Clinical pharmacology of anti-angiogenic drugs in oncology.

Abnormal vasculature proliferation is one of the so-called hallmarks of cancer. Angiogenesis inhibitor therapies are one of the major breakthroughs in cancer treatment in the last two decades. Two types of anti-angiogenics have been approved: monoclonal antibodies and derivatives, which are injected and target the extracellular part of a receptor, and protein kinase inhibitors, which are orally taken small molecules targeting the intra-cellular Adenosine Triphosphate -pocket of different kinases. They have become an important part of some tumors' treatment, both in monotherapy or in combination. In this review, we discuss the key pharmacological concepts and the major pitfalls of anti-angiogenic prescriptions. We also review the pharmacokinetic and pharmacodynamics profile of all approved anti-angiogenic protein kinase inhibitors and the potential role of surrogate markers and of therapeutic drug monitoring.

[Correlation between exposure to allergenic pollens and allergic manifestations].

Due to increase in allergic morbidity, better understanding of the relationships between environmental parameters and clinical responses of patients is needed. Serious analysis of such correlations requires examination of an entire population. So far there has been no study in Israel that examined an entire population in order to establish the distribution of inhalant allergens, the prevalence of skin hypersensitivity and allergic clinical morbidity. To examine these parameters we studied the population of Kibbutz Netzer Sereni, a rural community exposed to large amounts of various pollen allergens. Of the 505 members aged 4-70 years, 395 (78.2%) responded. Air sampling, once a month throughout the year, identified the most prevalent inhaled allergens and measured amounts. Allergic profiles were evaluated using prick tests with allergenic extracts, clinical questionnaires and medical records. The most prevalent allergenic pollens in the air were pecan, olive, cypress and palm trees, grasses and weeds such as English plantain, sagebrush, pigweed and lamb's quarters. Over 45% of 395 participants were atopic to 1 or more of the 27 allergenic extracts. The most prevalent causes of atopy were the house dust mite (28.9%), sagebrush (16.5%), grasses (18.2%), pecan (13.2%) and cypress (11.1%). Over 50% of atopic residents were symptomatic, while 22.9% of those non-atopic reported symptoms that could be attributed to allergy. This investigation provides solid data for the prevalence of atopy and allergy in the region of this kibbutz.

[Allergic responses to date palm and pecan pollen in Israel].

Date palm (Phoenix dactylifera) and pecan (Carya illinoensis) trees are commonly planted in Israel for fruit, for shade, or as ornamental plants. Pollen grains of both species are allergenic; however, the extent of exposure to such pollen and the incidence of allergic response have not been studied here. We therefore investigated skin-test responses to pollen extracts of 12 varieties of palm and 9 of pecan in 705 allergic patients living in 3 cities and 19 rural settlements. Sensitivity to the pollen extracts of both species was much higher among residents of rural than of urban communities. Moreover, there was a definite relationship between the abundance of these trees in a region and the incidence of skin responders to their pollen. Sensitivity was frequent in settlements rich in these 2 species, such as those with nearby commercial date or pecan plantations. In general, sensitivity to date pollen extracts was lower than to pecan. However, differences in skin responses to pollen extracts of various clones were substantiated. Air sampling revealed that pollen pollution decreased considerably with distance from the trees. At approximately 100 m from a source concentrations of airborne pollen were low. Since planting of male palm and pecan trees in population centers would increase pollen pollution, it should be avoided.

[Sensitization to pollens in a changing environment: Israel]. / La sensibilisation aux pollens dans un environnement changeant: Israël.

Israel was originally a country with desert climate and extensive agriculture. During the last 40 years, due to artificial irrigation, a rich vegetation and intensive agriculture have developed. Hayfever prevalence has risen between 1952 and 1986 from an average of 0.3% to 6.3% (with a range from 4% in the urban to 15% in the rural communities). Considering that significant (P less than 0.001) impact of pollen quantity upon hayfever incidence, an elementary pollen information system was organized (as described in the article) to help both allergists and allergic patients in their joint effort to avoid the harmful effect of a changing environment.

Clustering of allergenic pollen on the basis of skin responses of atopic patients by matrix analysis.

The responses of 148 atopic patients to some 43 different extracts of allergenic pollen were tested by prick tests. The measure of dissimilarity was introduced and calculated for all pairs of allergens. The investigated allergens were clustered into groups, according to their unbiased greatest similarity, by a matrix-structuring method. Results indicate that subgroups of allergens can be distinguished even within groups of closely related pollen allergens that were believed to be fully cross-reactive. A few cases are demonstrated for various varieties of olives, pecans, date palms, and turf grasses and for some wild chenopods and amaranths. The usefulness of the suggested solution for allergy research and for clinical practice is discussed.

Antigenicity of the pollen proteins of various cultivars of Olea europaea.

