A stability-indicating reversed-phase high-performance liquid chromatographic method was developed and validated as per the International Conference on Harmonization (ICH) guidelines to evaluate the ...reproducibility of batches of synthetic peptides included in a stability program, in particular cholecystokinin (CCK-4) peptide.
Both isothermal and nonisothermal approaches were used to determine stability under experimental conditions and the resulting degradation products were identified by liquid chromatography–mass spectrometry (LC–MS). The principal degradation product was the cyclic dimer, although another two products derived from it were also detected, due to the loss of one or two Phe-NH
2 residues. The dimerization follows first-order kinetics, whereas the hydrolytic cleavage implies both consecutive and in-parallel processes. The linear Arrhenius plot indicates that the degradation mechanism and kinetics do not change with temperature or the batch, but the degradation rate does depend on the batch, for example, the shelf-life at 25
°C was 2.54 days for batch 3, which is 13-times lower than batch 2. This variability is caused by a change in the synthesis process introduced by the manufacturer.
The combination of these two elements: the analytical and stability-evaluating methods provide enough data to establish a stability-indicating profile, as required by the guideline ICH-Q6B for biotechnological/biological products.
Background Psychological distress is frequent among dermatological patients. The development of a positive attitude toward diagnosis and treatment is thought to be critical for successful coping and ...mental health outcomes.
Objective The aim of this study was to assess the coping strategies and the psychological distress, due to anxiety and depression, in an unselected sample of dermatological patients.
Methods Self‐administered questionnaires (HADS, COPE) were given to 603 dermatological patients.
Results Out of 567 participants, 149 (26.2%) scored positive for Anxiety, and 52 (9.2%) scored positive for Depression. Multivariate analysis, adjusting for gender, age, socio‐economic status, and disease, showed that both Anxiety and Depression are associated with a less frequent use of Positive attitude coping.
Conclusion Our results reinforce the notion that while planning the treatment of dermatological patients, evaluating their mental health might help to provide optimal treatment. Since coping ability was found to be important for mental health status, policy implications could include emphasis on social programs to assist individuals to manage stress, as well as psychological support.
There is as yet no commercialized preparation for oral administration of flecainide acetate (FA) to children. In such cases, manipulation of commercial tablets is the usual practice in pharmacy ...services of hospitals and compounding pharmacies, to provide a suitable dosage form for this vulnerable pediatric population group. In this study, we have formulated FA as an oral solution, as an alternative to the suspension elaborated from commercial tablets. Due to this sensitivity of young patients, we have used the pure active pharmaceutical ingredient (API) and the lowest permitted levels of pediatric excipients. Despite being a highly soluble API, only one of the formulations appears as a transparent solution due to complete FA solubilization. The proposed formulation is physico-chemically and microbiologically stable and the mass and dose uniformity is appropriate for 30 days' storage at 25 °C.
Stability is a particular problem for biopharmaceutical products because the efficacy of peptides and proteins as therapeutic or diagnostic agents can be affected during preparation, shipping, and ...storage. A particular formulation may have no immediately apparent effect on physical or chemical stability, and the time required for these studies at ambient temperature can be very lengthy because chemical reactions proceed relatively slowly at low temperatures. Undoubtedly, accelerated and stress testing of stability can provide useful information for future product development. The many methods used to study kinetics in aqueous solution may be experimental or computational. Experimental approaches may be isothermal or non-isothermal. Non-linear and linear regression methods can be used to analyze data from these experimental approaches, and the Monte Carlo method could be useful to obtain information about uncertainties in experimental data.
The purpose of this review is to describe and to discuss options for the accelerated study of peptide and protein drugs. These options are not necessarily the same as those used for regulatory testing to set expiration dates. We also review statistical techniques to estimate kinetic parameters (rate constant, activation energy, and pre-exponential factor). Further, we establish the advantages and the limitations of both thermal approaches. We analyze and discuss all aspects using the most recent examples of peptide and protein stability.
Context: The formulation of an active pharmaceutical ingredient (API) as oral solution or suspension in pediatrics is a habitual practice, due to the non-existence of many commercialized medicines in ...pediatric doses. It is also the simplest way to prepare and administer them to this vulnerable population. The design of a formulation that assures the dose and the system stability depends on the physico-chemical properties of the API.
Objective: In this study, we formulate a class IV API, Acetazolamide (AZM) as suspension for oral administration to pediatric population. The suspension must comply attributes of quality, safety and efficacy for this route of administration.
Materials and methods: We use simple compounding procedures, as well as fewer pure excipients, as recommended for children. Mass and uniformity content assays and physical and chemical stability studies were performed. To quantify the API an UPLC method was used.
Results and discussion: We verified the physico-chemical stability of the suspensions and that they passed the mass test of the European Pharmacopeia (EP), but not the dose uniformity test.
Conclusions: This reveals that AZM must be formulated as liquid forms with a more complex system of excipients (not usually indicated in pediatrics), or otherwise solid forms capable of assuring uniformity of mass and dose for every dosage unit.
Objective
Sleep state misperception (SSM) is a term used in the International Classification of Sleep Disorders to indicate people who mistakenly perceive their sleep as wakefulness. SSM is a form of ...primary insomnia. The aim of this study was to record psychological functioning measures (anxiety, depression, ability to feel pleasure, obsessive–compulsive traits) in a population of patients with primary insomnia and to evaluate the relationship between these measures and the patients' perception of their sleep.
Materials and Methods
Seventy‐six consecutive patients with primary insomnia were enrolled: 34 men and 42 women, mean age 53.9 ± 13.1. Sleep study included the following: Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Berlin's Questionnaire and home‐based polysomnography. Psychometric evaluation included the following: Self‐Administered Anxiety Scale, Beck's Depression Inventory, Maudsley's Obsessive Compulsive Inventory, Snaith–Hamilton Pleasure Scale, Eating Attitude Test.
