Ro 21-7634, a new antiallergic agent with potent oral activity

Ro 21-7634 was examined for oral antiallergic activity in two in vivo models commonly used to evaluate anti-allergics. In the rat PCA test, this drug had an oral ID₅₀ of 1.14 mg/kg and was found to be more potent than several other antiallergics including Disodium Cromoglycate (cromoglycate), Oxatomide, Doxanthrazole, Xanoxate, 2,6-bis (ethoxyoxalylamino) pyridine, PRD-92-EA and M+B 22,948. In contrast to cromoglycate, Ro 21-7634 was found to be an orally active inhibitor of antigen-induced bronchoconstriction in passively sensitized rats (ID₅₀=0.2 mg/kg). In addition, Ro 21-7634 inhibited antigen-induced histamine release in an in vivo passive peritoneal anaphylaxis test system, following intraperitoneal administration. Ro 21-7634 demonstrated no end organ antagonism toward histamine, methacholine or serotonin in the guinea pig.     

In vitro studies on the mechanism of action of a new antiallergic,Ro 21-7634

The effects of Ro 21-7634 and disodium cromoglycate (cromoglycate) on the in vitro release of mediators of anaphylaxis from rat peritoneal cells and guinea pig lung tissue were compared. Ro 21-7634 was 25 fold more potent than cromoglycate as an inhibitor of antigen-induced histamine release from passively sensitized (IgE) rat peritoneal cells. Ro 21-7634 was also the more potent inhibitor of both compound 48/80- and concanavalin A-induced histamine release from rat peritoneal cells. The two drugs shared the common properties of producing the same maximal level of inhibition in each of the above releasing systems and exhibiting a time and concentration dependent loss of inhibitory activity when added to the cells prior to the releasing agent. Neither drug inhibited ionophore A23187- or ionophore X537A-induced histamine release from these cells. Ro 21-7634 inhibited antigen-induced (IgG₁) histamine and SRS-A release from actively sensitized guinea pig lung fragments, whereas cromoglycate did not. The results indicate that Ro 21-7634 and cromoglycate act through a common mechanism to inhibit allergic mediator release and that Ro 21-7634 is the more potent inhibitor.     

Rocastine (AHR-11325), a rapid acting,nonsedating antihistamine

Rocastine [AHR-11325, 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido-[3,2-f]-1,4-oxazepine-5(4H)-thione (E)-2-butenedioate)] is a rapid-acting, potent, nonsedating antihistamine. In guinea pigs challenged with a lethal dose of histamine, rocastine is as effective [based on 1 hr. oral, protective dose (PD₅₀s)] as brompheniramine, chlorpheniramine, pyrilamine, and promethazine and superior to astemizole, diphenhydramine, terfenadine, and oxaomide. Rocastine has a faster onset of action than does terfenadine; rocastine being as effective with a 15 min pretreatment time (PD₅₀=0.13 mg/kg) as it is with a 1 hr pretreatment time (PD₅₀=0.12 mg/kg), while the 15 min PD₅₀ of terfenadine (PD₅₀=44.0 mg/kg) is 22 times greater than the 1 hr PD₅₀ (PD₅₀=1.93 mg/kg). Against aerosolized histamine, rocastine was 7.12×, 2.63×, and equipotent to pyrilamine in preventing histamine-induced prostration at pretreatment times of 1, 3, and 6 hr, respectively. Rocastine protected guinea pigs from collapse induced by aerosolized antigen; rocastine was 36 × more potent (based on 1 hr PD₅₀) than diphenhydramine and as potent as oxatomide and terfenadine. Rocastine did not alter the EEG of cats at doses in vast excess (150×) of its antihistaminic dose nor did it potentiate yohimbine toxicity in mice. Further, rocastine possesses no anticholinergic, antiadrenergic, or antiserotonergic propertiesin vitro. Rocastine is a selective, nonsedating, H₁-antagonist with a rapid onset of action.     

