Shyh-Ying Chiou

Gamma Knife surgery used as primary and repeated treatment for idiopathic trigeminal neuralgia

OBJECT The purpose of this study was to assess the outcome of idiopathic trigeminal neuralgia (TN) treated with Gamma Knife surgery (GKS) as a primary and repeated treatment modality with a mean follow-up of 5.7 years. METHODS Between July 1999 and September 2005, a total of 89 patients with idiopathic TN underwent GKS as a primary treatment. The entry zone of the TN was targeted with a 4-mm collimator and treated with a maximal dose of 60-90 Gy (mean 79 Gy). The dose to the pontine margin was always kept < 15 Gy. Twenty patients received repeated GKS for recurrent or residual pain with a maximal dose of 40-76 Gy (mean 52 Gy). For the second procedure, the target was positioned at the same location as the first treatment. RESULTS The mean follow-up period was 68 months (range 32-104 months). Sixty-nine (77.5%) of the 89 patients experienced a favorable response, as follows: 50 (56%) had excellent, 12 (13.5%) had good, and 7 (7.8%) had fair outcomes. The mean time to pain relief was 1.1 months (range 2 days-6 months). No significant correlation, but more likely a tendency, was found between the dose and pain relief (p = 0.08). Also, no correlation was noted for facial numbness (p = 0.77). The mean follow-up period after repeated GKS was 60 months (range 32-87 months). Outcomes after repeated GKS were excellent in 11 patients (55%) and good in 1 (5%). Seven patients experienced facial numbness. No correlation was found between the additive dose and pain relief (p = 0.24) or facial numbness (p = 0.15). Final outcomes of primary and repeated GKS were excellent in 61 (68.5%), good in 13 (14.6%), and fair in 7 (7.9%). In total, 91% of the patients were successfully treated with this method. There was no statistical significance for efficacy between primary and repeated GKS (p = 0.65), but there was a significant difference for facial numbness (p = 0.007). CONCLUSIONS Gamma Knife surgery established durable pain relief when used as a primary and repeated surgery. Treatment was successful for a total of 91% of patients at a mean follow-up of 5.7 years, but facial numbness was also relatively higher.

Quantitative structure–activity relationships for the pre-steady-state inhibition of cholesterol esterase by 4-nitrophenyl-n-substituted carbamates

4-Nitrophenyl-N-substituted carbamates (1-6) are the pseudo-substrate inhibitors of porcine pancreatic cholesterol esterase. Thus, the first step of the inhibition (Ki step) is the formation of the enzyme inhibitor tetrahedral adduct and the second step of the inhibition (kc) is the formation of the carbamyl enzyme. The formation of the enzyme inhibitor tetrahedral adduct is further divided into two steps, the formation of the enzyme-inhibitor complex with the dissociation constant, KS, at the first step and the formation of the enzyme-inhibitor tetrahedral adduct from the complex at the second step. The two-step mechanism for the formation of the enzyme-inhibitor tetrahedral adduct is confirmed by the pre-steady-state kinetics. The results of quantitative structure-activity relationships for the pre-steady-state inhibitions of cholesterol esterase by carbamates 1-6 indicate that values of -logKs and logk2/k-2 are correlated with the Taft substituent constant, sigma*, and the rho* values from these correlations are -0.33 and 0.1, respectively. The negative rho* value for the -logKS-sigma*-correlation indicates that the first step of the two-step formation of the enzyme-inhibitor tetrahedral adduct (KS step) is the formation of the positive enzyme inhibitor complex. The positive rho* value for the logk2/k-2 -sigma*-correlation indicates that the enzyme inhibitor tetrahedral adduct is more negative than the enzyme inhibitor complex. Finally, the two-step mechanism for the formation of the enzyme inhibitor tetrahedral adduct is proposed according to these results. Thus, the partially positive charge is developed at nitrogen of carbamates 1-6 in the enzyme-inhibitor complex probably due to the hydrogen bonding between the lone pair of nitrogen of carbamates 1-6 and the amide hydrogen of the oxyanion hole of the enzyme. The second step of the two-step formation of the enzyme-inhibitor tetrahedral adduct is the nucleophilic attack of the serine of the enzyme to the carbonyl group of carbamates 1-6 in the enzyme-inhibitor complex and develops the negative-charged oxygen in the adduct.

