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Purpose A PET/CT scan of a uniformly filled 68Ga phantom resulted in an unexpectedly low SUVmean of 0.88. A potential contributing cause of underestimation of 68Ga SUV is overestimation of 68Ga activity in the Radionuclide Calibrator associated with the PET/CT scanner. To investigate this, a Radionuclide Calibrator cross-calibration exercise was performed. Methods A source of 68Ga was measured in 5 Capintec CRC-55tR calibrators using the pre-set 68Ga calibrator factor of 416, and a Veenstra VDC-505 calibrator using a factor recommended by the manufacturer. The source was then measured in an externally located Fidelis Secondary Standard Radionuclide Calibrator. Manual adjustments were made to the Capintec calibrator factors to match the decay corrected Fidelis measurement, followed by a repeat PET/CT scan of a uniform 68Ga phantom. Results The cross-calibration results showed that the 5 Capintec calibrators systematically overestimated 68Ga activity by 7.8–9.4% (mean 8.5%) compared to the Fidelis. The calibrator factors were adjusted to 456–464 to match the Fidelis measurement, and the repeat phantom scan resulted in a SUVmean of 0.97, within the local tolerance of 1.00 ± 5%. The result for the Veenstra calibrator was within the tolerance of ±5%. Conclusions Underestimation of 68Ga SUV was primarily caused by overestimation of 68Ga activity using the pre-set calibrator factor setting on a Capintec CRC-55tR. Improvement in quantification accuracy was achieved by adjusting the 68Ga calibrator factor based upon a cross-calibration exercise. We recommend SUV checks using a uniform phantom and regular calibrator cross-calibration exercises for all isotopes used for quantitative PET/CT imaging.

International audience; Hand hygiene plays a key role in nosocomial infection prevention. To achieve users' adherence, products' dermal tolerance is essential. We aimed at making a comparative assessment of skin irritation and phototoxicity of the 3 alcohols commonly used in alcohol-based hand rubs (Ethanol, Propan-2-ol, Propan-1-ol) at 60, 70, 80 or 85% w/w in water or with co-formulates (hydrating, emollient and skin protective agents). In vitro validated OECD methods 439 and 432 were used. For irritation, EpiSkin™ Small Model was the chosen Reconstructed Human Epidermis (RhE). For phototoxicity, co-formulates alone or in mixture with and without alcohol were tested using BALB/c 3T3 cell cultures. Whilst Ethanol and Propan-2-ol could not be differentiated and displayed good skin tolerance profiles, Propan-1-ol based products lead to significant viability impairments of RhE at 60, 70 or 80% and at 60% in the presence of co-formulates. However, these results could not be reproduced in another RhE model. Taking also into account bibliographic data on Propan-1-ol, this suggests that our results are probably related to a lack of specificity of the used RhE. Therefore, it can be relevant in case of significant results to use two different RhE models before performing any classification and/or performing any complementary tests.

Extreme precipitations (EP) could induce a series of social, environmental and ecological problems. Traditional EP analysis usually investigated the characteristics based on a fixed time scale and therefore ignored the continuity of EP occurrence. As a result, a comprehensive assessment on the influence and consequence of the EP occurring during consecutive time periods were largely eliminated. On the other hand, the characteristics of EP, including variables such as frequency, intensity and extreme volume, were commonly defined without sufficient consideration of the local tolerance capacity (which can be represented by a threshold level of EP) and therefore would sometimes be inappropriate. In this study, we proposed a concept of event-based extreme precipitation (EEP) by considering the continuity of EP and defined the statistical variables for the characteristics of an EEP event by taking account of local tolerance capacity. An EEP was identified as a collection of precipitation data over the consecutive time period in which all the precipitation amounts are above the pre-defined threshold, and EEP events are separated by at least one time step (e.g., day or hour) with precipitation amount below the threshold. As a case study which in fact motivated our proposal, we investigated the changes and variations of EEP with the consideration of potential non-stationarity in the Hanjiang River Basin of China (HJRB) during the time period of 1960–2013. Results showed that the concept of EEP, which could reflect the impact of continuity of EP occurrence and mirror the differences of local tolerance capacity, was more appropriate than the traditional method in the EP analysis.

Nonclinical animal studies are considered as an integral part of biosimilar development program to demonstrate similarity and safety. We have compiled, reviewed and summarized animal studies conducted for European Medicines Agency (EMA) and United States Food and Drug Administration (US FDA) submission from 2006 till December 2018. The commonest animal studies conducted included repeat-dose toxicity study along with toxicokinetic, local tolerance and immunogenicity assessments, while the least common included primary pharmacodynamic, pharmacokinetic, safety pharmacology and single-dose toxicity studies. Animal studies were designed based on pharmacology of the drug, disease condition and innovator studies. Studies mostly used EU-sourced reference products as a comparator. For biosimilars approved both in the US and European Union (EU), similar data packages were submitted to these regions. Despite the regulatory guidelines allowing waiver of animal studies based on analytical data, animal studies have been conducted for almost all the approved biosimilars in the US and EU. There is an increasing need to re-assess the relevance of animal studies to support regulatory approval of biosimilars. Stepwise assessment for biosimilarity and conducting animal studies only if required at the right instance based on residual uncertainties may assist in optimizing animal study requirement for biosimilar development.

