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Background: Sepsis is a life-threatening organ dysfunction occurring during infections. Meropenem is a hydrophilic β-lactam carbapenem antibiotic. Its pharmacokinetic parameters are expected to change due to sepsis-induced physiological alterations and will thus require altered dosing strategies for optimal treatment of sepsis patients. Aim: This is a review with the purpose to compare the pharmacokinetics of meropenem between healthy adults and adult septic patients and explore the potential covariates that affect the pharmacokinetic parameters. Methods: Articles that were explored were collected from PubMed and were screened through inclusion and exclusion criteria. Results: Total of 19 articles were identified and selected. Participants in the studies were in the age range of 18–91 years, with the weight range of 37–120 kg. Volume of distribution at steady-state in the healthy participants had a median of 22.2 L, while the volume of distribution in septic patients had median 27.6 L. Clearance had median 13.89 L/h in healthy, compared to the median 10.43 L/h in septic. The median half-life was 1 h in healthy, whereas in septic, the median half-life was 2.5 h. Patients with fluid overload from fluid therapy had larger Vd & lower Cl, while patients with creatinine clearance < 50 mL/min had lower Cl. Conclusions: The physiological alterations developing in sepsis lead to an increase of the meropenem’s distribution and a decrease of its elimination, which is exacerbated by fluid overload. These findings could be a good starting point for building a physiologically based pharmacokinetic model of meropenem in sepsis.

Background: Pharmaceutical development has taken new ground in recent decades and placed new demands on the regulations. Since 2005, a risk management plan (RMP) has been required when applying for a first marketing authorization for a drug. The RMP forms the basis for how identified risks with the drug are to be managed. In the RMP for all drugs, regular measures (rRMM) such as summary of product characteristics (SPC) are applied. As only rRMM is not considered sufficient, additional measures (aRMM) are also applied, which can be, for example, extra training material for prescribers or patients. aRMM material is today distributed to prescribers via physical letters. Are aRMM materials communicated today in a way that fulfills the purpose of the regulations? Aim: The aim of this study is to gain knowledge through qualitative interviews with the pharmaceutical industry and regulatory authority in Sweden about how risks with drugs are communicated. Methods: Semi-structured individual interviews were conducted with 7 persons from the pharmaceutical industry and 1 person from the regulatory authority in Sweden, during March and April 2022. The interviews were transcribed and the data were analyzed with systematic text condensation. Results: The five main identified desired improvements in the communication of aRMMs are  these; 1. National common database for aRMM materials, 2. Flagging and availability in prescribing systems, 3. Swedish Medical Products Agency labeled materials, 4. Dialogue between healthcare, pharmaceutical companies and the pharmaceutical authority, 5. Diversity and availability of aRMM materials to patients.  Conclusion: aRMM is considered in itself to be an effective tool for managing and minimizing risks with medicines, but the measures lose effect and purpose due to lack of communication and understanding.

Introduction: Type 2 diabetes (T2D) increases in prevalence and generates significant diseaseburden, where impairment in hormonal systems, such as glucagon, is suspected to contribute to T2Ddevelopment. Covariates such as obesity is a known risk factor for T2D development. Additionally,higher fasting insulin and glucagon concentrations, stronger adrenocorticotrophic hormone- (ACTH)and cortisol-response during hypoglycemia have been demonstrated in obese individuals. In contrast,bariatric surgery has shown to result in diabetes remission, independent of weight loss. The effect ofglucose and insulin on glucagon, ACTH and cortisol have been well studied, but not modelledduring hypoglycemia. Aim: To develop a population model of glucagon, ACTH and cortisol response during hypo- andhyperglycemia by characterizing the relationship between glucagon and glucose/insulin as well asACTH and glucose, connected with cortisol and explore impact of covariates. Followed byinvestigating changes in the concentration-response relationships after Roux-en-Y gastric bypass(RYGB). Methods: Data from a cross-over study with one arm being hyperinsulinemic-eu/hypoglycemicclamp, and the second arm being a hyperglycemic clamp was combined with data from two crossoverdesign studies with arms being hyperinsulineamic-eu/hypoglycemic clamps, conducted beforeand after RYGB. The pre-surgical combined data was used to create a population model throughnon-linear mixed effect modelling where additional delay mediating through an effect compartmentwas investigated on all response variables. Various structural models were explored in order todescribe glucose and/or insulins effect on glucagon response. Glucose inhibition on ACTH production was described through a sigmoidal Imax-model, which was combined with a surge modelto describe ACTH production caused by circadian rhythm. Cortisol production was modelled asbeing driven solely by ACTH concentrations and covariate relationships were investigated through astepwise covariate model. The models were validated with statistical and graphical analysis. Results and discussion: Glucagon production was dependent on an individuals’ insulin sensitivityand fasting glucose and insulin concentration. Glucose inhibition on glucagon productioncontributed with 77 % of the total inhibition in comparison to insulin, which contributed with 23 %.Glucose concentration had a steeper exposure-response relationship in comparison to insulinconcentration on glucagon production. Despite insulin concentrations having smaller effect incomparison to glucose on glucagon production, insulin had significant impact on the models fit tothe data. ACTH and cortisol responses were accurately described, despite some misspecificationswhich were independent of glucose concentrations. Production of ACTH was dependent on insulinsensitivity and fasting glucose. Alteration in glucagon and ACTH production, together with insulinsensitivity was sufficient to describe changes after RYGB. This model can be used in optimal designgenerations where clamping technique is used as guidance of appropriate hypoglycemic clamplevels. Conclusion: A population model of glucagon, ACTH and cortisol response was developed using datafrom hypo- and hyperglycemic studies. Glucagon production was described as dependent onglucose and insulin and ACTH production was described as dependent on glucose, with the ACTHconcentration driving the cortisol production. Insulin sensitivity was found to affect baselineglucose and the sensitivity of ACTH to glucose. The model could describe post-bariatric surgerydata when adjusting the estimating of baseline glucagon and ACTH.

