HLA-haploidentical hematopoietic stem cells transplantation with regulatory and conventional T-cell adoptive immunotherapy in pediatric patients with very high-risk acute leukemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) is still needed for many children with very high-risk acute leukemia. An HLA-haploidentical family donor is a suitable option for those without an HLA-matched donor. Here we present outcomes of a novel HLA-haploidentical HSCT (haplo-HSCT) strategy with adoptive immunotherapy with thymic-derived CD4+CD25+ FoxP3+ regulatory T cells (Tregs) and conventional T cells (Tcons) performed between January 2017 and July 2021 in 20 children with high-risk leukemia. Median age was 14.5 years (range, 4-21), 15 had acute lymphoblastic leukemia, 5 acute myeloid leukemia. The conditioning regimen included total body irradiation (TBI), thiotepa, fludarabine, cyclophosphamide. Grafts contained a megadose of CD34+ cells (mean 12.4 × 106/Kg), Tregs (2 × 106/Kg) and Tcons (0.5-1 × 106/Kg). All patients achieved primary, sustained full-donor engraftment. Only one patient relapsed (5%). The incidence of non-relapse mortality was 15% (3/20 patients). Five/20 patients developed ≥ grade 2 acute Graft versus Host Disease (aGvHD). It resolved in 4 who are alive and disease-free; 1 patient developed chronic GvHD (cGvHD). The probability of GRFS was 60 ± 0.5% (95% CI: 2.1-4.2) (Fig. 6), CRFS was 79 ± 0.9% (95% CI: 3.2-4.9) as 16/20 patients are alive and leukemia-free. The median follow-up was 2.1 years (range 0.5 months-5.1 years). This innovative approach was associated with very promising outcomes of HSCT strategy in pediatric patients.

Long-term assessment of clinical outcomes and disease progression in patients with corrected Tetralogy of Fallot.

OBJECTIVE: Understanding changes of right ventricular (RV) geometry and function in repaired Tetralogy of Fallot (rToF) patients can improve decision-making for pulmonary valve replacement. Therefore, we aimed to assess the magnitude and clinical correlations of RV changes in rToF patients. PATIENTS AND METHODS: Clinical and MRI data of rToF patients who underwent repeated cardiac magnetic resonance imaging (MRI) at two centers between December 2003 and September 2020 were analyzed together with anatomical factors, including RV outflow tract obstruction, pulmonary artery branch stenosis, and tricuspid regurgitation. Adverse cardiac events and/or NYHA class worsening were documented and correlated with MRI changes. QRS length was reported at each MRI. RESULTS: Two-hundred-and-nineteen rToF patients (53% males, aged 20.2 ± 10.1 years) were enrolled. An increase of ventricular dimensions, except LVEDVi, and worsening of right and left ejection fractions were found over an average period of 5 years of follow-up. These changes were statistically significant but within 10% of the initial value. No significant changes were reported on a year-to-year basis, except in a small group of patients (6%) in whom no predictive factors were identified. Despite similar RV dimensions at the first examination, younger patients had a higher RV ejection fraction and a different annual rate of change of ventricular dimensions compared to older ones. Patients with arrhythmias (20%) were more frequently older and had larger RV dimensions but showed no significant correlations with MRI changes/years. CONCLUSIONS:  Changes in RV dimensions and function occur rarely and very slowly in rToF patients. A small percentage of patients experience a significant worsening in a short time interval without any recognized risk factors. Arrhythmias appear to occur in a small percentage of cases in the late follow-up.

The role of 3D imaging in the follow-up of patients with repaired tetralogy of Fallot.

OBJECTIVE: The patients with repaired Tetralogy of Fallot (rToF) are a growing population due to the improvement of surgical management in neonatal age. However, the significant pulmonary regurgitation, consequent to the repair, is the most frequent sequelae and leads to a progressive right ventricle dilation over time. The latter, in turn, is responsible for the possible dysfunction of right and/or left ventricle and an increased risk of dangerous ventricular arrhythmias. Therefore, right ventricle monitoring is necessary for rToF patients and a 3D method is required due to its three anatomical and functional subunits. Magnetic resonance imaging (MRI) has become the 3D modality of choice in the evaluation of both cardiac anatomy and ventricular volumes in rToF patients since it is able to evaluate both the pathophysiology and anatomy, it is free of radiation and, when strictly necessary, it uses a non-iodinated contrast agent. Cardiac CT should be considered in the evaluation of the sequelae in rToF only in selected cases, given that it implies a radiation dose and iodinated contrast, in addition to not evaluating the pathophysiology as MRI.

