Evaluation of Individual and Crystal Population Dissolution Rates by Time-Resolved X-ray Microtomography.

The intrinsic dissolution rate (IDR) is an important parameter in pharmaceutical science that measures the rate at which a pure crystalline active pharmaceutical ingredient dissolves in the absence of diffusion limitations. Traditional IDR measurement techniques do not capture the complex interplay between particle morphology, fluid flow, and dissolution dynamics. The dissolution rate of individual particles can differ from the population average because of factors such as particle size, surface roughness, or exposure of individual crystal facets to the dissolution medium. The aim of this work was to apply time-resolved X-ray microtomography imaging and simultaneously measure the individual dissolution characteristics of a large population of crystalline particles placed in a packed bed perfused by the dissolution medium. Using NaCl crystals in three different size fractions as a model, time-resolved microtomography made it possible to visualize the dissolution process in a custom-built flow cell. Subsequent 3D image analysis was used to evaluate changes in the shape, size, and surface area of individual particles by tracking them as they are dissolved. Information about the particle population statistics and intrabatch variability provided a deeper insight into the dissolution process that can complement established IDR measurements.

Effect of co-processed excipient type on properties of orodispersible tablets containing captopril, tramadol, and domperidone.

An important feature of orodispersible tablets (ODTs) is the convenient administration of the drugs, in some cases, faster onset of action, stability maintenance, and dose precision. This work focused on the preparation of ODTs containing mannitol-based co-processed excipients Prosolv® ODT G2, Ludiflash® and Parteck® ODT in combination with tramadol, captopril, and domperidone by direct compression. Prosolv® ODT G2 showed high energy of plastic deformation due to the content of microcrystalline cellulose. Parteck® ODT provided compact tablets due to the content of granulated mannitol. All drugs decreased tensile strength, increased friability, prolonged disintegration time, and decreased the porosity of tablets. Tablets containing Prosolv® ODT G2 with captopril, domperidone, and tramadol; and Parteck® ODT with domperidone met the requirements for ODTs production, i.e., friability ≤ 1% and disintegration time ≤ 180 s, fast wetting time, high water absorption ratio, and adequate tensile strength. The disintegration time was tested using both the pharmacopeial method and the BJKSN-13 apparatus. The results indicate the significant difference between these methods, with the disintegration time being longer when tested with the BJKSN-13 instrument.

Immune system disorders in the early post-injury period in patients after severe brain injury from the perspective of the severity of the injury.

BACKGROUND: Brain injuries are the most common cause of death in productive age. Besides the extent of the injury, other systemic factors can also affect the outcome. Patients suffering from severe brain injury often experience extracranial inflammatory complications during the early period of treatment. Here, we investigate the changes in immunity in patients with brain injury. METHODS: 121 patients and 92 healthy controls were included in the research. Blood samples were collected on admission and analyzed by flow cytometry and biochemical methods. Multiple clusters of differentiation (CD) and antibody levels were investigated. The results were compared between patients and controls. In addition, results of two classes of severity (Glasgow Coma Scale, GCS, of 3-5 vs. 6-8) were also compared. RESULTS: Parameters of humoral immunity in patients immediately after admission were significantly lower than those from healthy donors, with the exception of IgE elevated as much as to resemble allergic reaction (p < 0.01). Of cellular parameters, only natural killer (NK) cluster CD56 + was elevated (p < 0.01). Extracranial infectious complications were more common in patients with GCS 3-5. CONCLUSIONS: Strong immune system disorders were observed in patients after severe brain injury, which may contribute to the worse outcome in such patients.

Pharmaceutical Product Characterization and Manufacturability of Surfactant-Enriched Oil Marbles with Abiraterone Acetate.

