Hair Color Changes Research Articles

MEDIPLEX: A phase 1 study of durvalumab (D) combined with pexidartinib (P) in patients (pts) with advanced pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer (CRC).

2579 Background: Targeting tumor associated macrophages is an emerging strategy to increase the responsiveness of PDAC and CRC to anti-PD(L)1. Pexidartinib (P) is an orally active, small-molecule kinase inhibitor that targets the colony-stimulating factor-1 receptor (CSF1R) on macrophages. Methods: Adult pts with advanced/ metastatic PDAC or CRC were treated with a fixed dose of D (1500mg q4w, IV) and ascending doses of P (400, 600, 800 and 1000mg/d, orally). Dose escalation was conducted according to a Likelihood Continual Reassessment Method with a 28-day window to evaluate dose-limiting toxicity (DLT), a stopping rule advised dose escalation termination in case of a high probability ( > 90%) for the next 6 pts to be assigned to the same dose. Following the determination of RP2D, 14 pts with PDAC and 14 pts with CRC who consented to serial tumor biopsies were enrolled in expansion cohorts to assess preliminary anti-tumor activity and biomarkers. Results: 19 pts (12M, 7F, median age, 56 y [range, 43-76y]) were enrolled in 4 dose escalation cohorts (P 400, 600 and 800mg/d: 3 pts each and P 1000mg/d: 10 pts). Pharmacokinetic analysis showed dose-dependent increase in the exposure of P from 400 to 1000 mg. Two DLTs (AST/ALT elevations including one with bilirubin increase) were seen at dose level P 1000mg/d. The most frequent ( > 2pts) related (to either D, P or both) AEs were: fatigue, maculopapular rash/pruritus/dry skin, hair color changes, anorexia, edema (periorbital, limbs or face), AST/ALT increases, bilirubin increases, nausea, vomiting and diarrhea. The most frequent (≥2pts) Grade ≥ 3 AEs related to P were: AST/ALT increase, ALP increase, neutrophil or white blood cell count decrease, and fatigue. Clinical benefit rate at 2 months was 21% (4 SD /19pts), 2 pts with MSI-H CRC had SD for more than 6 months including 1 pt still receiving single agent D after > 18 months. The RP2D for the combination was P 800mg/d + D 1500mg q4w. Enrolment in the expansion cohorts was completed in January 2019. Conclusions: Toxicity was consistent with the expected profiles of the individual drugs and no unexpected events were seen with the combination. Updated data will be presented at the meeting. Clinical trial information: NCT02777710.

Pexidartinib for advanced tenosynovial giant cell tumor (TGCT): Long-term efficacy and safety from the phase 3 ENLIVEN and phase 1 PLX108-01 (TGCT cohort) studies.

11042 Background: TGCT is a rare, locally aggressive neoplasm of the joint/tendon sheath linked to colony-stimulating factor 1 (CSF1) overexpression. Pexidartinib (pex), a selective inhibitor of CSF1 receptor, KIT, and FLT3-ITD, had a compelling tumor response rate in the TGCT cohort of a phase 1 study (NCT01004861) and significant tumor response vs placebo by RECIST v1.1 (39% vs 0%, P< 0.0001) and tumor volume score (TVS) (56% vs 0%, P< 0.0001) in the randomized, 2-part, crossover phase 3 ENLIVEN study (NCT02371369). Updated efficacy and safety with longer treatment are reported. Methods: Patients (pts) were ≥18 y with TGCT that was inoperable or for which surgery would likely be associated with worsening functional limitation or severe morbidity. Best overall response (complete or partial [CR/PR]) and duration of response (DOR) by RECIST and TVS were assessed by independent central review. Data cutoff was Jan 31, 2018, 16-67 mo after pts’ first dose. Results: In both studies 130 pts received pex, 61 ongoing at data cutoff. Median treatment duration was 17 mo (1, 60+). CR/PR rates were high and consistent and, together with DOR, improved with prolongation of treatment (Table). Most frequent adverse events were hair color change (75%), fatigue (60%), nausea (45%), arthralgia (38%), AST increase (30%), and diarrhea (30%). In ENLIVEN part 1, 3 of 61 (5%) pts had reversible ALT and AST ≥3 × ULN with TBil and ALP ≥2 × ULN; all started in the first 8 weeks of treatment, and no new cases emerged with continuation of treatment. Conclusions: Tumor response rate increased with continuation of pex treatment. The safety profile remained similar, with no new mixed or cholestatic hepatotoxicity. Clinical trial information: NCT01004861 and NCT02371369. [Table: see text]

