Milica Prostran

Pyridinium Oximes as Cholinesterase Reactivators. Structure-Activity Relationship and Efficacy in the Treatment of Poisoning with Organophosphorus Compounds

During more than five decades, pyridinium oximes have been developed as therapeutic agents used in the medical treatment of poisoning with organophosphorus compounds. Their mechanism of action is reactivation of acetylcholinesterase (AChE) inhibited by organophosphorus agents. Organophosphorus compounds (OPC) are used as pesticides and developed as warfare nerve agents such as tabun, soman, sarin, VX and others. Exposure to even small amounts of an OPC can be fatal and death is usually caused by respiratory failure resulting from paralysis of the diaphragm and intercostal muscles, depression of the brain respiratory center, bronchospasm, and excessive bronchial secretions. The mechanism of OPC poisoning involves phosphorylation of the serine hydroxyl group at the active site of AChE leading to the inactivation of this essential enzyme, which has an important role in neurotransmission. AChE inhibition results in the accumulation of acetylcholine at cholinergic receptor sites, producing continuous stimulation of cholinergic fibers throughout the central and peripheral nervous systems. Presently, a combination of an antimuscarinic agent, e.g. atropine, AChE reactivator such as one of the standard pyridinium oximes (pralidoxime, trimedoxime, obidoxime, HI-6) and diazepam has been used for the treatment of organophosphate poisoning in humans. Despite enormous efforts devoted to synthesis and development of new pyridinium oximes as potential antidotes against poisoning with OPC, only four compounds have found their application in human medicine so far. However, they differ in their activity in poisoning with warfare nerve agents and pesticides and there is still no universal broad-spectrum oxime capable of protecting against all known OPC. In this article, we review data on structure-activity relationship of pyridinium oximes and discuss their pharmacological and toxicological significance.

Reliable identification of "truly low" thromboembolic risk in patients initially diagnosed with "lone" atrial fibrillation: the Belgrade atrial fibrillation study.

Background— The CHA2DS2-VASc (Congestive heart failure, Hypertension, Age ≥75 years, Diabetes mellitus, previous Stroke/transient ischemic attack [TIA], Vascular disease, Age 65–74 years, and Sex category [female gender]) schema recently has been introduced to complement the CHADS2 (Congestive heart failure, Hypertension, Age >75 years, Diabetes mellitus, and previous stroke or TIA) score and improve the identification of atrial fibrillation (AF) patients at “truly low risk” for thromboembolism. We tested the predictive ability of the CHA2DS2-VASc, CHADS2, and van Walraven risk stratification schemes in a cohort of “lone” AF patients with a 12-year follow-up. Methods and Results— We conducted a registry-based, observational cohort study of 345 patients initially diagnosed with “lone” AF between 1992 and 2007. At baseline, all patients had the CHADS2 and van Walraven scores of 0, and 262 (75.9%) had a CHA2DS2-VASc score of 0. During follow-up (or within a year prior to stroke), 228 (66.1%), 234 (67.8%), and 150 patients (43.5%) retained the CHADS2, van Walraven, and CHA2DS2-VASc scores of 0, respectively. The overall rate of ischemic stroke was 0.19 (95% CI: 0.18–0.20) per 100 patient years. In the multivariable analysis, only the CHA2DS2-VASc score of 0 was significantly related to the absence of stroke (odds ratio 5.1, 95% CI: 1.5–16.8, P=0.008). Only the CHA2DS2-VASc score had a significant prediction ability (c-statistic 0.72 [0.61–0.84], P=0.031). Conclusions— The CHA2DS2-VASc score reliably identified the “lone” AF patients who were at “truly low risk” for thromboembolism, and was the only tested risk stratification scheme with a significant predictive ability for thromboembolism among lone AF patients.

Second-generation antipsychotics and extrapyramidal adverse effects.

Antipsychotic-induced extrapyramidal adverse effects are well recognized in the context of first-generation antipsychotic drugs. However, the introduction of second-generation antipsychotics, with atypical mechanism of action, especially lower dopamine receptors affinity, was met with great expectations among clinicians regarding their potentially lower propensity to cause extrapyramidal syndrome. This review gives a brief summary of the recent literature relevant to second-generation antipsychotics and extrapyramidal syndrome. Numerous studies have examined the incidence and severity of extrapyramidal syndrome with first- and second-generation antipsychotics. The majority of these studies clearly indicate that extrapyramidal syndrome does occur with second-generation agents, though in lower rates in comparison with first generation. Risk factors are the choice of a particular second-generation agent (with clozapine carrying the lowest risk and risperidone the highest), high doses, history of previous extrapyramidal symptoms, and comorbidity. Also, in comparative studies, the choice of a first-generation comparator significantly influences the results. Extrapyramidal syndrome remains clinically important even in the era of second-generation antipsychotics. The incidence and severity of extrapyramidal syndrome differ amongst these antipsychotics, but the fact is that these drugs have not lived up to the expectation regarding their tolerability.

