Prolonged Oral Administration Research Articles

Effects of prolonged hydroxychloroquine use on the pancreatic tissue and expected ameliorative effect of lactoferrin in rats (biochemical, histological, and morphometric study)

Hydroxychloroquine (HCQ), an antimalarial drug widely used in treating rheumatoid disorders. Many side effects have been reported with HCQ administration indicating its hazardous effects on various organs. No previous studies reported the effect of long-term administration of oral HCQ on pancreatic tissue. Our study assessed pancreatic tissues functional and histopathological alterations following prolonged oral administration of HCQ. We also investigated the possible ameliorative effects of the lactoferrin (LF) coadministration with HCQ in adult male albino rats. Forty adult male Wister albino rats were divided into: negative control, LF positive control (2 g/kg), HCQ-treated (200 mg/kg), and HCQ+LF treated. Biochemical, histological, immunohistochemical, and morphometric analyses of the pancreatic tissues were conducted. Our findings revealed that prolonged oral administration of HCQ induced significant disruption of the pancreatic acinar architecture, enlarged congested islets of Langerhans, and elevated plasma insulin, amylase, and lipase levels. Interestingly, LF administration ameliorated the deleterious effects of prolonged HCQ administration on pancreatic tissue of adult male albino rats. In conclusion, prolonged oral administration of HCQ induced pancreatic tissue damage in rats, while LF attenuates HCQ-induced pancreatic injury. Our results emphasized the necessity of prescribing HCQ with caution, considering both dosage and treatment duration.

Effect of Long-term Oral Administration of Different Dosages of Caffeine on Anesthetic Emerging Time

This paper aims to investigate the effect of prolonged oral ingestion of different doses of caffeine on anesthetic emergence time. In our experiment, eighteen male mice were selected and randomly divided into three groups of six mice, each according to the concentration of caffeine administered: a high-concentration caffeine group, a low-concentration caffeine group, and a blank control group. Mice were anesthetized with isoflurane and Zoletil 50, and the time of emergence was recorded for both anesthesia and the time of entry into anesthesia was recorded for Zoletil 50 anesthesia. Twenty-four hours after the anesthesia experiments, the mice were subjected to Morris water maze experiments, visual station experiments, hidden station experiments, and spatial exploration experiments. The results showed that both high-dose and low-dose coffee ig accelerated isoflurane and Zoletil 50 anesthesia emerging, with the high-dose being statistically more significant for the acceleration of anesthesia emerging. Prolonged oral coffee administration did not affect the time to enter anesthesia. Long-term oral coffee administration enhanced spatial exploration and spatial learning memory after anesthesia.

Spontaneous remyelination following dimethyl sulfoxide-induced demyelination is accompanied by behavioral and neurological alteration in mice

Introduction: Dimethyl sulfoxide (DMSO) is a commonly used solvent that can be applied in experimental studies for preparation of hydrophobic solutions as well as in capacity of a cryopreservative in transplantology. According to modern data acquired from in vitro experiments, DMSO is able to change the structure of myelin by decreasing synthesis of its main components and inhibiting oligodendrocyte genesis. Aim of the study: We studied influence of DMSO on anxiety and compulsive-like behavior, pain perception, motor coordination and myelin quantity in the corpus callosum of the C57BL/6 mice brain after prolonged oral administration of the solvent and 4 weeks after administration was stopped. Materials and Methods: All the experiments were conducted on male inbreed C57BL/6 mice. DMSO was added to drinking water to achieve 0.01% concentration, and the obtained solution was administered ad libitum for 6 weeks. After 6 weeks of administration of DMSO and 4 weeks after administration of DMSO was stopped, anxiety-like behavior in open field test, compulsive-like behavior in marble burying test, motor coordination in rotarod test, pain perception in tail-immersion test, as well as myelin quantity in the corpus callosum were evaluated. Results: It was established that DMSO consumed for 6 weeks was associated with decrease in the myelin quantity in thecorpus callosum and thermal hyperalgesia in tail-immersion test. During 4-week period after DMSO administration was stopped, attenuation of demyelination was observed, followed by an increase in thermal hyperalgesia in tail-immersion test, as well as vertical locomotion and exploratory activity in open field test. Conclusions: 6-week ad libitum administration of 0.01% DMSO solution was associated with demyelination in corpus callosum of С57BL/6 mice, followed by thermal hyperalgesia. Cessation of DMSO led to spontaneous remyelination with an increase in thermal hyperalgesia, vertical locomotion and exploratory activity of mice.

