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Once- vs Twice-Daily Tacrolimus: Survival Rates and Side Effects: Single-Center Experience.

Transplant Proc. 2019 Aug 07;:

Authors: Turunc V, Ari E, Guven B, Tabendeh B, Yildiz A

Abstract
BACKGROUND: This study aimed to determine whether de novo, prolonged-release tacrolimus- (PR-tacro) based immunosuppressive regimen affected graft and patient survival when compared to an immediate-release, twice-daily, tacrolimus- (IR-tacro) based regimen in kidney transplant recipients. We also aimed to determine the difference between the frequency of side effects, including diabetes control, in study groups.
METHODS: A total of 115 standard risk kidney transplant recipients were enrolled in this single center, retrospective study. Fifty-two patients received PR-tacro and 63 patients received IR-tacro as a calcineurin inhibitor. The primary outcome measures included incidence of graft loss and delayed graft function (DGF), biopsy-proven acute rejection , graft and patient survival, and creatinine clearance. Secondary outcome measures included the incidence of non-adherence, drug-induced tremor; post-transplant diabetes mellitus diagnosis rate; and control of diabetes in pre-transplant diabetic patients.
RESULTS: Baseline characteristics and mean tacrolimus trough levels were comparable between groups. Incidence of graft loss, DGF, and graft and patient survival were similar between groups (P > .05). Mean creatinine clearance level was also similar (P > .05). Mean serum levels of fasting glucose (P < .05) and A1C (P < .05) were lower in PR-tacro group when compared to IR-tacro group. Post-transplant diabetes mellitus diagnosis rate was also lower in PR-tacro group when compared to IR-tacro group (P = .040).
CONCLUSION: This study suggests that there is no statistically significant difference between PR-tacro and IR-tacro in terms of patient and graft survival, DGF, and biopsy-proven acute rejection rates in kidney transplant recipients. Post-transplant diabetes mellitus frequency is lower in non-diabetic patients, and glucose metabolism control is better in diabetic patients.

PMID: 31400977 [PubMed - as supplied by publisher]

RESTORE-IMI 1: A Multicenter, Randomized, Double-blind Trial Comparing Efficacy and Safety of Imipenem/Relebactam vs Colistin Plus Imipenem in Patients With Imipenem-nonsusceptible Bacterial Infections.

Clin Infect Dis. 2019 Aug 10;:

Authors: Motsch J, Murta de Oliveira C, Stus V, Köksal I, Lyulko O, Boucher HW, Kaye KS, File TM, Brown ML, Khan I, Du J, Joeng HK, Tipping RW, Aggrey A, Young K, Kartsonis NA, Butterton JR, Paschke A

Abstract
BACKGROUND: The β-lactamase inhibitor relebactam can restore imipenem activity against imipenem-nonsusceptible gram-negative pathogens. We evaluated imipenem/relebactam for treating imipenem-nonsusceptible infections.
METHODS: Randomized, controlled, double-blind, phase 3 trial. Hospitalized patients with hospital-acquired/ventilator-associated pneumonia, complicated intraabdominal infection, or complicated urinary tract infection caused by imipenem-nonsusceptible (but colistin- and imipenem/relebactam-susceptible) pathogens were randomized 2:1 to 5-21 days imipenem/relebactam or colistin+imipenem. Primary endpoint: favorable overall response (defined by relevant endpoints for each infection type) in the modified microbiologic intent-to-treat (mMITT) population (qualifying baseline pathogen and ≥1 dose study treatment). Secondary endpoints: clinical response, all-cause mortality, and treatment-emergent nephrotoxicity. Safety analyses included patients with ≥1 dose study treatment.
RESULTS: Thirty-one patients received imipenem/relebactam and 16 colistin+imipenem. Among mITT patients (n = 21 imipenem/relebactam, n = 10 colistin+imipenem), 29% had Acute Physiology and Chronic Health Evaluation II scores >15, 23% had creatinine clearance <60 mL/min, and 35% were aged ≥65 years. Qualifying baseline pathogens: Pseudomonas aeruginosa (77%), Klebsiella spp. (16%), other Enterobacteriaceae (6%). Favorable overall response was observed in 71% imipenem/relebactam and 70% colistin+imipenem patients (90% confidence interval [CI] for difference, -27.5, 21.4), day 28 favorable clinical response in 71% and 40% (90% CI, 1.3, 51.5), and 28-day mortality in 10% and 30% (90% CI, -46.4, 6.7), respectively. Serious adverse events (AEs) occurred in 10% of imipenem/relebactam and 31% of colistin+imipenem patients, drug-related AEs in 16% and 31% (no drug-related deaths), and treatment-emergent nephrotoxicity in 10% and 56% (P = .002), respectively.
CONCLUSIONS: Imipenem/relebactam is an efficacious and well-tolerated treatment option for carbapenem-nonsusceptible infections.
CLINICAL TRIALS REGISTRATION: NCT02452047.

