Pharmacokinetic characterization of favipiravir in patients with COVID-19.

This prospective observational study describes the pharmacokinetic characteristics of favipiravir in adult patients hospitalized for mild to moderate COVID-19 with a positive RT-PCR test. Favipiravir was administered for 5 days, with a loading dose of 3200 mg and a maintenance dose of 1200 mg/day. Serial blood samples were collected on Day 2 and Day 4 of the therapy. Laboratory findings of the patients (n = 21) and in-hospital mortality were recorded. Favipiravir concentrations exhibited substantial variability and a significant decrease during the treatment of COVID-19. The median favipiravir trough concentration (C0-trough ) on Day 2 was 21.26 (interquartile range [IQR], 8.37-30.78) µg/mL, whereas it decreased significantly to 1.61 (IQR, 0.00-6.41) µg/mL on Day 4, the area under the concentration-time curve decreased by 68.5%. Day 2 C0-trough of female patients was higher than male patients. Our findings indicate that favipiravir concentrations show significant variability during the treatment of COVID-19 and therapeutic drug monitoring may be necessary to maintain targeted concentrations.

The role of adenosine A1 receptors in the nucleus accumbens during morphine withdrawal.

Opioids are effective analgaesic agents, but serious adverse effects such as tolerance and withdrawal contribute to opioid dependence and limit their use. Opioid withdrawal is a common occurrence in human opiate addicts that is not life-threatening. Studies have shown that the mesocorticolimbic system, especially the nucleus accumbens, is an important region in drug addiction and adenosine receptors play a modulatory role in the mechanism of action of drug dependence and withdrawal. The aim of this study was to investigate the effects of the selective A1 receptor agonist CPA (N6 -cyclopentyladenosine) on withdrawal symptoms, and the concentration of dopamine and noradrenaline in the nucleus accumbens and locomotor activity behaviour during naloxone-precipitated withdrawal in morphine-dependent rats. The local administration of CPA (1.5, 3.0, and 6.0 mmol/L bilateral 250 nL) into the nucleus accumbens decreased the Gellert-Holtzman withdrawal scale, and increased concentrations of dopamine and noradrenaline in the same region during naloxone-induced withdrawal. Our findings suggest that administration of the A1 receptor agonist significantly decreased withdrawal behaviours and increased dopamine and noradrenaline concentrations in opioid withdrawal in a dose-dependent manner. These results demonstrate that adenosine receptors should be examined as a potential mechanism that could be exploited for the treatment of morphine withdrawal.

Effect of U-92032, T-Type Ca2+ Channel Blocker, on Rats with Genetic Absence Epilepsy.

INTRODUCTION: Absence epilepsy is associated with diffuse spike-and-wave discharges (SWD) on the electroencephalogram (EEG). Recent studies have demonstrated that the primary somatosensory cortex is also implicated in the generation of the SWDs. OBJECTIVE: This study investigated the effects of systemic and local administrations of U-92032 into the brain of Genetic Absence Epilepsy Rats from Strasbourg (GAERS). METHODS: GAERS animals underwent stereotaxic surgery for the placement of EEG recording electrodes and guide cannulas for U-92032 administration into the lateral ventricle (intracerebroventricular [i.c.v.]), upper lips area (S1Ulp) or barrel field area (S1B) of primary somatosensory cortex. Following 7 days of recovery, electrical activity was recorded continuously for 1 h before and 6 h after intraperitoneal (0.25; 1; 5 mg/kg i.p.) or local U-92032 or dimethyl sulfoxide (DMSO) injections. RESULTS: No changes were detected in the cumulative duration, mean duration, and number of SWDs following i.p. U-92032 injections. Local i.c.v. injections of U-92032 caused a significant decrease in the cumulative duration (i.c.v., 50 and 100 nmol/L), mean duration (i.c.v., 50, 100, and 250 nmol/L), and the number (i.c.v., 250 nmol/L) of SWDs compared to DMSO groups. Intra-cortical (S1Ulp and S1B) U-92032 injections caused a significant decrease in all 3 parameters compared to DMSO groups, as well. CONCLUSION: Intra-cortical injection of U-92032 caused almost complete removal of SWDs in GAERS and i.c.v. administration resulted in a significant reduction. However, systemic i.p. administration did not cause a significant change with the applied -doses.

