Safety and immunogenicity of a Herpes Zoster subunit vaccine in Japanese population aged ≥50 years when administered subcutaneously vs. intramuscularly.

Hum Vaccin Immunother. 2017 Mar 04;13(3):574-578

Authors: Vink P, Shiramoto M, Ogawa M, Eda M, Douha M, Heineman T, Lal H

Abstract
The impact of alternate routes of vaccine administration, subcutaneous (SC) or intramuscular (IM), on the safety and immunogenicity of herpes zoster subunit candidate vaccine (HZ/su) was assessed in Japanese adults aged ≥ 50 y. During this phase III open-label study, 60 subjects were randomized (1:1) to receive HZ/su through SC or IM routes in a 0, 2 month schedule. Vaccine response rates (VRRs) and geometric mean concentrations (GMCs) of varicella zoster virus glycoprotein E (gE)-specific antibodies were determined by ELISA. Solicited and unsolicited symptoms were recorded for 7 and 30 d after each vaccination and graded 1-3 in severity. Serious adverse events (SAEs) were recorded throughout the study. At one month post-dose 2, VRRs were 100% (95% Confidence Interval (CI): 88.1-100) in both groups; anti-gE antibody GMCs were 44126.1 mIU/ml (95% CI: 36326.1-53601.0) and 45521.5 mIU/ml (95% CI; 37549.5-55185.9) in the SC and IM groups, respectively. Injection site reactions (pain, swelling and redness) were common, and observed more frequently following SC administration. Grade 3 redness and swelling were more frequently observed after SC administration. Fatigue and headache were the most frequently reported general symptoms for both routes of administration. Ten and 7 unsolicited AEs were reported in the SC and IM group, respectively. Two unsolicited AEs (1 in SC; 1 in IM) were considered related to vaccination by the investigator. Three non-fatal SAEs considered unrelated to vaccination were reported during the study. Administration of the HZ/su vaccine candidate resulted in a substantial immune response that was comparable between SC and IM subjects, but local reactogenicity may be greater for SC.

PMID: 27936344 [PubMed - indexed for MEDLINE]

Immunogenicity and safety among laboratory workers vaccinated with Bexsero® vaccine.

Hum Vaccin Immunother. 2017 Mar 04;13(3):645-648

Authors: Hong E, Terrade A, Taha MK

Abstract
Neisseria meningitidis serogroup B is the most prevalent cause of invasive meningococcal disease in Europe and members of laboratories working on meningococci are at risk due to frequent handling. Recommendation for anti-meningococcal vaccination among these workers has been recently updated upon the licensure in Europe of Bexsero® vaccine. We tested the immunogenicity and safety of this vaccine among adults laboratory staff using the recommended schedule of 2 doses at 5 weeks interval. The vaccine was well tolerated in spite of frequent local side effects and all participants reported at least one side effect after each dose. Immunogenicity was evaluated 6 weeks and one year after the second dose. All participants showed increase in their bactericidal titers against the components of the vaccine 6 weeks after the second dose, however titers declined significantly one year later.

PMID: 27808594 [PubMed - indexed for MEDLINE]

Safety, immunogenicity and persistence of immune response to the combined diphtheria, tetanus, acellular pertussis, poliovirus and Haemophilus influenzae type b conjugate vaccine (DTPa-IPV/Hib) administered in Chinese infants.

Hum Vaccin Immunother. 2017 Mar 04;13(3):588-598

Authors: Li Y, Li RC, Ye Q, Li C, Liu YP, Ma X, Li Y, Zhao H, Chen X, Assudani D, Karkada N, Han HH, Van Der Meeren O, Mesaros N

