Drug Categories Research Articles

Chromatographic-mass spectrometric analysis of peptidic analytes (2-10kDa) in doping control urine samples.

Peptides with a molecular mass between 2 and 10kDa that are prohibited in elite sports usually require dedicated sample preparation and mass spectrometric detection that commonly cannot be combined with other (lower molecular mass) substances. In most instances, the physicochemical differences are too significant to allow for a generic analytical procedure. A simplification of established and comparably complex analytical approaches is therefore desirable and has been accomplished in the context of this study. With urine samples representing still the most frequently collected doping control specimens, efficient extraction of peptidic analytes from this matrix was a major goal of this method, as demonstrated for the included compounds such as insulins (human, lispro, aspart, glulisine, tresiba, glargine metabolite, bovine insulin, porcine insulin), growth hormone-releasing hormones (sermorelin, CJC-1295, tesamorelin) incl. their respective metabolites, insulin-like-growth factors (long-R3 -IGF-I, R3 -IGF-I, des1-3 -IGF-I), synacthen, gonadorelin and mechano growth factors (human MGF, MGF-Goldspink). Sample preparation and detection are controlled by five internal standards, covering all five included peptide drug categories. Nearly all requirements of the recent technical documents from the World Anti-Doping Agency (WADA) considering their minimum required performance levels (MRPL) are fulfilled, and the method was validated for its utilisation as initial testing procedure in doping controls. Finally, the approach was applied to authentic post-administration study urine samples (for insulins and gonadorelin) in order to provide proof of principle.

Polypharmacy of Older Surgical Patients With Extremity Fractures.

Fractures are often caused by falls in older people. Among various causes of falls, polypharmacy is known to be a risk of falls. Furthermore, potentially inappropriate medicines (PIMs), which interact with polypharmacy, include the drugs involved in falls. Here, we primarily aimed to investigate the prescribed drugs in older surgical patients with extremity fractures to determine the frequency of polypharmacy and identify PIMs. The second aim was to clarify the characterization of prescribed drugs of older patients with hip fracture. We retrospectively collected the following clinical data of consecutive patients aged ≥65years who underwent surgery for extremity fractures at our hospital between April 2019 and March 2021. A total of 19 categories were considered as PIMs. The Poisson regression models were used to examine the association between the number of prescribed drugs and hip fracture prevalence. A total of 590 patients were reviewed. Our data showed that 55% of older patients with extremity fractures took ≥6 prescription drugs. The frequency of prescription of hypnotics, antithrombotic drugs, diuretics, and non-steroidal anti-inflammatory drugs was comparatively high among the 19 categories of PIMs. Multivariable analysis revealed that polypharmacy was significantly associated with hip fractures. Among PIMs, antithrombotic drugs and diuretics were significantly associated with the prevalence of hip fractures. Finally, we found a significant positive association between the prevalence of hip fracture and the number of drug categories of PIMs among older patients with extremity fractures. The present study clarified the characterization of the prescribed drugs in older surgical patients with extremity fractures. Special attention should be paid to hip fractures of older patients with polypharmacy or prescribed with many drugs categories of PIMs, particularly antithrombotic drugs and diuretics.

Advancements in antiglaucoma medications: A comprehensive review

Abstract Glaucoma is a common ocular condition that has permanent effects and is a serious threat to everyone’s vision health. The course of the disease is still significantly influenced by increased intraocular pressure (IOP), also known as eye pressure. This emphasizes the significance of effective use of medications to treat this illness. Significant progress has been made in the development of glaucoma medications over time. There are several different ways to lower IOP using these drugs. This in-depth analysis examines the evolving field of pharmacological glaucoma treatments, covering a range of drug classes including beta-blockers, prostaglandin analogs, alpha agonists, carbonic anhydrase inhibitors, and rho kinase inhibitors. The mode of action, clinical effectiveness, and safety issues of each drug category are studied.

The causal relationship between antihypertensive drugs and depression: a Mendelian randomization study of drug targets.