Cytotoxicity of Anagallis arvensis L. Extracts: Implications for Traditional Healing

Anagallis arvensis L. comprises two species, specifically Anagallis foemina Mill. For centuries, the Navarra region in Spain has employed primulaceae as traditional wound healing remedies. Previous studies have established the antimicrobial and COX-inhibitory properties of this species. However, despite the known cytotoxic effects at high doses or with prolonged oral administration, there is a lack of definitive research to establish their toxicity. In this study, cytotoxicity was assessed using spectrophotometric methods, including the MTT and LDH assays, on PC12 and DHD/K12PROb cells. Notably, DHD/K12PROb cells exhibited heightened sensitivity to the extracts compared to PC12 cells, resulting in reduced cell survival and increased cell damage (LDH release). Significant reductions in cell survival were observed with methanol extracts exceeding 80 mg/ml. These findings suggest that the reported toxic effects in traditional medicine may be attributed to the cytotoxic nature of these plants.

Вплив aктовегіну на механізми розвитку окисного стресу у хворих на цукровий діабет 2-го типу з кардіоваскулярною автономною нейропатією

The effects of actovegin on the mechanisms of oxidative stress (OS) developing in the blood of patients with type 2 diabetes mellitus (DM2) and cardiovascular autonomic neuropathy (CVAN) were investigated. The aim of the study was to establish the effectiveness of treatment with actovegin for the pro- and antioxidant balance impairment and changes in gene expression of HIF-1α and mTOR in the blood of patients with DM2 and CVAN. It was shown that intravenous injections of actovegin at a dose of 1000 mg per day for 10 days and further prolonged oral administration of this drug at a dose of 800 mg per day for 90 days led to a decrease in the content of secondary products of lipid peroxidation in blood plasma and H2O2 production in erythrocytes of patients with DM2 and CVAN. These changes were indicative of a weakening of OS intensity. It was also shown that treatment with actovegin promoted an increase in total plasma SOD activity as well as reduced glutathione and glutathione peroxidase activity in erythrocytes from patients. Treatment with actovegin also raised the gene expression of HIF-1α and reduced the gene expression of mTOR in leukocytes of patients with DM2 and CVAN. These genetic changes may serve as a protective mechanism against the development of OS, which acts through different metabolic pathways. So, actovegin administration counteracting OS development due to the impact on the different components of pro- and antioxidant system as well as on HIF-1α and mTOR genes expression may offer new clinical avenues for pharmacological treatment of patients with DM2 and CVAN.

The Effect of Orally Administered Δ9-Tetrahydrocannabinol (THC) and Cannabidiol (CBD) on Obesity Parameters in Mice.

Prolonged cannabis users show a lower prevalence of obesity and associated comorbidities. In rodent models, Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) from the plant Cannabis sativa L. have shown anti-obesity properties, suggesting a link between the endocannabinoid system (ECS) and obesity. However, the oral administration route has rarely been studied in this context. The aim of this study was to investigate the effect of prolonged oral administration of pure THC and CBD on obesity-related parameters and peripheral endocannabinoids. C57BL/6 male mice were fed with either a high-fat or standard diet and then received oral treatment in ramping doses, namely 10 mg/kg of THC or CBD for 5 weeks followed by 30 mg/kg for an additional 5 weeks. Mice treated with THC had attenuated weight gain and improved glucose tolerance, followed by improvement in steatosis markers and decreased hypertrophic cells in adipose epididymal tissue. Mice treated with CBD had improved glucose tolerance and increased markers of lipid metabolism in adipose and liver tissues, but in contrast to THC, CBD had no effect on weight gain and steatosis markers. CBD exclusively decreased the level of the endocannabinoid 2-arachidonoylglycerol in the liver. These data suggest that the prolonged oral consumption of THC, but not of CBD, ameliorates diet-induced obesity and metabolic parameters, possibly through a mechanism of adipose tissue adaptation.