Favipiravir does not appear to be a major teratogen: Case series from Türkiye.

INTRODUCTION: Favipiravir has gained attention during the Coronavirus Disease-2019 pandemic due to its potential antiviral effect against Severe Acute Respiratory Syndrome Coronavirus-2. Favipiravir has been identified as a teratogen in animal studies, but there is limited human data. We aimed to evaluate the pregnancy outcomes of women exposed to favipiravir during the pandemic. MATERIAL AND METHODS: Pregnant women who were exposed to favipiravir and applied to Marmara University School of Medicine Medical Pharmacology Outpatient Clinic Teratology Information Service between December 2020-September 2021 are included in the study. The demographic information, medical and obstetric histories of patients were acquired during admission, the outcomes of the pregnancies and the characteristics of the infants were gathered by regular phone calls. The infants whose parents consented were evaluated by a pediatrician for general well-being and congenital anomalies. RESULTS: 22 pregnant women were included in this study. 81.8 % received the recommended favipiravir dose (8000 mg in 5 days), in the first trimester. Two patients were lost to follow-up, there was one elective termination and 19 live births. Congenital anomalies were found in 2 infants, one of whom had 9q34 duplication syndrome. Except for these, all newborns examined by the pediatrician were healthy. DISCUSSION: Within a limited case series, a subset of the infants exposed to favipiravir prenatally were followed up to 1 year of age. Two infants exhibited congenital malformations that cannot be directly linked to favipiravir due to confounding variables. Considering the limited data published, favipiravir does not appear to be a major teratogen.

The effects of regular swimming exercise and melatonin on the neurons localized in the striatum of hemiparkinsonian rats.

Parkinson's disease is a progressive neurodegenerative movement disorder. We aimed to investigate the effects of regular swimming exercise and melatonin applied in the 6-Hydroxydopamine-induced Parkinson's disease rats by analysing dendritic spine of striatal neurons. Twenty-four male Wistar albino rats were used. 6-Hydroxydopamine unilaterally injected four (control, exercise, melatonin and exercise + melatonin) groups were included in the study. Tyrosine hydroxylase expression was detected by immunohistochemistry. Neurons and structures were identified from three-dimensional images by Neurolucida software. There was not any apparent difference for tyrosine hydroxylase positive neurons in the substantia nigra pars compacta and fibres in the striatum between the lesion sides of hemiparkinsonian groups. The treatment groups blocked the apomorphine-induced increase in rotations compared to the control group. In stepping test, the treatment groups prevented the loss of stepping in the contralateral side of hemiparkinsonian groups. The melatonin mostly had a positive effect on motor activity tests. In morphological analyses, the 6-Hydroxydopamine-induced lesion led to the reduction of the total dendritic length and number of branches. In the treatment groups, the reduction of the dendritic parameters was not observed. 6-Hydroxydopamine lesion led to a decrease in the total spine density, spine densities of thin and mushroom types. The exercise and melatonin treatments prevented the loss of spine density. The exercise treatment prevented the loss of spine density of mushroom type spines. The melatonin treatment blocked the loss of spine density of stubby type. In conclusion, these results provide evidence for effective additional protective therapeutic strategies for Parkinson's disease. In conclusion, results from the current study provide evidence for swimming exercise and melatonin as a promising candidate for effective additional protective strategies for PD.

The effect of acute topiramate administration on morphine withdrawal syndrome and brain-derived neurotrophic factor in central nervous system.

