Safety and efficacy of quavonlimab, a novel anti-CTLA-4 antibody (MK-1308), in combination with pembrolizumab in first-line advanced non-small-cell lung cancer.

BACKGROUND: Quavonlimab (MK-1308), a novel anti-CTLA-4 antibody, in combination with pembrolizumab was investigated in a phase I study. PATIENTS AND METHODS: Dose-escalation (DE) phase: patients with advanced/metastatic solid tumors received an initial flat dose of quavonlimab as monotherapy [25 mg (cohort 1), 75 mg (cohort 2), or 200 mg (cohort 3)] followed by four treatments of the same quavonlimab dose plus pembrolizumab every 3 weeks (Q3W). Dose-confirmation phase (DC): patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) received first-line quavonlimab [25 mg Q3W (arm A), 25 mg Q6W (arm B), 75 mg Q6W (arm C), or 75 mg Q3W (arm E)] plus pembrolizumab. Primary objectives were safety and tolerability and establishment of the recommended phase II dose (RP2D) of quavonlimab when used with pembrolizumab. Objective response rate (ORR) was a secondary endpoint. Efficacy based on PD-L1 expression, tumor mutational burden (TMB), and changes in circulating CD4+/CD8+ cells were exploratory endpoints. RESULTS: Thirty-nine patients were enrolled in DE [n = 14 (cohort 1); n = 17 (cohort 2); n = 8 (cohort 3)] and 134 in DC [n = 40 (arm A); n = 40 (arm B); n = 40 (arm C); n = 14 (arm E)]. Maximum-tolerated dose was not reached. Grade 3-5 treatment-related adverse events (AEs; graded according to NCI CTCAE v4.03) occurred in 0%, 23.5%, and 75.0% of patients in DE cohorts 1, 2, and 3, respectively, and 35.0%, 30.0%, 35.0%, and 57.1% of patients in DC arms A, B, C, and E, respectively. Efficacy was observed at all dose levels/schedules in patients with NSCLC. ORRs were 40.0% [95% confidence interval (CI), 24.9-56.7; arm A], 37.5% (95% CI, 22.7-54.2; arm B), 27.5% (95% CI, 14.6-43.9; arm C), and 35.7% (95% CI, 12.8-64.9; arm E). PD-L1 expression and total number of circulating CD4+ cells correlated with ORR. CONCLUSIONS: Quavonlimab 25 mg Q6W plus pembrolizumab demonstrated similar efficacy and a better safety profile among all quavonlimab doses/schedules evaluated; this regimen was the chosen RP2D.

Establishing in vitro to clinical correlations in the evaluation of cardiovascular safety pharmacology.

Preclinical studies are vital in establishing the efficacy and safety of a new chemical entity (NCE) in humans. To deliver meaningful information, experiments have to be well defined and provide outcome that is relevant and translatable to humans. This review briefly surveys the various preclinical experiments that are frequently conducted to assess drug effects on cardiac conductivity in early drug development. We examine the different approaches used to establish correlations between non-clinical and clinical settings and discuss their value in the evaluation of cardiovascular risk.

Time of physical exercise practice after injury in cervical spinal cord-injured men is related to the increase in insulin sensitivity.

OBJECTIVES: Physical exercise has an important role in reducing body fat, risk of chronic disease and systemic inflammation. The aim of this study was to determine serum leptin and insulin concentrations and their relationship to the time of physical exercise after injury in men with cervical spinal cord injury (c-SCI). METHODS: c-SCI subjects with lesion level in C5-C7 (n=25) were divided into two groups: physically active (PA, n=13; those who practiced physical exercise for at least 3 months, three times per week or more, for a total minimum of 150 min of physical activity per week) and non-physically active (N-PA, n=9). Body composition was assessed by dual energy X-ray absorptiometry. Blood samples were obtained 12 h after an overnight fast to measure insulin and leptin in serum, and glucose and C-reactive protein (CRP) in plasma, by validated methods. RESULTS: Comparing the PA and N-PA group, the first presented lower: total body mass (-13%), body mass index (-16%), fat mass (kg -39%, FM% -30%), CRP (-23%), serum insulin (-61%), homeostasis model assessment (HOMA, -35%) and serum leptin (-62%; P<0.05). Both serum insulin (r=-0.561; P<0.05) and HOMA (r=-0.591; P<005) were inversely proportional to the time of practice of physical activity after injury. CONCLUSION: Our results suggest that exercise was able to reduce fat mass and increase insulin sensitivity, decreasing plasma levels of risk factors in c-SCI subjects.