Depression ranks as a leading contributor to the global disease burden. The potential causal relationship between the use of antihypertensive medications and depression has garnered significant interest. Despite extensive investigation, the nature of this relationship remains a subject of ongoing debate. Therefore, this study aims to evaluate the influence of antihypertensive medications on depression by conducting a Mendelian randomization study focused on drug targets. We focused on the targets of five antihypertensive drug categories: ACE Inhibitors (ACEIs), Angiotensin II Receptor Antagonists (ARBs), Calcium Channel Blockers (CCBs), Beta-Blockers (BBs), and Thiazide Diuretics (TDs). We collected single-nucleotide polymorphisms (SNPs) associated with these drug targets from genome-wide association study (GWAS) statistics, using them as proxies for the drugs. Subsequently, we conducted a Mendelian randomization (MR) analysis targeting these drugs to explore their potential impact on depression. Our findings revealed that genetic proxies for Beta-Blockers (BBs) were associated with an elevated risk of depression (OR [95%CI] = 1.027 [1.013, 1.040], p < 0.001). Similarly, genetic proxies for Calcium Channel Blockers (CCBs) were linked to an increased risk of depression (OR [95%CI] = 1.030 [1.009, 1.051], p = 0.006). No significant associations were identified between the genetic markers of other antihypertensive medications and depression risk. The study suggests that genetic proxies associated with Beta-Blockers (BBs) and Calcium Channel Blockers (CCBs) could potentially elevate the risk of depression among patients. These findings underscore the importance of considering genetic predispositions when prescribing these medications, offering a strategic approach to preventing depression in susceptible individuals.

고가 의약품 건강보험 급여 현황 분석

In recent years, the introduction of high-priced innovative pharmaceuticals has been on the rise, placing a burden on the national pharmaceutical expenditure. This study aimed to analyze the spending trends of high-priced drugs in South Korea over the past ten years and derive policy implications for the management of pharmaceutical expenditure. The claims data of National Health Insurance (NHI) were used as the data source, and drugs with annual per-patient costs exceeding ten million KRW were defined as 'high-priced drugs.' The study selected the each year’s list of high-priced drugs from 2010 to 2021 and analyzed the trends considering their spending size, manufacturer types, therapeutic groups, Risk-Sharing Agreements, and Economic Evaluation Exemption. The spending on high-priced drugs accounted for 8.0% of the NHI pharmaceutical expenditure in 2021, and it has been increasing annually by 14.3% since 2010. The expenditure on high-priced drugs introduced through the RSA (Risk-Sharing Agreement) rapidly increased, especially for oncology drugs and immunosuppressants. This study defined high-priced drugs based on per-patient costs and observed the trends in the expenditure of these drugs according to pharmaceutical characteristics. Based on this, it is significant in proposing issues and policy implications for noteworthy drug categories.

Identification of approved drugs with ALDH1A1 inhibitory potential aimed at enhancing chemotherapy sensitivity in cancer cells: an in-silico drug repurposing approach

The aldehyde dehydrogenase 1A1 (ALDH1A1) also known as retinal dehydrogenase, is an enzyme normally involved in the cellular metabolism, development and detoxification processes in healthy cells. However, it’s also considered a cancer stem cell marker and its high levels of expression in several cancers, including breast, lung, ovarian, and colon cancer have been associated with poor prognosis and resistance to chemotherapy. Given its crucial role in chemotherapy resistance by detoxification of chemotherapeutic drugs, ALDH1A1 has attracted significant research interest as a potential therapeutic target for cancer. Though a few synthetic inhibitors of ALDH1A1 have been synthesized and their efficacy has been proved in-vitro and in-vivo studies, none of them have passed clinical trials so far. In this scenario, we have performed an in-silico study to verify whether any of the already approved drugs used for various purposes has the ability to inhibit catalytic activity of ALDH1A1, so that they can be repurposed for cancer therapy. Keeping in mind the feasibility of repurposing in a larger population we have selected the approved drugs from five widely used drug categories such as antibiotic, antiviral, antifungal, anti diabetic and antihypertensive for screening. Computational techniques like molecular docking, molecular dynamics simulations and MM-PBSA binding energy calculation have been used in this study to screen the approved drugs. Based on the logical analysis of results, we propose that three drugs – telmisartan, irbesartan and maraviroc can inhibit the catalytic activity of ALDH1A1 and thus can be repurposed to increase chemotherapy sensitivity in cancer cells. Communicated by Ramaswamy H. Sarma

Trends in co-prescribed opioids and benzodiazepines, non-prescribed opioids and benzodiazepines, and schedule-I drugs in the United States, 2013 to 2019