Improved outcome with T-cell-depleted bone marrow transplantation for acute leukemia.

PURPOSE: To eliminate the risk of rejection and lower the risk of relapse after T-cell-depleted bone marrow transplants in acute leukemia patients, we enhanced pretransplant immunosuppression and myeloablation. PATIENTS AND METHODS: Antithymocyte globulin and thiotepa were added to standard total-body irradiation/cyclophosphamide conditioning. Donor bone marrows were depleted ex vivo of T lymphocytes by soybean agglutination and E-rosetting. This approach was tested in 54 consecutive patients with acute leukemia who received transplants from HLA-identical sibling donors or, in two cases, from family donors mismatched at D-DR. No posttransplant immunosuppressive treatment was given as graft-versus-host disease (GVHD) prophylaxis. RESULTS: Neither graft rejection nor GVHD occurred. Transplant-related deaths occurred in six (16.6%) of 36 patients in remission and in seven (38.8%) of 18 patients in relapse at the time of transplantation. The probability of relapse was .12 (95% confidence interval [CI], 0 to .19) for patients with acute myeloid leukemia and .28 (95% CI, .05 to .51) for patients with acute lymphoblastic leukemia who received transplants at the first or second remission. At a median follow-up of 6.9 years (minimum follow-up, 4.9 years), event-free survival for patients who received transplants while in remission was .74 (95% CI, .54 to .93) for acute myeloid leukemia patients and .59 (95% CI, .35 to .82) for acute lymphoblastic leukemia patients. All surviving patients have 100% performance status. CONCLUSION: Adding antithymocyte globulin and thiotepa to the conditioning regimen prevents rejection of extensively T-cell-depleted bone marrow. Even in the complete absence of GVHD, the leukemia relapse rate is not higher than in unmanipulated transplants.

Minimally invasive or interventional repair of atrial septal defects in children: experience in 171 cases and comparison with conventional strategies.

OBJECTIVES: The goal of this study was to evaluate percutaneous interventional and minimally invasive surgical closure of secundum atrial septal defect (ASD) in children. BACKGROUND: Concern has surrounded abandoning conventional midline sternotomy in favor of the less invasive approaches pursuing a better cosmetic result and a more rational resource utilization. METHODS: A retrospective analysis was performed on the patients treated from June 1996 to December 1998. RESULTS: One hundred seventy-one children (median age 5.8 years, median weight 22.1 kg) underwent 52 device implants, 72 minimally invasive surgical operations and 50 conventional sternotomy operations. There were no deaths and no residual left to right shunt in any of the groups. The overall complication rate causing delayed discharge was 12.6% for minimally invasive surgery, 12.0% for midline sternotomy and 3.8% for transcatheter device closure (p < 0.01). The mean hospital stay was 2.8 +/- 1.0 days, 6.5 +/- 2.1 days and 2.1 +/- 0.5 days (p < 0.01); the skin-to-skin time was 196 +/- 43 min, 163 +/- 46 min and 118 +/- 58 min, respectively (p < 0.001). Extracorporeal circulation time was 49.9 +/- 10.1 min in the minithoracotomy group versus 37.2 +/- 13.8 min in the sternotomy group (p < 0.01) but without differences in aortic cross-clamping time. Sternotomy was the most expensive procedure (15,000 EUR +/- 1,050 EUR vs. 12,250 EUR +/- 472 EUR for minithoracotomy and 13,000 EUR +/- 300 EUR for percutaneous devices). CONCLUSIONS: While equally effective compared with sternotomy, the cosmetic and financial appeal of the percutaneous and minimally invasive approaches must be weighed against their greater exposure to technical pitfalls. Adequate training is needed if a strategy of surgical or percutaneous minimally invasive closure of ASD in children is planned in place of conventional surgery.

Growth response of human myeloid leukemia cells to colony-stimulating factors.