OBJECTIVES: Nucleus accumbens plays an important role in opioid addiction. Topiramate, increases postsynaptic gamma-aminobutyric acid receptor activity and antagonizes glutamatergic activity. Brain-derived neurotrophic factor (BDNF), which plays a key role in synaptic plasticity, is produced from proBDNF. The aim of this study is to investigate the effects of 100 µM topiramate applied into the lateral ventricle or nucleus accumbens on naloxone-induced morphine withdrawal and the BDNF/proBDNF ratio in the frontal cortex. METHODS: In the study, 36 adult male Wistar rats weighing 250-350 g were used. Morphine dependence was created with morphine pellets following guide cannula implantations. Withdrawal findings were evaluated in naloxone-induced morphine withdrawal syndrome following topiramate administration, and locomotor activity measurements were performed simultaneously. The brains of sacrificed animals were removed for determination of BDNF/proBDNF ratio. RESULTS: Topiramate administered by either route significantly suppressed the number of jumps in morphine withdrawal. Topiramate applied into the nucleus accumbens significantly reduced stereotypical behavior in morphine withdrawal, but did not cause any changes in other locomotor activity behaviors. Topiramate applied into the lateral ventricle significantly decreased the BDNF/proBDNF ratio, whereas administered into the nucleus accumbens significantly increased this ratio. CONCLUSION: The findings of this study indicate that topiramate administered into the lateral ventricle and nucleus accumbens reduces naloxone-induced morphine withdrawal symptoms, stereotypical locomotor activity, and changes the BDNF/proBDNF ratio.

The Effects of Fentanyl on Testicular Ischemia-Reperfusion Injury.

OBJECTIVE: Testicular torsion is a condition that often occurs as a result of the rotation of the spermatic cord in childhood and adolescence in men, manifests with acute pain and causes infertility in the future even if emergency intervention is performed. The aim of this study is to investigate the protective and preventive effects of fentanyl, a potent analgesic agent frequently used in anaesthesia practice, on testicular ischemia reperfusion injury, which manifests through acute pain. METHODS: A total of 16 adult male Wistar rats, weighing 200-250 g, were used in this study. They were divided into two groups, consisting of eight animals in each group. Torsion was created in all rats by rotating left testicles 720 clockwise on the day of the experiment. 3 mM of fentanyl was applied intraperitoneally 30 minutes before detorsion to the fentanyl group. Following an hour of ischemia, the left testicle was reinstated, and tissues were repaired according to their physiology. Following 24 hours of reperfusion, the animals were euthanised after taking left testes and blood samples. RESULTS: Fentanyl, administered prior to testicular detorsion, significantly suppressed germ cell damage in torsioned tissue, catalase activity and malondialdehyde levels in blood samples taken from the heart. No significant differences were observed in plasma total thiol concentration, histological score, Leydig cell counts, percentage of necrosis and tubule rupture. CONCLUSION: These findings show that fentanyl administered before detortion creates a protective effect by preventing testicular ischemia reperfusion injury leading to infertility in the future.

The effect of telmisartan, an angiotensin receptor blocker, on alcohol consumption and alcohol-induced dopamine release in the nucleus accumbens.

Alcohol use disorder remains a major health problem. The mesocorticolimbic dopaminergic system, including the nucleus accumbens region and multiple neural circuits, is involved in its complex underlying mechanism. For instance, alcohol intake stimulates the central and peripheral renin-angiotensin system and increases angiotensin II levels, which predominantly affect angiotensin 1 receptors both in the periphery and in the brain. In this study, we aimed to investigate the effects of the intracerebroventricularly-administered angiotensin 1 receptor blocker telmisartan on the alcohol consumption of male Sardinian alcohol-preferring (sP) rats and on the alcohol-induced dopamine levels in the nucleus accumbens region in Wistar rats. Acute intracerebroventricular administration of telmisartan (100 nM) reduced the alcohol intake for 24 hours without affecting food and water consumption in sP rats. Acute intracerebroventricular injection of the opioid receptor antagonist naloxone (75 nM), tested as a reference compound, also reduced the alcohol consumption in sP rats; however, naloxone's effect lasted only for 30 minutes. In microdialysis experiments, telmisartan administered intracerebroventricularly did not change dopamine levels in the nucleus accumbens that had been induced by acute intraperitoneal alcohol administration in Wistar rats. According to these results, further studies are needed to elucidate the role of the renin-angiotensin system on alcohol use disorder pathophysiology.

