Pharmacokinetic–Pharmacodynamic Modeling of the Effectiveness and Safety of Buprenorphine and Fentanyl in Rats

Objective Respiratory depression is a serious and potentially life-threatening side-effect of opioid therapy. The objective of this investigation was to characterize the relationship between buprenorphine or fentanyl exposure and the effectiveness and safety outcome in rats. Methods Data on the time course of the antinociceptive and respiratory depressant effect were analyzed on the basis of population logistic regression PK–PD models using non-linear mixed effects modeling software (NONMEM). The pharmacokinetics of buprenorphine and fentanyl were described by a three- and two-compartment model, respectively. A logistic regression model (linear logit model) was used to characterize the relationship between drug exposure and the binary effectiveness and safety outcome. Results For buprenorphine, the odds ratios (OR) were 28.5 (95% CI, 6.9–50.1) and 2.10 (95% CI, 0.71–3.49) for the antinociceptive and respiratory depressant effect, respectively. For fentanyl these odds ratios were 3.03 (95% CI, 1.87–4.21) and 2.54 (95% CI, 1.26–3.82), respectively. Conclusion The calculated safety index (OR_{antinociception}/OR_{respiratory depression}) for fentanyl of 1.20 suggests that fentanyl has a low safety margin, implicating that fentanyl needs to be titrated with caution. For buprenorphine the safety index is 13.54 suggesting that buprenorphine is a relatively safe opioid.     

Epidemiology and molecular characterisation of metallo-β-lactamase-producing Enterobacteriaceae in a university hospital Intensive Care Unit in Greece

The molecular epidemiology of VIM-producing Enterobacteriaceae isolated at the beginning of an epidemic in the Intensive Care Unit (ICU) of a university hospital in Athens, Greece, was studied. All Gram-negative organisms isolated from March 2004 to November 2005 positive for metallo-β-lactamase (MBL) production were submitted to polymerase chain reaction (PCR) and sequencing, to repetitive sequence-based PCR (Rep-PCR) for molecular typing, and to S1 nuclease digestion for plasmid DNA characterisation. Conjugation experiments and isoelectric focusing were performed to identify co-existing β-lactamases. Amongst 23 patients, 12 suffered one or more clinical infections. Eighty-two isolates representing one isolate per clone, source and ICU patient were studied, including Klebsiella pneumoniae (77), Enterobacter cloacae (2), Citrobacter freundii (1) and Pseudomonas aeruginosa (2). High clonal diversity was detected amongst the K. pneumoniae, with 10 distinct clones identified. Conjugation was successful in 54.5% of K. pneumoniae, and five different-sized plasmids were detected. All K. pneumoniae and both E. cloacae isolates shared the same bla_VIM-1-containing class 1 integron structure also carrying aacA7, dhfrI and aadA1 gene cassettes. The C. freundii isolate carried a different integron that included bla_VIM-1 and aac(6′)-IIc. Both P. aeruginosa isolates were positive for bla_VIM-2. It was not possible to identify specific clones with the potential to cause clinical infections. In conclusion, a multiclonal cluster of MBL-producers was responsible for the first cases of colonisation and/or infection in the ICU. A single integron structure, common in Greek hospitals, efficiently disseminated between clones and species, suggesting that the epidemic was mainly the result of successful horizontal transfer of mobile genetic material rather than the result of horizontal transfer of one or a few clones.     

Pseudomonas aeruginosa infections in the Intensive Care Unit: can the adequacy of empirical beta-lactam antibiotic therapy be improved?

