Usefulness of resuscitative endovascular balloon occlusion of the aorta (REBOA) in controlling puerperal bleeding in patients with abnormal placental implantation.

BACKGROUND AND AIMS: Abnormalities of placental implantation, which make up the spectrum of placenta accreta, are associated with high maternal morbidity and mortality due to massive bleeding during delivery. Placing aortic occlusion balloons helps control the bleeding, facilitating surgical intervention. A new device, resuscitative endovascular balloon occlusion of the aorta (REBOA), minimizes the risks and complications associated with the placement of traditional aortic balloons and is also efficacious in controlling bleeding. The aim of this study is to evaluate the usefulness, efficacy, and safety of REBOA in puerperal bleeding due to abnormalities of placental implantation. MATERIAL AND METHODS: Between November 2019 and November 2021, our interventional radiology team placed six REBOA devices in six women scheduled for cesarean section due to placenta accrete. RESULTS: Mean blood loss during cesarean section after REBOA (3507.5 mL) was similar to the amounts reported for other aortic balloons. The mean number of units of packed red blood cells required for transfusion was 3.5. Using REBOA provided the surgical team with adequate conditions to perform the surgery. There were no complications derived from REBOA, and the mean ICU stay was <2 days. CONCLUSION: The technical characteristics of the REBOA device make it a safe and useful alternative for controlling massive bleeding in patients with placenta accreta.

Sacral neuromodulation for fecal incontinence in Latin America: initial results of a multicenter study.

BACKGROUND: Sacral neuromodulation (SNM) is a widely used therapeutic option for fecal incontinence (FI). Larger series are mainly from Western countries, while few reports address the results of SNM in less developed or less wealthy countries. The aim of the present study was to evaluate the efficacy of SNM in patients with FI in Latin America. METHODS: A retrospective study was conducted on patients with FI who had SNM between 2009 and 2016 at 15 specialized colorectal surgery centers in Latin America. Main outcomes measures were functional outcomes, postoperative complications, requirement of revisional surgery, and requirement of device removal. All patients had failed conservative management and had clinical assessment including recording of the validated Cleveland Clinic Florida Fecal Incontinence Score (CCF-FIS) and, when available, anal manometry and endoanal ultrasound. Patients were followed up for a median of 36.7 (1-84) months. RESULTS: One hundred and thirty-one patients [119 females, median age of 62.2 (range 19-87) years] were included. The most common etiology of FI was obstetric injury (n = 60; 45.8%). After successful test lead implantation, the stimulator was permanently placed in 129 patients (98.5%). One patient failed to respond in the test phase and one patient did not proceed to permanent implantation for insurance reasons. Nineteen patients (14.7%) had 19 complications including infection (n = 5, 3.8%), persistent implant site pain (n = 5, 3.8%), generator/lead dislodgment (n = 5, 3.8%), malfunctioning device (n = 3, 2.3%), and hematoma (n = 1, 0.7%). Reimplantation after the first and second stages was necessary in 2 (1.5%) and 3 patients (2.3%), respectively. The device removal rate was 2.2%. At a median follow-up of 36.7 (range 1-84) months, the CCF-FIS significantly improved from a preoperative baseline of 15.9 ± 2.98 to 5.2 ± 3.92 (95%CI: 15.46 vs 4.43; p < 0.0001). Overall, 90% of patients rated their improvement as "significant". CONCLUSIONS: Sacral nerve stimulation for FI is safe and efficient, even in less wealthy or less developed countries.

Characterization of the respiratory pattern in patients with chronic heart failure applying joint symbolic dynamics / Caracterización del patrón respiratorio de pacientes con insuficiencia cardíaca crónica mediante análisis de dinámica simbólica conjunta

Abstract: This work proposes a method to characterize the respiratory pattern of patients with chronic heart failure (CHF) to determine non-periodic breathing (nPB), periodic breathing (PB) and Cheyne-Stokes respiration (CSR) through non-linear, symbolic analysis of biological signals. A total of 43 patients were examined for their cardiorespiratory profiles, their ECG and respiratory pattern signals were processed, analyzed and studied for parameters that could be of potential use in clinical decision making, specifically in patient classification. Patients in the study were characterized through their cardiorespiratory signals, applying joint symbolic dynamics (JSD) analysis to cardiac beat and respiratory interval durations. The most statistically significant parameters across all groups were identified through a Kruskal-Wallis two tailed test (α = 0.05) and a linear discriminant analysis (LDA) classification method based on such parameters was developed. The best result achieved with this classification method uses 10 features to discriminate patients with a 97.67% Accuracy (Acc). The best features to discriminate among groups are related to cardiorespiratory interaction rather than just respiration patterns alone. Results further support the idea that abnormal breathing patterns derive from physiological abnormalities in chronic heart failure.

