Antipsychotic polypharmacy

The administration of more than one drug for a single medical condition is considered to be polypharmacy. There are many possible reasons for polypharmacy: (1) psychosis is a chronic disease that cannot be cured; (2) expectations to improve patients' quality of life beyond what drugs can actually do is high; (3) the lack of side effects and interactions can cause physicians to be more daring in terms of potential complications; (4) information from the Internet may cause patients and their families to demand medications; (5) the diluted mental health system allows legal guardians and other mental health professionals to force physicians to provide multiple drugs; (6) many new drugs are available; and (7) physicians are forced to shorten hospitalization days. The 1997 American Psychiatric Association Practice Research Network found that 17% of 146 patients with schizophrenia were treated concurrently with more than one antipsychotic medication. Polypharmacy may increase the risk of adverse effects, drug interactions, noncompliance, and medication errors. It is not wise to use polypharmacy only to prevent side effects and drug and interactions. Our attempts to reduce polypharmacy may fail, as academicians also propagate polypharmacy, and all of the algorithms indicate polypharmacy as an option, putting physicians in a legal and ethical bind. Techniques such as experimental ward, peer review, computer information feedback, and comparing different techniques may temporarily reduce polypharmacy but long-term outcome is not affected. Scientific data on the efficacy of polypharmacy is needed in order to sort out good and bad polypharmacy.     

High content screening analysis of phospholipidosis: Validation of a 96-well assay with CHO-K1 and HepG2 cells for the prediction of in vivo based phospholipidosis

Drug-induced phospholipidosis is marked by an excessive accumulation of phospholipids in lysosomes which can occur after exposure to cationic amphiphilic drugs. Phospholipidosis is considered as an adverse side effect and may delay or negatively affect registration of drug candidates. Currently, the gold standard method of phospholipidosis detection is electron microscopy on tissue samples. This technique is time consuming and only performed relatively late in drug development. Therefore, in vitro screening methods for phospholipidosis are essential in early drug development.In this study, an in vitro phospholipidosis detection assay is developed with CHO-K1 and HepG2 cells by using the fluorescent marker NBD-PE and high content screening analysis. Lysosomal localization of NBD-PE was demonstrated by colocalization with Lysotracker and lamellar body formation by electron microscopy. Upon drug exposure, lysosomal NBD-PE accumulation can be visualized and quantified. Validation with 56 reference compounds, divided in 25 phospholipidosis inducers and 31 negative compounds, showed that this new in vitro assay has a high sensitivity (CHO-K1 = 92.0% and HepG2 = 88.0%) and specificity (CHO-K1 = 87.1% and HepG2 = 80.6%) for predicting phospholipidosis in vivo. Thus a selective screening tool has been developed for early selection of drug candidates with low probability for phospholipidosis.     

Screening for phospholipidosis induced by central nervous drugs: Comparing the predictivity of an in vitro assay to high throughput in silico assays

Drug-induced phospholipidosis is a side effect for which drug candidates can be screened in the drug discovery phase. The numerous in silico models that have been developed as a first line of screening are based on the characteristic physicochemical properties of phospholipidosis-inducing drugs, e.g. high log P and pK_b values. However, applying these models on a predominantly high lipophilic, basic CNS chemistry results in a high false positive rate and consequently in a wrong classification of a large number of valuable drug candidates. Here, we tested 33 CNS-compounds (24 in vivo negative and 9 in vivo positive phospholipidosis-inducers) in our in house developed in vitro phospholipidosis screening assay (Mesens et al., 2009) and compared its predictivity with the outcome of three different, well established in silico prediction models. Our in vitro assay demonstrates an increased specificity of 79% over the in silico models (29%). Moreover, by considering the proposed plasma concentration at the efficacious dose we can show a clear correlation between the in vitro and in vivo occurrence of phospholipidosis, improving the specificity of prediction to 96%. Through its high predictive value, the in vitro low throughput assay is thus preferred above high throughput in silico assays, characterized by a high false positive rate.     

