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Adjuvants are components of vaccines that boost the intensity, duration, and breadth of the immune response. Insight into the mechanisms responsible for the immunotoxicity of both local and systemic adverse reactions following the use of adjuvants has been gained through research over the past twenty years. In the present study, single and repeated-dose toxicity and local tolerance of newly developed Water-in-Oil (W/O) and Water-in-Oil-in-Water (W/O/W) Emulsion adjuvants (Coralvac RZ 528, Coralvac RZ 506, Coralvac AT 318, Coralvac AT 318 SIS and Coralvac 252) by Coral Biotechnology Industry and Trade Incorporated Company were demonstrated after intramuscular injection in mice. In both toxicity studies, no adverse reactions such as death, general appearance, behavior, or weight loss were observed in the mice in the experimental groups. The results indicate that clinical chemistry parameters demonstrated normal function of the major organs and no irreversible damage to the mice in all adjuvant groups compared to the control group. In histopathologic investigation of single dose toxicity study, inflammation, edema, and large amounts of lipid droplets were observed on the 7th day in all experimental groups. On the 14th day, when the control group and the experimental groups were compared, it was seen that inflammation and edema had decreased considerably. Similarly, repeated dose toxicity study showed mild inflammation and edema in the control group, while quite widespread and severe inflammation, edema, and diffuse lipid droplets of varying sizes were observed in all adjuvant groups compared to the control group. These observations would be useful for the future development of oil-based adjuvants and their use in veterinary inactive vaccines. [ABSTRACT FROM AUTHOR]

The surface errors of freeform surfaces reflect the manufacturing complexities and significantly impact the feasibility of processing designed optical systems. With multiple degrees of freedom, freeform surfaces pose challenges in surface tolerance analysis in the field. Nevertheless, current research has neglected the influence of surface slopes on the directions of ray propagation. A sudden alteration in the surface slope will lead to a corresponding abrupt shift in the wavefront, even when the change in surface sag is minimal. Moreover, within the realm of freeform surface manufacturing, variation in surface slope across different frequency bands may give rise to unique surface variation. Within the context of this study, we propose a tolerance analysis method to analyze surface variation in freeform surfaces based on [Deng et al. Optica.9. 1039 (2022)], but further considering surface frequency band slopes based on real ray data. This approach utilizes real ray data to rapidly evaluate surface variation within a specified frequency band of surface slopes. Crucially, our proposed method yields the capability to obtain system surface variation with significant wavefront aberration perturbations, in contrast to previous methodologies. The feasibility and advantages of this framework are assessed by analyzing a single-mirror system with a single field and an off-axis two-mirror system. We expect to integrate the proposed methodology with freeform surface design and manufacturing, thereby expanding the scope of freeform optics. [ABSTRACT FROM AUTHOR]