#3722 CARBAPENEM-RESISTANT ENTEROBACTERIACEAE URINARY TRACT INFECTION IN RENAL TRANSPLANT RECIPIENTS: ROLE OF A NOVEL ANTIBIOTIC REGIMEN

Abstract Background and Aims Urinary tract infection (UTI), the most common bacterial infection among renal transplant recipients (RTRs), remains a challenge, particularly given the increased incidence of MDR organisms, including Carbapenem-resistant Enterobacteriaceae (CRE). CRE infections were associated with inferior patient and graft outcomes compared to other bacterial infections. Paradoxically, there have been no guidelines on managing CRE in RTRs besides multiple challenges, including the bacteriostatic nature, poor urinary concentration, and dose-limiting adverse effects of various antibiotics. The current study designed and assessed the outcomes of protocol-based therapy consisting of high-dose Meropenem in combination with other antibiotics followed by prolonged oral administration. Method This is a single-centre retrospective study conducted in the department of Nephrology and Renal transplantation, Sanjay Gandhi Post Graduate Institute of Medical Sciences, India, between 1st August 2016 till 31st July 2022. All the RTRs aged $ \ge $ 18 years admitted between 1st August 2016 and 31st July 2018 with symptomatic UTI and a urine culture positive for CRE were included in the study. Patients who received various antibiotics conventionally based on the treating physician's decision from August 2016 to July 2017 were considered under the Best available treatment (BAT) group, while the Standardized Therapeutic Antibiotic Regimen (STAR) group included patients treated from August 2017 to July 2018. The treatment of the STAR group consists of a therapeutic phase for at least six weeks (IV therapeutic phase for two weeks total or one week after the clinical recovery, whichever is later + Oral Therapeutic phase for four weeks) followed by an oral chemoprophylaxis phase for three months. Following the treatment of index UTI episodes due to CRE, follow-up both groups’ follow-up data until a minimum of four years were collected. Appropriate statistical tools were applied, and analyses were performed by SPSS software, version 25. Results A total of 37 patients fulfilling the inclusion criteria were included in the study, of which 13 patients were under the BAT group, and 24 were treated by the STAR-based protocol. The mean age of the study population was 37.6 $ \pm \ $12.3 years, and all were males. Most patients (70.2%) had the UTI due to CRE within one-month post-transplant, and the median duration of UTI post-transplant was 6.1 days (IQR: 4.5 – 33). The primary outcome, recurrence rates of UTI at 48-month follow-up among the patients in the STAR group, was significantly lower than those in the BAT group (30.4% vs 77.8%, p = 0.01). The death-censored graft survival was also significantly better among the STAR group than the BAT group (100% vs 75%, p = 0.03) after 48 months. Graft function at 48 months was also better in the STAR group (Serum creatinine- 1.4 ± 0.8 mg/dl vs 2.9 ± 2.2 mg/dl, p = 0.007). The patient survival, however, was similar among the two groups (95.8% vs 88.9%, p = 0.47). Conclusion Prolonged and combination antibiotic therapy followed by long-term antibiotic prophylaxis significantly reduced the recurrence of UTI due to CRE among the RTRs. Graft function and death-censored graft survival were also considerably better. Hence, the current study may pave the path for future RCTs based on combination antibiotic therapy as a solution to combat the challenge of CRE in RTRs.