PMID: 31400759 [PubMed - as supplied by publisher]

Conventional formulations, Challenges and Nanomedicines in Infective and Non-Infective Skin Diseases Therapy.

Recent Pat Antiinfect Drug Discov. 2019 Aug 09;:

Authors: Rahman M, Beg S, Akhter S

Abstract
Oral based formulations for treatment of topical infectious and non-infectious disorders causes numerous adverse reactions including of hepatic toxicity, higher metabolism, poor absorption and serious skin events such as drug - drug interactions resulted from metabolism through the cytochrome P450 system [1-3]. Other prefer routes is topical route, in which drug molecules deliver to the SC or epidermis and retained there for an optimum time to exert it therapeutic effect [3, 4-5]. The skin is an ideal site for drug delivery in treatment of topical infective and non-infective skin disease. But its barrier nature of the skin, diseased condition, physiochemical drug properties are major hurdle for drug delivery [6]. Conventional topical formulations such as creams and ointments have failed to gain achieve controlled drug release and drug targeting for the treatment of topical disorders. For effective anti-infective drug therapies, it must be administering and deliver the required quantity of drug into or through the skin to be fix into the epidermis/dermis via sustained release of drug [7]. But skin retention of the drug molecules is a challenging task to achieve due to restricted permeability through the skin. In this regard, the application of nanotechnology to the medicine entitled as nanomedicine has very bright features in the biomedical field [2-3]. Nanomedicines proved good results in the treatment of topical infectious and noninfectious disorders [8]. Nanomedicines overcomes the challenges with the conventional formulations, which based on the development and fabrication of nanostructures [9]. To date, there are various nanoparticulate system have been investigated as effective drug delivery systems, it includes lipidic micro/nano-emulsion system, lipidic vesicular, metallic nanoparticles, lipid nanoparticles, polymeric nanoparticles, lipid-polymer hybrid nanoparticle systems, etc [10]. Among these, the implementation of silver nanoparticles gained wider attention as topical nanocarriers and promising model in the design of effective therapeutics against many pathogenic bacteria. Furthermore, silver nanomedicine possesses several advantages including the targeted drug delivery, minimizes the solubility or stability issues of the drug, low dose and minimizes drug induced side effects [10].

PMID: 31400272 [PubMed - as supplied by publisher]

Relationship of clinical adverse event reports to models of arrhythmia risk.

J Pharmacol Toxicol Methods. 2019 Aug 06;:106622

Authors: Ether N, Leishman D, Bailie M, Lauver DA

Abstract
A vital aspect of the drug discovery and development process is the identification and filtering of drugs with high risk of dangerous adverse events. Torsade de Pointes (TdP) is one example of an adverse event that requires thorough in vitro and in vivo drug screening. This is because TdP, a tachycardic ventricular arrhythmia, can develop into fatal cardiac events if left unresolved and has been missed during drug development with profound consequences. These factors led to the development of pre-clinical screening guidelines based on the presence of drug induced QT prolongation (QTp), which has been linked to TdP. These guidelines have high sensitivity, but low specificity, as they tend to predict QTp, which precedes TdP events but does not always lead to TdP. Computational models have the potential to improve these prediction methods by bridging the gaps between preclinical and clinical data. This study proposes the use of adverse event reports obtained from the FDA Adverse Event Reporting System as a representation of clinical TdP risk. By incorporating these reports into computational models, a more accurate risk prediction may be developed.

PMID: 31398384 [PubMed - as supplied by publisher]

Immunogenicity of pembrolizumab in patients with advanced tumors.

