Double vitrification and warming does not compromise the chance of live birth after single unbiopsied blastocyst transfer.

STUDY QUESTION: Does double vitrification and thawing of an embryo compromise the chance of live birth after a single blastocyst transfer? SUMMARY ANSWER: The live birth rate (LBR) obtained after double vitrification was comparable to that obtained after single vitrification. WHAT IS KNOWN ALREADY: Double vitrification-warming (DVW) is commonly practiced to accommodate surplus viable embryos suitable for transfer, to allow retesting of inconclusively diagnosed blastocysts in preimplantation genetic testing (PGT), and to circumvent limitations associated with national policies on embryo culture in certain countries. Despite its popularity, the evidence concerning the impact of DVW practice on ART outcomes is limited and lacking credibility. This is the first thorough investigation of clinical pregnancy and LBR following DVW in the case where the first round of vitrification occurred at the zygote stage and the second round occurred at the blastocyst stage in the absence of biopsy. STUDY DESIGN SIZE DURATION: This is a retrospective observational analysis of n = 407 single blastocyst transfers whereby embryos created by IVF/ICSI were vitrified-warmed once (single vitrification-warming (SVW) n = 310) or twice (DVW, n = 97) between January 2017 and December 2021. PARTICIPANTS/MATERIALS SETTING METHODS: In the SVW group, blastocysts were vitrified on Day 5/6 and warmed on the day of embryo transfer (ET). In the DVW group, two pronuclear (2PN) zygotes were first vitrified-warmed and then re-vitrified on Day 5/6 and warmed on the day of ET. Exclusion criteria were ETs from PGT and vitrified-warmed oocyte cycles. All of the ETs were single blastocyst transfers performed at the University Hospital Zurich in Switzerland following natural or artificial endometrial preparation. MAIN RESULTS AND THE ROLE OF CHANCE: The biochemical pregnancy rate, clinical pregnancy rate (CPR), and LBR were all comparable between the DVW and SVW groups. The CPR for DVW was 44.3% and for SVW it was 42.3% (P = 0.719). The LBR for DVW was 30.9% and for SVW it was 28.7% (P = 0.675). The miscarriage rate was additionally similar between the groups: 27.9% for DVW and 32.1% for SVW groups (P = 0.765). LIMITATIONS REASONS FOR CAUTION: The study is limited by its retrospective nature. Caution should be taken concerning interpretation of these findings in cases where DVW occurs at different stages of embryo development. WIDER IMPLICATIONS OF THE FINDINGS: The result of the present study on DVW procedure provides a framework for counselling couples on their chance of clinical pregnancy per warming cycle. It additionally provides confidence and reassurance to laboratory professionals in certain countries where national policies limit embryo culture strategies making DVW inevitable. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the University Research Priority Program 'Human Reproduction Reloaded' of the University of Zurich. The authors have no conflict of interest related to this study to declare. TRIAL REGISTRATION NUMBER: N/A.

Higher miscarriage rate in subfertile women with endometriosis receiving unbiopsied frozen-warmed single blastocyst transfers.

Background: Assisted reproductive technology treatment is recommended to overcome endometriosis-associated infertility but current evidence is controversial. Endometriosis is associated with lower antral follicle count (AFC) and oocyte yield but similar clinical outcomes compared to controls. Unaffected ovarian stimulation response and embryological outcomes but lower clinical pregnancy and live birth rates and higher miscarriage rates have been reported, implying direct impact on endometrial receptivity. With evidence emerging on the benefit of frozen-warmed and blastocyst stage transfer, we investigated ART outcomes in endometriosis using homogeneous case-control groups. Methods: This is a retrospective observational case-control study including n = 66 frozen-warmed unbiopsied single blastocyst transfers of patients with endometriosis and n = 96 of women exhibiting idiopathic sterility. All frozen-warmed transfers followed artificial endometrial preparation. Results: In control women, the mean number of oocytes recovered at oocyte pick up was higher compared to women with endometriosis (15.3 ± 7.1 vs. 12.7 ± 5.2, p = 0.025) but oocyte maturation index (mature oocytes/total oocytes at oocyte pick up) was significantly higher for endometriosis (48.2% vs. 34.0%, p = 0.005). The same was shown for the subgroup of 44 endometriosis patients after endometrioma surgery when compared with controls (49.1% vs. 34.0%, p = 0.014). Clinical pregnancy rate was not higher in endometriosis but was close to significance (47.0% vs. 32.3%, p = 0.059) while live birth rate was comparable (27.3% vs. 32.3%, p = 0.746). Miscarriage rate was higher in the endometriosis group (19.7% vs. 7.3%, p = 0.018). A significantly higher AFC was observed in the control group in comparison with the endometriosis group (16.3 ± 7.6 vs. 13.4 ± 7.0, p = 0.014). Live birth rate did not differ when comparing all endometriosis cases (p = 0.746), ASRM Stage I/II and Stage III/IV (p = 0.348 and p = 0.888) with the control group but the overall pregnancy rate was higher in ASRM Stage I/II (p = 0.034) and miscarriage rate was higher in ASRM Stage III/IV (p = 0.030) versus control. Conclusion: Blastocyst transfers in women with endometriosis originate from cycles with lower AFC but higher share of mature oocytes than in control women, suggesting that endometriosis might impair ovarian reserve but not stimulation response. A higher miscarriage rate, independent of blastocyst quality may be attributed to an impact of endometriosis on the endometrium beyond the timing of implantation.