INTRODUCTION. This work is a continuation of the studies of an original biological product based on the secretome of human mesenchymal stromal cells (MSCs) and intended for the restoration of spermatogenesis and fertility. To ensure the safety of the product, it is necessary to conduct preclinical studies in two types of animals, including rodents (the results of rodent studies were presented earlier) and non-rodents.AIM. This study aimed to investigate the systemic toxicity, safety pharmacology, pyrogenicity, immunotoxicity, reproductive toxicity, and local tolerance of the original MSC secretome product in mature rabbits after two injections under the tunica albuginea of the testes.MATERIALS AND METHODS. The study was conducted in 50 male Soviet chinchilla rabbits (5 groups of 10 animals). The lyophilised MSC secretome product (MediReg) was reconstituted, mixed with collagen gel (Applicoll), and administered to rabbits subalbugineally on days 1 and 28 at a dose equal to the therapeutic dose (≥0.76 ng of vascular endothelial growth factor (VEGF)), 1.5 therapeutic doses (≥1.14 ng of VEGF), or 2.5 therapeutic doses (≥1.9 ng of VEGF). The control groups included intact rabbits and rabbits that received Applicoll mixed with water for injection. The animals were assessed in terms of their clinical condition, body temperature, electrocardiogram changes, heart and respiratory rates, blood pressure, modified Irwin test results, urinalysis findings, blood counts and biochemistry, haemostasis parameters, arterial blood gas measurements, and spermogram changes. Further, the animals were necropsied, and selected organs were weighed and subjected to histopathology. The follow-up period was 60 days.RESULTS. On day 3, the groups receiving 1.5 and 2.5 therapeutic doses of the medicinal product demonstrated a significant decrease in prothrombin time; however, only the placebo group still had decreased prothrombin time levels during the follow-up period. The histological examination revealed occasional splitting areas in the intertubular connective tissue with the formation of cavities filled with a loose substance with pronounced eosinophilic staining and deformation of the tubules along the walls of the cavities as a result of compression in 1–2 of 5 (20–40%) rabbits in all groups that received either the medicinal product or placebo. This was probably caused by mechanical compression of the tubules by the administration of large volumes of substances. In the placebo group, 2 of 5 (40%) animals had a transient increase in the size of the vesicular glands; the lobules were markedly expanded and contained a transparent secretion. The histological appearance of the vesicular glands was normal.CONCLUSIONS. When administered twice under the tunica albuginea of the testes of rabbits, the medicinal product comprising the MSC secretome and the Applicoll collagen gel carrier has an acceptable safety profile.

Spermicides have been identified as a potentially attractive alternative to hormonal contraceptives and/or intrauterine devices. Thus, this study aimed evaluating the efficacy and local tolerance of benzalkonium chloride (BKC) and myristalkonium chloride (MKC) contained in Pharmatex® vaginal formulations and compare them with nonoxynol-9 (N-9), the most common active ingredient in topical vaginal contraceptives. Human normozoospermic samples were assessed for motility, viability, acrosome status and penetration ability after exposure to control, N-9 or different BKC and MKC doses for 0 and 10 minutes. Local tolerance on HeLa cells was evaluated by the Trypan-blue and MTT assays. Exposure to BKC and MKC reduced acrosome integrity while promoting total immobilisation and complete loss of sperm viability (p <.001, n = 15). Both compounds also compromised sperm penetration ability upon exposure (p <.001, n = 15). N-9 induced the same outcomes (p <.001, n = 15); nevertheless, it was more toxic to HeLa cells than BKC and MKC (p <.05, n = 14). BKC and MKC present strong in vitro spermicidal activity at lower doses than N-9 and were better tolerated after immediate exposure than N-9. Available Pharmatex® galenic formulations were as effective as products based on N-9. [ABSTRACT FROM AUTHOR]

This article deals with the long-term preclinical validation of WIMAGINE® (Wireless Implantable Multi-channel Acquisition system for Generic Interface with Neurons), a 64-channel wireless implantable recorder that measures the electrical activity at the cortical surface (electrocorticography, ECoG). The WIMAGINE® implant was designed for chronic wireless neuronal signal acquisition, to be used e.g., as an intracranial Brain–Computer Interface (BCI) for severely motor-impaired patients. Due to the size and shape of WIMAGINE®, sheep appeared to be the best animal model on which to carry out long-term in vivo validation. The devices were implanted in two sheep for a follow-up period of 10 months, including idle state cortical recordings and Somato-Sensory Evoked Potential (SSEP) sessions. ECoG and SSEP demonstrated relatively stable behavior during the 10-month observation period. Information recorded from the SensoriMotor Cortex (SMC) showed an SSEP phase reversal, indicating the cortical site of the sensorimotor activity was retained after 10 months of contact. Based on weekly recordings of raw ECoG signals, the effective bandwidth was in the range of 230 Hz for both animals and remarkably stable over time, meaning preservation of the high frequency bands valuable for decoding of the brain activity using BCIs. The power spectral density (in dB/Hz), on a log scale, was of the order of 2.2, –4.5 and –18 for the frequency bands (10–40), (40–100), and (100–200) Hz, respectively. The outcome of this preclinical work is the first long-term in vivo validation of the WIMAGINE® implant, highlighting its ability to record the brain electrical activity through the dura mater and to send wireless digitized data to the external base station. Apart from local adhesion of the dura to the skull, the neurosurgeon did not face any difficulty in the implantation of the WIMAGINE® device and post-mortem analysis of the brain revealed no side effect related to the implantation. We also report on the reliability of the system; including the implantable device, the antennas module and the external base station.