[Prevalence of ano-rectal pathology in HIV/AIDS patients]. / Prevalencia de patología ano-rectal en pacientes portadores de VIH/SIDA.

INTRODUCTION: The ano-rectal pathology (ARP) is the most common surgical condition in patients with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). Our aim was to determine the current prevalence and clinical characteristics of the ARP in patients with HIV/AIDS in clinical control in the infectious diseases unit of the Hernán Henríquez Aravena Hospital in Temuco. STUDY DESIGN: Cross section. Location and period: Infectious Diseases Unit of the hospital during the month of June 2010. INCLUSION CRITERIA: Patients with HIV/AIDS under control in the unit, medical records were analyzed and complete physical examination was performed. RESULTS: In the period of study 384 patients were in control in the unit. Fifty had ARP which is a prevalence of 13%. Anal condyloma disease and hemorrhoidal disease were the most common diseases. Most patients (76%) were on antiretroviral therapy with good clinical response. CONCLUSION: The prevalence of ARP in HIV/AIDS patient has increased in recent years. This study shows a change in the pattern of presentation, being anal condyloma the most common ARP.

Prevalencia de patología ano-rectal en pacientes portadores de VIH/SIDA / Prevalence of ano-rectal pathology in HIV/AIDS patients

Introduction: The ano-rectal pathology (ARP) is the most common surgical condition in patients with human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). Our aim was to determine the current prevalence and clinical characteristics of the ARP in patients with HIV/AIDS in clinical control in the infectious diseases unit of the Hernán Henríquez Aravena Hospital in Temuco. Patients and Method: Study design: Cross section. Location and period: Infectious Diseases Unit of the hospital during the month of June 2010. Inclusion criteria: Patients with HIV/AIDS under control in the unit, medical records were analyzed and complete physical examination was performed. Results: In the period of study 384 patients were in control in the unit. Fifty had ARP which is a prevalence of 13%. Anal condyloma disease and hemorrhoidal disease were the most common diseases. Most patients (76%) were on antiretroviral therapy with good clinical response. Conclusion: The prevalence of ARP in HIV/AIDS patient has increased in recent years. This study shows a change in the pattern of presentation, being anal condyloma the most common ARP.

Introducción: La patología ano-rectal (PAR) es la afección quirúrgica más frecuente en pacientes portadores del virus de la inmunodeficiencia adquirida (VIH) y del síndrome de la inmunodeficiencia adquirida (SIDA). Nuestro objetivo fue determinar la prevalencia actual y las características clínicas de la PAR en pacientes portadores de VIH/SIDA en control clínico en la unidad de infectología del Hospital Doctor Hernán Henríquez Aravena de Temuco. Materiales y Método: Diseño de estudio: Corte transversal. Lugar y período: Unidad de Infectología del Hospital Doctor Hernán Henríquez Aravena de Temuco durante el mes de junio de 2010. Criterios de inclusión: Pacientes portadores de VIH-SIDA en control en la unidad, se analizó su historial clínico y se realizó un examen físico completo. Resultados: Durante el período 384 pacientes se encontraban en control en la unidad. Cincuenta presentaron PAR lo que constituye una prevalencia del 13%. La condilomatosis anal y la enfermedad hemorroidal fueron las patologías más frecuentes. La mayoría de los pacientes (76%) se encontraban en terapia anti-retroviral y con buena respuesta clínica. Conclusión: La prevalencia de patología ano-rectal en pacientes portadores de VIH/ SIDA se ha incrementado en los últimos años. Se aprecia un cambio en las características clínicas de presentación, siendo la condilomatosis anal la PAR más frecuente.

Assessing the probability of drug-induced QTc-interval prolongation during clinical drug development.

