Risk of gastrointestinal complications in breast cancer patients treated with neratinib: a meta-analysis

Backgrounds: Neratinib is a potent EGFR/HER2 kinase inhibitor. Gastrointestinal complications (i.e. diarrhea, vomiting and nausea) are the most common adverse events. In this study, we aimed to investigate (1) the overall incidence and relative risk (RR) of diarrhea, vomiting and nausea and (2) whether combination neratinib therapy increased the incidence of gastrointestinal complications versus neratinib alone.

Methods: Relevant studies were identified from the PubMed database, from abstracts presented at the American Society of Clinical Oncology annual conference and from the Web of Science database. Incidences, RRs, and 95% confidence intervals (CIs) were calculated.

Results: The incidences of all-grade diarrhea, vomiting and nausea in the neratinib groups were 89% (95% CI = 77–95%), 31% (95% CI = 25–37%) and 44% (95% CI = 33–55%), respectively. The neratinib arms significantly increased the risk of diarrhea and vomiting in comparison with the control groups (diarrhea: all-grade, RR = 2.06, 95% CI = 1.38–3.08, P = 0.0004; grade 3/4, RR = 8.77, 95% CI = 2.91–26.40, P = 0.0001; vomiting: all-grade, RR = 2.02, 95% CI = 1.10–3.71, P = 0.02; grade 3/4, RR = 7.10, 95% CI = 3.33–15.15, P < 0.00001).

Conclusions: Our meta-analysis demonstrates that the neratinib arms are associated with a significantly increased risk of diarrhea and vomiting.     

Efficacy of fulvestrant 500 mg in Japanese postmenopausal advanced/recurrent breast cancer patients and factors associated with prolonged time-to-treatment failure

Objective: We aimed to confirm the efficacy of fulvestrant in Japanese postmenopausal advanced/recurrent breast cancer (ABC) patients, and investigate factors contributing to time-to-treatment failure (TTF) prolongation.

Research design and methods: This retrospective study included 194 ABC patients who received fulvestrant (500 mg) from January 2012 to December 2014.

Main outcome measures: TTF (efficacy measure), overall survival (OS), factors prolonging TTF and adverse events were evaluated.

Results: The median age was 65 (42 – 90) years. Overall, TTF was 5.48 months. In patients without prior chemotherapy (n = 59), OS was significantly longer (p = 0.0131) than in patients with prior chemotherapy (n = 135). There was no strong correlation between TTF with fulvestrant and other endocrine therapies, total duration of endocrine therapy and maximum duration of endocrine therapy. TTF was significantly longer in patients with less than two prior chemotherapy regimens (p = 0.0093), de novo metastatic disease (p = 0.0124) and without liver metastasis (p = 0.0024). We observed one case each of pulmonary infarction and psychiatric disorder.

Conclusions: Fulvestrant is effective for ABC patients and may show greater efficacy in patients with few prior chemotherapy regimens, de novo metastatic disease and absence of liver metastasis. Prior endocrine therapy duration might not be a predictive factor for fulvestrant TTF in heavily treated ABC patients.     

In situ forming biodegradable poly(ε-caprolactone) microsphere systems: a challenge for transarterial embolization therapy. In vitro and preliminary ex vivo studies

Background: In situ forming biodegradable poly(ε-caprolactone) (PCL) microspheres (PCL-ISM) system was developed as a novel embolic agent for transarterial embolization (TAE) therapy of hepatocellular carcinoma (HCC). Ibuprofen sodium (Ibu-Na) was loaded on this platform to evaluate its potential for the treatment of post embolization syndrome.

Methods: The influence of formulation parameters on the size/shape, encapsulation efficiency and drug release was investigated using mixture experimental design. Regression models were derived and used to optimize the formulation for particle size, encapsulation efficiency and drug release profile for TAE therapy. An ex vivo model using isolated rat livers was established to assess the in situ formation of microspheres.

