A retrospective analysis of haematological side effects of olaparib in excess-weight and normal BMI patients with ovarian cancer.

Background: Olaparib is the first poly(ADP-ribose) polymerase inhibitor approved in Europe for the treatment of platinum-sensitive patients with newly diagnosed or recurrent platinum-sensitive ovarian cancer with a confirmed BRCA mutation or homologous recombination deficiency (HRD). Epidemiological studies have shown an incompatible association between ovarian cancer and obesity, but there have also been scientific reports indicating that obesity, especially severe obesity, increases the risk of ovarian cancer. Olaparib has a wide range of side effects, especially anaemia and neutropenia, which may lead to dose reduction or therapy discontinuation. Therefore, therapeutic drug monitoring (TDM) is recommended. The aim of the study was a retrospective analysis of threshold value of the trough concentration of olaparib (Ctrough) and haematological adverse reactions after olaparib treatment (300 mg/12 h) in excess-weight and normal body mass index (BMI) patients with ovarian cancer. Materials and methods: The pilot study was conducted on 38 ovarian cancer patients who were divided into two groups: I - normal BMI patients (BMI = 18.5-24.9 kg/m2; n = 14), II - excess-weight patients, i.e. overweight and obese patients (BMI ≥ 25 kg/m2; n = 24). The severity of neutropenia and anaemia was graded according to the Common Terminology Criteria for Adverse Events (CTCAE v5.0). The values of the mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular haemoglobin concentration (MCHC), and red blood cell distribution width (RDW) parameters were also taken into account. HPLC-UV method (λ = 254 nm) was applied to measure olaparib plasma concentrations. Results: There were no statistically significant differences in olaparib Ctrough between the groups - 1602.86 vs. 1567.40 ng/mL (p = 0.9156). However, the overweight and obese patients had slightly higher dose/kg-adjusted olaparib Ctrough - 204.17 vs. 159.32 ng/mL/mg/kg. The incidence of grade 1 anaemia in the groups was as follows: I - 42.86%, II - 41.67%. Grade 2 and 3 anaemia was observed only in group II - 4.17% and 8.33%, respectively. The incidence of neutropenia in the groups of patients was as follows: grade 1: group I - 21.43%, group II - 20.83%; grade 2: group I - 7.14%, group II - 4.17%. Conclusions: The incidence of haematological adverse reactions to olaparib, such as neutropenia and grade 1 anaemia in the group of overweight and obese patients was the same as in the normal BMI group. The overweight and obese patients were characterised by higher severity of haematological adverse reactions to olaparib and slightly higher dose/kg-adjusted olaparib Ctrough. After one month of treatment with olaparib the overweight and obese patients had significantly lower red blood cells (RBC) and haemoglobin (Hgb) levels than the patients with normal BMI, which may indicate that anaemia develops faster in this group of patients.

The influence of the coadministration of the p-glycoprotein modulator elacridar on the pharmacokinetics of lapatinib and its distribution in the brain and cerebrospinal fluid.

Background Lapatinib is a small-molecule tyrosine kinase inhibitor of human epidermal receptor 2 (HER2) and EGFR that has currently been approved for the treatment of HER2-positive advanced and metastatic breast cancer (BC). The ATP-binding cassette (ABC) family of transporters includes P-glycoprotein (P-gp; ABCB1) and breast cancer resistance protein (BCRP; ABCG2), which substantially restrict the penetration of drugs, including chemotherapeutics, through the blood-brain barrier and blood-cerebrospinal fluid barrier. The aim of this study was to investigate the effects of elacridar, an ABCB1 and ABCG2 inhibitor, on the brain and cerebrospinal fluid uptake of lapatinib. Methods Rats were divided into two groups: one group received 5 mg/kg elacridar and 100 mg/kg lapatinib (an experimental group), and the other group received 100 mg/kg lapatinib (a control group). Lapatinib concentrations in the blood plasma (BP), cerebrospinal fluid (CSF) and brain tissue (BT) were measured by liquid chromatography coupled with tandem mass spectrometry. Results Elacridar significantly increased lapatinib penetration into the CSF and BT (Cmax increase of 136.4% and 54.7% and AUC0-∞ increase of 53.7% and 86.5%, respectively). The Cmax of lapatinib in BP was similar in both experimental groups (3057.5 vs. 3257.5 ng/mL, respectively). Conclusion This study showed that elacridar influenced the pharmacokinetics of lapatinib. The inhibition of ABCB1 and ABCG2 transporters by elacridar substantially enhanced the penetration of lapatinib into the CSF and BT. The blocking of protein transporters could become indispensable in the treatment of patients with breast cancer and brain metastases.