This article deals with the long-term preclinical validation of WIMAGINE® (Wireless Implantable Multi-channel Acquisition system for Generic Interface with Neurons), a 64-channel wireless implantable recorder that measures the electrical activity at the cortical surface (electrocorticography, ECoG). The WIMAGINE® implant was designed for chronic wireless neuronal signal acquisition, to be used e.g., as an intracranial Brain–Computer Interface (BCI) for severely motor-impaired patients. Due to the size and shape of WIMAGINE®, sheep appeared to be the best animal model on which to carry out long-term in vivo validation. The devices were implanted in two sheep for a follow-up period of 10 months, including idle state cortical recordings and Somato-Sensory Evoked Potential (SSEP) sessions. ECoG and SSEP demonstrated relatively stable behavior during the 10-month observation period. Information recorded from the SensoriMotor Cortex (SMC) showed an SSEP phase reversal, indicating the cortical site of the sensorimotor activity was retained after 10 months of contact. Based on weekly recordings of raw ECoG signals, the effective bandwidth was in the range of 230 Hz for both animals and remarkably stable over time, meaning preservation of the high frequency bands valuable for decoding of the brain activity using BCIs. The power spectral density (in dB/Hz), on a log scale, was of the order of 2.2, –4.5 and –18 for the frequency bands (10–40), (40–100), and (100–200) Hz, respectively. The outcome of this preclinical work is the first long-term in vivo validation of the WIMAGINE® implant, highlighting its ability to record the brain electrical activity through the dura mater and to send wireless digitized data to the external base station. Apart from local adhesion of the dura to the skull, the neurosurgeon did not face any difficulty in the implantation of the WIMAGINE® device and post-mortem analysis of the brain revealed no side effect related to the implantation. We also report on the reliability of the system; including the implantable device, the antennas module and the external base station. [ABSTRACT FROM AUTHOR]

In this chapter, we will first consider the overall goal of nonclinical safety testing during drug development and have a brief overview of its regulatory background. We will then discuss some basic requirements of safety/toxicity testing before concentrating on the safety testing of RNA vaccines and developing a sample RNA vaccine safety testing program., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Abstract Intra-articular (IA) injection of hyaluronic acid (HA) in combination with nonsteroidal anti-inflammatory drugs, such as ketorolac (KL), have been clinically investigated to provide more rapid and profound pain relief in patients with osteoarthritis. However, its safety, local tolerance, and potential for pharmacokinetic interaction have not been assessed. In this study, the pharmacokinetics and toxicity of a combination of HA and KL were evaluated in normal rats following four-week repeated-dose injection. Rats received HA or KL alone at 4 mg/kg or 16 mg/kg, respectively, or HA/KL combination at 4/4 mg/kg, 4/8 mg/kg, or 4/16 mg/kg on a weekly basis. The rats exhibited temporal, reversible changes in hematology, serum chemistry, and urinalysis caused primarily by KL treatment. No deleterious effects were observed on the joint following repeated IA HA/KL administration, which showed only minimal to mild levels of temporary inflammatory changes in synovial membrane. The plasma KL level following IA injection rose as fast as that of intra-muscular injection, with no alteration with the co-administered HA. In conclusion, repeated IA administration of HA/KL combination was tolerated well in normal rats, encouraging future studies of IA injection of HA/KL combination on osteoarthritis-induced animal models and even patients. Highlights • Toxicity of hyaluronate/ketorolac combination was evaluated in normal rats following intra-articular injection. • Systemic exposure of ketorolac following intra-articular injection was similar to that of intramuscular injection. • No deleterious effects were observed on the joint after four-week repeated-dose intra-articular injection. • No Observed Adverse Effect Level (NOAEL) of the combination for both sexes of rats is determined to be 4/16 mg/kg. [ABSTRACT FROM AUTHOR]

