Adjunctive Drug Research Articles

Acceleration of Tuberculosis Treatment by Adjunctive Therapy with Verapamil as an Efflux Inhibitor

A major priority in tuberculosis (TB) is to reduce effective treatment times and emergence of resistance. Recent studies in macrophages and zebrafish show that inhibition of mycobacterial efflux pumps with verapamil reduces the bacterial drug tolerance and may enhance drug efficacy. Using mice, a mammalian model known to predict human treatment responses, and selecting conservative human bioequivalent doses, we tested verapamil as an adjunctive drug together with standard TB chemotherapy. As verapamil is a substrate for CYP3A4, which is induced by rifampin, we evaluated the pharmacokinetic/pharmacodynamic relationships of verapamil and rifampin coadministration in mice. Using doses that achieve human bioequivalent levels matched to those of standard verapamil, but lower than those of extended release verapamil, we evaluated the activity of verapamil added to standard chemotherapy in both C3HeB/FeJ (which produce necrotic granulomas) and the wild-type background C3H/HeJ mouse strains. Relapse rates were assessed after 16, 20, and 24 weeks of treatment in mice. We determined that a dose adjustment of verapamil by 1.5-fold is required to compensate for concurrent use of rifampin during TB treatment. We found that standard TB chemotherapy plus verapamil accelerates bacterial clearance in C3HeB/FeJ mice with near sterilization, and significantly lowers relapse rates in just 4 months of treatment when compared with mice receiving standard therapy alone. These data demonstrate treatment shortening by verapamil adjunctive therapy in mice, and strongly support further study of verapamil and other efflux pump inhibitors in human TB.

Thermo‐Reversible Green Tea Catechin Gel for Local Application in Chronic Periodontitis: A 4‐Week Clinical Trial

Green tea extract is a naturally occurring antimicrobial agent, consisting of polyphenols (catechin) with anticariogenic, anti-inflammatory, anticollagenolytic properties. Hence, in the present study, an attempt was made to develop a thermo-reversible sustained-release green tea gel and to study its clinical effects on patients with chronic periodontitis (CP). Thermo-reversible sustained-release green tea catechin gel was prepared and tested for its in vitro release characteristics. An in vivo controlled, randomized, split-mouth single-evaluator masked study was conducted. Thirty patients with two sites in the contralateral quadrants having probing depths (PDs) of ≥4 mm were selected. Assessment of gingival index (GI), PD, and relative clinical attachment levels (rCALs) was done at baseline and at 4 weeks. Green tea and placebo gels were placed at test and control sites as an adjunct to Phase 1 periodontal therapy. Comparison of the mean ± SD GI, PD, and rCAL values within the test group at baseline (1.92 ± 0.24, 4.93 ± 0.58, and 9.97 ± 0.72, respectively) and the end of 4 weeks (0.01 ± 0.04, 2.87 ± 0.51, and 7.87 ± 0.51, respectively) showed high statistical significance (P <0.001). Comparison of mean ± SD of GI, PD, and rCAL within the control group at baseline (1.95 ± 0.16, 4.77 ± 0.50, and 9.73 ± 0.45, respectively) and the end of 4 weeks (0.16 ± 0.11, 3.8 ± 0.48, and 8.76 ± 0.43, respectively) showed significance with P <0.001. High significance was observed between the delta of measurements (0 to 4 weeks) of GI, PD, and rCAL between test (1.91 ± 0.20, 2.06 ± 0.07, and 2.1 ± 0.21, respectively) and control (1.79 ± 0.05, 0.97 ± 0.02, and 0.97 ± 0.02, respectively) groups. Adjunctive local drug therapy with thermo-reversible green tea gel has shown to reduce pockets and inflammation during the 4 weeks of the clinical trial in patients with CP.

AB0795 Tacrolimus therapy for refractory dermatomyositis and polymyositis

BackgroundDermatomyositis (DM) and polymyositis (PM) are systemic inflammatory diseases affecting skeletal muscles, skin and variable other organs (1). Steroids are the mainstay of DM and PM therapy, but a first-line...