The effects of human recombinant granulocyte and granulocyte-macrophage- (G- and GM-CSF), and of purified macrophage-stimulating factors (CSF-1), were tested on populations of leukemia cells isolated from 18 patients with different types of acute myeloid leukemia. Cell proliferation and differentiation were studied by culturing the cells in suspension for 7 days in the presence of CSF or medium alone. Spontaneous cell proliferation, as assessed by tritiated thymidine uptake, was observed in 9 of the 18 cases. GM-CSF induced proliferation in seven of the nine cases without spontaneous growth and increased spontaneous proliferation in nine cases. G-CSF added alone was also found to strongly stimulate leukemic blast cell proliferation, in which a translocation involving the long arm of chromosome 17 was observed. Low levels of CSF-1 stimulation were also observed in some cases. No clear morphological modification supporting evidence of terminal differentiation was observed, whereas modulation of some cell surface antigens was detected by flow cytometry. Thus, most leukemia cells still depend on growth factors for their proliferation, GM-CSF appearing the most effective. On the other hand these factors were not able to induce terminal differentiation.

Next generation HLA-haploidentical HSCT.

Relapse is still the major cause of failure of allogeneic stem cell transplantation in high-risk acute leukemia patients. Indeed, whoever the donor and whatever the transplantation strategy, post-transplant relapse rates are ~30%, which is hardly satisfactory. The present phase 2 study analyzed the impact of adoptive immunotherapy with naturally occurring FoxP3+ T-regulatory cells (2 × 10(6) per kg) and conventional T lymphocytes (1 × 10(6) per kg) on prevention of GvHD and leukemia relapse in 43 high-risk adults undergoing full-haplotype mismatched transplantation without any post-transplant immunosuppression. Ninety-five percent of patients achieved full-donor type engraftment. Only 6/41 patients (15%) developed ⩾ grade II acute GvHD. Specific CD4(+) and CD8(+) for opportunistic pathogens emerged significantly earlier than after standard T-cell-depleted haplo-transplantation. The probability of disease-free survival was 0.56. At a median follow-up of 46 months (range 18-65 months), only 2/41 evaluable patients have relapsed. The cumulative incidence of relapse was significantly lower than in historical controls (0.05 vs 0.21; P = 0.03). These results demonstrate that the immunosuppressive potential of Tregs can be used to suppress GvHD without loss of the benefits of GvL activity. Humanized murine models provided insights into the mechanisms underlying separation of GvL from GvHD.

Folding in lipid membranes (FILM): a novel method for the prediction of small membrane protein 3D structures.

We present the results of applying a novel knowledge-based method (FILM) to the prediction of small membrane protein structures. The basis of the method is the addition of a membrane potential to the energy terms (pairwise, solvation, steric, and hydrogen bonding) of a previously developed ab initio technique for the prediction of tertiary structure of globular proteins (FRAGFOLD). The method is based on the assembly of supersecondary structural fragments taken from a library of highly resolved protein structures using a standard simulated annealing algorithm. The membrane potential has been derived by the statistical analysis of a data set made of 640 transmembrane helices with experimentally defined topology and belonging to 133 proteins extracted from the SWISS-PROT database. Results obtained by applying the method to small membrane proteins of known 3D structure show that the method is able to predict, at a reasonable accuracy level, both the helix topology and the conformations of these proteins.

Ligands of neuronal nicotinic acetylcholine receptor (nAChR): inferences from the Hansch and 3-D quantitative structure-activity relationship (QSAR) Models.

Neuronal acetylcholine ion channel receptors (nAChRs), that exist in several subtypes resulting from a different organisation of various subunits around the central ion channel, are involved in a variety of functions and disorders of the central nervous system. There is evidence to implicate a deficit of nAChRs in the symptomatology of severe neurologic pathologies, such as Alzheimer s and Parkinson s diseases. Reliable three-dimensional structures of nAChRs are not available yet, and this hampers adopting structure-based approaches in designing new ligands. Also pharmacophore models are not reliable enough to be used in ligand-based approaches to drug design and little structure-activity work has been reported so far. This paper deals with structure-activity relationships of a wide series of nicotinic ligands. It provides results from a study of the quantitative structure activity relationships (QSARs) based on literature data of about 270 nicotinic agonists, belonging to various chemical classes. The QSAR study was carried out by using either a classical Hansch approach or a Comparative Molecular Field Analysis (CoMFA). Within each congeneric series, Hansch-type equations revealed detrimental steric effects as the factors mainly modulating the receptor affinity, whereas CoMFA allowed us to merge progressively models obtained for each class of congeners into a more general one that showed good cross-validation statistics. The CoMFA coefficient isocontour maps illustrated, at the 3-D level, the most relevant interactions responsible for a high receptor affinity, whereas the robustness of the global three-dimensional QSAR/CoMFA (n = 206, q(2) = 0.749, r(2) = 0.847, s= 0.600) model was supported by the high value of the prediction statistics (r(2)pred = 0.961) and confirmed by the satisfactory predictions of the affinity data of an external set of 18 recently published ligands with chemical structures even quite diverse from those included in the training set.