Early in the course of clinical development of new non-antiarrhythmic drugs, it is important to assess the propensity of these drugs to prolong the QT/QTc-interval. The current regulatory guidelines suggest using the largest time-matched mean difference between drug and placebo (baseline-adjusted) groups over the sampling interval, thereby neglecting any potential exposure-effect relationship and nonlinearity in the underlying physiological fluctuation in QT values. Thus far, most of the attempted models for characterizing drug-induced QTc-interval prolongation have disregarded the possibility of model parameterization in terms of drug-specific and system-specific properties. Using a database consisting of three compounds with known dromotropic activity, we built a bayesian hierarchical pharmacodynamic (PD) model to describe QT interval, encompassing an individual correction factor for heart rate, an oscillatory component describing the circadian variation, and a truncated maximum-effect model to account for drug effect. The explicit description of the exposure-effect relationship, incorporating various sources of variability, offers advantages over the standard regulatory approach.

Neurosífilis en pacientes portadores y no portadores de VIH: descripción y comparación de dos cohortes históricas / Neurosyphilis in the patients with and without HIV infection: description and comparison of two historical cohorts

Neurosyphilis follows a more aggressive and different clinical course in HIV-infected patients compared to patients with normal immunity. Two historical series of patients with a diagnosis of neurosyphilis between 1995 and 2008 were compared: they included a group of 15 patients with y and 28 patients without HIV infection. Probability of neurosyphilis in patients with positive serum VDRL was increased in patients infected with HIV comparedto HIV negative patients (OR: 62.37 IC:95 percent (32.1-119.1) p value:< 0,001). Predominant clinical manifestations in neurosyphilis in the HIV negative group were ocular abnormality, vascular encephalic and spinal cord lesions. In the HIV positive group, they were fever, ocular abnormalities and headache. There were no differences in cerebrospinal fluid characteristics between both groups. Neurosyphilis was diagnosed even in patients with blood VDRL of < 1:32, that happened in 17.8 percent of the HIV positive patients with blood and in 60 percent of t he HIV negative patients. Penicillin sodium given at dose ¡Ý than 18.000.000 IU/day IV during 14 days was the most common treatment. In patients with clinical neurosyphilis, 93 percent of HIV negative group, and 54.2 percent of HIV positive group had persistent neurological after-effects. Three HIV positive patients died due to causes not related to neurosyphilis.

Population pharmacokinetic modelling of the enterohepatic recirculation of diclofenac and rofecoxib in rats.

BACKGROUND AND PURPOSE: Enterohepatic recirculation (EHC) is a common pharmacokinetic phenomenon that has been poorly modelled in animals. The presence of EHC leads to the appearance of multiple peaks in the concentration-time profile and increased exposure, which may have implications for drug effect and extrapolation across species. The aim of this investigation was to develop a population pharmacokinetic model for diclofenac and rofecoxib that describes EHC and to assess its consequence for the pharmacodynamics of both drugs. EXPERIMENTAL APPROACH: The pharmacokinetics of diclofenac and rofecoxib was characterized in male rats following intravenous, intraperitoneal and oral administration. Blood samples were collected at pre-defined time points after dosing to determine plasma concentrations over time. A parametric approach using nonlinear mixed effects modelling was applied to describe EHC, whilst simulations were used to evaluate its impact on PGE(2) inhibition. KEY RESULTS: For diclofenac, EHC was described by a compartmental model with periodic transfer rate and metabolite formation rate. For rofecoxib, EHC modelling required a conversion compartment with first-order recycling rate and lag time. Based on model predictions, EHC causes an increase of 95% in the systemic exposure to diclofenac and of 15% in the exposure to rofecoxib. In addition, EHC prolongs the inhibition of PGE(2) and increases the duration of the anti-inflammatory effect (24 h for rofecoxib 10 mg kg(-1)) without affecting maximum inhibition. CONCLUSIONS AND IMPLICATIONS: Our findings show the relevance of exploring EHC in a quantitative manner to accurately interpret pharmacodynamic findings in vivo, in particular when scaling across species.

Beta-cell tropin- and glucose-induced hypersecretion of insulin and amylin from perfused fatty rat pancreas.

