Structural-mechanical properties and swelling of protein complexes of hyaluronate and protein-chrondroitin-4-sulfate

Structural-mechanical strength and swelling of gels consisting of gelatin and potassium hyaluronate (PHY) or potassium protine-chondroitin-4-sulfate (PPCS) were shown to depend on the ratio between the components. With low concentrations of PHY and PPCS the minimum of structural-mechanical strength coincided with the maximum of swelling of the gels. In zones of neutralization of the positive electric charges of gelatin by macropolyanions, high structural-mechanical strength of the gels coincided with the minimum of swelling. In high concentrations of PHY, structural-mechanical strength and swelling of the gel became equal to the values characteristic of a gel consisting of gelatin only, but in high concentration of PPCS there was an additional parallel increase in this strength and in swelling of the gel.(Presented by Academician of the Academy of Medical Sciences of the USSR S. S. Debov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 82, No. 10, pp. 1211–1213, October, 1976.     

Mechanisms of taurine antihypoxic and antioxidant action

The study was undertaken to elucidate the effects of taurine on lipid peroxidation (LP) intensity and membrane Na+, K+-ATPase activity in a hypoxic rat model. It was shown that 3 intraperitoneal (i.p.) injections of 200 mg/kg of taurine prevented hypoxia-induced lactate accumulation and LP in brain, liver, and heart tissues and prevented the decrease of Na+, K+-ATPase activity in the liver. It is suggested that the effect of taurine on LP could be due to the taurine antiacidotic action as well as to its membrane stabilizing activity.     

Melatonin protects neurons from singlet oxygen-induced apoptosis

Abstract: Singlet oxygen (O₂[¹Δg]) is a very reactive molecule that can be produced by living cells and may contribute to cytotoxicity. The pineal hormone melatonin has been reported to possess potent antioxidant activity, and to be capable of scavenging O₂(¹Δg). We investigated whether melatonin might reduce the neurotoxic action of O₂(^lΔg). The cytotoxic effect of singlet oxygen was studied in primary cultures of cerebellar granule neurons pretreated with a photosensitive dye, rose bengal, and exposed to light—a procedure that generates O₂(¹Δg). We found that this procedure triggers neuronal death, which is preceded by mitochondrial impairment (assayed by the rate of the reduction of MTT, 3-[4,5-di-methylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide, into formazan), and by DNA fragmentation—a marker of apoptosis. DNA fragmentation was determined in situ by terminal deoxynucleotidyl transferase assay; cell death was assayed with 0.4% trypan blue solution—viable cells with an intact membrane are not permeable to trypan blue; dead cells are, and thus, they are stained blue. Neuroprotection was obtained with the pineal hormone melatonin. In a cell-free system, melatonin also protected the enzyme creatine kinase (EC 2.7.3.2) from the rose bengal-induced injury. The results suggest that melatonin might counteract the cytotoxic action of singlet oxygen. Further studies are needed to clarify the exact role singlet oxygen and melatonin might play in neurodegenerative diseases.     

Conversion from twice- to once-daily tacrolimus in pediatric kidney recipients: a pharmacokinetic and bioequivalence study

Background

The objectives of this study were to investigate pharmacokinetic and pharmacogenetic parameters during the conversion on a 1:1 (mg:mg) basis from a twice-daily (Prograf) to once-daily (Advagraf) tacrolimus formulation in pediatric kidney transplant recipients.

Methods

Twenty-four-hour pharmacokinetic profiles were analyzed before and after conversion in 19 stable renal transplant recipients (age 7–19 years). Tacrolimus pharmacokinetic parameters [area under the concentration-time curve (AUC_0–24), minimum whole-blood concentration (C_min), maximum whole-blood concentration (C_max), and time to achieve maximum whole-blood concentration (t_max)] were compared between Tac formulations and between CYP3A5 and MDR1 genotypes after dose normalization.

Results

Both AUC_0–24 and C_min decreased after conversion (223.3 to 197.5 ng.h/ml and 6.5 to 5.6 ng/ml; p?=?0.03 and 0.01, respectively). However, the ratio of the least square means (LSM) for AUC_0–24 was 90.8 %, with 90 % CI limits of 85.3 to 96.7 %, falling within bioequivalence limits. The CYP3A5 genotype influences the dose-normalized C_min with the twice-daily formulation only.

Conclusions

Both tacrolimus formulations are bioequivalent in pediatric renal recipients. However, we observed a decrease in AUC_0–24 and C_min after the conversion, requiring close pharmacokinetic monitoring during the conversion period.     