Concurrent opioid and benzodiazepine users are at increased risk of overdose death, compared to opioid-only users.The objective of this study was to understand recent time trends in opioid and benzodiazepine concurrent use, misuse, and schedule-I drug use, and how these differ by age, sex and geographic region. Commercial, United States medical insurance claims data and urine drug test results from 2013 to 2019 were used to study the outcomes of concurrent use (n = 756,258), schedule-I drug use (n = 746,672) and prescription misuse (n = 452,523). Drug use outcomes were studied at quarterly time points for each year.Data analysis included joinpoint regression models to estimate quarterly drug use rates, determined by positive urine tests for corresponding drug categories, and was conducted from November 2021 through January 2022. Concurrent use decreased from 19.3% to 9.8%, misuse generally decreased from 75.6% to 55.1%, and schedule-I use increased from 8.9% to 13.8%, from 2013 to 2019. Concurrent use decreased at greater rates after 2016, after the Centers for Disease Control and Food and Drug Administration guidelines against concurrent use were released, while schedule-I use increased, notably after the 2014 hydrocodone reschedule. This indicates a potential shift from prescription use to non-prescribed drug use, where most affected groups included males, younger individuals, and those residing in Northeastern regions.Study results support public health initiatives focused on policy that increases access to multimodal pain management and substance use disorder management programs—critical steps in preventing patients from seeking non-prescribed drugs for self- medicating due to pain or addiction.

A comparative analysis of antihypertensive drugs for hypertension and gestational hypertension among women in tertiary care hospitals in Lahore, Pakistan

Hypertension, characterized by persistently elevated blood pressure, poses severe risks, such as heart damage, artery hardening, and reduced blood and oxygen flow to the heart, which can also lead to kidney damage and stroke. Antihypertensive therapy for pregnant women differs from that for nonpregnant women because most antihypertensive medications used for nonpregnant hypertensive women are contraindicated for pregnant hypertensive patients. This study aimed to compare therapeutic regimens for treating hypertension between pregnant and nonpregnant women in various healthcare facilities. This cross-sectional study was conducted at several tertiary care hospitals in Lahore, Pakistan, recruiting 500 pregnant or nonpregnant female patients aged 18-55 years with hypertension. The data were collected through structured interviews and medical records reviews. Descriptive statistics and chi-square tests were used to analyze the data, with significance set at p &lt; 0.05. A significant difference in area of residence was observed, with 83.2% of nonpregnant women residing in urban areas compared to 52.4% of pregnant women residing in urban areas. A systolic blood pressure between 120 and 139 mmHg was observed in 82.8% of pregnant women, compared to 51.2% of nonpregnant women (p &lt; 0.001). Diastolic blood pressure between 80-99 mmHg was observed in 84.4% of pregnant women and 76.8% of nonpregnant women (p &lt; 0.001). CVDs were more prevalent among nonpregnant women (38.8%), while anemia was more common in pregnant women (25.6%). Pregnant women were primarily prescribed methyldopa (58%), labetalol (56%), and amlodipine (40.4%), whereas nonpregnant women were more frequently prescribed valsartan (39.2%), metoprolol (28.8%), nebivolol (28%), and a combination of furosemide and spironolactone (24%). This study highlighted significant differences in comorbid conditions and antihypertensive treatment regimens between pregnant and nonpregnant women, emphasizing the need for tailored hypertension management approaches. Moreover, safer antihypertensive agents were prescribed to both groups, considering the Food and Drug Administration (FDA) drug categories and the observed comorbid conditions.

Solubility Enhancement of Poorly Water-Soluble Drug Ritonavir using Polyvinylpyrrolidone and Chitosan-based Platform Technique

