D S Tikhonov

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This paper introduces a new computational algorithm for finding the path a chemical reaction takes going from starting materials to products. The method runs two simulations simultaneously — one starting from reactants, one from products — and merges them in the middle, inspired by quantum physics calculations. It was demonstrated on a model energy landscape and a real halogen-substitution reaction, and is particularly useful for quantum chemistry methods that do not provide energy gradients.

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This review synthesized current research on why some people with schizophrenia do not respond to antipsychotic drugs, a condition called treatment-resistant schizophrenia. The key biological explanations involve disrupted signaling in dopamine, glutamate, and GABA pathways, as well as broader systemic processes like neuroinflammation. Understanding these mechanisms could help clinicians choose better treatments and guide development of new therapies.

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Researchers tested three light-switchable drug compounds — QAQ, DENAQ, and AAQ — on nerve-muscle synapses in fly larvae to see how they affect signal transmission. Despite their similar chemical structures, the compounds had opposite effects: QAQ blocked postsynaptic glutamate receptors, DENAQ boosted nerve excitability by blocking potassium channels, and AAQ combined both actions. The same molecular targets had previously been identified in vertebrates, suggesting these mechanisms are conserved across evolution and that the light-sensitivity and mode of action must be evaluated separately for each compound.

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Brain scans of 84 men with schizophrenia and 86 healthy men were analyzed to see whether accelerated brain aging in schizophrenia is linked to abnormal resting-state brain connectivity. Schizophrenia patients had brains that appeared about 3 years older than expected, and greater biological aging in patients was tied to weaker connectivity of a right-hemisphere region spanning the frontal, temporal, and insular cortex. Weaker connectivity in that region was associated with poorer verbal working memory and language production, linking structural aging to well-known functional deficits in the disease.

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Researchers created a database called PLIC containing over 400 three-dimensional structures of ion channels that share a common architecture built around a membrane-re-entering loop, covering potassium, sodium, calcium, glutamate receptor channels, and others. All structures were aligned and given a universal residue-labeling system to make them directly comparable. Statistical analysis of these aligned structures revealed conserved and variable features across channel families, and identified structural outliers warranting further investigation.

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Using microwave pulses, researchers created and directly observed chiral tunneling dynamics in a molecule — the process by which a molecule oscillates between left-handed and right-handed forms through quantum tunneling. The experiment revealed how a coherent mixture of handed states evolves over time under field-free conditions. They also demonstrated precise control over the phase of this quantum coherence by modulating the pump pulses, a capability relevant to future molecular control experiments.

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Using ultrafast electron diffraction, researchers directly tracked the structural changes in acetylacetone — a small molecule with an internal hydrogen bond — within the first 700 femtoseconds after it absorbed ultraviolet light. The molecule rapidly breaks its ring-like shape, flattens out of its plane, and stretches its bonds, all while transitioning between electronic energy states. These results provide a direct structural view of photochemical dynamics that were previously only inferred from spectroscopy.

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A compound called DAB-19, derived from diazepine-benzimidazole, was tested for its effects on glutamate signaling in the brain and at nerve-muscle junctions. It suppressed evoked glutamate release in rat brain slices while simultaneously enhancing spontaneous signaling, acting through two mechanisms: boosting calcium-dependent neurotransmitter release and blocking sodium channels that carry nerve impulses. Tests in a seizure model showed DAB-19 delayed but did not prevent seizures, pointing to it as a multi-target candidate for nervous system disorders.

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The authors developed lightweight software and a database of 400 mass spectra to help investigators identify poisonous and explosive substances in forensic situations. The software uses four statistical metrics combined into a single score to match an unknown spectrum against the database, and also features automatic background removal. A workflow for expanding the database using theoretical calculations was also validated.

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Researchers studied whether a signaling enzyme called JNK is involved in age-related macular degeneration, a leading cause of blindness. JNK activity was not elevated simply with aging in healthy rats, but it was activated as macular degeneration-like disease progressed in a rat model of the condition. A selective JNK3 inhibitor called IQ-1S suppressed retinal degeneration and protected synapses, supporting it as a potential treatment strategy.