Inadequate empirical antibiotic therapy for serious Pseudomonas aeruginosa infections has been linked to increased mortality. We performed a retrospective cohort study of consecutive patients with ventilator-associated pneumonia, bacteraemia or other sterile-site infections caused by P. aeruginosa occurring during Intensive Care Unit admissions. One hundred and fifty-eight episodes of serious infection with P. aeruginosa occurred in 140 patients. Empirical antibiotic therapy was microbiologically adequate in 67% of episodes of infection. Patients with P. aeruginosa isolates resistant to piperacillin/tazobactam or cefepime were more likely to have received these antibiotics in the month prior to the P. aeruginosa infection or to have had a Gram-negative bacillus resistant to these antibiotics isolated in the month prior to the P. aeruginosa infection. From these data, we have developed simple algorithms for empirical antibiotic choice in seriously ill patients with suspected P. aeruginosa infections based on prior antibiotic exposure and prior isolation of antibiotic-resistant organisms. Application of these algorithms would have improved the adequacy of empirical antibiotic therapy from 67% to 80-84%. Routine empirical addition of amikacin to the beta-lactam would have increased the adequacy of the antibiotics to 96%. We conclude that knowledge of the prior receipt of beta-lactam antibiotics with activity against P. aeruginosa and the isolation of Gram-negative bacilli resistant to such antibiotics in the recent past can readily increase the adequacy of empirical antibiotic therapy for suspected P. aeruginosa infections.     

Safety of vedolizumab in the treatment of Crohn’s disease and ulcerative colitis

Introduction: Vedolizumab is the latest FDA-approved anti-integrin therapy for treatment of moderate-to-severe inflammatory bowel disease (IBD). The safety and efficacy of vedolizumab have been studied in short-term clinical trials.

Areas covered: This paper reviews the safety profile of vedolizumab compared with other biologics. It also highlights the mechanism of action of the medication. We discuss the current position of vedolizumab in our current algorithm for IBD management and comment on future prospects of the drug.

Expert opinion: Vedolizumab appears to be a safe and effective option in the treatment of moderate-to-severe IBD in the short term. Long-term observational studies and post-marketing safety data are needed to ascertain the long-term efficacy and side effect profile.     

Care of the stroke patient—communication between the community pharmacist and prescribers in the Republic of Ireland

Objective This study sought to examine the perceptions that community pharmacists have of communication with prescribers in both primary and secondary care in Ireland, with respect to care of stroke patients. Setting Community pharmacies across Ireland, stratified into the four representative administrative regions. Method Survey using a structured postal questionnaire. Main outcome measure Perceptions of communication with prescribers based in primary and secondary care; pharmacy and pharmacy premises demographics. Results A response rate of 52% (n = 314) was achieved. Community pharmacists’ perceptions of information provision from secondary care were low, the majority (83%) never received any information from the hospital, although they would welcome it. Communication with hospital based prescribers was considered by most (93%) to be poor. The majority (greater than 75%) of respondents expressed a desire for greater information provision concerning a stroke patient’s medication and diagnostic information. Pharmacists’ perceptions of interaction with general practitioners were generally regarded as good (63%) although information provision in both directions between pharmacist and general practitioner could be improved. Conclusion The findings of this study indicated that community pharmacists perceive that there is room for improvement in the communication between themselves and prescribers in the primary and secondary care settings, concerning the care of the stroke patient. This highlights the need for the development of formal communication channels between community pharmacists and other members of the healthcare team involved in the care of the stroke patient. However, the challenges of communicating patient information across healthcare sectors are recognized.     

In Vitro and in Vivo Transport of Zidovudine (AZT) Across the Blood–Brain Barrier and the Effect of Transport Inhibitors

The transport of the antiviral nucleoside analogue zidovudine (3-azido-3-deoxythymidine; AZT) into the central nervous system (CNS) was characterized in vitro and in vivo. The in vitro model consisted of primary cultures of isolated bovine capillary endothelial cells. The transport rate of AZT across the monolayer, expressed as endothelial permeability P, was determined following luminal and abluminal administration. P did not differ between the two administration sites (luminal, 1.65 ± 0.44 cm/min/10³; abluminal, 1.63 ± 0.28 cm/min/10³). The transport of AZT across the endothelial cell monolayer was found to be concentration independent in the range between 0.4 and 50 µg/mL. AZT transport was not affected by pre-treatment of the cells with either metabolic inhibitors (DODG and DODG/NaN₃) or probenecid. This suggests that AZT passes the monolayer mainly by passive diffusion. The in vivo transport of AZT across the blood–brain barrier and the blood–CSF barrier was studied in male Wistar rats after coadministration of potential inhibitors of active transport of AZT: probenecid (organic anion transport) and thymidine (nucleoside transport). Intracerebroventricular and intravenous coadministration of probenecid caused a significant (P < 0.001) increase in the CSF/plasma concentration ratio compared to the control phase, indicating that the organic anion carrier is involved in AZT transport from CSF to blood. Since there was no effect of probenecid on the transport of AZT in vitro, it is suggested that this carrier is located at the choroid plexus. Coadministration of thymidine did not affect the CSF/plasma concentration ratio, suggesting that a nucleoside carrier system is not involved in AZT transport into or out of the CNS.     