Endocrine abnormalities induced by the antiviral drugs and frequency of their occurrence.

Viral infections lead to many disorders with a different course and prognosis. Clinical trials are ongoing on new groups of antiviral drugs, which are very promising. However, treatment with antiviral drugs causes numerous adverse effects (AEs) including hormonal dysfunctions. The aim of this article is to discuss endocrine abnormalities induced by the antiviral drugs including frequency of their occurrence. The review is based on the available literature in the Medline database and considers the latest articles describing endocrine disorders with relation to antiviral therapy. The hormonal and metabolic dysfunctions were discussed, including the AEs like: osteoporosis, osteomalacia, hypoand hyperthyroidism, metabolic syndrome, lipodystrophy, hyperglycemia, diabetes mellitus and others. Awareness of frequency and type of complications caused by antiviral drugs, enables faster linking of the disease with the therapy, so it allows the personalization of treatment. It's necessary to monitor the general condition of the patients and appropriate diagnostic parameters that it can help diagnose hormonal disorders and adjust an individual antiviral therapy for the patient with endocrinopathy.

The concomitant use of lapatinib and paracetamol - the risk of interaction.

Lapatinib is a tyrosine kinase inhibitor used for the treatment of breast cancer. Paracetamol is an analgesic commonly applied to patients with mild or moderate pain and fever. Cancer patients are polymedicated, which involves high risk of drug interactions during therapy. The aim of the study was to assess the interaction between lapatinib and paracetamol in rats. The rats were divided into three groups of eight animals in each. One group received lapatinib + paracetamol (IL + PA), another group received lapatinib (IIL), whereas the last group received paracetamol (IIIPA). A single dose of lapatinib (100 mg/kg b.w.) and paracetamol (100 mg/kg b.w.) was administered orally. Plasma concentrations of lapatinib, paracetamol and its metabolites - glucuronide and sulphate, were measured with the validated HPLC-MS/MS method and HPLC-UV method, respectively. The pharmacokinetic parameters of both drugs were calculated using non-compartmental methods. The co-administration of lapatinib and paracetamol increased the area under the plasma concentration-time curve (AUC) and the maximum concentration (Cmax) of lapatinib by 239.6% (p = 0.0030) and 184% (p = 0.0011), respectively. Lapatinib decreased the paracetamol AUC0-∞ by 48.8% and Cmax by 55.7%. In the IL + PA group the Cmax of paracetamol glucuronide was reduced, whereas the Cmax of paracetamol sulphate was higher than in the IIIPA group. Paracetamol significantly affected the enhanced plasma exposure of lapatinib. Additionally, lapatinib reduced the concentrations of paracetamol. The co-administration of lapatinib decreased the paracetamol glucuronidation but increased the sulphation. The findings of this study may be of clinical relevance to patients requiring analgesic therapy.

THE EFFECT OF TOTAL AND PARTIAL NEPHRECTOMY ON THE PHARMACOKINETICS OF INTRAVENOUS PARACETAMOL IN HUMANS.