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This review examines how captopril, a blood pressure drug, protects the heart beyond just lowering pressure. In addition to its known effects on the renin-angiotensin system, captopril reduces oxidative damage and inflammation, which helps during events like heart attacks and in chronic conditions like heart failure. The authors call for more research to fully map captopril's molecular targets and expand its clinical applications.

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Researchers performed a detailed computational study of a known but poorly understood reaction: the rearrangement of phenylnitrile oxide into phenyl isocyanate, catalyzed by sulfur dioxide. Using high-accuracy quantum chemistry methods, they mapped the reaction mechanism, identified how substituents affect the reaction rate, and screened other potential catalysts including sulfur trioxide and selenium dioxide. The study originated from a humorous social media post and demonstrates how informal scientific discussion can seed rigorous research.

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Mice were given DMSO — a common laboratory solvent — in their drinking water at three concentrations for four or six weeks to test whether it causes neurological harm. At all concentrations tested, DMSO reduced the myelin content in the corpus callosum, the nerve fiber tract connecting the brain hemispheres, and altered both motor coordination and pain sensitivity. These findings indicate that DMSO has significant neurotoxic effects even at low doses and raise concerns about its use as a vehicle in animal studies.

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Using rotational spectroscopy, researchers studied how hydrochloric acid dissociates when surrounded by a small number of water molecules. For clusters with up to four water molecules, the H-Cl bond remains covalent, but at five and seven water molecules the acid spontaneously ionizes, forming a protonated water complex. This precisely identifies the minimum number of water molecules needed to trigger acid dissociation under isolated, cold conditions.

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Researchers measured how the ionization energy of clusters of a helically shaped carbon-ring molecule called helicene changes as the clusters grow from monomer to heptamer. Experimental photoelectron spectra were compared to quantum-chemical calculations to identify which cluster arrangements are most stable and how chirality affects aggregation. The results indicate that homochiral clusters (same-handed molecules) are energetically favored over mixed-chirality clusters as size increases, suggesting chirality-driven symmetry breaking in the formation of these molecular assemblies.

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This paper presents a simple analytical method for estimating the maximum electric charge a molecule can hold before it becomes more favorable to break apart. The approach uses ionization potentials, electron affinities, and bond dissociation energies as inputs, enabling construction of stability phase diagrams for highly charged species. The method was applied to polyenes, ring molecules, and helium clusters, showing how maximum stable charge scales with molecular size.

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Researchers used intense laser pulses to ionize fluorene — a carbon-ring molecule — and tracked the resulting ultrafast fragmentation and electronic dynamics using multiple simultaneous detection methods. They identified formation of an unstable quadruply charged fluorene ion, above-threshold ionization features, and extensive secondary fragmentation of the excited molecule and its ions. A global fitting procedure extracted 60 distinct lifetimes for the various transient species, providing a comprehensive picture of strong-field molecular dynamics.

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This study provides a systematic database of frequency scaling factors for 27 dispersion-corrected quantum chemistry methods, derived from 441 molecules ranging from simple diatomics to buckminsterfullerene. Two types of scaling are provided — one optimized for high frequencies and one for low frequencies — to improve agreement between calculated and experimental vibrational spectra. The resource allows researchers to directly correct computed infrared frequencies without re-parameterizing their methods.

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Several drugs known mainly as antiparasitic agents or protease inhibitors — including pentamidine, DAPI, and furamidine — were tested for their ability to block AMPA-type glutamate receptors in rat brain neurons. Most compounds preferentially blocked calcium-permeable AMPA receptors by entering the channel pore, with some also affecting calcium-impermeable receptors or binding to an additional surface site. Notably, pentamidine enhanced rather than blocked one type of AMPA receptor response, revealing an unexpectedly diverse pharmacological profile for this class of compounds.

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This paper introduces scaling factors — correction multipliers — that bring theoretically calculated rotational constants of molecules closer to values measured experimentally. Scaling factors were derived for several commonly used quantum chemistry methods and basis sets, and were validated by systematic comparison to experiment. The result is a practical tool for improving the accuracy of computed molecular spectra without additional computational cost.

