The effect of electrostatic interactions on the formation of pharmaceutical eutectics.

Over the past decade, the formation of pharmaceutical eutectics has become a very attractive strategy to increase the bioavailability of active pharmaceutical ingredients (APIs). A great advantage of a eutectic phase, which can be obtained by simple physical mixing of solid materials, is the possibility to obtain a material with desired physicochemical properties only by varying the molar ratio of the parent components. In this work, we have investigated the ability of two protic ionic liquids (PILs), which are hydrochloride salts of lidocaine and prilocaine, as well as their non-ionic counterparts, to form eutectic mixtures. To gain an insight into the calorimetric properties of the formed dipolar and ionic mixtures, differential scanning calorimetry was employed. The mechanism of formation of deep eutectic mixtures on the molecular level was investigated by ab initio quantum mechanics calculations. The effect of electrostatic interactions on the eutectic transition, glass forming ability and the physical stability of pharmaceutical eutectics was also revealed.

Toward a Better Understanding of the Physical Stability of Amorphous Anti-Inflammatory Agents: The Roles of Molecular Mobility and Molecular Interaction Patterns.

The aim of this article is to examine the crystallization tendencies of three chemically related amorphous anti-inflammatory agents, etoricoxib, celecoxib, and rofecoxib. Since the molecular mobility is considered as one of the factors affecting the crystallization behavior of a given material, broadband dielectric spectroscopy was used to gain insight into the molecular dynamics of the selected active pharmaceutical ingredients. Interestingly, our experiments did not reveal any significant differences in their relaxation behavior either in the supercooled liquid or in the glassy state. Hence, as a possible explanation for the enhanced physical stability of etoricoxib, its ability to undergo a tautomerization reaction was recognized. The occurrence of intramolecular proton transfer in the disordered etoricoxib was proven experimentally by time-dependent dielectric and infrared (IR) measurements. Additionally, IR spectroscopy combined with density functional theory calculations pointed out that in the etoricoxib drug, being in fact a binary mixture of tautomers, the individual isomers may interact with each other through a hydrogen bonding network. A possible explanation of this issue was achieved by performing dielectric experiments at elevated pressure. Since compression results in etoricoxib recrystallization, the possible influence of pressure on the observed stabilization effect is also carefully discussed.

Enhancement of the physical stability of amorphous indomethacin by mixing it with octaacetylmaltose. inter and intra molecular studies.

PURPOSE: To demonstrate a very effective and easy way of stabilization of amorphous indomethacin (IMC) by preparing binary mixtures with octaacetylmaltose (acMAL). In order to understand the origin of increased stability of amorphous system inter- and intramolecular interactions between IMC and acMAL were studied. METHODS: The amorphous IMC, acMAL and binary mixtures (IMC-acMAL) with different weight ratios were analyzed by using Dielectric Spectroscopy (DS), Differential Scanning Calorimetry (DSC), Raman Spectroscopy, X-ray Diffraction (XRD), Infrared Spectroscopy (FTIR) and Quantitative Structure-Activity Relationship (QSAR). RESULTS: Our studies have revealed that indomethacin mixed with acetylated saccharide forms homogeneous mixture. Interestingly, even a small amount of modified maltose prevents from recrystallization of amorphous indomethacin. FTIR measurements and QSAR calculations have shown that octaacetylmaltose significantly affects the concentration of indomethacin dimers. Moreover, with increasing the amount of acMAL in the amorphous solid dispersion molecular interactions between matrix and API become more dominant than IMC-IMC ones. Structural investigations with the use of X-ray diffraction technique have demonstrated that binary mixture of indomethacin with acMAL does not recrystallize upon storage at room temperature for more than 1.5 year. Finally, it was shown that acMAL can be used to improve solubility of IMC. CONCLUSIONS: Acetylated derivative of maltose might be very effective agent to improve physical stability of amorphous indomethacin as well as to enhance its solubility. Intermolecular interactions between modified carbohydrate and IMC are likely to be responsible for increased stability effect in the glassy state.

Extended-release niacin/laropiprant for lipid management: observational study in clinical practice.