Gamma Knife surgery for recurrent or residual trigeminal neuralgia after a failed initial procedure

OBJECT The purpose of this study was to assess outcomes of Gamma Knife surgery (GKS) as a second treatment for recurrent or residual trigeminal neuralgia (TN) after failure of 3 initial procedures: microvascular decompression (MVD), GKS, and percutaneous radiofrequency rhizotomy (PRR). METHODS Between 1999 and 2008, 65 patients (31 men [48%] and 34 women [52%]) with recurrent TN were treated with GKS. All 65 patients had undergone previous medical procedures that failed to achieve sufficient pain relief: 27 patients (42%) had undergone MVD, 8 (12%) had undergone PRR, and 30 (46%) had undergone GKS as the initial treatment. The entry zone of the trigeminal nerve was targeted using a 4-mm collimator and treated with 35-90 Gy. The isocenter was positioned so that the brainstem surface was usually irradiated at an isodose no greater than 20% (59 patients) to 30% (6 patients). The median duration of TN symptoms in these patients was 39 months (range 1-192 months). RESULTS At the clinical evaluation, 42 patients (65%) with idiopathic TN reported successful pain control at a median follow-up point of 64 months (range 18-132 months). Of these patients, 33 (51%) were no longer using medication. At the 1-, 2-, and 3-year follow-up examinations, 74%, 71%, and 66% of patients experienced successful pain control, respectively. There was no significant difference in pain relief in the initial MVD group compared with the initial GKS and initial PRR groups (74% vs 59% and 50%, respectively; p = 0.342). Recurrence of pain was noted in 23 patients. Twelve of these 23 patients underwent another GKS, resulting in pain control in 8 patients (67%); 8 other patients underwent MVD, resulting in pain relief in 7 patients (87.5%). The median time from GKS to pain recurrence was 7 months (range 3-48 months). There was no significant difference in new facial numbness among the 3 groups (p = 0.24); however, in the initial GKS group, facial numbness was significantly associated with freedom from pain (p = 0.0012). There was a significant correlation between the total radiation dose and facial numbness. The cutoff value for facial numbness ranged from 115 to 120 Gy (p = 0.037). CONCLUSIONS Gamma Knife surgery as a second treatment achieved acceptable levels of pain control in 65% of patients with residual or recurrent TN after long-term follow-up. Initial treatment was not a factor that affected pain control, but salvage surgery may be considered separately for each group.

Comparison of active sites of butyrylcholinesterase and acetylcholinesterase based on inhibition by geometric isomers of benzene-di-N-substituted carbamates.

We have reported that benzene‐1,2‐, 1,3‐, and 1,4‐di‐N‐substituted carbamates (1–15) are characterized as the conformationally constrained inhibitors of acetylcholinesterase and mimic gauche, eclipsed, and anti‐conformations of acetylcholine, respectively (J Biochem Mol Toxicol 2007;21:348–353). We further report the inhibition of butyrylcholinesterase by these inhibitors. Carbamates 1–15 are also characterized as the pseudosubstrate inhibitors of butyrylcholinesterase as in the acetylcholinesterase catalysis. Benzene‐1,4‐di‐N‐n‐hexylcarbamate (12) and benzene‐1,4‐di‐N‐n‐octylcarbamate (13) are the two most potent inhibitors of butyrylcholinesterase among inhibitors 1–15. These two para compounds, with the angle of 180° between two C(benzene)O bonds, mimic the preferable anti CO/CN conformers for the choline ethylene backbone of butyrylcholine during the butyrylcholinesterase catalysis. The second n‐hexylcarbamyl or n‐octylcarbamyl moiety of inhibitors 12 and 13 is proposed to bind tightly to the peripheral anionic site of butyrylcholinesterase from molecular modeling. Butyrylcholinesterase prefers para‐carbamates to ortho‐ and meta‐carbamates, whereas acetylcholinesterase prefers para‐ and meta‐carbamates to ortho‐carbamates. This result implies that the anionic site of butyrylcholinesterase is relatively smaller than that of acetylcholinesterase because meta‐carbamates, which may bind to the anionic sites of both enzymes, are not potent inhibitors of butyrylcholinesterase.