In an attempt to understand the unique toxicity of adjuvanted vaccines, we studied how toxicity develops over time following vaccine administration. In addition to on- and off-target toxicity typically observed with general pharmaceuticals, we observed toxicity associated with both the generation and the broad action of effectors (antibodies and/or cytotoxic T lymphocytes, CTLs). The impact on effector generation appears to be related to local tolerance specific to the adjuvant. The vaccine immune response by effectors serves to demonstrate species relevance as outlined in the recent WHO guideline on the nonclinical evaluation of adjuvanted vaccines. When regarded as pharmaceuticals that function at sites of local administration, adjuvants have inherent on- and off-target toxicity. On-target toxicity of the adjuvant is typically associated with effector generation, and could vary depending on animal species. Therefore, the use of species with sensitivity to adjuvants described in the WHO guidelines is required to evaluate the toxicity of the vaccine associated with effector generation. Changes in safety pharmacology endpoints would be considered off-target and further studies are conducted only if changes in these endpoints are observed in nonclinical or clinical studies. Thus our decision tree does not recommend the routine conduct of stand-alone safety pharmacology studies. [ABSTRACT FROM AUTHOR]

Objective. To evaluate the safety and tolerability of repeated intratympanic administration of the gel-formulated NMDA receptor antagonist AM-101 in acute patients with inner ear tinnitus. Study Design. Prospective, double-blind, randomized, placebocontrolled study. Setting. Sixty-nine secondary and tertiary sites in North America, Europe, and Asia. Subjects and Methods. In total, 343 subjects with persistent acute tinnitus after traumatic cochlear injury or otitis media were randomized to receive 3 intratympanic doses of either AM-101 0.87 mg/mL or placebo over 3 to 5 days. They were followed for 84 days. The primary safety end point was the incidence of a clinically meaningful hearing deterioration from baseline to study day 35. Further safety assessments included tympanic membrane closure rates, analysis of adverse events, hematology, blood chemistry, and vital signs. In addition, data were collected on applied anesthetics and injection techniques. Results. The treatment was well tolerated, with no intervention-related serious adverse events. The incidence of clinically meaningful hearing deterioration was low, comparable between treatment groups (P = .82 for the primary safety end point) and not different between treated and untreated ears in unilaterally treated subjects. The rate of treatment and procedure-related adverse events was similar among treatment groups. The tympanic membrane was closed in 92% of subjects within 1 week and in all subjects by study day 84. Blood values and vital signs were inconspicuous. Conclusion. Repeated intratympanic injections of AM-101 over a 3- to 5-day period appear to be safe and well tolerated, demonstrating the ability to potentially use this delivery approach over longer time periods. [ABSTRACT FROM AUTHOR]

Parenteral products should aim toward being isotonic and euhydric (physiological pH). Yet, due to other considerations, this goal is often not reasonable or doable. There are no clear allowable ranges related to pH and osmolality, and thus, the objective of this review was to provide a better understanding of acceptable formulation pH, buffer strength, and osmolality taking into account the administration route (i.e., intramuscular, intravenous, subcutaneous) and administration technique (i.e., bolus, push, infusion). This evaluation was based on 3 different approaches: conventional, experimental, and parametric. The conventional way of defining formulation limits was based on standard pH and osmolality ranges. Experimental determination of titratable acidity or in vitro hemolysis testing provided additional drug product information. Finally, the parametric approach was based on the calculation of theoretical values such as (1) the maximal volume of injection which cannot shift the blood's pH or its molarity out of the physiological range and (b) a dilution ratio at the injection site and by verifying that threshold values are not exceeded. The combination of all 3 approaches can support the definition of acceptable pH, buffer strength, and osmolality of formulations and thus may reduce the risk of failure during preclinical and clinical development. [ABSTRACT FROM AUTHOR]