Paracetamol is one of the most common analgesic and antipyretic drugs. Recently intravenous paracetamol has been widely used to treat moderate postoperative pain. Surgery is the main method of treatment of renal cancer. Total or partial nephrectomy can be performed, depending on the size and location of the tumor. Pharmacokinetics of drugs may depend on the type of surgery. The aim of the study was to compare the postinfusion pharmacokinetics of paracetamol in patients after total nephrectomy (TN) and nephron sparing surgery (NSS).The research was carried out on two groups of patients after nephrectomy: total (TN n = 37; mean [SD], age, 60.4 [10.9] years; BMI, 26.5 [3.8] kg/m2; creatinine clearance, Cl, 80.9 [37.1] mL/min) and nephron sparing surgery (NSS n = 17; 57.9 [16.5] years; BMI, 29.5 [5.3] kg/m2; Cl, 97.6 [27.8] mL/min). The patients were treated with paracetamol (PerfalganO Bristol-Myers Squibb) at an intravenous dose of 1.000 mg, which was infused for 15 minutes after surgery. The concentrations of paracetamol in the patients' plasma were determined by the HPLC method with UV detection (X = 261 run). The main pharmacokinetic parameters of paracetamol in the TN vs. NSS group were as follows: C.. 29.08 [17.39] vs. 27.54 [15.70] pg/mL (p = 0.6692); AUC5, 29.24 [13.86] vs. 34.85 [14.28] pg.h/mL (p = 0.2896); AUMC5,,,, 47.58 [26.08] vs. 62.02 [27.64] pg-h/mL (p = 0.1345); to. 2.34 [0.96] vs. 1.93 [0.50] h (p = 0.1415), respectively. In both groups the exposure to paracetamol was comparable. The t1/2 after nephron sparing surgery was shorter than after total nephrectomy. Therefore, these patients may demand more frequent drug administration. In the NSS group the C. of the analgesic was considerably reduced in men.

The effect of sunitinib on the plasma exposure of intravenous paracetamol and its major metabolite: paracetamol glucuronide.

The study aimed to examine the effect of sunitinib on the plasma exposure of intravenous paracetamol and its major metabolite, paracetamol glucuronide. Both drugs share metabolic pathways in the liver, and the drug interactions between sunitinib and paracetamol administered in higher doses were reported. These interactions resulted in hepatotoxicity. The adult New Zealand male rabbits were divided into three groups (6 animals each): rabbits receiving sunitinib and paracetamol (SUN + PC), rabbits receiving sunitinib (SUN), and a control group receiving paracetamol (PC). Sunitinib was administered orally (25 mg) and paracetamol was administrated intravenously (35 mg/kg). Blood samples for sunitinib and SU12662 assays were collected up to 96 h after drug administration and for paracetamol and paracetamol glucuronide up to 300 min after drug administration. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin were analysed before and after drug administration. A number of pharmacokinetic parameters were analysed. There were no differences in the levels of AST, ALT, and bilirubin among the groups at either time point. Significantly higher values of AUC0-t , AUC0-∞ , and C max and lower clearance and volume of distribution of paracetamol were observed in group PC vs. group SUN + PC (p < 0.01). The maximum plasma concentration of paracetamol glucuronide tended to be higher in group PC 213.27 µg/mL (90 % CI 1.06, 1.25; p = 0.0267). Statistically significant differences were revealed for paracetamol glucuronide mean residence time (MRT); MRT was higher in group SUN + PC than in group PC (p = 0.0375). The mean t max of paracetamol glucuronide was similar in both groups: SUN + PC and group PC (15 and 20 min, respectively). The mean t max of sunitinib was different in groups SUN + PC and SUN (10.0 and 7.0, respectively; p = 0.0134). At the studied doses, neither of the drugs, whether administered alone or together, had hepatotoxic effects. The present study was not able to confirm that sunitinib, administered at low doses in conjunction with paracetamol, displays a hepatoprotective effect. Significant differences were observed in some pharmacokinetic parameters of paracetamol.

The problems of urinary tract infections with Candida spp. aetiology in women.