Results: All PCL-ISM components affected the studied properties and fitting indices of the regression models were high (Radj² = 0.810 for size, 0.964 encapsulation efficiency, and 0.993 or 0.971 for drug release at 30 min or 48 h). The optimized composition was: PCL = 4%, NMP = 43.1%, oil = 48.9%, surfactant = 2% and drug = 2%. Ex vivo studies revealed that PCL-ISM was able to form microspheres in the hepatic arterial bed.

Conclusions: PCL-ISM system provides a novel tool for the treatment of HCC and post-embolization syndrome. It is capable of forming microspheres with desirable size and Ibu-Na release profile after injection into blood vessels.     

Renal dysfunctions/injury in adult epilepsy patients treated with carbamazepine or valproate

Objectives: Clinical and subclinical laboratory evidence of renal proximal tubular dysfunction had been reported in children with epilepsy as an adverse effect of some antiepileptic drugs (AEDs). This study aimed to determine kidney function in adult patients with monosymptomatic epilepsy of unknown etiology and treated with valproate (VPA) or carbamazepine (CBZ).

Methods: This study included 60 patients [mean age of 33.97 ± 6.70 years and treated with VPA (n = 24) or CBZ (n = 36) for mean duration of treatment of 6.03 ± 2.81years. Measurements of serum creatinine (sCr), urinary creatinine, creatinine clearance (CrCl) and serum kidney injury molecule 1 (KIM-1), markers of renal dysfunction/injury were done.

Results: Compared to controls, patients had higher sCr, KIM-1 and lower CrCl levels. Compared to patients on VPA, those on CBZ had relatively higher KIM-1 and lower CrCl levels. We reported only significant correlations between KIM-1 with sCr (r = 0.324, p = 0.001) and duration of treatment with AEDs (r = 0.301, p = 0.02).

Conclusion: Chronic VPA and CBZ therapy may be associated with subclinical renal glomerular and/or proximal tubular dysfunctions or injuries. The treating neurologist have to consider this while selection of AED on start treating patients or modifying the AED for patients at high risk of kidney injury.     

Cardiovascular effects of methadone and concomitant use of diazepam during methadone maintenance treatment induction: low concentration risk

Background: The aim is to evaluate the role of diazepam concentrations in development of low-concentration-methadone-associated QTc prolongation in patients with opioid use disorder during methadone maintenance treatment (MMT) induction.

Research design and methods: Individuals with addiction disorder on MMT were studied before the beginning of MMT and after one and six months of MMT. Serum concentrations of methadone, diazepam, electrolytes and ECG were analyzed.

Results: Thirty patients were enrolled. The mean methadone concentration at time points was 177 ± 119 ng/ml and 343 ± 182 ng/ml, while the mean diazepam concentration was 561 ± 437 ng/ml and 1045 ± 933 ng/ml. The QTc interval before the introduction of MMT, after 1 and 6 months of MMT were 412 ± 27 ms, 425 ± 18 ms and 424 ± 15 ms, respectively, showing statistically significant increase in the length of QTc interval after 1 and 6 months of MMT. Statistically significant correlation between the concentration of methadone and QTc interval length at observed time points (R² = 0.239, p = 0.018; R² = 0.513, p = 0.006) was shown, and it remained so if the concentration of diazepam was included (R² = 0.347, p = 0.026, R² = 0.513, p = 0.009).

Conclusions: The prolongation of QTc below the risk threshold in low methadone therapeutic doses has been recorded and concomitant use of diazepam could be a co-factor in such issue.     

Fractional laser-assisted topical delivery leads to enhanced,accelerated and deeper cutaneous 5-fluorouracil uptake

Background: Topical 5-Fluorouracil (5-FU) exhibits suboptimal efficacy for non-melanoma skin cancer, attributed to insufficient intracutaneous penetration. This study investigates the impact of ablative fractional laser (AFXL) at different laser-channel depths on cutaneous 5-FU pharmacokinetics and biodistribution.