The antiviral medication ritonavir (RTV) belongs to the biopharmaceutics classification system (BCS) class II drug category and is known for its high permeability and poor solubility. Therefore, the prime objective of this research was to increase the rate of dissolution and improve the solubility of RTV using a polymer system. Solid dispersions consisting of binary polymer components i.e., chitosan (CH) and polyvinylpyrrolidone (PVP) were prepared using microwave microwave-assisted physical mixing technique and optimization of solid dispersion was performed with 32 factorial designs. Dispersions were analyzed for their physicochemical characteristics by the use of X-ray diffraction (XRD), differential scanning calorimetry (DSC), and fourier transform infrared spectroscopy (FTIR). The polymeric dispersions prepared were evaluated for the release of RTV throughout 1 h in 0.1N sodium chloride in a USP class II dissolving device. The phase solubility study demonstrated a considerable improvement in the saturation solubility of RTV when CH and PVP K30 were present either individually or in combination. Virtual interaction studies between the drug and polymers revealed physical interactions driven by van der Waals and hydrophobic forces between RTV and excipients. Carbonyl, amine, and hydroxyl groups, among others, were probably present in both RTV and CH, which allowed for these interactions to take place. There was no discernible interaction between the RTV and the polymers included in the FTIR research. The dispersion strategies have improved the dissolving rate, according to the in-vitro drug release investigation. A formulation including a polymeric dispersion of the optimal concentration of PVP and chitosan may efficiently boost the release of RTV, according to the in-vitro release profile.

Unlocking the Medicinal Mysteries: Preventing Lacunar Stroke with Drug Repurposing.

Currently, only the general control of the risk factors is known to prevent lacunar cerebral infarction, but it is unknown which type of medication for controlling the risk factors has a causal relationship with reducing the risk of lacunar infarction. To unlock this medical mystery, drug-target Mendelian randomization analysis was applied to estimate the effect of common antihypertensive agents, hypolipidemic agents, and hypoglycemic agents on lacunar stroke. Lacunar stroke data for the transethnic analysis were derived from meta-analyses comprising 7338 cases and 254,798 controls. We have confirmed that genetic variants mimicking calcium channel blockers were found to most stably prevent lacunar stroke. The genetic variants at or near HMGCR, NPC1L1, and APOC3 were predicted to decrease lacunar stroke incidence in drug-target MR analysis. These variants mimic the effects of statins, ezetimibe, and antisense anti-apoC3 agents, respectively. Genetically proxied GLP1R agonism had a marginal effect on lacunar stroke, while a genetically proxied improvement in overall glycemic control was associated with reduced lacunar stroke risk. Here, we show that certain categories of drugs currently used in clinical practice can more effectively reduce the risk of stroke. Repurposing several drugs with well-established safety and low costs for lacunar stroke prevention should be given high priority when doctors are making decisions in clinical practice. This may contribute to healthier brain aging.

Graph-guided deep hashing networks for similar patient retrieval

With the rapid growth and widespread application of electronic health records (EHRs), similar patient retrieval has become an important task for downstream clinical decision support such as diagnostic reference, treatment planning, etc. However, the high dimensionality, large volume, and heterogeneity of EHRs pose challenges to the efficient and accurate retrieval of patients with similar medical conditions to the current case. Several previous studies have attempted to alleviate these issues by using hash coding techniques, improving retrieval efficiency but merely exploring underlying characteristics among instances to preserve retrieval accuracy. In this paper, drug categories of instances recorded in EHRs are regarded as the ground truth to determine the pairwise similarity, and we consider the abundant semantic information within such multi-labels and propose a novel framework named Graph-guided Deep Hashing Networks (GDHN). To capture correlation dependencies among the multi-labels, we first construct a label graph where each node represents a drug category, then a graph convolution network (GCN) is employed to derive the multi-label embedding of each instance. Thus, we can utilize the learned multi-label embeddings to guide the patient hashing process to obtain more informative and discriminative hash codes. Extensive experiments have been conducted on two datasets, including a real-world dataset concerning IgA nephropathy from Peking University First Hospital, and a publicly available dataset from MIMIC-III, compared with traditional hashing methods and state-of-the-art deep hashing methods using three evaluation metrics. The results demonstrate that GDHN outperforms the competitors at different hash code lengths, validating the superiority of our proposal.

A mitochondria-targeting dihydroartemisinin derivative as a reactive oxygen species -based immunogenic cell death inducer

Immunogenic cell death (ICD) can activate the anticancer immune response and its occurrence requires high reliance on oxidative stress. Inducing mitochondrial reactive oxygen species (ROS) is a desirable capability for ICD inducers. However, in the category of ICD-associated drugs, numerous reported ICD inducers are a series of anthracyclines and weak in ICD induction. Herein, a mitochondria-targeting dihydroartemisinin derivative (T-D) was synthesized by conjugating triphenylphosphonium (TPP) to dihydroartemisinin (DHA). T-D can selectively accumulate in mitochondria to trigger ROS generation, leading to the loss of mitochondrial membrane potential (ΔΨm) and ER stress. Notably, T-D exhibits far more potent ICD-inducing properties than its parent compound. Invivo, T-D-treated breast cancer cell vaccine inhibits metastasis to the lungs and tumor growth. These results indicate that T-D is an excellent ROS-based ICD inducer with the specific function of trigging vigorous ROS in mitochondria and sets an example for incorporating artemisinin-based drugs into the ICD field.