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The local tolerability of lornoxicam (Xefo) after single and repeated intraarticular administration was assessed in the rabbit and compared to established standard therapies (hyaluronic acid-Synvisc and the glucocorticoid triamcinolone-Triam), and the results are discussed in the context of the literature. Two local tolerance studies were performed using five male rabbits per group. Lornoxicam and competitor products were administered into the right knee joint in a volume of 500 μL. The contralateral left knee joint of the same animal was used as the control and was injected with water for injection. Three out of five animals were killed 72 h after the last administration, whereas the remaining two animals were subjected to a 2- or 6-week recovery period in the first and the second study, respectively. Findings revealed adaptive changes related to the mechanical irritation of the injection and to adaptive responses of the synoviocytes, but no signs of toxicity to bone or chondrotoxicity. Toxicokinetic analysis showed a fast and almost complete absorption of lornoxicam from the joints into the systemic circulation. As a conclusion, repeated intraarticular administration of lornoxicam was well tolerated in rabbits. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Leptospirosis is the bacterial zoonosis more overspread in the world. As a control measure some whole cell vaccines has been developed and registered. These biopharmaceutical products have as principal disadvantages the absence of cross-protection against serovars not included on formulations and reactogenicity at inoculation site. In this paper it is discussed the local toxicity at inoculation site elicited by a proteoliposome vaccine candidate obtained form outer membrane cell wall of Leptospira spp using the Mesocricetus auratus as biomodel. The experimental animals (both sexes) were inoculated with two doses of vaccine candidate (21 days between them) via intramuscular. The results obtained did not show statistical differences among immunized and animal controls for the variables: corporal weight, water and food intake. Neither macroscopic lesions of toxicological importance were observed. The histopathological findings describes are part of immunological response consequence against vaccine candidate. Besides the immunological relevance of the biomodel was check by means of IgG quantification. Agreement with these results, it can conclude that a single dose of the vaccine candidate immunized via intramuscular in Mesocricetus auratus did not show toxic potential at inoculation site. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

The island of Sulawesi is an ecologically diverse and anthropogenically complex region in the Indonesian archipelago; it is home to multiple macaque species and a key locus of human–nonhuman primate interconnections. Here, we review the ethnoprimatology of Sulawesi by exploring two primary domains of the human–macaque interface: overlapping resource use and cultural perceptions of macaques. Crop raiding is the primary form of overlapping resource use. While the raiding of cacao plantations predominates in Central and South Sulawesi, subsistence crops (e.g., sweet potato and maize) are most vulnerable on Buton, Southeast Sulawesi. Despite this overlap levels of conflict are generally low, with farmers showing considerable tolerance. This tolerance can be explained by positive perceptions of the macaques despite their crop raiding behavior, and the finding that in some areas macaques figure prominently in local folklore, hence affording them protection. These findings provide some hope for the future management and conservation of these endemic macaques. Am. J. Primatol. 72:848–854, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

This study evaluates safety of FINLAY-FR-02, a vaccine candidate against SARS-CoV-2 based on the recombinant receptor binding domain conjugated to tetanus toxoid, in a preclinical, repeat-dose toxicity and local tolerance study. Sprague Dawley rats were randomly allocated to three experimental groups: control (receiving physiological saline solution); placebo (receiving all vaccine components except antigens) and vaccine group (receiving three doses of the vaccine candidate, 37.5 µg of RBD) administered intramuscularly in hind limbs at 24 h intervals during three days. We evaluated physiological condition, pain, food and water consumption, body temperature, dermal irritability, injection site temperature and inflammation, immunological response, blood chemistry, relative organ weight, histopathology and immunotoxicology. The product was well tolerated; no clinically relevant changes, pain, local effects or adverse systemic toxicological changes or deaths were observed. These preliminary results permitted the Cuban regulatory authorities to authorize clinical trials in humans. [ABSTRACT FROM AUTHOR]

