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In the Netherlands, it is against the law to possess, sell or produce drugs. Soft drugs are less damaging to health than hard drugs. Therefore, in the Netherlands, coffee shops are permitted to sell cannabis under certain strict conditions. A coffee shop is an establishment where cannabis is sold but no alcoholic drinks are sold or consumed. This is part of the Dutch policy of toleration. However, the Netherlands has a policy of toleration regarding soft drugs. This means that the sale of small quantities of soft drugs in coffee shops is a criminal offence but the Public Prosecution Service does not prosecute coffee shops for this offence. Neither does the Public Prosecution Service prosecute members of the public for possession of small quantities of soft drugs. These quantities are defined as follows:. Coffee shops:. Municipalities determine whether to allow coffee shops to operate within their boundaries, and if so, how many. They can also impose additional rules. The objective is to combat the nuisance and crime associated with coffee shops. Coffee shops must become smaller and focus on the local market. This policy will make Dutch coffee shops less attractive to drug users from abroad. To combat drug-related crime and nuisance, the Dutch government introduced a new toleration rule on 1 January only 'residents of the Netherlands' are permitted to visit coffee shops and purchase cannabis there. A resident of the Netherlands is someone who lives in a Dutch municipality and is registered there. Whether this rule is actively enforced differs from municipality to municipality. Coffee shop owners are required to check whether all those admitted to the shop, and allowed to purchase cannabis there, are residents of the Netherlands aged 18 years or older. They should check these facts, for instance, by asking the person to produce a valid identity document or residence permit, in combination with an extract from the municipal population register. It is against the law to grow marijuana and cannabis plants. In cases where no more than 5 plants are grown for personal consumption, the police will generally only seize the plants. If more than 5 plants are found, the Public Prosecution Service will prosecute. In combating cannabis growing, the police collaborate with organisations including housing associations, the Tax and Customs Administration, and energy companies. Tenants found to be growing cannabis may be evicted. The energy company will impose an additional retrospective assessment on those who illegally tap electricity. Toleration policy regarding soft drugs and coffee shops In the Netherlands, it is against the law to possess, sell or produce drugs.

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Almere buying MDMA pills

Introduction Liver cirrhosis can have a major impact on drug pharmacokinetics and pharmacodynamics. Patients with cirrhosis often suffer from potentially preventable adverse drug reactions. Guidelines on safe prescribing for these patients are lacking. The aim of this study is to develop a systematic method for evaluating the safety and optimal dosage of drugs in patients with liver cirrhosis. Methods and analysis For each drug, a six-step evaluation process will be followed. This protocol will be applied in the evaluation of a selection of drugs: A drugs used to treat complications of liver cirrhosis, and B drugs frequently prescribed to the general population. Ethics and dissemination Since this study does not directly involve human participants, it does not require ethical clearance. Besides implementation on a website and in clinical decision support systems, we aim to publish the generated advices of one or two drug classes in a peer-reviewed journal and at conference meetings. You will be able to get a quick price and instant permission to reuse the content in many different ways. This is the first protocol describing a six-step method to develop advices about the safety of drugs in patients with liver cirrhosis. The first four steps involve gathering evidence and an assessment by an expert panel. Steps five and six consist of implementing prescribing advice in all relevant clinical decision support systems in the Netherlands and regularly updating the advices. We have designed a safety classification to support healthcare providers and patients to efficiently judge drug safety in liver cirrhosis. A potential limitation of this protocol is the number of published studies available concerning the use of drugs in patients with liver cirrhosis. However, the combination with expert opinion will make it possible to give specific advices. Liver cirrhosis is a slowly progressive disease characterised by fibrosis and conversion of normal liver architecture into structurally abnormal nodules. Liver cirrhosis results from ongoing inflammation of the liver. The liver is the main organ for metabolism and detoxification of endogenous and exogenous substances. Several pathophysiological changes that occur in liver cirrhosis influence this detoxification of exogenous substances, that is, drug pharmacokinetics. Decreased plasma protein