Urinary tract infections (UTIs) in women are a growing clinical concern. The most frequent risk factors of UTIs with fungal aetiology in women are: antibiotic therapy (especially broad-spectrum antibiotics), immunosuppressive therapy, diabetes, malnutrition, pregnancy, and frequent intercourse. The aim of the study was to analyse urinary tract infections with Candida spp. aetiology in women hospitalised at the Clinical Hospital in Poznan, Poland, between 2009 and 2011. The investigations revealed that as many as 71% of positive urine cultures with Candida fungi came from women. The following fungi were most frequently isolated from the patients under analysis: C. albicans (47%), C. glabrata (31%), C. tropicalis (6%), C. krusei (3%). In order to diagnose a UTI the diagnosis cannot be based on a single result of a urine culture. Due to the small number of antifungal drugs and high costs of treatment, antifungal drugs should be applied with due consideration and care.

Drug-related problems among breastfeeding patients treated for depressive spectrum disorders.

Introduction: Depressive spectrum disorders are common and can hinder breastfeeding success. While medications typically pose minimal risk, the concerns persist. This is the first study that investigates the prevalence and characteristics of drug-related problems among breastfeeding mothers with depressive spectrum disorders. We analyzed those problems to understand their nature, severity, and contributing factors. Additionally, we evaluated the outcomes of pharmacist-led interventions in reducing them. Understanding drug-related problems is crucial for informing evidence-based practices to optimize both maternal mental health and breastfeeding success. Materials and methods: This prospective observational study was conducted at a specialized pharmacy office in Poznan, Poland, which focuses on lactation support and medication consultations. 47 breastfeeding patients were enrolled. Pharmaceutical consultations were conducted according to Joint Commission of Pharmacy Practitioners Pharmacists' Patient Care Process standards. Novel MILC Questionnaire was used for efficient and optimal pharmaceutical interview. Drug-related problems were assessed basing on PCNE Classification System version 9.1. For adverse events in lactation, MedDRA v27 nomenclature was used; for causality, Naranjo Scale and LCAT were utilized. CTCAE was used for grading. Results: Among the 47 patients, pharmacist identified 49 medication-related problems, with inadequate treatment effect due to underdosing or not taking the medication at all being the most common (57.1%). Pharmacist interventions focused on medication safety information and counseling. Overall, 78.7% of patients accepted these interventions, resulting in problem resolution for 71.4%. Twelve mothers (25.5%) reported adverse events in their infants, but after causality evaluation, only four (8.5%) might have been linked to maternal medication. None required medical intervention beyond one hospitalization for a serious adverse event possibly connected to maternal medication. Conclusion: The study identified high rates of drug-related problems among breastfeeding mothers with depression, primarily due to non-adherence. Pharmacist interventions significantly improved DRP outcomes. Adverse events were reported, but most were mild and did not require intervention. Our findings suggest that lactating mothers with depressive spectrum disorders may benefit from pharmacist-led support to optimize treatment adherence and address medication safety concern.

Bidirectional pharmacokinetic drug interactions between olaparib and metformin.

OBJECTIVE: Olaparib is a PARP (poly-ADP-ribose polymerase) inhibitor used for maintenance therapy in BRCA-mutated cancers. Metformin is a first-choice drug used in the treatment of type 2 diabetes. Both drugs are commonly co-administered to oncologic patients with add-on type 2 diabetes mellitus. Olaparib is metabolized by the CYP3A4 enzyme, which may be inhibited by metformin through the Pregnane X Receptor. In vitro studies have shown that olaparib inhibits the following metformin transporters: OCT1, MATE1, and MATE2K. The aim of the study was to assess the influence of 'the perpetrator drug' on the pharmacokinetic (PK) parameters of 'the victim drug' after a single dose. To evaluate the effect, the AUC0→∞ (area under the curve) ratio was determined (the ratio between AUC0→∞ in the presence of the perpetrator and AUC0→∞ without the presence of the perpetrator). METHODS: Male Wistar rats were assigned to three groups (eight animals in each group), which were orally administered: metformin and olaparib (IMET+OLA), vehiculum with metformin (IIMET), and vehiculum with olaparib (IIIOLA). Blood samples were collected after 24 h. HPLC was applied to measure the concentrations of olaparib and metformin. The PK parameters were calculated in a non-compartmental model. RESULTS: Metformin did not affect the olaparib PK parameters. The AUC0→∞ IMET+OLA/IIIOLA ratio was 0.99. Olaparib significantly increased the metformin Cmax (by 177.8%), AUC0→t (by 159.8%), and AUC0→∞ (by 74.1%). The AUC0→∞ IMET+OLA/IIMET ratio was 1.74. CONCLUSIONS: A single dose of metformin did not affect the PK parameters of olaparib, nor did it inhibit the olaparib metabolism, but olaparib significantly changed the metformin pharmacokinetics, which may be of clinical importance.