The incidence of positive skin test responses among atopic subjects with suspected respiratory allergy was investigated with commercial and autochthonous pollen extracts of various cultivars of Olea europaea. Pollen was collected from olive trees of well-defined cultivars, extracted, and separated by SDS-PAGE. Immunoblots were used to identify the various IgE-binding proteins of the pollen extracts of the various cultivars. The results revealed six predominant IgE-binding bands, some of which appear in all the cultivars examined. The 18-20-kDa band (Ole e 1) appeared in only eight of the cultivars, but not in the nine others. The presence of specific IgE-binding bands in the various pollen extracts and their correlation with the incidence of positive skin tests are discussed.

Forecasting pollen pollution: correlation with floral development.

Variations in the time course of flowering and in its intensity were recorded for regions in Israel along with variable climatic conditions. Such variations had an effect on pollen release into the air and on pollen counts. Two approaches for forecasting allergenic pollen dispersion were compared: (1) a survey of floral development and flowering intensity and (2) a survey of airborne pollen. There was a positive correlation between the survey of flowering and airborne pollen counts, although pollen was occasionally found after the flowering season. Further, it predicted fairly accurately the beginning of the flowering time of each species in each regio, the expected flowering duration, and intensity. Conducting a survey of flowering is a simple, easy and inexpensive operation. It is highly recommended for regions with variable climates.

Positive skin tests to fern spore extracts in atopic patients.

Thirty-six atopic and eight non-atopic adult volunteers who had been exposed to ferns in their homes, were skin tested with extracts obtained from seven species of house ferns. Out of the 36 atopic patients, 18 had positive skin reactions to at least one out of seven species of the most common house ferns, whereas none of the non-atopic, healthy controls had positive reactions to any of the ferns.

Positive skin tests to pollen extracts of four species of Pistacia in Israel.

Fifty-eight atopic and nine non-atopic volunteers, all residents of the Tel Aviv metropolitan area, Israel, were skin tested with extracts made from filtered pollen of Pistacia atlantica, P. lentiscus, P. palaestina and P. vera. Twenty-four out of the fifty-eight patients examined (41.4%) had positive skin reactions to at least one of the four examined species of Pistacia: seven of the patients reacted to all the examined extracts, whereas the other seventeen reacted to only some of them. Fifteen patients reacted to extracts of P. atlantica, sixteen patients reacted to extracts of P. lentiscus, ten patients reacted to extracts of P. palaestina and seven patients reacted to extracts of pollen of P. vera. None of the healthy, non-atopic volunteers reacted to any of the extracts. To the best of our knowledge, this is the first report of immunological reactions to pollen extracts of the genus Pistacia.

Podocarpus gracilior and Callitris verrucosa--newly identified allergens that crossreact with Cupressus sempervirens.

Thirty-six symptomatic patients, with positive skin reactions to Cupressus sempervirens pollen extract were skin-tested with pollen extracts of Podocarpus gracilior and Callitris verrucosa, of these 17 (47%) had positive responses to P. gracilior, nine (25%) to C. verrucosa, and six (17%) to both. None of the non-atopic healthy controls had positive reactions to either of the extracts. Radioallergosorbent test (RAST)-inhibition studies were performed with pooled sera from three patients. Fifty per cent inhibition was obtained with 11 micrograms protein of C. sempervirens, 54 micrograms of P. gracilior, and 71 micrograms of C. verrucosa; however, when pollen extract of Olea europaea, an unrelated allergen, was tested, 265 micrograms protein were needed to obtain 50% inhibition. One-dimension sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis of pollen extracts from the three species revealed that they had several very similar protein bands. Using Western blot analysis, several closely related IgE binding proteins were identified in the three species. It was concluded that the pollen grains of P. gracilior and of C. verrucosa are potentially allergenic. The presence of common allergenic proteins indicate partial crossreactivity with C. sempervirens.

Atrial natriuretic peptide induces acrosomal exocytosis in bovine spermatozoa.

The induction of acrosomal exocytosis in capacitated bull spermatozoa by atrial natriuretic peptide (ANP) was studied in vitro. ANP markedly stimulated acrosomal exocytosis in a calcium-dependent manner. Typically, ANP exerts its action via activation of the ANP receptor (ANPR-A), a particulate guanylyl cyclase-linked receptor, and subsequent formation of guanosine 3',5'-cyclic monophosphate (cGMP). We found that the ANP-induced acrosome reaction was inhibited by the competitive ANPR-A receptor antagonist-anantin, indicating a receptor-mediated effect. We could mimic the effect of ANP on the acrosome reaction by using 8-bromo-cGMP, suggesting that cGMP may serve as a signal transducer mediating the acrosome reaction. Indeed, the ANP-induced acrosome reaction was associated with elevation of cGMP levels. cGMP can also be formed by activation of the soluble form of guanylyl cyclase. Sodium nitroprusside (SNP) stimulated cGMP accumulation and acrosome reaction of capacitated spermatozoa. Thus ANP and the nitric oxide-releasing compound SNP, via activation of guanylyl cyclase (the former activating the particulate and the latter activating the soluble form of the enzyme), may play a significant role in the induction of the acrosome reaction.

