Amoxicillin,a potential epileptogenic drug

Beta‐lactams are known to cause a wide spectrum of neurotoxic manifestations including epileptic seizures. The neurotoxicity of penicillin was first reported in 1945 by Johnson and Walker and is believed to exert an inhibitory effect on gamma‐aminobutyric acid transmission of cortical pyramidal cells, due to its beta‐lactam ring structure. Epileptogenicity is also a feature of the semisynthetic beta‐lactams including aminopenicillins. In this report, we present a patient with a recurrent history of discrete body twitching/jerks of epileptic nature in the context of amoxicillin exposure. The EEG revealed intermittent generalized short bursts of beta‐frequency polyspikes. This electro‐clinical picture was reversed by amoxicillin discontinuation.     

Pathophysiology of tension-type headache: potential drug targets

The pathophysiology of tension-type headache is still far from clear, although recent advances in basic and clinical research have increased our knowledge about mechanisms underlying this disorder. Experimental studies suggest that increased excitability of the CNS generated by repetitive and sustained pericranial myofascial input may be responsible for transformation of episodic tension-type headache into chronic form. Future studies should focus on the identification of the source of peripheral nociception in patients with tension-type headache and the development of more effective and specific treatment modalities.     

Lithium, a potential protective drug in Alzheimer's disease

Alzheimer's disease is characterized by the presence of two histopathological aberrant structures, the senile plaques and the neurofibrillary tangles. The main component of these tangles is the cytoskeletal protein tau in hyperphosphorylated form. Since a main tau kinase is glycogen synthase kinase 3 (GSK-3), the use of specific GSK-3 inhibitors, like lithium, could be a potential therapy in Alzheimer's disease. In this short article, we have done a review on tau phosphorylation in Alzheimer's disease and other tauopathies, and on the inhibition of kinases like GSK-3, involved in tau modification.     

Pharmacodynamics and pharmacokinetics of AHR-11748, a new antiepileptic agent, in rodents

AHR-11748, the desmethyl metabolite of fluzinamide (an effective antiepileptic), was active in preventing maximal seizures induced in mice or rats by electroshock and threshold seizures induced in mice by Metrazol, bicuculline, and picrotoxin. The compound showed a profile of anticonvulsant activity similar to those of phenobarbital and valproic acid and different from those of phenytoin and ethosuximide. ED50s were less than those of valproic acid, but greater than those of phenobarbital. Analysis of plasma and whole brain homogenates of mice indicated that AHR-11748 has an apparent terminal half-life (t1/2, beta) of 1.0 h. The brain:plasma ratio of AHR-11748 was 3.4:1 from 0.5 h to 6 h.     

Pharmacological properties of EXP 561, a potential antidepressant drug

Summary The compound EXP 561 (1-amino-4-phenylbicyclo-[2, 2, 2]-octane), an inhibitor of the noradrenaline (NA), 5-hydroxytryptamine (5-HT) and dopamine (DA) uptake, a potential antidepressant agent, was studied in tests for evaluation of antidepressant drugs (AD). In most experiments (the apomorphine and reserpine hypothermia, the behavioural despair test, the blood pressure increases induced by NA and 5-HT) EXP 561 revealed similar activities as tricyclic AD. EXP 561 evoked stimulation of the hind limb flexor reflex in spinal rats, blocked by prazosin, metergoline and clomipramine. EXP 561 administered repeatedly in mice (twice daily for 14 days) did not evoke the adaptive changes induced by AD inhibiting the amine uptake, i.e. it did not enhance the amphetamine locomotor hyperactivity, did not potentiate the clonidine aggressiveness (at a lower dose, while at a higher one it acted less potently than when given acutely) or did not change the reserpine effect on the locomotor activity. EXP 561 showed a poor affinity to ₁-adrenoceptor (IC₅₀ was 135,000 nM).The results indicate that the inability to induce adaptive changes is a feature which differentiates EXP 561 from tricyclic AD.     