Abstract
We conducted 3 phase III, randomized, open-label, clinical trials assessing the safety, reactogenicity (all studies), immunogenicity (Primary vaccination study) and persistence of immune responses (Booster study) to the combined diphtheria, tetanus, pertussis, poliomyelitis, and Haemophilus influenzae type b vaccine (DTPa-IPV/Hib) in Chinese infants and toddlers. In the Pilot study (NCT00964028), 50 infants (randomized 1:1) received 3 doses of DTPa-IPV/Hib at 2-3-4 (Group A) or 3-4-5 months of age (Group B). In the Primary study (NCT01086423), 984 healthy infants (randomized 1:1:1) received 3 doses of DTPa-IPV/Hib at 2-3-4 (Group A) or 3-4-5 (Group B) months of age, or concomitant DTPa/Hib and poliomyelitis (IPV) vaccination at 2-3-4 months of age (Control group); 825 infants received a booster dose of DTPa/Hib and IPV at 18-24 months of age (Booster study; NCT01449812). In the Pilot study, unsolicited symptoms were more frequent in Group A (16 versus 1 infant; mostly upper respiratory tract infection and pyrexia); this observation was attributed to an epidemic outbreak of viral infections. Non-inferiority of 3-dose primary vaccination with DTPa-IPV/Hib over separately administered DTPa/Hib and IPV was demonstrated for Group A (primary objective). Similar antibody concentrations were observed in all groups, except for anti-polyribosyl-ribitol phosphate and anti-poliovirus types 1-3 which were higher in DTPa-IPV/Hib recipients. Protective antibody levels against all vaccine antigens remained high until booster vaccination. Three-dose vaccination with DTPa-IPV/Hib had a clinically acceptable safety profile.

PMID: 27768515 [PubMed - indexed for MEDLINE]

14 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2017/10/24

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

First-in-man phase I study assessing the safety and pharmacokinetics of a 1-hour intravenous infusion of the doxorubicin prodrug DTS-201 every 3 weeks in patients with advanced or metastatic solid tumours.

Eur J Cancer. 2017 Oct 19;86:240-247

Authors: Schöffski P, Delord JP, Brain E, Robert J, Dumez H, Gasmi J, Trouet A

Abstract
PURPOSE: DTS-201 is a doxorubicin (Dox) prodrug that shows encouraging data in experimental models in terms of both efficacy and safety compared with conventional Dox. The purpose of this phase I study was to assess the safety profile, to establish the recommended dose (RD) for clinical phase II studies and to assess potential anticancer activity of the compound.
EXPERIMENTAL DESIGN: DTS-201 was administered as a 1-hour infusion every 3 weeks in eligible patients with advanced solid tumours according to common clinical phase I criteria. Dose escalation was performed according to a modified Fibonacci schema.
RESULTS: Twenty-five patients with a median age of 58 years (range, 30-72) were enrolled in the study. The median number of treatment cycles was 2 (range, 1-8). DTS-201 was administered at four dose levels (DLs) ranging from 80 to 400 mg/m(2), which is equivalent to 45-225 mg/m(2) of conventional Dox. No dose-limiting toxicity (DLT) occurred at the first two DLs. Three DLTs were observed at DL3 and DL4 (diarrhoea for DL3, vomiting and neutropenia for DL4). DL4 (400 mg/m(2)) was considered the maximum tolerated dose. Myelosuppression was the main toxicity, and NCI-CTC grade III-IV neutropenia was common at RD. Non-haematological adverse reactions were mild to moderate and included nausea, anorexia, asthenia and alopecia. No treatment-related severe cardiac adverse events were observed.
CONCLUSIONS: DTS-201 is well tolerated and safe in heavily pretreated solid tumour patients. A high equivalent dose of Dox could be delivered without severe drug-related cardiac events. DTS-201 showed evidence of clinical activity with a confirmed partial response in a patient with soft-tissue sarcoma. The recommended phase II dose is 400 mg/m(2).

PMID: 29055839 [PubMed - as supplied by publisher]

Is there a change of paradigm towards more effective treatment early in the course of apparent high-risk MS?