The present study investigates the physicochemical properties and stability of a novel lipid-based formulation-surfactant-enriched oil marbles containing abiraterone acetate. While the biopharmaceutical performance of this formulation has been reported recently, this study aims to fill the gap between a promising in vivo performance and industrial applicability. A series of techniques were employed to assess the solid-state characteristics of oil marble cores along with their physicochemical properties upon stability testing. The chemical stability of abiraterone acetate in the formulation was also investigated. The core of the formulation was found to be stable both physically and chemically over 12 months of storage. The in vitro performance of stressed samples was evaluated using a dissolution experiment. The formulation has successfully self-emulsified upon incubation in bio-relevant media, resulting in a fast and complete API release. An important issue connected with the excipient used as a covering material of oil marbles has been identified. The seemingly insignificant water sorption caused agglomeration of the oil marbles and consequently compromised the dissolution rate in some of the stressed samples. Replacing HPMC with lactose as a covering material resulted in more favorable properties upon storage. Overall, it has been shown that oil marbles are an industrially applicable concept of the solidified lipid-based formulation.

Model-Based Evaluation of Drying Kinetics and Solvent Diffusion in Pharmaceutical Thin Film Coatings.

PURPOSE: Fluid-bed coating processes make it possible to manufacture pharmaceutical products with tuneable properties. The choice of polymer type and coating thickness provides control over the drug release characteristics, and multi-layer pellet coatings can combine several active ingredients or achieve tailored drug release profiles. However, the fluid-bed coating is a parametrically sensitive process due to the simultaneous occurrence of polymer solution spraying and solvent evaporation. Designing a robust fluid-bed coating process requires the knowledge of thin film drying kinetics, which in turn critically depends on an accurate description of concentration-dependent solvent diffusion in the polymer. METHODS: This work presents a mathematical model of thin film drying as an enabling tool for fluid-bed process design. A custom-built benchtop drying cell able to record and evaluate the drying kinetics of a chosen polymeric excipient has been constructed, validated, and used for data collection. RESULTS: A semi-empirical mathematical model combining heat transfer, mass transfer, and film thickness evolution was formulated and used for estimating the solvent diffusion coefficient and solvent distribution in the polymer layer. The combined experimental and computational methodology was then used for analysing the drying kinetics of common polymeric excipients: poly(vinylpyrrolidone) and two grades of hydroxypropyl methylcellulose. CONCLUSIONS: The experimental setup together with the mathematical model represents a valuable tool for predictive modeling of pharmaceutical coating processes.

Antibiotic depot system with radiofrequency controlled drug release.

Drug depot systems have traditionally relied on the spontaneous dissolution and diffusion of drugs or prodrugs from a reservoir with constant exposure to the surrounding physiological fluids. While this is appropriate for clinical scenarios that require constant plasma concentration of the drug over time, there are also situations where multiple bursts of the drug at well-defined time intervals are preferred. This work presents a drug depot system that enables repeated on-demand release of antibiotics in precise doses, controlled by an external radiofrequency magnetic field. The remotely controlled depot system consists of composite microcapsules with a core-shell structure. The core contains micronized drug particles embedded in a low-melting hydrophobic matrix. The shell is formed by a hydrogel with immobilised magnetic nanoparticles that facilitate local heat dissipation after exposure to a radiofrequency magnetic field. When the melting point of the core material is locally exceeded, the embedded drug particles are mobilised and their surface is exposed to the external aqueous phase. It is shown that drug release can be controlled in an on/off manner by a chosen sequence and duration of radiofrequency pulses. The capacity of the depot system is shown to be significantly higher than that of purely diffusion-controlled systems containing a pre-dissolved drug. The functionality of the depot system is demonstrated in vitro for the specific case of norfloxacin acting on E. coli.

The efficacy of surgical treatment of cerebral arteriovenous malformations in a single academic institution: a case series.