Methods: In vitro porcine skin underwent AFXL-exposure using a fractional 10,600 nm CO₂-laser, generating microscopic ablation zones (MAZ) reaching the dermoepidermal junction (MAZ-ED), superficial-(MAZ-DS), or mid-dermis(MAZ-DM). 5-FU in AFXL-exposed and control skin was measured in Franz diffusion cells at 4 and 24 hours (n = 55). HPLC quantified 5-FU in full-thickness skin, specific skin depths of 100μm-1500μm, and transcutaneous receiver-compartments. Qualitative matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) visualized 5-FU in selected samples.

Results: Overall, AFXL enhanced and accelerated 5-FU uptake versus unexposed controls, with increased accumulation in deep skin layers (p < 0.01). While total, 24-hour 5-FU uptake in control skin was 0.096 mg/cm³ (0.19% of applied concentration), AFXL delivered up to 4.707 mg/cm³ (MAZ-DM; 9.41% uptake, 49-fold enhancement) (p = 0.002; 24 hours). Indicating accelerated delivery, 5-FU in laser-exposed samples at 4 hours was at least 10-fold that of 24-hour controls (p = 0.002). Deeper laser-channels increased delivery throughout the skin (MAZ-ED vs. MAZ-DM; p<0.01). MALDI-MSI confirmed enhanced, accelerated, deeper and more uniform 5-FU distribution after AFXL versus controls.

Conclusions: AFXL offers laser-channel depth-dependent, enhanced and accelerated 5-FU uptake, with increased deposition in deep skin layers.     

Safety and efficacy of propofol anesthesia for pediatric target-controlled infusion in children below 3 years of age: a retrospective observational study

Background: Although the requirement of propofol in children is increasing, propofol for induction and maintenance of anesthesia below 3 years old has not been approved in Korea. This study can provide a clinical evidence to increase the range of approval.

Research design and methods: We reviewed the medical records of patients below 3 years of age who underwent surgery between September 2013 and December 2016. Safety was evaluated on the basis of vital signs, and laboratory findings and efficacy were evaluated on the basis of the bispectral index (BIS). Adverse events were examined.

Results: A total of 109 patients anesthetized with propofol (propofol group) were compared with 109 patients with volatile anesthetics (volatile group) after propensity score matching. There was a difference in the proportion of patients showing decreased systolic pressure (P < 0.001) and heart rate (P = 0.03), but there was no difference in diastolic pressure (P = 0.238), mean arterial pressure (P = 0.175) during surgery. After surgery, there was no difference in all vital signs and the proportion patients who experienced adverse events of two groups.

Conclusions: Propofol anesthesia by target-controlled infusion was effective and didn’t show serious propofol-related perioperative adverse events.     

Corneal perforation: another side effect of nicorandil

Context: Nicorandil is an antianginal drug used for 20 years in Japan and introduced in France in 1994. Since 1997, side effects such as mucocutaneous ulcerations have regularly been reported.

Objective: To describe the first case of a patient with a spontaneous corneal perforation associated with mucocutaneous ulcerations while taking Nicorandil.

Materials and methods: A 81-year-old patient, with no past history of ocular disease but a long past history of cardiovascular disease, presented with a spontaneous paracentral corneal perforation. This was consecutive to 5 months of recurrent keratoconjunctivitis and mucocutaneous ulcerations resistant to conventional therapy. (He was taking nicorandil for 5 years.) A penetrating keratoplasty was performed in emergency.

Results: Inflammatory and infectious causes of spontaneous corneal perforation were ruled out. After initial uneventful post-operative wound healing, an epithelial ulcer appeared on the graft. Dermatologists suggested the iatrogenic role of nicorandil and the drug was discontinued. Both mucocutaneous and corneal ulcerations resolved rapidly.

Discussion: Although mucocutaneous ulcerations have been attributed several times to nicorandil, this is, to our knowledge, the first major corneal damage due to this antianginal drug. Timing, pattern of illness, absence of other aetiology, recurrence of epithelial ulceration on the corneal graft and its spontaneous healing after nicorandil discontinuation make it highly apparent probable that nicorandil was directly involved in this corneal perforation.

Conclusion: Ophthalmologists and dermatologists should be aware of the risk of severe but reversible corneal ulcerations in patients treated with nicorandil. A pharmacovigilance warning statement should be compulsory.     