AIMS: Patients with dyslipidaemia or hypercholesterolemia carry a substantially increased cardiovascular risk and need optimal treatment of this key risk factor. We aimed to investigate the utilisation, efficacy and tolerability of the single pill combination extended-release niacin/laropiprant 1000 mg/20 mg or 2000 mg /40 mg under conditions of primary care practice. METHODS: The present study was a prospective, non-interventional, observational study involving 885 primary care physicians throughout Germany. Data on adult patients treated with niacin/laropiprant one or two tablets daily within the labelled indication were documented for an average of 23 ± 7 weeks. The study was registered in the Association of research-based pharmaceutical companies (VFA) database under no. 354. RESULTS: A total of 2359 patients were analysed in the intent-to-treat population (mean age 61.1 years, 67% males) of whom 1917 could be followed up. Background statin therapy was often discontinued and only about 50% of patients received two tables niacin/laropiprant at the end of the study. Individual goal attainment rates as subjectively determined by the investigator were for LDL-C 59.4%, total cholesterol 59.5%, HDL-C 72.8% and TG 51.5%, respectively. Objective (laboratory) goal attainment rates according to NCEP ATP III criteria were lower: LDL-C <100 mg/dl goal was achieved in 17.8%, HDL-C >40 in males or >50 mg/dl in females in 37.9% and TG <150 mg/dl in 18.7%. Totally, 422 adverse events were noted in 231 patients (9.7%), of which 317 were considered drug-related. Flushing occurred in 15%. CONCLUSION: Niacin/laropiprant resulted in beneficial effects on serum lipids and was generally well tolerated. The full potential of the drug combination was not explored by most physicians due to discontinuation of statins and lack of titration of the combination. Overall, treatment effects were consistent with those seen in controlled trials.

[Regional differences in the treatment of dyslipidemia in Germany]. / Regionale Unterschiede in der Behandlung von Fettstoffwechselstörungen innerhalb Deutschlands?

BACKGROUND AND OBJECTIVE: DYSIS (Dyslipidemia International Study) is an international multicenter cross-sectional trial. The objective of the regional analysis was to identify differences in lipid-lowering therapy and attainment of goal/normal lipid levels in Germany. METHODS: 4,260 patients who were at least 45 years of age and receiving regular statin therapy at 748 centers (office practices / outpatient clinics) in Germany were assessed at a routine ambulant appointment. Results from centers in the northern, eastern, southern, and western part of Germany were compared. RESULTS: The mean age of the patients was 66.6 - 67.9 years (p < 0.01, range over the four regions) and the proportion of males was 53 - 60 % (p < 0.01). There were significant regional differences in the number of cardiovascular risk factors and cardiovascular conditions, e. g. arterial hypertension (82 - 88 %), smoking (12 - 17 %), family history of coronary heart disease (CHD) (30 - 42 %), lack of exercise (38 - 48 %), CHD (only in women, 27 - 42 %), peripheral artery vascular disease (11 - 15 %), and heart failure (16 - 20 %). No regional differences were found for body mass index (BMI), waist circumference, metabolic syndrome, or diabetes mellitus. The mean LDL-cholesterol level in the four regions was 107 - 108 mg/dl (p = 0.53), HDL-cholesterol was 50 - 51 mg/dl (p = 0.62), and triglycerides 141 - 148 mg/dl (p = 0.68). The mean simvastatin (or simvastatin-equivalent) dosage was approximately 27 mg/day (p = 0.62). About half of the patients (49 - 53 %, p = 0.11) failed to attain their LDL-cholesterol target despite statin therapy. In addition to elevated LDL-cholesterol, 30 % of the patients had elevated triglycerides and/or low HDL-cholesterol. CONCLUSION: DYSIS showed the existence of significant regional differences in the characteristics of statin-treated patients but not in the type or dosage of statin therapy or in adherence to target/normal lipid levels as per guidelines. In a high proportion of patients the lipid-lowering therapy will need to be reviewed, as guideline target levels have not been attained.

Primary tuberculosis of the TMJ: presentation of a case and literature review.

Tuberculosis (TB) is a frequent health problem. The prevalence of extrapulmonary TB has increased in the last couple of years. Head and neck tuberculosis forms nearly 10% of all extrapulmonary manifestations of the disease. TB of the temporomandibular joint (TMJ) is rare; only a few cases have been reported. The clinical appearance of TB infection of the TMJ has been described as unspecific, resembling arthritis, osteomyelitis, cancer or any kind of chronic joint diseases. This article describes a 22-year-old woman with pain and left preauricular swelling. Magnetic resonance imaging and computed tomography showed an expansive process with destruction of the left condyle and condylar fossa. A fine needle aspiration examination of the swelling showed non-specific granulomatous inflammation. In the following days, a preauricular fistula developed, of which a swab and biopsy specimens were taken. Histological and microbiological examinations revealed an infection with Mycobacterium tuberculosis. The initial antituberculosis treatment consisted of a combination of four antibiotics and could be reduced to two antibiotics in the course of treatment. The treatment was completed successfully after 9 months.

Efficacy and safety of losartan 100 mg or losartan 100 mg plus hydrochlorothiazide 25 mg in the treatment of patients with essential arterial hypertension and CV risk factors: observational, prospective study in primary care.