J Immunother Cancer. 2019 Aug 08;7(1):212

Authors: van Vugt MJH, Stone JA, De Greef RHJMM, Snyder ES, Lipka L, Turner DC, Chain A, Lala M, Li M, Robey SH, Kondic AG, De Alwis D, Mayawala K, Jain L, Freshwater T

Abstract
BACKGROUND: Pembrolizumab is a potent, humanized, monoclonal anti-programmed death 1 antibody that has demonstrated effective antitumor activity and acceptable safety in multiple tumor types. Therapeutic biologics can result in the development of antidrug antibodies (ADAs), which may alter drug clearance and neutralize target binding, potentially reducing drug efficacy; such immunogenicity may also result in infusion reactions, anaphylaxis, and immune complex disorders. Pembrolizumab immunogenicity and its impact on exposure, safety, and efficacy was assessed in this study.
PATIENTS AND METHODS: Pembrolizumab immunogenicity was assessed in 3655 patients with advanced or metastatic cancer treated in 12 clinical studies. Patients with melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, colorectal cancer, urothelial cancer, and Hodgkin lymphoma were treated with pembrolizumab at 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, or 200 mg every 3 weeks. An additional study involving 496 patients with stage III melanoma treated with 200 mg adjuvant pembrolizumab every 3 weeks after complete resection was analyzed separately.
RESULTS: Of 3655 patients, 2000 were evaluable for immunogenicity analysis, 36 (1.8%) were treatment-emergent (TE) ADA-positive; 9 (0.5%) of these TE-positive patients had antibodies with neutralizing capacity. The presence of pembrolizumab-specific ADAs did not impact pembrolizumab exposure, nor did pembrolizumab immunogenicity affect the incidence of drug-related adverse events (AEs) or infusion-related reactions. There was no clear relationship between the presence of pembrolizumab-specific ADAs and changes in tumor size across treatment regimens. Of the 496 patients treated with pembrolizumab as adjuvant therapy, 495 were evaluable, 17 (3.4%) were TE ADA-positive; none had neutralizing antibodies.
CONCLUSIONS: The incidence of TE (neutralizing positive) ADAs against pembrolizumab was low in patients with advanced tumors. Furthermore, immunogenicity did not appear to have any clinically relevant effects on the exposure, safety, or efficacy of pembrolizumab.
TRIAL REGISTRATION: ClinicalTrials.gov, NCT01295827 (February 15, 2011), NCT01704287 (October 11, 2012), NCT01866319 (May 31, 2013), NCT01905657 (July 23, 2013), NCT02142738 (May 20, 2014), NCT01848834 (May 8, 2013), NCT02255097 (October 2, 2014), NCT02460198 (June 2, 2015), NCT01953692 (October 1, 2013), NCT02453594 (May 25, 2015), NCT02256436 (October 3, 2014), NCT02335424 (January 9, 2015), NCT02362594 (February 13, 2015).

PMID: 31395089 [PubMed - in process]

Drug Interactions in Space: a Cause for Concern?

Pharm Res. 2019 May 31;36(8):114

Authors: Berman E, Eyal S

Abstract
PURPOSE: Crewmembers aboard the International Space Station (ISS) have free access to an increasing number of medications within medical kits. The aim of the current study was to assess the number, severity and reliability of potential drug-drug interactions (DDIs) involving those medications.
METHODS: We evaluated the information obtained from clinical decision support systems. Searches for potential DDIs were applied to published lists of medications available to US astronauts in medical kits aboard the ISS.
RESULTS: A total of 311 potential DDIs were identified by Lexi-Interact, of which approximately half were recognized by Micromedex as well. Major, moderate and minor interactions consisted 23.5%, 68.5% and 8.0% of entries, respectively. The reliability of 71.1% of alerts was fair. Commonly used drugs, including zolpidem and zaleplon, were involved in multiple potential interactions that were classified as major based on additive CNS depression.
CONCLUSIONS: Most potential DDIs likely to be encountered in space are unestablished even in terrestrial medicine and their assignment is based on class-effects. Yet, some drug combinations may be associated with clinically-relevant consequences. Future DDI rating should be adjusted to space-related outcomes. Until that happens, it would be advisable to avoid non-established drug combinations in space when possible.

PMID: 31152244 [PubMed - indexed for MEDLINE]

Do Statins Have a Positive Impact on Patients with Coronary Microvascular Dysfunction on Long-Term Clinical Outcome? A Large Retrospective Cohort Study.