The effect of oral administration of monosodium glutamate on epileptogenesis in infant rats.

Glutamate is an excitatory neurotransmitter that is widely distributed throughout the brain. An increase in glutamate concentration or sensitivity of glutamate receptors triggers neurodegenerative diseases, epilepsy in particular. Monosodium glutamate is a substance added to foods to enhance flavour. We investigated the effect of monosodium glutamate on epileptogenesis, as well asheight and weight, in rats that were just weaned. Twenty-four male and female 21-day-old Wistar Albino rats were divided into two groups: one with monosodium glutamate added to the drinking water, and a control in which NaCl was added to the drinking water. The electrical stimulation threshold values were determined in animals to which the hippocampal kindling process was applied, and the stimulations at these threshold values were invariably applied to the animals until they were kindled. The electrical stimulation threshold values of the monosodium glutamate group did not statistically change, whereas the number of required stimulations for kindled rats was significantly lower compared with the control group. These results reveal that long-term oral administration of glutamate salts causes an increase in excitability in the central nervous system during ontogenetic development.

Time-dependent changes in distribution of basic fibroblast growth factor immunoreactive cells in hippocampus after kainic acid injection in rat pups.

Five-day-old Wistar albino rats were injected with kainic acid (KA) or saline i.p. to investigate time-dependent alterations in morphology and number of basic fibroblast growth factor (bFGF) immunoreactive (-ir) astrocytes and neurons in hippocampus at 15, 30, and 90 days after the injections. Sections were stained with cresyl violet for morphological evaluation and bFGF immunohistochemistry was used for quantitative evaluation of bFGF-ir cell density. Fifteen days after KA injection, there was gliosis but no neuronal loss although disorganization in CA1, CA3, CA4 pyramidal layers and neuronal loss were evident 30 and 90 days after the injection. KA injected rats demonstrated significantly increased number of bFGF-ir astrocytes throughout the hippocampus and pyramidal neurons in CA2 after 15 days and decreased number of bFGF-ir cells after 30 and 90 days. The decrease in the number of bFGF-ir astroglia and neurons in long term after KA injection may indicate a decrease in the production of bFGF and/or number of bFGF-ir cells suggesting that protective effects of bFGF may be altered during epileptogenesis in hippocampus.

Time-dependent changes in distribution of basic fibroblast growth factor immunoreactive cells in rat hippocampus after status epilepticus.

OBJECTIVE: In this study, we aimed to examine time-dependent morphologic changes and quantitative alterations in the density of basic fibroblast growth factor (bFGF)-immunoreactive (ir) astrocytes and CA2 pyramidal neurons in dorsal hippocampus of rats after status epilepticus (SE) induced by kainic acid (KA) injection. METHODS: Wistar albino rats were injected with saline or KA i.p. to investigate time-dependent alterations in morphology and the number of bFGF-ir astrocytes and neurons in the dorsal hippocampus 15, 30 and 90 days after KA injection. RESULTS: Fifteen days after KA injection, gliosis was present throughout the hippocampus and neuronal loss was evident in CA1 and CA3 regions, which was more severe after 30 and 90 days. KA-injected rats demonstrated significantly increased number of both bFGF-ir astrocytes throughout the hippocampus and pyramidal neurons in CA2 after 15 days and decreased number after 30 and 90 days. CONCLUSION: The decrease in the number of bFGF-ir astroglia and neurons in long term after KA injection may indicate a decrease in the production of bFGF and/or number of bFGF-ir cells, suggesting that protective effects of bFGF might be altered during epileptogenesis in the hippocampus.