Characterization of drug-drug interactions in patients whose substance intake was objectively identified by detection in urine

Background: Identification of drug-drug interactions (DDIs) typically relies on patient medication lists which are prone to inaccuracies. This study describes use of a mass spectrometry test to detect recently ingested substances in urine with subsequent identification of DDIs.

Research design and methods: This was a retrospective analysis of the prevalence of DDIs identified in patients with chronic pain, addiction and/or behavioral health conditions in the U.S. Relationships between patient demographics, polypharmacy and the occurrence of DDIs were also described.

Results: Of 15,004 patients, 2964 (20%) had a DDI identified. There was a positive association between the number of substances detected in urine and the number of interactions identified (r = 0.5033, p-value = 0.0001). Of patients with polypharmacy, 15.6% had contraindicated or severe interactions identified compared to only 3.2% of those without polypharmacy. For polypharmacy patients, the youngest population studied had a much higher likelihood of having one or more DDIs identified compared to the other age groups (p-value = 0.0002).

Conclusions: By utilizing a mass spectrometry test to objectively detect recently ingested substances followed by identification of DDIs, healthcare providers may be able to better characterize the true incidence of DDIs. Study findings may not be generalizable to healthcare populations outside of pain management, addiction treatment, and behavioral health.     

Comparing the efficacy of benzodiazepines and serotonergic anti-depressants for adults with generalized anxiety disorder: a meta-analytic review

Introduction: Generalized anxiety disorder (GAD) is a common form of anxiety disorder. Selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), and benzodiazepines (BZs) are the most commonly prescribed medications for GAD, but little is known about the relative efficacy of these pharmacological treatments.

Areas covered: This study provides a meta-analytic review of the efficacy of these medications in the treatment of adults with GAD. A comprehensive literature search yielded 54 articles reporting 56 unique studies with 12,655 participants treated with either pill placebo (6,191 participants), SSRIs (16 trials, 2,712 participants), SNRIs (17 trials, 2,603 participants), or BZs (23 trials, 1,149 participants). The overall combined effect size was modest to moderate (Hedges’ g = 0.37, p < 0.0001). Effect sizes decreased significantly over time. SSRIs (Hedges’ g = 0.33) and SNRIs (Hedges’ g = 0.36) demonstrated significantly lower effect sizes than BZs (Hedges’ g = 0.50). These findings were not due to differences in treatment length or publication year.

Expert opinion: The results of this study suggest that the most common forms of pharmacotherapy for adult GAD are moderately effective, with BZs being the most effective drug.     

Predictors of skeletal-related events among cancer patients with bone metastases treated with zoledronic acid: a secondary analysis of a randomized study

Background: The purpose of the current study is to assess the predictors of skeletal-related events (SREs) among advanced cancer patients with bone metastases treated with zoledronic acid within a randomized study.

Research design and methods: This is a secondary analysis of patient-level data of advanced cancer patients with bone metastases who were treated with monthly zoledronic acid in the NCT00330759 clinical trial.

Results: A total of 702 patients were included in the current analysis. In univariate logistic regression analysis, higher body mass index (P = 0.034) and lytic nature of bone metastasis (P = 0.008) were found to be predictive of a higher probability of SREs. When the two factors were included in a multivariate logistic regression model, both of them were predictive of the later development of SREs (P value for higher body mass index = 0.015; P value for lytic bone lesions = 0.005).

Conclusion: Among advanced cancer patients with bone metastases, lytic nature of metastases, as well as higher body mass index, are associated with a higher probability of SREs.

Trial registration number: this clinical trial was registered at clinicaltrials.gov with the number: nct0033     

Impact of total body weight on acute kidney injury in patients with gram-negative bacteremia

Background: The impact of total body weight (TBW) on the development of acute kidney injury (AKI) associated with gram-negative bacteremia has not been previously evaluated.