β‐Adrenergic receptor agonist alleviates memory interference control deficits in APPswe/PS1dE9 mice

AbstractBackgroundEarlier studies have demonstrated that memory dysfunction during early Alzheimer’s disease (AD) is associated with an increased susceptibility to memory interference (MI). In this study, we examined whether previously stored memory representations interfered with novel similar input patterns in 2‐month‐old APPswe/PS1dE9 (APP/PS1), mice. APP/PS1 over‐expresses the Swedish mutation of amyloid precursor protein together with presenilin1 deleted in exon 9. Amyloid beta (Aβ) plaque deposition is observed at 4‐6 months of age, not at 2 months providing us with a window to study the earliest behavioural deficits that are independent of Aβ plaque deposition.Method(1) We introduced a proactive interference step to the well‐established novel object recognition paradigm (NOR), by exposing the mice to multiple objects of different shape, size and colour. (2) Earlier studies have demonstrated that prolonged oral administration of β‐adrenoreceptor (β‐AR) agonist (−)‐Isoproterenol hydrochloride (IPE) to mice protected them from hippocampal impairment by Aβ oligomers, and enhanced hippocampal synaptic plasticity. We provided the IPE in drinking water for three weeks from P26 till P47.ResultOur results demonstrate that NOR is intact in APP/PS1 at 2 months of age. However, introducing a short‐term object based priming or interference prior to NOR leads to recognition memory deficits. This finding indicates that 2‐month‐old APP/PS1 is susceptible to proactive MI unlike their Wild Type counterpart who could clearly discriminate between a novel and a familiar object. Our findings indicate that, object‐based priming can activate its presence during target memory encoding, and thus negate learning in 2‐month‐old APP/PS1 mice before amyloidosis onset. β‐AR agonist treatment restored performance of APP/PS1 mice to normal levels protecting them from the effects of priming during the object recognition task.ConclusionThese results indicate that integration or discrimination component of object memory representations relies on and can be modulated by β‐AR activation.

Impact of Chronic Oral Administration of Gold Nanoparticles on Cognitive Abilities of Mice.

The influence of gold nanoparticles after their prolonged oral administration to mice (during pregnancy and lactation) on spatial memory and anxiety levels in offspring was investigated. Offspring were tested in the Morris water maze and in the elevated Plus-maze. The average specific mass content of gold which crossed the blood-brain barrier was measured using neutron activation analysis and constituted 3.8 ng/g for females and 1.1 ng/g for offspring. Experimental offspring showed no differences in spatial orientation and memory compared to the control, while their anxiety levels increased. Gold nanoparticles influenced the emotional state of mice exposed to nanoparticles during prenatal and early postnatal development, but not their cognitive abilities.

Evaluation of the effectiveness of anticonvulsant and hormonal therapy for epileptic spasms in the group of Russian patients

Introduction. Epileptic spasms (ES) are a special type of epileptic seizures, accompanied by hypsarrhythmia on the interictal electroencephalogram (EEG) and regression of psychomotor development. ES are the most common cause of epileptic encephalopathy in infancy. Materials and methods. We examined two hundred three children with the age of onset of epileptic spasms up to 2 years. The patient were selected in retrospective group including 180 children (boys - 95/180 (52.7%), girls - 85/180 (47.3%)) (χ2=0.9, p=0.3428) and prospective group consisted of 23 children (boys - 13/23 (56.5%), girls - 10/23 (43.5%) (χ2 = 0.3478, p = 0.5553. Results. The present study demonstrates the need for sleep electroencephalogram in children with developmental delay or regression. Our work confirms in general, antiepileptic drugs, with the exception of vigabatrin in children with tuberous sclerosis-associated epilepsy, to show low efficacy in the group of children without tuberous sclerosis as seizures were stopped in 14.3% of cases. The use of methylprednisolone (the regimen includes pulse therapy followed by prolonged oral administration of the drug) makes it possible to achieve the cessation of seizures and the disappearance of hypsarrhythmia in 69.5% of patients. Methylprednisolone is a fairly safe and well tolerated hormone. The study did not record any life-threatening side effects among the prospective and retrospective groups.The treatment regimen using methylprednisolone shows equal efficacy with the regimen using tetracosactide. Conclusion. The results of the study demonstrate the need for early corticosteroid therapy in ES children.