Mult Scler Relat Disord. 2017 Oct;17:75-83

Authors: Fernández Ó

Abstract
BACKGROUND: Aggressive, highly active, or rapidly evolving severe relapsing-remitting multiple sclerosis (RRMS) is characterized by frequent relapses and active disease on magnetic resonance imaging, ultimately leading to a high risk for rapid disability accumulation. The treatment approach for high-risk patients is evolving into a model of individualized therapy in which early initiation of high-efficacy disease-modifying therapy (DMT), which I refer to as "early and strong" therapy, is viewed as a rational strategy to prevent the irreversible damage that occurs at disease onset and early in the disease course. This approach uses an individualized benefit-risk assessment to match the level of DMT efficacy with the patient's risk of disease progression and balances it against the risk of drug-related adverse events. It also includes consideration of the patient's risk tolerance and desire for a high-efficacy treatment. This paper discusses the rationale for early treatment, and summarizes the available clinical data on high-efficacy and moderately-high efficacy DMTs in patients with high-risk RRMS.
METHODS: Literature searches were conducted using search terms "aggressive RRMS", "highly active RRMS", and "severe RRMS" alone and in conjunction with the terms "natalizumab", "fingolimod", "alemtuzumab", "mitoxantrone", and "cyclophosphamide". Studies of drug efficacy in these high-risk populations were reviewed.
RESULTS: Subgroup analyses of pivotal trials of natalizumab, fingolimod, and alemtuzumab were available, as well as an independent study of mitoxantrone and a pilot study of cyclophosphamide. In each study, DMT reduced relapses versus either placebo, active comparator, or baseline relapse rate.
CONCLUSION: Data for the high-efficacy DMTs natalizumab and alemtuzumab, and the moderately high-efficacy DMT fingolimod, suggest they are effective in this patient population. Further studies are warranted, and clinical trial data to inform treatment decisions for this high-risk group represent a significant unmet need.

PMID: 29055479 [PubMed - in process]

Everolimus in advanced, progressive, well-differentiated, nonfunctional neuroendocrine tumors: RADIANT-4 lung subgroup analysis.

Cancer Sci. 2017 Oct 21;:

Authors: Fazio N, Buzzoni R, Delle Fave G, Tesselaar ME, Wolin E, Van Cutsem E, Tomassetti P, Strosberg J, Voi M, Pacaud LB, Ridolfi A, Herbst F, Tomasek J, Singh S, Pavel M, Kulke MH, Valle JW, Yao JC

Abstract
In the phase 3, RADIANT-4 study, everolimus improved median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated (grade 1 or grade 2), nonfunctional lung or gastrointestinal neuroendocrine tumors (NETs) vs placebo (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.35-0.67; P < .00001). This exploratory analysis reports the outcomes of the subgroup of patients with lung NETs. In RADIANT-4, patients were randomized (2:1) to everolimus 10 mg/d or placebo, both with best supportive care. This is a post hoc analysis of the lung subgroup with PFS, by central radiology review, as the primary endpoint; secondary endpoints included objective response rate and safety measures. Ninety of the 302 patients enrolled in the study had primary lung NET (everolimus, n = 63 and placebo, n = 27). Median PFS (95% CI) by central review was 9.2 (6.8-10.9) months in everolimus arm vs 3.6 (1.9-5.1) months in placebo arm (HR, 0.50; 95% CI, 0.28-0.88). More patients who received everolimus (58%) experienced any tumor shrinkage compared with placebo (13%). Most frequently reported (≥ 5% incidence) grade 3-4 drug-related adverse events (everolimus vs placebo) included stomatitis (11% vs 0%), hyperglycemia (10% vs 0%), and any infections (8% vs 0%). In patients with advanced, progressive, well-differentiated, nonfunctional lung NET, treatment with everolimus was associated with a median PFS improvement of 5.6 months, with a safety profile similar to that of the overall RADIANT-4 population. These results support the use of everolimus in patients with advanced, nonfunctional lung NET. This article is protected by copyright. All rights reserved.

PMID: 29055056 [PubMed - as supplied by publisher]

Intravenous Zanamivir in Hospitalized Patients With Influenza.