Clinical-pharmacological strategies to assess drug interaction potential during drug development.

Drug interactions in patients receiving multiple drug regimens are a constant concern for the clinician. With the increased availability of new drugs and their concomitant use with other drugs, there has been a rise in the potential for adverse drug interactions as demonstrated by the recent withdrawals of newly marketed drugs because of unacceptable interaction profiles. Therefore, the interaction potential of a new compound has to be assessed in detail, starting with preclinical in vitro and in vivo studies at candidate selection and continuously followed up through preclinical and clinical development. Since formal in vivo studies of all possible drug interactions are neither practicable nor suggestive, a careful selection of a limited number of drug combinations to be investigated in vivo during the development phase is indicated. Based on knowledge of pharmacokinetic and biopharmaceutical properties, a well balanced link between in vitro investigations and carefully selected in vivo interaction studies allows full assessment of the potential of a new drug to cause clinically relevant pharmacokinetic drug-drug interactions, prediction of a lack of interactions and derivation of the proper dose recommendations. Clinical pharmacology plays a number of key roles within the process of collecting information on drug interactions during preclinical and clinical development: addressing issues and/or favourable properties to be expected, thus contributing to the scientific assessment of development potential; setting up a rational in vivo drug-drug interaction programme; performing early mechanistic studies to link in vitro with in vivo information (employing 'cocktail' approaches if possible); reviewing co-medication sections for clinical trials; and conducting labelling-oriented interaction studies, after proof of concept. The fact that interactions can occur between various active substances should by itself be a conclusive argument against unnecessary polypharmacy. Prescribing fewer drugs on a rational basis can reduce the risk of adverse effects secondary to drug interactions and may help to improve the quality of drug treatment and to save costs.     

Neither dosage nor serum levels of antiepileptic drugs are predictive for efficacy and adverse effects

In order to assess whether doses or serum levels are predictive for the efficacy and adverse effects of antiepileptic drugs (AEDs), measures for exposure to drug combinations have to be used. For doses, the ratio of the observed prescribed daily dose (PDD) and the average defined daily dose (DDD) considered effective for the main indication of the drug was used. In analogy for serum levels, the OSL/ATL ratio,i.e. the ratio of the observed serum level and the average therapeutic level was used. In polypharmacy these ratios can be summed as they are normalized measures of strength. The correlations of these ratios with outcome measures were studied in 200 patients attending out-patient clinics of special centres for epilepsy; half of these patients were treated with monopharmacy and half with polypharmacy. As outcome measures the following indices were used: the index of seizures, which quantifies seizure type and frequency, the seizure activity index, the neurotoxicity score, the systemic toxicity score, and the composite index of impairments, which is the sum of the seizure activity index and the neurotoxicity score and the systemic toxicity score. When all data were pooled, the correlation coefficient between the PDD/DDD ratio and the OSL/ATL ratio was 0.77. However, when the data were examined separately for the monopharmacy and polypharmacy groups, the correlation was 0.31 for the monopharmacy group and 0.50 for the polypharmacy group. Neither the PDD/DDD ratio nor the OSL/ATL ratio correlated with the composite index of impairments or with any of the individual indices. Factors such as the difficulty of titrating the endpoint of seizure suppression and the development of tolerance to adverse drug effects may perhaps be responsible for these findings. This observational study signals the problem.     