Interstitial pneumonitis after hyperfractionated total body irradiation in HLA-matched T-depleted bone marrow transplantation.

Interstitial pneumonia is one of the major causes of morbidity and mortality after bone-marrow transplantation. We here report a series of 58 patients suffering from hematological malignancies who received HLA-matched T-lymphocyte depleted bone-marrow transplants between July 1985 and January 1990. Interstitial pneumonia occurred in 7/58 patients (12%) and was fatal in six. Three different pre-bone-marrow transplantation conditioning regimens were employed. Total body irradiation was delivered according to a hyperfractionated scheme of 12 fractions given three per day 5 hr apart for 4 days. Twenty-three patients received 36 mg/Kg procarbazine, 1275 UL/Kg antithymocite globulin, 14.4 Gy hyperfractionated total body irradiation and 120 mg/Kg cyclophosphamide. Only one patient developed interstitial pneumonia, but two rejected the graft and 10 relapsed. As a consequence, the total hyperfractionated scheme was increased to 15,6 Gy, cyclophosphamide to 200 mg/Kg, antithymocite globulin to 3400 UL/Kg and procarbazine eliminated. There were three cases of interstitial pneumonia, no rejection and four relapses in the 17 patients who received this regimen. In the last 18 patients hyperfractionated total body irradiation was reduced to 15 Gy, cyclophosphamide to 100 mg/Kg, and 10 mg/Kg of the myeloablative agent thiothepa added to enhance the cytoreductive effect without significantly increasing extramedullary toxicity. Three cases of interstitial pneumonia, one relapse but no rejection were recorded. Our results demonstrate that the absence of graft-versus-host disease due to T-cell depletion, and radio-chemotherapy doses and schedules used for the conditioning regimen each contributed to reducing the risk of interstitial pneumonitis. Hyperfractionated total body irradiation therefore, seems to play an important role in lowering the incidence of this complication.

Structure-activity relationship of the ficin hydrolysis of phenyl hippurates. Comparison with papain, actinidin, and bromelain.

A study of the hydrolysis of 30 substituted-phenyl hippurates by the enzyme ficin has been made. From the results the following quantitative structure--activity relationship (QSAR) has been derived: log 1/Km = 0.79 pi'3 + 0.58 sigma + 0.28 MR4,5 + 3.70. In this expression Km is the Michaelis constant, pi'3 refers to the more hydrophobic of the two meta substituents, and MR4,5 is the molar refractivity of substituents in the 4- and 5-positions of the phenyl ring. This QSAR is compared with those from papain, actinidin, bromelain B, and bromelain D.

Actinidin hydrolysis of substituted-phenyl hippurates: a quantitative structure-activity relationship and graphics comparison with hydrolysis by papain.

The hydrolysis of 29 phenyl hippurates (XPhOCOCH2NHC(=O)C6H5) by the cysteine protease actinidin has been studied and a quantitative structure-activity relationship (QSAR) has been formulated: log 1/Km = 0.74 sigma + 0.50 pi'3 + 0.24MR4 + 2.90. In this expression Km is the Michaelis constant, sigma is the Hammett constant, pi'3 is the hydrophobic parameter for the more hydrophobic of the two meta substituents, and MR4 is the molar refractivity of para substituents. The QSAR for actinidin is compared with a similar one obtained for another cysteine plant protease papain. A color stereo computer graphics model constructed from the X-ray crystallographic coordinates of actinidin is compared with those of our previously reported models for papain.

Synthesis and cognition activating properties of some mono- and bicyclic lactam derivatives.

