Molecular Engineering of Efficacious Mono-Valent Ultra-Long Acting Two-Chain Insulin-Fc Conjugates.

Here, we describe molecular engineering of monovalent ultra-long acting two-chain insulin-Fc conjugates. Insulin-Fc conjugates were synthesized using trifunctional linkers with one amino reactive group for reaction with a lysine residue of insulin and two thiol reactive groups used for re-bridging of a disulfide bond within the Fc molecule. The ultra-long pharmacokinetic profile of the insulin-Fc conjugates was the result of concertedly slowing insulin receptor-mediated clearance by (1) introduction of amino acid substitutions that lowered the insulin receptor affinity and (2) conjugating insulin to the Fc element.

Molecular Engineering of Insulin Icodec, the First Acylated Insulin Analog for Once-Weekly Administration in Humans.

Here, we describe the molecular engineering of insulin icodec to achieve a plasma half-life of 196 h in humans, suitable for once-weekly subcutaneously administration. Insulin icodec is based on re-engineering of the ultra-long oral basal insulin OI338 with a plasma half-life of 70 h in humans. This systematic re-engineering was accomplished by (1) further increasing the albumin binding by changing the fatty diacid from a 1,18-octadecanedioic acid (C18) to a 1,20-icosanedioic acid (C20) and (2) further reducing the insulin receptor affinity by the B16Tyr → His substitution.

Structure, Aggregation, and Activity of a Covalent Insulin Dimer Formed During Storage of Neutral Formulation of Human Insulin.

A specific covalently linked dimeric species of insulin high molecular weight products (HMWPs), formed during prolonged incubation of a neutral pharmaceutical formulation of human insulin, were characterized in terms of tertiary structure, self-association, biological activity, and fibrillation properties. The dimer was formed by a covalent link between A21Asn and B29Lys. It was analyzed using static and dynamic light scattering and small-angle X-ray scattering to evaluate its self-association behavior.

[Hyperhidrosis is a silent handicap].

Hyperhidrosis affects 2.8% of the population and has severe negative influence on life quality. The disease is represented in many specialties but can unfortunately be incorrectly treated or not treated at all.

Rituximab in paediatric onset multiple sclerosis: a case series.

Paediatric onset multiple sclerosis (POMS) is characterized by high inflammatory activity. No disease modifying treatment has been approved for POMS. The objective of this report was to report the use of rituximab, a B cell depleting monoclonal anti-CD20-antibody, in POMS.

Purification and identification of high molecular weight products formed during storage of neutral formulation of human insulin.

Purpose: To identify High Molecular Weight Products (HMWP) formed in human insulin formulation during storage.

Methods: Commercial formulation of human insulin was stored at 37°C for 1 year and HMWP was isolated using preparative size exclusion chromatography (SEC) and reverse phase (RP) chromatography. The primary structure of the isolated species was analysed using liquid chromatography mass spectrometry (LC-MS) and tandem mass spectrometry (MS/MS).

Changes in glucose and fat metabolism in response to the administration of a hepato-preferential insulin analog.

Endogenous insulin secretion exposes the liver to three times higher insulin concentrations than the rest of the body. Because subcutaneous insulin delivery eliminates this gradient and is associated with metabolic abnormalities, functionally restoring the physiologic gradient may provide therapeutic benefits. The effects of recombinant human insulin (HI) delivered intraportally or peripherally were compared with an acylated insulin model compound (insulin-327) in dogs.

Effect of botulinum toxin concentration on reduction in sweating: a randomized, double-blind study.

Dose-response studies of botulinum toxin for reduction of sweating are sparse in the literature. The aim of this study was to determine the most appropriate concentrations of Botox®, Dysport®, Xeomin® and NeuroBloc®, respectively, in order to achieve the greatest reduction in sweating, thus reducing the costs and increasing the safety of treatment. Four concentrations of each product were investigated.

Clinical experience of dose conversion ratios between 2 botulinum toxin products in the treatment of cervical dystonia.

Objectives: The units of different botulinum toxin products are not identical, and the dose equivalence has been debated for several years. In the year 2000, our clinic changed the recommended botulinum toxin product from Botox to Dysport for the treatment of cervical dystonia. Based on published reports, where dose conversion ratios from 1:1 to 1:6 (Botox:Dysport) had been used, and our own clinical experience, the dose conversion ratio was set to 1:2.

Traveling-wave ion mobility mass spectrometry of protein complexes: accurate calibrated collision cross-sections of human insulin oligomers.

Rationale: The collision cross-section (Ω) of a protein or protein complex ion can be measured using traveling-wave (T-wave) ion mobility (IM) mass spectrometry (MS) via calibration with compounds of known Ω. The T-wave Ω-values depend strongly on instrument parameters and calibrant selection. Optimization of instrument parameters and calibration standards are crucial for obtaining accurate T-wave Ω-values.

Bilateral forearm intravenous regional anesthesia with prilocaine for botulinum toxin treatment of palmar hyperhidrosis.