Hypersensitivity to pollen of Olea europaea in Israel.

The incidence of skin-tested sensitivity to olive pollen allergens among subjects with suspected atopic respiratory allergy was investigated in various populations of Israelis. This incidence was correlated with the olive cultivars, with the abundance of trees in the patient's neighborhoods, and with the history of exposure of the studied populations to olive pollen. Positive skin reactions to olive pollen, among atopic patients of the Jewish population, is rather high where olive trees are abundant (66%), and lower (29%) where trees are scarce (P < 0.003). Sensitization was significantly lower (P < 0.003) among a population of Israeli atopic Arabs (16%), though these Arabs have lived in an olive-rich area for several generations.

Atrial natriuretic peptide induces acrosomal exocytosis of human spermatozoa.

Acrosomal exocytosis in mammalian spermatozoa is a process essential for fertilization. We report here that atrial natriuretic peptide (ANP) markedly stimulates acrosomal exocytosis of capacitated human spermatozoa. Typically, ANP exerts some of its actions via activation of the ANP receptor (ANPR-A), a particulate guanylyl cyclase-linked receptor, and subsequent formation of guanosine 3',5'-cyclic monophosphate (cGMP). We found that ANP-stimulated acrosome reaction was inhibited by the competitive ANPR-A antagonist anantin, indicating a receptor-mediated process. A linear fragment of ANP, ANP-(13-28), and another ANP-like compound, brain natriuretic peptide, were inactive. The stimulatory effect of ANP on acrosome reaction was mimicked by the permeable cGMP analog, 8-bromo-cGMP (8-BrcGMP). Addition of the protein kinase C (PKC) inhibitors, staurosporine and GF-109203X, resulted in a dose-related inhibition of ANP-induced acrosome reaction. Also, downregulation of endogeneous PKC activity resulted in inhibition of ANP- but not 8-BrcGMP-induced acrosome reaction. Removal of extracellular Ca2+ abolished ANP-induced acrosome reaction. Thus ANP via Ca2+ influx, PKC activation, and stimulation of particulate guanylyl cyclase may play a role in the induction of acrosome reaction of human spermatozoa.

The importance of the pecan tree pollen in allergic manifestations.

BACKGROUND: Pecan tree pollen is considered to be highly allergenic. However, no specific scientific data about its role in causing allergic diseases are available. OBJECTIVE: To study the role of pecan tree pollen in the development of allergy. METHODS: The presence of pecan tree pollen was determined by weekly and monthly counting of airborne grains. The incidence of pecan tree pollen atopy and clinical manifestations were studied in 395 participants, aged 4-70 years, who comprised 78.2% of the whole eligible population of a rural community. The participants were skin tested for different extracts of allergens, completed detailed questionnaires, and their medical files were evaluated. RESULTS: During May, pecan tree pollen grains comprised 70% of the total airborne grains. A positive skin-prick test (SPT) to pecan was shown by 46 (11.6%) participants, constituting 25.4% of the atopic population. Of those who were found atopic to one or more allergens 50.3% had symptoms, whereas the parallel figure for those atopic to pecan pollen was 76.1% (P < 0.005); 58.7% of the pecan atopic participants had hay fever, 43.5% had asthma, and 31.5% had both hay fever and asthma. Among pecan atopic participants the incidence of hay fever increased with age (P = 0.05), while the incidence of bronchial asthma, as a sole manifestation of allergy, decreased in the > 17-year-old age group (P < 0.01). Of the pecan atopics 65.2% had clinical symptoms coinciding only with the pecan pollen season and an additional 10.9% had perennial symptoms. CONCLUSION: Pecan tree releases highly allergenic pollen grains, which are correlated to the incidence of hay fever in the exposed population. The contribution of pecan tree pollen to the symptoms was highly significant after discounting olive and cypress trees that also pollinate in the spring. In children, the pecan tree constitutes a possible etiologic agent for the development of asthma.

Allergenicity of the pollen of Pistacia.

Differences in IgE binding and skin responses to pollen extracts of four species of Pistacia, and some immunochemical characteristics of this pollen were investigated. The incidence of positive SPT among atopic patients varied between 31.5% to the pollen extracts of P. vera and 24.6% to P. palaestina. The antigens are located on the exine of the grains as well as in their cytoplasm. Some of the antigens are common to all four species, whereas others seem to be specific. Cross-reactivity was found among the four species of Pistacia and between them and Schinus terebintifolious. Five conspicuous IgE-binding bands were observed in the immunoblots of the four examined species, the bands of 49, 57, 64, 68, and 79 kDa. The 36-37-kDa band of P. lentiscus and the 60- and 84-kDa bands of P. atlantica and P. vera were also noticeable. As the flowering seasons of Pistacia and Schinus do not overlap, the patients are exposed to such pollen for more than 4 months a year. Apparently, Pistacia pollen is a major source of allergy.