Neuroprotective peptide drug delivery and development: potential new therapeutics

Alzheimer's disease and related neurodegenerative disorders are prevalent among the elderly and might be considered as the plague of the 21st century. It is thus imperative to find cures for these conditions. The use of nerve growth factor proteins as neuroprotective therapeutics is limited by their hindered mobility through the blood–brain barrier. Peptides provide an attractive alternative. However, do peptide derivatives retain the activity of the entire protein? Are they stable? Would peptides cross the blood–brain barrier and what are the potential side effects? Examples are put forth to strengthen our opinion that peptides are important candidates for future drug development.     

Hypericin as a potential drug for treating Alzheimer's disease and type 2 diabetes with a view to drug repositioning

Aims

Alzheimer's disease (AD) and type 2 diabetes (T2D) are two of the most common diseases in elderly population and they have a high rate of comorbidity. Study has revealed that T2D is a major risk factor of AD, and thus exploring therapeutic approaches that can target both diseases has drawn much interest in recent years. In this study, we tried to explore drugs that could be potentially used to prevent or treat both AD and T2D via a drug repositioning approach.

Methods

We first searched the known drugs that may be effective to T2D treatment based on the network distance between the T2D-associated genes and drugs deposited in the DrugBank database. Then, via molecular docking, we further screened these drugs by examining their interaction with islet amyloid polypeptide (IAPP) and Aβ42 peptide, the key components involved in the pathogenesis of T2D or AD. Finally, the binding between the selected drug candidates and the target proteins was verified by molecular dynamics (MD) simulation; and the potential function of the drug candidates and the corresponding targets were analyzed.

Results

From multiple resources, 734 T2D-associated genes were collected, and a list of 1109 drug candidates for T2D was obtained. We found that hypericin had the lowest binding energy and the most stable interaction with either IAPP or Aβ42 peptide. In addition, we also found that the target genes regulated by hypericin were differentially expressed in the tissues related to the two diseases.

Conclusion

Our results show that hypericin may be able to bind with IAPP and Aβ42 stably and prevent their accumulation, and thus could be a promising drug candidate for treating the comorbidity of AD and T2D.     

Anticonvulsant profile and teratogenicity of 3,3-dimethylbutanoylurea: a potential for a second generation drug to valproic acid

Purpose: The purpose of this study was to evaluate the anticonvulsant activity and teratogenic potential of branched aliphatic acylureas represented by isovaleroylurea (IVU), pivaloylurea (PVU) and 3,3‐dimethylbutanoylurea (DBU), as potential second‐generation drugs to valproic acid (VPA). Methods: The anticonvulsant activity of IVU, PVU, and DBU was determined in mice and rats utilizing the maximal electroshock seizure (MES) and the pentylenetetrazole (scMet) tests. The ability of DBU to block electrical‐, or chemical‐induced seizures was further examined in three acute seizure models: the psychomotor 6 Hz model, the bicuculline and picrotoxin models and one model of chronic epilepsy (i.e., the hippocampal kindled rat model). The induction of neural tube defects (NTDs) by IVU, PVU, and DBU was evaluated after i.p. administration at day 8.5 of gestation to a mouse strain highly susceptible to VPA‐induced teratogenicity. The pharmacokinetics of DBU was studied following i.v. administration to rats. Results: DBU emerged as the most potent compound having an MES‐ED ₅₀ of 186 mg/kg (mice) and 64 mg/kg (rats) and an scMet‐ED ₅₀ of 66 mg/kg (mice) and 26 mg/kg (rats). DBU underwent further evaluation in the hippocampal kindled rat (ED ₅₀ = 35 mg/kg), the psychomotor 6 Hz mouse model (ED ₅₀ = 80 mg/kg at 32 mA and ED ₅₀ = 133 mg/kg at 44 mA), the bicuculline‐ and picrotoxin‐induced seizure mouse model (ED ₅₀ = 205 mg/kg and 167 mg/kg, respectively). In contrast to VPA, DBU, IVU, and PVU did not induce a significant increase in NTDs as compared to control. DBU was eliminated by metabolism with a half‐life of 4.5 h. Conclusions: DBU's broad spectrum and potent anticonvulsant activity, along with its high safety margin and favorable pharmacokinetic profile, make it an attractive candidate to become a new, potent, and safe AED.     