Pediatrics. 2017 Oct 19;:

Authors: Bradley JS, Blumer JL, Romero JR, Michaels MG, Munoz FM, Kimberlin DW, Pahud B, DeBiasi RL, Yamamoto G, Roberts G, Hossain M, Shortino D, Yates PJ, Adams B, Peppercorn A

Abstract
BACKGROUND: Children with severe influenza infection may require parenteral therapy if oral or inhaled therapies are ineffective or cannot be administered. Results from a study investigating intravenous (IV) zanamivir for the treatment of hospitalized infants and children with influenza are presented.
METHODS: This phase II, open-label, multicenter, single-arm study assessed the safety of investigational IV zanamivir in hospitalized children with influenza. Safety outcomes included treatment-emergent adverse events (TEAEs), clinical laboratory measurements, and vital signs. Clinical outcomes, pharmacokinetics, and virologic efficacy data were collected as key secondary outcomes.
RESULTS: In total, 71 children received treatment with investigational IV zanamivir (exposure comparable to 600 mg twice daily in adults). TEAEs and serious TEAEs (STEAEs) were reported in 51 (72%) and 15 (21%) patients, respectively. The mortality rate was 7%, and median durations of hospital and ICU stays were 6 and 7.5 days, respectively. No STEAEs or deaths were considered related to IV zanamivir treatment, and no patterns of TEAEs, laboratory abnormalities, or vital signs were observed. The mean zanamivir exposures from 34 patients with normal renal function who received 12 mg/kg, 14 mg/kg, or 600 mg of IV zanamivir ranged from 64.5 to 110 hour·µg/mL. The median change from baseline in the viral load was -1.81 log10 copies per mL after 2 days of treatment.
CONCLUSIONS: The safety profile of IV zanamivir was favorable, with no drug-related STEAEs reported. The majority of children experienced virologic response and clinical improvement during the treatment course. Systemic zanamivir exposures in children were consistent with adults.

PMID: 29051331 [PubMed - as supplied by publisher]

Pharmacokinetics and drug-drug interaction between enalapril, enalaprilat and felodipine extended release (ER) in healthy subjects.

Oncotarget. 2017 Sep 19;8(41):70752-70760

Authors: Li D, Xu S, Wang Y, Li D, Li X, Pan J, Xu P

Abstract
Since angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists have complimentary mechanisms of action, enalapril, an ACE inhibitor, is used in combination with felodipine, a vascular selective dihydropyridine calcium antagonist, for the treatment of hypertension. The present study was designed to investigate the possible drug-drug interaction between these two agents in Chinese healthy subjects. A randomized, open-label, multiple-dose, 3-treatment, 3-period, 6-sequence cross-over study enrolling 12 healthy subjects (six male and six female subjects) was performed. Plasma pharmacokinetic studies were performed after 5 mg of enalapril and 5 mg of felodipine were administered alone or concomitantly twice per day for six days, and once in the morning of day seven. All 12 healthy subjects (mean [SD] age, 24.3 [2.8] years; body weight, 57.3 [5.7] kg; height, 163.2 [5.2] cm) completed all scheduled pharmacokinetic studies. Geometric mean ratios (with 90% CIs) of AUCτ,ss and Cmax,ss for enalapril administered concomitantly with felodipine vs. enalapril administered alone were 1.025 (0.80-1.25) and 1.065 (0.70-1.43), respectively. Geometric mean ratios (with 90% CIs) of AUCτ,ss and Cmax,ss for felodipine administered concomitantly with enalapril vs. felodipine administered alone were 1.14 (0.97-1.31) and 0.80 (0.65-0.95), respectively. There were no severe or serious drug-related adverse events observed during the study. Our results revealed that the co-administration of enalapril and felodipine affected the pharmacokinetics of felodipine, but not that of enalapril. Although the difference in PK parameters was statistically significant, its clinical significance may be limited, considering safety profile observed in the present study.

PMID: 29050316 [PubMed]

Citric Acid Metabolism in Resistant Hypertension: Underlying Mechanisms and Metabolic Prediction of Treatment Response.