Leukotriene antagonists and inhibitors as modulators of IgE-mediated reactions

Conclusions The biological activities of the leukotrienes and the fact that they are produced in elevated amounts in asthmatic subjects are consistent with their playing a role in IgE-mediated diseases. Clinical trials of results obtained with potent leukotriene D₄ receptor antagonists such as MK-571, MK-679 and ICI 204,219 are consistent with leukotriene D₄ receptor activation being a central feature of the disease. Such receptor antagonists will also be of use in defining the role of leukotriene D₄ receptor activation in other IgE-mediated human diseases such as allergic conjunctivitis and allergic rhinitis. The role of leukotriene B₄ in diseases mediated through IgE reactions remains to be defined. First generation leukotriene biosynthesis inhibitors such as Zileuton and MK-886 have not shown efficacy comparable to potent leukotriene D₄ receptor antagonists, consistent with the fact that they have not been fully effective at suppressing leukotriene production in man. It will clearly be of interest to test more potent leukotriene biosynthesis inhibitors such as ICI D2318 and MK-0591 in chronic IgE-mediated diseases and compare the results with those already obtained with leukotriene D₄ receptor antagonists.     

Inhibition of IgE-mediated allergic histamine release from rat peritoneal mast cells by azelastine and selected antiallergic drugs

The ability of azelastine to inhibit IgE-mediated allergic histamine release from the peritoneal mast cells of actively sensitized rats was investigated and compared with selected antiallergic agents. Azelastine added simultaneously with the allergic stimuli (ovalbumin, OA, 10 g/ml + phosphatidylserine, PS, 10 g/ml) or preincubated with cells for 10 min prior to antigen challenge produced similar concentration-dependent inhibition of allergic histamine release. The IC_50s (M) following 10-min preincubation were as follows: azelastine = 4.8; astemizole = 86.3; ketotifen = 112.2; diphenhydramine = 133 and theophylline = 2040.3. At IC₅₀ level azelastine was about 18, 23, 28 and 425 times as effective as astemizole, ketotifen (newer histamine H₁-receptor antagonists), diphenhydramine (a traditional H₁-receptor antagonist), and theophylline (a phosphodiesterase inhibitor), respectively. Sodium cromoglycate in a concentration range or 1–1000 M (0 or 10-min preincubation) failed to exert any inhibitory effect. These data showed that among six drugs tested azelastine is the most potent inhibitor of allergic histamine release from rat peritoneal mast cells.     

The characterization of lodoxamide,a very active inhibitor of mediator release,in animal and human models of asthma

A most active biologue of disodium cromoglycate (DSCG) available, lodoxamide tromethamine (LT), has been studied and characterized pharmacologically, in animal and human models of asthma. It has self-tachyphylaxis, but has oral activity (lodoxamide ethyl) in rats, primates, and man. In rats (LT) was 2,500× more active than DSCG (ID₅₀=0.001 mg/kg), in primates the drug was also active by several routes (inhalation 1 g/kg, IV 0.001 mg/kg, and oral 10 mg/kg). In isolated rat peritoneal mast cells, the compound displayed a biphasic dose response inhibition to histamine release initiated by (48/80, anti-IgE, and the calcium ionophore A23,187) with IC₅₀ values of 0.1–50 M. The consistent finding relating to its mode of action was its ability to inhibit⁴⁵calcium flux into the mast cell in response to antigen or A23,187.Clinical evaluations of lodoxamide tromethamine showed that at aerosol doses of 1.0 mg or less, it demonstrated significant inhibitory activity against antigen or exercise induced bronchospasm. However, in pilot evaluation studies in clinical asthma settings, the compound could not be shown to spare bronchodilator usage, relative to placebo, or be shown to be more effective than placebo treated patients based on other clinical endpoints. The reason for rat and primate models not being predictive for human long-term clinical asthma in the characterization of anti-release compounds is not known.     