Reasons for polypharmacy among psychiatric patients

INTRODUCTION: Increasing attention has recently been focused on polypharmacy, which is often referred to as an indicator of irrational drug consumption. Although polypharmacy is an important risk factor for problems arising from drug therapies, certain health concerns and conditions or patient-specific factors may justify the need for polypharmacy. In recent years there no data have been published regarding polypharmacy in Hungary. OBJECTIVE: The authors examined the frequency of polypharmacy among psychiatric patients. The study also looked at the extent to which comorbidity and demographic characteristics (age, gender) were responsible for the multiple drug use. METHODS: An inpatient database of the year 2001 at the psychiatric department was analysed. Based on the standard definition of polypharmacy the authors enrolled into the polypharmacy group those patients who were on more than five drugs as part of chronic and simultaneous therapy. The data were analysed with the SPSS 9.0 statistics program package. RESULTS: Among the psychiatric patients included in the study (N = 984) the frequency of polypharmacy was 33.6%. Significant correlation was found between the investigated factors (age, gender, comorbidity) and polypharmacy. On the basis of OR-values, comorbidity was the strongest inducer of polypharmacy. CONCLUSION: Polypharmacy cannot be fundamentally regarded as unnecessary drug use. Numerous facts prove that in certain diseases and conditions adequate polypharmacy is necessary.     

Drug-drug interactions affected by the transporter protein, P-glycoprotein (ABCB1, MDR1) II. Clinical aspects

The simultaneous use of several drugs (polypharmacy) for the treatment of cancer, HIV, and other diseases and for multiple ailments of the elderly is a common practice in modern medicine. Co-administration of drugs may result in unwanted side effects. One reason for these side effects can be the altered function of transport proteins, especially of P-glycoprotein (Pgp), due to its simultaneous interaction with several drugs. We describe here some of the observed, unexpected side effects of polypharmacy in the clinic. We also describe intentional modulation of the function of Pgp that is introduced when facilitation of absorption of a drug through the intestines is needed and in cancer chemotherapy. In addition, we mention some methods of testing and ways by which doctors and patients can be alerted to potential side effects.     

Polypharmacy among COVID-19 patients: A systematic review

BackgroundPolypharmacy, the concomitant use of 5 or more medications, is highly prevalent among older adults and individuals with multimorbid conditions and has been linked to suboptimal clinical outcomes in various diseases. However, little is known about the impact of polypharmacy on clinical outcomes among coronavirus disease 2019 (COVID-19) patients.ObjectiveThis systematic review summarizes the available literature on the association between polypharmacy and specific drug classes, and clinical outcomes among COVID-19 patients.MethodsWe conducted an electronic database search on Embase, Medline, Cochrane, Scopus, Google Scholar, clinicaltrials.gov, LITCOVID, PubMed, PubMed Central (PMC), and China national knowledge infrastructure for studies on Polypharmacy among COVID-19 patients using relevant combinations of the keywords. Only studies published between November 2019 to September 2020 were included. Seven articles out of 1502 unique articles met the inclusion criteria and were used for the current study. We adopted the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline in conducting and reporting this systematic review.ResultsThe total sample size of all studies was 474,342, out of which 10,519 patients were COVID-19 positive, and 4818 COVID-19 positive patients experienced polypharmacy. Five out of the 7 included studies found associations between polypharmacy and negative clinical outcomes among COVID-19 patients. Polypharmacy was associated with increase in the relative risk of a positive COVID-19 test result (P < 0.01), death among male COVID-19 patients (P < 0.001), increase in the rate of acute kidney injury (P = 0.003), and adverse drug reactions (P < 0.001). Antipsychotic drugs were associated with severe COVID-19 morbidity (OR = 2.79; 95% CI 2.23–3.49) and increased risk of death among COVID-19 infected men (OR = 1.71; 95% CI 1.18–2.48) and women (OR = 1.96; 95% CI 1.41–2.73).ConclusionPolypharmacy and selected drug classes are associated with increased risk of adverse clinical outcomes among COVID-19 patients. Understanding these relationships can enhance risk stratification and evidence-based decision-making that may improve care and clinical outcomes of COVID-19 patients.     