Results
All patients with insomnia had psychometric scores higher than the general population, but very few patients, in both groups, had anxiety or depression scores consistent with severe mood or anxiety disorders. Comparisons between subjective and objective scores confirmed that most sleep parameters were underestimated. Patients with SSM had lower anxiety scores as compared to patients without SSM.
Conclusions
The study did not succeed in identifying any predictor of sleep misperception. We speculate that a group of patients, rather than being extremely worried by their insomnia, may have a sort of agnosia of their sleep.
An integrated and cost-effective sensor system to monitor the state of reinforced concrete structures from the corrosion point of view was developed. The sensor provides measurements of the open ...circuit potential of rebars, the corrosion current density of rebars, the electrical resistivity of concrete, the availability of oxygen, the chloride ions concentration in concrete, and the temperature inside the structure. The integrated system consists of different electrodes embedded in concrete and a software system that acquires and analyses the data. The results obtained so far show the capabilities of this type of sensor to determine the corrosion state of existing as well as new concrete structures.
The quality of drug products may be affected from manufacture to dispensing, particularly at high temperature and humidity as in Mauritania. This country is not included in the World Health ...Organization reports on poor quality products due to the lack of a qualified laboratory and monitoring system. Ensuring the quality of medicine is even more relevant in the case of diseases such as Tuberculosis, due to its high prevalence, complex treatment and continuous bacterial resistance. The aim was to develop a monitoring system to assess the quality of antituberculosis drugs products, by the substandard detection based on European and United States Pharmacopeial recommendations regarding quality control. In addition to studying the influence of accelerated storage conditions (40 ± 2°C/75 ± 5% relative humidity) on their qualities and comparing the dissolution profiles to contrast the quality. 18 antituberculosis drug products were taken from Europe and Mauritania, and quality was studied through visual inspection and according to the compliance of the mass uniformity, uniformity of dosage units, dissolution, disintegration and friability pharmacopeial tests. Furthermore, a dissolution profile comparison was carried out to examine quality. A stability study was conducted to assess the influence of climatic conditions on the content and the dissolved amount of the active pharmaceutical ingredients, which were determined by an ultra-performance liquid chromatography system. As result, 69.3% of 13 Mauritanian formulations had a substandard quality mainly due to non-compliance with the test for friability or content uniformity of these medicines. All European drug products complied with pharmacopeia specifications. In addition, storage conditions affected the dissolution rate of ethambutol and the uniformity of the 4 antituberculosis combination drug products.
Cytokines may influence brain activities especially during stressful conditions, and elevated levels of IL-6 and C-reactive protein have been pointed out in subjects with Major Depression. If ...pro-inflammatory cytokines play a causative role in major depressive disorders, one would expect that antidepressants may down-regulate these cytokines or interfere with their actions, leading to improvement of depressive symptoms. Accumulating evidence has been published that antidepressants modulate cytokine production and this is particularly true for Tricyclics and Selective serotonin reuptake inhibitors (SSRIs), but the influence of newer antidepressants acting on both serotonin (5-HT) and norepinephrine (NE) such as venlafaxine, duloxetine and mirtazapine on cytokine levels has not been extensively studied. However, both pre-clinical and clinical studies examined in this review have demonstrated that newer serotonin-noradrenalin antidepressants can inhibit the production and/or release of pro-inflammatory cytokines and stimulate the production of anti-inflammatory cytokines, suggesting that reductions in inflammation might contribute to treatment response. Moreover, the results of the present review support the notion that the serotonin-noradrenalin antidepressants venlafaxine and mirtazapine may influence cytokine secretion in patients affected by MD, restoring the equilibrium between their physiological and pathological levels and leading to recovery. To date, no studies have evaluated the effect of duloxetine, the newest serotonin-noradrenalin antidepressant, on cytokine levels and therefore this should be evaluated in future studies.
Kinetic modelling was applied to predict the stability of cholecystokinin fragment CCK-4 in aqueous solution, which was analyzed by isothermal and nonisothermal methods using a validated stability ...indicating HPLC method.
The isothermal studies were performed in the temperature range 40 to 80 degrees C at pH 12 and ionic strength 0.01 M as constants, whereas nonisothermal stability studies were performed using a linear increasing temperature program, heating rate 0.25 degrees C/h and a temperature interval 40-82 degrees C. The isothermal studies require two-step linear regression to estimate the parameters, resulting in a well-defined confidence interval. Nonisothermal kinetic studies require nonlinear or linear regression by previous transformation of data to estimate the parameters. In this case, the two most popular approaches, derivative and integral, were used and compared.
Under isothermal conditions, an apparent first-order degradation process was observed at all temperatures. The linear Arrhenius plot suggested that the CCK-4 degradation mechanism was the same within the studied temperature range, with quite large uncertainties due to the small number of degrees of freedom based only on the scatter in the plot, and giving an estimated shelf life at 25 degrees C of 35.2 days. The derivative approach yields high variability in the Arrhenius parameters, since they are dependent on the number of polynomial terms chosen, so several statistical criteria were applied to select the best model. The integral approach allows activation parameters to be calculated directly from experimental data, and provides results in good agreement with those of the traditional method, but have the advantage that the uncertainty in the final result directly reflects the goodness of fit of the experimental data to the chosen kinetic model. The application of the bootstrap technique to estimating confidence limits for the Arrhenius parameters and shelf life is also illustrated, and shows there is no difference between the asymptotic and bootstrap confidence intervals.
Nonisothermal studies give us fast and valuable information about drug stability, although their potential for predicting isothermal behaviour is conditioned by the data analysis method applied.