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ASIC1a channels display a progressive decrease in response amplitude when activated repeatedly — a phenomenon called tachyphylaxis — and this study investigated its mechanism. The researchers showed that tachyphylaxis is a slow form of desensitization that only occurs when the channel is open, recovers slowly with time, and is independent of the usual fast desensitization process. Drugs that facilitate channel opening accelerate slow desensitization while pore blockers reduce it, explaining why modulation of channel gating state controls this phenomenon.

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Nafamostat, sepimostat, and diminazene — drugs with positively charged chemical groups — were found to potently block acid-sensing ion channels in rat brain neurons and recombinant ASIC1a channels by physically entering the channel pore. All three acted by a foot-in-the-door mechanism, preventing channel closure after opening. Nafamostat, which is already used clinically, could be a candidate for treating conditions linked to ASIC overactivation such as inflammatory pain and stroke.

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Researchers designed and tested a series of light-switchable compounds based on the DENAQ scaffold to find better photopharmacological tools for studying NMDA receptors. One compound, PyrAQ, emerged as the most potent, inhibiting NMDA receptors with a concentration for half-maximal effect of 2 micromolar under ambient light, with full and rapid reversal upon illumination. Its activity was independent of receptor activation state, agonist concentration, and membrane voltage, making it a clean tool for optical control of NMDA receptors.

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This computational study examined how residue-residue interactions change between different structural states of the acid-sensing ion channel ASIC1a to understand how the channel opens and closes. Analysis of optimized structures supported previously proposed mechanisms for conformational collapse of the acidic pocket during activation, and provided evidence for a proton-sharing mechanism between two glutamate residues in the lower part of the protein as a gating trigger. The work reveals the complexity of interactions involved and provides testable structural predictions.

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Five compounds related to 2-aminobenzimidazole were tested for their ability to modulate acid-sensing ion channels in rat neurons. Two compounds — Ru-1355 and Ru-1199 — strongly enhanced responses of the ASIC2a subtype, which currently lacks potent and selective modulators, and also potentiated other ASIC subtypes. The potentiation produced an additional slow current component that was less sensitive to a standard pore blocker, suggesting these compounds promote a distinct, slowly desensitizing open state of the channel.

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Researchers demonstrated that microwave pulses can temporarily create an excess of one mirror-image form of a molecule that normally interconverts between left and right-handed forms too quickly to separate. Using a sequence of five precisely timed and phase-controlled pulses, they induced a chiral wave packet in a chosen rotational state of benzyl alcohol and detected the resulting enantiomeric enrichment. This is the first experimental demonstration of inducing transient chirality in a quantum racemic mixture, an important step toward controlling flexible chiral molecules.

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Researchers tested whether a JNK enzyme inhibitor called IQ-1S could protect the retina in rats that naturally develop a condition resembling age-related macular degeneration. Treatment with IQ-1S during the period of active disease development improved blood circulation, reduced a protein that promotes abnormal vessel growth, and protected photoreceptors and inner retinal neurons. The drug also increased the number of mitochondria in retinal cells, which had been depleted by the disease, suggesting IQ-1S has potential as a preventive strategy for macular degeneration.

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A new parameterization approach for metadynamics — a simulation method used to accelerate the study of rare chemical events — was developed for reactions involving bond breaking. The key insight is a mathematical similarity between the bias potential used in metadynamics and the quantum potential from Bohmian mechanics, which provides a principled way to set simulation parameters. The method was validated on proton transfer reactions and a ring-opening reaction.

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This work evaluates a quantum sampling method called Wigner sampling for computing molecular properties that are affected by nuclear quantum effects and vibrational anharmonicity. The method was tested on three types of calculations — rotational constants, infrared spectra, and photoelectron spectra — across a range of molecular systems. A simplified version of the method was introduced that performs well even for large, flexible molecules where more exact quantum approaches become impractical.

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Researchers tested the idea that acid-sensing ion channels in the brain might compensate for the inhibitory effect of acidity on glutamate receptors during synaptic transmission. Patch-clamp recordings from different types of rat brain neurons showed that the balance between ASIC and glutamate receptor responses varies dramatically by cell type — striatal interneurons have strong ASIC responses relative to glutamate responses, while hippocampal pyramidal neurons have the opposite. Overall, the combined response to glutamate remained relatively stable across a wide pH range, consistent with ASICs playing a compensatory role.