AIM: To report on patients who underwent surgical treatment of arteriovenous malformations (AVMs) at our institution. METHODS: This retrospective single-center case series enrolled the patients who underwent surgical treatment of pial AVM at the Department of Neurosurgery, University Hospital Brno, between 2005 and 2019. The data are summarized as descriptive statistics presenting basic characteristics in all the patients and in sex or age subgroups. RESULTS: Fifty patients were enrolled. The majority of AVMs were of Spetzler-Martin grade II (n=27; 54%), localized supratentorialy (n=43; 86%), and half of AVMs were ruptured. A total resection was performed in 48 patients (96%), and a good overall outcome was achieved in 44 patients (88%). Surgery-associated morbidity was 2%, and the mortality rate was 0% due to meticulous selection of patients for surgical treatment. CONCLUSION: Microsurgery is an appropriate method of treatment for S-M grade I-III pial AVMs. Microsurgery may be used to treat the majority of small-nidus AVMs with a low mortality and morbidity, when precisely planned and performed by an expert vascular team. The meticulous selection of patients for surgical treatment is crucial.

What is the risk of venous cerebellar infarction in the supracerebellar infratentorial approach?

The supracerebellar infratentorial approach (SCITA) is a standard approach used in a neurosurgical practice. It carries some risk of associated complications including cerebellar venous infarction with possible serious sequelae. The objective of this study is to address the incidence of cerebellar venous infarction in SCITA. A search through the currently available literature was performed in September 2019 from the year 2000 until September 2019 dealing with 'supracerebellar infratentorial approach'. Out of the 578 patients found in thirteen case series, two venous infarctions were present; the remaining four patients were published as case reports. By analysing the case series, we calculated the risk of such a complication to be 0.345% (95% CI [0.061%, 1.248%]). Case reports were not included. The real risk is estimated to be higher. The risk of cerebellar venous infarction is an unpredictable, infrequent but real complication with potentially dreadful sequelae. Each neurosurgeon using this approach should be aware of this event when employing this approach. The avoidance of cerebellar venous infarction can be lowered by leaving as many bridging veins intact as possible.

Current Treatment of Anterior Communicating Artery Aneurysms: Single Center Study.

INTRODUCTION: Anterior communicating artery aneurysms (ACoAAs) are the most frequent intracranial aneurysms treated at neurosurgical departments with a vascular program. MATERIAL AND METHODS: We reviewed patients with ACoAAs in a single institution over ten years (2008-2017). The focus was on the final outcome; complications, age, and clinical condition with respect to modalities were analyzed. RESULTS: A total of 198 patients treated during this period was included in the study: 176 patients had a ruptured ACoAA and 22 had an unruptured ACoAA. Then, 127 (71%) were treated surgically and 51 (29%) by endovascular means. Out of the whole series, a good recovery occurred in 123 patients (62%), moderate disability in 11 (5.5%), severe disability in 19 (10%), vegetative state in 11 (5.5%), and death in 34 (17%). In the 157 patients (72.5%) with a subarachnoid hemorrhage (SAH), both modalities had a favorable outcome: 27.5% had an unfavorable outcome, 12% had complications in surgery versus 17.6% during endovascular treatment. No statistical difference in outcome, complications, and age was noted between modalities. Surgical treatment was more frequently adopted for patients in a better clinical condition (p ≤ 0.05). CONCLUSION: More than two thirds of the patients (72.5%) reached a favorable outcome. There was no difference in age between the treatment modalities. Risks of complications are present and specific for both modalities.

Middle cerebral artery aneurysms with intracerebral hematoma-the impact of side and volume on final outcome.