Pharmacokinetic interaction between regorafenib and atorvastatin in rats.

BACKGROUND: Regorafenib is used in the treatment of colorectal cancer and hepatocellular carcinoma. Due to the co-morbidity of hyperlipidemia in these conditions, statins, including atorvastatin, are used as potential adjuvant therapy agents. Both regorafenib and atorvastatin are metabolized by CYP3A4. In addition, atorvastatin is a P-gp and BCRP substrate, whereas regorafenib and its active metabolites M-2 and M-5 are inhibitors of these transporters. Hence, the concomitant use of both drugs may increase the risk of a clinically significant drug-drug interaction. Therefore, the present study aimed to assess the pharmacokinetic interactions of atorvastatin and regorafenib and their active metabolites. METHODS: Male Wistar rats were assigned to three groups (eight animals in each) and were orally administered: regorafenib and atorvastatin (IREG+ATO), a carrier with regorafenib (IIREG), and atorvastatin with a carrier (IIIATO). Blood samples were collected for 72 h. UPLC-MS/MS was the method of measurement of regorafenib and atorvastatin concentrations. The pharmacokinetic parameters were calculated with a non-compartmental model. RESULTS: A single administration of atorvastatin increased the exposure to regorafenib and its active metabolites. In the IREG+ATO group, the Cmax, AUC0-t, and AUC0-∞ of regorafenib increased 2.7, 3.2, and 3.2-fold, respectively. Atorvastatin also significantly increased the Cmax, AUC0-t, and AUC0-∞ of both regorafenib metabolites. Regorafenib, in turn, decreased the AUC0-t and AUC0-∞ of 2-OH atorvastatin by 86.9% and 67.3%, and the same parameters of 4-OH atorvastatin by 45.0% and 46.8%, respectively. CONCLUSIONS: This animal model study showed a significant pharmacokinetic interaction between regorafenib and atorvastatin. While this interaction may be clinically significant, this needs to be confirmed in clinical trials involving cancer patients.

The need to assay the real MIC when making the decision to eradicate Staphylococcus aureus with vancomycin.

PURPOSE: The aim of the study was a comparison of the MIC (minimal inhibitory concentration) evaluated in the automatic system Vitek 2 and the real MIC of vancomycin by the Etest method for S. aureus strains isolated from clinical materials. MATERIAL AND METHODS: Over a twelve-month study period we compared the results obtained with two commercial methods - the automatic system VITEK 2 and the real MIC by Etest - for 359 strains of S. aureus isolated from clinical materials. RESULTS: Most of the strains of S. aureus were cultured from wounds (84), the ear (60) and nose (42). MSSA (methicillin-sensitive Staphylococcus aureus) was isolated in 342 cases and MRSA (methicillin-resistant Staphylococcus aureus) in 17 cases. The test with the Vitek automatic method showed that vancomycin had MIC values of ≤1.0 µg/ml in more than 96% and 2.0 µg/ml in over 3% of cases. Using the Etest technique MIC ≤ 1.0 µg/ml was obtained in only 16.4% of cases and values of >1.0 µg/ml in 83.6% of cases. DISCUSSION: In view of such big differences between the MIC values obtained with the two methods the authors suggest that the Etest method of assaying the real MIC is more useful than the automatic method.

Stability of calcium folinate (Teva) in concentrate after re-use and in dilute infusions in 0.9% NaCl in polyethylene bags.

