Amputation and prosthetics of the lower extremity: The 2020 Dutch evidence-based multidisciplinary guideline.

BACKGROUND: Lower-limb amputations are rare but debilitating events in the lives of affected persons. Treatment of persons with amputation inherently involves many different health care professions at different stages leading to and after an amputation. There are prevailing clinical questions within the work field related to different facets of care including peri/postoperative aspects, prosthetic components, rehabilitation treatment, and health care processes. OBJECTIVES: To provide an up-to-date multidisciplinary evidence-based guideline for health care professionals involved in the treatment of persons with lower-limb amputation in the Netherlands. METHODS: Identification of key questions in a focus group, systematic review of the evidence (up to March 2019, using Embase and MEDLINE databases), and weighing considerations, culminating in clinical recommendations. RESULTS: Twelve key questions were formulated. Recommendations of two key questions were upheld in line with the previous 2012 guideline. Ten systematic literature searches were performed, leading to the inclusion of 59 studies. CONCLUSION: A summary of evidence-based conclusions, considerations, and recommendations of the 2020 guideline is presented.

In vitro in vivo relations for the parenteral liposomal formulation of Amphotericin B: A biorelevant and clinically relevant approach.

There is limited information on how to perform in vitro release tests for intravenously administered parenteral formulations and how to relate the in vitro release with an in vivo pharmacokinetic parameter after the administration of the formulation. In this study, the effect of hydrodynamics (using sample and separate and continuous flow conditions) and medium components (synthetic surfactants, albumin and buffers) on the release of Amphotericin B from the liposomal Ambisome® formulation were investigated. Pharmacokinetic modeling of plasma concentration profiles from healthy subjects administered Ambisome® was used to estimate the in vivo release rate constant of drug from the formulation in order to compare it with the in vitro release profiles. With the estimated in vivo and in vitro release rate constants, release profiles were generated. Two approaches were followed: comparison of in vivo and in vitro release rate constants and comparison of the area under the percent release-time curve from observed in vitro release data and simulated in vivo release data. Albumin was found to be most critical factor for the release of the drug by having a negative effect on the amount of Amphotericin B released. The release profiles obtained with the sample and separate method in both Krebs Ringer buffer- and Phosphate Saline buffer - albumin 4.0% w/v were predictive of the in vivo release profiles in healthy subjects. Determining the factors affecting drug release from parenteral formulations and relating the release profiles to a pharmacokinetic parameter in vivo supports the development of in vitro in vivo relations for parenteral products.

In vitro - in vivo relations for the parenteral liposomal formulation of Amphotericin B: A clinically relevant approach with PBPK modeling.

In vitro release testing is a useful tool for the quality control of controlled release parenteral formulations, but in vitro release test conditions that reflect or are able to predict the in vivo performance are advantageous. Therefore, it is important to investigate the factors that could affect drug release from formulations and relate them to in vivo performance. In this study the effect of media composition including albumin presence, type of buffer and hydrodynamics on drug release were evaluated on a liposomal Amphotericin B formulation (Ambisome®). A physiologically based pharmacokinetic (PBPK) model was developed using plasma concentration profiles from healthy subjects, in order to investigate the impact of each variable from the in vitro release tests on the prediction of the in vivo performance. It was found that albumin presence was the most important factor for the release of Amphotericin B from Ambisome®; both hydrodynamics setups, coupled with the PBPK model, had comparable predictive ability for simulating in vivo plasma concentration profiles. The PBPK model was extrapolated to a hypothetical hypoalbuminaemic population and the Amphotericin B plasma concentration and its activity against fungal cells were simulated. Selected in vitro release tests for these controlled release parenteral formulations were able to predict the in vivo AmB exposure, and this PBPK driven approach to release test development could benefit development of such formulations.

Circumferential suction-assisted lipectomy in the treatment of primary and secondary end-stage lymphoedema of the leg.