Resumen: El trabajo propone un método para identificar el patrón respiratorio de pacientes con insuficiencia cardiaca crónica (CHF) con la finalidad de determinar respiración no periódica (NPB), respiración periódica (PB) y respiración de Cheyne-Stokes (CSR) a través de análisis simbólico no lineal de señales biológicas. Se examinaron los perfiles cardiorrespiratorios de 43 pacientes; sus señales de ECG y patrón respiratorio fueron procesados, analizados y estudiados en busca de parámetros que pudieran ser de utilidad, específicamente en la clasificación de pacientes. Estos pacientes se caracterizaron por medio de sus señales cardiorrespiratorias, aplicando un análisis de dinámica simbólica de conjuntos al ritmo cardíaco y a la duración de los intervalos respiratorios. Los parámetros de mayor significancia estadística entre todos los grupos se identificaron a través de una prueba Kruskal-Wallis de dos colas ( α = 0,05) y mediante un método de clasificación por análisis discriminante lineal (LDA). El mejor resultado conseguido con este método utiliza 10 características para discriminar a los pacientes con una precisión de 97,67% (Acc). Las características para discriminar entre grupos estuvieron relacionados con la interacción cardiorrespiratoria más que con solo los patrones de respiración, respaldando así la idea de que los patrones de respiración anormales derivan de anomalías fisiológicas presentes en la insuficiencia cardíaca crónica.

Mechanical unloading of bone in microgravity reduces mesenchymal and hematopoietic stem cell-mediated tissue regeneration.

Mechanical loading of mammalian tissues is a potent promoter of tissue growth and regeneration, whilst unloading in microgravity can cause reduced tissue regeneration, possibly through effects on stem cell tissue progenitors. To test the specific hypothesis that mechanical unloading alters differentiation of bone marrow mesenchymal and hematopoietic stem cell lineages, we studied cellular and molecular aspects of how bone marrow in the mouse proximal femur responds to unloading in microgravity. Trabecular and cortical endosteal bone surfaces in the femoral head underwent significant bone resorption in microgravity, enlarging the marrow cavity. Cells isolated from the femoral head marrow compartment showed significant down-regulation of gene expression markers for early mesenchymal and hematopoietic differentiation, including FUT1(-6.72), CSF2(-3.30), CD90(-3.33), PTPRC(-2.79), and GDF15(-2.45), but not stem cell markers, such as SOX2. At the cellular level, in situ histological analysis revealed decreased megakaryocyte numbers whilst erythrocytes were increased 2.33 fold. Furthermore, erythrocytes displayed elevated fucosylation and clustering adjacent to sinuses forming the marrow-blood barrier, possibly providing a mechanistic basis for explaining spaceflight anemia. Culture of isolated bone marrow cells immediately after microgravity exposure increased the marrow progenitor's potential for mesenchymal differentiation into in-vitro mineralized bone nodules, and hematopoietic differentiation into osteoclasts, suggesting an accumulation of undifferentiated progenitors during exposure to microgravity. These results support the idea that mechanical unloading of mammalian tissues in microgravity is a strong inhibitor of tissue growth and regeneration mechanisms, acting at the level of early mesenchymal and hematopoietic stem cell differentiation.

Model of music cognition and amusia.

INTRODUCTION: The study of the neural networks involved in music processing has received less attention than work researching the brain's language networks. For the last two decades there has been a growing interest in discovering the functional mechanisms of the musical brain and understanding those disorders in which brain regions linked with perception and production of music are damaged. DISCUSSION: Congenital and acquired musical deficits in their various forms (perception, execution, music-memory) are grouped together under the generic term amusia. In this selective review we present the "cutting edge" studies on the cognitive and neural processes implicated in music and the various forms of amusia. CONCLUSIONS: Musical processing requires a large cortico-subcortical network which is distributed throughout both cerebral hemispheres and the cerebellum. The analysis of healthy subjects using functional neuroimaging and examination of selective deficits (e.g., tone, rhythm, timbre, melodic contours) in patients will improve our knowledge of the mechanisms involved in musical processing and the latter's relationship with other cognitive processes.