BACKGROUND: Middle cerebral artery aneurysms (MCA aneurysms) belong to the most frequent type of intracranial aneurysms forming an intracerebral hematoma. The consequences of the hematoma-the laterality, the impact of ICH volume and size of the aneurysm with the final outcome of these patients had not been studied in detail in this location, and we focused on the analysis of these factors. METHODS: Patients with MCA aneurysms and associated intracerebral hematomas with a volume ≥10 ml were studied; these were treated from January 2006 to December 2015. During this period, more than 700 patients with spontaneous subarachnoid hemorrhage were admitted to the Department of Neurosurgery, University Hospital Brno. The data were collected from the subarachnoid hemorrhage database of the unit and from the local hospital registry. All consecutive patients at the treating center were involved in this retrospective study. We collected clinical data such as age, gender, aneurysm location, preoperative hematoma size, Hunt-Hess grade and type of surgical procedures. We focused on the analysis of the final outcome [Glasgow Outcome Scale (GOS) score] in relation to ICH volume, side of bleeding and finally the relationship between aneurysm size and the volume of ICH. RESULTS: Fifty-eight patients with an MCA aneurysm and ICH were included; the mean age of this series was 59.4 years. Thirty-six patients (62%) had clinical status Hunt-Hess 4-5 on admission. The mean size of the intracerebral hematoma was 47.1 ml (10-133 ml). Most frequently, in 30 patients (52%), the hematoma had bled into the temporal lobe. Fifty three patients were operated on, and 5 were treated conservatively because of their poor condition. Twenty-three patients (40%) had a favorable Glasgow Outcome Scale score, and 35 (60%) had an unfavorable outcome including 20 patients (35%) who died. Of the 53 patients operated on, 20 (38%) underwent decompressive hemicraniectomy (DHC). Patients with an unfavorable outcome had significantly larger hematomas with a median size of 54 ml, whereas those with a favorable outcome had a median size of 26 ml (p = 0.0022). Larger hematomas were found on the right side. The cutoff volume for an unfavorable outcome in ICH was 25 ml. The outcomes were not related to the side of the ICH (p = 0.42), and the aneurysm size did not predetermine the ICH volume (p = 0.3159). CONCLUSION: Our study confirms the benefit of the active treatment of patients with MCA aneurysms and associated ICH. A significant proportion of these patients achieves a favorable outcome. No association between the side of bleeding and outcome was demonstrated. Hematomas larger than 25 ml have a greater tendency to lead to an unfavorable outcome. The treatment decision-making process should not differ for either side.

Microneurosurgical management of anterior choroid artery aneurysms.

OBJECTIVE: Anterior choroid artery aneurysms (AChAAs) constitute 2%-5% of all intracranial aneurysms. They are usually small, thin walled with one or several arteries originating at their base, and often associated with multiple aneurysms. In this article, we review the practical microsurgical anatomy, the preoperative imaging, surgical planning, and the microneurosurgical steps in the dissection and the clipping of AChAAs. METHODS: This review, and the whole series on intracranial aneurysms (IAs), are mainly based on the personal microneurosurgical experience of the senior author (J.H.) in two Finnish centers (Helsinki and Kuopio) that serve, without patient selection, the catchment area in Southern and Eastern Finland. RESULTS: These two centers have treated more than 10,000 patients with IAs since 1951. In the Kuopio Cerebral Aneurysm Database of 3005 patients with 4253 IAs, 831 patients (28%) had altogether 980 internal carotid artery (ICA) aneurysms, of whom 95 patients had 99 (2%) AChAAs. Ruptured AChAAs, found in 39 patients (41%), with median size of 6 mm (range = 2-19 mm), were associated with intracerebral hematoma (ICH) in only 1 (3%) patient. Multiple aneurysms were seen in 58 (61%) patients. CONCLUSIONS: The main difficulty in microneurosurgical management of AChAAs is to preserve flow in the anterior choroid artery originating at the base and often attached to the aneurysm dome. This necessitates perfect surgical strategy based on preoperative knowledge of 3 dimensional angioarchitecture and proper orientation during the microsurgical dissection.

Microsurgical principles for anterior circulation aneurysms.

Microneurosurgical techniques introduced by Prof. Yasargil have been modified by the senior author (JH) when treating more than 4,000 patients with aneurysms at two of the Departments of Neurosurgery in Finland, Kuopio and Helsinki, with a total catchment area of close to three million people. This experience is reviewed, and the treatment of anterior circulation aneurysms by simple, fast, normal anatomy preserving strategy is presented.Most of the aneurysms of the anterior circulation are treated by using the lateral supraorbital approach, a less invasive, more frontally located modification of the pterional approach. To avoid extensive skull base surgery, a slack brain is needed and achieved by experienced neuroanesthesia and by surgical tricks for removal of CSF.Diagnosis of cerebral aneurysm before rupture improves treatment results more than any technical advances. Until this is realized, we continue to treat cerebral aneurysms by simple, fast, preserving normal anatomy-strategy, which has served our patients well.Patients with cerebral aneurysms should be treated at specialized neurovascular centers.

