin-twin transfusion syndrome. DESIGN: Hemodynamic response to acute fetal demise and laser interrupted anastomoses is analysed using the model previously developed for monochorionic twins. Efficacy of therapeutic interventions in twin-twin transfusion syndrome is analysed by combining the estimated incidence of placental anastomotic patterns with three previously proposed pathophysiologic mechanisms. RESULTS: Fetal demise may cause sequelae for the co-twin in all anastomotic patterns except unidirectional arteriovenous and single venovenous anastomoses which are predicted to be hemodynamically harmless. In twin-twin transfusion syndrome, laser interruption of all anastomoses mitigates further transfusion. This is of benefit for the twins in equally but not in unequally shared placentas. Analysis predicts that approximately 75% fetal survival could be achieved interrupting only arteriovenous anastomoses. Amniocentesis may only prolong pregnancies that lack progressively increasing discordance, assuming that placental anastomoses remain patent following polyhydramnios. This proposed mechanism of action predicts current therapeutic efficacy accurately and could explain the significantly higher reported serious morbidity compared with laser (15/81 = 19+/-5% versus 4/146=3%, P=0.00004). However, if therapeutic interventions could match the syndrome's individual placental anatomy, the analysis suggests approximately 10-15% laser related mortality (premature rupture of membranes) and <3% severe morbidity could possibly become achievable goals. CONCLUSION: Our predictions allow clinical testing. This information may contribute to an improved management of monochorionic twins.

Amniocentesis↗
PubMed1999

Maximizing therapeutic gain with gemcitabine and fractionated radiation.

PURPOSE/OBJECTIVE: The nucleoside analogue gemcitabine inhibits cellular repair and repopulation, induces apoptosis, causes tumor growth delay, and enhances radiation-induced growth delay. After single doses of drug and radiation, maximum enhancement of tumor response was obtained when gemcitabine preceded radiation by at least 24 h. Conversely, the cellular radioresponse of the normal gastrointestinal epithelium was slightly protected when gemcitabine and radiation were separated by 24 h. This differential response created a time frame within which therapeutic gain could be maximized. In our present investigation, we sought to define the most therapeutically beneficial scheme of gemcitabine administration when combined with fractionated radiotherapy. METHODS AND MATERIALS: C3Hf/Kam mice were given identical drug and radiation schedules of administration, and both normal tissue (jejunal mucosa) and tumor (Sa-NH) responses were measured. Irradiation was given once per day for 5 days in normal tissue and tumor growth delay studies and twice per day for the tumor cure endpoint. A total dose of 25 mg/kg gemcitabine was given i.p. in 1 of 3 schedules: a single dose of 25 mg/kg 24 h before the start of fractionated irradiation, 12.5 mg/kg 24 h before the first and third radiation doses, or 24 h before each of 5 radiation doses. Groups of mice bearing 7- or 8-mm diameter tumors were treated with gemcitabine alone or in combination with fractionated irradiation under ambient or hypoxic conditions. The survival response of the jejunal mucosa was quantified by the microcolony assay and histologically by quantifying apoptosis, mitosis, S-phase fraction, and crypt cellularity. RESULTS: For tumor growth delay, dose-modifying factors (DMFs) were similar (1.34-1.46) for all 3 schedules of drug administration. In contrast, the response of the jejunum was strongly dependent on the schedule of gemcitabine administration. A single dose of gemcitabine before the start of fractionated radiotherapy resulted in slight radioprotection (DMF 0.96). Two doses and 5 daily doses of gemcitabine enhanced radiation response by factors of 1.09 and 1.23, respectively. Major factors affecting the response of the jejunal mucosa were apoptotic death of S-phase cells exposed to gemcitabine and cell cycle synchrony of surviving cells. Tumor reoxygenation was found to be a major mechanism for tumor radioenhancement, in addition to those reported earlier. CONCLUSION: All 3 schedules of drug administration produced therapeutic gain; however, when gemcitabine was given more than once in a 5-fraction radiation treatment schedule, normal tissue toxicity increased. The highest therapeutic gain (1.4) was achieved by giving a single dose of gemcitabine (25 mg/kg) 24 h before the start of fractionated radiotherapy.

