Optimal Affinity of a Monoclonal Antibody: Guiding Principles Using Mechanistic Modeling

Affinity optimization of monoclonal antibodies (mAbs) is essential for developing drug candidates with the highest likelihood of clinical success; however, a quantitative approach for setting affinity requirements is often lacking. In this study, we computationally analyzed the in vivo mAb-target binding kinetics to delineate general principles for defining optimal equilibrium dissociation constant (\( {K}_D^{opt} \)) of mAbs against soluble and membrane-bound targets. Our analysis shows that in general \( {K}_D^{opt} \) to achieve 90% coverage for a soluble target is one tenth of its baseline concentration (\( {K}_D^{opt}=0.1\times {S}_0 \)), and is independent of the dosing interval, target turnover rate or the presence of competing ligands. For membrane-bound internalizing targets, it is equal to the ratio of internalization rate of mAb-target complex and association rate constant (\( {K}_D^{opt}=\raisebox{1ex}{${k}_{elDM}$}\!\left/ \!\raisebox{-1ex}{${k}_{on}$}\right. \)). In cases where soluble and membrane-bound forms of the target co-exist, \( {K}_D^{opt} \) lies within a range determined by the internalization rate (\( {k}_{elDM} \)) of the mAb-membrane target complex and the ratio of baseline concentrations of soluble and membrane-bound forms (\( \raisebox{1ex}{${S}_0$}\!\left/ \!\raisebox{-1ex}{${M}_0$}\right. \)). Finally, to demonstrate practical application of these general rules, we collected target expression and turnover data to project \( {K}_D^{opt} \) for a number of marketed mAbs against soluble (TNFα, RANKL, and VEGF) and membrane-bound targets (CD20, EGFR, and HER2).     

Fluorescence imaging: applications in drug delivery research

In the context of drug delivery it is crucial to gain knowledge of nature of the cell's internal barriers, as well as one needs to be aware of requirements for the study of spatial and temporal interactions of drug delivery vehicles with the cell. Fluorescent imaging technology can be a great innovation in the field of science as far as study of live cell imaging and dynamic events are concerned. The technique has also demonstrated the ability to integrate the anatomic, functional, and statistical data. The current review article discusses various fluorescent techniques and also elaborates the scope of fluorescent imaging in the field of drug delivery.     

Principles of Bracing in the Early Management of Developmental Dysplasia of the Hip

Bracing is considered a gold standard in treating Developmental Dysplasia of the Hip (DDH) in infants under 6 months of age with reducible hips. A variety of braces are available that work on similar principles of limiting hip adduction and extension. This paper summarises the current evidence regarding bracing in DDH. Most of the literature pertains to the Pavlik harness (PH) and there are few studies for other brace types. Bracing eliminates dislocating forces from the hamstrings, the block to reduction of the psoas and improves the muscle line of pull to stabilise the hip joint. Recent studies have shown no benefit in bracing for stable dysplasia. The rates of PH treatment failure in Ortolani-positive hips have been reported to be high. Barlow positive hips have lower Graf grades and are more amenable to PH treatment. There is consensus that the earlier the diagnosis of DDH and initiation of PH treatment, the better the outcome. Failure rates due to unsuccessful reduction and AVN are higher with treatment initiated after age 4–6 months. Studies have shown no benefits of staged weaning of braces. While there is no maximum time in brace, current consensus suggests a minimum of 6 weeks. The key to successful bracing lies in education and communication with the family.     

Simple Mobile Application for Calculating “Ergotrauma” Made Using an Excel Sheet

How to cite this article: Anand A, Saigal S, Panda R, Kodamanchili S, Shrivastava P, Das A, et al. Simple Mobile Application for Calculating “Ergotrauma” Made Using an Excel Sheet. Indian J Crit Care Med 2021;25(9):1081.     

Laparoscopic Management of Nonpuerperal Uterine Inversion

Uterine inversions are a rare entity, and most occur in the postpartum period. Nonpuerperal inversion accounts for only 16% of cases and are mostly associated with a submucous myoma. A 38-year-old woman with a submucous myoma presented with severe lower abdominal pain, acute retention of urine, and hypotension. Because the clinical examination was inconclusive due to severe pain and the ultrasound was dubious, diagnosis was made with magnetic resonance imaging. Successful laparoscopic hysterectomy was contemplated after correcting uterine inversion. This case highlights the diagnostic dilemmas and the key points during laparoscopic management of uterine inversion.     

