Acute onset of severe dilated cardiomyopathy during bromocriptine therapy

OBJECTIVE: To report a case of severe dilated cardiomyopathy (DCMP) in a patient on bromocriptine therapy for a microprolactinoma. CASE SUMMARY: A 31-year-old African American female, who had been receiving bromocriptine 5 mg orally daily for a microprolactinoma during the preceding month, developed severe DCMP. An echocardiogram showed a markedly dilated left ventricle with severe reduction in the left-ventricular ejection fraction in the absence of any other identifiable causes of DCMP such as a peripartum state, ethanol use, preceding systemic viral illness, chronic hypocalcemia, chronic hypophosphatemia, or chronic uncontrolled tachycardia. She improved substantially (both symptomatically and echocardiographically) after cessation of bromocriptine therapy and initiation of supportive treatment of congestive heart failure (CHF). She showed no recurrence of CHF at a follow-up visit 2 months after withdrawal of the supportive care. The patient was not rechallenged with bromocriptine due to the clinical/ethical gravity of this probable adverse effect. DISCUSSION: Although cardiopulmonary adverse effects have been reported with the use of cabergoline (another dopamine agonist), to the best of our knowledge, this is the first case report of severe life-threatening DCMP associated with bromocriptine therapy. Causality assessment using the Naranjo probability scale revealed that the adverse drug event was probable. CONCLUSIONS: Bromocriptine was probably associated with DCMP in a patient being treated for a microprolactinoma. Severe DCMP needs to be considered a potentially life-threatening but reversible adverse effect of bromocriptine therapy for microprolactinoma of the pituitary gland.     

A Mid-term Comparison of the Functional Outcomes of Medial Pivot and Rotating Platform Mobile-Bearing Total Knee Arthroplasty in the Indian Population

BackgroundBoth medial pivot (MP) and rotating platform (RP) mobile-bearing (MB) total knee arthroplasty (TKA) have been developed to better mimic the natural knee kinematics and femoral roll back in flexion. The purpose of this retrospective study was to compare the mid-term functional outcomes and range of motion (ROM) of MP and RP types of total knee arthroplasty.Methods116 patients (mean age of 66.3 years) undergoing TKA (52 Medial pivot design and 64 Rotating Platform design) were evaluated retrospectively with Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) knee score, knee society score (KSS) with its subgroups namely, Knee Score (KSKS) and Functional Score (KSFS) and forgotten joint score (FJS) at a mean follow-up of 7.1 years. Range of motion (ROM) and tibiofemoral anatomic angle on the radiographs were also compared.ResultsMean ROM, WOMAC and KSKS improved significantly from pre-operative to postoperative knees in both the groups. There was, however, no significant difference between the two groups at the final follow-up. In contrast, mean KSFS score improved to 89.5 ± 8.1 in MP group and 86.3 ± 7.1 in RP Group (p = 0.025), while mean FJS was 85.6 ± 4.1 and 80.9 ± 5.4 in the MP and RP groups, respectively (p = < 0.0001).ConclusionSatisfactory clinical and functional outcomes can be obtained using either a MP or RP knee joint in tricompartmental osteoarthritis of knee. The MP design scores better on the KSFS score and FJS than the RP-TKA.     

An active film-coating approach to enhance chemical stability of a potent drug molecule

Peliglitazar, a PPAR α/γ agonist, was found to undergo acid as well as base catalyzed degradation. The acid catalyzed degradation led to the formation of benzylic alcohol and glycine carbamate and the base catalyzed degradation led to formation of p-hydroxyanisole and an amine degradant. In capsule formulations, the capsules with the lowest drug-loading exhibited maximum instability even at 25 °C/60% RH storage condition. Incorporation of pH-modifiers to maintain 'micro-environmental pH' acidic did not prevent the formation of the base-catalyzed degradants. Traditional dry granulated tablet formulation which is qualitatively similar to the capsule formulations showed the presence of acid-catalyzed degradants even without the presence of an acidifying agent. On the other hand, traditional wet granulated tablet formulation showed mainly base-catalyzed degradants. Stability problems of the tablet formulation were aggravated because the potent molecule required low tablet strengths which resulted in low drug to excipient ratio. To stabilize the molecule, an active film-coating approach was explored. In this approach, the drug was sprayed with the coating material onto non-active containing tablet cores. This approach of trapping the drug particles into the coating material provided tablets with satisfactory chemical stability. The stability enhancement observed in the active coating approach is attributed to the higher drug to excipient ratio in the film coat of non-reactive coating material compared to that in the traditional dry or wet granulated formulations.     

Significance of Unfolding Thermodynamics for Predicting Aggregation Kinetics: A Case Study on High Concentration Solutions of a Multi-Domain Protein

Purpose

To enable aggregation rate prediction over a broad temperature range for complex multi-domain proteins at high concentrations.

Methods

Thermal unfolding, non-isothermal kinetics and storage stability studies were conducted on a model multi-domain protein (MDP) at moderate to high concentrations (25–125 mg/mL) over a broad temperature range (4–40°C).