Cytotoxicity, acute and sub-chronic toxicities of the fruit extract of Tetrapleura tetraptera (Schumm. & Thonn.) Taub. (Fabaceae)

BackgroundTetrapleura tetraptera is a medicinal spice traditionally used to treat cancer, diabetes, and several other ailments. This study analyzed the cytotoxicity of the dichloromethane methanol extract of T. tetraptera fruits (TTF) and its constituents. The toxicity profile of the TTF extract was also evaluated in rats.MethodsThe Cytotoxicity of this extract was evaluated using the resazurin reduction assay (RRA). Acute and sub-chronic toxicity studies were performed according to the protocol described by the Organisation for Economic Cooperation, and Development (OECD). Hematological, serum, and urine biochemical parameters, as well as histological sections of the liver and kidney, were also evaluated based on standard methods.ResultsThe TTF extract, compound 5, and the reference drug doxorubicin were active in all 9 tested cancer cell lines. The recorded IC50 ranged from 18.32 μM (against B16-F1 murine melanoma cells) to 36.18 μM (against SKMel-505 BRAF wildtype melanoma cells) for TTF, from 10.02 μM (towards MaMel-80a BRAF-V600E homozygous mutant melanoma cells) to 31.73 μM (against SKMel-28 BRAF-V600E homozygous mutant melanoma cells) for compound 5, and from 0.22 μM (against B16-F1 cells) to 9.39 μM (against SKMel-505 cells) for doxorubicin. The study of acute toxicity test showed that the lethal dose (LD50) of this extract was greater than 5000 mg/kg body weight. In the sub-chronic toxicity studies, variations were observed in some biochemical parameters, especially at higher doses.ConclusionTTF and its most active compound (5) are found to be potential cytotoxic agents, meanwhile, TTF was safe when given a single oral dose of 5000 mg/kg. However, caution is necessary in case of prolonged oral administration due to potential alterations of renal function at high doses (> 1000 mg/kg).

Kolaviron ameliorates chronic colitis induced by prolonged oral administration of Dextran Sulphate Sodium in Balb/c mice

Ulcerative colitis is an idiopathic disease attributed to an aggressive dysregulated immune response that results in epithelial injury and diffuse inflammation in the colon. Ulcerative colitis may be acute or chronic with unpredictable relapse. Kolaviron, a bioflavonoid extracted from Garcinia kola has been reported to possess gastroprotective properties. We have previously reported the protective effect of kolaviron on acute colitis. This study investigated the effect of kolaviron on dextran sulphate sodium-induced chronic ulcerative colitis in Balb/c mice. Mice were randomly assigned to four groups of 10 mice each. Group I (Control) mice received corn oil at 2 ​ml/kg for forty-nine days. Group II mice received kolaviron at 200 ​mg/kg for forty-nine days. Group III mice received 3 cycles of dextran sulphate sodium (DSS) (2.5% w/v) in drinking water (each cycle is defined as 7 days of 2.5% DSS followed by 7 days of normal drinking water). Group IV received Kolaviron at 200 ​mg/kg body weight for 7 days before co-administration with 3 cycles of DSS (2.5% w/v). Administration of kolaviron significantly ameliorated increases in disease activity index in DSS-induced chronic ulcerative colitis in mice. Furthermore, kolaviron suppresses the expression of inducible nitric oxide synthase and cyclooxygenase-2 in DSS-treated mice. Additionally, kolaviron protected against colonic oxidant stress damage by augmenting the endogenous antioxidant with concomitant decrease in myeloperoxidase activity, tumor necrosis factor alpha, Interleukin-1β, and lipid peroxidation levels in DSS-treated mice. Moreover, kolaviron attenuated the disruption of the colonic histological architecture and reduced neutrophil infiltration in DSS-treated mice. In conclusion, kolaviron ameliorated DSS-induced chronic ulcerative colitis via antioxidant and anti-inflammatory mechanisms.