The effect of clofibrate in near term newborns with non hemolytic jaundice

The aim of this study was to evaluate the efficacy of clofibrate in reducing total serum bilirubin levels in near term neonates with non hemolytic jaundice. A randomized controlled study was carried out in the neonatal ward of Children's Hospital, Tabriz, Iran, over one year period. Sixty eight healthy near term infants with non hemolytic hyperbilirubinemia were randomized to receive phototherapy plus clofibrate (n=35) or phototherapy and placebo (n=33). There were no significant differences in the weight, gender, modes of delivery and age of neonates between two groups. Similarly, the mean total serum bilirubin (TSB) level at the time of admission was not significantly different between the two groups (19.72±1.79 versus 20.05±2.82 mg/dl, P=0.57). The mean TSB 48 h after phototherapy (8.06±1.34 versus 10.94±2.87 mg/dl P=0.02) and the mean duration of phototherapy (64.32±12.48 versus 87.84±29.76 h P<0.0001) was significantly lower in clofibrate treated group. Clofibrate is an effective adjunctive drug in neonatal hyperbilirubinemia and results to lower TSB level and reduced duration of phototherapy in near term newborns. Key words: Clofibrate, near term neonate, non hemolytic jaundice, phototherapy.

Anti‐infective therapy of peri‐implantitis with adjunctive local drug delivery or photodynamic therapy: 12‐month outcomes of a randomized controlled clinical trial

The objective of the study is to compare the clinical, microbiological and host-derived effects in the non-surgical treatment of initial peri-implantitis with either adjunctive local drug delivery (LDD) or adjunctive photodynamic therapy (PDT) after 12months. Forty subjects with initial peri-implantitis, that is, pocket probing depths (PPD) 4-6mm with bleeding on probing (BoP) and radiographic bone loss ≤2mm, were randomly assigned to two treatment groups. All implants were mechanically debrided with titanium curettes and with a glycine-based powder airpolishing system. Implants in the test group (N=20) received adjunctive PDT, whereas minocycline microspheres were locally delivered into the peri-implant pockets of control implants (N=20). At sites with residual BoP, treatment was repeated after 3, 6, 9 and 12months. The primary outcome variable was the change in the number of peri-implant sites with BoP. Secondary outcome variables included changes in PPD, clinical attachment level (CAL), mucosal recession (REC) and in bacterial counts and crevicular fluid (CF) levels of host-derived biomarkers. After 12months, the number of BoP-positive sites decreased statistically significantly (P<0.05) from baseline in both groups (PDT: 4.03±1.66-1.74±1.37, LDD: 4.41±1.47-1.55±1.26). A statistically significant (P<0.05) decrease in PPD from baseline was observed at PDT-treated sites up to 9months (4.19±0.55mm to 3.89±0.68mm) and up to 12months at LDD-treated sites (4.39±0.77mm to 3.83±0.85mm). Counts of Porphyromonas gingivalis and Tannerella forsythia decreased statistically significantly (P<0.05) from baseline to 6months in the PDT and to 12months in the LDD group, respectively. CF levels of IL-1β decreased statistically significantly (P<0.05) from baseline to 12months in both groups. No statistically significant differences (P>0.05) were observed between groups after 12months with respect to clinical, microbiological and host-derived parameters. Non-surgical mechanical debridement with adjunctive PDT was equally effective in the reduction of mucosal inflammation as with adjunctive delivery of minocycline microspheres up to 12months. Adjunctive PDT may represent an alternative approach to LDD in the non-surgical treatment of initial peri-implantitis.

Recent advances in the molecular basis of anti-neoplastic mechanisms of oridonin

Oridonin, a diterpenoid isolated from Rabdosia rubescens, has been proven to possess various pharmacological and physiological effects such as anti-inflammation, anti-bacterial, and anti-neoplastic, although in recent years, more attention has been paid to its anti-neoplastic effects. For example, oridonin can trigger cell cycle arrest, apoptosis, and autophagy in different neoplastic cell lines. This review summarizes the considerable knowledge about the action mechanisms of oridonin that has been studied in recent years. The present observations reveal the novel anti-neoplastic effects of oridonin, suggesting that it may be effective as a potent alternative or adjunct drug to conventional chemotherapy.

Optimal choice of coronary revascularization and stent type in diabetic patients with coronary artery disease.