The study concerned the stability of calcium folinate in concentrate in glass vials and diluted in polyethylene (PE) bags stored at 15-25 degrees C and 2-8 degrees C for up to 34 days. Original vials of calcium folinate injection (10 mg/mL, Teva) were stored at room and refrigerator temperatures and subjected to re-piercing at 1, 2, 3, 7, 14, 22, 28, 30 and 34 days following the initial piercing. Calcium folinate infusions at nominal concentrations of 0.12 mg/mL were prepared in 0.9% sodium chloride (250 mL) in PE bags. Chemical stability was measured with a stability-indicating high-performance liquid chromatography (HPLC) assay. Physical stability was assessed by visual inspection in normal light. The concentration of calcium folinate at each sampling time in the analyzed solutions remained > 90% of the initial concentration, regardless of the container. No changes in color or turbidity were observed in any of the vials or in the prepared solutions. Calcium folinate, both undiluted in glass containers and diluted with NaCl 0.9% in PE bags, remains stable (< 10% degradation) for at least 30 days at room and refrigerator temperatures when protected from light.

[Optimization of antibiotic therapy in pregnancy--clinical implications]. / Optymalizacja antybiotykoterapii w ciazy--implikacje kinczne.

The aim of the antibacterial therapy during pregnancy is to select a proper antibiotic and determine its effective dose, at the same time excluding the risk of potential teratogenic effect. Pregnancy is characterized by many physiological, disease-predisposing changes, particularly of bacterial etiology that have an influence on different pharmacokinetic of drugs. When determining an effective dose of an antibiotic, one should take into account changes in the pharmacokinetics (PK) of drugs in pregnant women, involving mainly the phase of distribution (increased volume of body fluids, cardiac output, reduced concentration of albumins), metabolism (induction of hepatic enzymes: CYP3A4, CYP2D6, CYP2C9, UGT1A4, UGT2B7, inhibition of CYP1A2, CYP2C19), and excretion (increased glomerular filtration rate). Results of few pharmacokinetic studies on pregnant patients point to the need of increasing the dose or reducing dosage intervals for some antibiotics (e.g. penicillin V ampicillin, piperacillin, imipenem, clindamycin). The aim of this study was to summarize current knowledge regarding the PK of antibiotics during pregnancy.

[Attitudes of pharmacy and dentistry students of Poznan Medical University towards smoking]. / Postawy studentów Farmacji i Stomatologii Uniwersytetu Medycznego w Poznaniu wobec nalogu palenia tytoniu.

The aim of this study was to compare the attitude of students of the Faculty of Pharmacy and Division of Dentistry (Poznan University of Medical Sciences) towards smoking. Information was collected using a self-completion questionnaire for students. 114 students of the 5th year of Faculty of Pharmacy and 60 students of 4th year of Division of Dentistry took part in the survey. Most of the students were non-smokers (77% in the Faculty of Pharmacy and 72% in the Division of Dentistry). The main reason for abandoning smoking in both groups was knowledge on the dangers of addiction obtained in medical studies.

The physical and chemical stability of cisplatin (Teva) in concentrate and diluted in sodium chloride 0.9%.

AIM OF THE STUDY: The subject of study was the stability of cisplatin in concentrate in glass vials and diluted in polyethylene (PE) bags stored at 15-25°C for up to 30 days. MATERIAL AND METHODS: Original vials of cisplatin injection (1 mg/ml, Teva) were stored at room temperature and subjected to re-piercing after 1, 2, 3, 7, 14, 21, 28 and 30 days following the initial piercing. Cisplatin infusions at nominal concentrations of 0.1 mg/ml were prepared in 0.9% sodium chloride (1000 ml) in PE bags. Chemical stability was measured by means of a stability-indicating high-performance liquid chromatography (HPLC) assay. Physical stability was assessed by visual inspection in normal light. RESULTS: The concentration of cisplatin at each sampling time in the analysed solutions remained within 92.0-100.7% of initial concentration, regardless of the container. No changes in colour or turbidity were observed in any of the vials or prepared solutions. CONCLUSIONS: Cisplatin, both undiluted in glass containers and diluted with NaCl 0.9% in PE bags, remains stable (< 10% degradation) for at least 30 days at room temperature when protected from light.

