Mohamed Salah

Aqueductal stenting with an intra-catheter endoscope—a technical note

IntroductionAqueductoplasty as well as aqueductal stenting is an accepted therapy option in short-segment aqueductal stenosis and isolated fourth ventricle. Over the years, different techniques with only slight modifications by using a conventional neuroendoscope with a working sheath to introduce different instruments have been presented. In summary, the use of Fogarty balloon catheters or flexible endoscopes to pass the narrowed aqueduct is recommended.MethodsThis technical report describes a substantially new technique for this purpose. Six patients underwent aqueductal stenting with a new intracatheter endoscope.ResultsAqueductal stenting was possible in 4 out of 6 cases. No complications occurred. Handling of this new technique was good and easy without a prolonged learning curve. All four stents did work appropriately, and the procedure was considered to be successful. Of the two failures, the technique was abandoned and endoscopic third ventriculostomy (ETV) was performed in one. In the other case, suboccipital shunting was done.ConclusionThis technical report describes a substantially new technique for aqueductal stenting. The combination of an intracatheter miniature endoscope and a prepared ventricular catheter enables careful and elegant aqueductal stenting. Large or flexible endoscopes, balloons, or special instruments to place a stent have become completely obsolete in selected cases.

First Dual Inhibitors of Steroid Sulfatase (STS) and 17β-Hydroxysteroid Dehydrogenase Type 1 (17β-HSD1): Designed Multiple Ligands as Novel Potential Therapeutics for Estrogen-Dependent Diseases

STS and 17β-HSD1 are attractive targets for the treatment of estrogen-dependent diseases like endometriosis and breast cancer. The simultaneous inhibition of both enzymes appears more promising than blockage of either protein alone. We describe a designed multiple ligand approach resulting in highly potent dual inhibitors. The most interesting compound 9 showed nanomolar IC50 values for both proteins, membrane permeability, and no interference with estrogen receptors. It efficiently reversed E1S- and E1-induced T47D cell proliferation.

Endoscopic-Assisted Burr Hole Reservoir and Ventricle Catheter Placement

BACKGROUNDnAccurate positioning of a ventricle catheter is of utmost importance. Various techniques to ensure optimal positioning have been described. Commonly, after catheter placement, additional manipulation is necessary to connect a burr hole reservoir or shunt components. This manipulation can lead to accidental catheter dislocation and should be avoided. Here, we present a new technique that allows direct endoscopic insertion of a burr hole reservoir with an already mounted ventricle catheter.nnnMETHODSnBefore insertion, the ventricle catheter was slit at the tip, shortened to the correct length, and connected to the special burr hole reservoir. An intracatheter endoscope was then advanced through the reservoir and the connected catheter. This assemblage allowed using the endoscope as a stylet for shielded ventricular puncture. To confirm correct placement of the ventricle catheter, the endoscope was protruded a few millimeters beyond the catheter tip for inspection.nnnRESULTSnThe new technique was applied in 12 procedures. The modified burr hole reservoir was inserted for first-time ventriculoperitoneal shunting (nxa0= 1), cerebrospinal fluid withdrawals and drug administration (nxa0= 2), or different stenting procedures (nxa0= 9). Optimal positioning of the catheter was achieved in 11 of 12 cases. No subcutaneous cerebrospinal fluid collection or fluid leakage through the wound occurred. No parenchymal damage or bleeding appeared.nnnCONCLUSIONSnThe use of the intracatheter endoscope combined with the modified burr hole reservoir provides a sufficient technique for accurate and safe placement. Connecting the ventricle catheter to the reservoir before the insertion reduces later manipulation and accidental dislocation of the catheter.