Apparent diffusion coefficients for evaluation of the response of brain tumors treated by Gamma Knife surgery: Clinical article

OBJECT Cellular density is a major factor for change in the apparent diffusion coefficient (ADC). The authors hypothesized that loss of tumor cells after Gamma Knife surgery (GKS) may alter the ADC value and used diffusion weighted MR imaging (DW imaging) to evaluate cellular changes in brain tumors to detect their treatment response and the efficacy of GKS. METHODS In this paper the authors describe a prospective trial involving 86 patients harboring 38 solid or predominantly solid brain metastases, 30 meningiomas, and 24 acoustic neuromas that were treated by GKS. The patients underwent serial MR imaging examinations, including DW imaging, before treatment and at multiple intervals following GKS. Follow-up MR images and clinical outcomes were reviewed at 3-month intervals for metastatic lesions and at 6-month intervals for benign tumors. Apparent diffusion coefficients were calculated from echo planar DW images, and mean ADC values were compared at each follow-up. RESULTS The mean ADC value for all meningiomas was 0.82 ± 0.15 × 10-3 mm2/sec before GKS. The mean ADC value as of the last mean follow-up of 42 months was 1.36 ± 0.19 × 10-3 mm2/sec, a significant increase compared to that before treatment (p < 0.0001). Calcification (p = 0.006) and tumor recurrence (p = 0.025) significantly prevented a rise in the ADC level.The mean ADC value for all solid acoustic neuromas was 1.06 ± 0.17 × 10-3 mm2/sec before GKS. The mean ADC value as of the last mean follow-up of 36 months was 1.72 ± 0.26 × 10-3 mm2/sec, a significant increase (p =0.0002) compared with values before GKS. At the last mean MR imaging follow-up there appeared to be tumor enlargement in 3 patients (12.5%); however, since the ADC values in these patients were significantly higher than the preradiosurgery values, the finding was considered to be a sign of radiation necrosis rather than tumor recurrence. The mean ADC value of metastatic tumors was 1.05 ± 0.12 × 10-3 mm2/sec before GKS. This value rose significantly(p < 0.0001) to 1.64 ± 0.18 × 10-3 mm2/sec after GKS at a mean follow-up of 9.4 months. Magnetic resonance imaging showed that 89% of these tumors had been controlled by GKS. In 2 patients there were enlarged lesions, but the ADC values were the same as pre-GKS levels, and therefore, the lesions were deemed recurrent. CONCLUSIONS Apparent diffusion coefficient values may be useful in evaluating treatment results before a definitive change in volume is evident on imaging studies. In some patients in whom imaging findings are equivocal, ADC values may also be used to distinguish radiation-induced necrosis from tumor recurrence.(DOI: 10.3171/2010.7.GKS10864)

Molecular docking of different inhibitors and activators to butyrylcholinesterase

There are three major active sites of butyrylcholinesterase: catalytic site, peripheral site, and activator site. In this study, pseudosubstrate inhibitors, 1,3,5-alkylcarbamyloxybenzenes (1–11), were designed as the catalytic site directed inhibitors of the enzyme. Automated docking of 1,3,5-tri-n-octylcarbamyloxybenzene 1 into the X-ray crystal structure of butyrylcholinesterase suggested that the configuration of the inhibitor in the enzyme complex is in the (1,3,5)-(cis,trans,trans)-form. Thus, the cis n-octylcarbamyl group of 1 extended itself to the peripheral site; furthermore, two trans n-octylcarbamyl moieties of 1 shielded W82 of the anionic site. 5-N-n-Butylcarbamyloxyresorcinol (12) was further used to characterize the butyryl group binding site of the catalytic site. Automated docking of 12 into the enzyme showed that the best bound rotamer of the inhibitor in the enzyme complex was the trans form. Moreover, the butylcarbamyl moiety of 12 was bound well into the butyryl group binding site of the enzyme. Docking of cage amines into the enzyme indicated that these compounds were bound into the peripheral site of the enzyme. We also found that a small cave, located outside the enzyme around A277-Y282, might play an important role in the activation of the enzyme. Two activators of butyrylcholinesterase, n-butyl-N-carbamyloxy-3,3-dimethylbutane and 2,4,6-trinitrotoluene, were docked well into the above-mentioned cave.