synthesis causes lower plasma protein concentrations and possibly a higher fraction of unbound drug. A reduction or impairment of drug-metabolising enzymes in the liver may cause reduced metabolism. These changes often result in an elevated drug exposure, possibly causing side effects and toxicity. Hence, the efficacy of drugs could be different in patients with liver cirrhosis. Moreover, patients with cirrhosis are more vulnerable to certain adverse drug reactions ADRs , such as effects on coagulation or nephrotoxicity. However, they can be difficult to obtain and interpret for a busy healthcare professional not frequently dealing with patients with cirrhosis. What is missing is the translation of all literature into a regularly updated and easy manageable source of information on safe prescribing in patients with liver cirrhosis. This study wants to address this problem by developing advices for the safe use of medications in patients with liver cirrhosis. To guarantee the quality of these advices, it is important that the method for evaluating is performed in a uniform, transparent manner leading to a standardised report. The aim of this study is to describe the systematic method used for evaluating the safety and optimal dosage of drugs in patients with liver cirrhosis. Six steps will be performed for evaluating a drug figure 1. Below, the six steps are described in detail. Steps 1—3 will be performed by a pharmacist with experience in the evaluation of drug safety in the context of clinical decision support systems RW. Flow chart of the six-step process used per drug for evaluating the safety and optimal dosage in liver cirrhosis. Information concerning the pharmacokinetics of the drug in healthy volunteers and patients with liver cirrhosis will be collected from the official Product Characteristics as published by the responsible authorities European Medicines Agency EMA , Food and Drug Administration and the Medicines Evaluation Board in the Netherlands. For products registered by the EMA, the European Public Assessment Report will be searched on information about dosage in liver cirrhosis. Special warnings regarding the safety of the drug in patients with liver cirrhosis will also be collected. The search in electronic literature databases aims to review published literature about the alterations in pharmacokinetic parameters and the safety of the drug in patients with liver cirrhosis. Studies with and without a control group will be included. If a drug is compared to another intervention, data about the control group will be included in the data extraction. There will be no limit to the time periods searched. Exclusion criteria are: 1 animal studies, 2 cellular and molecular research, 3 studies in patients with other hepatic diseases, such as hepatocellular carcinoma, non-alcoholic fatty liver disease or primary biliary cholangitis, that do not mention the inclusion of a subpopulation with liver cirrhosis and 4 studies about drug-induced liver injury in patients without liver cirrhosis. These databases will be searched this includes reviews published by the Cochrane library by the search strategy outlined in table 1. A more specific search will be performed if there is excessive literature. In this case, a stepwise search strategy will be used starting with PubMed as a database. Filters that indicate studies with a high level of evidence will be used to limit the number of studies. The pharmacists responsible for the collection of evidence will judge whether sufficient data are collected to answer the research question. This step is checked by another pharmacist and will be discussed and finally confirmed by the expert panel. Additional articles will be obtained through citation snowballing to locate primary sources. The following characteristics of included studies will be extracted: study design, number and characteristics of included patients and controls eg, severity of liver cirrhosis and details on the intervention. Concerning the outcome s , the following data will be extracted:. Safety: data on the number of adverse events observed during use of the drug in patients with cirrhosis and on the consequences of these adverse events eg, discontinuation of treatment, dose reductions , preferably compared with patients without liver cirrhosis. Data will be reported in summary tables for each outcome and sorted by level of evidence. The level of evidence of each study will be assessed according to the criteria for treatment harms of the Oxford Centre for Evidence-Based Medicine. The summary tables will be checked by a second pharmacist. Details on the electronic database search search strategy, study selection process in a flow chart. All information from the report will be used to suggest a safety classification and a dose per individual drug, if applicable sorted by severity of liver cirrhosis. The severity will be expressed using the Child-Pugh classification. To support healthcare providers and patients to efficiently judge drug safety in liver cirrhosis, we designed a safety classification table 2. For drugs in liver cirrhosis, we will use the following categories: safe, no additional