S Sussan

Hebrew University of Jerusalem, Jerusalem, Jerusalem District, Israel

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Publications (6)15.86 Total impact

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    ABSTRACT: Glycine is a major inhibitory neurotransmitter and recent reports have shown that certain lipophilic derivatives of glycine demonstrate anticonvulsant activity in intact animals. In these studies, glycinamide derivatives were found to be more potent than their corresponding glycine analogues. Consequently, the objective of the current study was to investigate the pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following phenyl derivatives of glycinamide: N'-benzyl glycinamide, N-benzyloxycarbonyl glycinamide (Z-glycinamide), Z-glycine, N-Z,N'-benzyl glycinamide and N-phenylacetyl glycinamide. The antiepileptic activity and neurotoxicity was carried out in classical animal models for antiepileptic screening. The pharmacokinetics of the active compounds were studied in dogs, a common animal model for comparative crossover pharmacokinetic studies. Of the compounds investigated in this study, Z-glycinamide, N'-benzyl glycinamide and N-Z,N'-benzyl glycinamide were found to be active. Therefore, the disposition of Z-glycinamide and N-Z,N'-benzyl glycinamide in comparison to Z-glycine was studied in plasma, brain, liver and urine of rats. The disposition of Z-glycinamide and N-Z,N'-benzyl glycinamide into the brain was better than that of Z-glycine. Unlike glycine or glycinamide, Z-glycinamide and N-Z,N'-benzyl glycinamide showed antiepileptic activity in animal models due to their better pharmacodynamic and pharmacokinetic properties. The pharmacokinetics of Z-glycinamide was similar in dogs and rats. Substitution of the Z group with the analogous phenylacetyl moiety led to inactive compounds. In an analogous series of compounds, the loss of the anticonvulsant activity may be due to pharmacodynamic and pharmacokinetic reasons. This study provides certain clues concerning the structural requirements for the design of antiepileptic-active glycine derivatives.
    Epilepsy Research 05/1999; 34(2-3):207-20. · 2.24 Impact Factor
  • S Sussan, A Dagan, M Bialer
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    ABSTRACT: The objective of this study was to investigate the pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of a series of amide derivatives of glycinamide in order to explore their structure pharmacokinetic-pharmacodynamic relationship and to discover a glycinamide derivative which might have the potential to become a new antiepileptic agent. The following compounds were investigated: glycylglycine, glycylglycinamide, gaboylglycinamide, N-acetylglycine, N-acetylglycinamide, N-acetylglycylglycinamide, N-acetyl, N'-benzylglycinamide, N-benzyloxycarbonylglycine or Z-glycine, Z-glycinamide, Z-glycylglycine and Z-glycylglycinamide. The anticonvulsant activity and neurotoxicity study was carried out in classical animal models for anticonvulsant screening. The pharmacokinetics of the active compounds was studied in dogs, which is a common animal model for a comparative crossover pharmacokinetic studies. Of the compounds investigated in this study, all the dipeptides of glycinamide and the glycine derivatives were found to be inactive. The only two active compounds were: N-acetyl,N'-benzylglycinamide (VII) and Z-glycinamide (IX). These compounds demonstrated similar pharmacokinetic profiles. Unlike glycine or glycinamide, compounds VII and IX, being lipophilic derivatives of glycinamide, showed anticonvulsant activity in animal models due to their better pharmacodynamic and pharmacokinetic properties. The pharmacodynamics and pharmacokinetics of compounds VII and IX were similar to that of the potential new antiepileptics; N-valproylglycinamide and phthaloylglycinamide. This study provides certain clues concerning the structural requirements for the design of anticonvulsant-active glycine derivatives.
    Epilepsy Research 02/1999; 33(1):11-21. · 2.24 Impact Factor
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    ABSTRACT: While the three classical pharmacokinetic (PK) parameters, AUC, Cmax and tmax are adequate to assess bioequivalence of immediate release (IR) formulations, they are not designed to fully characterize the pharmacokinetic (PK) performance of controlled release (CR) formulations and provide only limited insight into the function of carbamazepine (CBZ) CR products. Thus, for reliable assessment of bioequivalence in CR formulations, there is a role for the use of additional criteria (parameters). The following are the proposed new parameters: MRT (mean residence time), Cmax/AUC, plateau time or POT (the time span associated with the concentrations within 25% of Cmax), tapical (the arithmetic mean of the times associated with POT) and Capical (the arithmetic mean of the concentrations within 25% of Cmax). The above proposed parameters, were utilized in a recent PK study of new CR products of CBZ (600 mg) designed for once daily dosing. The comparative PK analysis was conducted in a three-way crossover single dose studies of three CBZ CR formulations (Teril 600 CR tablet, CBZ 600 granulate and Timonil 600 Retard tablet). Teril 600 CR was found to be bioequivalent to Timonil 600 Retard while CBZ 600 granulate was not. This conclusion was reached utilizing both the classical and the proposed new parameters. The new parameters showed that CBZ 600 granulate has similar rate of absorption as the two 600 mg CR tablets, but its extent of absorption was lower. The new parameters examined in this paper are more attractive than the single point parameters, Cmax and tmax, for assessment of rate of absorption and the flatness of the plasma concentration versus time curve. Their potential benefit and practical utility was confirmed in this study, which demonstrated bioequivalence between a new CR and an innovator CBZ (600 mg) tablet. Absorption rate assessment is important in light of concentration-related side effects associated with CBZ therapy and the impact of fluctuations and the flatness of the CBZ plasma concentration curve on the drug efficacy and tolerability.