Serum oxytocin concentrations in elective caesarean delivery: a randomized comparison of three infusion regimens.

BACKGROUND: The aim of this study was to determine serum oxytocin concentrations following different regimens of prophylactic oxytocin administration in women undergoing elective caesarean delivery. METHODS: Thirty healthy pregnant patients were randomized, after clamping of the umbilical cord, to receive intravenous oxytocin in one of the following groups: G1 (n=9), 10 IU of oxytocin infused over 30 min (0.33 IU/min); G2 (n=11), 10 IU of oxytocin infused over 3 min and 45 s (2.67 IU/min); and G3 (n=10), 80 IU of oxytocin infused over 30 min (2.67 IU/min). Both patient and surgeon were blinded to allocation. Uterine tone was assessed by surgical palpation. Serum oxytocin concentration was determined by enzyme immunoassay before anaesthesia (T0) and at 5 (T5), 30 (T30) and 60 (T60) min after the start of oxytocin infusion. RESULTS: Serum oxytocin concentrations (mean±standard error, ng/mL) were not significantly different in the groups at T0 (0.06±0.02, 0.04±0.02 and 0.07±0.04, respectively, P=0.76), and T60 (0.65±0.26, 0.36±0.26 and 0.69±0.26, respectively, P=0.58). G3 showed higher concentrations than G1 at T5 (3.65±0.74 versus 0.71±0.27, P=0.01) and at T30 (6.19±1.19 versus 1.17±0.37, P<0.01), and were higher than G2 at T30 (6.19±1.19 versus 0.41±0.2, P<0.01). Haemodynamic data and uterine tone were considered satisfactory and similar in all groups. No additional uterotonic agents were needed. CONCLUSION: Serum oxytocin measurements made using enzyme immunoassay in healthy pregnant women undergoing elective caesarean delivery showed that administration of 80 IU oxytocin over 30 min resulted in higher serum oxytocin levels after 5 and 30 min than the two other regimens. The concentrations did not differ between groups at 60 min.

Evaluation of tear production with modified Schirmer tear test-1 during the neonatal period in cats / Avaliação da produção lacrimal pelo teste da lágrima de Schirmer-1 modificado durante o período neonatal em gatos

The study aimed to evaluate tear production by means of modified Schirmer tear tes-1 (mSTT-1) in neonate cats. Likewise, correlation between mSTT-1 and STT-1 was assessed in vitro. Standard SST strips were cut in half and after eye lid opening, tear production of neonates (n=15) was daily measured in both eyes (mSTT-1), until the 7th day, and at day 14, 21, and 28. Animals were daily weighted until 28 days of age. Results were compared statistically (P<0.05). During the first 7 days, the overall mSTT-1 mean was 0.76 wetting/minute. Significant differences between right and left eyes were not observed at any time point (P=1.00). Tear secretion increased significantly, from the 14th to 28th day, in comparison with 7 first days (P<0.05). Positive correlation between maturity parameters and tear secretion was observed (P<0.0001). Distance between slopes of each strip changed significantly (P<0.0001). It was concluded that tear secretion in the neonatal period of cats is very below the reference values described for young and adults of the same species. It is not possible to extrapolate results obtained with mSTT-1 to standard STT-1.