Evaluation of Outcome Prediction of Flow Diversion for Intracranial Aneurysms.

BACKGROUND AND PURPOSE: Identifying and predicting which aneurysms are likely to quickly occlude and which ones are likely to remain open following treatment with flow-diverting devices is important to develop optimal patient management strategies. The purpose of this study was to evaluate predictions based on computational fluid dynamics models using the elastase rabbit aneurysm model. MATERIALS AND METHODS: A series of 13 aneurysms created in rabbits were treated with flow diverters, and outcomes were angiographically assessed at 8 weeks' follow-up. Computational fluid dynamics models were constructed from pretreatment 3D rotational angiograms and Doppler ultrasound flow velocity measurements. Postimplantation mean aneurysm inflow rate and flow velocity were used to prospectively predict aneurysm occlusion blinded to the actual outcomes. Specifically, if both variables were below their corresponding thresholds, fast occlusion was predicted, while if one of them was above the threshold, slow or incomplete occlusion was predicted. RESULTS: Of the 13 aneurysms included, 8 were incompletely occluded 8 weeks after treatment, and 5 were completely occluded. A total of 10 computational fluid dynamics-based predictions agreed with the angiographic outcome, reaching 77% accuracy, 80% sensitivity, and 75% specificity. Posttreatment mean velocity alone was able to achieve the same predictive power as the combination of inflow rate and velocity. CONCLUSIONS: Subject-specific computational fluid dynamics models of the hemodynamic conditions created immediately after implantation of flow-diverting devices in experimental aneurysms created in rabbits are capable of prospectively predicting, with a reasonable accuracy, which aneurysms will completely occlude and which ones will remain incompletely occluded.

Regional Aneurysm Wall Enhancement is Affected by Local Hemodynamics: A 7T MRI Study.

BACKGROUND AND PURPOSE: Aneurysm wall enhancement has been proposed as a biomarker for inflammation and instability. However, the mechanisms of aneurysm wall enhancement remain unclear. We used 7T MR imaging to determine the effect of flow in different regions of the wall. MATERIALS AND METHODS: Twenty-three intracranial aneurysms imaged with 7T MR imaging and 3D angiography were studied with computational fluid dynamics. Local flow conditions were compared between aneurysm wall enhancement and nonenhanced regions. Aneurysm wall enhancement regions were subdivided according to their location on the aneurysm and relative to the inflow and were further compared. RESULTS: On average, wall shear stress was lower in enhanced than in nonenhanced regions (P = .05). Aneurysm wall enhancement regions at the neck had higher wall shear stress gradients (P = .05) with lower oscillations (P = .05) than nonenhanced regions. In contrast, aneurysm wall enhancement regions at the aneurysm body had lower wall shear stress (P = .01) and wall shear stress gradients (P = .008) than nonenhanced regions. Aneurysm wall enhancement regions far from the inflow had lower wall shear stress (P = .006) than nonenhanced regions, while aneurysm wall enhancement regions close to the inflow tended to have higher wall shear stress than the nonenhanced regions, but this association was not significant. CONCLUSIONS: Aneurysm wall enhancement regions tend to have lower wall shear stress than nonenhanced regions of the same aneurysm. Moreover, the association between flow conditions and aneurysm wall enhancement seems to depend on the location of the region on the aneurysm sac. Regions at the neck and close to the inflow tend to be exposed to higher wall shear stress and wall shear stress gradients. Regions at the body, dome, or far from the inflow tend to be exposed to uniformly low wall shear stress and have more aneurysm wall enhancement.