    Epilepsy Research 12/1998; 32(3):371-8. · 2.24 Impact Factor
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    ABSTRACT: The three classical pharmacokinetic parameters used to assess bioequivalence, AUC (total area from zero to infinity), Cmax (peak plasma concentration), and tmax (time to reach Cmax), are suitable to determine the extent and rate of absorption of immediate-release drug products. However, they may fail to evaluate the pharmacokinetic performance, particularly the rate of absorption of sustained-release (SR) formulations, which yield flat plasma curves with multiple peaks. This paper evaluates the inclusion of the following criteria for bioequivalence assessment of diltiazem SR formulations: MRT (mean arithmetic time), Cmax/AUC, peak occupancy time (POT), t(apical) (the arithmetic mean of the times associated with the concentrations within 25% of Cmax), C(apical) (the arithmetic mean of the concentration within 25% of Cmax), percent fluctuation and flatness of the curve as assessed by the coefficient of variation of the Css (steady state concentration) values obtained during a dosing interval at steady state. The above proposed criteria, as well as the classical parameters AUC, Cmax, and tmax were utilized in a recent pharmacokinetic study of a new SR product of diltiazem, Dilapress 240 (formulation A). Formulation A was analyzed following single (240 mg) and multiple (240 mg qd for 6 days) dosing at steady state (day 6) in comparison to Cardizem CD (formulation B). The bioavailability of formulation A relative to that of formulation B following single and multiple dosing was 92 +/- 28% and 90 +/- 24%, respectively. The 90% confidence intervals (Cl) over a mean AUC ratio of 89% were 78-101% (single dose, SD) and 77-101% (multiple dose, MD). following the administration of formulations A and B, identical mean values of the peak plasma concentration were obtained: 84 ng/mL (SD) and 132 ng/mL (MD). The 90% Cl over a mean Cmax ratio of 100% were 83-115% (SD) and 86-115% (MD). In the SD study, subject 8 had a relative bioavailability value of 24%, which deviated by 7.5 standard errors (SE) from the mean AUC ratio. Consequently, we repeated the single dose analysis without subject 8. The mean bioavailability data was 97 +/- 37% with a 90% Cl of 80-114% over a mean AUC ratio of 92%. ANOVA analysis did not show any formulation or period effect in all tested pharmacokinetic parameter s. On the basis of these results, these two formulations were judged to be bioequivalent. In contrast to the AUC and Cmax ratio, the 90% Cls associated with the ratio of the proposed criteria, with the exception of C(apical), did not fall within the acceptable limits. In the current study, a discrepancy was found between the above pharmacokinetic parameters, which were examined concerning their ability to detect differences in bioequivalence between SR products and the classical parameters regularly used for bioequivalence assessment. Although the parameters examined are theoretically more attractive than the single point parameters Cmax and tmax for rate of absorption assessment, their utility in bioequivalence would require further examination.
    Journal of Pharmaceutical Sciences 11/1995; 84(10):1160-3. · 3.13 Impact Factor
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    ABSTRACT: Glycine, in addition to GABA, is one of the most important neurotransmitter amino acids. The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the possibility of utilizing phthaloyl derivatives of glycine as new antiepileptics. This was carried out by investigating the pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following four phthalimide derivatives: phthaloyl glycine, phthaloyl glycinamide, N,N-diethyl phthaloyl glycinamide and N,N-diisopropyl phthaloyl glycinamide. Phthaloyl glycine did not demonstrate anticonvulsant activity, possibly because of its poor pharmacokinetics, high clearance, low volume of distribution and short half life. The three glycinamide derivatives showed anticonvulsant activity and had better pharmacokinetic profiles, longer half life and mean residence time, than phthaloyl glycine. Phthaloyl glycinamide was more potent than one of the major antiepileptic agents--valproic acid and showed a better margin between activity and neurotoxicity. The four investigated phthaloyl glycine derivatives did not operate as chemical drug delivery systems (CDDS) of glycine, but acted rather as drugs on their own. Phthaloyl glycine was excreted unchanged in the urine while the urinary metabolites of the glycinamide derivatives were phthaloyl glycine and phthaloyl glycinamide. In this analogous series of phthalimide derivatives, minor chemical changes affected dramatically the compounds' pharmacokinetics. The current study demonstrates the benefit of the SPPR approach in developing and selecting a potent antiepileptic compound in intact animals based not only on its intrinsic pharmacodynamic activity, but also on its better pharmacokinetic profile.(ABSTRACT TRUNCATED AT 250 WORDS)
    Pharmaceutical Research 11/1994; 11(10):1429-34. · 4.74 Impact Factor
  • International Journal of Clinical Pharmacy 17(10). · 1.27 Impact Factor