Nirmatrelvir–remdesivir association for non-hospitalized adults with COVID-19, point of view

Inflammopharmacology - The efforts of the scientific world directed to identifying new antiviral drugs and therapies effective against SARS-CoV-2 continue. New oral antivirals against SARS-CoV-2...     

Alprazolam: pharmacokinetics, clinical efficacy, and mechanism of action

Alprazolam, a triazolobenzodiazepine, is the first of this new class of benzodiazepine drugs to be marketed in the United States and Canada. It achieves peak serum levels in 0.7 to 2.1 hours and has a serum half-life of 12 to 15 hours. When given in the recommended daily dosage of 0.5 to 4.0 mg, it is as effective as diazepam and chlordiazepoxide as an anxiolytic agent. Its currently approved indication is for the treatment of anxiety disorders and symptoms of anxiety, including anxiety associated with depression. Although currently not approved for the treatment of depressive disorders, studies published to date have demonstrated that alprazolam compares favorably with standard tricyclic antidepressants. Also undergoing investigation is the potential role of alprazolam in the treatment of panic disorders. Alprazolam has been used in elderly patients with beneficial results and a low frequency of adverse reactions. Its primary side effect, drowsiness, is less than that produced by diazepam at comparable doses. Data on toxicity, tolerance, and withdrawal profile are limited, but alprazolam seems to be at least comparable to other benzodiazepines. Drug interaction data are also limited, and care should be exercised when prescribing alprazolam for patients taking other psychotropic drugs because of potential additive depressant effects.     

新型冠状病毒肺炎疫苗临床研究进展

至2021年2月,新型冠状病毒引起的新型冠状病毒肺炎疫情全球大流行已造成1亿以上的报告病例和超过200万的致死病例。随着临床治疗、病理学、流行病学和病毒分子生物学研究取得进展,疫苗研发也获得了重大突破。目前已有多款疫苗完成初步的临床安全性和效力评估,并获得紧急使用或有条件上市批准。此文对研究进展较快的多种类型新型冠状病...     

Glycopeptides and glycodepsipeptides in clinical development: a comparative review of their antibacterial spectrum, pharmacokinetics and clinical efficacy

Hemi-synthetic derivatives of glycopeptides have demonstrated bactericidal activity towards Gram-positive bacteria, including vancomycin-resistant strains (oritavancin and telavancin), and a prolonged half-life, allowing for once-daily (oritavancin and telavancin) or once-weekly (dalbavancin) administration. These compounds have proved effective for the treatment of infections caused by multidrug-resistant Gram-positive bacteria, including complicated skin and skin structure infections (oritavancin, telavancin and dalbavancin), bacteremia (oritavancin and dalbavancin) and nosocomial pneumonia. This review compares the antibacterial activity and clinical activity of three glycopeptides, oritavancin, telavancin and dalbavancin, and the natural lipoglycopeptide, ramoplanin, which, being unstable in the bloodstream, is administered orally to treat Clostridium difficile colitis and for digestive tract decontamination. All of these compounds, with the exception of oritavancin, have received Fast Track designation from the FDA because of their clinical efficacy.     

An evaluation of rosuvastatin: pharmacokinetics, clinical efficacy and tolerability

BACKGROUND: The HMG Co-A reductase inhibitors (statins) are the most efficacious agents for lowering cholesterol. Statins reduce clinical cardiovascular events and are generally well tolerated. OBJECTIVE: To review the efficacy and safety of rosuvastatin, the newest and most potent of the approved statins. METHODS: A comprehensive (PubMed) search was performed to identify relevant publications up to May 2007. RESULTS/CONCLUSIONS: Rosuvastatin reduces LDL cholesterol (LDL-C) by up to 50%, and by 70% when combined with ezetimibe. Rosuvastatin also reduces plasma triglycerides and increases HDL-C, and slows atherosclerosis progression in coronary and carotid arteries in both low-risk and high-risk individuals. Tolerability is comparable with other statins. Clinical trials to evaluate cardiovascular outcomes have recently been published (CORONA) or are underway.     