Comparative neuropharmacology of buspirone and MJ-13805, a potential anti-anxiety drug

Buspirone is a clinically efficacious anti-anxiety drug without any other benzodiazepine-like activity. Although buspirone can displace ligands for dopamine (DA) receptors, its equipotent analog, MJ-13805, cannot. Buspirone can potently increase dopaminergic impulse flow and metabolism, primarily due to inhibition of DA autoreceptors. However, MJ-13805 does not block striatal nerve ending DA autoreceptors and slightly increases striatal DA metabolism. Both drugs potently reverse catalepsy due to either DA receptor blockade or DA depletion which indicates an effect within the extrapyramidal system efferent from the DA neuron. Amantadine is at least ten fold less potent than these drugs for reversal of catalepsy. These data indicate that altered dopaminergic neurotransmission may not be important for the anti-anxiety effect of buspirone and that buspirone should be tested for efficacy in various models of movement disorders. The site and mechanism of action for buspirone and MJ-13805 remains obscure. A metabolite of buspirone, 1-piperazinylpyrimidine, does not reverse catalepsy although this drug is known to be active in anti-anxiety screening tests. Thus, buspirone may have separate mechanisms of action for reduction of anxiety and reversal of catalepsy.     

Targeting thalamic nuclei is not sufficient for the full anti-absence action of ethosuximide in a rat model of absence epilepsy

Absence epilepsy is characterised by recurrent periods of physical and mental inactivity coupled to bilateral, synchronous spike and wave discharges (SWDs) on the electroencephalogram. The mechanism of action of ethosuximide (ETX), a drug specific for absence seizures, is believed to involve a reduction in the low threshold T-type Ca(2+) current in thalamocortical and nucleus reticularis thalami (NRT) neurones, although other electrophysiological data have questioned this. Here, we employed a genetic rat model of absence seizures to investigate the effects of directly administering ETX to the thalamus.SWDs were immediately and substantially reduced (approximately 90%) by systemic administration of ETX (177-709 micromol/kg), or by bilateral microinfusion into the thalamus of the GABA(B) antagonist, CGP 36742 (5-27 nmol per side). However, infusion of ETX (1-200 nmol per side) into the ventrobasal complex or the NRT resulted in a reduction of SWDs that was delayed (30-60 min) and less marked (approximately 50%). Administration of ETX (0.2 mM to 1M) to a greater volume of thalamus by reverse microdialysis also produced significant but delayed reduction of SWDs at concentrations >1mM. Only at 5mM were seizures significantly reduced (approximately 70%) within 30 min of administration.These results suggest that targeting of the thalamus alone may be insufficient for an immediate and full anti-absence action for ETX. Concomitant or exclusive actions in the cortex remain a possibility.     

Urine phenobarbital drug screening: potential use for compliance assessment in neonates

This study was done to determine if urine phenobarbital measurements provide a reliable indicator of presence of the drug in neonates. Urine was collected from neonates treated with phenobarbital for clinical indications within 4 to 6 hours of clinically indicated collection of serum phenobarbital levels. Urine samples were also collected from control neonates not treated with phenobarbital. One aliquot was assayed fresh, another frozen at -30°C and assayed 1 to 3 months later. Phenobarbital was assayed using the ONLINE TDM Roche/Hitachi automated clinical chemistry analyzer. Serum and urine concentrations were compared as were fresh and frozen urine measurements. Serum phenobarbital ranged from 5.6 to 52.7 μg/mL. Matched urine samples were 56.6 ± 12.5% of the serum level. Frozen samples were 98.3 ± 8.0% of the fresh samples. Urine phenobarbital concentrations, either fresh or frozen, can be used in neonates as a noninvasive estimate of drug levels.     