The neurointermediate pituitary peptide beta-cell tropin (BCT) has potent insulin-releasing and lipogenic properties and is elevated in obesity and type-2 diabetes. The effects of BCT and glucose on the release of insulin and amylin from the perfused pancreas of obese 'fatty' (fa/fa) rats and lean (Fa/?) controls were measured. Pancreata were perfused, sequentially, with buffer containing: 5.6 mmol glucose/l (basal); basal glucose +/- 0.5 nmol BCT/l; 16.7 mmol glucose/l (high). Insulin and amylin release during basal glucose treatment was eight to nine times greater from pancreata from fatty than from lean rats. BCT induced a fivefold greater monophasic insulin and amylin release from fatty compared with lean pancreata. When not preceded by BCT there was a twofold greater high glucose-induced amylin release from fatty pancreata but no difference in insulin secretion. When preceded by BCT stimulation, high glucose induced twofold greater insulin and fourfold larger amylin release from fatty compared with lean pancreata. Molar secretion ratios of insulin:amylin varied between 30:1 and 50:1. In view of the elevated levels of BCT found in the fatty rat and in the light of the above findings, it is concluded that the peptide may have a role in the development of hyperinsulinaemia, hyperamylinaemia and insulin resistance in this animal model of obesity and diabetes.

Elevated plasma concentrations of beta-cell tropin (ACTH22-39) in diet-treated type II diabetic patients.

beta-Cell tropin, the pituitary peptide ACTH22-39, is a potent insulin secretagogue and stimulates lipogenesis in adipose tissue in rodents. Plasma beta-cell tropin was measured fasting and after glucose infusion (5 mg.kg glucose ideal body weight-1.min0-1 for 90 min) in 10 mild diet-treated non-insulin-dependent (type II) diabetic subjects and 10 control subjects (body mass index) (BMI): 26.4 +/- 3.2 and 24.1 +/- 2.0 kg/m-2, NS, fasting plasma glucose 7.8 +/- 2.7 mM and 4.7 +/- 0.3 mM, respectively). The diabetic subjects had raised fasting plasma beta-cell tropin compared with the normal subjects (geometric mean (1 SD range): 0.49 (0.25-0.96) nM and 0.17 (0.10-0.28) nM, respectively, P = 0.007). In response to the glucose infusion, plasma glucose rose higher in the diabetic subjects (mean +/- 1 SD: 13.7 +/- 3.1 and 9.6 +/- 0.9 mM, P = 0.007) and plasma insulin was impaired in the diabetic compared with the nondiabetic subjects (geometric mean (1 SD range): 14 (8-26) and 34 (18-63), P less than 0.01). beta-Cell tropin concentrations in the diabetic subjects rose to 1.31 (0.74-2.30) nM (P = 0.007), whereas beta-cell tropin did not change in the normal subjects at 0.19 (0.11-0.91) nM. There was no overlap between glucose-stimulated plasma beta-cell tropin in the two groups (P = 0.0002). Pituitary-adrenal function, as assessed by plasma cortisol, did not differ between the two groups when fasting and did not change after the glucose infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlation between plasma beta-cell tropin concentrations and body weight in obese rhesus monkeys.

The fasting plasma concentration of the pituitary peptide beta-cell tropin [beta-CT, adrenocorticotropic hormone-(22-39)] was measured in 17 rhesus monkeys from a colony known to develop spontaneous obesity. The weight of the animals was 9.4-23.9 kg (12-46% body fat). Plasma beta-CT concentrations were 0.03-0.84 nmol/l and were strongly correlated with body weight (P = 0.014, r = 0.584). Plasma beta-CT was also correlated with plasma insulin concentration as a power function (P = 0.011, r = 0.600) and with percent body fat up to 40% (P = 0.003, r = 0.0804). Plasma insulin is also correlated with body weight (P = 0.015, r = 0.578) but does not decline when body fat is in excess of 40%, supporting the hypothesis that beta-CT may be involved in a feed-back control mechanism, perhaps mediated by insulin. Because beta-CT has been shown in rodent studies to be a potent insulin secretagogue and lipogenic agent, it is possible that beta-CT is causally involved in the development of obesity and that there may be central determinants of obesity mediated through pituitary secretion of beta-CT.