Piperacillin sodium: antibacterial spectrum, pharmacokinetics, clinical efficacy, and adverse reactions

Piperacillin sodium is a beta lactam antibiotic with a broad range of antibacterial activity that includes gram-negative bacilli, gram-positive cocci (except penicillinase-producing S. aureus) and anaerobic pathogens such as Clostridium difficile, and Bacteroides fragilis. Piperacillin inhibits many of the members of the Enterobacteriaceae, including Klebsiella sp and Pseudomonas, at lower concentrations than required for carbenicillin and ticarcillin. Piperacillin sodium is administered by intramuscular and intravenous injection and is widely distributed throughout body fluids and tissues. Like other newer penicillins, piperacillin is excreted by both renal and biliary mechanisms. The primary route of elimination is by glomerular filtration, which results in high urinary concentrations of the unchanged compound. Piperacillin has been approved for patients with serious infection caused by susceptible strains of specific organisms in intra-abdominal, urinary tract, gynecologic, lower respiratory tract, skin and skin structure, bone and joint, and gonococcal infections and septicemia. As with other penicillins, piperacillin has a low frequency of toxicity. The usual dose of piperacillin in adults with serious infections with normal renal function is 3-4 g every 4-6 hr as a 20-30 min infusion, with a maximum dose of 24 g per day. It is stable in most large volume parenteral solutions. Less serious infectins (requiring smaller dosages) may be treated by intramuscular injection; however, no more than 2 g should be given at any one injection site. Overall, piperacillin has a greater degree of activity than other penicillins. Evidence from prospective studies indicates that piperacillin is a highly effective agent for the treatment of patients with infections caused by susceptible organisms.     

Pharmacodynamics,pharmacokinetics and clinical efficacy of phosphodiesterase-5 inhibitors

Introduction: Phosphodiesterase type 5 inhibitors (PDE5Is) are the first-line drugs in the management of erectile dysfunction (ED). However, over the past two decades tremendous efforts have been made to identify new clinical uses of PDE5Is beyond their roles in ED.

Areas covered: Basic science articles, clinical trials, reviews, and meta-analysis published between 1996 and 2015 were searched using MEDLINE (PubMed interface) to collect the most relevant and impactful studies from our perspectives as practicing urologists. This review mainly focuses on the level one evidence-based clinical efficacy and drug-related toxicity of oral PDE5Is. In addition, drug discovery, pharmacokinetics and pharmacodynamics, potential use in other diseases, and future directions are discussed.

Expert opinion: On-demand PED5Is for the treatment of ED has shifted toward chronic administration in a broad spectrum of conditions that are thought to be associated with endovascular health. Several studies have shown that PDE5Is may play a cardioprotective or neuroprotective role. Further studies are under way to verify beneficial effects of PDE5I in non-urological conditions.     

Grepafloxacin: an overview of antibacterial activity, pharmacokinetics, clinical efficacy and safety