A comparison of intranasal betamethasone valerate and sodium cromoglycate in seasonal allergic rhinitis

A double-blind comparison of betamethasone valerate and sodium cromoglycate both given by the nasal route was carried out in forty patients with seasonal rhinitis caused by grass pollen. All patients kept daily symptom score cards, and half of them measured both oral and nasal peak expiratory flow rates twice daily. Adrenal function was monitored in thirty-one patients and found to be normal throughout. Sixteen of those patients receiving the steroid aerosol recorded success and two failure of treatment. By contrast, of those receiving sodium cromoglycate there were only two treatment successes and twelve failures. The total symptom score recorded in the group receiving betamethasone valerate was about half that recorded by the sodium cromoglycate group (P<0.01). No difference was observed between the two treatments in respect of nasal peak flow rate; specific IgE blood levels and weal sizes following prick tests were not significantly altered throughout the period of the trial, although total IgE was significantly increased. These results suggest that nasal betamethasone valerate offers patients with allergic rhinitis marked symptomatic benefit without the disadvantages previously associated with steroids.     

Inhibition of allergic reactions by cromoglycate and by a new anti-allergy drug U-42,585E. I. Activity in rats.

A new inhibitor of IgE-mediated allergic reactions has been studied in rats. This new inhibitor is chemically different from cromoglycate and shows qualitative and quantitative advantages over it. It is 2,500 times more active in rats than disodium cromoglycate and shows oral activity. This new inhibitor possesses no bronchodilator or end-organ antagonism activity and does not raise intracellular cAMP levels but as cromoglycate acts by inhibition of mediator release. Multiple high (25 mg/kg) doses in rats lead to tachyphylaxis. This effect is reversed both by decreasing the first dose and increasing the time between doses. Over a 5- to 10-fold concentration range, this inhibitor in mast cells can be stimulatory or inhibitory to 45Ca++ flux into cells. This ability to inhibit ionophore-induced 45Ca++ flux correlates well with inhibition of histamine release.     

The anti-allergic effects of FPL 52694

The substituted chromone carboxylic acid FPL 52694 inhibited models of IgE-mediated immediate hypersensitivity reactions in the rat by a mechanism similar to that of sodium cromoglycate. The compound was more potent than sodium cromoglycate but unlike cromoglycate was active following oral administration.     

IL-5 priming of the PMA-induced oxidative metabolism of human eosinophils from allergic and normal subjects during a pollen season

Aim To study the effect of IL‐5 priming on the PMA‐induced oxidative metabolism of blood eosinophils from allergic patients and healthy controls, during pollen exposure. Methods Twenty birch pollen allergic patients with seasonal symptoms of rhinitis or rhinitis plus asthma were studied during the birch pollen season of Sweden. Eosinophils were purified to > 95% by Percoll gradients followed by the MACS system. Oxidative metabolism was measured by a lucigenin enhanced chemiluminescence (CL) assay. Eosinophils were primed with IL‐5 and subsequently stimulated with PMA. The signal transduction mechanisms of IL‐5 priming were studied using the MEK inhibitor PD 98059, the PkC inhibitors Staurosporine, Ro 318220, Gö 6983 and the PI₃kinase inhibitor Wortmannin. Results During the season, the eosinophils from the allergic patients showed a reduced t_½rise compared to the non‐allergic controls (P = 0.019) after stimulation. IL‐5 reduced the total PMA CL response both in control and patients’ cells (P = 0.012 and 0.0054 resp.), whereas it primed it in terms of the t_½rise of the curves, in both groups (P = 0.012 and 0.0015 resp.). The PMA‐induced CL reactions were inhibited by PD 98059, all PkC‐inhibitors and Wortmannin. IL‐5 priming counteracted only the MEK inhibition significantly. Conclusions Blood eosinophils from allergic patients are primed in vivo, as compared to eosinophils from non‐allergic controls, during a pollen season. Interleukin‐5 primes equally the PMA‐induced oxidative metabolism of human eosinophils from healthy or allergic subjects. The mechanism of IL‐5 priming after PMA stimulation of oxygen radical production is MEK independent.     