Animals↗
PubMed2000

Plasma concentrations of the enantiomers of methadone and therapeutic response in methadone maintenance treatment.

Methadone is a 50:50 mixture of two enantiomers and (R)-methadone accounts for the majority of its opioid effect. The aim of this study was to determine whether a blood concentration of (R)-methadone can be associated with therapeutic response in addict patients in methadone maintenance treatment. Trough plasma concentrations of (R)-, (S)- and (R,S)-methadone were measured in 180 patients in maintenance treatment. Therapeutic response was defined by the absence of illicit opiate or cocaine in urine samples collected during a 2-month period prior to blood sampling. A large interindividual variability of (R)-methadone concentration-to-dose-to-weight ratios was found (mean, S.D., median, range: 112, 54, 100, 19-316 ng x kg/ml x mg). With regard to the consumption of illicit opiate (but not of cocaine), a therapeutic response was associated with (R)- (at 250 ng/ml) and (R,S)-methadone (at 400 ng/ml) but not with (S)-methadone concentrations. A higher specificity was calculated for (R)- than for (R,S)-methadone, as the number of non-responders above this threshold divided by the total number of non-responders was higher for (R,S)-methadone (19%) than for (R)-methadone (7%). The results support the use of therapeutic drug monitoring of (R)-methadone in cases of continued intake of illicit opiates. Due to the variability of methadone concentration-to-dose-to-weight ratios, theoretical doses of racemic methadone could be as small as 55 mg/day and as large as 921 mg/day to produce a plasma (R)-methadone concentration of 250 ng/ml in a 70-kg patient. This demonstrates the importance of individualizing methadone treatment.

Adult↗
PubMed1996

Analytical methods for the quantitative determination of selective serotonin reuptake inhibitors for therapeutic drug monitoring purposes in patients.

Five selective serotonin reuptake inhibitors (SSRIs) have been introduced recently: citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. Although no therapeutic window has been defined for SSRIs, in contrast to tricyclic antidepressants, analytical methods for therapeutic drug monitoring of SSRIs are useful in several instances. SSRIs differ widely in their chemical structure and in their metabolism. The fact that some of them have N-demethylated metabolites, which are also SSRIs, requires that methods be available which allow therapeutic drug monitoring of the parent compounds and of these active metabolites. most procedures are based on prepurification of the SSRIs by liquid-liquid extraction before they are submitted to separation by chromatographic procedures (high-performance liquid chromatography, gas chromatography, thin layer chromatography) and detection by various detectors (UV, fluorescence, electrochemical detector, nitrogen-phosphorus detector, mass spectrometry). This literature review shows that most methods allow quantitative determination of SSRIs in plasma, in the lower ng/ml range, and that they are, therefore, suitable for therapeutic drug monitoring purposes of this category of drugs.

1-Naphthylamine↗
PubMed2003

Design of controlled release delivery systems using a modified pharmacokinetic approach: a case study for drugs having a short elimination half-life and a narrow therapeutic index.

The objectives of peroral controlled release drug delivery systems (CRDDS) are to maintain therapeutically effective plasma drug concentration levels for a longer duration thereby reducing the dosing frequency and to minimise the plasma drug concentration fluctuations at steady state by delivering drug in a controlled and a reproducible manner. Drug delivery rate, duration of delivery and the dosing interval are the target features for any temporal CRDDS. The classical pharmacokinetic model for designing CRDDS [Drug Dev. Ind. Pharm. 15 (1989) 1073] assumes the time of drug delivery (t(del)) to be less than the dosing interval. However, termination of drug release from such a CRDDS at t(del) and/or a declining drug input function towards the terminal phase of t(del) from a first order kinetic CRDDS can have severe implications on plasma drug concentration and steady state fluctuations for a drug with very short half-life. A case study is presented in this paper, wherein by means of theoretical calculations using a classical pharmacokinetic approach, it is shown that a first order kinetic CRDDS for hypothetical drugs with short elimination half-life and different pharmacokinetic conditions would result in sub-therapeutic plasma concentrations at least for some time during the dosing interval at steady state. In order to avoid sub-therapeutic plasma drug concentrations a modification in classical pharmacokinetic model is proposed and discussed through theoretical calculations for different hypothetical pharmacokinetic situations and a practical single dose pharmacokinetic study with a first order kinetic CRDDS for nifedipine (a short half-life drug; about 2h). It is shown that improved therapeutic efficacy could be expected from a CRDDS developed based on proposed modification in the classical pharmacokinetic model.