The treatment of respiratory tract infection is the most common reason for antibiotic prescribing. However, therapeutic options are diminishing as antibiotic resistance to penicillins and macrolides in key respiratory pathogens is increasing. As resistance increases, there are parallel rises in the number of treatment failures and the total cost of infection management. New generation broad-spectrum fluoroquinolones, such as grepafloxacin, have recently been recommended as a first-line treatment option in guidelines for lower respiratory tract infection. Grepafloxacin is an oral fluoroquinolone, with a microbiological and clinical profile that is particularly suited to the treatment of community-acquired respiratory infections. In vitro, it is rapidly bactericidal, and compared with earlier quinolones, its broad spectrum activity encompasses all important respiratory pathogens; Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Mycoplasma pneumoniae, Chlamydia pneumoniae and Legionella pneumophila, including strains which are resistant to penicillin, other beta-lactam antibiotics and macrolides. In addition, grepafloxacin achieves high lung concentrations, and its long half-life (up to 15 h) enables once daily dosing. Overall, grepafloxacin combines the positive properties of the beta-lactam antibiotics against conventional Gram-positive and Gram-negative respiratory pathogens, with the activity of the macrolides against atypical pathogens. In patients with bacteriologically documented infections, clinical studies in community-acquired pneumonia have shown that treatment for 7-10 days once daily (o.d.) with approximately 600 mg is equivalent to that with either twice daily (b.i.d.) clarithromycin 250 mg, or three times daily (t.i.d.) cefaclor 500 mg, and superior to that with t.i.d. amoxycillin 500 mg. In these studies, grepafloxacin proved effective in the treatment of both typical and atypical pneumonia. In acute bacterial exacerbations of chronic bronchitis (ABECB), 7-10 days treatment with o.d. grepafloxacin 400 mg or 600 mg has been shown to be equivalent to that with either t.i.d. amoxycillin 500 mg, or b.i.d. ciprofloxacin 500 mg. In patients with a documented bacterial pathogen, microbiological success with both grepafloxacin dosage regimens was superior to amoxycillin 500 mg t.i.d. In addition, short course treatment of ABECB with 400 mg of grepafloxacin given o.d. for five days has been shown to be as effective, clinically and microbiologically as a ten-day course of the same dose. The safety profile of grepafloxacin has been well-characterised from data from over 12,000 patients treated in Phase II/III and post-marketing studies, and over 400,000 patients treated worldwide in routine clinical practice. The most commonly reported adverse events are gastrointestinal, mainly nausea and unpleasant taste. The potential for photosensitivity and central nervous system effects is low, and there have been no reports of convulsions. No unique or unexpected.     

Grepafloxacin: an overview of antibacterial activity,pharmacokinetics, clinical efficacy and safety

Introduction: GPR119 is a recently deorphanised G-protein coupled receptor which has been suggested to be important in mediating systemic metabolic homeostasis. Research to date has primarily focused on the ability of GPR119 to promote euglycaemia and thus as a therapeutic target for the treatment of type 2 diabetes mellitus (T2DM). Indeed, previous studies have shown that GPR119 promotes glucose-stimulated insulin secretion, pancreatic β-cell function and glucagon-like peptide-1 release, all of which provide valid mechanisms through which GPR119 may improve systemic glucose homeostasis.

Areas covered: In the current review, the authors provide a brief overview of the known functions of GPR119 and then discuss the novel potential for GPR119 to regulate metabolic function in skeletal and cardiac muscle and how this may translate to improvements or impairments in systemic health.

Expert opinion: GPR119 is largely purported as being anti-diabetic and has been rapidly progressed to clinical trials, mainly as anti-diabetic agents. However, emerging data suggest that this class of agonists may have a detrimental effect at the level of the muscle. This may potentiate the development and progression of metabolic diseases such as T2DM. Therefore, further research is required before GPR119 receptor agonists can be prescribed with confidence as an anti-diabetic agent.     

Azelastine hydrochloride:a review of pharmacology,pharmacokinetics, clinical efficacy and tolerability

ABSTRACT

Introduction: Azelastine hydrochloride (Astelin) nasal spray 0.1% solution is a second-generation intranasal antihistamine available in the US for treatment of both seasonal allergic rhinitis (SAR) and nonallergic vasomotor rhinitis (VMR).

Scope: Searches of journal articles including the title word ‘azelastine’ from 1979 through the present were conducted by the product manufacturer primarily through Medline and EMBASE but also included, at various times, Dialog, Biosis, Toxline, and Diogenes (an adverse-event database). One limitation of the present review is that it could not exclude the possibility of publication bias, whereby findings from smaller studies and/or trials with negative findings may not have been published.

Findings: Azelastine is a phthalazinone derivative with H₁-receptor binding approximately tenfold greater than chlorpheniramine on a milligram-per-milligram basis. Azelastine has demonstrated a wide range of pharmacologic effects on chemical mediators of inflammation including leukotrienes, kinins, and platelet activating factor in vitro and in vivo. The molecule also has been shown to downregulate intercellular adhesion molecule-1 expression and to reduce inflammatory cell migration in patients with rhinitis. Well-controlled studies in SAR and VMR demonstrated that azelastine nasal spray improves nasal symptoms of rhinitis, including congestion and postnasal drip, and has a rapid onset of action that appears likely due to topical activity. Azelastine nasal spray has demonstrated greater efficacy when used in combination with fluticasone propionate nasal spray when compared to either agent alone, and this combination may provide benefit for patients with moderate-to-severe rhinitis. Bitter taste is the most common side effect associated with azelastine nasal spray and this problem can be mitigated by the dosing technique recommended by the manufacturer in the product labeling. The incidence of somnolence also may be reduced with the recommended administration technique.