Evaluation of errors in preparation and administration of intravenous medications in critically ill patients.

Intravenous medications have greater complexity and require multiple steps in their preparation and administration, which is considered a high risk for patients. To determine the incidence of intravenous medications preparation and administration errors in critically ill patients. This was an observational, cross-sectional, prospective study design. The study was performed conducted in Wad Medani Emergency Hospital, Sudan on with 33 nurses. All nurses working at the study setting were observed over nine days. During the study period, a total number of 236 drugs were observed and evaluated. The total error rate was 940 (33.4%), of which 136 (57.6%) errors with no harm, 93 (39.4%) errors with harm and 7 (3%) of errors associated with mortality. 17 different drug categories were involved, in which antibiotic was the highest error rate 104 (44.1%) and 39 different drugs were involved, in which metronidazole was the most drug involved 34 (14.4%). The total error rate was associated with nurse experience, OR (95% CI); 3.235 (1.834-5.706), and nurse education level, OR (95% CI); 0.125 (0.052-0.299). The study reported high frequency of IV medications preparation and administration errors. Nurse education level, and experiences were influenced the total errors.

Combination Therapy of Denosumab and Teriparatide in Osteoporosis.

Osteoporosis is a chronic disease that often requires long-term treatment for many years. The clinician should know about all the drugs that are currently being used for treatment in osteoporosis and their mechanism of action, efficacy, safety profile, mode of administration and number of years they can be given safely without causing significant adverse effects. The categories of drugs that are currently being used for osteoporosis are antiresorptives such as oral and intravenous bisphosphonates, denosumab, and anabolics like teriparatide. This article will focus on the combination therapy of denosumab and teriparatide and will discuss how this combination is better than other class of drugs when given alone or in combination in osteoporosis patients especially those who are at high risk of fragility fractures.

Antiretroviral drug use and the risk of falls in people living with HIV: a systematic review and meta-analysis

Objective: The risk of falls in people living with HIV (PLHIVs) on antiretroviral therapy (ART) has received little attention in the literature. The aim of the meta-analysis is to quantify the association between fall risk and various categories of drugs used in ART. Material and Methods: PubMed, Google Scholar, Embase, and the Cochrane Central Register of Controlled Trials were systematically searched from inception to January 2023. Any observational study or controlled trial that reported on the relationship of at least one antiretroviral drug with falls in PLHIVs was included. Data on the frequency of single fallers, multiple fallers (≥2 falls), and non-fallers were extracted and studied for each drug and drug category. The pooled results were reported as an odds ratio (OR) with a 95% confidence interval (CI). Results: A total of five observational studies (51 675 participants) were included out of 414 articles obtained through a literature review. Stavudine use was found to be associated with an increased risk of single falls in PLHIVs (OR: 1.69, 95% CI: 1.08–2.66, P=0.02). However, efavirenz (OR: 0.82, 95% CI=0.76–0.89, P&lt;0.001) and zidovudine (OR: 0.82, 95% CI=0.77–0.92, P&lt;0.001) were found protective against the single falls. Didanosine had no significant association with fall risk (OR: 1.23, 95% CI: 0.78–1.93, P=0.37). Likewise, protease inhibitors, integrase inhibitors, nucleoside reverse transcriptase inhibitors, and non-nucleoside reverse transcriptase inhibitors were discovered to have no significant association with fall risk. Conclusion: Most drug categories of ART have no significant association with the risk of falls in PLHIVs. However, certain drugs, such as didanosine and stavudine, which have the inherent effect of causing balance deficits and neuropathy, should be used cautiously.

Factor XI/XIa Inhibitors: A New Approach to Anticoagulation.