Present state of microneurosurgery of cerebral arteriovenous malformations.

Microneurosurgical excision is known to be the definitive treatment for brain arteriovenous malformation (AVMs). The most important factors governing the operability of an AVM are location, size, age of the patient, and the neurosurgeon's and team's experience. We present in this review the surgical experience of the senior author (JH) in microneurosurgical treatment of brain AVMs. This consists of the following steps: (1) accurate preoperative embolization; (2) optimal selection of the surgical approach; (3) accurate definition and preservation of the normal arterial vessels of passage; (4) temporary clipping of the feeding arteries; (5) a special method of coagulation called "dirty coagulation" of the deep small difficult vessels inside apparently normal brain around the AVM; (6) removal of all AVM; (7) meticulous hemostasis; (8) intra- and postoperative digital subtraction angiography (DSA); (9) clinical and radiological follow-up. These steps are not possible in AVMs lying entirely within central eloquent areas. Nine out of ten small- and medium-sized arteriovenous malformations (AVMs) are suitable for direct surgery, but surgical complications increase drastically with the size of the AVM. Nevertheless, the actual results of combined treatment with preoperative Onyx embolization followed by microsurgery have decreased these risks.

Application of microscope integrated indocyanine green video-angiography during microneurosurgical treatment of intracranial aneurysms: a review.

Indocyanine Green Video Angiography (ICG-VA) is recently introduced to the practice of cerebrovascular neurosurgery. This technique is safe and noninvasive and provides reliable real-time information on the patency of blood vessels of any size, as well as residual filling of aneurysms. In this article, a review of the literature and our experience with ICG-VA during microneurosurgery of intracranial aneurysms is presented.

Microneurosurgical management of internal carotid artery bifurcation aneurysms.

BACKGROUND: Internal carotid artery bifurcation aneurysms form 2% to 9% of all IAs. They are more frequent in younger patients than other IAs. In this article, we review the practical microsurgical anatomy, the preoperative imaging, surgical planning, and the microneurosurgical steps in the dissection and the clipping of ICAbifAs. METHODS: This review and the whole series on IAs are mainly based on the personal microneurosurgical experience of the senior author (JH) in 2 Finnish centers (Helsinki and Kuopio), which serve, without patient selection, the catchment area in Southern and Eastern Finland. RESULTS: These 2 centers have treated more than 11 000 patients with IAs since 1951. In the Kuopio Cerebral Aneurysm Database of 3005 patients with 4253 IAs, 831 (28%) patients had altogether 980 ICA aneurysms, of whom 137 patients had 149 (4%) ICAbifAs. Ruptured ICAbifAs, found in 78 (52%) patients, with median size of 8 mm (range, 2-60 mm), were associated with ICH in 15 (19%) patients. Ten (7%) ICAbifAs were giant (> or = 25 mm). Multiple aneurysms were seen in 59 (43%) patients. The ICAbifAs represented 18% of all IAs ruptured before the age of 30 years. CONCLUSIONS: The main difficulty in microneurosurgical management of ICAbifAs is to preserve flow in all the perforators surrounding or adherent to the aneurysm dome. This necessitates perfect surgical strategy based on preoperative knowledge of 3D angioarchitecture and proper orientation during the microsurgical dissection.

Vascular clamp-assisted clipping of thick-walled giant aneurysms.