Stereoselective inhibition of butyrylcholinesterase by enantiomers of exo- and endo-2-norbornyl-N-n-butylcarbamates

Enantiomers of exo- and endo-2-norbornyl-N-n-butylcarbamates were characterized as pseudo substrate inhibitors of butyrylcholinesterase. These inhibitions discriminate enantiomers of the inhibitors and therefore show stereoselectivity for the enzyme. For inhibitions by (R)-(+)- and (S)-(–)-exo-2-norbornyl-N-n-butylcarbamates, R-enantiomer is a more potent inhibitor than S-enantiomer. But, for inhibitions by (R)-(+)- and (S)-(–)-endo-2-norbornyl-N-n-butylcarbamates, S-enantiomer is a more potent inhibitor than R-enantiomer. Optically pure (R)-(+)-exo-, (S)-(–)-exo-, (R)-(+)-endo-, and (S)-(–)-endo-2-norbornyl-N-n-butylcarbamates were synthesized from condensations of optically pure (R)-(+)-exo-, (S)-(–)-exo-, (R)-(+)-endo-, and (S)-(–)-endo-2-norborneols with n-butyl isocyanate, respectively. Optically pure norborneols were obtained from kinetic resolution of their racemic esters by lipase catalysis in organic solvent.

Synthesis of enantiomers of exo‐2‐norbornyl‐N‐n‐butylcarbamate and endo‐2‐norbornyl‐N‐n‐butylcarbamate for stereoselective inhibition of acetylcholinesterase

The acetylcholinesterase inhibition by enantiomers of exo- and endo-2-norbornyl-N-n-butylcarbamates shows high stereoselelectivity. For the acetylcholinesterase inhibitions by (R)-(+)- and (S)-(-)-exo-2-norbornyl-N-n-butylcarbamates, the R-enantiomer is more potent than the S-enantiomer. But, for the acetylcholinesterase inhibitions by (R)-(+)- and (S)-(-)-endo-2-norbornyl-N-n-butylcarbamates, the S-enantiomer is more potent than the R-enantiomer. Optically pure (R)-(+)-exo-, (S)-(-)-exo-, (R)-(+)-endo-, and (S)-(-)-endo-2-norbornyl-N-n-butylcarbamates are synthesized from condensations of optically pure (R)-(+)-exo-, (S)-(-)-exo-, (R)-(+)-endo-, and (S)-(-)-endo-2-norborneols with n-butyl isocyanate, respectively. Optically pure norborneols are obtained from kinetic resolutions of their racemic esters by lipase catalysis in organic solvent.

Qsar for Acetylcholinesterase and Butyrylcholinesterase Inhibition by Cardiovascular Drugs and Benzodiazepines

Five common cardiovascular drugs, lovastatin, simvastatin, amlodipine besylate, nifedipine, and hydralazine hydrochloride, and two common benzodiazepines, diazepam and chlordiazepoxide hydrochloride, are all reversible mixed-type inhibitors of acetylcholinesterase and butyrylcholinesterase. The pKi values for acetylcholinesterase and butyrylcholinesterase inhibitions by these drugs are linearly correlated with the molecular weights, with slopes of 0.005 and 0.0021, respectively. Therefore, van der Waals’ interactions between acetylcholinesterase and these drugs are stronger than those between butyrylcholinesterase probably due to a small active site gorge and a significant peripheral anionic site for acetylcholinesterase. The fact that the pKi values for both butyrylcholinesterase and acetylcholinesterase inhibitions are linearly correlated with each other suggests that both enzyme inhibitions proceed via a common mechanism. Furthermore, acetylcholinesterase and butyrylcholinesterase inhibitors such as tacrine, donepezil, rivastigmine, and galantamine are currently used to manage Alzheimer’s disease. Since amlodipine besylate is a very potent inhibitor of both cholinesterases, amlodipine besylate may, like donepezil, be useful in Alzheimer’s disease treatment.

Activation Mechanisms of Butyrylcholinesterase by 2,4,6-Trinitrotoluene, 3,3-Dimethylbutyl-N-n-butylcarbamate, and 2-Trimethylsilyl-ethyl-N-n-butylcarbamate

The goal of this work was to propose a possible mechanism for the butyrylcholinesterase activation by 2,4,6-trinitrotoluene (TNT), 3,3-dimethylbutyl-N-n-butylcarbamate (1), and 2-trimethylsilyl-ethyl-N-n-butylcarbamate (2). Kinetically, TNT, and compounds 1 and 2 were characterized as the nonessential activators of butyrylcholinesterase. TNT, and compounds 1 and 2 were hydrophobic compounds and were proposed to bind to the hydrophobic activator binding site, which was located outside the active site gorge of the enzyme. The conformational change from a normal active site gorge to a more accessible active site gorge of the enzyme was proposed after binding of TNT, and compounds 1 and 2 to the activator binding site of the enzyme. Therefore, TNT, and compounds 1 and 2 may act as the excess of butyrylcholine in the substrate activator for the butyrylcholinesterase catalyzed reactions.