Biomed Res Int. 2019;2019:4069097

Authors: Luo WH, Guo Y, Huang JW, Zhang PD

Abstract
Objectives: To investigate the influence of statins on major adverse cardiovascular events (MACE) in patients with coronary microvascular dysfunction (CMVD).
Participants: 23,494 patients who received coronary angiography (CAG) were included. Thrombolysis in Myocardial Infarction, Myocardial Perfusion Grading (TMPG), a useful angiographic method, was used to evaluate CMVD.
Results: Using multivariate analysis, NYHA III/IV (HR, 1.44; 95% CI, 1.03-2.01; P=0.031), PCI history (HR, 3.69; 95% CI, 2.57-5.31; P<0.001), TG (HR, 1.15; 95% CI, 1.06-1.26; P=0.001), creatinine (HR, 1.00; 95% CI, 1.00-1.01; P<0.001), cTnT (HR, 0.98; 95% CI, 0.96-0.99; P<0.001), heart rate (HR, 0.98; 95% CI, 0.97-0.99; P=0.001), β-blocker (HR, 0.68; 95% CI, 0.51-0.91; P=0.008), aspirin (HR, 0.38; 95% CI, 0.24-0.61; P<0.001), and statins (HR, 0.33; 95% CI, 0.19-0.60; P<0.001) significantly correlated with reduced MACE in CMVD patients. In subgroups analysis, statins decreased MACE overall (HR, 0.33; 95% CI, 0.19-0.59; P<0.001) and in CMVD patients with smoking history (HR, 0.64; 95% CI, 0.43-0.93; P=0.014), diabetes (HR,0.27; 95% CI,0.12-0.61; P=0.002), hypertension (HR, 0.10; 95% CI, 0.03-0.36; P=0.001), and hypertension and diabetes (HR, 0.09; 95% CI, 0.014-0.53; P=0.008).
Conclusion: Statins could reduce MACE in patients with CMVD.

PMID: 31008104 [PubMed - indexed for MEDLINE]

Posaconazole salvage therapy: The Posifi study.

Mycoses. 2019 Jun;62(6):526-533

Authors: Fortun J, Gioia F, Cardozo C, Gudiol C, Diago E, José Castón J, Muñoz P, López J, Puerta-Alcalde P, Enzenhofer M, Ramos A, Frutos A, Machado M, Garcia-Vidal C, Parody R, Martín-Dávila P

Abstract
BACKGROUND: Posaconazole (PCZ) is used mainly for the prevention of invasive fungal infection (IFI).
METHODS: A multicentre retrospective, investigational study using a non-randomized, single-arm design carried out in six tertiary hospitals in Spain to evaluate the use of PCZ in different forms of administration in the (non-prophylactic) treatment of IFI.
RESULTS: Over an eight-year-period, 67 patients were included in this study. PCZ was administered as salvage therapy (intolerant or refractory to a previous antifungal agent) in 65/67 (97%); of these, it was used against Aspergillosis (68.6%), Zygomycosis (13.4%), other moulds (8.9%) and yeast (10.5%). The median duration of PCZ therapy was 75 days. The oral solution was associated with low serum levels (<0.7 mg/L) in 63% of available patients. Clinical response at 3 and 12 months of PCZ therapy were for aspergillosis: 47.8% and 41.3%; for zygomycosis: 55.5% and 55.5%; and for other mycoses: 69.2% and 69.2%, respectively. Suspension by toxicity was only observed in 6% and 7.5% of patients at 3 and 12 months, respectively, mainly with grade III/IV elevations of liver function test (LFTs).
CONCLUSIONS: Posaconazole salvage therapy, especially oral tablets, can be an effective alternative option for patients with IFI who cannot tolerate or do not respond to other antifungal therapies.

PMID: 30864238 [PubMed - indexed for MEDLINE]

Real-world use-Isavuconazole at a large academic medical center.