Alpha-2 agonists: can they modify the outcomes in the Postanesthesia Care Unit?

While most patients recover uneventfully from the effects of anesthesia and surgery, for a small percentage of patients the immediate postoperative period can be a period of significant physiological stress. Hence the goal for a Post Anesthesia Care Unit (PACU) is to provide a safe environment for a patient to recover, while avoiding the undesirable side effects of pain, nausea, vomiting and shivering, and to monitor for potentially life threatening hemodynamic and respiratory complications that may require admission into the intensive care unit (ICU). Anesthetic techniques in the operating room are extremely important as these may have significant bearing on the post-operative course. The type of surgery, the patients' co morbid conditions, anticipated extubation and recovery of the patient, as well as the sophistication of the PACU and the expertise of its staff, all influence the choice of anesthetic technique. These agents, however, may themselves contribute to some of the complications and unpleasant events encountered in the PACU. Therefore, evaluation of newer and safer agents, which promote a smoother PACU transition, are warranted. Alpha 2 agonists are increasingly being used as adjuvant therapeutic agents in the perioperative period because of their ability to block the sympathetic stress response, complete with their anesthetic and analgesic sparing properties, lack of respiratory depression and low and predictable side effect profile.     

Evaluation of single nucleotide polymorphisms in the miR-183–96–182 cluster in adulthood attention-deficit and hyperactivity disorder (ADHD) and substance use disorders (SUDs)

Attention deficit-hyperactivity disorder (ADHD) is a neuropsychiatric disorder characterized by inappropriate and impaired levels of hyperactivity, impulsivity and inattention. Around 75% of adults with ADHD show comorbidity with other psychiatric disorders such as disruptive behavior disorders or substance use disorders (SUDs). Recently, there has been growing interest in studying the role of microRNAs (miRNAs) in the susceptibility to complex disorders. Interestingly, converging evidence suggests that single nucleotide polymorphisms (SNPs) within miRNAs or miRNA target sites may modulate the miRNA-mediated regulation of gene expression through the alteration of the miRNA maturation, structure or expression pattern as well as the silencing mechanisms of target genes. Genetic studies and animal models support the involvement of the serotonin receptor (HTR1B) in ADHD. We evaluated the contribution of one SNP in the miR-96 target site at HTR1B and eight tagSNPs within the genomic region containing this miRNA in 695 adults with ADHD (266 and 396 subjects with and without comorbid SUD, respectively), 403 subjects with SUD without life-time diagnosis of ADHD and 485 sex-matched controls from Spain. Single and multiple marker analyses revealed association between two SNPs located at the 3′ region of miR-96 (rs2402959 and rs6965643) and ADHD without SUD. Our results provide preliminary evidence for the contribution of two sequence variants at the miR-183–96–182 cluster to ADHD without comorbid SUD, and emphasize the need to take comorbidities into account in genetic studies to minimize the effect of heterogeneity and to clarify these complex phenotypes.     