Drug-induced phospholipidosis

Summary In three species chronic treatment with the anorectic drug chlorphentermine causes a profound alteration of the phospholipid/lipid metabolism in the organism, resulting in an increase of the fractions of phospholipids and lipids, e.g. in lungs, livers and adrenals. The results are interpreted as drug-induced generalized phospholipidosis, which is caused by amphiphilic drugs, like chlorphentermine and others. Its extent depends on several factors, like content, pattern and turnover rate of phospholipids in different organs, and on the species.     

Development of a combination drug-eluting bead: towards enhanced efficacy for locoregional tumour therapies

Drug-eluting beads (DEBs) are becoming a mainstay locoregional therapy for hepatic malignancies but are currently loaded with single drugs alone. Here, we wished to prepare DEB containing different drug combinations, to screen their efficacy using an in-vitro cell culture assay and to include any promising combinations that demonstrate additive efficacy in an in-vivo model of locoregional tumour treatment. A modified in-vitro assay was used based upon the use of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) with either HepG2 liver cancer or PSN1 pancreatic cancer cell lines. The comparative cytotoxicity of DEB combinations prepared containing doxorubicin, irinotecan, topotecan and rapamycin was evaluated. Those combinations that demonstrated an additive cytotoxicity effect were investigated in vivo using a nude mouse xenograft model of pancreatic cancer. Although many of the DEB combinations showed either no effect or a slight antagonistic effect, the combination of doxorubicin and rapamycin DEBs demonstrated synergistic activity. On the basis of these findings, a method was developed to prepare a doxorubicin/rapamycin dual-loaded DEB, which was shown to possess the same drug-loading capacities, drug elution properties and HepG2 cell cytotoxicity synergy as the single drug-loaded DEB combination. Evaluation of this dual-loaded combination DEB versus the respective single drug-loaded DEBs in a mouse xenograft model of pancreatic cancer showed an equivalent tumour volume reduction as the doxorubicin DEB, but with less toxicity than the rapamycin DEB. The doxorubicin/rapamycin combination DEB offers great potential for enhanced efficacy in the locoregional treatment of malignant tumours.     

Cellular responses associated with dibucaine-induced phospholipidosis

A wide range of cationic amphiphilic drugs (CADs) from different therapeutic areas are known to cause phospholipidosis both in vivo and in vitro. Although the relevance of this storage disorder for human health remains uncertain, CADs have been repeatedly associated with clinical side effects, and as a result, phospholipidosis is of major concern for drug development in the pharmaceutical industry. An important unresolved question in this field is whether phospholipidosis is really linked to cellular toxicity. This work was focused on studying cellular responses associated with CAD-induced phospholipidosis in cultured mammalian kidney cells. Dibucaine (2-butoxy-N-[2-diethylaminoethyl]quinoline-4-carboxamide), an amide-type anesthetic with poorly defined cytotoxic effects, was used to induce phospholipidosis in Vero cells. The results from several assays that measure cell viability, proliferation, and morphological changes indicated that dibucaine-induced lysosomal phospholipidosis was accompanied by cellular defense responses such as transient growth arrest and autophagy, under mild stress conditions. Conversely, when tolerance limits were exceeded treated Vero cells underwent extensive and irreparable injury, leading ultimately to cell death. Our data provide additional information that may be of considerable interest for drug safety assessment.     

In vitro assays and biomarkers for drug-induced phospholipidosis

Drug-induced phospholipidosis is the cytoplasmic accumulation of phospholipids as a result of xenobiotic exposure. This accumulation results in a unique histological effect in cells noted as electron-dense lamellar inclusions or whorls in the cytoplasm when observed with transmission electron microscopy. Electron microscopy has been the widely accepted standard for classification of the phospholipidosis effect. Molecules that have been prone to induce such an effect are made up of a lipophilic region and a positively charged region. Phospholipidosis has most commonly been associated with drugs that are cationic, amphiphilic drugs and can occur in a variety of tissues. Although phospholipidosis is not considered adverse in isolation, depending on the tissue affected or the occasional circumstance of concurrent toxicity, phospholipidosis can be perplexing if identified in early drug development. In most circumstances, characterisation of the effect with in vivo studies allows for determination of exposure and the magnitude of the effect. On occasion in drug development, there may be an interest to screen early stage compounds to minimise phospholipidosis. In such circumstances, in silico and in vitro assays can be employed in a strategy with in vivo assessments. In addition, there may be an interest to monitor for the potential development of phospholipidosis in longer-term animal studies. In such cases, biomarker approaches could be used. The challenge in the overall assessment of phospholipidosis remains the question of the possible relevance to any toxicity, and, therefore, any screening approach, while assessing the potential to induce phospholipidosis, must be considered in relation to prediction of findings in vivo. The status of current assays and biomarkers is presented with strategies for screening.     