The PK/PD index (CMAX/MIC) for ciprofloxacin in patients with cystic fibrosis.

In order to evaluate the efficacy of an antibacterial therapy, three basic PK/PD indexes were defined: the ratio between the maximum drug concentration obtained after a single dose and minimum inhibitory concentration MIC (CMAX/MIC), the ratio between the area under the curve of dependence between the drug concentration in blood and time within 24 hours to MIC (AUC24/MIC), and the time when the concentration of the drug in blood is higher than MIC (T > MIC). The aim of the study was an analysis of the pharmacokinetics of ciprofloxacin and the PK/PD: CMAX/MIC index in patients with cystic fibrosis. Six patients with cystic fibrosis, with the identified microbiological factor were subjected to the examination. The patients received ciprofloxacin in the dose of 400 mg/12 h (i.v.). Plasma drug concentration was measured by HPLC-UV method after the first dose (Cmax1) and at steady state (Cssmax, Cssmin). The following mean values of ciprofloxacin blood concentrations were obtained from the analyzed patients: Cmax1 = 2.34 (+/- 1.15) microg/mL, Cssmax = 2.49 (+/- 1.44) pg/mL, Cssmin = 0.42 (+/- 0.22) pg/mL. The mean values of the Cmax1/MIC and Cssmax/MIC indexes were 3.66 +/- 2.34) and 3.38 (+/-1.73), respectively. Low values of the Cmax/MIC index for ciprofloxacin in the analyzed patients may indicate too low concentrations of the drug in the blood in relation to the MIC value of pathogens and the need to verify the assumed administration scheme.

The Effects of Bariatric Surgery and Gastrectomy on the Absorption of Drugs, Vitamins, and Mineral Elements.

Bariatric surgery, which is an effective treatment for obesity, and gastrectomy, which is the primary treatment method for gastric cancer, alter the anatomy and physiology of the digestive system. Weight loss and changes in the gastrointestinal tract may affect the pharmacokinetic parameters of oral medications. Both bariatric and cancer patients use drugs chronically or temporarily. It is important to know how surgery affects their pharmacokinetics to ensure an effective and safe therapy. The Cochrane, PubMed, and Scopus databases were searched independently by two authors. The search strategy included controlled vocabulary and keywords. Studies show that bariatric surgery and gastrectomy most often reduce the time to maximum plasma concentration (tmax) and decrease the maximum plasma concentration (Cmax) in comparison with the values of these parameters measured in healthy volunteers. Vitamin and mineral deficiencies are also observed. The effect depends on the type of surgery and the properties of the drug. It is recommended to use the drugs that have been tested on these groups of patients as it is possible to monitor them.

Pharmacokinetic Drug Interaction Study of Sorafenib and Morphine in Rats.

A combination of the tyrosine kinase inhibitor-sorafenib-and the opioid analgesic-morphine-can be found in the treatment of cancer patients. Since both are substrates of P-glycoprotein (P-gp), and sorafenib is also an inhibitor of P-gp, their co-administration may affect their pharmacokinetics, and thus the safety and efficacy of cancer therapy. Therefore, the aim of this study was to evaluate the potential pharmacokinetic drug-drug interactions between sorafenib and morphine using an animal model. The rats were divided into three groups that Received: sorafenib and morphine (ISOR+MF), sorafenib (IISOR), and morphine (IIIMF). Morphine caused a significant increase in maximum plasma concentrations (Cmax) and the area under the plasma concentration-time curves (AUC0-t, and AUC0-∞) of sorafenib by 108.3 (p = 0.003), 55.9 (p = 0.0115), and 62.7% (p = 0.0115), respectively. Also, the Cmax and AUC0-t of its active metabolite-sorafenib N-oxide-was significantly increased in the presence of morphine (p = 0.0022 and p = 0.0268, respectively). Sorafenib, in turn, caused a significant increase in the Cmax of morphine (by 0.5-fold, p = 0.0018). Moreover, in the presence of sorafenib the Cmax, AUC0-t, and AUC0-∞ of the morphine metabolite M3G increased by 112.62 (p < 0.0001), 46.82 (p = 0.0124), and 46.78% (p = 0.0121), respectively. Observed changes in sorafenib and morphine may be of clinical significance. The increased exposure to both drugs may improve the response to therapy in cancer patients, but on the other hand, increase the risk of adverse effects.