risks known, additional risks known, unsafe and unknown. Pharmacokinetic data will be used to judge whether a dose adjustment is necessary in patients with cirrhosis. It applies for most drugs that if the AUC is more than doubled, a dose reduction will be recommended. Both the proposed classification and suggested dose are checked by a second pharmacist, before discussion by the expert panel. An expert panel will evaluate the validity and clinical relevance of the initial classification, the suggested dose and the data extraction. This panel will meet five times during the study to discuss the assessment reports. The final report is a combination of the available evidence and expert opinions. The expert panel will conclude by consensus. The expert panel consists of the following specialists: the pharmacist responsible for the data collection, extraction and initial evaluation RW , professionals with expertise regarding our two main outcomes; altered safety or pharmacokinetics in patients with liver cirrhosis DB and NH , representatives of the specialists responsible for prescribing: hepatologists JD and HM , general practitioner MB , representatives of specialists responsible for dispensing: clinical pharmacists DB and NH , a community pharmacist SvP , a clinical pharmacokinetics assessor of the Medicines Evaluation Board MM-S and two pharmacists working with the national drug databases in the Netherlands Pharmabase and G—Standard: MK and SB. The general practitioner and community pharmacist will contribute to the implementation from the perspective of primary care. The pharmacists working for the national drug databases will assure that the advices can be implemented in clinical decision support systems. There is also an epidemiologist SB in the expert panel who will pay attention to the methodology. All conflicts of interest of the members of the expert panel will be identified, disclosed and published on the website see implementation. The chair of the expert panel SB has no conflicts of interest. Advices about the safety of a drug and the optimal dosage in patients with liver cirrhosis will be implemented in the two national drug databases in the Netherlands Pharmabase and G-Standard. This will generate specific alerts for healthcare professionals when they prescribe or dispense a drug with risks to a patient with liver cirrhosis. The advices will also be published on a website. On this website, a summary will be included which starts with the key recommendations ie, safety classification of drug and dosing advices and describes background information on the advice and body of evidence ie, number of studies retrieved, number of participants and level of evidence of the studies. The full assessment report can be accessed through a hyperlink. The advices will be in Dutch, since they will be implemented in national clinical decision support systems. The summary of finding tables derived from the English literature will be left in English. Conflicts of interest of the members of the expert panel will be mentioned on the website. There will also be a part on the website intended for patients with liver cirrhosis. This part will contain a simple, patient-friendly version of the advices with directions to consult their doctor or pharmacist in case of further questions. These advices will be made in collaboration with the Dutch Liver Patients Association. Before publication of the website, the finding and understanding of the content will be tested by patients and healthcare professionals. Via user testing, a group of patients and a group of healthcare professionals will test the website. To assure up-to-date advices, literature searches will be saved and checked yearly for relevant literature. Comments from patients and professionals using the guidelines will be reviewed and included, if applicable. The expert panel will check yearly if the advices need to be updated based on their specific clinical expertise. An overview of the drugs that will be evaluated in this study is presented in table 3. We have developed a systematic method to evaluate the safety and optimal dosage of drugs in patients with liver cirrhosis. Our method combines a systematic literature review with expert opinion and contains many aspects of the development of guidelines. It is important that this report contains the information healthcare professionals need for clinical decision-making. In the development of an assessment report, we were inspired by a checklist that identifies the most important elements that should be included in drug—drug interaction management guidelines. We designed a safety classification to help healthcare professionals to efficiently judge the safety of a drug in a patient with cirrhosis. We think our safety classification results in concrete advices, thereby preventing dissatisfaction and alert fatigue of healthcare professionals. The strengths of our study are the combination of evidence from the literature and expert opinion, the implementation in clinical decision support systems and the continuity. First, the published evidence of drugs in liver cirrhosis is variable, and studies often have a limited