Administration, Oral↗
PubMed1997

Therapeutic doses of theophylline exert proconvulsant effects in developing mice.

We studied the effect of therapeutic doses of theophylline on electrically-induced convulsions in developing mice. A theophylline dose as small as 3 mg/kg increased seizure susceptibility of 21-day-old mice, but not of 42-day-old mice. These findings were consistent with clinical reports that theophylline at the therapeutic blood concentrations occasionally induced convulsions in children. The age-dependent proconvulsant effect of theophylline was well inhibited by phenobarbital (PB), dose-dependently, but not by other well-established antiepileptic drugs (AEDs). PB may be a good choice of AED in patients with bronchial asthma and seizure disorders, if PB is indicative for their seizure types. The proconvulsant effect of theophylline in 21-day-old mice was counteracted by not only an adenosine A1 agonist, but also an NMDA antagonist and a histamine H3 antagonist. Several studies have established that the proconvulsant effect of theophylline intoxication is mainly due to the blockade of adenosine A1 receptors. The present findings suggested that the proconvulsant properties of therapeutic doses of theophylline in developing period were different from those of theophylline intoxication. Combination of therapeutic doses of theophylline and centrally-acting histamine H1 antagonists showed proconvulsant effects even in 42-day-old mice, suggesting that peripherally acting histamine H1 antagonists, such as astemizole, evastine and epinastine, were much safer than centrally acting histamine H1 antagonists for patients with both allergy and seizure history.

Aging↗
PubMed2001

HPLC and GC-MS screening of Chinese proprietary medicine for undeclared therapeutic substances.

Traditional Chinese medicine includes raw medicinal materials and Chinese proprietary medicine (CPM). Despite being of natural origin, toxic effects, adulteration with synthetic therapeutic substances and even deaths had been associated with CPM. There is thus a need to develop analytical technique to rapidly screen for undeclared toxic and therapeutic substances in CPM. In this study, a high performance liquid chromatography-diode-array detection method was developed and used to screen for undeclared therapeutic substances in CPM. An ultraviolet (UV) library of 266 drugs had been compiled. Solute identification was performed by comparing the analytical data (UV spectra, retention time and relative retention time) with those of the 266 standards. Gas chromatography-mass spectrometry was used as a confirmation method. These chromatographic methods had been shown to be selective and reproducible in screening for undeclared drugs in CPM. Using the method developed, 41 CPM samples in seven categories were screened for undeclared therapeutic substances. One anti-asthmatic CPM was found to contain codeine.

Chromatography, High Pressure Liquid↗
PubMed2004

[Stem cells and therapeutic cloning, medical perspectives under discussion].

Innovative biotechnical progress over the past few years regards stem cells and therapeutic cloning, which open promising medical horizons for many presently incurable diseases. THE CURRENT DEBATE: The research work in France has been stalled because of the prohibitions listed in the so-called "bioethical" laws of 1994. The ongoing revision of these laws is based on a certain number of ethical questions and launches a disputable parlementary debate. Other than reproductive cloning and research on the embryo, the possibilities provided by stem cells and therapeutic cloning should be emphasized and the different positions advanced specified, showing an evolution in the laws in France. ABUSIVE LEGISLATIVE PROHIBITIONS: The proposed law, which maintains the prohibition for research on the embryo, with a 5-Year dispensation, and which explicitly prohibits therapeutic cloning, is not in keeping with the widening of in this field expected by research teams. Many scientists and physicians, supported by patients' associations, are aware of the importance of therapeutic progress attached to such research. They should not be stalled in their studies by the prohibitions maintained in the new law.

Adult↗