Local Tolerance studies for vaccine products are a main link in the chain of Regulatory Requirements for toxicological preclinical studies. Mainly considering that the use of mucosal road seems to be a current tendency due to the advantages it offers. Sprague Dawley rats of both sexes weighing 100-120 g (reception weight) provided by CENPALAB with the corresponding certificates of sanitary and genetic quality were used in this test. Local tolerance study lasted 17 days. Rats were distributed in 5 groups (3 groups with different cochleate concentrations, one without inoculation and another one that received the diluents of the product in test. Measurement of weight increase, food and water consumption, as well as the anatomopathologic studies in the two times of sacrifice, at 12 and 17 days were performed. Main histopathological studies were carried out in brain and nasal nostrils in three levels of their extension (anterior, medium and posterior areas). In addition, immunological assays such as the determination of IgG in serum, saliva and cerebrospinal fluid (CSF) were carried out. Results showed a sustained weight increase. There were no clinical alterations during water and food consumption, while the existence of discreet acute inflammatory changes was found by anatomopathological studies, which were directly related to the increase of the product concentration. The presence of IgG antibodies in saliva and in sera of the rats inoculated with the cochleates showed significant differences (P <0.05) compared to the non inoculated control group and to the animals inoculated with the diluent. CSF studies resulted negative regarding the presence of specific IgG antibodies. The existence of a direct relation among the concentrations of the product in test and the inflammatory processes in the medium and posterior levels of the nasal nostril was proven, therefore it is considered that cochleates applied by this route and in the concentrations used are innocuous and immunogenic. [ABSTRACT FROM AUTHOR]

Objective: To compare the efficacy, tolerability, and convenience of two formulations of the follitropin-α (Gonal-f) pen device versus the conventional form in Iranian women undergoing ovarian stimulation for intracytoplasmic sperm injection. Design: Randomized, single-center trial, parallel-group, single blind. Setting: Tertiary referral center, University Hospital. Patient(s): A total of 100 patients undergoing intracytoplasmic sperm injection. Intervention(s): After down-regulation with busereline acetate, patients were randomized to receive the pen device or the conventional syringe of follitropin-α. A computer-generated randomization list was used to allocate the patients to one of these two groups. Main Outcome Measure(s): The primary outcomes were patients'' satisfaction, convenience, occurrence of local tolerance symptoms, and pain. Total dose of follitropin-α, duration of follitropin-α treatment, number of oocyte retrieved, number of viable embryos, and clinical pregnancies were secondary outcome measures. Data collection was performed by means of a questionnaire designed for the purpose of this study. The pain scored according to the Visual Analogue Scale. Result(s): Self-administration and patients'' satisfaction were significantly higher in the pen device group than the conventional syringe group. Local reactions at injection sites and pain were significantly higher in the conventional syringe group than in the pen device group. There were no statistically differences in secondary outcome measures and convenience between two groups. Conclusion(s): Among the Iranian patients that we studied, the pen device of Gonal-f is safe, convenient, and less painful, with more patients'' satisfaction than the conventional syringe form, but both forms have equal efficacy in intracytoplasmic sperm injection cycles. [Copyright &y& Elsevier]

Objectives: This study compares the efficacy and patient tolerance of follitropin-β (recagon) administered using a pen device with conventional syringe in infertile couples undergoing in vitro fertilization/intracytoplasmic sperm injection treatment. Methods: Data for 481 patients were retrieved retrospectively for the analysis. Conventional syringe group constituted 204 patients with 217 cycles and 265 patients with 294 cycles in the pen-device group. Down-regulation was achieved with GnRH agonist. Results: Comparison of follitropin-β administered with pen and syringe showed the following data, respectively. A total dose of 1909·38/2100·65 IU ( P < 0·001), duration of stimulation, 9·70/10·47 days ( P < 0·05), oestradiol levels on the day of human chorionic gonadotropin, 1488·34/1067·63 pg/ml, number of follicles reaching >16-mm size, 9·75/7·34 ( P < 0·05), number of oocytes retrieved, 13·84/9·55 ( P < 0·001) and number of embryos available for freezing, 4·56/1·30 ( P < 0·05), the above data were observed in pen/conventional syringe groups, respectively. The live birth rates per cycle were 28·85% and 30·95% in the conventional syringe/pen-device groups, respectively. Patient tolerance with respect to pain at injection site was better with the pen device ( P < 0·025). Conclusion: The data show that follitropin-β administered with pen device is well tolerated and more efficacious with respect to ovarian stimulation outcome compared with the conventional syringe. [ABSTRACT FROM AUTHOR]