Mycoses. 2019 Jun;62(6):534-541

Authors: Hassouna H, Athans V, Brizendine KD

Abstract
BACKGROUND: Isavuconazole use in the real-world setting has not been extensively described. Subgroups of patients with particular prognostic significance, such as previous triazole prophylaxis or treatment and the important subgroup treated empirically for invasive fungal infection, have beforehand been excluded from trials.
OBJECTIVES: We aimed to determine treatment response and safety in these patients at a large US transplant and cancer centre.
PATIENTS/METHODS: We conducted a retrospective cohort study of all adult inpatients administered ≥3 doses of isavuconazole between June 2015 and October 2017.
RESULTS: Ninety-one adults were identified. Six (7%) received primary prophylaxis, 10 (11%) treatment then secondary prophylaxis and 75 (82%) treatment only. Overall treatment response was 62%. Six-week mortality was 24%. Sixty-three per cent of 32 patients treated with isavuconaozle following prophylaxis with another antifungal agent exhibited a treatment response. Among 49 patients switched from treatment with another agent, 53% had a treatment response. Thirty-four patients received isavuconazole empirically, and 65% demonstrated a treatment response. Individuals given isavuconazole prophylaxis developed no breakthrough invasive fungal infections. One patient discontinued isavuconazole due to hepatotoxicity.
CONCLUSIONS: Real-world isavuconazole use appears safe and is associated with treatment responses in varied patients including critically important subgroups previously unreported.

PMID: 30851214 [PubMed - indexed for MEDLINE]

Suspected Carboplatin Extravasation Reactions in Seven Dogs.

J Am Anim Hosp Assoc. 2018 Nov/Dec;54(6):360-367

Authors: Miller KB, Lejeune A, Regan R, Szivek A, Kow K

Abstract
Carboplatin is a platinum chemotherapeutic agent commonly used in veterinary oncology that is currently classified as an irritant to local tissues when extravasated. To the authors' knowledge, there are no reports of vesicant injuries associated with carboplatin administration reported in the veterinary literature. In this case series, seven dogs are described to have experienced injuries following a suspected carboplatin extravasation resembling vesicant injuries a median of 7 days after carboplatin administration (range 4-15 days). Wounds healed with a variety of treatments, including medical management and/or surgical debridement, a median of 25.5 days (range 7-49 days) after observation of the suspected extravasation injury. There were no obvious similarities involving carboplatin administration among patients to explain why these reactions occurred. Extravasation injury should be considered a possible local complication associated with carboplatin chemotherapy.

PMID: 30272477 [PubMed - indexed for MEDLINE]

Potential hepatoxicity risk of the shell of Herpetospermum caudigerum Wall in rats based on 1H-NMR metabonomics.

J Pharm Biomed Anal. 2019 Aug 01;176:112800

Authors: Feng X, Xu H, Chen JF, Ruan LY, Zhao WL, Meng HH, Liu WY, Zhao WL, Zheng Q, Liu ZC, Kan ZB, Zhong GJ, Wang JS

Abstract
The Herpetospermum caudigerum Wall (HCW) is a traditional Tibetan medicine and is widely used in clinical practice. However, the shell of the HCW (SHCW) has rarely been studied, and some researchers have suggested that the SHCW may be toxic. Therefore, in this study, SHCW was administered to rats at two doses (0.1 and 0.33 g/kg) once a day for 21 days. The hepatic stimuli induced by SHCW in rats were investigated for the first time by 1H-NMR-based metabolomics combined with histopathological observation and biochemical detection. Histopathological sections showed a certain degree of hepatocyte edema and hepatic sinus congestion in the liver tissue of the rats in the drug-administered group. Serum biochemical indicators revealed a significant increase in ALT, AST, and MDA, and a significant decrease in SOD. Metabolomic results showed that the metabolites in rats were changed after gavage administration of extracts from SHCW. By multivariate statistical analysis and univariate analysis, it was found that SHCW could cause the disorder of energy metabolism, oxidative stress and amino acid metabolism in rats, leading to liver damage. This comprehensive metabolomics approach demonstrates its ability to describe the global metabolic state of an organism and provides a powerful and viable tool for exploring drug-induced toxicity or side effects.

PMID: 31394304 [PubMed - as supplied by publisher]

Dandelion Root and Lemongrass Extracts Induce Apoptosis, Enhance Chemotherapeutic Efficacy, and Reduce Tumour Xenograft Growth In Vivo in Prostate Cancer.