Recent advances in the study of (–)clausenamide: chemistry,biological activities and mechanism of action

Clausenamide (clau) is one of seven novel compounds isolated from Clausena lansium (Lour) skeels. Clau is unusual in that it contains 4 chiral centers yielding 8 pairs of enantiomers. After identification of the configuration of these enantiomers, the synthesis of 16 enantiomers, including optically active clau and (+) and (–)clau was carried out. During this study, many stereochemical and synthetic difficulties were solved and the Baldwin principle was updated. Production scale is now sufficient to meet the needs of clinical practice. In a pharmacological study numerous models and indicators showed that (–)clau is the active enantiomer, while (+)clau is inactive and elicits greater toxicity than (–)clau. The principal pharmacological effects of (–)clau are to increase cognition, demonstrated in ten models of memory impairment, as well as to inhibit β-amyloid (Aβ) toxicity, blocking neurofibrillary tangle formation by inhibiting the phosphorylation of tau protein. This anti-dementia effect is characterized by increased synaptic plasticity both in efficacy and in structure and provides new support for the theory that synaptic loss is the main cause of dementia. (–)Clau is considered to be a promising drug candidate for treatment of Alzheimer׳s disease and other neurodegenerative disorders.KEY WORDS: (–)Clausenamide, Enantiomers, Cognition, Alzheimer׳s disease pathology, Tau, High phosphorylation, Synaptic plasticity     

Opinion of the Scientific Committee on Consumer Safety (SCCS) – Final version of the opinion on Phenoxyethanol in cosmetic products

The SCCS considers 2-phenoxyethanol safe for use as a preservative with a maximum concentration of 1.0%, taking into account the information provided.The toxicokinetics default factor of 4.0 can be reduced to 1.0 yielding a minimum Margin of Safety (MoS) of 25 instead of 100 for the safety assessment of 2-phenoxyethanol.Therefore, the MoS of about 50 for children also covers this specific age group who might be higher exposed to 2-phenoxyethanol than adults.This Opinion does not take into account exposure from sources other than cosmetics.     

Effectiveness of a new tobramycin (0.3 % ) and dexamethasone (0.05 % ) formulation in the treatment of experimental Pseudomonas keratitis

ABSTRACT

Objective: To quantitatively determine, in a Pseudomonas keratitis model, the anti-inflammatory and bactericidal properties of a new formulation of tobramycin (0.3?%?) and dexamethasone (0.05?%?) that utilizes a xanthan gum vehicle.

Research methods: In a randomized and masked fashion, rabbit corneas (n?≥?16 eyes per group) were intrastromally injected with 10³ colony-forming units (CFU) of P. aeruginosa. Eyes were untreated or were administered a single drop every 15?min between 16 and 17?h postinfection (PI) and then a single drop every 30?min between 17 and 22?h PI, a total of 15 drops of either 0.1?%?dexamethasone and 0.3?%?tobramycin (TobraDex; Tdex) or a new formulation 0.3?%?tobramycin and 0.05?%?dexamethasone with xanthan gum (TobraDex ST; ST). Slit lamp examination scores (SLE?±?SEM) were derived from grading seven parameters at 22?h PI. Rabbits were sacrificed at 23?h PI and the log CFU?±?SEM per cornea was determined.

Results: Untreated eyes had SLE scores of 11.11?±?0.43 and had log CFU of 7.27?±?0.06. Eyes treated with Tdex, as compared to the untreated eyes, had significantly lower SLE scores (7.39?±?0.21, p?<?0.0001) and significantly fewer bacteria (6.32?±?0.29 log CFU, p?=?0.0213). Eyes treated with ST had a SLE score (6.56?±?0.19) that was significantly lower than both the untreated eyes (p?<?0.0001) and the eyes treated with Tdex (p?=?0.0124). Furthermore, eyes treated with ST had significantly fewer log CFU (5.78?±?0.30) than untreated eyes (p?=?0.0001) or eyes treated with Tdex (p?=?0.0434).

Conclusions: The ST formulation with xanthan gum demonstrated statistically superior anti-inflammatory and bactericidal properties as compared to Tdex.

Limitations: Variations in inoculation procedures produced limited eye-to-eye differences in the infection.     