BACKGROUND: The treatment of end-stage lymphoedema of the leg is challenging, especially when conservative treatment fails and there is a large volume difference between the affected and unaffected legs. Circumferential suction-assisted lipectomy (CSAL) has been described as a treatment option for end-stage lymphoedema of the leg. Here, the long-term results of CSAL in end-stage primary and secondary lymphoedema of the leg were analysed. METHODS: This was a descriptive study of patients treated with CSAL for unilateral chronic irreversible lymphoedema of the leg. Compression therapy was resumed after surgery. Leg volumes were measured before surgery, and at 1, 6, 12 and 24 months after the procedure. RESULTS: A total of 47 patients with primary lymphoedema had a median preoperative volume difference between affected and unaffected legs of 3686 (i.q.r. 2851-5121) ml. Two years after surgery, this volume difference was reduced to 761 ml, a 79 per cent reduction. In the 41 patients treated for secondary lymphoedema, the median preoperative volume difference was 3320 (i.q.r. 2533-4783) ml, decreasing after 2 years to -38 ml (101 per cent reduction). The preoperative volume difference and the sex of the patient significantly influenced the final outcome after 2 years. The outcome was not related to BMI or other patient characteristics. CONCLUSION: CSAL is an effective method for treating both primary and secondary lymphoedema of the leg.

Engineering and manufacturing of pharmaceutical co-crystals: a review of solvent-free manufacturing technologies.

Design and synthesis of pharmaceutical cocrystals have received great interest in recent years. Cocrystallization of drug substances offers a tremendous opportunity for the development of new drug products with superior physical and pharmacological properties such as solubility, stability, hydroscopicity, dissolution rates and bioavailability. It is now possible to engineer and develop cocrystals via 'green chemistry' and environmentally friendly approaches such as solid-state synthesis in the absence of organic solvents. In addition, significant efforts have been directed towards computational screening, cocrystal manufacturing in a continuous manner and real-time monitoring for quality purposes by using various analytical tools. Pharmaceutical cocrystals are not fully exploited yet and there is a lot of ground to cover before they can be successfully utilized as medical products.

A painless swelling of the abdominal wall.

Case report. A man with a painless swelling of the abdominal wall. A 77-year-old male presented with a progressively increasing painless swelling of the abdominal wall due to nodular fasciitis.

Inclusion of water insoluble drugs in amorphous silica nanoparticles.

Amorphous silica nanoparticles (a-SiNPs) with high surface area and small pore size have been synthesized using a zwitterionic surfactant in acid media. The produced nanoparticles displayed large specific surface area (-850 m2/g) with an average particles size of 45 nm. The loading efficiency was assessed by incorporating three model water insoluble active substances Carbamazepine (CBZ), Ibuprofen (IBU) and Cyclosporin (CyA) via passive loading and it was found to varying from 15-40%. The loaded silica nanoparticles were analyzed using X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) to investigate the state of the adsorbed active agents. CyA was found to be in amorphous state, IBU was partially crystalline while CBZ was transformed into form I. The dissolution profiles showed rapid release for CBZ while IBU and CyA demonstrated prolonged release for 24 hr. The viability of Caco-2 cells was not affected in the presence of a-SiNPs showing negligible cytotoxicity (85%) at high concentrations up to 15 mg/ml.

Prospective, randomized, controlled trial comparing a new two-component compression system with inelastic multicomponent compression bandages in the treatment of leg lymphedema.

BACKGROUND: New, less-bulky, short-stretch compression bandages could be a valuable alternative in the management of lymphedema of the leg. OBJECTIVE: To compare the effectiveness of a two-component compression (2CC) system in the treatment of leg lymphedema with that of the traditional treatment with conventional inelastic multicomponent compression bandages (IMC). METHODS: Thirty hospitalized patients with moderate to severe unilateral lymphedema (stage II-III) of the leg were included. Patients were divided in two groups; one (n=15) received a 2CC, and the other (n=15) received IMC. Primary outcome was volume reduction of the affected leg; secondary outcome was loss of interface pressure. RESULTS: Median leg volumes before bandaging were 4,150 mL (2CC) and 4,360 mL (IMC). Median volume reduction after 2 hours was 120 mL (2.9%) with the 2CC system and 80 mL (1.8%) with IMC (p>.05). After 24 hours, volume reduction was 8.4% and 4.4% respectively (p>.05). Interface pressure dropped significantly within 2 hours of bandage application in both groups. CONCLUSION: Our results indicate that the 2CC system forms a suitable alternative to IMC in the conventional treatment of moderate to severe lymphedema.