Basophil allergen threshold sensitivity,CD‐sens,is a measure of allergen sensitivity in asthma

Background Allergic asthma is IgE‐mediated and the IgE‐sensitisation is usually demonstrated by skin prick tests (SPT) and IgE antibody determinations in serum. The SPT and IgE‐antibody values do not directly predict if the allergy clinically contributes to the asthma. There is therefore a need for new objective tests that may indicate the clinical importance of an IgE‐sensitisation. Objective To evaluate basophil allergen threshold sensitivity (CD‐sens) as a measure of allergen sensitivity in allergic asthma. Methods Twenty‐six subjects with stable, intermittent allergic asthma were tested with SPT and spirometry, and methacholine and allergen inhalation challenges to determine methacholine PD₂₀ (provocative dose causing a 20% drop in forced expiratory volume in 1 s) and allergen PD₂₀. The results were compared with CD‐sens and serological parameters, i.e. IgE‐ and IgG4 antibodies to the relevant allergens. Results A significant correlation was found between CD‐sens and allergen PD₂₀ (P=0.01; r=0.49; n=26) as well as between CD‐sens and the ratio of allergen PD₂₀ to methacholine PD₂₀ (P=0.007; r=0.52; n=26). In patients with a moderate to low degree of bronchial hyperresponsiveness there was an excellent correlation (P=0.0001; r=0.88, n=13) between CD‐sens and allergen sensitivity. No relation to either allergen PD₂₀ or the ratio was found for basophil allergen reactivity measured as CD63 up‐regulation at high concentrations of the respective allergen. Conclusions and Clinical Relevance CD‐sens was found to be an objective marker of airway allergen sensitivity in stable allergic asthmatics, that may be used to predict airway responsiveness when bronchial challenge tests cannot be performed. Cite this as: B. Dahlén, A. Nopp, S. G. O. Johansson, M. Eduards, M. Skedinger and J. Adédoyin, Clinical & Experimental Allergy, 2011 (41) 1091–1097.     

Pharmacological investigations with different protein kinase C inhibitors on IgE-dependent and IgE-independent activation of human basophils

In the present study different selective inhibitors of the multifunctional serine/threonine kinase protein kinase C (PKC) were investigated on classical activation pathways of basophils in comparison to the nonselective protein kinase inhibitor staurosporine. The potent inhibitors Ro 31-7549, Ro 31-8220, calphostin C and ilmofosine (BM 41.440), which show selectivity for PKCin vitro, significantly potentiated FcRI-mediated histamine release up to 50% vs. controls at concentrations >10^–7 mol/l but were without any intrinsic histamine releasing activity. Direct activation of cellular PKC by phorbol ester was suppressed by all compounds apart from ilmofosine at the same concentrations. We did not observe statistically significant effects of selective PKC inhibitors on exocytosis induced by the peptide formylmeth-leu-phe (FMLP) or the ionophore A23187, whereas staurosporine potentiated the FMLP-induced histamine release in a dose-dependent fashion: maximum potentiation was 63.5±8.9% vs. control at 1 mol/l (n=4). The findings suggest that PKC exhibits differential functions during biochemical events of stimulus-secretion coupling in human basophils supposedly by its distinct subtypes. With respect to the present data, TPA-induced and IgE-mediated signals are not closely correlated.     

Immediate and delayed allergy to nickel with contact urticaria, rhinitis, asthma and contact dermatitis

A 27-year-old woman had for 2 years performed manual grinding of metal castings that contained nickel. She had previously had allergic contact dermatitis from nickel but started to get contact urticaria, rhinitis and asthmatic attacks at work. The symptoms disappeared at weekends and on holiday. Scratch chamber tests, open tests, specific IgE determinations (RAST), and RAST-inhibition test indicated that she had developed an IgE-mediated allergy to nickel; the bronchial provocation reaction with NiSO₄ was, however, a late one. Patch tests confirmed her allergic contact dermatitis to be caused by nickel. This is the first patient, to the best of our knowledge, reported to have developed allergic contact dermatitis, allergic contact urticaria, rhinitis and asthma from nickel.     