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Forty-four men with treatment-resistant schizophrenia received rhythmic transcranial magnetic stimulation tailored to their predominant symptoms — depressive, hallucinatory, negative, or delusional. Patients with depressive, hallucinatory, and negative symptoms showed significant reductions in symptom severity scores after 15 sessions, with effects sustained three weeks later. Patients with delusional symptoms initially worsened, but improved after additional medication, suggesting that symptom type must guide TMS protocol selection.

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This study used computational modeling to explain why two chemically similar drugs — a DHP agonist and a DHP antagonist — have opposite effects on the same L-type calcium channel. The key difference lies in whether the drug stabilizes a straight or kinked form of a transmembrane helix called S6IV: the antagonist locks the helix in its straight form, while the agonist promotes a kink that rearranges the channel gate region and favors channel opening. This structural mechanism resolves a long-standing puzzle about how structurally similar drugs can have opposite functional effects.

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Two light-switchable compounds containing azobenzene groups were shown to rapidly and reversibly block glutamate-activated ion channels in rat brain neurons when switched between light states. The compounds preferentially blocked NMDA receptors and calcium-permeable AMPA receptors, and their binding positions in the two channel types were confirmed by computer modeling — sitting deeper in the AMPA receptor pore and shallower in the NMDA receptor due to pore geometry differences. These findings establish a structural basis for designing more potent and selective light-controlled blockers of glutamate receptors.

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Nickel coatings were deposited on surfaces and modified by adding graphene oxide particles treated with microwave radiation. The graphene oxide addition produced finer grain structure in the coating, increasing hardness by 40% and reducing corrosion rate in saltwater by 70% compared to plain nickel. The improved performance was attributed to uniform dispersion of graphene oxide throughout the nickel matrix without the particle clumping that typically limits graphene-based composite coatings.

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A new mathematical method was developed for extracting radial distribution functions from electron diffraction data, which describe how atoms are arranged relative to one another in a molecule. The approach propagates experimental measurement uncertainties directly into the final result and includes a criterion for choosing the optimal regularization parameter. The method also applies to x-ray and neutron diffraction of liquids.

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This study examined whether schizophrenia patients who have experienced auditory verbal hallucinations differ from those who have not in their executive control of language and in brain connectivity. Patients with a history of hallucinations showed lower verbal fluency, shorter utterances, and reduced functional connectivity between the left inferior frontal gyrus and the anterior cingulate cortex — regions involved in speech production and self-monitoring. These findings suggest that deficits in planning and monitoring self-generated speech are specific neuropsychological and neural markers of the hallucination-prone subtype.

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Researchers tested how a series of tetraalkylammonium ions — positively charged molecules with four alkyl groups — interact with acid-sensing ion channels, which open in response to drops in pH. The largest compound, tetrapentylammonium, blocked most ASIC subtypes but unexpectedly potentiated ASIC3 steady-state currents with an effect that was voltage-independent and diminished under strong acidification. Molecular modeling placed this compound in the acidic pocket of the channel, suggesting it prevents a structural collapse normally associated with channel desensitization.

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Glutamate, the brain's main excitatory neurotransmitter, was found to enhance the sensitivity of ASIC1a channels to acidification when tested on receptors expressed in cells. At concentrations below 1 millimolar, glutamate shifted the pH threshold for ASIC1a activation toward less acidic values by up to 0.4 pH units. This means that at glutamatergic synapses, where glutamate is naturally released alongside acidification, ASIC1a channels may be intrinsically primed to respond to pH drops that would otherwise be too mild to activate them.

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Blood levels of aripiprazole and its active metabolite were measured in schizophrenia patients using high-performance liquid chromatography-mass spectrometry to personalize dosing. Average drug concentrations varied widely across patients, and equations linking dose to blood concentration were derived separately for aripiprazole and its metabolite. The results highlight extensive individual variability in drug metabolism and support routine therapeutic drug monitoring to optimize aripiprazole treatment.

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This review compares experimentally determined structures of P-loop ion channels — a large family including potassium, sodium, calcium, and glutamate receptor channels — with structures predicted by the AI tool AlphaFold2. Overall folding was well reproduced by AlphaFold2, including subtle differences between channel subfamilies, but the models inconsistently reproduced pi-helical bulges in transmembrane helices that are thought to be functionally important for gating. The discrepancy between predicted and experimental bulge patterns highlights a limitation of current AI structure prediction for capturing dynamic features of ion channels.