Conclusions: Azelastine is an effective, rapid-acting, and well-tolerated second-generation antihistamine that improves nasal symptoms associated with SAR and VMR. Clinical studies demonstrated that azelastine nasal spray can improve symptoms of SAR in patients who remained symptomatic after treatment with oral antihistamines and that azelastine nasal spray in combination with fluticasone nasal spray provided significantly (?p < 0.05) greater relief than either agent alone in patients with SAR.     

Chloroquine,hydroxychloroquine, and COVID-19: Systematic review and narrative synthesis of efficacy and safety

The COVID-19 pandemic has required clinicians to urgently identify new treatment options or the re-purposing of existing drugs. Of particular interest are chloroquine (CQ) and hydroxychloroquine (HCQ). The aims of this systematic review are to systematically identify and collate 24 studies describing the use of CQ and HCQ in human clinical trials and to provide a detailed synthesis of evidence of its efficacy and safety. Of clinical trials, 100% showed no significant difference in the probability of viral transmission or clearance in prophylaxis or therapy, respectively, compared to the control group. Among observational studies employing an endpoint specific to efficacy, 58% concurred with the finding of no significant difference in the attainment of outcomes. Three-fifths of clinical trials and half of observational studies examining an indicator unique to drug safety discovered a higher probability of adverse events in those treated patients suspected of, and diagnosed with, COVID-19. Of the total papers focusing on cardiac side-effects, 44% found a greater incidence of QTc prolongation and/or arrhythmias, 44% found no evidence of a significant difference, and 11% mixed results. The strongest available evidence points towards the inefficacy of CQ and HCQ in prophylaxis or in the treatment of hospitalised COVID-19 patients.     

Cefetamet pivoxil: a review of its microbiology, toxicology, pharmacokinetics and clinical efficacy

Cefetamet pivoxil is an oral, third-generation cephalosporin whose broad spectrum of antibacterial activity and favorable pharmacokinetic profile make it particularly suitable for the treatment of a wide range of infectious diseases. Cefetamet has high in vitro activity against both gram-positive and gram-negative bacteria that cause a number of respiratory tract and urinary tract infections. These include penicillin-sensitive Streptococcus pneumoniae, Streptococcus spp, Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Proteus spp., Klebsiella spp. and Neisseria gonorrhoeae. It is not active against staphylococci, enterococci, Pseudomonas spp. or Bacteroides fragilis but does inhibit most bile-sensitive (oral) Bacteroides spp. Animal toxicology studies indicate that neither cefetamet pivoxil nor the active compound cefetamet have significant teratogenic, mutagenic, photogenic or allergenic potential. Cefetamet is eliminated unchanged in the urine with a half-life of 2.2 h. Volume of distribution approximates the extracellular fluid space (0.3 1/kg), protein binding is minima (22%) and oral bioavailability of cefetamet pivoxil is approximately 50% when taken with food. No significant drug interactions have been noted to date. The efficacy and tolerability of cefetamet pivoxil have been evaluated in the treatment of gram-positive and gram-negative infections in almost 5,000 patients. In comparative studies, cefetamet pivoxil was at least as effective, and in many cases clinically superior, to most currently recommended antibiotics for the treatment of urinary tract infections including gonorrhea and complicated infections in high risk patients. Efficacy has also been demonstrated in acute exacerbations of chronic bronchitis, pneumonia and infections of the ear, nose and throat. Clinical trials have shown that a 7 day treatment period with cefetamet pivoxil is as effective as a 10 day course of phenoxymethylpenicillin in the treatment of pharyngotonsillitis. Cefetamet pivoxil has been well-tolerated in clinical trials with only 1.2% of patients on standard doses discontinuing therapy prematurely. The most common adverse effects are gastrointestinal (diarrhea, nausea, vomiting) which occur in less than 10% of patients. Many current antibiotic treatment regimens involve the administration of three or more daily doses. However, standard doses of cefetamet pivoxil 500 mg twice daily provide unbound plasma concentrations of cefetamet which generally exceed the MIC(90) for susceptible organisms throughout the dosing interval and have been demonstrated to be clinically effective. This should result in good compliance with therapy in out-patients. Dosing regimens for cefetamet pivoxil should be adjusted in patients with impaired renal function while standard doses can be given to elderly patients and those with liver disease. Standard doses in children are 10 mg/kg or alternatively, children may receive a dose reduced in proportion to the ratio of their body surface area to that of an adult.     