Effects of metformin on breast cancer cell proliferation, the AMPK pathway and the cell cycle.

AIM: The aim of this study was to compare the effects and mechanisms of action of metformin on estrogen receptor (ER)-positive and ER-negative breast cancer cell lines. METHODS: The anti-proliferative effects of metformin, and of the direct activator of adenosine monophosphate-activated protein kinase (AMPK), A-769662, on MCF-7 (ER-positive) and MDA-MB-231 (ER-negative) breast cancer cell lines were evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide, a yellow tetrazole) assays. Fluorescence-activated cell sorting was also used to examine the effect of metformin on the cell cycle. Finally, phosphorylation of the metformin target AMPK, and of its potential downstream targets including acetyl-CoA carboxylase (ACC), p53, p70-S6K and Raptor, was examined using immunoblotting. RESULTS: Metformin and A-769662 caused significant, concentration-dependent suppression of cell proliferation with G1 cell cycle arrest in both MCF-7 and MDA-MB-231 cells. The proliferation suppression effect was more profound in MCF-7 cells. A concentration-dependent phosphorylation of AMPK was detected following metformin treatment, as was phosphorylation of ACC in both cell lines, but not p53, p70-S6k or Raptor. CONCLUSION: Metformin acts as a growth inhibitor in both ER-positive and ER-negative breast cancer cells in vitro, and arrests cells in G1 phase, particularly in the ER-positive MCF-7 cells. The effect is likely to be mediated by AMPK activation, in part by inhibition of fatty acid synthesis via ACC phosphorylation.

High incidence of hepatitis B infection after treatment for paediatric cancer at a teaching hospital in Baghdad.

This study estimated the incidence of viral hepatitis in children treated for cancer, to identify variables that could affect this incidence and to assess the role of hepatitis B virus (HBV) vaccination in preventing infection. Between September 2007 and June 2008, 256 children in the haemato-oncology unit at the Children's Welfare Teaching Hospital, Baghdad, were studied prospectively. Demographic and clinical data and vaccination history were recorded. Patients were tested for HBV at the time of diagnosis (all were negative) and after starting chemotherapy. On admission to the unit, 231 patients (90.2%) were revaccinated. At reassessment after treatment for cancer, HBV infection was found in 70 patients (27.3%). The variables that significantly increased the risk for HBV infection were a diagnosis of leukaemia and receiving more than 3 units of blood. A higher number of HBV vaccinations in hospital reduced the risk for HBV infection. The high rate of acquisition of HBV infection found in this study indicates the need for better screening of blood products and adherence to aseptic techniques in management of this group of patients.

High incidence of hepatitis B infection after treatment for paediatric cancer at a teaching hospital in Baghdad

This study estimated the incidence of viral hepatitis in children treated for cancer, to identify variables that could affect this Incidence and to assess the role of hepatitis B virus [HBV] vaccination In preventing infection. Between September 2007 and June 2008, 256 children in the haemato-oncology unit at the Children's Welfare Teaching Hospital, Baghdad, were studied prospectively. Demographic and clinical data and vaccination history were recorded. Patients were tested for HBV at the time of diagnosis [all were negative] and after starting chemotherapy. On admission to the unit, 231 patients [90.2%] were revaccinated. At reassessment after treatment for cancer, HBV infection was found in 70 patients [27.3%]. The variables that significantly increased the risk for HBV infection were a diagnosis of leukaemia and receiving more than 3 units of blood. A higher number of HBV vaccinations in hospital reduced the risk for HBV infection. The high rate of acquisition of HBV infection found in this study indicates the need for better screening of blood products and adherence to aseptic techniques In management of this group of patients

Pharmacokinetics of fluphenazine, a highly lipophilic drug, estimated from a pulse dose of a stable isotopomer in dogs at steady state.