The effects of insulin and the pituitary peptide beta-cell tropin on the incorporation of D-3-3H-glucose into lipid in brown adipocytes from lactating and non-lactating rats.

Lactating and non-lactating rat brown adipocytes were used to study the dose-dependent stimulation of lipogenesis by Beta-cell tropin (BCT) and insulin. In non-lactating animals BCT increased lipogenesis approximately 2-fold compared to a 3-fold stimulation with insulin; however BCT was effective at a substantially lower molar concentration than insulin. In lactating animals resistance was observed to both BCT and insulin action.

Splicing of the Drosophila P element ORF2-ORF3 intron is inhibited in a human cell extract.

P element transposition in Drosophila melanogaster is regulated by germline-specific splicing of the P element ORF2-ORF3 intron. This regulation has been shown to depend on a cis-acting sequence located in the exon 12-31 bases from the 5' splice site. Mutations within this sequence disrupt the regulation and result in splicing of the ORF2-ORF3 intron in all tissues, indicating that the sequence is required to inhibit splicing of this intron in the soma. We now show that a trans-acting factor in a human (HeLa) cell extract can inhibit splicing of the intron, suggesting that this regulatory mechanism is conserved from flies to humans.

Identification of a cis-acting sequence required for germ line-specific splicing of the P element ORF2-ORF3 intron.

P element transposition in Drosophila melanogaster is limited to the germ line because the third intron (the ORF2-ORF3 intron) of the P element transcript is spliced only in germ line cells. We describe a systematic search for P element sequences that are required to regulate the splicing of the ORF2-ORF3 intron. We have identified three adjacent mutations that abolish the germ line specificity and allow splicing of this intron in all tissues. These mutations define a 20-base regulatory region located in the exon, 12 to 31 bases from the 5' splice site. Our data show that this cis-acting regulatory sequence is required to inhibit the splicing of the ORF2-ORF3 intron in somatic cells.

B-cell variant of mouse T200 (Ly-5): evidence for alternative mRNA splicing.

The complete cDNA sequence of mouse T200 glycoprotein from the pre-B-cell line 70Z/3 has been determined. The deduced protein sequence differs from that previously reported for a T-cell form of the molecule [Saga, Y., Tung, J.-S., Shen, F.-W. & Boyse, E. A. (1986) Proc. Natl. Acad. Sci. USA 83, 6940-6944] by the insertion of 139 amino acid residues in the amino-terminal region of the molecule. RNA transfer blotting using a cDNA probe encoding this sequence established that the predominant T200 mRNA species from B cells and cytotoxic T-cell clones but not T-helper cell clones or thymocytes contain all or part of the insert. Overlapping genomic clones of murine T200 were isolated and analysis of the intron-exon structure at the 5' end of the gene provides evidence that variants of T200 glycoprotein are generated by alternative mRNA splicing.

The effects of structural modifications on the insulin-releasing activity of beta-cell-tropin.

The minimal effective concentration of the pituitary insulin secretagogue beta-cell-tropin (beta-CT) on the in vitro perfused pancreas was established and the effects of various modifications of the peptide on its potency were tested: iodination with 127I and acetylation reduced the insulin-releasing activity of beta-cell-tropin, and the C-terminal fragments beta-CT-(2-18), beta-CT-(3-18) and beta-CT-(6-18) were all less potent than the intact molecule; beta-CT-(1-6) was not active and did not inhibit beta-CT-induced insulin release.

Sequence of rat liver alpha 2-macroglobulin and acute phase control of its messenger RNA.

Six alpha 2-macroglobulin cDNA clones were isolated from two liver cDNA libraries produced from rats undergoing acute inflammation. The coding sequence for rat alpha 2-macroglobulin including its 27-residue signal peptide and the 3' - and part of the 5' nontranslated regions were determined. The mature protein consisting of 1445 amino acids is coded for by a 4790 +/- 40 nucleotide messenger RNA. It contains a typical internal thiol ester region and 25 cysteine residues which are conserved between rat and human alpha 2-macroglobulin. Although the amino acid sequences of rat and human alpha 2-macroglobulin share 73% identity, two small divergent areas of 17 and 38 residues were found, corresponding to 29 and 11% identity, respectively. These areas are located in the bait region and, therefore, may confer specific proteinase recognition capabilities on rat alpha 2-macroglobulin. Following an inflammatory stimulation, rat alpha 2-macroglobulin mRNA levels increased 214-fold over control values and reached a maximum at 18 h. By 24 h the levels had decreased to less than 30% of the maximum value. Transcription rates from the alpha 2-macroglobulin gene as measured in nuclear run-on experiments showed a less than 3-fold increase in nuclei from acutely inflamed rats as compared to controls. These results suggest that the accummulation of alpha 2M mRNA is due to the combined effects of increased transcription rates and post-transcriptional processing.