The pharmacokinetics, pharmacodynamics, clinical efficacy, safety and tolerability of linaclotide

INTRODUCTION: Linaclotide is a novel intestinal secretagogue that is in the advanced stages of development for the treatment of irritable bowel syndrome with constipation (IBS-C) and chronic constipation. These functional gastrointestinal disorders are highly prevalent in adults and children and often do not respond satisfactorily to available treatments. Linaclotide appears to be a promising new agent for patients who are not satisfied with currently available agents. AREAS COVERED: This article is formed from a literature review of all the studies published about linaclotide up to January 2011. It covers the pharmacodynamics and pharmacokinetics of this novel agent. It also provides a summary of the published clinical trials concerning efficacy and safety in patients with chronic constipation and IBS-C. The authors provide the reader with a better understanding of how the molecular pathophysiology of certain enteropathic diarrheal bacteria lead to the development of this novel prosecretory drug. The reader will also learn about the development of molecularly-based treatment options for chronic constipation and other constipation-associated disorders such as IBS-C. EXPERT OPINION: Linaclotide appears to be a well-tolerated and effective agent for many patients with chronic constipation and IBS-C. Two Phase III studies in chronic constipation and two in IBS-C have provided promising data on the efficacy and safety of this agent for these two disorders. The positioning of linaclotide among the various available agents for these two disorders remains to be established after approval from the FDA is granted.     

Hydroxychloroquine lung pharmacokinetics in critically ill patients with COVID-19

Different dosage regimens of hydroxychloroquine (HCQ) have been used to manage COVID-19 (coronavirus disease 2019) patients, with no information on lung exposure in this population. The aim of our study was to evaluate HCQ concentrations in the lung epithelial lining fluid (ELF) in patients infected with SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the virus that causes COVID-19. This was a retrospective, observational, multicentre, pharmacokinetic study of HCQ in critically ill COVID-19 patients. No additional interventions or additional samples compared with standard care of these patients were conducted in our teaching hospital. We included all intubated COVID-19 patients treated with crushed HCQ tablets, regardless of the dosage administered by nasogastric tube. Blood and bronchoalveolar lavage samples (n = 28) were collected from 22 COVID-19 patients and total HCQ concentrations in ELF were estimated. Median (interquartile range) HCQ plasma concentrations were 0.09 (0.06–0.14) mg/L and 0.07 (0.05–0.08) mg/L for 400 mg × 1/day and 200 mg × 3/day, respectively. Median HCQ ELF concentrations were 3.74 (1.10–7.26) mg/L and 1.81 (1.20–7.25) for 400 mg × 1/day and 200 mg × 3/day, respectively. The median ratio of ELF/plasma concentrations was 40.0 (7.3–162.7) and 21.2 (18.4–109.5) for 400 mg × 1/day and 200 mg × 3/day, respectively. ELF exposure is likely to be underestimated from HCQ concentrations in plasma. In clinical practice, low plasma concentrations should not induce an increase in drug dosage because lung exposure may already be high.     