Design and Sample Size for Evaluating Combinations of Drugs of Linear and Loglinear Dose-Response Curves

The study of drug combinations has become important in drug development due to its potential for efficacy at lower, less toxic doses and the need to move new therapies rapidly into clinical trials. The goal is to identify which combinations are additive, synergistic, or antagonistic. Although there exists statistical framework for finding doses and sample sizes needed to detect departure from additivity, e.g., the power maximized F-test, different classes of drugs of different does-response shapes require different derivation for calculating sample size and finding doses. Motivated by two anticancer combination studies that we are involved with, this article proposes dose-finding and sample size method for detecting departures from additivity of two drugs with linear and log-linear single dose-response curves. The first study involves combination of two drugs, where one single drug dose-response curve is linear and the other is log-linear. The second study involves combinations of drugs whose single drug dose-response curves are linear. The experiment had been planned with the common fixed ratio design before we were consulted, but the resulting data missed the synergistic combinations. However, the experiment based on the proposed design was able to identify the synergistic combinations as anticipated. Thus we shall summarize the analysis of the data collected according to the proposed design and discuss why the commonly used fixed ratio method failed and the implications of the proposed method for other combination studies.     

Studies on the mechanism of phospholipid storage induced by amantadine and chloroquine in Madin Darby canine kidney cells

Previous studies suggested that hepatic lipidosis caused by cationic amphiphilic drugs in rats is related to the capacity of these drugs to concentrate in liver lysosomes. These drugs inhibit lysosomal phospholipases, causing phospholipid accumulation. Amantadine, an inhibitor of influenza A virus replication, is a cationic amphiphilic drug which concentrates in the lysosomes of the Madin Darby canine kidney (MDCK) cell. In the present study, amantadine and chloroquine were shown to inhibit soluble lysosomal phospholipases isolated from MDCK cell in. vitro. Both amantadine and chloroquine concentrated in MDCK cell lysosomes. These drugs caused phospholipid storage in cultured MDCK cells, and the amounts of the respective agents required to cause phospholipid storage correlated with the capacities of the agents to inhibit lysosomal phospholipases. The mechanisms involved in this phenomenon are discussed, and a three-step hypothesis is presented predicting which agents will cause phospholipidosis.     

Anticholinergic Accumulation: A Slumbering Interaction between Drugs and Food Supplements

Many compounds display anticholinergic effects which might give rise to cognitive impairment and even delirium. These side effects are caused by their ability to bind to muscarinic receptors in our brain. Especially with combination of compounds, these serious effects are seen. This phenomenon, known as anticholinergic accumulation, is especially seen in the elderly. A classification of drugs for anticholinergic side effects has been made based on clinical observations, the ACB score. Here, we aimed to substantiate this classification by comparing the affinity of numerous drugs for the muscarinic receptors to the ACB score. Additionally, a number of supplements were screened. The affinity of the compounds was determined by their ability to displace the radioligand [³H]pirenzepine of the muscarinic receptor induced by these compounds. Our results show that the affinity of a compound for the muscarinic receptors correlated with its ACB score. Also food supplements appeared to bind to these muscarinic receptors. Moreover, several drug–drug, supplement–supplement and supplement–drug combinations had an affinity that is higher than the affinity of single compounds. This explains the phenomenon of anticholinergic accumulation. In conclusion, care should be taken to drug–drug and supplement–drug combinations with respect to anticholinergic accumulation.     