Acute Toxicity and Effect of Prolonged Oral administration of Zingiber officinale ethanol extract on Liver and Kidney Histology in Rats

The study aimed to evaluate the effect of 28-day repeated administration of Zingiber officinale on the histology of the liver and kidney in Wistar rats. An acute toxicity test was carried out using 12 rats. In phase one, nine rats were allotted into three groups and received Zingiber officinale ethanol extract at 10mg/kg, 100mg/kg, and 1000mg/kg respectively. In phase two, three rats received Zingiber officinale ethanol extract at 1600mg/kg, 2900mg/kg, and 5000mg/kg respectively. Twenty-five rats were distributed into five groups. The groups received distilled water and ethanol extract of Zingiber officinale at 25 mg/kg, 50 mg/kg, 75 mg/kg, and 150 mg/kg respectively for 28 days. On the 29th day, all the rats were euthanized. The oral LD50 of Zingiber officinale ethanol extract was calculated to be 3800 mg/kg in rats. The rats that received Zingiber officinale ethanol extract up to 1600 mg/kg showed no signs of toxicity and mortality. The liver of rats that received Zingiber officinale at 150 mg/kg showed distorted hepatocytes and pyknosis. The kidney of 75 mg/kg and 150 mg/kg Zingiber officinale treated rats showed normal glomerulus and normal Bowman’s capsule with severe renal tubular distortion. In conclusion, Zingiber officinale is less toxic. However, long term administration might lead to liver and kidney damage and eventual death.

PI3K/AKT/mTOR signalling inhibitor chrysophanol ameliorates neurobehavioural and neurochemical defects in propionic acid-induced experimental model of autism in adult rats.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder marked by social and communication deficits as well as repetitive behaviour. Several studies have found that overactivation of the PI3K/AKT/mTOR signalling pathways during brain development plays a significant role in autism pathogenesis. Overexpression of the PI3K/AKT/mTOR signalling pathway causes neurological disorders by increasing cell death, neuroinflammation, and oxidative stress. Chrysophanol, also known as chrysophanic acid, is a naturally occurring chemical obtained from the plant Rheum palmatum. This study aimed to examine the neuroprotective effect of CPH on neurobehavioral, molecular, neurochemical, and gross pathological alterations in ICV-PPA induced experimental model of autism in adult rats. The effects of ICV-PPA on PI3K/AKT/mTOR downregulation in the brain were studied in autism-like rats. Furthermore, we investigated how CPH affected myelin basic protein (MBP) levels in rat brain homogenate and apoptotic biomarkers such as caspase-3, Bax, and Bcl-2 levels in rat brain homogenate and blood plasma samples. Rats were tested for behavioural abnormalities such as neuromuscular dysfunction using an actophotometer, motor coordination using a beam crossing task (BCT), depressive behaviour using a forced swim test (FST), cognitive deficiency, and memory consolidation using a Morris water maze (MWM) task. In PPA-treated rats, prolonged oral CPH administration from day 12 to day 44 of the experimental schedule reduces autistic-like symptoms. Furthermore, in rat brain homogenates, blood plasma, and CSF samples, cellular, molecular, and cell death markers, neuroinflammatory cytokines, neurotransmitter levels, and oxidative stress indicators were investigated. The recent findings imply that CPH also restores abnormal neurochemical levels and may prevent autism-like gross pathological alterations, such as demyelination volume, in the rat brain.