Oral paliperidone extended-release: chemistry, pharmacodynamics, pharmacokinetics and metabolism, clinical efficacy, safety and tolerability

INTRODUCTION: Paliperidone is a second-generation (atypical) antipsychotic approved for the treatment of schizophrenia in adults and in adolescents aged 12 - 17 years. It is also approved for the treatment of adults with schizoaffective disorder, both as a monotherapy and as adjunctive therapy to mood stabilizers and/or antidepressants. Paliperidone is the active metabolite of risperidone. AREAS COVERED: The purpose of this review is to describe the pharmacokinetic profile of paliperidone and its clinical implications in the treatment of schizophrenia and schizoaffective disorder. Background information is also provided regarding chemistry, pharmacodynamics, clinical efficacy and safety/tolerability data. EXPERT OPINION: The recommended dose of paliperidone extended-release (ER) in adults is 6 mg/day and no initial dose titration is required. Higher doses may provide additional benefit as well as dose-related increases in some adverse reactions. The maximum recommended dose is 12 mg/day. Peak plasma concentrations are reached approximately 24 h after dosing. Pharmacokinetics are dose-proportional. Terminal half-life is approximately 23 h. Renal excretion is the major route of elimination. Although paliperidone is the active metabolite of risperidone, paliperidone's route of metabolism and elimination is quite different from that for risperidone and paliperidone ER may be preferred over risperidone when liver disease, drug-drug interactions or other alterations in metabolism render the appropriate dosing of risperidone difficult to determine for an individual patient. The use of paliperidone ER will need to be considered within the context of its cost and availability as risperidone is now a generic product.     

Pharmacology, clinical efficacy, and tolerability of phosphodiesterase-4 inhibitors: impact of human pharmacokinetics

Since more than two decades anti-inflammatory effects of inhibitors of phosphodiesterase-4 have been described in numerous cellular and animal studies and were finally confirmed in clinical trials. The path from an early, pioneering study with Ro20-1724 showing reduction of psoriatric plaque size in 1979 to modern PDE4 inhibitors such as oral apremilast in development for psoriasis, the inhaled PDE4 inhibitor GSK256066 in development for asthma and COPD and finally roflumilast, the first PDE4 inhibitor approved and currently marketed as an oral, once-daily remedy for severe COPD was marked by large progress in chemical optimization based on improved understanding of PDE4 biology and drug-like properties determining the appropriate pharmacokinetic profile. In this chapter aspects of the pharmacology and clinical efficacy of PDE4 inhibitors, which have been in clinical development over the years are summarized with specific emphasis on their clinical pharmacokinetic properties.     

A comparative evaluation of moxalactam: antimicrobial activity, pharmacokinetics, adverse reactions, and clinical efficacy

Although moxalactam is not, technically speaking, a cephalosporin it is chemically and microbiologically so closely related to those compounds that it can be viewed as a member of the cephalosporin family. Moxalactam has a spectrum of activity that includes both gram positive and gram negative bacteria. Its gram positive activity is less than earlier cephalosporins, but its activity against the Enterobacteriaceae is similar to that of the aminoglycoside family of antibiotics in most comparative studies. Although moxalactam is considerably less active against gram positive bacteria than cefotaxime, another third generation cephalosporin, its higher and more prolonged serum levels probably offset this disadvantage. Compared to cefoperazone, the stability of moxalactam to many types of beta lactamases produced by gram negative bacteria may be advantageous in the therapy of infections caused by hospital-acquired pathogens. Clinical studies suggest that moxalactam can be used for empiric therapy of suspected gram negative infections when Pseudomonas and other non-fermentative bacteria, such as Acinetobacter, are not suspected. Impressive improvements in the survival of patients with gram negative enteric bacillary meningitis have been reported. Although moxalactam, cefotaxime, and cefoperazone have activity against Pseudomonas aeruginosa, none of these antibiotics should be used alone as therapy for suspected or proven severe systemic infections caused by this pathogen. Cost is a major problem with all of the new cephalosporin-like antibiotics. While this high cost may be partially balanced by the use of a single agent compared to an antibiotic combination for therapy in some situations, these antibiotics are not cost effective for prophylactic use. Superinfection with fungi, such as Candida, and Streptococcus faecalis have occurred, and toxicities, such as bleeding due to vitamin K deficiency and disulfuram-like reactions, have also been reported. Reports of resistance to moxalactam and the other third generation cephalosporins are of major concern and indicate the need to closely monitor antibiotic susceptibility patterns of hospital acquired organisms if these antibiotics are to be used for empiric therapy of suspected gram negative non-pseudomonas sepsis.