Opinion of the Scientific Committee on Consumer Safety (SCCS) – Final version of the Opinion on Vitamin A (retinol,retinyl acetate and retinyl palmitate) in cosmetic products

The SCCS has estimated that exposure to Vitamin A (retinol, retinyl palmitate, and retinyl acetate) and via body lotion at the maximum concentration of 0.05% and via hand cream, face cream and other leave-on or rinse-off products at the maximum concentration of 0.3% per se is safe.The exposure from all cosmetic products may lead to a daily systemic dose of 4855 IU for an adult. The teratogenic potential of Vitamin A was considered and effects on liver and local effects in the skin are the most     

Progress in acetylcholinesterase reactivators and in the treatment of organophosphorus intoxication: a patent review (2006–2016)

Introduction: organophosphorus compounds act as irreversible inhibitors of the vital enzyme acetylcholinesterase (AChE). this leads in the accumulation of acetylcholine (ACh) leading to cholinergic crisis and death. The main therapeutic approach is based on immediate administration of an ache reactivator as an antidote enabling recovery of the ache function.

Areas covered: This review covers the development of AChE reactivators in order to introduce a new efficient drug that will overcome significant failures of common antidotes. Further options together with methods of detection are also discussed in order to assure a complete insight into the treatment of intoxication.

Expert opinion: Since organophosphates belong to the most toxic chemical warfare agents, efficient antidotes are a matter of importance. The solution of how to limit the basic drawbacks of clinically used reactivators remained a spotlight for many researches worldwide. Recent strategies of the treatment of OP exposure bring us new possibilities which may overcome classic antidotes. The importance of detection of OP also has to be taken into consideration. Especially, with the fast spreading toxic effect when death can occur within minutes.     

Evaluation of sigma (σ) receptors in the antidepressant-like effects of ketamine in vitro and in vivo

Ketamine is an NMDA antagonist and dissociative anesthetic that has been shown to display rapid acting and prolonged antidepressant activity in small-scale human clinical trials. Ketamine also binds to σ receptors, which are believed to be protein targets for a potential new class of antidepressant medications. The purpose of this study was to determine the involvement of σ receptors in the antidepressant-like actions of ketamine. Competition binding assays were performed to assess the affinity of ketamine for σ(1) and σ(2) receptors. The antidepressant-like effects of ketamine were assessed in vitro using a neurite outgrowth model and PC12 cells, and in vivo using the forced swim test. The σ receptor antagonists, NE-100 and BD1047, were evaluated in conjunction with ketamine in these assays to determine the involvement of σ receptors in the antidepressant-like effects of ketamine. Ketamine bound to both σ(1) and σ(2) receptors with μM affinities. Additionally, ketamine potentiated NGF-induced neurite outgrowth in PC12 cells and this effect was attenuated in the presence of NE-100. Ketamine also displayed antidepressant-like effects in the forced swim test; however, these effects were not attenuated by pretreatment with NE-100 or BD1047. Taken together, these data suggest that σ receptor-mediated neuronal remodeling may contribute to the antidepressant effects of ketamine.     

Opinion of the Scientific Committee on Consumer Safety (SCCS) – Revision of the opinion on o-Phenylphenol,Sodium o-phenylphenate and Potassium o-phenylphenate (OPP), in cosmetic products