OBJECTIVE: The prognosis of giant aneurysms remains poor despite recent advances in microneurosurgery. Thick-walled and partially calcified giant aneurysms with an atheromatic base are difficult to clip safely. Special techniques allowing reshaping of the base and ensuring the stability of clips are often needed. We present our experience with direct clipping of thick-walled giant aneurysms with the aid of the DeBakey cardiovascular clamp (Aesculap, Tuttlingen, Germany). METHODS: Eighty-two patients with a giant aneurysm (>/=25 mm) were treated actively at the Department of Neurosurgery, Helsinki University Central Hospital, Helsinki, Finland, between 1997 and 2007. The vascular clamp technique was used in 8 of 50 patients in whom direct clipping was performed. The remaining patients were treated with bypass and trapping, trapping only, proximal occlusion, coiling, or explorative surgery. RESULTS: The vascular clamp (DeBakey in 5 cases, Crile forceps [Medicon Medizin-Technik, Tuttlingen, Germany] in 2 cases, and Halsted-Mosquito forceps [Medicon Medizin-Technik, Tuttlingen, Germany] in 1 case) was used in 7 saccular middle cerebral artery aneurysms and 1 fusiform basilar bifurcation aneurysm. Two patients had postoperative infarctions, 1 attributable to occlusion of perforators by a clip and the other caused by clips sliding down the calcified base, occluding a major branch. Six patients had no neurological sequelae, 1 patient had transient upper limb paresis, and the patient with the occluded major branch died. CONCLUSION: The DeBakey vascular clamp is helpful in assisting direct clipping of thick-walled giant aneurysms with a partially calcified atheromatic base. Some practical features of this instrument require further refinement.

Microsurgical management of pineal region lesions: personal experience with 119 patients.

BACKGROUND: Lesions of the pineal region are histopathologically heterogeneous but often accompanied with severe progression of clinical signs. Surgical treatment remains challenging because of the close vicinity of the deep venous system and the mesencephalo-diencephalic structures in this region. We present the surgical approaches and techniques in a consecutive series of 119 patients treated by the senior author (J.H.) between 1980 and 2007 at 2 different neurosurgical university centers in Kuopio and Helsinki, Finland. METHODS: Of the included patients, 107 (90%) presented with pineal region tumors and 12 (10%) with vascular malformations. The ITSC route was used for removal of the lesion in 111 (93%) patients and the OIH approach in 8 (7%) patients. All except one patient were operated on in a sitting position. RESULTS: We reviewed all clinical data and radiographic images and analyzed all surgical videos. The pineal lesions were removed completely in most cases (88%). There was no surgical mortality. Twenty-two (18%) of the patients had complications in the postoperative period; these included 1 epidural hematoma, 9 transient Parinaud syndrome, 2 meningitis, 3 wound infections, 2 transient memory disturbances, 2 mild hemiparesis, 1 CSF fistula, and 2 cranial nerves palsies (IV and VI). During a 3.5-year follow-up, 12 patients with malignant lesions died; all patients with benign tumors survived. CONCLUSIONS: The ITSC route is a safe and effective surgical approach, associated with low morbidity, complete lesion removal, and definitive histopathologic diagnosis. Considering risk vs benefit, we therefore believe that the surgical treatment can be offered in most cases as the first treatment option for pineal tumors.

Microsurgical treatment of third ventricular colloid cysts by interhemispheric far lateral transcallosal approach--experience of 134 patients.

BACKGROUND: Colloid cysts are rare tumors (incidence 3.2/1000000 pear year) located in the anterosuperior part of the third ventricle. In this article, we present our microneurosurgical experience on 134 patients focusing on the nuances of ITA with demonstrative videoclips. METHODS: This surgical series is based on the microsurgical experience of the senior author (JH) at 2 Finnish neurosurgical centers (Helsinki and Kuopio, 1980-2007). Surgical anatomy is demonstrated, and the pitfalls of the different surgical steps are analyzed to avoid complications. The series reflects the whole patient profile of Southern and Eastern Finland, without any selection bias. RESULTS: There was no surgical mortality, and morbidity remained mainly transitory among 134 patients treated by ITA. CONCLUSIONS: Favorable overall outcome of this series demonstrates that removal of third ventricular colloid cyst via transcallosal approach is a direct and safe way to treat these lesions.