Evid Based Complement Alternat Med. 2019;2019:2951428

Authors: Nguyen C, Mehaidli A, Baskaran K, Grewal S, Pupulin A, Ruvinov I, Scaria B, Parashar K, Vegh C, Pandey S

Abstract
Many conventional chemotherapies have indicated side effects due to a lack of treatment specificity and are thus not suitable for long-term usage. Natural health products are well-tolerated and safe for consumption, and some have pharmaceutical uses particularly for their anticancer effects. We have previously reported the anticancer efficacy of dandelion (Taraxacum officinale) root and lemongrass (Cymbopogon citratus) extracts. However, their efficacy on prostate cancer and their interactions with standard chemotherapeutics have not been studied to determine if they will be suitable for adjuvant therapies. If successful, these extracts could potentially be used in conjunction with chemotherapeutics to minimize the risk of drug-related toxicity and enhance the efficacy of the treatment. We have demonstrated that both dandelion root extract (DRE) and lemongrass extract (LGE) exhibit selective anticancer activity. Importantly, DRE and LGE addition to the chemotherapeutics taxol and mitoxantrone was determined to enhance the induction of apoptosis when compared to individual chemotherapy treatment alone. Further, DRE and LGE were able to significantly reduce the tumour burden in prostate cancer xenograft models when administered orally, while also being well-tolerated. Thus, the implementation of these well-tolerated extracts in adjuvant therapies could be a selective and efficacious approach to prostate cancer treatment.

PMID: 31391857 [PubMed]

Final results of the phase 1/2, open-label clinical study of intravenous recombinant human N-acetyl-α-d-glucosaminidase (SBC-103) in children with mucopolysaccharidosis IIIB.

Mol Genet Metab. 2019 02;126(2):131-138

Authors: Whitley CB, Vijay S, Yao B, Pineda M, Parker GJM, Rojas-Caro S, Zhang X, Dai Y, Cinar A, Bubb G, Patki KC, Escolar ML

Abstract
Mucopolysaccharidosis IIIB is caused by a marked decrease in N-acetyl-α-d-glucosaminidase (NAGLU) enzyme activity, which leads to the accumulation of heparan sulfate in key organs, progressive brain atrophy, and neurocognitive decline. In this open-label study, 11 eligible patients aged 2 to <12 years (developmental age ≥ 1 year) were sequentially allocated to recombinant human NAGLU enzyme (SBC-103) in 3 staggered- and escalating-dose groups (0.3 mg/kg [n = 3], 1.0 mg/kg [n = 4], or 3.0 mg/kg [n = 4]) by intravenous infusion every 2 weeks for 24 weeks, followed by a 4-week interruption (Part A), treatment at 1.0 and/or 3.0 mg/kg every 2 weeks starting at week 28 (Part B), and treatment at 5.0 or 10.0 mg/kg every 2 weeks (Part C) for approximately 2 total years in the study. The primary objective of the study was safety and tolerability evaluation; secondary objectives included evaluation of SBC-103 effects on total heparan sulfate levels in cerebrospinal fluid (CSF), brain structural magnetic resonance imaging (cortical gray matter volume), and neurocognitive status (age equivalent/developmental quotient). During the study, 13 treatment-emergent serious adverse events (SAEs) occurred in 3 patients; 32 infusion-associated reactions (IARs) occurred in 8 patients. Most AEs were mild and intravenous treatment with SBC-103 was well tolerated. Mean (SD) changes from baseline at 52 weeks in Part C for the 5.0 and 10.0 mg/kg doses, respectively, were: -4.7% (8.3) and - 4.7% (14.7) for heparan sulfate levels in CSF, -8.1% (3.5) and - 10.3% (9.4) for cortical gray matter volume, +2.3 (6.9) points and +1.0 (9.2) points in cognitive age equivalent and -8.9 (10.2) points and -14.4 (9.2) points in developmental quotient. In summary, SBC-103 was generally well tolerated. Changes in heparan sulfate levels in CSF were small and were not maintained from earlier study time points, there was no clear evidence overall of clinically meaningful improvement in neurocognitive function at the higher doses investigated, and no dose-dependent effects were observed.

PMID: 30635159 [PubMed - indexed for MEDLINE]

Recovery of metabolic impairment in patients who cleared chronic hepatitis C infection after direct-acting antiviral therapy.

Int J Antimicrob Agents. 2019 May;53(5):559-563

Authors: Lanini S, Scognamiglio P, Pisapia R, Minosse C, Agresta A, Ippolito G

Abstract
Chronic hepatitis C (CHC) is a complex disease that can affect different metabolic processes, including glucose and lipid metabolic pathways, with a significant impact on the development of heart disease and stroke. Recent therapy with direct-acting antivirals (DAAs), beyond its high efficacy on CHC eradication, showed a beneficial impact on glucose and lipid metabolism. This review aimed to describe current evidence regarding the association between hepatitis C virus (HCV) infection and impairment of glucose and lipid metabolism and also discusses potential public-health implications in light of the new DAA therapies and their availability at a global level. The excellent safety profile and efficacy of DAAs offer an exceptional opportunity to control the HCV pandemic at a global level and represent an opportunity for developing an operational research framework aimed at investigating the complex dynamics between host, pathogen and therapy that lead to metabolic damage in subjects with infectious diseases.