TOKSISITAS AKUT INFUSA KULIT ARI KACANG TANAH (Arachis hypogea L.) PADA MENCIT BALB/ C

ABSTRACTPeanut shell (PS) infusion has been shown to be antithrombocytopenia, but there has been no research on safety standards. This study aims to identify the symptoms of toxic effects, the potency of toxicity and histopathology of liver male Balb/C mice after a single dose of PS infusion. This research uses randomized matched posttest only control group design. Twenty five mice were divided into 5 orally dosage groups, ie, PS infusion with a dose of 0,026; 0.052; 0.104; 0.208 g/20gBW; and negative control of CMC Na 0.5%. The observation period is for 14 days. The results showed that single dose of PS infusion had a pseudo LD50 value ie > 0.208g/20gBW which was practically non toxic. Symptoms to watch out for the BW infusion were passive behavior, bradycnea, hair color change, hair loss, and weight loss at doses of 3 and 4. It is unclear whether liver damage ie inflammation, necrosis, and albuminous degeneration caused by PS infusion or other causes.keywords: acute toxicity, infusion, peanut shell

Influence of different cosmetic vehicles in mechanical and physical properties of hair treated with oxidative hair dyes

Hair care products play a significant role in the cosmetic market and aim at improving hair brightness, breakage resistance, and color change. In this study, we analyzed the possibility of the formulation of oxidative dyes in different vehicles impacting the hair’s both mechanical and physical properties. Light brown and light blond dyes were prepared using eight different vehicles. Among these, four vehicles were emulsifying agents and four gelling agents. Each formulation was applied to two types of virgin Caucasian hair (light blond and dark brown). Physical, chemical, and organoleptic properties of each formulation were assessed, as well as changes in hair parameters after oxidative dyeing, such as staining intensity, brightness, and breaking strength. The parameters of color and brightness differed in some formulations, but the hair type also responded differently. Brightness parameter was increased in dark brown hair colored with both dyes, whereas light blond hair showed the opposite result. Regarding the breaking strength, there were no significant differences between the two kinds of tresses. Cosmetic formulations should adjust the consumer desired effects (e.g. color change) in order to present minimal drawbacks (e.g. decrease of hair brightness and strength). Thus, the study of different vehicles is important when establishing the best oxidative dye formulation.

Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer’s Disease

BackgroundAlzheimer’s disease is characterized by the deposition of amyloid-beta (Aβ) plaques in the brain. Aβ is produced from the sequential cleavage of amyloid precursor protein by β-site amyloid precursor protein–cleaving enzyme 1 (BACE-1) followed by γ-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the Aβ level in the cerebrospinal fluid of patients with Alzheimer’s disease.MethodsWe conducted a randomized, double-blind, placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate Alzheimer’s disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimer’s Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function).ResultsA total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P=0.63 for the comparison between the 12-mg group and the placebo group and P=0.46 for the comparison between the 40-mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS-ADL score was −8.4 in the 12-mg group, −8.2 in the 40-mg group, and −8.9 in the placebo group (P=0.49 for the comparison between the 12-mg group and the placebo group and P=0.32 for the comparison between the 40-mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group.ConclusionsVerubecestat did not reduce cognitive or functional decline in patients with mild-to-moderate Alzheimer’s disease and was associated with treatment-related adverse events. (Funded by Merck; ClinicalTrials.gov number, NCT01739348.)