Influence of obesity on pharmacokinetics and analgesic effect of ketoprofen administered intravenously to patients after laparoscopic cholecystectomy.

BACKGROUND: Ketoprofen is an analgesic drug commonly applied in the postoperative period, e.g., to patients after laparoscopic cholecystectomy. Many patients who undergo this procedure are obese. As pathophysiological changes are observed in obesity, the efficacy of ketoprofen may be altered in this group of patients. The aim of the study was to compare the pharmacokinetic parameters and analgesic effect of ketoprofen administered to obese and non-obese patients after laparoscopic cholecystectomy. METHODS: The study was conducted on 41 patients after laparoscopic cholecystectomy, who were divided into two groups: obese (n = 21) and non-obese (n = 20). Ketoprofen was administered intravenously at a dose of 100 mg. Plasma ketoprofen concentrations were measured by means of validated high-performance liquid chromatography with ultraviolet detection. The pharmacokinetic parameters of the drug were calculated using the non-compartmental method. Additionally, pain intensity was assessed during the study using NRS scale. RESULTS: The obese patients had significantly lower AUC0-∞ (1.4-fold), AUMC0-t (1.8-fold), AUMC0-∞ (3.2-fold), MRT0-t (1.4-fold), MRT0-∞ (2.3-fold), t0.5 (2.3-fold) and Vz/kg (2.3-fold) and higher kel (2.2-fold) than the non-obese group. Moreover, 4 h and 6 h after the administration of the drug, pain intensity was significantly higher in the obese patients. CONCLUSIONS: The drug was eliminated faster and the analgesic effect of ketoprofen in the obese patients was decreased as compared with the non-obese subjects. However, pain intensity did not increase to the level, which required additional analgesic treatment. Therefore, it seems that dosage adjustment of intravenous ketoprofen is not necessary in obese patients.

The Influence of Paracetamol on the Penetration of Sorafenib and Sorafenib N-Oxide Through the Blood-Brain Barrier in Rats.

BACKGROUND AND OBJECTIVE: Sorafenib is an oral, multikinase inhibitor with established single-agent activity in several tumor types. Sorafenib was moderately transported by P-glycoprotein (P-gp) and more efficiently by breast cancer resistance protein. The constitutive androstane receptor (CAR) is a ligand-activated transcription factor involved in P-gp regulation in the brain microvasculature. Paracetamol is a CAR activator. The purpose of this study was to investigate the effect of paracetamol on the brain uptake of sorafenib and sorafenib N-oxide. METHODS: The rats were assigned to two groups-rats receiving oral paracetamol 100 mg/kg and sorafenib 100 mg/kg (n = 42, ISR+PA) and rats receiving oral vehicle and sorafenib 100 mg/kg (n = 42, IISR). The sorafenib and sorafenib N-oxide concentrations in blood plasma and brain tissue were determined by a high-performance liquid chromatography method with ultraviolet detection. Brain-to-plasma partition coefficient (Kp) was calculated as a ratio of the area under the curve from zero to 24 h (AUC) in the brain and plasma. A drug targeting index (DTI) was estimated as the group ISR+PA Kp to group IISR Kp ratio. RESULTS: Pharmacokinetic analysis revealed increased brain exposure to sorafenib and sorafenib N-oxide after co-administration of paracetamol. The brain maximum concentration (Cmax) and the AUC of the parent drug in the ISR+PA group compared with the IISR group were greater by 49.5 and 77.8%, respectively, and the same parameters for the metabolite were higher by 51.4 and 50.9%. However, the Kp values of sorafenib and sorafenib N-oxide did not differ significantly between the two animal groups and the DTI values were close to 1. CONCLUSION: Paracetamol increases exposure to sorafenib and sorafenib N-oxide in the brain, likely due to increased exposure in plasma.