Hypertension. 2017 Nov;70(5):1049-1056

Authors: Martin-Lorenzo M, Martinez PJ, Baldan-Martin M, Ruiz-Hurtado G, Prado JC, Segura J, de la Cuesta F, Barderas MG, Vivanco F, Ruilope LM, Alvarez-Llamas G

Abstract
Resistant hypertension (RH) affects 9% to 12% of hypertensive adults. Prolonged exposure to suboptimal blood pressure control results in end-organ damage and cardiovascular risk. Spironolactone is the most effective drug for treatment, but not all patients respond and side effects are not negligible. Little is known on the mechanisms responsible for RH. We aimed to identify metabolic alterations in urine. In addition, a potential capacity of metabolites to predict response to spironolactone was investigated. Urine was collected from 29 patients with RH and from a group of 13 subjects with pseudo-RH. For patients, samples were collected before and after spironolactone administration and were classified in responders (n=19) and nonresponders (n=10). Nuclear magnetic resonance was applied to identify altered metabolites and pathways. Metabolites were confirmed by liquid chromatography-mass spectrometry. Citric acid cycle was the pathway most significantly altered (P<0.0001). Metabolic concentrations were quantified and ranged from ng/mL malate to μg/mL citrate. Citrate and oxaloacetate increased in RH versus pseudoresistant. Together with α-ketoglutarate and malate, they were able to discriminate between responders and nonresponders, being the 4 metabolites increased in nonresponders. Combined as a prediction panel, they showed receiver operating characteristiccurve with area under the curve of 0.96. We show that citric acid cycle and deregulation of reactive oxygen species homeostasis control continue its activation after hypertension was developed. A metabolic panel showing alteration before spironolactone treatment and predicting future response of patients is shown. These molecular indicators will contribute optimizing the rate of control of RH patients with spironolactone.

PMID: 28874460 [PubMed - indexed for MEDLINE]

Regorafenib induced severe toxic hepatitis: characterization and discussion.

Liver Int. 2016 Nov;36(11):1590-1594

Authors: Sacré A, Lanthier N, Dano H, Aydin S, Leggenhager D, Weber A, Dekairelle AF, De Cuyper A, Gala JL, Humblet Y, Sempoux C, Van den Eynde M

Abstract
BACKGROUND: Regorafenib is the first small-molecule multikinase inhibitor which showed survival benefits in pretreated metastatic colorectal cancer (mCRC) patients. Besides classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect.
MATERIAL AND METHODS: Patients with refractory mCRC treated with regorafenib in our institution were reviewed. Severe treatment-related liver toxicity was investigated. Clinical history, liver histology and genetic assessment (sequence analysis) of cytochrome P3A4 (CYP3A4) and uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) involved in regorafenib metabolization were here reported for patients with severe hepatotoxicity.
RESULTS: Among the 93 reviewed patients, 3 presented severe and icteric toxic hepatitis which was fatal for 1 patient. Histopathological liver lesions were different depending on the onset of hepatotoxicity (acute or subacute): acinar zone 3 necrosis in case of acute symptoms, and portal tract inflammation with porto-central bridging and fibrosis in the delayed presentation. None of the patients had CYP3A4 gene mutations. Similar polymorphisms in UGT1A9 gene promoter region (UGT1A9 variant -118T9>10 [rs3832043]) were found in both patients who presented acute hepatitis. Moreover, it appears retrospectively that both of them already experienced significant toxicity under irinotecan-based chemotherapy.
CONCLUSION: This is the first report of severe hepatotoxicity with available liver histology and genetic assessment of enzymes involved in regorafenib metabolization. This report also reminds the importance of close liver tests monitoring during regorafenib treatment.

PMID: 27500989 [PubMed - indexed for MEDLINE]

[Hepatotoxicity in healthy infants exposed to nevirapine during pregnancy].

Enferm Infecc Microbiol Clin. 2016 Jan;34(1):39-44

Authors: Iveli P, Noguera-Julian A, Soler-Palacín P, Martín-Nalda A, Rovira-Girabal N, Fortuny-Guasch C, Figueras-Nadal C