The Effects of Preferred Color on Stress in Hair Coloring: Focusing on color therapy effects

Today, color has infiltrated modern life in many ways, and it has the power to make both the inner and the outer selves change. Color perception can rejuvenate a person both psychologically and mentally and help him/her gain peace and comfort. Hair color has an influence on impression formation and changes in internal and external images by changing color. As people’s interest in and perception of hair color increase, this study investigated the effects of preferred color on stress in hair coloring. For this, ‘red’ and ‘green’, which represent vitality and stability, respectively, were chosen. The results found the following: The two colors were effective in reducing stress. While ‘green’ brought stability, ‘red’ generated vitality. In terms of preferred color, in particular, stress decreased when ‘red’ was applied to those whose preferred color was ‘red’. In addition, it dramatically declined when ‘green’ was applied to those who preferred green. Therefore, the color therapy images of ‘green’ - stability, peace and comfort - were confirmed through hair color changes. The effects of color therapy were found in hair color changes as well. It appears that this study could be applied to the development of the beauty industry and marketing as well as used as educational material.

Increased dietary intake of tyrosine upregulates melanin deposition in the hair of adult black-coated dogs.

The principle determinant of melanin derived hair colour and patterning in mammals is genetic, but environmental factors are now thought to play a role. It has been shown that the concentration of melanins in cat hair is influenced by the amino acid composition of their diets. Also, puppies were found to require tyrosine (Tyr) intake significantly greater than that recommended for normal growth and development in order to optimize melanin expression in their coats. Much of the work to date has been conducted in growing animals. Less is known about the relationship between nutrition and hair melanin deposition in healthy adult animals. In this study, we fed 2 groups of adult black Labrador retrievers (12 dogs/group) different concentrations of Phe + Tyr (5.6 vs. 3.5 g/Mcal) for 24 weeks and used spectrophotometric measurements every 8 weeks to detect any associated changes in the dogs’ hair colour. The higher intake dogs showed reduced dilution of their black coat pigment compared with the lower intake dogs. Specifically, following 16 weeks at the higher intake, the dogs showed less yellow pigmentation to their coats (P = 0.0032), and after 24 weeks at the higher intake, the dogs showed less red (P < 0.0001) and yellow (P< 0.0001), as well as greater overall dark pigmentation (P < 0.0001). In conclusion, we have demonstrated for the first time that colour expression in the hair-coat of adult dogs is dependent on dietary intake of Tyr, and that the requirement appears to be in excess of the minimum level recommended to maintain health.

Phenylketonuria: Our Experience in Nine Years at a Tertiary-level Referral Institute.

Introduction:Phenyl ketonuria is an inborn error of amino acid metabolism resulting in excessive phenyl alanine levels in blood resulting in a spectrum of neurological defects.Patients and Methods:We retrospectively went through the records of patients diagnosed as Phenyl ketonuria in the last nine years in our team and patients who's data could be accessed were analyzed in detail. Details of laboratory tests, imaging clinical features, course were recorded.Observation:A total of 32 patients were identified in nine years of which data was available only for 15 patients. Age at diagnosis varied from 2.5 years to 7 years. 73% were males. Global developmental delay, Microcephaly. Seizures blond hair, spasticity, regression, Ocular Hypertelorism, low set ears, Seborrhea, Hypotonia, Family history of mental retardation and Consanguinity was common one patient showed a large hypo pigmented area in left arm with eczematous rash.Results of Lab Tests:Urine ferric chloride test and DNPH was positive in all cases. Tandem mass spectroscopy showed elevated phenyl alanine, normal tyrosine and elevated PHE tyrosine ratio in all cases. MRI showed symmetrical Flair hyperintensities in T2 weighted images in the parieto occipital region hypo on T1 with no diffusion restriction in 11 cases and MRS was normal. Genetic testing showed one non consanguineous family having carrier state. Follow up is from 1 year to 5 years. Seizures controlled in all. Regular fallow up shows change in hair color and gain of mile stones. There was no mortality.Conclusion:Phenyl ketonuria is a controllable metabolic disease. However there is considerable delay before diagnosis resulting in persistence of sequelae in children with PKU as well as normal children born to PKU mothers which needs attention to prevent these complications.