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Male schizophrenia patients were followed for 20 to 25 years after disease onset to characterize long-term outcomes and their relationship to immune system markers. Three outcome types were identified: personality deterioration, predominant negative symptoms, and persistent mixed positive and negative symptoms; all patients showed elevated immune enzyme activity compared to healthy controls. Immunological differences between outcome types suggest that ongoing inflammation level influences long-term disease trajectory, with lower inflammation potentially linked to genetic rather than inflammatory mechanisms.

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A lactate biosensor was developed with a linear response range spanning 0.5 to 100 millimolar, covering lactate concentrations in both sweat and blood, by adding a special diffusion-limiting membrane that slows analyte access to the enzyme. Unlike existing lactate sensors that degrade within hours, this sensor maintained full response for dozens of hours even at high lactate concentrations. Validation in blood serum and undiluted fresh sweat confirmed suitability for wearable devices monitoring oxygen deficiency during physical stress.

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The study analyzed depression that emerges in adolescent patients recovering from a first psychotic episode, identifying two subtypes: one with emotionally active, anxious depression and another with flat, negative-symptom-dominated depression. The two types differed in how the initial psychosis presented, in their scores on standard depression and suicidality scales, and in their likely prognosis and treatment needs. Recognizing these subtypes is important for tailoring post-psychosis depression management in young patients.

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Using extreme ultraviolet photons and multi-mass ion imaging, researchers measured the energy released when doubly and triply charged versions of three polycyclic aromatic hydrocarbons — fluorene, phenanthrene, and pyrene — break apart. Total kinetic energy release values were determined for multiple fragmentation channels using a recoil-frame covariance analysis method, yielding precise measurements ranging from about 2 to 5 electron volts. Molecular dynamics simulations supported the experimental findings, providing insight into how these interstellar molecules behave under high-energy radiation.

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Brain temperature patterns in schizophrenia patients were measured using microwave radiothermometry and compared with blood markers of inflammation and treatment response. Patients with uniform brain temperatures had higher inflammatory activity and tended to respond to therapy, while those with uneven temperature patterns showed depleted inflammatory responses, higher brain-specific antibodies, more severe disease, and treatment resistance. The results suggest that brain thermometry provides clinically useful information about the inflammatory and treatment-response status of patients.

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This theoretical study proposes an experiment to observe how a flat molecule temporarily becomes chiral when an out-of-plane vibration is excited. The key is breaking the left-right symmetry of the vibrational excitation using a Raman process in an electric field, so that molecules oscillate with a net chiral bias detectable via photoelectron circular dichroism. The proposal, worked out for carbonyl chlorofluoride, is achievable with current laser and synchrotron technology.

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Three polycyclic aromatic hydrocarbon molecules — fluorene, phenanthrene, and pyrene — were ionized with extreme ultraviolet laser pulses and their subsequent fragmentation was tracked using ultrafast ion and electron imaging. The study extracted electronic relaxation times for singly, doubly, and triply charged states, and showed that fragmentation pathways evolve on femtosecond to picosecond timescales with a preference for losing even numbers of carbon atoms. These results shed light on how PAH molecules, which are abundant in space, respond to the high-energy radiation they encounter in interstellar environments.

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Blood samples from kidney cancer patients were analyzed by mass spectrometry to identify proteins carrying post-translational modifications, then structural modeling was used to examine how these modifications affect protein shape. Fifteen modified proteins were identified, and in all cases the modifications were located in compact, solvent-exposed structural regions, where they increased the surface area accessible to solvent. The findings link post-translational signaling changes to the structural alterations that may drive abnormal cell proliferation in kidney cancer.

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A screen of common anticonvulsant drugs for activity against AMPA glutamate receptors found that only phenytoin had significant potency, blocking calcium-impermeable AMPA receptors with a half-maximal concentration of 30 micromolar. The mechanism matched that of the pore blocker pentobarbital, and structural similarity between the two compounds supported a shared binding site inside the channel pore. This is the first evidence that AMPA receptor blockade contributes to phenytoin's anticonvulsant action and possibly its side effects.