Objetivou-se avaliar a produção lacrimal, por meio do teste da lágrima de Schirmer-1 modificado (TLS-1m) em gatos neonatos. Outrossim, estabelecer in vitro a existência de correlação entre o TLS e o TLS-1m. Tiras pa-dronizadas para realização do TLS foram partidas ao meio e após a abertura das pálpebras, a produção lacrimal dos neonatos (n=15) foi aferida em ambos os olhos (TLS-1m), diariamente, até o sétimo e aos 14, 21 e 28 dias. Os animais foram pesados diariamente até os 28 dias de idade. Os resultados foram comparados estatisticamente (p<0,05). Durante os primeiros sete dias de avaliação, a média geral obtida pelo TLS-1m foi de 0,76±0,08 mm/minuto. Não se constatou diferença significativa entre os olhos direito e esquerdo, em nenhum dos períodos avaliados (p=1,00). A produção lacrimal elevou-se significativamente, do 14º até o 28º dia, comparativamente aos primeiros sete dias (p<0,05). Observou-se correlação positiva entre parâmetros de maturidade e a produção lacrimal (p<0,0001). A distância entre as linhas de cada tira foi significativa (p<0,0001). Conclui-se que a produção lacrimal no período neonatal em gatos é bem inferior aos valores de referência descritos para adultos e jovens da mesma espécie. Não é possível extrapolar valores obtidos com o TLS-1 modificado para o TLS-1 padrão.

Relationship between insulin resistance, inflammation and liver cell apoptosis in patients with severe obesity.

BACKGROUND: In obesity, insulin resistance appears frequently after activation of proinflammatory molecules. Caspase-generated cytokeratin-18 (CK-18) fragments are produced during the apoptosis of hepatic cells. The main objective in the present study is to investigate the relationship between insulin resistance and caspase-generated CK-18 fragments in patients with severe obesity. METHODS: Sixty-two patients selected for bariatric surgery were clinically studied (sex, age, weight, waist diameter, body mass index, arterial pressure and type 2 diabetes mellitus) and analytic parameters were measured in blood (glucose concentration, cholesterol, triglycerides, insulin, glycosylated hemoglobin, aspartate aminotransferase, alanine aminotransferase, high-sensitivity C-reactive protein, adiponectin, interleukin 6, interleukin 18 and CK-18 fragments). Patient group division was based on 70th percentile of insulin resistance as measured by homeostasis model assessment (HOMA) and also according to liver histology. RESULTS: Patients with greater insulin resistance (percentile > 70th) showed higher values of CK-18 fragments, interleukin 6 and transaminases. A positive correlation between the HOMA score, value of CK-18 fragments and triglyceride level was found. A correlation between CK-18 fragments with interleukin 6, triglycerides and transaminases was also observed. HOMA score and value of CK-18 fragments correlated with the degree of liver fibrosis. CONCLUSIONS: Greater degree of insulin resistance induces apoptosis of hepatic cells as measured by the serum levels of CK-18 fragments.

[A clinical study of adult autoimmune hepatitis in Valencia, Spain]. / Estudio clínico de la hepatitis autoinmune del adulto en Valencia.

OBJECTIVE: the clinical phenotype of autoimmune hepatitis (AIH) varies among geographical areas. The aim of this study is to determine the salient features of AIH in adult patients from the province of Valencia, Spain. MATERIAL AND METHODS: eighty-one patients with AIH attended to in eight acute-care hospitals between 1994 and 2003. New patients diagnosed with AIH during year 2003 were evaluated prospectively. Data from patients currently attending follow-up visits and diagnosed before 2003 were collected retrospectively. RESULTS: a total of 94% of patients were females. Forty-three percent were asymptomatic, 27% had acute hepatitis, and 30% had chronic hepatitis. Type 1 AIH was diagnosed in 90% of cases. Type 2 AIH was more frequent in younger patients, and presented with an acute pattern. One third of patients had cirrhosis at onset. Patients with cirrhosis were older than 60 years more frequently. Immunosuppressants were given to 57 patients, with complete or partial remission in 87.7%. There were no significant differences in response to immunosuppression according to presentation pattern or AIH subtype. CONCLUSIONS: AIH in Valencia was predominantly diagnosed in asymptomatic women. Most cases were type 1, and in 25% of patients another autoimmune disease coexisted. At the time of diagnosis one third of patients had cirrhosis, particularly those over 60 years.

Anionic selectivity sequence of the Cl(-)-H+ symporter in the synaptosomal preparation from rat brain cortex.