Case: Secondary polycythemia due to pazopanib in patients with metastatic renal cell carcinoma.

Clear-cell renal cell carcinoma (RCC) is the most common primary malignant renal neoplasm. Up to 30% of patients have metastatic disease at the time of initial diagnosis.1 Small molecule inhibitors of vascular endothelial growth factor receptor tyrosine kinase (VEGFR TKIs) are used as first-line treatment for most patients with incurable RCC. Pazopanib is a TKI inhibiting VEGFR,1-3 as well as plateletderived growth factor receptors (PDGFRs) α and β and stem cell receptor c-kit. The most common side effects of pazopanib are diarrhea, hypertension, changes in hair colour, anorexia, nausea, and vomiting. Severe hepatic toxicity is the adverse effect of greatest concern,but is uncommon. Myelosuppressive effects are also noted, such as anemia, thrombocytopenia, and leukopenia, and are presumably mediated through c-kit inhibition. Erythrocytosis is a wellrecognized paraneoplastic syndrome associated with RCC; however, erythrocytosis due to pazopanib therapy has only recently been described. We report two cases and review of the literature related to this phenomenon.

Review: Mechanism of Hair Dying and their safety aspects

An original hair color change by application of chemical dye is a common practice among the men and women. Hair dyes are classified into the following category based on their color retention property, namely temporary, semi permanent, demi permanent and permanent. Temporary dyes are otherwise called as non-oxidative dyes; because coloring process was carried out without any oxidizing agent, it reduced stay time on the fiber, removing the hair during the first shampoo wash. Semi permanent products consist of nitro aromatic amines or aromatic amino nitroanthroquinone dyes, which diffuse into the hair and bind to the hair; however do not attach firmly. Permanent hair dyes are called oxidation hair dyes; because of the oxidizing agent used for the color development. An active intermediate reacts further with coupler and provides the color to the hair and in general oxidation hair dyes provides shampoo resistant hair dyes. Some hair dyes can cause allergic reactions or sensitization that may result in skin irritation and hair loss. People can develop sensitivities with repeated exposure. Also, formulations may change over time. The primary toxicological concerns of hair dyes, primarily oxidation hair dyes, are with contact dermatitis and long-term “potential” systemic effects. The para diamine oxidation derivative dyes reported to having more sensitizing potential when compared to other amine derivatives. P-Phenylenediamine is the major component of oxidation hair dyes, and oxidation dyes are the most widely used of all hair dyes. Therefore PPD is the sensitizer of prime concern.

Drug-induced hair colour changes.

Hair colour modifications comprise lightening/greying, darkening, or even a complete hair colour change, which may involve the scalp and/or all body hair. Systemic medications may cause hair loss or hypertrichosis, while hair colour change is an uncommon adverse effect. The rapidly increasing use of new target therapies will make the observation of these side effects more frequent. A clear relationship between drug intake and hair colour modification may be difficult to demonstrate and the underlying mechanisms of hair changes are often unknown. To assess whether a side effect is determined by a specific drug, different algorithms or scores (e.g. Naranjo, Karch, Kramer, and Begaud) have been developed. The knowledge of previous similar reports on drug reactions is a key point of most algorithms, therefore all adverse events should be recognised and reported to the scientific community. Furthermore, even if hair colour change is not a life-threatening side effect, it is of deep concern for patient's quality of life and adherence to treatment. We performed a review of the literature on systemic drugs which may induce changes in hair colour.

A retrospective analysis of 14 consecutive Chinese patients with unresectable or metastatic alveolar soft part sarcoma treated with sunitinib.