Inflammatory and oxidative stress biomarkers in allergic rhinitis: the effect of smoking

Background Accumulating evidence confirms the presence of pan‐airway inflammation in allergic rhinitis patients. Smoking is known to affect the asthmatic airway inflammation. However, no study has evaluated the impact of smoking on airway inflammation of allergic rhinitis patients. Objective The aim of the present study was to evaluate the impact of smoking on inflammatory and oxidative stress biomarkers in patients with seasonal allergic rhinitis, using non‐invasive methods for sample collection. Methods Forty patients with seasonal allergic rhinitis (20 smokers and 20 non‐smokers) and 30 healthy subjects (15 smokers and 15 non‐smokers) were recruited for the study during pollen season. All subjects were submitted to measurement of the fraction of exhaled NO (FeNO), exhaled breath condensate (EBC) collection, nasal lavage collection, pre‐ and post‐ bronchodilation spirometry and metacholine bronchial challenge testing. pH, leukotriene B₄ (LTB₄) and 8‐isoprostane were determined in EBC and nasal lavage samples. Results Patients with allergic rhinitis presented higher LTB₄ and 8‐isoprostane levels in nasal lavage (P<0.0001 for both comparisons), with no significant differences between smokers and non‐smokers. Patients with allergic rhinitis also presented higher LTB₄ levels and lower pH in EBC (P<0.001 and P=0.004, respectively), with prominent differences between smokers and non‐smokers (P<0.0001 and P=0.003, for LTB₄ and pH, respectively). A significant correlation between nasal lavage and EBC LTB₄ values was observed (r_s=0.313, P=0.048). Conclusions Patients with allergic rhinitis present increased LTB₄ and 8‐isoprostane in their nasal cavity, however, with no significant differences between smokers and non‐smokers. In contrast, smokers with allergic rhinitis present higher LTB₄ levels and lower pH in EBC, suggesting that these patients may be more susceptible to the deleterious effects of smoking, compared with non‐smokers.     

Relationship between nasal hyperreactivity, mediators and eosinophils in patients with perennial allergic rhinitis and controls

Background In perennial allergic rhinitis, patients are almost daily exposed to aeroallergens. This ongoing allergic reaction results in increased sensitivity to allergens and non-specific stimuli. It is generally known that inflammatory cells and mediators are involved in the pathogenesis of the allergic reaction. Objectives To study the relationship between nasal hyperreactivity and nasal inflammation during natural allergen exposure. Methods In 48 patients with perennial allergic rhinitis and in 11 volunteers a nasal brush, a nasal lavage and a histamine challenge were performed. Nasal inflammation was estimated by the number of eosinophils, levels of albumin, tryptase, prostaglandin D₂ (PGD₂), eosinophil cationic protein (ECP) and leukotriene C₄/D₄/E₄ (LTC₄/D₄/E₄). Results In contrast to PGD₂ and tryptase, eosinophils (1.9 vs 0%, P = 0.0023), LTC₄/ D₄/E₄ (17.51 vs 1.43pg/mL, P= 0.0001) and albumin (8.61 vs 2.37mg/mL, P= 0.0008) were significantly increased in rhinitis patients as compared with controls. Patients also showed increased responses to nasal histamine challenge assessed using a composite symptom score (21.5 vs 4 points, P=0.0001). The nasal response to histamine was weakly correlated with the total number of eosinophils in the cytospin (correlation coefficient r=0.38, P= 0.009). Conclusion Nasal hyperreactivity is correlated with the percentage of eosinophils in patients with perennial rhinitis. The patients' mediator profiles suggest that eosinophils are important in the ongoing allergic reaction and nasal hyperreactivity.     