A 96-well flow cytometric screening assay for detecting in vitro phospholipidosis-induction in the drug discovery phase

Drug-induced phospholipidosis is caused by lysosomal accumulation of the drug, resulting in the disturbance of phospholipid degradation and a consequent excessive phospholipid accumulation. Depending on the type and number of tissues affected, phospholipidosis occurrence in test animals can raise safety issues, which may be critical for the risk assessment. Safety profiling of potential phospholipidosis-inducing drugs in the drug discovery phase can predict these late obstructions of drug development. For this purpose, a flow cytometric assay based on the difference in fluorescent phospholipid accumulation in a human monocyte cell line was initially established. Modifying the assay studying degradation of the fluorescent phospholipids instead of accumulation drastically improved sensitivity. By testing various phospholipidosis-inducers and negative compounds, it was found that the assay could detect the occurrence of phospholipidosis by a 2-fold difference in fluorescence compared to control cells, demonstrating the superior sensitivity of the novel approach. Implementation of a higher throughput 96-well flow cytometric set up did not affect the sensitivity of detection or the reproducibility of the assay. Based on an extended test set of reference compounds a profiling approach was introduced, by which we show we can rank our drug candidates according to their phospholipidosis-inducing potential.     

Combination bronchodilator therapy

Bronchodilators may be classified into 3 groups: anticholinergics, beta-adrenoceptor agonists and methylxanthines. These drugs act through related biochemical pathways and there are theoretical reasons for expecting beneficial additive or synergistic interactions between them. While there is in vitro evidence of synergistic interactions producing bronchodilatation, in vivo studies indicate that the interactions are additive rather than synergistic but still of therapeutic value. There have been no clinical studies on methylxanthines combined with anticholinergic drugs, but there is an extensive and growing literature on the other combinations. The majority show clear evidence of an additive bronchodilator effect when anticholinergics are combined with beta 2-adrenoceptor agonists, although atropine sulphate is less effective in this regard than atropine methylnitrate or ipratropium bromide. This type of combination has only been tested by inhalation and, because of the slower onset of action of the anticholinergic group, it is preferable that the beta 2-adrenoceptor agonist be inhaled first. There is no evidence for an additive interaction of the side effects of these drugs. In general, bronchitics respond better than asthmatics to anticholinergic drugs. Studies on methylxanthines (usually theophylline) and adrenoceptor agonists may be divided into 2 groups: those using ephedrine and those using more selective beta-adrenoceptor agonists. Ephedrine is a relatively ineffective bronchodilator and often fails to add any useful bronchodilatation to theophylline. Also, there does seem to be a synergistic increase in side effects of the two drugs and this combination is therefore undesirable. Ephedrine has now been superseded by the more selective beta 2-adrenoceptor agonist drugs all of which, whether given orally, intravenously or by inhalation, appear to have an additive effect with the methylxanthines. It is often possible to achieve the same therapeutic effect with half doses of drugs from 2 different groups as with a full dose of 1 drug. This may sometimes, but not always, reduce side effects. There is evidence that giving 2 drugs by different routes is a useful therapeutic procedure; for example, the addition of an inhaled beta 2-adrenoceptor agonist may improve upon the maximal bronchodilatation achieved with intravenous theophylline. When theophylline is administered plasma levels of the drug should be monitored and it is possible that, when used in combination with a beta 2-adrenoceptor agonist, a therapeutic range lower than that normally recommended may apply. There is no longer any place for fixed combination bronchodilators and, in spite of recent suggestions, there is no evidence that bronchodilator combinations are responsible for an increase in asthma mortality. Further studies to clarify some aspects of bronchodilator combinations are needed. The therapeutic use of various combinations is briefly discussed.