PMID: 30550818 [PubMed - indexed for MEDLINE]

Intrathecal heparan-N-sulfatase in patients with Sanfilippo syndrome type A: A phase IIb randomized trial.

Mol Genet Metab. 2019 02;126(2):121-130

Authors: Wijburg FA, Whitley CB, Muenzer J, Gasperini S, Del Toro M, Muschol N, Cleary M, Sevin C, Shapiro E, Bhargava P, Kerr D, Alexanderian D

Abstract
BACKGROUND: Sanfilippo syndrome type A (mucopolysaccharidosis type IIIA) is a lysosomal disorder wherein deficient heparan-N-sulfatase (HNS) activity results in the accumulation of heparan sulfate in the central nervous system and is associated with progressive neurodegeneration in early childhood. We report on the efficacy, pharmacokinetics, safety, and tolerability of intrathecal (IT) administration of recombinant human HNS (rhHNS) from a phase IIb randomized open-label trial.
METHODS: Twenty-one patients, randomized 1:1:1 to rhHNS IT 45 mg administered every 2 weeks (Q2W), every 4 weeks (Q4W), or no treatment, were assessed for amelioration in neurocognitive decline as determined by the Bayley Scales of Infant and Toddler Development®, Third Edition. The primary efficacy goal was defined as ≤10-point decline (responder) in at least three patients in a dosing cohort after 48 weeks. Other efficacy assessments included adaptive behavioral function, assessments of cortical gray matter volume, and glycosaminoglycan (GAG) levels in urine.
RESULTS: A clinical response to rhHNS IT was observed in three treated patients (two in the Q2W group, one in the Q4W group). Cerebrospinal fluid heparan sulfate and urine GAG levels were reduced in all treated patients. However, most secondary efficacy assessments were similar between treated patients (n = 14; age, 17.8-47.8 months) and untreated controls (n = 7; age, 12.6-45.0 months). Treatment-emergent adverse events that occurred with rhHNS IT were mostly mild, none led to study discontinuation, and there were no deaths.
CONCLUSION: rhHNS IT treatment reduced heparan sulfate and GAG levels in treated patients. Though the primary neurocognitive endpoint was not met, important lessons in the design and endpoints for evaluation of cognitive and behavioral diseases resulted.
TRIAL REGISTRATION: ClinicalTrials.govNCT02060526; EudraCT 2013-003450-24.

PMID: 30528227 [PubMed - indexed for MEDLINE]

What do we know about cancer immunotherapy? Long-term survival and immune-related adverse events.

Allergol Immunopathol (Madr). 2019 May - Jun;47(3):303-308

Authors: Miranda Poma J, Ostios Garcia L, Villamayor Sanchez J, D'errico G

Abstract
Immunotherapy delivered a new therapeutic option to the oncologist: Ipilimumab (anti-CTLA-4), Nivolumab and Pembrolizumab (anti-PD1), and Atezolizumab (anti-PD-L1) increase overall survival and show a better safety profile compared to chemotherapy in patients with metastatic melanoma, lung, renal cancer among others. But all that glitters is not gold and there is an increasing number of reports of adverse effects while using immune-checkpoint inhibitors. While chemotherapy could weaken the immune system, this novel immunotherapy could hyper-activate it, resulting in a unique and distinct spectrum of adverse events, called immune-related adverse events (IRAEs). IRAEs, ranging from mild to potentially life-threatening events, can involve many systems, and their management is radically different from that of cytotoxic drugs: immunosuppressive treatments, such as corticoids, infliximab or mycophenolate mofetil, usually result in complete reversibility, but failing to do so can lead to severe toxicity or even death. Patient selection is an indirect way to reduce adverse events minimizing the number of subjects exposed to this drugs: unfortunately PDL-1, the actual predictive biomarker, would not allow clinicians select or exclude patients for treatment with checkpoint inhibitors.

PMID: 29983240 [PubMed - indexed for MEDLINE]

Prevalence of Drugs as Triggers of Exacerbations in Chronic Urticaria.