Upon reductive cyclization cyano esters 2, 3, and 9 yielded piperidones and perhydropyrrolo[3,4-c]pyridine lactams, generally as a mixture of diasteromeric cis-trans forms. X-ray crystallographic analyses were carried out on bicyclic dilactam derivatives 6 and 10, and a cis configuration at the ring junction was determined in both cases. A series of neuropsychopharmacological tests performed on the title compounds indicated that they are generally nontoxic even at high doses (up to 1000 mg/kg ip). The cognition activating properties of lactams 4, 5, 6, and 10 were evaluated in enhancing retention for passive avoidance learning in rats without and after electroconvulsive shock (ECS); compounds 5 and 10 were found to be more potent than piracetam in the amnesia-reversal testing.

Coumarins derivatives as dual inhibitors of acetylcholinesterase and monoamine oxidase.

A set of 17 coumarin and 2 chromone derivatives with known inhibitory activity toward monoamine oxidase (MAO) A and B were tested as acetylcholinesterase (AChE) inhibitors. All compounds inhibited AChE with values in the micromolar range (3-100 microM). A kinetic study showed that most compounds acted as noncompetitive AChE inhibitors. This finding may be of interest in the context of Alzheimer's disease because recent observations suggest that MAO and AChE inhibition might decrease beta-amyloid deposition.

Inhibition of monoamine oxidases by functionalized coumarin derivatives: biological activities, QSARs, and 3D-QSARs.

A large series of coumarin derivatives (71 compounds) were tested for their monoamine oxidase A and B (MAO-A and MAO-B) inhibitory activity. Most of the compounds acted preferentially on MAO-B with IC(50) values in the micromolar to low-nanomolar range; high inhibitory activities toward MAO-A were also measured for sulfonic acid esters. The most active compound was 7-[(3, 4-difluorobenzyl)oxy]-3,4-dimethylcoumarin, with an IC(50) value toward MAO-B of 1.14 nM. A QSAR study of 7-X-benzyloxy meta-substituted 3,4-dimethylcoumarin derivatives acting on MAO-B yielded good statistical results (q(2)() = 0.72, r(2)() = 0.86), revealing the importance of lipophilic interactions in modulating the inhibition and excluding any dependence on electronic properties. CoMFA was performed on two data sets of MAO-A and MAO-B inhibitors. The GOLPE procedure, with variable selection criteria, was applied to improve the predictivity of the models and to facilitate the graphical interpretation of results.

Inhibition of monoamine oxidase-B by 5H-indeno[1,2-c]pyridazines: biological activities, quantitative structure-activity relationships (QSARs) and 3D-QSARs.

A large series (66 compounds) of indeno[1,2-c]pyridazin-5-ones (IPs) were synthesized and tested on their monoamine oxidase-A (MAO-A) and MAO-B inhibitory activity. All of the tested compounds acted preferentially on MAO-B displaying weak (nonmeasurable IC50 values) to high (submicromolar IC50 values) activities. The most active compound was p-CF3-3-phenyl-IP (IC50 = 90 nM). Multiple linear regression analysis of the substituted 3-phenyl-IPs yielded good statistical results (q2 = 0.74; r2 = 0.86) and showed the importance of lipophilic, electronic, and steric properties of the substituents in determining inhibitory potency. Various comparative molecular field analysis studies were performed with different alignments and including the molecular lipophilicity potential. This led to a model including the steric, electrostatic and lipophilicity fields and having a good predictive value (q2 = 0.75; r2 = 0.93).

X-ray crystal structure, partitioning behavior, and molecular modeling study of piracetam-type nootropics: insights into the pharmacophore.

To detect possible molecular determinants of amnesia-reverting activity, the conformational properties of a number of rigid and flexible piracetam-type cognition enhancers have been assessed by X-ray diffraction, NMR spectroscopy, and ab initio and high-temperature-quenched molecular dynamics (QMD) calculations. The structures of the preferred conformers in solution derived from 1H-NMR spectral analysis were in good agreement with those found by QMD calculations. Interestingly, the calculation of the average molecular lipophilicity potential on the water-accessible surface of the selected conformers was helpful in interpreting the partitioning behavior observed by measuring octanol-water partition coefficients and capacity factors in reversed-phase high-performance liquid chromatography. While lipophilicity does not play a relevant role, the distance between polar groups, accounted for by the distance between carbonyl oxygens, emerges as a factor, among others, which should influence the amnesia-reversal activity of piracetam-type nootropics.

Novel 2-phenylimidazo[1,2-a]pyridine derivatives as potent and selective ligands for peripheral benzodiazepine receptors: synthesis, binding affinity, and in vivo studies.