Patients with diabetes mellitus (DM) are prone to a diffuse and accelerated form of coronary artery disease (CAD), which in turn is a major cause of cardiac-related morbidity and mortality. Compared with patients without diabetes, patients with diabetes undergoing coronary revascularization are at higher risk of procedural, short-, and long-term cardiovascular events and mortality. Although coronary artery bypass grafting (CABG) has been regarded as the primary revascularization strategy in diabetic patients with complex CAD, percutaneous coronary intervention (PCI) is an effective revascularization alternative, due to remarkable advances in stent devices and adjunctive drug therapies. Outcomes data, from subgroup analyses and small-sized clinical trials and large registries, have suggested that PCI with current stent technology showed comparable long-term risks of mortality and hard endpoints, but higher risk of repeat revascularization for the diabetic population compared to CABG. However, the recent landmark International Future REvascularization Evaluation in patients with diabetes mellitus: optimal management of Multivessel disease (FREEDOM) trial provides compelling evidence of the superiority of CABG over PCI in reducing the rates of death, myocardial infarction, at the expense of stroke, in patients with diabetes with advanced CAD. When opting for PCI in patients with diabetes, currently used drug-eluting stents (DES) are more efficient in reducing the risk of repeat revascularization without compromising safety outcomes, compared to bare-metal stents. The selection of a specific type of DES in patients with diabetes is controversial and therefore more data comparing second- and newer-generation DES for patients with diabetes are currently needed. Also, efforts to make more advanced DES platforms suitable for patients with diabetes with complicated angiographic features are still ongoing.

Cases from NACCT acute and intensive care symposium: Altered mental status, seizures, and rash in a fumigation company employee

Context. Methyl bromide is a halogenated aliphatic hydrocarbon that exists as a colorless gas or a volatile liquid. Methyl bromide historically had been used in fire extinguishers but is more commonly used as a gas fumigant for soil-borne diseases and pests. Methyl bromide is being phased out due to concerns for ozone depletion but can still be found. It is readily absorbed through the lungs while dermal absorption can also occur. Signs and symptoms of severe exposures include headache, respiratory distress, pulmonary hemorrhage, and seizures. In large pulmonary exposures, death can occur as rapidly as 1 h usually from respiratory failure. Methyl bromide can penetrate clothing and protective equipment presenting challenges to first responders. There is a debate over the mechanism of toxicity of methyl bromide and the role of hemodialysis and chelation in treatment. Case details. A 22-year-old female employee of a fumigation company contacted emergency medical services (EMS) after opening a tank of compressed methyl bromide in her car. She was initially combative and confused. She underwent two water dermal decontaminations and was transported to the nearest tertiary center. She rapidly progressed to obtundation with seizure-like activity and dysrhythmias. Despite the supportive care and resuscitative efforts, she died approximately 1 h after her call to EMS. Discussion. Methyl bromide exposures can be fatal, and this case highlights the difficulty in managing these acutely poisoned patients. Questions for consideration after this case include time spent on decontamination, use of adjunctive anti-epileptic drugs, role of chelation therapy, and the role of hemodialysis in the treatment of methyl bromide poisoning.

Targeting Plasmodium falciparum Hsp90: Towards Reversing Antimalarial Resistance.

Malaria continues to exact a great human toll in tropical settings. Antimalarial resistance is rife and the parasite inexorably develops mechanisms to outwit our best drugs, including the now first-line choice, artesunate. Novel strategies to circumvent resistance are needed. Here we detail drug development focusing on heat shock protein 90 and its central role as a chaperone. A growing body of evidence supports the role for Hsp90 inhibitors as adjunctive drugs able to restore susceptibility to traditionally efficacious compounds like chloroquine.