For more than 60 years, anticoagulation drugs have served as a mainstay in preserving and improving the cardiovascular health of patients across the globe. Functioning to reduce a patient's ability to produce blood clots, prescription rates for anticoagulants have been steadily rising year-over-year both in the United States and abroad. Despite decades of clinical usage, modern-day anticoagulants have been shown to predispose an individual to pathological bleeding. Even in seemingly benign instances of bleeding, patients on anticoagulation therapy might require intensive and expensive medical procedures or monitoring. Understanding the clinical implications of pathological bleeding, research and development of future anticoagulants seeking to minimize these effects. One emerging category of anticoagulant drugs are Factor XI/XIa (FXI) inhibitors. Targeting the coagulation cascade, clinical trials of Factor XIa inhibitors have shown promising results in preventing blood clot formation without increasing the instances of spontaneous and/or pathological bleeding events. While still in phase II and III clinical trials, and potentially years away from being implemented as standard of care, these novel drugs might have the potential to improve the safety and quality of life of patients taking anticoagulants. In this review, we discuss a brief history of anticoagulation therapy, followed by an analysis of the potential risks, benefits, and implications of Factor XI/XIa inhibitors across elements of patient care.

Direct long-acting antibodies: updating the language of RSV prevention to reflect the evolution of mAbs.

The language of medicine is constantly evolving, typically to better describe a new understanding of disease, adjust to changing social sensibilities, or simply to reflect a new drug class or category. We address the need for an updated language around monoclonal antibodies, or "mAbs" - a widely used medical term, but one which is now too general to accurately reflect the range of mAb pharmaceuticals, their effects, and the intended patients. The question of "what should we call a monoclonal antibody immunisation against respiratory syncytial virus (RSV) to ensure accurate understanding of the product?" was the basis for a virtual advisory panel in May 2022. The panel was convened by Sanofi with the intention of reviewing appropriate language in terminology in the context of mAb-based prophylaxis for RSV. The panel comprised several global experts on RSV and vaccination, a trained linguist specialising in doctor-patient interactions and medical language, and several experts in marketing and communications. We suggest the term "Direct Long-acting Antibody" (DLA) for a specific sub-class of mAbs for use in prevention of RSV disease in infants. This terminology should differentiate from other mAbs, which are generally not used as therapies in infants. This change will more accurately convey the specific mode of action of a mAb in infants, and how it could impact the prevention of communicable diseases: this class of mAbs is not an active treatment, but rather will offer direct and rapid protection lasting at least 5 months.

HPR160 An Ecological Study of 4 Drug Categories Consumption Inequities in Spain

HPR160 An Ecological Study of 4 Drug Categories Consumption Inequities in Spain

Prescribing by Physician Associates and Nurse Practitioners in Older Adults Is Outpacing Traditional Prescribers: Implications for Practice in American Medicine.

Prescribing is a significant activity undertaken by physicians, physician associates/assistants (PAs), and nurse practitioners (NPs). We analyzed prescribing data to understand better the growing presence of PAs and NPs in older adults. A trend in frequently prescribed medications was compared with other physicians. All prescriptions in Medicare Part D were grouped into broad categories of drugs and linked to each type of provider. The analysis spanned 9 years (2013-2021). The results revealed that all five providers similarly prescribed the top three main drug classes (antacids, antihypertensives, and statins). In addition, there was a decline in the number of unique prescribers and prescriptions for all three types of physicians (family medicine, internal medicine, and general practice physicians). Concurrently, the number and share of prescriptions for NPs and PAs increased yearly. The findings are consistent with data that PAs and NPs are backfilling physician shortages in treating older adults.

Spectrophotometric and Chromatographic Review on NSAIDs include: Zaltoprofen, Loxoprofen, Ketoprofen and Flurbiprofen

Non-steroidal anti-inflammatory drugs are the common and novel category of drugs which are widely used for the treatment of pain, inflammation and fever. NSAIDs inhibit the synthesis prostaglandins by the action on the cyclooxygenase enzymes. This review revealed the analytical method reported in literature for the determination of zaltoprofen, loxoprofen, ketoprofen, and flurbiprofen in pharmaceutical formulations in alone and combinations with other drugs. The comparison of twenty one analytical methods, including HPLC, UV-Spectrophotometry, and bioanalytical procedures, is most effectively illustrated in this comprehensive overview. To produce trustworthy data for regulatory filings, analytical development needs to be tested. A revolution in human health was brought about by the development of pharmaceuticals.