Visit‐to‐visit systolic blood pressure variability predicts treatment‐related adverse event of hyponatremia in SPRINT

Hypertension is a common condition and an important cardiovascular risk factor. SPRINT trial showed that the beneficial effects of targeting systolic blood pressure <120 mm Hg were accompanied by more adverse events. De‐identified SPRINT database was used for this analysis. All subjects in each group that achieved their respective target blood pressure (<120, intensive; <140, standard) were included. Only readings after reaching target blood pressure for the first time were included. Subjects that never reached target or had <2 readings upon reaching target were excluded. Coefficient of Variation (CV) of systolic blood pressure was calculated for each subject to characterize variability. Cox proportional hazards regression was used in the overall cohort as well as the intensive and standard treatment subgroups separately, to identify the effect of CV of systolic blood pressure on occurrence of hyponatremia. P<.05 was considered statistically significant. A total of 8884 subjects met the inclusion criteria; 4323 in intensive and 4561 in standard group. Two hundred and sixty five hyponatremic events occurred in the overall cohort; 168 in intensive, and 127 in standard treatment group. CV of systolic blood pressure consistently and independently predicted a greater hazard of hyponatremia on overall (HR 1.08, P<.001), as well as separate regressions by treatment arms (each HR=1.08 and P<.05). In conclusion, visit‐to‐visit systolic blood pressure variability is independently associated with a small but significant risk of hyponatremia in the SPRINT trial .     

Impact of Adaptive Radiotherapy on Locally Advanced Head and Neck Cancer - A Dosimetric and Volumetric Study

Objective of the study is to evaluate volumetric and dosimetric alterations taking place during radiotherapy for locally advanced head and neck cancer (LAHNC) and to assess benefit of replanning in them. Materials and Methods: Thirty patients with LAHNC fulfilling the inclusion and exclusion criteria were enrolled in a prospective study. Planning scans were acquired both pre-treatment and after 20 fractions (mid-course) of radiotherapy. Single plan (OPLAN) based on initial CT scan was generated and executed for entire treatment course. Beam configuration of OPLAN was applied to anatomy of interim scan and a hybrid plan (HPLAN30) was generated. Adaptive replanning (RPLAN30) for remaining fractions was done and dose distribution with and without replanning compared for remaining fractions. Results: Substantial shrinkage of target volume (TV) and parotids after 4 weeks of radiotherapy was reported (p<0.05). No significant difference between planned and delivered doses was seen for remaining fractions. Hybrid plans showed increase in delivered dose to spinal cord and parotids for remaining fractions. Interim replanning improved homogeneity of treatment plan and significantly reduced doses to cord (Dmax, D2% and D1%) and ipsilateral parotid (D33%, D50% and D66%) (p<0.05). Conclusions: Use of one or two mid-treatment CT scans and replanning provides greater normal tissue sparing alongwith improved TV coverage     

Acute and sub acute toxicity and efficacy studies of Hippophae rhamnoides based herbal antioxidant supplement

Objectives:

Present study was carried out to evaluate acute and subacute toxicity and efficacy of Seabuckthorn (Hippophae rhamnoides) based herbal antioxidant supplement (HAOS).

Materials and Methods:

In vivo toxicity studies were performed in male balb ‘C’ mice by oral administration. Acute toxicity study was done at doses ranging from 2000 to 10 000 mg/ kg while in subacute studies, HAOS was given at doses of 2000, 4000, and 8000 mg/kg body weight. Animals were observed for any toxic sign and symptoms periodically. At completion of study animals were sacrificed; their hematological, biochemical parameters were analyzed and histopathology of vital organs was done. In vivo efficacy studies in human volunteers were done and the levels of vitamin A and Vitamin C in blood samples were analyzed in comparison to a similar commercially available formulation.

Results:

No mortality and any clinical signs of toxicity were found in HAOS administered group of animals. There were no significant alterations in hematological and biochemical parameters. Histopathological analysis of vital organs showed normal architecture in all the HAOS administered groups. Human studies showed an increase of 32% and 172% in Vitamin A and Vitamin C levels respectively in term of bioavailability.

Conclusion:

The data obtained indicate no toxicity of this antioxidant supplement up to the highest dose studied. Efficacy in terms of increased bioavailability of vitamin A and C in human volunteers indicates the clinical usefulness of the supplement.KEY WORDS: Acute and subacute toxicity, herbal antioxidant supplement, seabuckthorn, histopathology and bioavailability