Ondansetron and simvastatin added to treatment as usual in patients with schizophrenia: study protocol for a randomized controlled trial

BackgroundNegative symptoms and cognitive deficits are two partially-related features of schizophrenia which have a major negative impact on social function and objective quality of life. Standard drug treatments have little impact on either. There is some evidence that anti-inflammatory treatment may have beneficial effects in schizophrenia and major depression. Statins are cholesterol-lowering agents that have been found to be anti-inflammatory agents and are also known to decrease C-reactive protein (CRP). Ondansetron is a serotonin (5-HT3) receptor antagonist widely used to prevent nausea and vomiting in patients receiving chemotherapy for cancer. Small studies have suggested that ondansetron is effective as an adjunct drug in improving the symptoms of schizophrenia.Methods/designThis is a two center, six-month, double-blind placebo controlled, factorial design study of ondansetron and/or simvastatin added to treatment as usual for patients suffering from schizophrenia, schizoaffective disorder, psychosis not otherwise specified or schizophreniform disorder. This will be a 2 × 2 design, with 54 patients in each cell, giving a total of 216 patients over three years. There will be a screening, a randomization and seven follow-up visits. Full clinical and neurocognitive assessments will be carried out at baseline (randomization), 14 weeks and at 26 weeks, while the positive and negative syndrome scale (PANSS), pill count and side effects checklist will be carried out at every visit. Simvastatin will be started at 20 mg once daily (OD), this will be increased to 40 mg after four weeks. Ondansetron will be administered in an 8 mg dose.DiscussionAnti-inflammatory treatments have been shown to have some beneficial effects in schizophrenia. Both simvastatin and ondansetron provide some evidence of a reduction in symptoms compared to treatment as usual. The aim of this study is to establish the degree of improvement in negative symptoms with the addition of ondansetron and/or simvastatin to treatment as usual.Trail registrationClinicalTrails.gov NCT01602029

A simple HPLC method for simultaneous analysis of 7 bioactive constituents for Liuwei Dihuang Pill and its application in quality consistency evaluation

A combinative method using HPLC fingerprinting and quantitative analysis was developed and validated for manufacturer-to-manufacturer quality consistency evaluation of Liuwei Dihuang pills (LDP). Seven bioactive constituents of LDP, including gallic acid, 5-hydroxymethyl furfural, morroniside, paeoniflorin, sweroside, loganin and paeonal, were selected as markers to evaluate the similarities of 20 samples from 16 manufacturers. The similarity values for the 20 LDP samples were all greater than 0.92, indicating that there is a general quality consistency for different manufacturers. Additionally, the 7 selected bioactive compounds were in accordance with the compatibility principle of “the monarch drug, the ministerial drug, the adjunctive drug and the messenger drug” of Traditional Chinese Medicine (TCM) prescription and the multi components quality evaluation requirements of TCM as well. The detection and quantification limits for these 7 bioactive components were all less than 0.11 μg mL−1 and 0.38 μg mL−1, respectively. The mean recovery for all the investigated constituents was acceptable with an accuracy of 98–102%. The intra- and inter-day precisions of this method were less than 4.73%, and stability and repeatability were less than 3.23%. This method is simple and reliable, and also shows that the combination of the chromatographic fingerprint and quantitative analysis offers an efficient solution to quality consistency evaluation of herbal preparations.

Antipsychotic‐Like Effect of Trimetazidine in a Rodent Model

Trimetazidine (TMZ) has been used as an anti-ischemic agent for angina pectoris, chorioretinal disturbances, and vertigo. Also, it can induce extrapyramidal type adverse reaction such as parkinsonism, gait disorder, and tremor via blockade of D2 receptors. In the present study, we evaluated the effect of TMZ on novelty-induced rearing behavior and apomorphine-induced stereotypy behavior in male rats. Four groups of rat (n = 7) were administrated with TMZ (10 and 20 mg/kg, i.p.), chlorpromazine (1 mg/kg, i.p.), or isotonic saline. One hour later, apomorphine (2 mg/kg, s.c.) was administrated to each rat. Our results showed that both doses of TMZ significantly decreased the rearing behavior in rats, whereas the decrease with chlorpromazine was higher. TMZ also decreased the stereotypy scores in a dose-dependent manner. We concluded that TMZ has beneficial effects on rearing behavior and stereotypy, which are accepted to be indicators of antipsychotic effect. Taken together, with its antioxidative and cytoprotective properties, TMZ is worthy of being investigated for its anti-psychotic effects as a primary or an adjunctive drug.