Pharmacokinetics,Pharmacodynamics, and Exposure‐Response of Lanadelumab for Hereditary Angioedema

Hereditary angioedema (HAE) with C1 inhibitor deficiency is a rare disorder characterized by unpredictable, potentially life‐threatening recurrent angioedema attacks. Lanadelumab is a fully human monoclonal antibody with selective binding to active plasma kallikrein, and prevents the formation of cleaved high molecular weight kininogen (cHMWK) and bradykinin, thereby preventing HAE attacks. The clinical pharmacology of lanadelumab was characterized following subcutaneous administration in 257 subjects (24 healthy subjects and 233 patients with HAE). The pharmacokinetics of lanadelumab were described using a one‐compartment model with first‐order rate of absorption and linear clearance, showing slow absorption and a long half‐life (14.8 days). A covariate analysis retained body weight and health status on apparent clearance (CL/F) and body weight on volume of distribution (V/F). Population estimates of CL/F and V/F were 0.0249 L/hour (0.586 L/day) and 12.8 L, respectively. An indirect‐response Imax model showed 53.7% maximum suppression in cHMWK formation with a low potential for interactions with concomitant medications (analgesic, anti‐inflammatory, and antirheumatic medications). A 300 mg dose administered Q2W was associated with a mean steady‐state minimum concentration (C_min,ss; 25.4 μg/mL) that was ~ 4.5‐fold higher than the half‐maximal inhibitory concentration for cHMWK reduction (5.71 μg/mL). Exposure‐response analyses suggest that 300 mg Q2W dosing was associated with a significantly reduced HAE attack rate, prolonged time to first attack after treatment initiation, and lower need for concomitant medications. The response was comparable across patient body weight groups. Findings from this analysis support the dosing rationale for lanadelumab to prevent attacks in patients with HAE.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

☑ Hereditary angioedema (HAE) is a long‐term, debilitating, and potentially life‐threatening disease caused by C1‐inhibitor deficiency. Lanadelumab is a fully human monoclonal antibody inhibitor of plasma kallikrein that is effective in preventing attacks in patients with HAE.

• WHAT QUESTION DID THIS STUDY ADDRESS?

☑ What are the pharmacokinetic and pharmacodynamic characteristics of lanadelumab, and how are they related to the observed efficacy of lanadelumab in preventing HAE attacks?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

☑ Lanadelumab clearance and volume of distribution are dependent on body weight; however, significant attack rate reduction is still observed in patients with high body weight, and dose adjustment is not necessary. The findings of this study provide a greater understanding of the factors driving the efficacy and safety of lanadelumab to ensure optimal use.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

☑ Selective binding of lanadelumab to plasma kallikrein provides a novel approach for long‐term prophylaxis against HAE attacks.

Hereditary angioedema (HAE) is a rare, debilitating, and potentially life‐threatening disease with an estimated prevalence of 1 in 50,000. ¹ It manifests clinically as unpredictable, intermittent attacks of subcutaneous or submucosal edema of the face, larynx, gastrointestinal tract, limbs, and/or genitalia. Swelling may last several days, and most patients have multiple attacks per year. ² Symptoms usually begin during childhood, sometimes as young as age 2 years, and persist throughout life. ² HAE is caused by mutations in SERPING1, the gene encoding C1 inhibitor (C1‐INH), resulting in deficiency of C1‐INH protein or function. ³ C1‐INH is involved in regulating the contact, complement, and coagulation systems. ³ In the contact system, C1‐INH is the natural inhibitor of plasma kallikrein. Dysregulated contact system activation and subsequent uncontrolled plasma kallikrein activity lead to production of cleaved high molecular weight kininogen (cHMWK) and the edema‐inducing peptide bradykinin, which initiates signaling pathways leading to HAE attacks. Management of patients with HAE involves on‐demand medications to treat attacks when they occur, and long‐term or short‐term prophylaxis to prevent attacks. ¹ , ² Lanadelumab is a fully human immunoglobulin G1 monoclonal antibody that binds specifically to active plasma kallikrein. ⁴ It is approved in several countries for the prevention of HAE attacks in patients ≥ 12 years of age. In clinical trials, treatment with lanadelumab significantly reduced attack rates in patients with HAE, and this was associated with a reduction in cHMWK levels. ⁵ , ⁶ The pharmacokinetics (PK), pharmacodynamics (PD), exposure‐response relationships, and potential interactions of lanadelumab with rescue medications (for treatment of attacks that occur during long‐term prophylaxis), and with medications commonly used concomitantly in patients with HAE, were characterized using data from clinical studies to support the dosing rationale for long‐term prophylaxis with lanadelumab in patients with HAE.