RGD-modified liposomes targeted to activated platelets as a potential vascular drug delivery system

Local drug delivery has become an important treatment modality for the prevention of thrombotic events following coronary angioplasty. In this study, we investigate the ability of liposomes bearing surface conjugated linear Arg-Gly-Asp (RGD) peptide (GSSSGRGDSPA) moieties to target and bind activated platelets, and the effect of such RGD-modified liposomes on platelet activation and aggregation. The binding of RGD-liposomes to human platelets was assessed by fluorescence microscopy, phase contrast microscopy and flow cytometry. The effect of RGD-modified liposomes on platelet activation and aggregation was investigated in vitro, with and without platelet agonists. RGD-liposomes were found to bind activated platelets at levels significantly greater than the control RGE-liposomes. The RGD-liposomes did not exhibit any statistically significant effect on platelet activation or aggregation. The results demonstrate the ability of the RGD-modified liposomes to target and bind activated platelets without causing significant platelet aggregation and suggests a feasible way for the development of a platelet-targeted anti-thrombogenic drug delivery system. Furthermore, the approach can be extended to the development of liposomes for other vascular targets, for application in drug delivery or gene therapy.     

The anticonvulsant action of AHR-11748 on kindled amygdaloid seizures in rats

The anticonvulsant effectiveness of AHR-11748 (3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide) was evaluated in the kindled amygdaloid seizure model in rats. Doses of AHR-11748 that did not cause prestimulation toxicity significantly attenuated elicited afterdischarge durations and the severity of the accompanying behavioral convulsive response in previously kindled rats. AHR-11748 (25-100 mg/kg i.p.) was evaluated at 30 min in previously kindled rats using both threshold (20 microA increments) and suprathreshold (400 microA) paradigms. AHR-11748 (50-100.mg/kg) reduced suprathreshold elicited after discharges and seizure severity. Utilizing a suprathreshold kindling paradigm, the maximum anticonvulsant effectiveness for the 100 mg/kg i.p. dose of AHR-11748 was seen at 180 min. AHR-11748 significantly elevated seizure thresholds only at the 100 mg/kg dose. AHR-11748 (25-100 mg/kg) significantly reduced the severity of threshold elicited seizures. When AHR-11748 (50 and 100 mg/kg i.p.) was administered daily during kindling acquisition, the number of daily trials necessary to complete kindling significantly increased. A reduction in both the duration and the severity of the responses induced by the daily stimulations during the acquisition period was seen with AHR-11748 treatment. This study has demonstrated that AHR-11748 significantly modifies both the acquisition of kindling and the fully kindled amygdaloid seizures at doses that do not cause behavioral toxicity.     

Anticonvulsant action of fluzinamide (AHR-8559) on kindled amygdaloid seizures

The anticonvulsant properties of fluzinamide (AHR-8559) were evaluated in the kindled amygdaloid seizure model in rats. Fluzinamide significantly attenuated afterdischarge durations and the severity of the accompanying convulsive responses in previously kindled rats at doses that did not cause sedation or ataxia. After acute intraperitoneal injections, the maximum anticonvulsant effectiveness against suprathreshold (400 microA) stimulation was seen at 30 min. Fluzinamide (10-80 mg/kg i.p.) was also evaluated in previously kindled rats using threshold (20-microA increments) seizures. Low doses of fluzinamide significantly elevated seizure threshold and reduced both elicited afterdischarge durations and seizure severity. When administered daily during kindling acquisition, fluzinamide (20 and 40 mg/kg i.p.) significantly increased the number of trials necessary to complete kindling. The duration and the severity of the responses induced by stimulations during the acquisition period were reduced. Previous studies have shown that the anticonvulsant profile for fluzinamide, as determined by traditional electrical and clinical models of epilepsies, most closely resembled phenobarbital and valproic acid, and differed from phenytoin and ethosuximide. The current study is consistent with this profile, with fluzinamide--like phenobarbital and valproic acid--significantly modifying both acquisition of kindling and the fully kindled amygdaloid seizure.