Abstract
BACKGROUND: The use of nevirapine in HIV-infected pregnant women is discouraged due to its potential to cause hepatotoxicity. There is limited information available on the toxicity in non-HIV infected newborn exposed to this drug during pregnancy. The aim of the study is to determine the extent of hepatotoxicity in the newborn exposed to nevirapine and HIV during pregnancy.
METHODS: A cross-sectional, observational, multicenter study was conducted on a cohort of healthy infants born to HIV-infected mothers, in whom the first determination of alanine aminotransferase (ALT), before 6weeks of age, was collected. Patients were allocated to 2groups according to exposure to nevirapine during pregnancy. Hepatotoxicity was rated according to the AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS).
RESULTS: This study included 160newborns from 159pregnancies (88exposed to nevirapine-based regimens and 71 exposed to protease inhibitors-based therapies). No cases of hepatotoxicity were observed according to the DAIDS Table for Grading. Two cases of ALT above normal values (2.8%; 95%CI: 0.3-9.8%) were observed in patients not exposed to nevirapine, and one case (1.1%; 95%CI: 0.0-6.1%) in the group exposed to nevirapine (P=.585).
CONCLUSION: The lack of differences between groups suggests that highly active antiretroviral treatment regimens including nevirapine administered during pregnancy do not involve a higher risk of liver disease compared to other treatment combinations.

PMID: 25487604 [PubMed - indexed for MEDLINE]

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2017/10/20

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

13 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2017/10/20

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2017/10/19

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2017/10/17

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

12 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2017/10/17

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

11 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

("drug-induced" OR "drug-related") AND ("adverse events" OR "side effects" OR "side-effects")

These pubmed results were generated on 2017/10/15

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Dietary Supplements, Isotretinoin, and Liver Toxicity in Adolescents: A Retrospective Case Series.

Pediatrics. 2017 Oct;140(4):

Authors: DeKlotz CMC, Roby KD, Friedlander SF

Abstract
Isotretinoin is the most effective acne therapy available, but has the potential for a number of adverse side effects, including transaminitis. The iPLEDGE isotretinoin program recommends avoiding some herbals and supplements due to potential side effects. However, little is known about the effects of protein supplements on the liver, particularly in patients taking isotretinoin. We designed a retrospective chart review to evaluate the symptoms, diagnosis, treatment, and outcome of patients on or preparing to take isotretinoin therapy who were concurrently ingesting protein or herbal supplementation and who developed transaminitis. In 100% (8/8) of cases, dietary supplementation was determined to be at least a possible cause of elevated liver transaminases. In 75% (6/8) of cases, dietary supplement appears to be the most likely cause at some point in their evaluation. Most of our patients' elevations in aspartate aminotransferase and/or alanine aminotransferase were likely caused by supplementation with protein, creatine, or herbal extracts, rather than prescribed isotretinoin or tetracycline antibiotics for acne. Hence, dietary supplementation may cause liver function abnormalities. As supplement usage appears common in teenagers, clinicians should consider counseling their patients to avoid these products, particularly when prescribing known hepatotoxic drugs.

PMID: 28864554 [PubMed - indexed for MEDLINE]

Goldilocks' Determination of What New In Vivo Data are "Just Right" for Different Common Drug Development Scenarios, Part 1.

Birth Defects Res B Dev Reprod Toxicol. 2016 Aug;107(4-5):185-194

Authors: Bowman CJ, Chapin RE

Abstract
As alternative models and scientific advancements improve the ability to predict developmental toxicity, the challenge is how to best use this information to support safe use of pharmaceuticals in humans. While in vivo experimental data are often expected, there are other important considerations that drive the impact of developmental toxicity data to human risk assessment and product labeling. These considerations include three key elements: (1) the drug's likelihood of producing off-target toxicities, (2) risk tolerance of adverse effects based on indication and patient population, and (3) how much is known about the effects of modulating the target in pregnancy and developmental biology. For example, there is little impact or value of a study in pregnant monkeys to inform the risk assessment for a highly specific monoclonal antibody indicated for a life-threatening indication against a target known to be critical for pregnancy maintenance and fetal survival. In contrast, a small molecule to a novel biological target for a chronic lifestyle indication would warrant more safety data than simply in vitro studies and a literature review. Rather than accounting for innumerable theoretical possibilities surrounding each potential submission's profile, we consolidated most of the typical situations into eight possible scenarios across these three elements, and present a discussion of these scenarios here. We hope that this framework will facilitate a rational approach to determining what new information is required to inform developmental toxicity risk of pharmaceuticals in context of the specific needs of each program while reducing animal use where possible.

PMID: 27601206 [PubMed - indexed for MEDLINE]