The substituent effects at positions 6 and 8 (compounds 17-31) as well as at the amide nitrogen (compounds 32-40) of a series of 2-phenylimidazo[1,2-a]pyridineacetamides were evaluated at both central (CBR) and peripheral (PBR) benzodiazepine receptors. The structure-activity relationship studies detailed herein indicate the key structural features required for high affinity and selectivity for PBR. Substitution on the imidazopyridine nucleus at position 8 with lipophilic substituents and the presence of one chlorine atom at the para position of the phenyl ring at C(2) are crucial features for high binding affinity and selectivity toward PBR. A small subset of active ligands (i.e., 17, 20, 26, 34, and 35) were evaluated in vitro in Xenopus oocytes expressing cloned human GABA(A) receptors for their effects at CBR and in vivo for their ability to stimulate the synthesis of neurosteroids such as pregnenolone, progesterone, allopregnanolone, and allotetrahydrodeoxycorticosterone (THDOC). Compounds 17, 20, 26, and 34 markedly increased the levels of neuroactive steroids in plasma and cerebral cortex, unlike compound 35.

Inhibition of monoamine oxidase-B by condensed pyridazines and pyrimidines: effects of lipophilicity and structure-activity relationships.

A number of condensed pyridazines and pyrimidines were synthesized and tested for their monoamine oxidase-A (MAO-A) and MAO-B inhibitory activity. Their lipophilicity was examined by measuring partition coefficients and RP-HPLC capacity factors, revealing some peculiar electronic and conformational effects. Further insights were obtained by X-ray crystallography and a thermodynamic study of RP-HPLC retention. Structure-activity relations highlighted the main factors determining both selectivity and inhibitory potency. Thus, while most of the condensed pyridazines were reversible inhibitors of MAO-B with little or no MAO-A effects, the pyrimidine derivatives proved to be reversible and selective MAO-A inhibitors. Substituents on the diazine nucleus modulated enzyme inhibition. A QSAR analysis of X-substituted 3-X-phenyl-5H-indeno[1,2-c]pyridazin-5-ones showed lipophilicity to increase MAO-B and not MAO-A inhibitory activity.

Conformationally constrained butyrophenones with mixed dopaminergic (D(2)) and serotoninergic (5-HT(2A), 5-HT(2C)) affinities: synthesis, pharmacology, 3D-QSAR, and molecular modeling of (aminoalkyl)benzo- and -thienocycloalkanones as putative atypical antipsychotics.

A series of novel conformationally restricted butyrophenones (2-(aminoethyl)- and 3-(aminomethyl)thieno- or benzocycloalkanones bearing (6-fluorobenzisoxazolyl)piperidine, (p-fluorobenzoyl)piperidine, (o-methoxyphenyl)piperazine, or linear butyrophenone fragments) were prepared and evaluated as atypical antipsychotic agents by in vitro assays of affinity for dopamine receptors (D(1), D(2)) and serotonin receptors (5-HT(2A), 5-HT(2C)) and by in vivo assays of antipsychotic potential and the risk of inducing extrapyramidal side effects. Potency and selectivity depended mainly on the amine fragment connected to the cycloalkanone structure. As a group, compounds with a benzisoxazolyl fragment had the highest 5-HT(2A) activities, followed by the benzoylpiperidine derivatives; in general, alpha-substituted cycloalkanone derivatives were more active than the corresponding beta-substituted congeners. CoMFA (comparative molecular field analysis) and docking studies showed electrostatic, steric, and lipophilic determinants of 5-HT(2A) and D(2) affinities and 5-HT(2A)/D(2) selectivity. The in vitro and in vivo pharmacological profiles of N-[(4-oxo-4H-5, 6-dihydrocyclopenta[b]thiophene-5-yl)ethyl]-4-(6-fluorobenzisox azol-3 -yl)piperidine (23b, QF 0510B), N-[(4-oxo-4,5,6, 7-tetrahydrobenzo[b]thiophene-5-yl)ethyl]-4-(6-fluorobenzisoxazol- 3-y l)piperidine (24b, QF 0610B), and N-[(7-oxo-4,5,6, 7-tetrahydrobenzo[b]thiophene-6-yl)ethyl]-4-(6-fluorobenzisoxazol- 3-y l)piperidine (29b, QF 0902B) suggest that they may be effective antipsychotic drugs with low propensity to induce extrapyramidal side effects.