Methods: The cohort included 323 patients >/ = 18 years old with gram-negative bacteremia (1/1/2008–8/31/2011) who received >/ = 48 hours of antibiotics. We compared the incidence of AKI in patients with a TBW </ = 80kg vs. >80kg with a multivariable stepwise logistic regression adjusting for age >/ = 70 years, baseline serum creatinine of > 2.0 mg/dl, and receipt of a vasopressor. AKI was defined as an increase of 0.5 mg/dL or a > 50% increase from baseline for at least two consecutive days.

Results: The cohort was 62% TBW </ = 80kg and 38% TBW >80kg. TBW >80kg patients had higher risk of AKI (24% vs. 9%, p < 0.001), which was significant in the multivariable analysis (OR 3.41, 95% CI 1.73–6.73). A baseline serum creatinine of > 2.0 mg/dl and vasopressor use were also independently associated with AKI.

Conclusions: TBW >80kg was associated with the development of AKI. However, the mechanism for this association is not clear.     

Effects of metformin on clinical outcome in diabetic patients with advanced HCC receiving sorafenib

Background and objective: Several studies have reported an association between type 2 diabetes mellitus and hepatocellular carcinoma (HCC). Data from several retrospective studies and meta-analyses have highlighted a reduction of about 50% in the risk of developing HCC in cirrhotic patients treated with metformin for diabetes. The aim of this study was to evaluate the different outcomes of patients who received or did not receive metformin during treatment with sorafenib.

Methods: We analyzed 93 patients consecutively treated with sorafenib. Forty-two (45.2%) patients were diabetic, of whom 31 were on metformin. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and compared with the log-rank test.

Results: The concomitant use of sorafenib and metformin was associated with a median PFS of 2.6 months (95% CI 1.9–3.3) compared to 5.0 months (95% CI 2.5–8.2) for patients receiving sorafenib alone (p = 0.029). The median OS of patients treated with the combination was 10.4 months (95% CI 3.9–14.4) compared to 15.1 months (95% CI 11.7–17.8) for those who were not given metformin (p = 0.014).

Conclusions: Our findings could be the result of increased tumor aggressiveness and resistance to sorafenib in metformin-treated patients.     

Comparison of glycemic variability in Japanese patients with type 1 diabetes receiving insulin degludec versus insulin detemir using continuous glucose monitoring: a randomized,cross-over,pilot study

Objective: To use continuous glucose monitoring (CGM) to compare glycemic variability in patients with type 1 diabetes (T1D) treated with insulin degludec (IDeg) versus insulin detemir (IDet).

Methods: Ten patients with T1D were randomly assigned to receive once-daily IDeg, followed by twice-daily IDet, or vice versa. Glucose variability was evaluated by CGM after >4 weeks of the first insulin and again after crossover to the second insulin.

Results: The total daily insulin dose (U/kg/day) and the total daily basal insulin dose (U/kg/day) were significantly lower during treatment with IDeg than with IDet [median (interquartile range): 0.55 (0.54–0.73) vs. 0.64 (0.54–0.83); P = 0.028, 0.24 (0.19–0.36) vs. 0.30 (0.19–0.39); P = 0.027]. The 24-hour mean glucose levels were not significantly different. However, their standard deviation (SD) was significantly smaller during treatments with IDeg than those with IDet [59.5 (39.5–71.0) vs. 72.8 (61.8–92.8); P = 0.008]. Their mean fasting glucose levels and the mean postprandial peak levels after breakfast and after dinner were significantly lower with IDeg.

Conclusions: A CGM-based comparison demonstrated that once-daily IDeg showed fewer glycemic fluctuations than twice-daily IDet. IDeg appears to stabilize blood glucose levels better during both daytime and nighttime (particularly, before and after breakfast) with a lower insulin dosage.     

Renal impairment in patients with chronic hepatitis C treated with first generation protease inhibitors

Background: The incidence, course and risk factors associated with renal impairment (RI) in patients treated with triple therapy (TT) with pegylated interferon, ribavirin and telaprevir/boceprevir (PR/TVR/BOC) vs. dual therapy (DT) with PR were analyzed in this study. The association between RI and the decline of hemoglobin (Hb) was also examined.