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Apoptosis can be triggered in two different ways, through the intrinsic or the extrinsic pathway. The intrinsic pathway is mediated by the mitochondria via the release of cytochrome C while the extrinsic pathway is prompted by death receptor signals and bypasses the mitochondria. These two pathways are closely related to cell proliferation and survival signaling cascades, which thereby constitute possible targets for cancer therapy. In previous studies we introduced two plant derived isomeric flavonoids, flavone A and flavone B which induce apoptosis in highly tumorigenic cancer cells of the breast, colon, pancreas, and the prostate. Flavone A displayed potent cytotoxic activity against more differentiated carcinomas of the colon (CaCo-2) and the pancreas (Panc28), whereas flavone B cytotoxic action is observed on poorly differentiated carcinomas of the colon (HCT 116) and pancreas (MIA PaCa). Apoptosis is induced by flavone A in better differentiated colon cancer CaCo-2 and pancreatic cancer Panc 28 cells via the intrinsic pathway by the inhibition of the activated forms of extracellular signal-regulated kinase (ERK) and pS6, and subsequent loss of phosphorylation of Bcl-2 associated death promoter (BAD) protein, while apoptosis is triggered by flavone B in poorly differentiated colon cancer HCT 116 and MIA PaCa pancreatic cancer cells through the extrinsic pathway with the concomitant upregulation of the phosphorylated forms of ERK and c-JUN at serine 73. These changes in protein levels ultimately lead to activation of apoptosis, without the involvement of AKT.

3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) inhibitors, commonly known as statins, may possess cancer preventive and therapeutic properties. Statins are effective suppressors of cholesterol synthesis with a well-established risk-benefit ratio in cardiovascular disease prevention. Mechanistically, targeting HMGCR activity primarily influences cholesterol biosynthesis and prenylation of signaling proteins. Pravastatin is a hydrophilic statin that is selectively taken up by a sodium-independent organic anion transporter protein-1B1 (OATP1B1) exclusively expressed in liver. Simvastatin is a hydrophobic statin that enters cells by other mechanisms. Poorly-differentiated and well-differentiated cancer cell lines were selected from various tissues and examined for their response to these two statins. Simvastatin inhibited the growth of most tumor cell lines more effectively than pravastatin in a dose dependent manner. Poorly-differentiated cancer cells were generally more responsive to simvastatin than well-differentiated cancer cells, and the levels of HMGCR expression did not consistently correlate with response to statin treatment. Pravastatin had a significant effect on normal hepatocytes due to facilitated uptake and a lesser effect on prostate PC3 and colon Caco-2 cancer cells since the OATP1B1 mRNA and protein were only found in the normal liver and hepatocytes. The inhibition of cell growth was accompanied by distinct alterations in mitochondrial networks and dramatic changes in cellular morphology related to cofilin regulation and loss of p-caveolin. Both statins, hydrophilic pravastatin and hypdrophobic simvastatin caused redistribution of OATP1B1 and HMGCR to perinuclear sites. In conclusion, the specific chemical properties of different classes of statins dictate mechanistic properties which may be relevant when evaluating biological responses to statins.

Background: Diclofenac is an analgesic, antipyretic and anti-inflammatory drug that may have harmful effects on the environment, It has contributed to the death of fish exposed to the substance through discharges into lakes and seas. Even birds, especially vultures, have died after exposure to diclofenac by consuming carcasses that were treated before they died. Aim: The purpose of this study was to assess the sales of diclofenac around Lake Mälaren. Method: Data were obtained from the Swedish eHealth Agencys statistics database Concise, for the time period 2018–2021. The counties studied were Uppsala, Västmanland, Södermanland and Örebro, which have waste water treatment plants with Lake Mälaren as the recipient. The amount sold in kg was calculated using DDD, number of packages and package size and analyzed by season, time, sales method and region. Results: Uppsala accounted for the highest sales of diclofenac of the counties studied and over-the-counter sales at pharmacies sold most of the various sales methods. During the winter there was an increase of sold diclofenac while no other seasonal variations were observed. Following the prescription in June 2020, sales of tablets and capsules decreased, while other forms of preparation were not affected. For each year studied, the number of kg of diclofenac sold has decreased. Conclusion: Sales of diclofenac have declined during the period of 2018-2021, which is positive from an environmental point of view as reduced use means reduced emissions to nature.  This data can be used to investigate farmacies and citys on a lower level.