The potential utility of a pulse dose of a deuterium-labeled isotopomer (FLU-D(4)) in elucidating the pharmacokinetics of fluphenazine (FLU) at steady state was investigated in dogs. The single-dose oral pharmacokinetics of FLU in dogs were established. After resting the dogs for 3 weeks, the animals were dosed to steady state with oral FLU administered at 12-h intervals. Following 15 doses, one dose of FLU was replaced by a pulse dose of FLU-D(4), after which dosing with FLU was resumed. FLU and FLU-D(4) plasma concentrations were determined by tandem mass spectrometry. Comparable estimates of apparent oral clearance were calculated from (i) a single dose of FLU, (ii) a pulse dose of FLU-D(4), and (iii) over a dosing interval at steady state. Average steady-state plasma concentrations were reliably predictable from a pulse dose of FLU-D(4).

Home intravenous antibiotic treatment for febrile episodes in immune-compromised pediatric patients.

The purpose of this work was to assess the feasibility of home intravenous antibiotic treatment (HIAT) for febrile episodes in immune-compromised (neutropenic, splenectomized), low-risk pediatric patients. Thirty hematology-oncology patients who presented to our emergency room from January 1993 to January 1995 and who suffered from a febrile episode and were considered at low risk for septic complications were immediately discharged on HIAT. Patients were followed for at least 3 weeks after recovery. Patients and parents were retrospectively questioned about adverse effects and about their degree of satisfaction with home treatment. Patients who required hospitalization during this period were considered unresponsive to HIAT and were analyzed for causes and adverse effects. Thirteen out of 60 (22%) febrile episodes, or eight out of 42 (19%) episodes of fever and neutropenia eventually led to hospitalization. Pseudomonas species infections were associated with the highest rate of unresponsiveness (88%). A central venous catheter infection developed in two cases following HIAT (two cases out of 640 days of therapy). No other complications were identified. No infection-related morbidity was observed. Patients and parents were highly satisfied with HIAT and wanted to use it again, if necessary. Immediate discharge on HIAT for low-risk pediatric immune-compromised patients suffering from a febrile episode is feasible, safe, and well accepted by patients and families. Patients who are found to have Pseudomonas infections should probably be hospitalized. Our results are preliminary and must be confirmed by a prospective, randomized trial before definite recommendations can be made.

Pharmacokinetic analysis and antiepileptic activity of two new isomers of N-valproyl glycinamide.

Valproyl glycinamide (TV 1901-VPGD) is a new antiepileptic drug, which is currently undergoing clinical trials. The present study explored the pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of two new isomers of valproyl glycinamide: valnoctyl glycinamide (VCGD) and diisopropylacetyl (DIGD). Both VCGD and DIGD showed anticonvulsant activity and a safety margin in mice similar to those of VPGD. Following i.v. administration (556 mg) to six dogs, VCGD had a clearance (Cl) value of 3.8 +/- 1.1 Lh-1 (mean +/- SD), a volume of distribution (Vss) of 15 +/- 2 L, and a half-life (t1/2) of 1.9 +/- 0.3 h. DIGD had Cl, Vss, and t1/2 values of 10 +/- 0.8 Lh-1, 19 +/- 3 L, and 1.6 +/- 0.2 h, respectively. Neither VCGD nor DIGD operated as chemical drug delivery systems (CDDSs) of glycine, valnoctic acid, or diisopropyl acetic acid and both showed antiepileptic profiles different from that of valproic acid (VPA). Both glycinamides were biotransformed to their glycine analogues with similar fractions metabolized (fm): 59 +/- 5% (VCGD) and 62 +/- 15% (DIGD). The two glycine metabolites, valnoctyl glycine (VCGA) and diisopropylacetyl glycine (DIGA), were also administered to the same dogs in order to calculate the above fm values. Both VCGA and DIGA had higher Cl and lower Vss values than VCGD and DIGD and therefore their mean t1/2 values were 0.43 +/- 0.02 and 0.30 +/- 0.07 h, respectively. VCGA and DIGA were excreted mainly intact in the urine, with fractions excreted unchanged (fe) of 60 +/- 9 and 55 +/- 7%, respectively. The improved pharmacokinetic profile of VCGD and DIGD relative to their glycine analogues may explain the similarity of their anticonvulsant activity to that of valproyl glycinamide. The current study demonstrates the benefit of the structure-pharmacokinetic-pharmacodynamic relationship (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 improved pharmacokinetic profile.

Alteration of cytosolic calcium induced by angiotensin II and norepinephrine in mesangial cells from diabetic rats.