Studies on insulin secretion and the pituitary insulin secretagogue beta-cell-tropin in the sand-rat (Psammomys obesus).

The sand-rat (Psammomys obesus) is an animal model for the study of human maturity onset diabetes which appears to be controlled by caloric intake. In the present investigations, these animals have been studied in relation to the influence of low- and high-energy diets on body weight, plasma insulin and blood glucose levels, and on insulin secretion from the perfused pancreas and the secretion of corticotropin-like intermediate lobe peptide (CLIP, ACTH18-39) and the insulin secretagogue beta-cell-tropin (beta-CT, ACTH22-39) from the pituitary neurointermediate lobe. The sand-rats maintained on the high-energy diet all became obese. Insulin secretion from the perfused pancreas of the obese sand-rat in the presence of 5.6 mM glucose was significantly higher than in the lean controls maintained on low-energy diets. Increasing the glucose concentration to 16.7 mM only produced a small stimulation of insulin secretion in the obese animals, and the difference between the two groups was not significant. Stimulation of insulin secretion by beta-CT was variable, but the obese animals appeared to be more responsive. Pituitary neurointermediate lobes were incubated for 4 h to measure the secretion of the ACTH related peptide. These were separated by gel filtration and the concentrations measured by radioimmunoassay with a CLIP antiserum and a CLIP standard. In all experiments beta-CT was 4-6 per cent of the total CLIP immunoreactive material. In these experiments the obese animals maintained on a high-energy diet were divided into two groups, those with plasma insulin levels less than 500 mu u/ml and those with insulin levels greater than 500 mu u/ml. The latter group had a significantly higher blood glucose level, presumably due to the insulin resistance resulting from the severe hyperinsulinaemia. It was also observed that CLIP-IRM and beta-CT secretion was lower in this group than in the animals maintained on low-energy diets or those on high-energy diets with moderate hyperinsulinaemia. This suggests a possible feedback inhibition by insulin on the secretion of beta-CT.

Evidence for the presence of the pituitary insulin secretagogue beta-cell trophin in human plasma.

It has been demonstrated that the insulin secretagogue beta-cell-trophin, ACTH(22-39), is present in human plasma. The hormone, separated from plasma by affinity chromatography on a corticotrophin-like intermediate-lobe peptide antibody column, behaves similarly to synthetic beta-cell-trophin on a gel filtration column and on reverse-phase high-performance liquid chromatography. Sufficient amounts of the hormone were isolated from the plasma of two patients with Nelson's syndrome to demonstrate its biological activity on the perfused rat pancreas.

Nucleotide sequence of cDNA encoding human alpha 2-macroglobulin and assignment of the chromosomal locus.

Six alpha 2-macroglobulin (alpha 2M) cDNA clones were isolated from a human liver cDNA library by using synthetic oligonucleotides as hybridization probes. One of these, p alpha 2M1, carries a 4.6 kilobase-pair insert, which was sequenced. The insert contains the coding sequences for the mature alpha 2M polypeptide (1451 amino acids) and for a 23-amino acid signal peptide at the NH2 terminus of the precursor pro-alpha 2M. At the 3' end of the insert a poly(A) addition signal A-A-T-A-A-A and part of the poly(A) tail of the messenger RNA were found. The protein sequence deduced from the nucleotide sequence agrees with the published alpha 2M amino acid sequence for all except three residues. The alpha 2M locus was assigned to human chromosome 12 by Southern blot analysis with DNA from a panel of mouse/human somatic cell hybrids, using alpha 2M cDNA as a hybridization probe.