Antibiotics and muscle relaxation

Anesthesiologists use quite a few medications during anesthesia of a patient. Those include inhaled anesthetics, intravenous anesthetics, opioids, muscle relaxants, cholinesterase inhibitors, anticholinergic drugs, adrenergic agonists and antagonists, hypotensive agents, local anesthetics, and several adjunct drugs. We are usually well-trained in the administration of these drugs and aware of their actions and side effects. How about antibiotics? The anesthesiologists do not seem to have as much interest in antibiotics as their own favorite drugs. Antimicrobial agents can be used for prophylaxis to reduce the incidence of postoperative infections or for treatment of obvious preexisting infection. It is frequently requested to the anesthetic part to administer the prescribed antibiotics perioperatively. Many institutions have much debate as to the actual administration of the antibiotics, as well as the responsibility for their actions and side effects between anesthesiologists and surgeons. The truth is, each institution has its own protocol for antibiotic administration for the prophylaxis of surgical site infections and updates the protocol occasionally according to the rapid change of the drugs and information. There are potential difficulties that anesthesiologists be made aware of in association with the use of antibiotics, such as allergic reactions, end-organ damage and prolongation of neuromuscular block [1]. Most antibiotics can cause neuromuscular blockade alone and also potentiate blockade when combined with neuromuscular blockers. These can happen by the two different mechanisms, including inhibition of the prejunctional acetylcholine release and depression of postjunctional nicotinic acetylcholine receptor sensitivity to acetylcholine. Because gentamicin covers gram-negative organisms, and clindamycin covers gram-positive and anaerobic organisms, the combination therapy of those is a common treatment for postpartum endometritis. There are few reports about the effect of gentamicin and clindamycin on neuromuscular blockade caused by rocuronium. In this edition of the Journal, Lee et al. [2] studied about the effect of gentamicin and clindamycin to rocuronium-induced neuromuscular blockade in rat phrenic nerve-hemidiaphragm preparations. So far, the authors have succeeded in finding out the effect of a variety of drugs on neuromuscular blockade in a series of in vitro studies. They have presented us with beautiful sigmoid curves to show a relationship between drug concentration and response on the single twitch and tetanic fade in their articles. Their consecutive findings are as follows: 1. Clindamycin and gentamicin interfere with neuromuscular transmission. Neostigmine and calcium antagonize the neuromuscular blockade caused by gentamicin, but augment that caused by clindamycin [3]. 2. Neostigmine partially antagonizes the neuromuscular blockade that is induced by a combination of clindamycin and rocuronium [4]. 3. Bupivacaine inhibits neuromuscular conduction and enhances rocuronium-induced neuromuscular blockade [5]. 4. Gentamicin or a combination of gentamicin and clindamycin enhances rocuronium-induced neuromuscular blockade [2]. All the above laboratory results can be applied clinically in the operating room and intensive care unit. Since anesthesiologists will perhaps not be able to avoid a responsibility in administration of antibiotic regimen as time goes on, we should have the latest knowledge concerning antibiotics, including the interaction with the muscle relaxants.

Zotarolimus-eluting stent-induced hypersensitivity pneumonitis

Zotarolimus-eluting stent-induced hypersensitivity pneumonitis

Psychological interventions for adults who have sexually offended or are at risk of offending

Sexual offending is a serious social and public health problem. Surveys report high levels of psychiatric morbidity in survivors of sexual offences. Biological treatments of sex offenders include anti-libidinal medication: hormonal drugs that have a testosterone-suppressing effect and non-hormonal

Beneficial effects of ginsenoside-Rg1 on ischemia-induced angiogenesis in diabetic mice

Neovascularization and the formation of collateral vessels are often impaired in diabetes mellitus (DM) population compared with non-diabetics. Alterations in vascular endothelial growth factor (VEGF) signaling and endothelial nitric oxide synthase (eNOS) dysfunction have been confirmed to play a crucial role in impaired neovascularization in diabetic mice. Accumulating data have suggested that Rg1, a main component of Panax ginseng, has the ability to promote tubulogenesis of human umbilical vein endothelial cells (HUVECs) in vitro, and that the mechanism involves increased expression level of VEGF as well as increased eNOS activation. Thus, we speculated that Rg1 might also have therapeutic effects on the impairment of neovascularization in diabetic individuals. The aim of the present study was to investigate whether Rg1 could improve angiogenesis in ischemic hindlimb of diabetic mice in vivo. Our data demonstrated that Rg1 treatment resulted in improved angiogenesis in the diabetic ischemic hindlimb, and the potential mechanism might involve increased eNOS activation, upregulated VEGF expression, and inhibited apoptosis. Our results suggest that Rg1 may be used as a novel and useful adjunctive drug for the therapy of peripheral arterial disease in DM.