During the development of a new vaccine, the purpose of nonclinical studies is to provide safety information to support the clinical development and licensure of the product. In this article the study designs currently accepted for the nonclinical safety testing of new vaccines are described for single dose, local tolerance, repeat dose toxicity and safety pharmacology studies; these studies together form the basis of a typical nonclinical safety evaluation dossier. The detailed design of the preclinical package must take account of the intended clinical use, patient population, route of administration, formulation, dose level and immunisation schedule. The test item that is used for these studies must be adequately representative of the intended clinical formulation. The animal model used for these studies must be selected on criteria of relevance. Single dose toxicity studies provide information on acute actions or the potential effect of accidental overdose, but this information is often available from the repeat dose toxicity study, obviating the need for the acute study. Local tolerance studies provide information on tissue reactions at the site of administration. Evaluation of the findings must distinguish between normal tissue responses to injected material and findings indicative of undesirable pathological changes. The repeated dose toxicity studies are the principal studies that support the safety profile of the vaccines. The design of these studies must take full account of the features of the vaccine in the choice of treatment regime, dose levels, pharmacodynamic monitoring and timing of investigations and sacrifice. Safety pharmacology studies are performed to evaluate the potential for undesirable secondary pharmacological actions of vaccines if there is data to suggest that such studies are needed; this evaluation is made on a case by case basis. In the absence of specific guidance the design of studies for therapeutic vaccines follows the same general principles as those for anti-infective vaccines.

Subcutaneous administration of human IgG is an alternative to intravenous replacement therapy that is associated with more stable serum IgG levels and fewer systemic adverse events. Highly concentrated IgG solutions are most convenient to minimize infusion volume, but their preparation and stability presents substantial technical difficulties. We report on the stability and local tolerance of IgPro20, an l -proline-stabilized, 20% polyvalent human IgG developed for subcutaneous administration. Stability was tested according to ICH guidelines. Local tolerance and vasoactivity were examined in rabbit and rat models, respectively. The presence of l -proline in IgPro20 reduced viscosity and addition of Polysorbate 80 and inert gassing improved the appearance of the solution. After storage at 25 °C for 24 months, monomer + dimer content, aggregates, and fragments were within specification (≥90.0%, ≤4.0%, and ≤10.0%, respectively), and Fc function and antibody activities were maintained. In rats, intravenous injection of IgPro20 produced mild and transient hypotension comparable to that seen with intravenous IgG products. Local tolerance of IgPro20 in rabbits was comparable to that of a marketed subcutaneous IgG, Beriglobin ® P. Functionality and quality of IgPro20 are maintained during storage at 25 °C for at least 24 months. The product is well tolerated as assessed in animal models.

Purpose It is desirable to achieve accurate quantification in PET/CT imaging as routinely assessed using SUV measurement, including for Gallium-68 (68Ga) labelled tracers. A PET/CT scan of a uniformly filled 68Ga phantom on a GE D710 scanner unexpectedly resulted in a low SUV mean of 0.88, outside of the local tolerance of 1.0 ± 5%. A possible cause of underestimation of quantification is inaccuracy of the activity measurement of 68Ga in the dose calibrator associated with the PET/CT scanner. Methods A source of 68Ga (maximum activity of 599 MBq in 4ml in a P6 vial) was measured in 5 Capintec CRC-55t calibrators (including that used with the D710 PET/CT scanner) using the default 68Ga pre-set calibrator factor of 416. The source was then measured in an externally located Fidelis secondary standard calibrator. Based upon the results, manual adjustments were made to the Capintec factors to match the decay corrected Fidelis measurement. A repeat PET/CT scan of a uniformly filled 68Ga phantom was then performed. Results The cross-calibration results showed that the 5 Capintec calibrators systematically overestimated the activity measurement by 8–9% compared to the Fidelis when using the default factor of 416. The factors were adjusted to 457–463 to match the decay corrected Fidelis measurement. After adjustment of factors, a repeat uniform phantom scan resulted in a SUV mean of 0.97, within the local tolerance. Conclusions Underestimation of PET/CT quantification of 68Ga was caused by overestimation of 68Ga activity measurement using the pre-set dose calibrator factor settings on a Capintec CRC-55t. Improvement in quantification accuracy was achieved by adjusting the calibrator factor based upon an external cross-calibration. Similar results have been recently reported by a group in Australia [1] . We recommend SUV checks using a uniform phantom and regular calibrator cross-calibration exercises for all isotopes used clinically or in clinical trials for quantitative PET/CT imaging.

Important reproductive events including implantation, trophoblast invasion, placental development, and immune protection are regulated by the immune system at the maternal-fetal interface. This maternal-fetal immune interaction is complex, and it is difficult to perceive the whole process based on one mechanism of action. Clearly, there are multiple mechanisms for the induction of peripheral and local tolerance during pregnancy that prevent fetal rejection while maintaining a strong and active immune surveillance against viral or bacterial infections, which may endanger the successful outcome and the survival of the species.