J Investig Allergol Clin Immunol. 2019;29(2):112-117

Authors: Sánchez J, Sánchez A, Cardona R

Abstract
BACKGROUND AND OBJECTIVE: Many patients with chronic spontaneous urticaria (CSU) report various drugs as triggers of their symptoms and often avoid medication unnecessarily. Objective: To estimate the clinical impact of the drugs patients most frequently suspect of inducing CSU exacerbations.
METHODS: The prevalence of self-reported drug reactions was evaluated by questioning patients about their clinical history of urticaria and drug reactions and performing challenge tests with the suspect drugs. A group of healthy persons were included as controls to evaluate the prevalence of self-reported drug reactions.
RESULTS: The study population comprised 245 patients with CSU and 127 healthy individuals. At least 1 adverse drug reaction was reported by 92 (37.5%) patients and 30 (23.6%) controls. Nonsteroidal anti-inflammatory drugs (NSAIDs) (27.7%) and ß-lactams (9.4%) were the most commonly reported drugs in the CSU group and the control group, respectively. Positive results in the challenge tests were less common than self-reports in the CSU group (13%) and the control group (0.7%).
CONCLUSIONS: Self-reporting is generally not sufficient to confirm a drug reaction. Drug reactions to NSAIDs and ß-lactams are more frequent among patients who experience CSU than in those who do not. Drug challenge tests should be offered early during medical evaluation to avoid unnecessary restrictions.

PMID: 29956666 [PubMed - indexed for MEDLINE]

ProTox-II: a webserver for the prediction of toxicity of chemicals.

Nucleic Acids Res. 2018 07 02;46(W1):W257-W263

Authors: Banerjee P, Eckert AO, Schrey AK, Preissner R

Abstract
Advancement in the field of computational research has made it possible for the in silico methods to offer significant benefits to both regulatory needs and requirements for risk assessments, and pharmaceutical industry to assess the safety profile of a chemical. Here, we present ProTox-II that incorporates molecular similarity, pharmacophores, fragment propensities and machine-learning models for the prediction of various toxicity endpoints; such as acute toxicity, hepatotoxicity, cytotoxicity, carcinogenicity, mutagenicity, immunotoxicity, adverse outcomes pathways (Tox21) and toxicity targets. The predictive models are built on data from both in vitro assays (e.g. Tox21 assays, Ames bacterial mutation assays, hepG2 cytotoxicity assays, Immunotoxicity assays) and in vivo cases (e.g. carcinogenicity, hepatotoxicity). The models have been validated on independent external sets and have shown strong performance. ProTox-II provides a freely available webserver for in silico toxicity prediction for toxicologists, regulatory agencies, computational and medicinal chemists, and all users without login at http://tox.charite.de/protox_II. The webserver takes a two-dimensional chemical structure as an input and reports the possible toxicity profile of the chemical for 33 models with confidence scores, and an overall toxicity radar chart along with three most similar compounds with known acute toxicity.

PMID: 29718510 [PubMed - indexed for MEDLINE]

Immunologic adverse reactions of β-blockers and the skin.

Exp Ther Med. 2019 Aug;18(2):955-959

Authors: Tatu AL, Elisei AM, Chioncel V, Miulescu M, Nwabudike LC

Abstract
β-Blockers are a widely utilised class of medication. They have been in use for a variety of systemic disorders including hypertension, heart failure and intention tremors. Their use in dermatology has garnered growing interest with the discovery of their therapeutic effects in the treatment of haemangiomas, their potential positive effects in wound healing, Kaposi sarcoma, melanoma and pyogenic granuloma, and, more recently, pemphigus. Since β-blockers are deployed in a variety of disorders, which have cutaneous co-morbidities such as psoriasis, their pertinence to dermatologists cannot be overstated. Likewise, β-blockers, like any other drug category, carry risks of side effects, some of which are dermatologic. These include triggering and exacerbation of psoriasis, psoriatic and rheumatoid arthritis, anaphylaxis, contact dermatitis, occupational contact dermatitis, Raynaud's disease, alopecia, lichen planus-like drug eruption, hyperhydrosis and vitiligo. While recent articles have focussed on the positive uses of β-blockers, it may also be wise to call our attention to the potential dermatologic adverse effects that may follow β-blocker use, as well as possible therapeutic approaches to these. This short review will focus on those dermatoses resulting from β-blocker use, which have an immunologic basis.

PMID: 31384329 [PubMed]