Therapeutic antibodies against CGRP or its receptor

CGRP is an extensively studied neuropeptide that has been implicated in the pathophysiology of migraine. While a number of small molecule antagonists against the CGRP receptor have demonstrated that targeting this pathway is a valid and effective way of treating migraine, off-target hepatoxicity and formulation issues have hampered the development for regulatory approval of any therapeutic in this class. The development of monoclonal antibodies to CGRP or its receptor as therapeutic agents has allowed this pathway to be re-investigated. Herein we review why CGRP is an ideal target for the prevention of migraine and describe four monoclonal antibodies against either CGRP or its receptor that are in clinical development for the treatment of both episodic and chronic migraine. We describe what has been publically disclosed about their clinical trials and future clinical development plans.     

Risk of venous thromboembolic disease associated with hormonal contraceptives and hormone replacement therapy: a clinical review

Venous thromboembolic events (VTEs) represent a serious complication related to hormonal contraception and hormone replacement therapy (HRT). Evidence on hormonal contraceptive- and HRT-related VTEs is derived almost exclusively from observational studies and points to a 2- to 6-fold increased relative risk of VTEs with either therapy. Oral contraceptive pills that contain third-generation progestins (desogestrel or gestodene) seem to be associated with greater VTE risk than those that contain levonorgestrel. Oral contraceptive pill use and HRT are associated with exponentially higher VTE relative risks when used by women who carry an inherited hypercoagulable state. The indication of a lower or a lack of VTE risk associated with the use of progestin-only contraceptives and with transdermal HRT suggests that these therapies may be safer than combination oral contraceptive pills and oral HRT for women in whom oral estrogen therapy is considered contraindicated. Data that support such safety advantages are limited and should be interpreted with caution.     

Survival of patients with malignant biliary stricture based on endoscopic brushing and on bilirubinemia

BACKGROUND: Pancreatic cancer and cholangiocarcinoma are the main causes of malignant biliary stricture. Both types of cancers have dismal survival rates, and treatment has little or no effect on prolonging the patients lives. Prognostic definition at initial endoscopic retrograde cholangiopancreatography is important to choose the most suitable management. AIM: To analyse endoscopic brushing and bilirubinemia importance in determination of the survival of patients with malignant biliary stricture. METHODS: Patients with biliary strictures diagnosed during endoscopic retrograde cholangiopancreatography were submitted to double brushing cytology. Serum samples were taken from all patients for bilirubinemia assay. Patients were followed to determine the final diagnosis and survival rates. RESULTS: A total of 50 patients with biliary stricture underwent endoscopic retrograde cholangiopancreatography (40 ultimately found to have a final diagnosis of malignant disease). Hyperbilirubinemia or cytology brushing positive for malignancy was related to a shorter survival rate. CONCLUSION: This research data demonstrate the possibility of determining the prognosis of patients with malignant biliary stricture using endoscopic brushing results and bilirubinemia levels.     

Chronic Chagas' disease in rhesus monkeys (Macaca mulatta): evaluation of parasitemia,serology, electrocardiography,echocardiography, and radiology

Severe chronic damage to the heart and gastrointestinal tract in patients with Chagas' disease are often observed 10-20 years after the acute phase. The course of long-lasting infection with the Colombian strain of Trypanosoma cruzi was studied in seven rhesus monkeys infected for 15-19 years. Subpatent parasitemia was detected in all studied animals, using hemoculture (two of seven), artificial xenodiagnosis (three of seven), and a polymerase chain reaction PCR (six of six). High titers of specific IgG antibody to T. cruzi persisted throughout the chronic phase of infection. Abnormal electrocardiographic (three of six) and echocardiographic (one of six) patterns detected in the T. cruzi-infected monkeys were possibly related to parasite-triggered myocardial damage. The results suggest that rhesus monkeys experimentally infected with T. cruzi, besides reproducing the acute phase of Chagas' disease, also develop chronic chagasic cardiomyopathy.     

Developmental changes of cardiac repolarization in rabbits: implications for the role of sex hormones

OBJECTIVES: Firstly, to compare gender-dependent differences of cardiac repolarization in both adult and young rabbits. Secondly, to analyze the effect of gonadectomy on these gender differences in cardiac repolarization. METHODS: We evaluated potential gender differences in cardiac repolarization with both microelectrode and ECG recordings. QT(end), JT(end), and T(peak-end) intervals and action potential durations at 30%, 50% and 90% of full repolarization were used to assess ventricular repolarization in adult (normal and gonadectomized) and young rabbits of both sexes. RESULTS: Adult rabbits exhibited clear gender-related differences in repolarization evidenced by significantly longer JT(end) and T(peak-end) intervals and significantly longer APD30, APD50 and APD90 in females. These gender-related differences in repolarization were absent in young rabbits and were abolished by gonadectomy. CONCLUSIONS: Developmental changes of repolarization are present in rabbits. These changes are in agreement with those reported in humans and may further support the role played by sex hormones in the modulation of cardiac repolarization.     

Experimental leptospirosis in marmoset monkeys (Callithrix jacchus): a new model for studies of severe pulmonary leptospirosis

Experimental infection of marmoset monkeys (Callithrix jacchus) with Leptospira interrogans serovar Copenhageni showed microscopic patterns of tissue reactions comparable to those seen in the severe forms of human leptospirosis, including intra-alveolar hemorrhage. The most impressive microscopic changes were seen in the lung and kidney of animals killed at days 6 and 12 after inoculation. There were extensive and irregular areas of hemorrhage predominating around main bronchial branches or diffusely spread to the pulmonary parenchyma, as well as severe tubulointerstitial nephritis. Antibody response detected by the microscopic agglutination test was quantitatively similar to those seen in humans and paralleled severity of tissue lesions. The distribution of leptospires or antigenic debris in infected tissues was observed by immunofluorescence and confocal laser scanning microscopy. Large numbers of typical leptospires were seen in the lumen of proximal renal tubules. Positive reactions showing antigenic debris were closely associated with sites of tissue damage.