The Na(+)/H(+) exchanger has been the only unequivocally demonstrated H(+)-transport mechanism in the synaptosomal preparation. We had previously suggested that a Cl(-)-H(+) symporter (in its acidifying mode) is involved in cytosolic pH regulation in the synaptosomal preparation. Supporting this suggestion, we now show that: (1) when synaptosomes are transferred from PSS to either gluconate or sulfate solutions, the Fura-2 ratio remains stable instead of increasing as it does in 50 mM K solution. This indicates that these anions do not promote a plasma membrane depolarization. (2) Based in the recovery rate from the cytosolic alkalinization, the anionic selectivity of the Cl(-)-H(+) symporter is NO(3)(-) > Br(-) > Cl(-) >> I(-) = isethionate = sulfate = methanesulfonate = gluconate. (3) PCMB 10 muM inhibits the gluconate-dependent alkalinization by 30 +/- 6%. (4) Neither Niflumic acid, 9AC, Bumetanide nor CCCP inhibits the recovery from the cytosolic alkalinization.

Three-yr follow-up of a type 1 diabetes mellitus patient with an islet xenotransplant.

In order to alleviate the shortage of human donors, the use of porcine islets of Langerhans for xenotransplantation in diabetic patients has been proposed as a solution. To overcome rejection, we have developed a procedure for protecting the islets by combining them with Sertoli cells and placing them in a novel subcutaneous device, that generates an autologous collagen covering. A type 1 diabetic woman was closely monitored for 10 months, and then transplanted in two devices with two months of difference and a third time after 22 months. Here we present a three-yr follow-up. The close monitoring induced a rapid decrease in exogenous insulin requirements, which stabilized between 19 and 28 IU/d for nine months. After transplantation, the requirements reduced further to below 6 IU/d and for some weeks she was insulin free. Glycosylated hemoglobin levels decreased concomitantly. Porcine insulin could be detected in the serum after a glucose challenge and insulin positive cells inside a removed device after two yr. No complications have arisen and no porcine endogenous retrovirus infection has been detected through PCR and RT-PCR. This case demonstrates the feasibility of using the xenotransplantation of porcine cells to alleviate metabolic complications and insulin requirements in type 1 diabetic patients.

The decay accelerating factor mutation I197V found in hemolytic uraemic syndrome does not impair complement regulation.

Hemolytic uremic syndrome is the clinical triad of thrombocytopenia, microangiopathic hemolytic anaemia and acute renal failure. Cases not associated with a preceding Shiga-like toxin producing Escherichia coli are described as atypical HUS (aHUS). Approximately 50% of patients with aHUS have mutations in one of three complement regulatory proteins, Factor H (CFH), membrane cofactor protein (MCP;CD46) or factor I (IF). A common feature of these three proteins is that they regulate complement by cofactor activity. Decay accelerating factor (DAF; CD55) regulates the complement system by disassociating the alternative and classical pathway convertases. Like CFH and MCP, the gene for DAF lies within the regulators of complement activation (RCA) gene cluster at 1q32. In 1998, we described linkage to this region in families with aHUS which led to the discovery of mutations in CFH and MCP. We therefore genotyped DAF in a panel of 46 aHUS patients including families with linkage to the RCA cluster. A mutation, I197V, was identified in one patient with familial HUS which was not found in 100 healthy controls. Molecular modelling of this mutation shows that the I197V mutation does not reside in an area which would be predicted to be important in decay accelerating activity. The expression of I197V on EBV-transformed B lymphocytes was equivalent to that of wild type controls. There was no significant decrease in decay acceleration activity of the recombinantly produced I197V mutant compared with wild type, as measured by a complement-mediated lytic assay. In conclusion, this study, identifies only one mutation in DAF in 46 patients with aHUS. This mutation, I197V, does not impair complement regulation and cannot be implicated in the pathogenesis of aHUS in this patient. This suggests that the complement regulatory abnormality in aHUS is principally one of deficient cofactor activity rather than of decay acceleration activity.

[Disassociation between agrammatic and anomic patients in their production of verb forms]. / Disociación entre pacientes agramáticos y anómicos en la producción de formas verbales.