To evaluate functional alterations of mesangial cells induced by diabetes (DMC), we observed the changes of cytosolic calcium ([Ca]i) in response to the vasoconstrictor agonists angiotensin II (Ang II) and norepinephrine (NOR). DMC were obtained from rats with streptozotocin-induced diabetes, cultured in normal medium and identified as mesangial cells (MC) in the third subculture. [Ca]i was measured using fura-2 as a fluorophore. Basal calcium levels (60 to 80 nM) in DMC were not different from control mesangial cells (CMC). The high glucose (30 mM) medium concentration reduced the response of CMC and DMC to Ang II and NOR. This was not an osmotic effect since mannitol did not alter these responses. When DMC were stimulated with Ang II, a desensitized response was always observed, with a transient variation of [Ca]i (N = 6, P < 0.05). In contrast, a non-desensitized response with a sustained pattern of [Ca]i increases was obtained in NOR-stimulated DMC. Therefore, the present results suggest that DMC show a modified response to stimulation of the Ang II receptor, which is expressed phenotypically in culture by desensitization. Furthermore, these alterations induced by diabetes environment in MC in vivo were maintained in vitro despite a long period (approximately 5 months) in which the cells were grown in normal culture medium.

Proteoglycans and glycosaminoglycans synthesized in vitro by mesangial cells from normal and diabetic rats.

In the renal glomerulus, two extracellular matrices have been identified, the glomerular basement membrane and the mesangial matrix. Accumulation of glomerular extracellular matrix is a conspicuous feature of most forms of progressive glomerular disease, including diabetic nephropathy. Since proteoglycans are prominent components of the extracellular matrix, we examined the glycosaminoglycans and proteoglycans synthesized in vitro by mesangial cells from normal and diabetic rats. A mixture of dermatan sulfate and heparan sulfate was recovered. Dermatan sulfate was the predominant glycosaminoglycan synthesized and most of it was released to the culture medium, in contrast to heparan sulfate which was found to be cell associated to a higher degree. The dermatan sulfate chains are composed by D-glucuronic and L-iduronic acid-containing disaccharides and are highly sulfated. Mesangial cells from diabetic rats produce much more glycosaminoglycans than mesangial cells from normal rats, especially dermatan sulfate and this increase was proportional to the duration of diabetes. In contrast, exposure of mesangial cell from normal rats to elevated glucose did not lead to any changes in glycosaminoglycan synthesis, indicating that this short-term culture conditions may not adequately simulate diabetes mellitus. Other factors related to diabetes environment may be responsible for the observed alterations. The dermatan sulfate was secreted to the medium as proteoglycan. Two dermatan sulfate proteoglycans were identified, with molecular weights of 120 and 85 kDa respectively. The proteoglycan core protein M(r) was 45 kDa and the dermatan sulfate chains were 35 kDa. It is possible that the two proteoglycans represent two populations, one with two dermatan sulfate side chains (120 kDa) and the other with only one side chain (85 kDa), presumably fitting in the decorin/biglycan family of small proteoglycans.

Pharmacokinetic analysis and antiepileptic activity of tetra-methylcyclopropane analogues of valpromide.

PURPOSE: The described structure pharmacokinetic pharmacodynamic relationships (SPPR) study explored the utilization of tetramethylcyclopropane analogues of valpromide (VPD), or tetramethylcyclopropane carboxamide derivatives of valproic acid (VPA) as new antiepileptics. METHODS: The study was carried out by investigating the pharmacokinetics in dogs and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following three cyclopropane analogues of VPD: 2,2,3,3-tetramethylcyclopropane carboxamide (TMCD), N-methyl TMCD (M-TMCD) and N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycinamide (TMC-GLD). RESULTS: The three investigated compounds showed a good anticonvulsant profile in mice and rats due to the fact that they were metabolically stable VPD analogues which were not biotransformed to their nonactive acid, 2,2,3,3-tetramethylcyclopropane carboxylic acid (TMCA). M-TMCD was metabolized to TMCD and TMC-GLD underwent partial biotransformation to its glycine analogue N-[(2,2,3,3-tetramethylcyclopropyl)carbonyl]-glycine (TMC-GLN). Unlike TMC-GLN, the above mentioned amides had low clearance and a relatively long half life. CONCLUSIONS: In contrast to VPD which is biotransformed to VPA, the aforementioned cyclopropane derivatives were found to be stable to amide-acid biotransformation. TMCD and M-TMCD show that cyclic analogues of VPD, like its aliphatic isomers, must have either two substitutions at the beta position to the carbonyl, such as in the case of TMCD, or a substitution in the alpha and in the beta positions like in the VPD isomer, valnoctamide (VCD). This paper discusses the antiepileptic potential of tetramethylcyclopropane analogues of VPD which are in animal models more potent than VPA and may be non-teratogenic and non-hepatotoxic.