Methods: Retrospective analysis included 110 patients with genotype 1b chronic HCV infection, aged 18 – 80 years, who underwent TT (48TVR/14BOC) or DT (48 patients). The estimated glomerular filtration rate (eGFR), serum creatinine concentration (SCr) and Hb were measured at baseline, at weeks 4, 12, 24, 48 of treatment, and post-treatment week 24.

Results: RI occurred in 9/62 (14.5%) patients who underwent TT, eight of whom were treated with TVR, one with BOC, and none treated with DT. The risk factors associated with RI were the following: TT (p = 0.0078), usage of nephrotoxic drugs (p = 0.0288), and older age (p < 0.0001). RI was reversible. A drop of Hb was associated with RI, older age and TT.

Conclusions: RI is not a rare but a reversible complication of TT. It is necessary to monitor SCr and eGFR, especially in patients with a potential risk factor of RI occurrence. The Hb drop is more severe in patients with RI than in those without it.     

Memantine in Japanese patients with moderate to severe Alzheimer’s disease: meta-analysis of multiple-index responder analyses

Background: Responder analyses assessing clinical worsening have attempted to clarify clinically meaningful drug efficacy enhancements in patients with Alzheimer’s disease (AD).

Research design and methods: This was a meta-analysis of two multicenter, randomized, double-blind, parallel-group, 24-week studies of 633 Japanese patients with moderate to severe AD receiving memantine 20 mg/day (n = 318) or placebo (n = 315). The clinical trial registration number is UMIN000026013.

Results: Overall odds ratios (OR) for a reduced likelihood of clinical worsening (memantine versus placebo) were statistically significant on the following individual and combined rating scales: Severe Impairment Battery-Japanese version (SIB-J, OR 0.52; 95% CI: 0.37, 0.73; p = 0.0001); Behavioral Pathology in AD Rating Scale (BEHAVE-AD, OR 0.53; 95% CI: 0.37, 0.75; p = 0.0003); and SIB-J + Clinician’s Interview-Based Impression of Change-plus-Japanese version (SIB-J + CIBIC-plus-J; OR 0.53; 95% CI: 0.37, 0.77; p = 0.0009). A significantly reduced risk of triple worsening was evident in the memantine versus placebo group on the combined SIB-J + CIBIC-plus-J + BEHAVE-AD rating scales (OR 0.38; 95% CI: 0.22, 0.65; p = 0.0003).

Conclusions: Memantine is a viable treatment option for patients with AD presenting not only with cognitive impairment, but also with a broader range of symptoms, including the behavioral and psychological symptoms of dementia.     

Clinical safety and tolerability of tedizolid phosphate in the treatment of acute bacterial skin and skin structure infections

Background: We evaluated safety and tolerability of tedizolid phosphate at the 200-mg once-daily dose approved for 6-day treatment of skin and skin-structure infections.

Research design and methods: Clinical adverse event (AE) and laboratory data were pooled across completed clinical studies (13 phase 1, two phase 2, and two phase 3), for all participants who received ≥1 dose of tedizolid 200 mg, linezolid 600 mg (phase 3 only), or placebo (phase 1 only).

Results: 1280 participants received tedizolid (phase 1: n = 355; phase 2/3: n = 925). In total, 13% received >6 doses of tedizolid (range: 7–21); in phase 2/3, 94% of participants received ≥5 doses (range: 5–10). Drug-related AEs occurred in 27% of participants (most commonly gastrointestinal reactions in 13% of participants and headache in 4%). Most AEs were mild-moderate in severity; <1% of participants discontinued treatment due to AEs. Tedizolid and linezolid had similar frequency, severity, and types of drug-related AEs. Tolerability in clinically important subpopulations (obese, n = 346; elderly, n = 99; renal impairment, n = 40; hepatic disease/impairment, n = 294) appeared comparable to the overall population.

Conclusions: Tedizolid, given orally or intravenously at 200 mg, has a favorable safety profile. Clinical trial and postmarketing experience with treatment ≥7 days is limited.     