5-hydroxytryptamine release in the anterior hypothalamic and the hippocampal areas of cholestatic rats.

Cholestasis contributes to the genesis of fatigue through several mechanisms. Among these mechanisms, affected serotonergic neurotransmission is important in the pathogenesis of central fatigue. Previously, elevated levels of 5-hydroxyindole acetic acid (5-HIAA), the metabolite of 5-hydroxytryptamine (5-HT) and increased 5-HT(2) receptor density were demonstrated in the anterior hypothalamus and in the hippocampus of bile duct resected rats (BDR), respectively. The aim of this paper is to demonstrate evoked 5-HT release in selected brain regions like anterior hypothalamus and hippocampal CA1 regions of cholestatic rats using BDR rats as an experimental model for cholestasis. In this study, we analyzed the K+ evoked 5-HT and its metabolite 5-HIAA levels by using HPLC with electrochemical detection in the microdialysis samples collected from anterior hypothalamic and hippocampal CA1 regions of sham-operated and BDR rats (n = 6). The ratios of [5-HIAA] to [5-HT] following perfusion with 100 mM K+ artificial cerebrospinal fluid was used for the comparison of the evoked release of 5-HT. Locomotor activity was used to assess the signs of cholestasis associated fatigue in the BDR rats. The vertical and horizontal activity counts within 15 min were found to be decreased in the BDR rats compared to sham-operated rats (p < 0.05). Besides, the number of fecal boli (an index of emotionality) was also significantly fewer in the cholestatic rats (p < 0.05). No significant difference between the sham-operated and the BDR rats was detected in the basal 5-HT and 5-HIAA levels of anterior hypothalamus. K+ stimulation yielded a more profound increase in the [5-HIAA]/[5-HT] in the BDR rats (p < 0.05). The basal levels of 5-HT in CA1 region of the BDR rats was found to be lower than that of sham-operated group (p < 0.05), but no significant difference was observed in terms of evoked 5-HT release in both sham-operated and BDR rats. These findings imply the presence of affected serotonergic system in cholestasis.

Amygdala kindling in the WAG/Rij rat model of absence epilepsy.

PURPOSE: The kindling model in rats with genetic absence epilepsy is suitable for studying mechanisms involved in the propagation and generalization of seizure activity in the convulsive and nonconvulsive components of epilepsy. In the present study, we compared the amygdala kindling rate and afterdischarge characteristics of the nonepileptic Wistar control rat with a well-validated model of absence epilepsy, the WAG/Rij rat, and demonstrated the effect of amygdala kindling on spike-and-wave discharges (SWDs) in the WAG/Rij group. METHODS: Electrodes were stereotaxically implanted into the basolateral amygdala of rats for stimulation and recording and into the cortex for recording. After a recovery period, the animals were stimulated at their afterdischarge thresholds. EEG was recorded to analyze SWDs and afterdischarge durations. The seizure severity was evaluated by using Racine's 5-stage scale. RESULTS: All nonepileptic control and four of seven WAG/Rij animals reached a stage 5 seizure state, whereas three animals failed to reach stage 3, 4, or 5 and stayed at stage 2 after application of 30 stimulations. Interestingly, WAG/Rij rats, resistant to kindling, demonstrated a significantly longer duration of SWDs on the first day of the experiment before kindling stimulation than did the kindled WAG/Rij animals. Additionally, the cumulative total duration and the number of SWDs after the kindling stimulation were statistically increased compared with SWDs before kindling stimulation. CONCLUSIONS: The results of our study demonstrate that the progress of amygdala kindling is changed in rats with genetic absence epilepsy, perhaps as a consequence of the hundreds of daily SWDs.