INTRODUCTION: Electrophysiological and neuroimaging studies suggest that regular and irregular verbs are differently represented in the brain. Findings from studies of patients seem to agree with this view, but there are discordant data. AIM: To test if there is a dissociation in regular and irregular verb processing between patients with anterior lesions, characterized as Broca's aphasics, and patients with posterior lesions, characterized as anomics. PATIENTS AND METHODS: 10 aphasic patients participated in the study: five presenting evidence of Broca's aphasia and five presenting evidence of anomia. The task required patients to complete 58 sentences with a verb conjugated in the past tense form. 29 sentences required an irregular verb and 29 required a regular verb. RESULTS: Statistical analyses indicate a main effect due to differences between the different types of patients, and an interaction between this effect of patient type and the effect of verb type. The interaction was due to the fact that anomic patients had more difficulty in completing sentences using irregular verbs. CONCLUSIONS: The results of this study support a dual route model, which assumes that regular verbs are processed by application of morphological rules whereas irregular verbs are processed through the addressed recovery of conjugated forms.

Euchromatic variant 16p+. Implications in prenatal diagnosis.

BACKGROUND: Euchromatic imbalances at the cytogenetic level are usually associated with phenotypic consequences. Among the exceptions are euchromatic variants of chromosome 16 (16p+) with normal phenotype. There is a growing list of euchromatic duplications and deletions involving both G-positive and G-negative bands that seem to be phenotypically neutral, but these euchromatic variants are rare. OBJECTIVE: The aim of this report is to describe a new familial case of euchromatic variant 16p+ and to emphasise the misinterpretation of these rare euchromatic variants particularly when ascertained at prenatal diagnosis. METHODS AND RESULTS: Fluorescence in situ hybridisation with clone RP11-261A7 showed an amplified signal in the larger chromosome 16. This clone contains FLJ43855 gene, similar to sodium- and chloride-dependent creatine transporter. CONCLUSION: So, this 16p+ variant that involves amplification of pseudogenetic sequences is considered a polymorphism in normal individuals.

Comparative study of three diagnostic approaches (FISH, STRs and MLPA) in 30 patients with 22q11.2 deletion syndrome.

The 22q11.2 deletion syndrome is commonly diagnosed using fluorescence in situ hybridization (FISH) with commercial probes. The chromosomal breakpoints and deletion size are subsequently characterized by short tandem repeat (STR) segregation tests or by further FISH probes. Recently, a multiplex ligation-dependent probe amplification (MLPA) single tube assay was developed to detect deletions of the 22q11.2 region and other chromosomal regions associated with DiGeorge/velocardiofacial syndrome. We have compared the results of these three techniques in a group of 30 patients affected with 22q11.2 deletion syndrome. MLPA correctly called all patients who had been previously diagnosed by FISH. The MLPA results were concordant in all patients with the STR analysis in respect to deletion size. Furthermore, this novel technique resolved seven cases that were undetermined by STR analysis. These results confirm the efficiency of MLPA as a rapid, reliable, economical, high-throughput method for the diagnosis of 22q11.2 deletion syndrome.

Clinical evaluation of drug-induced hepatitis.

OBJECTIVE: To ascertain the epidemiological characteristics, clinical symptoms, and evolution of drug-induced hepatitis over the last 22 years. EXPERIMENTAL DESIGN AND SUBJECTS: An observational, retrospective study between 1982 and 1993, and prospective study between 1994 and 2003. All patients in our department diagnosed with having drug-induced hepatitis were studied analyzing epidemiological (age, sex, cases per year, hospitalization) and clinical features (previous liver disease, hepatic symptoms, laboratory results), and follow-up (complete recovery or chronicity). RESULTS: A total of 61 patients were diagnosed as having drug-induced hepatitis, 26 men and 35 women (57%), mean age 52.4 years +/- 17 years, of which 72.2% were older than 40 years. A total of 43% were admitted to hospital. In 87% of cases, two or more drugs were involved, the most frequent being antituberculosis (19 cases), psychotropic (26 cases), and non-steroidal anti-inflammatory drugs (45 cases). Evolution showed that 94% of patients recovered after the withdrawal of suspected causal drugs. CONCLUSIONS: The incidence of drug-induced hepatitis is higher in patients over 40 years of age, it being more common in females. Non-steroidal anti-inflammatory, psychotropic, and anti-tuberculosis agents were the main drugs involved. Most patients made a complete recovery after withdrawal of the suspected causal drug.

Genetic basis of erythromycin resistance in oral bacteria.

We determined the prevalence of erythromycin-resistant bacteria in the oral cavity and identified mef and erm(B) as the most common resistance determinants. In addition, we demonstrate the genetic linkage, on various Tn1545-like conjugative transposons, between erythromycin and tetracycline resistance in a number of isolates.