Background The study was aim to assess the efficacy and safety of sunitinib on 14 Chinese patients with locally unresectable or metastatic Alveolar Soft Part Sarcoma (ASPS) at two institutions retrospectively. Methods Patients were treated with 37.5mg of sunitinib once daily continuously without a scheduled off-treatment period. Dose holds or reductions were recommended for grade 3 AEs but were required for grade 4 AEs. Restarting treatment of sunitinib was allowed when AEs returned back to grade 1 or disappeared. The treatment was continued until progression disease (PD), unacceptable toxicity or death. Results From January 2011 to December 2015, 14 patients with unresectable or metastatic ASPS received sunitinib treatment. Among them, 4 patients achieved partial remission (PR), and 10 patients achieved stable disease (SD). Median progression free survival (PFS) was 41.0months (95% CI: 7.7 to 74.4month). Median overall survival (OS) was not reached. The 1- and 4-year OS rates were 90.0% and 60.0% respectively. Two patients with primarily unresectable ASPS received complete surgical resection after neoadjuvant treatment of sunitinib. The majority of toxicities encountered were grade 1 or 2 and manageable. The most common adverse events (AEs) were bleeding (35.7%), hair & skin color change (37.5%) and mucositis (28.6%). Conclusions Sunitinib is effective in locally unresectable or metastatic ASPS with a good safety profile. Neoadjuvant treatment with sunitinib improves the chance of resection for patients with locally advanced ASPS.

Sunitinib in metastatic renal cell carcinoma (mRCC): a developing country experience. Do our patients behave differently than the Western patients?

Metastatic renal cell carcinoma (mRCC) has historically been refractory to cytotoxic and hormonal agents. IL-2 and IFN-α provide response in a minority of patients. Small molecule tyrosine kinase inhibitors and monoclonal antibodies have established a role in the setting of mRCC. However, there is a lack of data from the Indian subcontinent. The aim of this study was to look whether our patients behave similarly as reported in the Western data to targeted agents, especially sunitinib. The study was a prospective observational study conducted for a period of 5years from 2011 to 2016. Sixty-three patients received targeted agents and were recruited in the study. Five patients were excluded for various reasons, and three were lost to follow-up. Fifty-five patients were properly studied and followed up. Fifty patients received sunitinib, four patients received sorafenib, and one patient received parenteral temsirolimus. Patients were followed for AEs and survival. The most common AEs in patients taking sunitinib were fatigue (70%), hand-foot syndrome (62%), skin rash (58%), mucosal inflammation (58%), anorexia (42%), skin discoloration (42%), followed by dry mouth, dysgeusia, dyspepsia, dry skin, dry mouth, hair color changes, hypothyroidism, alopecia, oral pain/stomatitis, hypertension, decreased weight, photosensitivity, peripheral edema, erythema, and others. The median overall survival in our patients was 13.2 (95% CI 10.1-16.5), progression-free survival was 8.1months (95% CI 6.4-10.5), and objective response was seen in 36%. Non-Western patients behave differently with sunitinib therapy compared to Western patients. Our patients have more mucocutaneous side effects and lesser overall survival.

Development of a methylation marker set for forensic age estimation using analysis of public methylation data and the Agena Bioscience EpiTYPER system

Individual age estimation has the potential to provide key information that could enhance and extend DNA intelligence tools. Following predictive tests for externally visible characteristics developed in recent years, prediction of age could guide police investigations and improve the assessment of age-related phenotype expression patterns such as hair colour changes and early onset of male pattern baldness. DNA methylation at CpG positions has emerged as the most promising DNA tests to ascertain the individual age of the donor of a biological contact trace. Although different methodologies are available to detect DNA methylation, EpiTYPER technology (Agena Bioscience, formerly Sequenom) provides useful characteristics that can be applied as a discovery tool in localized regions of the genome. In our study, a total of twenty-two candidate genomic regions, selected from the assessment of publically available data from the Illumina HumanMethylation 450 BeadChip, had a total of 177 CpG sites with informative methylation patterns that were subsequently investigated in detail. From the methylation analyses made, a novel age prediction model based on a multivariate quantile regression analysis was built using the seven highest age-correlated loci of ELOVL2, ASPA, PDE4C, FHL2, CCDC102B, C1orf132 and chr16:85395429. The detected methylation levels in these loci provide a median absolute age prediction error of ±3.07years and a percentage of prediction error relative to the age of 6.3%. We report the predictive performance of the developed model using cross validation of a carefully age-graded training set of 725 European individuals and a test set of 52 monozygotic twin pairs. The multivariate quantile regression age predictor, using the CpG sites selected in this study, has been placed in the open-access Snipper forensic classification website.