Rufinamide for refractory focal seizures: An open-label, multicenter European study

PurposeThe present study aimed to assess the efficacy and tolerability of rufinamide as adjunctive drug for the treatment of a large series of children, adolescents and adults with refractory cryptogenic or symptomatic focal epilepsy. MethodsPatients were recruited in a prospective, add-on, open-label treatment study from six Italian and one German centers for pediatric and adolescent epilepsy care. Inclusion criteria were: (1) age 3 years or more; (2) diagnosis of cryptogenic or symptomatic focal epilepsy refractory to at least three previous antiepileptic drugs (AEDs), alone or in combination; (3) more than one seizure per month in the last 6 months; (4) use of at least one other AED, but no more than three, at baseline; (5) informed consent from parents and/or caregivers. ResultsSixty-eight patients (40 males, 28 females), aged between 3 and 63 years (mean 19.9 years, median 16.0)±SD 12.58, with cryptogenic (28 pts, 41.2%) or symptomatic focal epilepsy (40 pts, 58.8%), were recruited in the study. After a mean follow-up period of 10.4±10.29 months, twenty-two patients (32.3%) had a 50–99% seizure reduction, and none became seizure-free. Twelve patients (17.6%) had a 25–49% seizure decrease, while in 30 (44.1%) seizure frequency was unchanged. A seizure worsening was reported in 5 patients (7.3%). A better response to rufinamide occurred in frontal lobe seizures (51.6%) and secondary generalized tonic–clonic seizures (50%). ConclusionRufinamide was effective against focal-onset seizures, particularly in the treatment of secondary generalized frontal lobe seizures.

Adjunctive drugs hasten sedation in the emergency department

Adjunctive drugs hasten sedation in the emergency department

Adjunctive Atropine Versus Metoclopramide: Can We Reduce Ketamine‐associated Vomiting in Young Children? A Prospective, Randomized, Open, Controlled Study

Pediatric procedural sedation and analgesia (PPSA) with ketamine administration occurs commonly in the emergency department (ED). Although ketamine-associated vomiting (KAV) is a less serious complication of ketamine administration, it seems to be cumbersome and not uncommon. The authors evaluated the incidence of KAV and the prophylactic effect of adjunctive atropine and metoclopramide in children receiving ketamine sedation in the ED setting. This prospective, randomized, open, controlled study was conducted in children receiving ketamine sedation in the ED of a university-affiliated, tertiary hospital with 85,000 ED visits, including 32,000 pediatric patients from October 2010 to September 2011. The primary outcome was a measure of the incidence of KAV in the ED and after discharge according to the adjunctive drug administered. Secondary outcome measures included the time to resumption of a normal diet after ketamine sedation. Of the 1,883 children administered ketamine for primary wound repair during the study period, a convenience sample of 338 patients aged 4 months to 5 years was enrolled. The incidences of KAV were 28.4% in the ketamine alone group, 27.9% in the ketamine with adjunctive atropine group, and 31.2% in the ketamine with adjunctive metoclopramide group (p = 0.86). The vomiting rate after discharge was 9.2% in the ketamine alone group. The nothing-by-mouth (NPO) status before sedation did not influence the incidence of KAV in any of the groups. Mean times to resumption of normal diet after ketamine administration were 7 hours 59 minutes in the ketamine alone group, 7 hours 35 minutes in the ketamine with atropine group, and 8 hours 1 minute in the ketamine with metoclopramide group (p = 0.64). In this study, a high rate (28.4%) of KAV was observed, consistent with prior reports using the intramuscular (IM) route. However, the authors were unable to reduce KAV using adjunctive atropine or metoclopramide. Parents or caregivers should be given more detailed discharge instructions about vomiting and diet considering the relatively long time to resuming a normal diet after ketamine sedation and the fact that KAV often occurred after ED discharge.

Acute pain in small animals: how far have we come and where are we going?

Acute pain in small animals: how far have we come and where are we going?