Treatment of estrogen-dependent diseases: Design, synthesis and profiling of a selective 17β-HSD1 inhibitor with sub-nanomolar IC50 for a proof-of-principle study

Current endocrine therapeutics for the estrogen-dependent disease endometriosis often lead to considerable side-effects as they act by reducing estrogen action systemically. A more recent approach takes advantage of the fact that the weak estrogen estrone (E1) which is abundant in the plasma, is activated in the target cell to the highly estrogenic estradiol (E2) by 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). 17β-HSD1 is overexpressed in endometriosis and thus a promising target for the treatment of this disease, with the prospect of less target-associated side-effects. Potent inhibitors from the class of bicyclic substituted hydroxyphenylmethanones with sulfonamide moiety recently described by us suffered from high molecular weight and low selectivity over 17βHSD2, the physiological adversary of 17β-HSD1. We describe the structural optimizations leading to the discovery of (5-(3,5-dichloro-4-methoxyphenyl)thiophen-2-yl)(2,6-difluoro-3-hydroxyphenyl)methanone 20, which displayed a sub-nanomolar IC50 towards 17β-HSD1 as well as high selectivity over the type 2 enzyme, the estrogen receptors α and β and a range of hepatic CYP enzymes. The compound did neither show cellular toxicity, nor PXR activation nor mutagenicity in the AMES II assay. Additional favourable pharmacokinetic properties (rat) make 20 a suitable candidate for proof-of-principle studies using xenotransplanted immunodeficient rats.

Development of novel 2,4-bispyridyl thiophene–based compounds as highly potent and selective Dyrk1A inhibitors. Part I: Benzamide and benzylamide derivatives

The protein kinase Dyrk1A modulates several processes relevant to the development or progression of Alzheimers disease (AD), e. g. through phosphorylation of tau protein, amyloid precursor protein (APP) as well as proteins involved in the regulation of alternative splicing of tau pre-mRNA. Therefore, Dyrk1A has been proposed as a potential target for the treatment of AD. However, the co-inhibition of other closely related kinases of the same family of protein kinases (e.g. Dyrk1B and Dyrk2) or kinases from other families such as Clk1 limits the use of Dyrk1A inhibitors, as this may cause unpredictable side effects especially over long treatment periods. Herein, we describe the design and synthesis of a series of amide functionalized 2,4-bispyridyl thiophene compounds, of which the 4-fluorobenzyl amide derivative (31b) displayed the highest potency against Dyrk1A and remarkable selectivity over closely related kinases (IC50: Dyrk1Au202f=u202f14.3u202fnM; Dyrk1Bu202f=u202f383u202fnM, Clk1u202f>u202f2u202fμM). This degree of selectivity over the frequently hit off-targets has rarely been achieved to date. Additionally, 31b inhibited Dyrk1A in intact cells with high efficacy (IC50u202f=u202f79u202fnM). Furthermore, 31b displayed a high metabolic stability inxa0vitro with a half-life of 2u202fh. Altogether, the benzamide and benzylamide extension at the 2,4-bispyridyl thiophene core improved several key properties, giving access to compound suitable for future inxa0vivo studies.

Intra-catheter endoscopy for various shunting procedures—a retrospective analysis on surgical practicability, catheter placement, and failure rates

BackgroundThe long-term function of a cerebral shunt is directly influenced by the placement of the ventricle catheter. In this work, an intra-luminal endoscope for best possible catheter positioning was used. Practicability, postoperative imaging, and shunt failure rates were retrospectively evaluated.MethodsBetween January 2012 and June 2016, an intra-catheter endoscope was applied in 71 procedures. Endoscopic technique was used for catheter placement in first-time shunting or cerebrospinal fluid reservoir insertion (nxa0=xa038), revision surgery in proximal shunt failure (nxa0=xa013), and various intraventricular stenting procedures (nxa0=xa020). Catheter positioning was graded on postoperative imaging using a four-point scale. All patients were regularly followed up (mean, 31.6xa0months) to recognize shunt failures.ResultsEndoscopic application could be completed as intended in 68 of 71 procedures. Postoperative imaging could exclude complete misplacement of all catheters, but optimal positioning was only achieved in 64.7% (44/68 cases). Four catheters had to be revised due to malfunction (failure rate, 5.8%). Another five catheters had to be removed due to infectious complications or wound-healing disorders. Direct correlations between catheter complications and suboptimal catheter positioning were not seen. Slit or distorted ventricles also did not prove to be a risk factor for the observed complications.ConclusionsVersatile application possibilities of the intra-catheter endoscope reflect the advantages of the technique. Independent of the performed procedure, unintended positionings or even complete catheter misplacements could be avoided. However, in more than one-third of all cases, suboptimal catheter placements became obvious. Interestingly, negative influences on later shunt failures were not seen.

