Therapeutic strategies for chemotherapy-induced neutropenia in patients with solid tumors

Introduction: Chemotherapy-induced neutropenia (CIN) is a common adverse event during treatment of cancer patients, associated with increased morbidity, mortality, health care costs and impairment of patients’ quality of life which necessitate dose reductions.

Areas covered: A computerized systematic literature search was performed through Medline, PubMed, Google Scholar and the Cochrane Library to identify peer reviewed publications relevant to CIN, pathophysiology and epidemiology, patient risk-assessment and existing treatment approaches. Additionally, emerging issues such as alternative therapeutic options and implications in elderly care were addressed.

Expert opinion: Although CIN represents a common adverse event in the management of patients with solid tumors, the heterogeneity in clinical practice across different settings underlines the need to improve existing tools for accurate patient classification. Moreover, the definition of the optimal implementation of out-patient treatment and the use of colony-stimulating factor as add-on treatment together with antibiotics should be further investigated in order to accumulate more solid data. Finally, physician education is required to ensure that scientific knowledge is implemented in the daily clinical practice.     

Development of a Novel Oral Cavity Compartmental Absorption and Transit Model for Sublingual Administration: Illustration with Zolpidem

Intraoral (IO) delivery is an alternative administration route to deliver a drug substance via the mouth that provides several advantages over conventional oral dosage forms. The purpose of this work was to develop and evaluate a novel, physiologically based oral cavity model for projection and mechanistic analysis of the clinical pharmacokinetics of intraoral formulations. The GastroPlus™ Oral Cavity Compartmental Absorption and Transit (OCCAT™) model was used to simulate the plasma concentration versus time profiles and the fraction and rate of intraoral drug transit/absorption for Intermezzo® sublingual tablets (zolpidem tartrate). The model was evaluated by the goodness-of-fit between simulated and observed concentrations and the deviation of key PK parameters (e.g., C_max, T_max, and AUC). In addition, a sensitivity analysis was conducted to demonstrate the interplay and impact of key modeling parameters on the fraction absorbed via oral mucosa (F_{a_IO}). The OCCAT™ model captured the observed pharmacokinetics for Intermezzo® sublingual tablets (R² > 0.9). The predicted deviations (%) for C_max, AUC_0–inf, AUC_0–20 min, and T_max were 5.7, 28.0, 11.8, and 28.6%, respectively, indicating good prediction accuracy. The model also estimated ~18% of total drug was absorbed via the IO route. Furthermore, the sensitivity analysis indicated that the F_{a_IO} was not only associated with drug diffusivity and unbound fraction in epithelium tissue (f_ut) but also depended on the physicochemical properties of compounds for IO delivery (e.g., solubility and logD_pH = 7.4). The novel physiologically based IO absorption OCCAT™ model showed satisfactory performance and will be helpful to guide development of future intraoral formulations.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-015-9727-7) contains supplementary material, which is available to authorized users.KEY WORDS: diffusivity, intraoral delivery, oral cavity compartmental absorption and transit (OCCAT™) model, unbound fraction in epithelium tissue, zolpidem     

Renal artery thrombosis caused by stent fracture in a single kidney patient.

PURPOSE: To report a case of incomplete expansion, fracture, and thrombosis of a stent in the renal artery. CASE REPORT: A 47-year-old man with right renal artery occlusion underwent direct stenting of the left renal artery using a balloon-expandable stent. Completion angiography showed satisfactory patency of the vessel although the stent was not fully expanded in its central segment. The patient received 5000 units of heparin during the procedure, but no additional anticoagulant or antiplatelet therapy in the peri/postinterventional period. Twenty-five days later, he presented with acute renal insufficiency and uncontrolled hypertension. Angiography revealed in-stent thrombosis and collateral flow in the distal segment of the left renal artery. He underwent an aortorenal bypass, which salvaged the kidney. The stent, after removal from the vessel, was fractured and not completely expanded. CONCLUSIONS: Incomplete expansion and fracture of the stent associated with insufficient antiplatelet therapy produced in-stent thrombosis. Collateral flow prevented kidney necrosis.     