Prolonged oral antimicrobial administration prevents doxorubicin-induced loss of active intestinal stem cells

ABSTRACT Acute intestinal mucositis is a common off-target effect of chemotherapy, leading to co-morbidities such as vomiting, diarrhea, sepsis, and death. We previously demonstrated that the presence of enteric bacteria modulates the extent of jejunal epithelial damage induced by doxorubicin (DXR) in mice. Despite conventional thinking of the crypt as a sterile environment, recent evidence suggests that bacterial signaling influences aISC function. In this study, we labeled aISCs using transgenic Lgr5-driven fluorescence or with immunostaining for OLFM4. We examined the effect of DXR in both germ free (GF) mice and mice depleted of microbiota using an established antimicrobial treatment protocol (AMBx). We found differences in DXR-induced loss of aISCs between GF mice and mice treated with AMBx. aISCs were decreased after DXR in GF mice, whereas AMBx mice retained aISC expression after DXR. Neither group of mice exhibited an inflammatory response to DXR, suggesting the difference in aISC retention was not due to differences in local tissue inflammation. Therefore, we suspected that there was a protective microbial signal present in the AMBx mice that was not present in the GF mice. 16S rRNA sequencing of jejunal luminal contents demonstrated that AMBx altered the fecal and jejunal microbiota. In the jejunal contents, AMBx mice had increased abundance of Ureaplasma and Burkholderia. These results suggest pro-survival signaling from microbiota in AMBx-treated mice to the aISCs, and that this signaling maintains aISCs in the face of chemotherapeutic injury. Manipulation of the enteric microbiota presents a therapeutic target for reducing the severity of chemotherapy-associated mucositis.

An Adaptive Biosystems Engineering Approach towards Modeling the Soluble-to-Insoluble Phase Transition of Clofazimine.

Clofazimine (CFZ) is a weakly basic, small-molecule antibiotic used for the treatment of mycobacterial infections including leprosy and multidrug-resistant tuberculosis. Upon prolonged oral administration, CFZ precipitates and accumulates within macrophages throughout the host. To model the pharmacokinetics of CFZ, the volume of distribution (Vd) was considered as a varying parameter that increases with continuous drug loading. Fitting the time-dependent change in drug mass and concentration data obtained from CFZ-treated mice, we performed a quantitative analysis of the systemic disposition of the drug over a 20-week treatment period. The pharmacokinetics data were fitted using various classical compartmental models sampling serum and spleen concentration data into separate matrices. The models were constructed in NONMEM together with linear and nonlinear sigmoidal expansion functions to the spleen compartment to capture the phase transition in Vd. The different modeling approaches were compared by Akaike information criteria, observed and predicted concentration correlations, and graphically. Using the composite analysis of the modeling predictions, adaptive fractional CFZ sequestration, Vd and half-life were evaluated. When compared to standard compartmental models, an adaptive Vd model yielded a more accurate data fit of the drug concentrations in both the serum and spleen. Including a nonlinear sigmoidal equation into compartmental models captures the phase transition of drugs such as CFZ, greatly improving the prediction of population pharmacokinetics and yielding further insight into the mechanisms of drug disposition.

The impact of oral ciprofloxacin on the structure and functions of rat gastric mucosa

Ciprofloxacin (CPX), is a fluoroquinolone antibiotic used to treat a number of gram-negative and gram-positive bacterial infections. Ciprofloxacin can cause severe side effects, ranging from tendon problems, nerve damage, to serious mood or behavior changes.The purpose of this study was to investigate how ciprofloxacin affects gastric cell lines in rats with a distinctive emphasis on physiological, histopathological, and bacteriological changes. Male albino rats (n = 21) were distributed into three groups; control, CPX, and CPX-withdrawal groups. The treated rats were given CPX tablets (12.5 mg/kg) dissolved in carboxymethyl cellulose (CMC) 0.5% orally once daily via gavage for sixty consecutive days. Control rats received only the vehicle. The withdrawal group was treated for 60 days and the drug was withdrawn for another sixty days. After completion of the experiment, all rats were sacrificed and gastric tissues were treated for light, immunohistochemical, and scanning electron microscopic examination. Image J software was used to measure immune-labeled gastric epithelial cells. Blood samples were also collected for H. Pylori immunoglobulins IgM, IgA, and IgG. Results showed that treated rats acquired significantly strongly positive tumor necrosis factor (TNFα) and significant reduction of serum level of H. pylori IgM, IgA, and IgG in all the study groups. It could be concluded that prolonged oral CPX administration to albino rats changes the gastric mucosal architecture and bacteriology.