A receiver- and assessor-blind, randomized, single-centre, crossover study was performed in 60 healthy women volunteers, to compare the local tolerance of two recombinant FSH preparations administered by a pen device (delivering 150 IU follitropin-beta) or by conventional syringe (delivering 150 IU follitropin-alpha). Volunteers were randomized to one of two treatment sequences: pen device followed by conventional syringe, or the reverse. Each preparation was injected once, subcutaneously in the umbilical region and local tolerance reactions were assessed within 5 min, at 1 and 24 h after each administration. In addition, subjects were asked to rate the pain experienced during a period of 24 h after each injection by means of a visual analogue scale (VAS). At administration (within 5 min), severe to moderate pain was experienced in 70.0% of subjects injected by the conventional syringe, whereas only 21.7% of subjects treated with the pen device experienced pain. This difference was highly significant (P

In a prospective open study, 24 patients with cancer pain receiving parenteral opioids were administered highly concentrated solutions of hydromorphone in order to assess the local tolerance to the subcutaneous infusion. Patients received a mean concentration of hydromorphone of 30 ±15 mg/mL at a mean rate of infusion of 0.3 ± 0.25 mL/hr. Of 22 evaluable patients, 17 (77%) had a site duration of more than 7 days with their first subcutaneous site (mean concentration of 34 ± 8 mg/mL of hydromorphone). Four of the five remaining patients (80%) had site duration of more than 7 days with their second subcutaneous site. Only one patient (5%) did not reach a 7-day duration after three consecutive site changes. Out of 7 subcutaneous sites that presented signs of toxicity before 7 days of infusion, the main problem was erythema in three cases, swelling in two cases, and bleeding in two cases. All sites improved spontaneously and did not require any medical treatment. No correlation was found between the concentration or rate of infusion of hydromorphone and the duration of the subcutaneous site. The duration of the site was significantly correlated with weight, tricep skinfold, subscapular skin fold, and age of the patients. Our findings suggest that hydromorphone can be safely administered in concentrations that are much higher than those commercially available. The availability of highly concentrated formulations of different opioids for parenteral use will make home management simpler and cheaper.

Eleven European burns centres in five countries (Belgium, England, Germany, Italy, Switzerland) participated in a prospective, randomized clinical trial comparing a new wound dressing Inerpan with conventional dressings such as petroleum jelly gauze, petroleum jelly gauze with antibiotics and silver sulphadiazine cream. The indication was partial skin thickness burns and 62 patients were included. In each patient, two similar lesions (with respect to depth and surface area) were compared, one being treated with Inerpan, the other one with a control dressing. The following parameters were studied: healing time, quality of healing, intensity of pain, local tolerance and frequency of dressing changes. Analysis of the results showed that Inerpan-treated sites healed faster than conventional ones, and were associated with a highly significant reduction of pain. The frequency of dressing changes was greatly reduced and the local tolerance was good.

Benzydamine displays a clear-cut anti-inflammatory effect on foot edema induced by carrageenin in rats, both after oral administration and local application on the skin. In both cases it accumulates in the inflamed tissue in concentrations ranging from 5 to 20 μg/g. In the perfused rabbit's ear, benzydamine (5 μg/ml) inhibits vascular changes produced by histamine and acetycholine. It is therefore assumed that benzydamine acts in particular on the vascular component of the inflammatory process. The local tolerance to the drug was studied in acute and chronic trials carried out in mice, rats and rabbits. The results obtained suggest that clinical trials aimed at evaluating the efficacy of a topical use of benzydamine in therapy would be useful.

Summary Five types of penicillin, for intramuscularinjection were evaluated for intensity of local reaction: (1) benzathine penicillin G suspension, 600,000 units in 1 c.c.; (2) benzathine penicillin G suspension, 600,000 units, with 5 mg. of cortisone in 1 c.c.; (3) benzathine penicillin G suspension, 600,000 units, with 2 mg. of 9-alphafluoro-hydrocortisone alcohol in 1 c.c.; (4) benzathine penicillin G, 300,000, units plus aqueous procaine penicillin, 300,000 units in 1 c.c.; and (5) aqueous procaine penicillin, 600,000 units in 1 c.c. A total of 244 children were evaluated at twenty-four hours after injection and the following percentages of local reaction were recorded for the five penicillin suspensions listed: (1) 44 per cent, (2) 77 per cent, (3) 50 per cent, (4) 12 per cent and (5) 5 per cent. The addition of steroids to benzathine penicillin G did not alter the high rate of local muscle soreness in this group of children. A mixture of 300,000 units of benzathine penicillin G and 300,000 units of aqueous procaine penicillin gave the lowest local reaction rate for both intensity and duration when compared with other repository preparations containing benzathine penicillin G. Although many of the children complained of pain for twelve hours following the injection of such a mixture, when evaluated at twenty-four hours most of the symptoms had subsided.