Left atrial systolic function in primary and familial amyloidosis: assessment from left atrial volume change

The severity of left ventricular involvement may differ between primary (PA) and familial amyloidosis (FA). This study examined whether differences in left atrial (LA) systolic function are also present. Twenty-eight patients (18 men, 10 women, aged 59 +/- 12 years) with PA, 17 (11 men, 6 women, aged 40 +/- 11 years) with FA, and 25 normal controls (18 men, 7 women, aged 56 +/- 14 years) underwent transthoracic M-mode, two-dimensional, and Doppler echocardiography. Left atrial volumes were determined at mitral valve (MV) opening (maximal, Vmax), electrocardiographic P wave (onset of atrial systole, Vp), and MV closure (minimal, Vmin) from the apical two-and four-chamber views using the biplane area-length method. Left atrial systolic function was assessed with the LA active emptying volume (ACTEV) = Vp-Vmin and fraction (ACTEF) = ACTEV/Vp. The E/A ratio was increased (1.34 +/- 0.93 vs. 0.89 +/- 0.3), whereas deceleration time was decreased (168.1 +/- 33.7 vs. 196.2 +/- 34.2 ms) in PA compared with FA (p<0.05). Vmax and Vp were similar in PA and FA and greater than in the controls (46.6 +/- 14 vs. 40 +/- 11.4 vs. 27.1 +/- 6.3 cm3/m2, p<0.01, and 33.4 +/- 11.6 vs. 29.7 +/- 10.8 vs. 16.8 +/- 3.8 cm3/m2, p<0.01, respectively). The ACTEV was lower in PA and in the controls than in FA (6.7 +/- 2 vs. 6.2 +/- 2.2 vs. 8.5 +/- 3.3, respectively, p<0.05). The ACTEF was lower in PA than in FA and both were lower than those in the controls (20 +/- 5% vs. 28 +/- 7% vs. 36 +/- 11%, respectively, p<0.01). Despite a similar increase in LA volume, LA systolic dysfunction is more pronounced in PA than in FA. This is most likely due to the restrictive left ventricular physiology possibly associated with depressed LA contractility in the former.     

Brain hemisphericity and developmental dyslexia

The present study examined the link between brain hemisphericity and dyslexia in secondary school students, using the Preference Test (PT), a widely used self-report index of preferred hemisphere thinking styles. The hypothesis was that differences would be revealed between the dyslexic group and their peers in hemispheric preference. A total of 45 secondary school students who were diagnosed with dyslexia and attended regular public schools formed the learning disabled group. A comparison group was formed of pupils who attended the same classes (N = 90), and these were matched for age and sex with dyslexics (1 dyslexic: 2 control). The results revealed that significantly more dyslexic pupils displayed a preference for a right hemisphere thinking style compared to their peers who adopted a left hemisphere thinking style. This finding is in line with the suggestion of the greater right hemisphere involvement in the expression of developmental dyslexia.     

COVID-19 and the heart

An outbreak of coronavirus disease 2019 (COVID-19) occurred in December 2019 due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is a strain of SARS-CoV. Patients infected with the virus present a wide spectrum of manifestations ranging from mild flu-like symptoms, cough, fever and fatigue to severe lung injury, appearing as bilateral interstitial pneumonia or acute respiratory failure. Although SARS-CoV-2 infection predominantly offends the respiratory system, it has been associated with several cardiovascular complications as well. For example, patients with COVID-19 may either develop type 2 myocardial infarction due to myocardial oxygen demand and supply imbalance or acute coronary syndrome resulting from excessive inflammatory response to the primary infection. The incidence of COVID-19 related myocarditis is estimated to be accountable for an average of 7% of all COVID-19 related fatal cases, whereas heart failure (HF) may develop due to infiltration of the heart by inflammatory cells, destructive action of pro-inflammatory cytokines, micro-thrombosis and new onset or aggravated endothelial and respiratory failure. Lastly, SARS-CoV-2 can engender arrhythmias through direct myocardial damage causing acute myocarditis or through HF decompensation or secondary, through respiratory failure or severe respiratory distress syndrome. In this comprehensive review we summarize the COVID-19 related cardiovascular complications (acute coronary syndromes, myocarditis, HF, arrhythmias) and discuss the main underlying pathophysiological mechanisms.     

Heart failure with preserved ejection fraction: A distinct heart failure phenotype?

The present work discusses the serious confusion resulting from the arbitrary nomenclature of heart failure with preserved ejection fraction (HFpEF), the presumed underlying pathophysiology, and the supposed features. A consequence of this misconception is that HFpEF trials have recruited patients with entirely different characteristics rendering the extrapolation of the results of one study to the other infeasible and dramatically affecting diagnosis and treatment.