Bronchial responsiveness and airway inflammation in patients with nonallergic rhinitis with eosinophilia syndrome

Background: Nonallergic rhinitis with eosinophilia syndrome (NARES) is characterized by persistent nasal symptoms without allergy and by a marked eosinophil recruitment in the nasal cavities. Objective: We studied whether patients with NARES had bronchial responsiveness to methacholine and airway inflammation and examined the relationship between these factors. Methods: We selected a group of 39 patients referred to our allergy clinic for symptoms of perennial rhinitis. Atopic status was excluded by skin prick tests and RASTs. None of the patients had a history of respiratory symptoms. We preliminarily performed nasal lavage in all patients, and the diagnosis of NARES was made on the basis of the presence of at least 10% eosinophils in nasal lavage fluid. A methacholine challenge and sputum induction were also done on two different days. Results: Eosinophils in nasal lavage fluid ranged between 10% and 86%. Serum IgE levels were within normal range. Total circulating eosinophils ranged between 40 and 890/mm³. Methacholine PD₂₀ values were measurable in only 18 patients (range, 0.32 to 22.56 μmol; group 1). In the remaining 21 patients, methacholine PD₂₀ values were greater than 24 μmol (group 2). We found that differential cell counts in nasal lavage fluid in group 1 were not different from those in group 2. Methacholine PD₂₀ values were not significantly related to any cell count in the nasal lavage fluid. Induced sputum was accomplished only in 22 patients. Eosinophils in induced sputum ranged between 0% and 56.5%. Numbers of total cells, macrophages, lymphocytes, neutrophils, and epithelial cells in the two subgroups were not different. The number of metachromatic cells tended to be higher in group 1 compared with group 2 (0.31% vs 0.05%), but the difference was not significant. The eosinophil count in the induced sputum was significantly higher in group 1 compared with group 2 (16.8% vs 3.1%; p < 0.05). In the entire population, methacholine PD₂₀ values were significantly correlated with the number of eosinophils in sputum (r = –0.63; p < 0.001). Conclusion: We showed that 46% of patients with NARES but without histories of respiratory symptoms had a measurable bronchial responsiveness. The presence of bronchial responsiveness was associated with an increased number of eosinophils in induced sputum but not with the inflammatory process in the nose. (J Allergy Clin Immunol 1997;100:775-80.)     

The effect of phenylalanine on the electrical properties of proximal tubule cells in the frog kidney

The present study was designed to elucidate the effects of sodium-coupled transport on the electrical properties of proximal tubule cells in the isolated perfused frog kidney. Cable analysis techniques have been employed to determine the resistance of the luminal and peritubular cell membranes in parallel (R _m) and the apparent ratio of the luminal over the peritubular cell membrane resistance (VDR). Furthermore, the sensitivity of the potential difference across the peritubular cell membrane (PD_pt) to 6-fold increases of peritubular potassium concentration (PD_k) was taken as a measure of the relative potassium conductance of this membrane. In the absence of luminal phenylalanine, PD_pt amounts to –60±1 mV (n=90),R _m to 36±3 k cm (n=22), VDR to 1.81±0.14 (n=20), and PD_k to 15.0±0.9 mV (n=25). The application of 10 mmol/l phenylalanine replacing 10 mmol/l raffinose leads to a rapid (within 30 s) depolarisation of PD_pt to 50±5% of its control value and to a delayed (within 12 min) recovery to 95±5% of control. The rapid depolarisation is associated with a decline ofR _m and VDR, indicating a decrease mainly of the luminal cell membrane resistance. During recovery of PD_pt there is a parallel increase of VDR and a further decline ofR _m pointing to a decline of the basolateral cell membrane resistance. PD_k is decreased during rapid depolarisation but increases again during the recovery phase. Thus, phenylalanine initially decreases but then increases above control the apparent potassium conductance. Removal of phenylalanine leads to a transient hyperpolarisation and increased apparent potassium conductance. If a cell is depolarised by current injection into a neighbouring cell, a similar decrease of PD_k is observed which shows also a similar recovery (partial repolarisation) despite continued injection of constant current. The data point to a potential-dependent peritubular K⁺-conductance (of the inwardly rectifying type) and to a regulatory increase within some ten minutes, when the cell is depolarised either by sodium entry across the luminal cell membrane or by current injection into a neighbouring cell.     