Biokinetics of ultrafine gold nanoparticles (AuNPs) relating to redistribution and urinary excretion: a long-term in vivo study

Gold nanoparticles (AuNPs) of ultrafine size have drawn attention for their use in drug delivery systems. Tissue toxicity may be an issue when AuNPs are used for such applications. We investigated the long-term biokinetics (90 d), redistribution, and urinary excretion of three different-sized (2 ± 0.5 nm, 5 ± 1 nm, and 10 ± 2 nm) AuNPs after a single intravenous (i.v.) administration of 1250 µg/kg dose in mice. ICP-AES analysis of lungs, liver, spleen, heart, kidney, brain, blood, and urine revealed highest accumulation of gold in spleen around 15 d after injection. A low concentration was detected in brain after 1 d without any residual AuNPs after 30 d. Ultrastructural study of brain tissue also showed few AuNPs in lysosome with no changes in cellular architecture. Renal retention of AuNPs was limited indicating low nephrotoxic potential. AuNPs were detectable in urine till 30 d after single injection indicating slow excretion from the body. No evidence of significant toxicity was observed in hemogram, serum biochemistry, and tissue histology. No mortality, changes in behavior, hair color, weight, and food intake was observed as compared to control mice. Therefore, we conclude that the ultrafine AuNPs are predominantly excreted in urine without any systemic toxicity following i.v. administration and are hence safe for use in drug delivery systems.

Tolerability of Capsaicinoids from Capsicum Extract in a Beadlet Form: A Pilot Study.

A single center, open-label, dose-finding adaptive study was conducted in twelve healthy overweight female subjects. The study was to evaluate the safety and tolerability of the capsaicinoids (CAPs) from Capsicum extract in a beadlet form compared to placebo in a healthy overweight population. The investigational product capsaicinoids (CAPs) from Capsicum extract in a beadlet form (Capsimax®) a proprietary encapsulated form of Capsicum extract in beadlet form supplemented at 2 mg, 4 mg, 6 mg, 8 mg and 10 mg of CAPs. An ascending dose protocol evaluated a total dose of 10 mg daily given in five divided doses (2 mg, 4 mg, 6 mg, 8 mg and 10 mg of CAPs). Each dose was given for a week. Safety and tolerability were assessed. Primary outcomes were tolerability assessments and reports of adverse events. Tolerability assessments were observed on skin color and any changes in skin, bowel movement, digestion, mouth or throat, hair color or changes in hair color, urination includes frequency and burning sensations, breathing, any changes in their health. Secondary outcomes were body weight, body mass index (BMI), blood pressure (SBP/DBP), vital signs, electrocardiograms, clinical chemistry parameters including liver function tests, lung function tests and kidney function tests and complete blood count (CBC). No dose effective changes were observed. The escalating dose levels of CAPs in a beadlet form product found was tolerable and safe for weight management studies. Tolerability assessments and safety blood markers showed no significant changes from baseline. No significant serious adverse events were reported throughout the duration of the study. Further longer term studies are required to explore the tolerability of the product. This trial is registered with ISRCTN: # ISRCTN10975080.

An Analysis of Ultrastructure of the Hair of Children Treated With Valproic Acid

Background: Valproic acid (VPA) is one of the most widely used antiepileptic drugs. Hair loss, color changes, thinning, and curliness have been reported in patients treated with VPA. In the present study, we aimed to analyze the ultrastructure of the hair of children treated with VPA via electron microscope. Methods: This cross-sectional study was performed with 12 epileptic children who had been treated with VPA for at least 12 months. The hair samples of children were examined via electron microscopy. Results: Scanning electron microscopy of hairs in patients demonstrated normal ultrastructural appearance of the hair surface and cuticular pattern. Conclusion: The present study is retrospective. The drug-induced changes might be temporary. Therefore, prospective research projects involving larger groups might be helpful. Int J Clin Pediatr. 2016;5(3-4):41-43 doi: https://doi.org/10.14740/ijcp257w