Inhibitors of 17β-hydroxysteroid dehydrogenase type 1, 2 and 14: Structures, biological activities and future challenges

During the past 25 years, the modulation of estrogen action by inhibition of 17β-hydroxysteroid dehydrogenase types 1 and 2 (17β-HSD1 and 17β-HSD2), respectively, has been pursued intensively. In the search for novel treatment options for estrogen-dependent diseases (EDD) and in order to explore estrogenic signaling pathways, a large number of steroidal and nonsteroidal inhibitors of these enzymes has been described in the literature. The present review gives a survey on the development of inhibitor classes as well as the structural formulas and biological properties of their most interesting representatives. In addition, rationally designed dual inhibitors of both 17β-HSD1 and steroid sulfatase (STS) as well as the first inhibitors of 17β-HSD14 are covered.

The view through the ventricle catheter – The new ShuntScope for the therapy of pediatric hydrocephalus

PURPOSEnCorrect placement of the ventricle catheter directly influences the function of cerebral shunt systems. The incidence of proximal catheter misplacement reaches up to 45%. To avoid misplacements and revisions a new intra-catheter endoscope for precise ventricle catheter placement in children was evaluated.nnnMETHODSnThe semi-rigid ShuntScope (Karl Storz GmbH & Co.KG, Tuttlingen, Germany) with an outer diameter of 1.0u202fmm and an image resolution of 10,000u202fpixels was used in a series of 27 children and adolescents (18u202fmales, 9u202ffemales, age range 2u202fmonths-18u202fyears). Indications included catheter placement in aqueductal stenting (nu202f=u202f4), first time shunt placement (nu202f=u202f5), burr hole reservoir insertion (nu202f=u202f4), catheter placement after endoscopic procedures (nu202f=u202f7) and revision surgery of the ventricle catheter (nu202f=u202f7).nnnRESULTSnShuntScope guided precise catheter placement was achieved in 26 of 27 patients. In one case of aqueductal stenting, the procedure had to be abandoned. One single wound healing problem was noted as a complications. Intraventricular image quality was always sufficient to recognize the anatomical structures. In case of catheter removal, it was helpful to identify adherent vessels or membranes. Penetration of small adhesions or thin membranes was feasible. Postoperative imaging studies demonstrated catheter tip placements analogous to the intraoperative findings.nnnCONCLUSIONSnMisplacements of shunt catheters are completely avoidable with the presented intra-catheter technique including slit ventricles or even aqueductal stenting. Potential complications can be avoided during revision surgery. The implementation of the ShuntScope is recommended in pediatric neurosurgery.

Development of novel amide–derivatized 2,4-bispyridyl thiophenes as highly potent and selective Dyrk1A inhibitors. Part II: Identification of the cyclopropylamide moiety as a key modification

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) is a potential target in Alzheimers disease (AD) because of the established correlation between its over-expression and generation of neurofibrillary tangles (NFT) as well as the accumulation of amyloid plaques. However, the use of Dyrk1A inhibitors requires a high degree of selectivity over closely related kinases. In addition, the physicochemical properties of the Dyrk1A inhibitors need to be controlled to enable CNS permeability. In the present study, we optimized our previously published 2,4-bispyridyl thiophene class of Dyrk1A inhibitors by the synthesis of a small library of amide derivatives, carrying alkyl, cycloalkyl, as well as acidic and basic residues. Among this library, the cyclopropylamido modification (compound 4b) was identified as being highly beneficial for several crucial properties. 4b displayed high potency and selectivity against Dyrk1A over closely related kinases in cell-free assays (IC50: Dyrk1Au202f=u202f3.2u202fnM; Dyrk1Bu202f=u202f72.9u202fnM and Clk1u202f=u202f270u202fnM) and inhibited the Dyrk1A activity in HeLa cells with high efficacy (IC50: 43u202fnM), while no significant cytotoxicity was observed. In addition, the cyclopropylamido group conferred high metabolic stability and maintained the calculated physicochemical properties in a range compatible with a potential CNS activity. Thus, based on its favourable properties, 4b can be considered as a candidate for further inxa0vivo testing in animal models of AD.