A comparison of the effects of oral cetirizine and inhaled beclomethasone on early and late asthmatic responses to allergen and the associated increase in airways hyperresponsiveness

Background Cetirizine is a non-sedating H₁ antihistamine which is effective in the treatment of allergic rhinitis and urticaria. It inhibits eosinophil and basophil chemotaxis in late cutaneous allergic reactions in skin windows. Its effect on early (EAR) and late asthmatic reactions (LAR) is less certain. Methods We examined the effect on EAR and LAR of 3 days treatment with oral cetirizine (15mg twice daily) compared with a single dose of inhaled beclomethasone 10min prior to allergen challenge in a placebo-controlled (oral and inhaled) doubleblind cross-over design with three treatment arms separated by 14 days. Results Cetirizine did not significantly inhibit either the EAR or LAR documented by maximum percentage fall in FEV₁ (0-3 and 6-9h) or as area under the curve (AUC between 0 and 3 and 6–9 h), Beclomethasone inhibited the LAR compared with placebo (P = 0.02) when expressed as AUC (6–9h). This did not quite reach statistical significance (P = 0.06) when expressed as maximal percentage late fall in FEV₁ between 6 and 9h. A greater than twofold increase in airways responsiveness to methacholine was observed 3h after challenge which was significantly reduced by beclomethasone compared with placebo (P < 0.02) and cetirizine (P < 0.05). The data suggest that oral cetirizine does not significantly inhibit either the EAR or LAR. Beclomethasone inhibited both the early increase in airways responsiveness and the subsequent LAR. Our study also confirms the view that early increases in airway responsiveness precede the late response and suggests that these associated events are not dissociable by the pharmacological treatments employed in this study.     

Ouabain decreases apparent potassium-conductance in proximal tubules of the amphibian kidney

According to a previous study from this laboratory, the electrochemical gradient for potassium across the peritubular cell membrane of proximal tubules in the isolated perfused frog kidney increases following the application of ouabain. In order to test, if this phenomenon were due to a decrease of potassium conductance, the effects of ouabain on cell membrane resistances and the sensitivity of the peritubular cell membrane potential difference (PD_pt) to step changes of peritubular potassium and bicarbonate concentration were studied. In the absence of ouabain, PD_pt averaged –60±3 mV (n=25). A step increase of peritubular potassium concentration from 3 to 18 mmol/l (pH 8.07) depolarises PD_pt (PD_k) by +24±2 mV (n=8). An increase of bicarbonate from 20 to 40 mmol/l (pH 8.07) hyperpolarises PD_pt (PD_b) by –2.8±0.4 mV (n=9). The resistance of the luminal and peritubular cell membranes in parallel (R _m) amounts to 45±9 k cm (tubule length) (n=4) and the voltage divider ratio (VDR) to 1.4±0.2 (n=7). The resistance of the cellular cable (cellular core,R _c) approaches 131±37 M/cm (n=4). Peritubular application of 0.1 mmol/l ouabain leads to a gradual decline of PD_pt (t _1/2 approx. 30 min), to an increase ofR _m, a decrease of PD_k and an increase of PD_b. VDR andR _c are not changed significantly. The data point to a functional link between the sodium/potassium ATPase and the potassium conductance of the peritubular cell membrane.     

Treatment of seasonal allergic rhinitis with 2% sodium cromoglycate (BP) solution

Forty patients with seasonal allergic rhinitis, not responding to antihistamines, were treated for 6 weeks, beginning 1 June 1972, with either a 2% solution of sodium cromoglycate or placebo in a double blind group comparative trial. The solution was administered intranasally by means of a spray pack. There was a statistical significance in favour of the active material (P<0.025) with regard to the success or failure.