The Antinociceptive Effects of Anticonvulsants in a Mouse Visceral Pain Model

BACKGROUND:There is evidence supporting the antinociceptive effects of carbamazepine, oxcarbazepine, gabapentin, and topiramate in various models of neuropathic pain as well as inflammatory somatic pain. Data are lacking on the antinociceptive potential of these drugs against visceral pain. In this study, we examined and compared the effects of carbamazepine, oxcarbazepine, gabapentin, and topiramate in the writhing test as a visceral pain model in the mouse. In addition, the influence of these anticonvulsants on motor performance was examined to compare the tolerability of these anticonvulsants when used against acute visceral pain. METHODS:The antinociceptive effects of these anticonvulsants were examined in the acetic acid writhing test in mice. The side effect propensity of these drugs was examined using the rotarod test. RESULTS:Carbamazepine (25–60 mg/kg; p.o.), oxcarbazepine (10–40 mg/kg; p.o.), gabapentin (10–70 mg/kg; p.o.), and topiramate (5–30 mg/kg; p.o.) caused a significant dose-dependent reduction the number of writhes in the writhing test. In the rotarod test, carbamazepine (60–140 mg/kg; p.o.) and oxcarbazepine (120–450 mg/kg; p.o.) significantly reduced the time spent on the rotarod in a dose- and time-dependent manner. Gabapentin (1000–2000 mg/kg; p.o.) and topiramate (400–1500 mg/kg; p.o.) did not produce significant impairment of motor performance at the highest doses used. The therapeutic index (motor impairing dose TD50/writhing ED50) values were topiramate (>148.5) > gabapentin (>60.2) > oxcarbazepine (15.2) > carbamazepine (2.3). CONCLUSIONS:These results indicate that oxcarbazepine, gabapentin, and topiramate are effective in the writhing model in mice, in a dose range, which is not related to motor impairment; topiramate is the most potent and the most tolerable drug.

The anti-hyperalgesic effects of carbamazepine and oxcarbazepine are attenuated by treatment with adenosine receptor antagonists.

Abstract The antinociceptive effects of carbamazepine and oxcarbazepine, and the influence of caffeine, were examined in a paw pressure test in rats. Carbamazepine (10–40 mg/kg; intraperitoneal, i.p.) and oxcarbazepine (40–160 mg/kg; i.p.) caused a significant dose‐dependent reduction of the paw inflammatory hyperalgesia induced by concanavalin A (Con A), intraplantarly (i.p1.). A comparable pattern of antinociceptive effect of carbamazepine and oxcarbazepine was observed; the only difference is their potency, in that carbamazepine was about three times more potent than oxcarbazepine. Caffeine (5–20 mg/kg; i.p.), a non‐selective adenosine receptor antagonist, significantly depressed the antinociceptive effects of carbamazepine and oxcarbazepine, in a dose‐ and time‐dependent manner. Also, a significant depression of the antinociceptive effects of carbamazepine and oxcarbazepine was observed by pretreatment with 1,3‐dipropyl‐8‐cyclopentylxantine (DPCPX, 0.4 and 0.8 mg/kg; i.p.), an adenosine A1 receptor antagonist. These findings indicate that, in a paw inflammatory hyperalgesia in rats, the antinociceptive effects of both drugs are, at least partially, mediated by adenosine A1 receptors. In conclusion, the present study suggests the potential clinical importance of carbamazepine and oxcarbazepine in the treatment of inflammatory pain. In addition, caffeine consumption could possibly depress the analgesic effects of both anticonvulsive drugs.

The synthesis and preliminary pharmacological evaluation of 4-methyl fentanyl

The synthesis of 4-methyl fentanyl, a prototype of a novel class of fentanyl analogues has been effected in 5 steps, starting from N-ethoxycarbonyl-4-piperidone (approximately 20% overall yield). In the key step, N-phenylation of secondary aliphatic amide intermediare was achieved by a novel reaction, using diphenyliodonium chloride for the phenyl group transfer. Preliminary pharmacological results indicate that 4-methyl fentanyl is a super potent narcotic analgesic, about four times more potent than fentanyl.