Effect of 24-week treatment with ipragliflozin on proinsulin/C-peptide ratio in Japanese patients with type 2 diabetes

Background: Chronic hyperglycemia has an adverse influence on beta-cell function, which is known as ‘glucotoxicity’. Sodium-glucose cotransporter-2 (SGLT2) inhibitors lower the blood glucose concentration by enhancing urinary glucose excretion. This study was performed to clarify the influence of the SGLT2 inhibitor ipragliflozin on beta-cell function assessed from the plasma intact proinsulin/C-peptide ratio in Japanese patients with type 2 diabetes.

Research design and methods: This was a 24-week, prospective, single-center, open-label, single-arm study. The subjects were 19 Japanese patients with type 2 diabetes. After a 4- to 8-week period of lifestyle modification, ipragliflozin (50 mg/d) was added to their existing treatment. At baseline and at 12 and 24 weeks after starting ipragliflozin treatment, a meal test was performed to evaluate the fasting and 2-hour proinsulin/C-peptide ratio.

Results: After 24 weeks, the body mass index, fasting plasma glucose, and hemoglobin A1c were all decreased significantly. Both the fasting and 2-hour proinsulin/C-peptide ratio decreased significantly from 25.0 ± 18.9 × 10^–3 to 14.3 ± 9.0 × 10^–3 and from 23.2 ± 14.9 × 10^–3 to 13.7 ± 5.4 × 10^–3, respectively (both p < 0.01 vs. baseline).

Conclusions: These findings indicate that ipragliflozin might have a beneficial effect on beta-cells.     

Oral liquid levothyroxine solves the problem of tablet levothyroxine malabsorption due to concomitant intake of multiple drugs

Background: Unlike the tablet (TAB) formulation, liquid L-T4 (LIQ) is directly absorbed in the intestine. The aim of this study was to assess whether LIQ was superior to TAB, such that it would overcome the interference induced by co-ingestion of multiple interfering drugs (ID).

Methods: In this prospective cohort study, we recruited 11 patients with apparent reduced TAB absorption due to ≥ 2 ID, and switched them to LIQ while maintaining the daily dose and the co-ingestion of the ID. Serum TSH was assayed at least twice every eight weeks.

Results: Serum TSH was significantly lower on LIQ compared with TAB (P < 0.0001), in patients who took L-T4 for either replacement (P = 0.002) or TSH-suppression (P < 0.0001). This difference was evident already at the first measurement post-switch (P = 0.008 or P = 0.03). Regardless of the purpose of L-T4 therapy, patients who took two ID had lower serum TSH on LIQ compared with patients who took three ID (P = 0.0006). Interestingly, 2/3 patients who failed to reach target TSH levels while on LIQ took three ID.

Conclusions: LIQ overcomes the concurrent interference exerted by the ingestion of multiple ID. In such cases, switching from TAB to LIQ permits patients to reach target TSH within 8 weeks.     

Needle-free cutaneous delivery of living human cells by Er:YAG fractional laser ablation

Background: Dermatological diseases, including most skin cancers and rare genetic conditions frequently originate in the epidermis. Targeted, topical cell-based therapy is a promising therapeutic strategy. Here, we present the first report demonstrating that fractional laser ablation enables local ‘needle-free’ intraepidermal delivery of living human cells.

Methods: The cells penetrated porcine ear skin via microchannels created by Er:YAG fractional laser ablation; cell delivery was quantified using a haemocytometer. Cutaneous distribution was confirmed visually by laser scanning confocal microscopy and histological analysis.

Results: Total cell delivery (sum of amounts permeated and deposited) after 24 h increased from 5.7 ± 0.1 x10⁵ to 9.6 ± 1.6 x10⁵ cells/cm² when increasing pore density from 300 to 600 pores/cm², – corresponding to 19- and 32-fold increases over the control. At 600 pores/cm², cell deposition was 136-fold greater than cell permeation – the latter most likely due to transport from micropores into appendageal pathways. Production of GFP post-delivery confirmed cell remained viability.

Conclusion: The results demonstrate the feasibility of using controlled laser microporation to achieve local ‘needle-free’ cutaneous delivery of living human cells to the epidermis and dermis. This raises the possibility of using this technique for targeted new approaches for dermatological therapy in these regions.