BACKGROUND: Patients with high cardiovascular risk are prevalent in ambulatory care. To achieve adequate blood pressure control, such patients require higher drug doses and/or combination therapy. We aimed to assess the efficacy and safety of losartan 100 mg as monotherapy or in fixed-dose combination with hydrochlorothiazide 25 mg. DESIGN AND METHODS: Multicentre, prospective, open observational study over 13 weeks in patients with essential hypertension, whose blood pressure was not adequately controlled despite pretreatment. Main outcome parameters were the systolic (SBP) and diastolic (DBP) blood pressure reduction, the rate of normalized patients at study end compared to baseline, and the number and type of adverse events (AEs). RESULTS: Of the 7702 documented patients, 53.1% (N = 4088) were men, with a mean age of 63.5 +/- 10.7 years. Comorbidities were frequent (diabetes mellitus in 57.4% [N = 4418], coronary heart disease in 30.3% [N = 2330], left ventricular hypertrophy in 28.2% [N = 2172], heart failure in 14.0% [N = 1079], and peripheral arterial disease in 9.0% [N = 690]). Patients received losartan 100 mg in 45.7% (N = 3521), losartan/HCTZ in 53.8% (N = 4143); additional antihypertensive drugs were given in 45.5% (N = 3505). Physicians reported somewhat lower target values than those stipulated by the guidelines (irrespective of age, gender, and concomitant diseases except for diabetes). Mean SBP/DBP decreased from a baseline value of 158/93 mmHg by 24/12 mmHg at study end. The BP lowering effect was similar in subgroups by treatment or comorbidity, respectively, however target attainment rates were substantially higher in non-diabetic patients. Metabolic and renal parameters (fasting glucose, HbA(1c), serum creatinine and albumin in urine) showed trends for improvement. Tolerability was very good, as only 0.43% (N = 33) experienced an AE (in 0.31% [N = 24] serious AEs), and 0.08% (N = 6) discontinued therapy due to reasons related to study drug. CONCLUSION: In high-risk patients, treatment with losartan 100 mg or losartan/HCTZ 100/25 mg was effective and well tolerated, irrespective of comorbidity. These findings from a real-life setting are in line with those from randomized controlled trials.

Reconstruction of the palatal aponeurosis with autogenous fascia lata in secondary radical intravelar veloplasty: a new method.

Velopharyngeal insufficiency in cleft patients with muscular insufficiency detected by nasendoscopy is commonly treated by secondary radical intravelar veloplasty, in which the palatal muscles are reoriented and positioned backwards. The dead space between the retro-displaced musculature and the posterior borders of the palatal bone remains problematic. Postoperatively, the surgically achieved lengthening of the soft palate often diminishes due to scar tissue formation in the dead space, leading to reattachment of the reoriented muscles to the palatal bone and to decreased mobility of the soft palate. To avoid this, the dead space should be restored by a structure imitating the function of the missing palatal aponeurosis. The entire dead space was covered using a double layer of autogenous fascia lata harvested from the lateral thigh, which should allow sufficient and permanent sliding of the retro-positioned musculature. A clinical case of a 9-year-old boy who underwent the operation is reported. Postoperatively, marked functional improvements were observable in speech assessment, nasendoscopy and nasometry. The case reported here suggests that the restoration of the dead space may be beneficial for effective secondary palatal repair. Fascia lata seems to be a suitable graft for this purpose.

Calcium pyrophosphate dihydrate crystal deposition disease of the temporomandibular joint.

A case of a 74-year-old woman with calcium pyrophosphate dihydrate crystal deposition disease of the temporomandibular joint (TMJ) is presented. This disease rarely involves the TMJ and is not usually considered in the differential diagnosis of TMJ disorders. To our knowledge, only 23 cases have been reported in the literature and only four without any destructive changes of the condyle as in the present case.

Metastatic adenocarcinoma of the temporomandibular joint from the cardia of the stomach: a case report.

A case is presented of a 67-year-old man with adenocarcinoma of the gastric cardia that metastasised to the temporomandibular joint (TMJ). A carcinoma of the cardia metastatic to the TMJ has not previously been reported. The case is unusual in many respects. The condyle and disc were anteriorly displaced by the tumour, resulting in progressive mandibular deviation and crossbite. Radiographically, however, no destructive changes of the joint were observable. Tumour staging showed this lesion to be the only distant metastasis.

[Laryngeal chondromas: review of the literature and report of three cases]. / Chrzestniaki krtani--przeglad literatury i opis trzech przypadków.

The authors present three cases of laryngeal chondroma. One of them was localized on the thyroid cartilage and on the cricoid cartilage in two cases. Direct laryngoscopy and biopsy make diagnosis. But it is not always easy to obtain an adequate biopsy sample from cartilaginous tumors because of their submucosal location and consistency. The radiological findings turned out to be very helpful in chondroma of the larynx. All our patients were treated surgically, one of them performed a partial laryngectomy, and two required a total laryngectomy. Laryngeal chondromas are very rare. As well a brief review of the literature is presented.