Pharmacokinetics of a new Autogel formulation of the somatostatin analogue lanreotide after a single subcutaneous dose in healthy volunteers.

The pharmacokinetics/tolerability of lanreotide Autogel have been evaluated. Healthy volunteers (n = 24) first received immediate-release lanreotide as a single subcutaneous (s.c.) injection. After two days, 40 or 60 mg lanreotide Autogel was injected subcutaneously. Blood was sampled at various intervals for 56 days. Systemic/local adverse events and changes in biological profile/vital signs were recorded. Lanreotide Autogel produced a prolonged-release pharmacokinetic profile: mean area under the serum concentration-time curve from time 0 to infinity (AUC) was 53.73 +/- 8.99 and 79.48 +/- 13.06 ng mL(-1) day for 40 and 60 mg, respectively, mean peak serum concentration (C(max)) was 4.38 +/- 2.91 and 5.71 +/- 3.52 ng mL(-1), respectively, median time to reach C (minimum-maximum) was 0.50 (0.083-18.0) and 0.38 (0.083-9.01) days, respectively, mean apparent elimination half-life was 21.63 +/- 9.42 and 22.01 +/- 9.87 days, respectively, and relative bioavailability was 0.93 +/- 0.12 and 0.82 +/- 0.15, respectively. Thus, lanreotide Autogel exhibited linear pharmacokinetics for the doses studied. Pharmacokinetic profiles were similar in both genders, apart from statistically significant differences in C(max) and C(max)/AUC. The Autogel formulation of lanreotide was well tolerated, with systemic adverse events being mild/moderate. Erythema and a painless subcutaneous induration were the most common local adverse events. Lanreotide Autogel provided a prolonged dosing interval and good tolerability for treating acromegaly and carcinoid syndrome.

Self-association process of a peptide in solution: from beta-sheet filaments to large embedded nanotubes.

Lanreotide is a synthetic octapeptide used in the therapy against acromegaly. When mixed with pure water at 10% (w/w), Lanreotide (acetate salt) forms liquid crystalline and monodisperse nanotubes with a radius of 120 A. The molecular and supramolecular organization of these structures has been determined in a previous work as relying on the lateral association of 26 beta-sheet filaments made of peptide noncovalent dimers, the basic building blocks. The work presented here has been devoted to the corresponding self-association mechanisms, through the characterization of the Lanreotide structures formed in water, as a function of peptide (acetate salt) concentration (from 2% to 70% (w/w)) and temperature (from 15 degrees C to 70 degrees C). The corresponding states of water were also identified and quantified from the thermal behavior of water in the Lanreotide mixtures. At room temperature and below 3% (w/w) Lanreotide acetate in water, soluble aggregates were detected. From 3% to 20% (w/w) long individual and monodisperse nanotubes crystallized in a hexagonal lattice were evidenced. Their molecular and supramolecular organizations are identical to the ones characterized for the 10% (w/w) sample. Heating induces the dissolution of the nanotubes into soluble aggregates of the same structural characteristics as the room temperature ones. The solubilization temperature increases from 20 degrees C to 70 degrees C with the peptide concentration and reaches a plateau between 15% and 25% (w/w) in peptide. These aggregates are proposed to be the beta-sheet filaments that self-associate to build the walls of the nanotubes. Above 20% (w/w) of Lanreotide acetate in water, polydisperse embedded nanotubes are formed and the hexagonal lattice is lost. These embedded nanotubes exhibit the same molecular and supramolecular organizations as the individual monodisperse nanotubes formed at lower peptide concentration. The embedded nanotubes do not melt in the range of temperature studied indicating a higher thermodynamic stability than individual nanotubes. In parallel, the thermal behaviors of water in mixtures containing 2-80% (w/w) in peptide have been studied by differential scanning calorimetry, and three different types of water were characterized: 1), bulk water melting at 0 degrees C, 2), nonfreezing water, and 3), interfacial water melting below 0 degrees C. The domains of existence and coexistence of these different water states are related to the different Lanreotide supramolecular structures. All these results were compiled into a binary Lanreotide-water phase diagram and allowed to propose a self-association mechanism of Lanreotide filaments into monodisperse individual nanotubes and embedded nanotubes.