The article presents a study that evaluated the local tolerance of the antiretroviral spermicide WHI-07-loaded gel-microemulsion in a physiologically relevant and sensitive porcine model. The gilts employed in the study were administered with either a single or a daily intravaginal application of 2.0% WHI-07 via a gel-microemulsion for six days. It was found that the scatter profile of cervicovaginal lavage (CVL) immune cells and basal levels of proinflammatory cytokines in CVL fluid were not affected by intravaginal exposure to 2% WHI-07.

The meningococcal B vaccine contains purified outer membrane vesicles of serogroup B meningococcus of strain (Cu- 385 - 83) B: 4:P1.19, 15. The vaccination scheme proposed for humans consists in three doses of 0.5 mL, separated by an optimal interval of eight weeks. The objective of this toxicity study in Sprague Dawley (SD) rats was to determine potential toxicity, lethality, sensitive organs and systems and other adverse events as well as toxicity at the inoculation site after administration of one dose of the vaccine under study. Results indicated that, under the study conditions and according to the criteria established to evaluate results, the meningococcal B vaccine does not produce toxic effects in the animal model used. Only granulomatous formations at the level of the inoculation site were observed. These formations have been reported to characteristic of deposit adjuvants like aluminium hydroxide used in other parenteral vaccines. It is concluded that the meningococcal B vaccine resulted to be satisfactory in the tests of toxicity by single dose and local tolerance carried out in rats. [ABSTRACT FROM AUTHOR]

Abstract: The purpose of this study was to evaluate the local tolerance of vaginal gels (three gels containing dapivirine, the placebo gel, and Conceptrol®) with the Slug Mucosal Irritation test and to compare the results with those of the rabbit vaginal irritation test. The irritation potential on the slug mucosa was assessed by the mucus production caused by a repeated treatment for 5 successive days. Additionally, membrane damage was estimated by the protein and enzyme release. By means of a classification prediction model the formulations were classified into four irritation classes. The effect of a 10-day intravaginal application of the gels on the rabbit vaginal and cervical mucosa was evaluated by means of macroscopic and microscopic examination. The placebo and dapivirine gels induced no irritation of the slug mucosa (low mucus production and protein release, no enzyme release) and no vaginal or cervical irritation in rabbits. Conceptrol® caused severe irritation of the slug mucosa (increased mucus production, protein release, and enzyme release) and irritation of the rabbit vagina and cervix. The results obtained with the Slug Mucosal Irritation test were comparable to those of the rabbit vaginal irritation test. [Copyright &y& Elsevier]

The feasibility of administering a relatively high dose of the gonadotrophin-releasing hormone (GnRH) antagonist ganirelix by means of a needle-free injection device, which could be useful in the long-term treatment of sex-steroid-dependent disorders, was evaluated in a randomized, crossover study in 16 healthy females. Local tolerance and pharmacokinetics of ganirelix administered by MediJector® versus conventional needle injections were compared. Additionally, the pharmacodynamic effect was evaluated. Two milligrams of ganirelix was administered s.c. once daily for 7 days by Medi-Jector® or conventional needle in a randomized sequence, without a washout period. No apparent differences in local tolerance were observed. Most injections (87.5%) gave either no or only a mild reaction. Of the moderate reactions, swelling and redness were reported most frequently (overall 4.9 and 8.5% per injection, respectively). Administration by Medi-Jector® was bioequivalent to conventional needle injection with respect to the peak concentration and area under the curve. A profound suppression of luteinizing hormone and follicle stimulating hormone was observed. Serum oestradiol and progesterone concentrations were relatively low prior to treatment and remained low during the entire study period. In conclusion, administration of a relatively high dose of ganirelix by Medi-Jector® might be useful for long-term treatment of sex-steroid dependent disorders. [ABSTRACT FROM PUBLISHER]