Results

Storage stability studies indicated the aggregation of MDP in solution to be a second order process. Application of Arrhenius kinetics to accelerated stability data resulted in underestimation of the aggregation rate under refrigerated conditions. Additional studies undertaken to understand the mechanism of the aggregation process highlighted the association of the monomer (or the aggregation competent species) to be the rate-limiting step for aggregation over the temperature range studied. Thermal unfolding studies in the presence of urea were used to calculate the heat capacity change upon unfolding (Δc_p,un). The resulting value of Δc_p,un when used in the extended Lumry-Eyring model resulted in a more accurate and a conservative estimate of the aggregation rate under refrigerated condition. Some complicating factors for the aggregation rate prediction for multi-domain proteins at high concentration are discussed.

Conclusions

The work highlights (i) the significance of incorporating unfolding thermodynamics in protein aggregation rate prediction, (ii) the advantages and challenges associated with the use of the extended Lumry-Eyring (ELE) model for rate prediction and (iii) the utility of using the Arrhenius and the ELE models in tandem during product development.     

Mercury poisoning from artisanal gold mining equipment

Artisanal and small-scale gold mining uses mercury to isolate gold from ore. Although uncommon in the United States, it is more common in poor and undeveloped countries. This practice requires heating mercury, which vaporizes into an odorless gas that can be inspired and absorbed into the blood. Inspired mercury vapors place individuals at risk of acute mercury toxicity and its subsequent chronic sequelae. We report a case of incidentally detected mercury foreign bodies in a 56-year-old male with a prior history of accidental mercury poisoning due to prior contact with artisanal gold mining equipment.     

Design of pH-independent controlled release matrix tablets for acidic drugs

The rate and extent of drug release from most controlled release systems are influenced by the pH of the dissolution medium for drugs with pH-dependent solubility. This dependency of drug release on pH may lead to additional inter- and intra-subject variability in drug absorption. In the present study, a pH-independent controlled release matrix system for acidic drugs was designed by incorporating release-modifiers in the formulation. Controlled release matrix tablets were prepared by compression of divalproex sodium, Methocel K4M and Eudragit E 100 or Fujicalin as the release-modifier. For formulations without any release-modifier, the extent and rate of drug release at pH 6.8 was much higher than that at pH 1.0. Formulations containing Eudragit E 100 provided drug release that was essentially independent of pH. This was achieved because Eudragit E 100 significantly increased the drug release in acidic medium and slightly decreased the release rate at higher pH. The increased release in the acidic medium can be attributed to the elevation of the micro-environmental pH in the swollen polymer gel layer. Formulations containing Fujicalin were less effective than those containing Eudragit E 100. This was attributed to the relative inability to elevate the pH and shorter residence time of Fujicalin in the matrix relative to Eudragit E 100.     

Diagnosis and therapy of oral squamous cell carcinoma

Oral squamous cell carcinoma ranks among the top ten most common cancers worldwide. Despite the success in diagnosis and therapy during the past 30 years, oral squamous cell carcinoma still belongs to the tumor types with a very unfavorable prognosis. In an effort to identify genomic alterations with prognostic relevance, we applied the comparative genomic hybridization technique on oral squamous cell carcinoma. The tumors exhibited from five up to 47 DNA copy number alterations, indicating a considerable degree of genomic imbalance. Out of 35 tumors, 19 showed a gain of chromosome band 7p12. Genomic imbalances were investigated by hierarchical cluster analysis and clustered image mapping to investigate whether genomic profiles correlate with clinical data. Results of the present investigation show that profiling of genomic imbalances in general, and especially of the epidermal growth factor receptor (EGFR) on 7p12, may be suitable as prognostic factors. In order to identify small-molecule inhibitors for EGFR, we established a database of 531 natural compounds derived from medicinal plants used in traditional Chinese medicine. Candidate compounds were identified by correlation analysis using the Kendall tau-test of IC50 values of tumor cell lines and microarray-based EGFR mRNA expression. Further validation was performed by molecular docking studies using the AutoDock program with the crystal structure of EGFR tyrosine kinase domain as docking template. We estimate these results will be a further step toward the ultimate goal of individualized, patient-adapted tumor treatment based on tumor molecular profiling.     

Co-solubilization of poorly soluble drugs by micellization and complexation

The use of combined approach of surfactants and cyclodextrins in solubilization of poorly soluble drugs has been described in literature. In this report, a mathematical model has been developed to provide the quantitative basis for this approach. First, by way of hypothetical examples and simulations, the influence of various interaction parameters on the phase solubility profile is presented. Additionally, the model results are compared with (a) results reported by Yang et al., with NSC-639829, sodium lauryl sulfate (SLS) and sulfobutyl-ether-beta-cyclodextrin ((SBE)(7M)-beta-CD) and (b) solubility of methylprednisolone, a model poorly soluble drug, in the presence of its water-soluble 'surfactant-like' prodrug, methylprednisolone 21-hemisuccinate, and (SBE)(7M)-beta-CD. The model shows good agreement with experimental data. Furthermore, theoretical simulations show that the combined solubility is less than the sum of the individual solubility values in cyclodextrins and surfactants. Based on the hypothetical case and the two examples, the factors affecting the phase solubility profile in mixed solutions of surfactants and cyclodextrins are presented. Finally, the limitations of the model to explain co-solubilization by surfactants and cyclodextrins are discussed.