scope or a selective patient population. Combination with expert opinion adds the clinical and pharmacological experience to the published literature. This combination will make it possible to give specific advices, which is even more relevant in case little published literature is available. Second, the advices will be implemented in the two main clinical decision support systems in the Netherlands, automatically reaching all hospitals, community pharmacies and general practices. Healthcare professionals will receive a notification if a contraindicated drug is prescribed or dispensed to a patient with liver cirrhosis. This implementation can quickly result in a huge improvement in the medication safety of patients with cirrhosis in the Netherlands. We believe that this Dutch approach of monitoring the safety of drug use is unique, 29 and hope to inspire others to implement this in their healthcare systems. Third, to safeguard continuity, it is important that this guideline will be updated regularly and that these updates will be included in new signals. The advices will get updated yearly if there is new literature or if we receive comments. This is a major advantage in comparison to all reviews published on this topic. We expect that we will not perform a standard systematic review for all drugs. In this case, we will include literature from the highest level of evidence and stop extracting if we have sufficient information to classify the drug. The expert panel will also decide whether sufficient information is collected to classify the drug. Another limitation is that we will evaluate a restricted number of drugs in this study. Future research can enlarge the amount of drugs evaluated. Also, this study will expose knowledge gaps in the current literature with respect to the pharmacokinetics and safety of certain drugs in liver cirrhosis. Specific pharmacokinetic or pharmacodynamic studies can possibly fill this gap. Another interesting future research area is the implementation; do healthcare professionals follow our advices? How can the information obtained in our study be used to improve official drug labelling? Ultimately, does our study result in optimisation of medication use, that is, reduction in the number of adverse drug events experienced by patients with liver cirrhosis? In conclusion, this protocol describes a method to evaluate the safety and optimal dosage of drugs in patients with liver cirrhosis. This will lead to advices concerning the safety and optimal dosage of the drugs mostly used in liver cirrhosis and reveal gaps in the literature for future research. Since this study does not directly involve human participants, it does not require ethical clearance. The advices generated by the method described in this study will be published on a website and in two drug databases see Implementation section. We also aim to publish the generated advices of one or two drug classes in a peer-reviewed journal and at conference meetings. Contributors RW and SB wrote and drafted the protocol. All authors contributed to the development of the study protocol and read and approved the final manuscript. ZonMw is the Dutch national organisation for health research and healthcare innovation. ZonMw did not influence the content of the guideline. Provenance and peer review Not commissioned; externally peer reviewed. Skip to main content. Log In More Log in via Institution. Log in via OpenAthens. Log in using your username and password For personal accounts OR managers of institutional accounts. Forgot your log in details? Register a new account? Forgot your user name or password? Search for this keyword. Advanced search. Latest content Archive For authors About Browse by collection. Log in via Institution. You are here Home Archive Volume 6, Issue 10 Evaluating the safety and dosing of drugs in patients with liver cirrhosis by literature review and expert opinion. Email alerts. Article Text. Article menu. Gastroenterology and hepatology. Evaluating the safety and dosing of drugs in patients with liver cirrhosis by literature review and expert opinion. Abstract Introduction Liver cirrhosis can have a major impact on drug pharmacokinetics and pharmacodynamics. Statistics from Altmetric. Introduction Liver cirrhosis is a slowly progressive disease characterised by fibrosis and conversion of normal liver architecture into structurally abnormal nodules. Methods Six steps will be performed for evaluating a drug figure 1. Figure 1 Flow chart of the six-step process used per drug for evaluating the safety and optimal dosage in liver cirrhosis. Step 1: collection of evidence Summary of Product Characteristics SmPC Information concerning the pharmacokinetics of the drug in healthy volunteers and patients with liver cirrhosis will be collected from the official Product Characteristics as published by the responsible authorities European Medicines Agency EMA , Food and Drug Administration and the Medicines Evaluation Board in the Netherlands. Literature search in electronic databases The search in electronic literature databases aims to review published literature about the alterations in pharmacokinetic parameters