Background: Treatment of palmar hyperhidrosis with botulinum toxin (BTX) requires effective anesthesia, but previous methods have not provided enough pain relief or have resulted in a prolonged impaired hand function.

Objective: This is a study of bilateral forearm intravenous regional anesthesia using prilocaine for BTX treatment of palmar hyperhidrosis.

Methods: In all, 166 patients (100 female and 66 male) were treated bilaterally with intracutaneous BTX type A injections using intravenous regional anesthesia with prilocaine (5 mg/mL).

Kinetic evidence for the sequential association of insulin binding sites 1 and 2 to the insulin receptor and the influence of receptor isoform.

Through binding to and signaling via the insulin receptor (IR), insulin is involved in multiple effects on growth and metabolism. The current model for the insulin-IR binding process is one of a biphasic reaction. It is thought that the insulin peptide possesses two binding interfaces (sites 1 and 2), which allow it to bridge the two alpha-subunits of the insulin receptor during the biphasic binding reaction.

Dose equivalence of two commercial preparations of botulinum neurotoxin type A: time for a reassessment?

Background: The units of different preparations of botulinum neurotoxin type A (BoNT-A) have different potencies, and dosing recommendations for each product are not interchangeable. Historically, there has been debate concerning the dose-equivalence ratio that should be used in clinical practice.

Methods: Published evidence was considered to establish an appropriate dose-conversion ratio for the two main commercially available preparations of BoNT-A--Dysport (Dp) and Botox (Bx).

Equipotent concentrations of Botox and Dysport in the treatment of palmar hyperhidrosis.

There are indications that the dilution of botulinum toxin affects dose-response. This must be considered when comparing different products. The aim of this study was to estimate a concentration of Dysport in physiological saline that is approximately equivalent to Botox 100 U/ml with respect to anhidrotic and muscular effect.

Anhidrotic effect of intradermal injections of botulinum toxin: a comparison of different products and concentrations.

Botulinum toxin is used in various fields of medicine, including in the treatment of hyperhidrosis. Three products containing botulinum toxin are commercially available in Sweden; Botox, Dysport and Neurobloc. In the literature dose-response has varied with respect to these 3 products.

Sweat gland morphology and periglandular innervation in essential palmar hyperhidrosis before and after treatment with intradermal botulinum toxin.

Background: Intradermal botulinum toxin (Btx) produces long-lasting relief of focal hyperhidrosis, but its mechanism of action is poorly understood.

Objective: To study the effect of Btx A on the size and innervation of sweat glands in patients with palmar hyperhidrosis.

Methods: Palmar skin biopsy was performed in 26 hyperhidrotic patients before scheduled Btx treatment and in 11 controls.

Treatment of dyshidrotic hand dermatitis with intradermal botulinum toxin.

Background: Botulinum toxin (Btx A) has recently been used in the treatment of focal hyperhidrosis. Hyperhidrosis is also an aggravating factor in nearly 40% of patients with dyshidrotic hand eczema.

Objective: The objective of this study was to evaluate the effect of intradermal injections of Btx A on dermatitis in patients with vesicular hand dermatitis.

Functional studies of Ycf3: its role in assembly of photosystem I and interactions with some of its subunits.

The Ycf3 protein is essential for the accumulation of the photosystem I (PSI) complex and acts at a post-translational level. The sequence of Ycf3 is conserved in cyanobacteria, algae, and plants and contains three tetratrico-peptide repeats (TPR). TPRs have been shown to function as sites for protein-protein interactions.

Side-effects of intradermal injections of botulinum A toxin in the treatment of palmar hyperhidrosis: a neurophysiological study.

Focal palmar hyperhidrosis can be effectively abolished by intradermal injections with botulinum toxin. Muscle weakness of finger grip has been reported as a reversible side-effect of this new treatment. The objective of this work was to measure muscular side-effects after treatment of palmar hyperhidrosis with botulinum toxin.

Botulinum A toxin improves life quality in severe primary focal hyperhidrosis.

Focal hyperhidrosis is a condition that may disturb emotional, social and professional life. Treatment options for severe cases are surgical sympathectomy and local chemical sweat gland denervation by intradermal injections of botulinum toxin A (Btx A). The Dermatology Life Quality Index (DLQI) is a simple validated questionnaire designed to measure and compare disability in different skin diseases.

Palmar and axillary hyperhidrosis treated with botulinum toxin: one-year clinical follow-up.

Focal hyperhidrosis is a common and sometimes handicapping condition for which the presently most effective treatment, sympathectomy, often leads to irreversible side-effects. We aimed to study effectiveness and tolerability of an alternative treatment with botulinum toxin injections over a period of one year for this condition. Twenty-eight patients with palmar (n = 19) and/or axillary (n = 13) hyperhidrosis were treated with intracutaneous injections of botulinum toxin (Botox(R)) 2 U/4 cm2.