Cabozantinib for the treatment of progressive metastatic medullary thyroid cancer

Cabozantinib (XL-184) is a potent inhibitor of MET, VEGFR 2/KDR, RET and other receptor tyrosine kinases, such as KIT, AXL and FLT3. Its efficacy against MTC has been demonstrated in a prospective, randomized, placebo-controlled study (EXAM). Cabozantinib comparing to placebo significantly prolonged progression free survival both in hereditary and sporadic MTC, 11.2 vs 4.0 months, respectively. Final analysis showed no global differences in overall survival (OS) between cabozantinib and placebo. However, in a subgroup with RET M918T mutation the difference in OS was significant: 44.3 vs 18.9 months, respectively. Among the most frequent cabozantinib-related adverse events (AEs), observed in >30% of patients were diarrhea, palmar-plantar erythrodysesthesia, decreased weight, decreased appetite, nausea, fatigue, dysgeusia, hair color changes and hypertension. Expert Commentary: Cabozantinib constitutes an effective treatment option with acceptable toxicity in MTC patients showing either germinal or sporadic tumor RET M918T mutation as the drug prolonged OS in these subjects.

Structure-Guided Blockade of CSF1R Kinase in Tenosynovial Giant-Cell Tumor

BackgroundExpression of the colony-stimulating factor 1 (CSF1) gene is elevated in most tenosynovial giant-cell tumors. This observation has led to the discovery and clinical development of therapy targeting the CSF1 receptor (CSF1R).MethodsUsing x-ray co-crystallography to guide our drug-discovery research, we generated a potent, selective CSF1R inhibitor, PLX3397, that traps the kinase in the autoinhibited conformation. We then conducted a multicenter, phase 1 trial in two parts to analyze this compound. In the first part, we evaluated escalations in the dose of PLX3397 that was administered orally in patients with solid tumors (dose-escalation study). In the second part, we evaluated PLX3397 at the chosen phase 2 dose in an extension cohort of patients with tenosynovial giant-cell tumors (extension study). Pharmacokinetic and tumor responses in the enrolled patients were assessed, and CSF1 in situ hybridization was performed to confirm the mechanism of action of PLX3397 and that the pattern of CSF1 expression was consistent with the pathological features of tenosynovial giant-cell tumor.ResultsA total of 41 patients were enrolled in the dose-escalation study, and an additional 23 patients were enrolled in the extension study. The chosen phase 2 dose of PLX3397 was 1000 mg per day. In the extension study, 12 patients with tenosynovial giant-cell tumors had a partial response and 7 patients had stable disease. Responses usually occurred within the first 4 months of treatment, and the median duration of response exceeded 8 months. The most common adverse events included fatigue, change in hair color, nausea, dysgeusia, and periorbital edema; adverse events rarely led to discontinuation of treatment.ConclusionsTreatment of tenosynovial giant-cell tumors with PLX3397 resulted in a prolonged regression in tumor volume in most patients. (Funded by Plexxikon; ClinicalTrials.gov number, NCT01004861.)

Types of Hair Dye and Their Mechanisms of Action

Hair color change by dye application is a common procedure among women. Hair dyes are classified, according to color resistance, into temporary, semipermanent, demipermanent and permanent. The first two are based on molecules which are already colored. Temporary dyes act through dye deposition on cuticles, but semipermanent may penetrate a little into the cortex and so the color resists up to six washes. Demipermanent and permanent dyes are based on color precursors, called oxidation dyes, and the final shade is developed by their interactions with an oxidizing agent, but they differ from the alkalizing agent used. In oxidation systems, there is an intense diffusion of the molecules into the cortex, what promotes a longer color resistance. Dyes and color precursors present differences related to chromophore groups, hair fiber affinity, water solubility, and photo stability. The aim of this review is to discuss the differences among hair dye products available in the market and their action mechanisms, molecular structures, application methods, and some aspects of formulations.