and the safety of the drug in patients with liver cirrhosis. View this table: View inline View popup. Citation tracking Additional articles will be obtained through citation snowballing to locate primary sources. Step 2: data extraction and presentation The following characteristics of included studies will be extracted: study design, number and characteristics of included patients and controls eg, severity of liver cirrhosis and details on the intervention. Concerning the outcome s , the following data will be extracted: altered Pharmacokinetics: data on pharmacokinetic parameters eg, area under the curve AUC , elimination half-life and steady state concentration of the drug in patients with liver cirrhosis, preferably compared with patients without liver cirrhosis. All data will be summarised in an assessment report. This standardised report will contain: Data from the SmPC Details on the electronic database search search strategy, study selection process in a flow chart Summary tables with pharmacokinetic and safety data References. Step 3: classification and suggested dose All information from the report will be used to suggest a safety classification and a dose per individual drug, if applicable sorted by severity of liver cirrhosis. Table 2 Safety classification of drugs used in liver cirrhosis. Suggested dose Pharmacokinetic data will be used to judge whether a dose adjustment is necessary in patients with cirrhosis. Step 4: discussion and conclusion by the expert panel An expert panel will evaluate the validity and clinical relevance of the initial classification, the suggested dose and the data extraction. Step 5: implementation Advices about the safety of a drug and the optimal dosage in patients with liver cirrhosis will be implemented in the two national drug databases in the Netherlands Pharmabase and G-Standard. Step 6: continuity To assure up-to-date advices, literature searches will be saved and checked yearly for relevant literature. Table 3 Drugs to be evaluated in the current study. Discussion We have developed a systematic method to evaluate the safety and optimal dosage of drugs in patients with liver cirrhosis. Liver cirrhosis. Lancet ; : — The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol ; 58 : — Liver cirrhosis mortality in countries between and a systematic analysis. BMC Med ; 12 : Transection of the oesophagus for bleeding oesophageal varices. Food and Drug Administration. Guidance for industry. Pharmacokinetics in patients with impaired hepatic function: study design, data analysis, and impact on dosing and labeling. Updated European Medicines Agency. Guideline on the evaluation of the pharmacokinetics of medicinal products in patients with impaired hepatic function. Verbeeck RK. Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction. Eur J Clin Pharmacol ; 64 : — Dose adjustment in patients with liver disease. Drug Saf ; 28 : — Some considerations on the predictions of pharmacokinetic alterations in subjects with liver disease. Expert Opin Drug Metab Toxicol ; 10 : — Dose adjustment in patients with liver cirrhosis: impact on adverse drug reactions and hospitalizations. Eur J Clin Pharmacol ; 69 : — Drug administration in chronic liver disease. Drug Saf ; 17 : 47 — Review article: prescribing medications in patients with cirrhosis—a practical guide. Aliment Pharmacol Ther ; 37 : — A prediction model of drug exposure in cirrhotic patients according to Child—Pugh classification. Clin Pharmacokin ; 54 : — Pharmacokinetic changes of psychotropic drugs in patients with liver disease: implications for dose adaptation. Drug Saf ; 32 : — OpenUrl PubMed. Drug Saf ; 31 : — Checklist for standardized reporting of drug-drug interaction management guidelines. Eur J Clin Pharmacol ; 70 : — The Oxford Levels of Evidence 2. Oxford Centre for Evidence-Based Medicine. Raynor DK. User testing in developing patient medication information in Europe. Res Social and Adm Pharm ; 9 : — 5. Hepatic encephalopathy in chronic liver disease: practice guideline by the European association for the study of the liver and the American association for the study of liver diseases. J Hepatol ; 61 : — European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol ; 53 : — EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol ; 57 : — European Association for Study of Liver. EASL clinical practice guidelines: management of hepatitis C virus infection. J Hepatol ; 60 : — Heidelbaugh JJ , Sherbondy M. Cirrhosis and chronic liver failure: part II. Am Fam Physician ; 74 : — Use of proton pump inhibitors in the management of gastroesophageal varices: a systematic review. Ann Pharmacother ; 49 : — BMJ ; : i Woosley R , Romero K. QTdrugs list. Guide to drug porphyrogenicity prediction and drug prescription in the acute porphyrias. Br J Clin Pharmacol ; 64 : — Risk classification systems for drug use during pregnancy: are they a reliable source of information? Drug Saf ; 23 : — Pharmaceutical care in community pharmacy: practice and research in the Netherlands. Ann Pharmacother ; 39 : — 5. BMJ ; : b Read the full text or download the PDF:. Log in.

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