FK 506: effects on glomerular hemodynamics and on mesangial cells in culture.

FK 506 is a new immunosuppressive drug that, like cyclosporine A (CsA), presents nephrotoxicity. Glomerular hemodynamic studies showed that acute FK 506 infusion (N = 9, 3 mg/kg body wt, i.v. in bolus) caused a 57% reduction in glomerular filtration rate (GFR) (0.74 +/- 0.03 to 0.32 +/- 0.02 ml/min, P < 0.05) and a 40% reduction in single nephron glomerular filtration rate (SNGFR; 43.0 +/- 5.2 to 26.0 +/- 2.5 nl/min, P < 0.05) due to a 25% reduction in glomerular plasma flow rate (QA) (133.4 +/- 19.8 to 99.8 +/- 12.0 nl/min) and a 22% reduction in glomerular ultrafiltration coefficient (Kf; 0.1009 +/- 0.0203 to 0.0790 +/- 0.0130 nl/sec. mm Hg). After 10 days of FK treatment (N = 8, 0.6 mg/kg body wt, i.p.), we observed a reduction of 23% in GFR (0.97 +/- 0.02 to 0.75 +/- 0.04 ml/min, P < 0.05) and of 23% in SNGFR (37.9 +/- 3.0 to 29.1 +/- 1.9 nl/min, P < 0.05) due to a 42% reduction in Kf (0.1486 +/- 0.0101 to 0.0870 +/- 0.0110 nl/sec.mm Hg, P < 0.05) and a 38% reduction in QA (117.6 +/- 10.2 to 73.5 +/- 6.1 nl/min, P < 0.05). The latter was consequent to the increment of 72% in total arteriolar resistance (RT) (3.1 +/- 0.2 to 5.2 +/- 0.5 +/- 0.5 10(10).dyn.sec.cm-5, P < 0.05). Thus, the pattern of FK 506 effect on glomerular hemodynamics was similar in both acute and chronic treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacokinetic analysis and antiepileptic activity of N-valproyl derivatives of GABA and glycine.

PURPOSE: To explore the possibility of utilizing valproyl derivatives of GABA and glycine as new antiepileptics by using the structure pharmacokinetic-pharmacodynamic relationship (SPPR) approach. METHODS: The pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following four conjugation products of valproic acid (VPA), glycine and GABA were investigated: valproyl glycine, valproyl glycinamide, valproyl GABA and valproyl gabamide. RESULTS: Only valproyl glycinamide showed a good anticonvulsant profile in both mice and rats due to its better pharmacokinetic profile. Valproyl glycinamide was more potent than one of the major antiepileptic agents--VPA and showed a better margin between activity and neurotoxicity. Valproyl glycine and valproyl GABA were partially excreted unchanged in the urine (fe = 50% and 34%, respectively), while the urinary metabolites of the amide derivatives were valproyl glycine and valproyl GABA. CONCLUSIONS: The four investigated valproyl derivatives did not operate as chemical drug delivery systems (CDDS) of glycine or GABA, but acted rather as drugs on their own. 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.

Comparative pharmacokinetic and pharmacodynamic analysis of phthaloyl glycine derivatives with potential antiepileptic activity.

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)

Can we develop improved derivatives of valproic acid?

Valproic acid is one of the major antiepileptic drugs. In animal models, valproate showed less anticonvulsant potency than the other three established antiepileptic drugs: phenobarbital, phenytoin and carbamazepine. In addition, two major side-effects, teratogenicity and hepatotoxicity, have been associated with valproate therapy. Due to the above and the shortage of new antiepileptic drugs there is a substantial need to develop improved derivatives of valproate. This paper analyses three kinds of valproate derivatives: valpromide, the primary amide of valproate, and its analogues; monoester prodrugs of valproate and an active metabolite of valproate, 2-n-propyl-2-pentenoate. The comparative evaluation was carried out by pharmacokinetic and pharmacodynamic analyses in animals. From the data accumulated so far, we can conclude that 2-n-propyl-2-pentenoate and/or a valpromide isomer, which does not undergo amide-acid biotransformation and preferably is not an epoxide hydrolase inhibitor, may prove to be improved derivatives of the parent compound valproic acid.