Accumulation and Effect of Silver Nanoparticles Functionalized with Spirulina platensis on Rats.

The effect of unmodified and functionalized Spirulina platensis biomass silver nanoparticles on rats during prolonged oral administration was assessed. Silver nanoparticles were characterized by using transmission electron microscopy, while their uptake by the biomass was confirmed using scanning electron microscopy and energy dispersive analysis. The content of silver in the different organs of rats after a period of administration (28 days) or after an additional clearance period (28 days) was ascertained by using neutron activation analysis. In animals administrated with the unmodified nanoparticles, the highest content of silver was determined in the brain and kidneys, while in animals administrated with AgNP-Spirulina, silver was mainly accumulated in the brain and testicles. After the clearance period, silver was excreted rapidly from the spleen and kidneys; however, the excretion from the brain was very low, regardless of the type of nanoparticles. Hematological and biochemical tests were performed in order to reveal the effect of nanoparticles on rats. The difference in the content of eosinophils in the experimental and control groups was statistically significant. The hematological indices of the rats did not change significantly under the action of the silver nanoparticles except for the content of reticulocytes and eosinophils, which increased significantly. Changes in the biochemical parameters did not exceed the limits of normal values. Silver nanoparticles with the sizes of 8–20 nm can penetrate the blood–brain barrier, and their persistence after a period of clearance indicated the irreversibility of this process.

Hepatorenal Functions Following Prolonged Oral Administration of Caffeine on Male Wistar Rats

Hepatorenal Functions Following Prolonged Oral Administration of Caffeine on Male Wistar Rats

Toxicity Studies on Aqueous Stem Bark of Khaya senegalensis Extract of Kidneys and Its Biochemical Parameters in Wistar Rats

Introduction: Khaya senegalensis is a genus of seven species of trees in the mahogany family Meliaceae, native to tropical Africa and Madagascar. Mahogany in English, Aganwo in Yoruba, Madachi in Hausa and Ono in Igbo. All species become big trees 30–35m tall, rarely 45m, with a trunk over 1 m trunk diameter, often buttressed at the base. The leaves are pinnate, with 4-6 pairs of leaflets, the terminal leaflet absent; each leaflet is 10–15 cm long abruptly rounded toward the apex but often with an acuminate tip.
 Aim: The aim of the study was to determine the Toxic effect of prolonged oral administration of the aqueous stem bark of Khaya senegalensis extract on the histology of Kidneys and its biochemical parameters in wistar rats.
 Methods: This work is an experimental research. A total of 20 wistar rats were randomly divided in to 5 groups each of which consist of 4 rats. Group 1 received distilled water to serve as control while group 2, 3, 4, and 5 received 500 mg/kg bw, 1000 mg/kg bw 2000 mg/kg bw and 4000 mg/kg bw of the aqueous extract respectively for 60 days after which they were sacrificed, processed in Automatic Tissue Processor machine, Sectioned and stained with H &E.
 Results: There was statistical significant increase in urea and potassium in all the test groups but is not dose dependent. The creatinine was significantly increased in groups 2, 4 and 5. While other parameters such as sodium, chloride and bicarbonate no significant difference when compared to the control group. The kidney sections showed normal structure in group 1 when compared with the test groups. However, there was significant infiltration of inflammatory cell across all the groups which were suggestive of kidney damage or injury. Similarly phenomenon was noticed in group 5 with additional congestion in the glomerulus and more polymorphs seen.
 Conclusion: The LD50 was found to be greater than 5000 mg/kg bw, therefore, 400 mg/kgbw was used as higher dose in the experimental wistar rats. There were statistical significant increases in some parameters groups while some groups not significant. The kidney section showed significant infiltration of polymorphs across all the groups more marked in group 5 with distension and damaging of the glomerulus indicating renal injury.