Potentially Inappropriate Prescribing in Older Primary Care Patients

Objectives The aim of the study was to determine the rate of Potentially Inappropriate Medicines (PIM) and Potential Prescription Omissions (PPO) according to Screening Tool of Older Persons potentially inappropriate Prescriptions/Screening Tool to Alert doctors to the Right Treatment (STOPP/START) criteria. Study Design A cross-sectional survey in community pharmacy. Method A prospective cross-sectional study was performed, during March-May 2012, in five community pharmacies. Patients aged ≥65 years, who collected one or more prescribed medications, were asked to participate in the study, and an interview was scheduled. Patients were asked to provide their complete medical and biochemical record from their general practitioner. Results 509 patients, mean age 74.8±6.5 years, 57.4% female, participated in the study. 164 PIM were identified in 139 patients (27.3%). The most common were: long-term use of long-acting benzodiazepines (20.7%), use of non-steroidal antiinflammatory drugs (NSAID) in patients with moderate-severe hypertension (20.1%), use of theophylline as monotherapy for chronic obstructive pulmonary disease (COPD, 15.9%) and use of aspirin without appropriate indication (15.2%). Patients with more than four prescpritions had a higher risk for PIM (OR 2.85, 95% CI 1.97–4.14, p<0.001). There were 439 PPO, identified in 257, (50.5%) patients. Predictors for PPO were older age, presence of diabetes, myocardial infarction, osteoporosis, stroke, COPD and/or angina pectoris. Conclusion STOPP/START criteria may be useful in identifying inappropriate prescribing and improving the current prescribing practices. Pharmacists should focus more on patients with more than four medications and/or patients with gout or pain accompanied with arterial hypertension because those patient may be at higher risk of PIM. Additionlly, patients older than 74 years with diabetes, osteoporosis, myocardial infarction, stroke, angina pectoris and/or COPD may have an increased risk of PPO.

Experimental diabetes induced by alloxan and streptozotocin: The current state of the art.

Diabetes mellitus is a chronic metabolic disorder with a high prevalence worldwide. Animal models of diabetes represent an important tool in diabetes investigation that helps us to avoid unnecessary and ethically challenging studies in human subjects, as well as to obtain a comprehensive scientific viewpoint of this disease. Although there are several methods through which diabetes can be induced, chemical methods of alloxan- and streptozotocin-induced diabetes represent the most important and highly preferable experimental models for this pathological condition. Therefore, the aim of this article was to review the current knowledge related to quoted models of diabetes, including to this point available information about mechanism of action, particular time- and dose-dependent protocols, frequent problems, as well as major limitations linked to laboratory application of alloxan and sterptozotocin in inducing diabetes. Given that diabetes is known to be closely associated with serious health consequences it is of fundamental importance that current animal models for induction of diabetes should be continuously upgraded in order to improve overall prevention, diagnosis and treatment of this pathological condition.

The effects of α2-adrenoceptor agents on anti-hyperalgesic effects of carbamazepine and oxcarbazepine in a rat model of inflammatory pain

&NA; In this study, the effects of yohimbine (&agr;2‐adrenoceptor antagonist) and clonidine (&agr;2‐adrenoceptor agonist) on anti‐hyperalgesia induced by carbamazepine and oxcarbazepine in a rat model of inflammatory pain were investigated. Carbamazepine (10–40 mg/kg; i.p.) and oxcarbazepine (40–160 mg/kg; i.p.) caused a significant dose‐dependent reduction of the paw inflammatory hyperalgesia induced by concanavalin A (Con A, intraplantarly) in a paw pressure test in rats. Yohimbine (1–3 mg/kg; i.p.) significantly depressed the anti‐hyperalgesic effects of carbamazepine and oxcarbazepine, in a dose‐ and time‐dependent manner. Both drug mixtures (carbamazepine–clonidine and oxcarbazepine–clonidine) administered in fixed‐dose fractions of the ED50 (1/2, 1/4 and 1/8) caused significant and dose‐dependent reduction of the hyperalgesia induced by Con A. Isobolographic analysis revealed a significant synergistic (supra‐additive) anti‐hyperalgesic effect of both combinations tested. These results indicate that anti‐hyperalgesic effects of carbamazepine and oxcarbazepine are, at least partially, mediated by activation of adrenergic &agr;2‐receptors. In addition, synergistic interaction for anti‐hyperalgesia between carbamazepine and clonidine, as well as oxcarbazepine and clonidine in a model of inflammatory hyperalgesia, was demonstrated.

Fentanyl Analogs: Structure-Activity-Relationship Study

Fentanyl is the prototype of the 4-anilidopiperidine class of synthetic opioid analgesics. This study was aimed to review the structure-activity-relationship (SAR) of fentanyl analogs substituted in the position 3, or 4 of the piperidine ring. Pharmacological results show that the groups in position 3 of the piperidine ring, which are larger than methyl, severely reduce the analgesic potency compared to fentanyl. It is likely that the steric factor alone (i.e. voluminosity of the group and cis/trans isomerism), rather than the polarity and/or chemical reactivity, plays a crucial role in the analgesic potency of this series. Although the duration of action, in general, does not depend on the stereochemistry, longer action of the most potent 3-alkyl fentanyl analogs such as cis-3-methyl- and cis-3-ethyl fentanyl, is more likely influenced by pharmacodynamic, rather than pharmacokinetic variables. Also, it is possible that the introduction of a functional group such as 3-carbomethoxy reduces the duration of action by altering pharmacokinetic properties. SAR findings obtained by evaluating the neurotoxic effects of fentanyl analogs substituted in the position 3 of the piperidine ring parallel the SAR findings on analgesia in regard to potency and duration of action. This might suggest that similar receptors are involved in producing both antinociceptive and neurotoxic effects of these drugs. It appears that both the potency and the duration of action in the series of fentanyl analogs substituted in position 4 of the piperidine ring is influenced only by the steric requirement and not by the chemical nature of the substituent.