o-Phenylphenol, Sodium o-phenylphenate, Potassium o-phenylphenate, CAS n. 90-43-7, 132-27-4, 13707-65-8 as preservatives are regulated in Annex V/7 of the Cosmetics Regulation (EC) n. 1223/2009 at a maximum concentration of 0.2% (as phenol).In February 2013, the Commission received a risk assessment submitted by the French Agency ANSM (Agence nationale de sécurité des médicaments et des produits de santé) which rose concerns about the use of o-Phenylphenol as preservatives in cosmetic products.In the context of the ANSM report (Evaluation du risque lié à l'utilisation de l'orthophénylphénol CAS n. 90-43-7 dans les produits cosmétiques) o-Phenylphenol has been identified as likely to be an endocrine disruptor. The report concludes that the maximum authorised concentration (currently of 0.2%) of o-Phenylphenol for use as a preservative should be revised due to low margin of safety.In January 2014, in response to a call for data on o-Phenylphenol by the Commission, Industry submitted a safety dossier in order to defend the current use of o-Phenylphenol, Sodium o-phenylphenate, Potassium o-phenylphenate, CAS n. 90-43-7, 132-27-4, 13707- 65-8 as preservatives in cosmetic formulations at a maximum concentration of 0.2% (as phenol).o-Phenylphenol as preservative with a maximum concentration of 0.2% in leave-on cosmetic products is not safe. Also, in view of further exposures including noncosmetic uses (see Anses, 2014), the maximum concentration of o-Phenylphenol in leave-on cosmetic products should be lowered. However, the proposed maximum use concentration of up to 0.15% by the applicant can be considered safe.The use of o-Phenylphenol as preservative with a maximum concentration of 0.2% in rinse-off cosmetic products is considered safe.Based on the information provided, no conclusions of safe use can be drawn for Sodium o-phenylphenate and Potassium o-phenylphenate.In vitro data indicate an absent or very weak binding affinity of OPP to the oestrogen receptor, in line with limited stimulation of proliferation in oestrogen responsive cells.No information is available on androgenic and anti-androgenic effects of OPP in vitro.Agonistic or antagonistic effects on thyroid hormones were not observed with OPP.There might be a potential of injury to the vision system attributable to OPP.Aggregate exposure to OPP should be considered.     

Safety and Toxicokinetics of Intravenous Liposomal Amphotericin B (AmBisome ®) in Beagle Dogs

Purpose. Amphotericin B (AmB) in small, unilamellar liposomes (AmBisome ^®) has an improved therapeutic index, and altered pharmacokinetics. The repeat-dose safety and toxicokinetic profiles of AmBisome were studied at clinically relevant doses. Methods. Beagle dogs (5/sex/group) received intravenous AmBisome (0.25, 1,4, 8, and 16 mg/kg/day), empty liposomes or vehicle for 30 days. AmB was determined in plasma on days 1, 14, and 30, and in tissues on day 31. Safety parameters included body weight, clinical chemistry, hematology and microscopic pathology. Results. Seventeen of twenty animals receiving 8 and 16 mg/kg were sacrificed early due to weight loss caused by reduced food intake. Dose-dependent renal tubular nephrosis, and other effects characteristic of conventional AmB occurred at 1 mg/kg/day or higher. Although empty liposomes and AmBisome increased plasma cholesterol, no toxicities unique to AmBisome were revealed. Plasma ultrafiltrates contained no AmB. AmBisome achieved plasma levels 100-fold higher than other AmB formulations. AmBisome kinetics were non-linear, with clearance and distribution volumes decreasing with increasing dose. This, and nonlinear tissue uptake, suggest AmBisome disposition was saturable. Conclusions. AmBisome has the same toxic effects as conventional AmB, but they appear at much higher plasma exposures. AmBisome's non-linear pharmacokinetics are not associated with increased risk, as toxicity increases linearly with dosage. Dogs tolerated AmBisome with minimal to moderate changes in renal function at doses (4 mg/kg/day) producing peak plasma concentrations of 18–94 µg/mL.     

Innovative strategies in the diagnosis and treatment of tuberculosis: a patent review (2014–2017)

Introduction: Tuberculosis (TB) is a disease caused due to an infection of Mycobacterium tuberculosis (M TB) bacilli affecting millions of people worldwide. It is the ninth leading cause of death and ranks above the HIV/AIDS. The unique intracellular life cycle, more dangerous drug-resistant forms of bacilli, and insufficient investments in the TB research and development hindered the occurrence of optimum diagnostic, preventive, and treatment strategy against this disease.

Areas covered: The aim of this review is to provide an update and overview of the current trends in the diagnosis, prevention, and treatment of the disease. It summarizes a recent patent literature (2014–2017) available on the same.

Expert opinion: Some questions like ‘why most of these inventions do not reach up to the market for public use? Are these inventions being explored only to get a financial return to a particular industry or do they have any societal benefit?’ emphatically come to mind. Together with the efforts taken by various governmental and nongovernmental organizations, a public awareness about the recent advancements in the diagnosis and treatment of the disease is of the highest importance to make ‘the end of TB’ from the universe.