OBJECTIVE

To investigate the relationship between fetal growth restriction and decreased ovarian reserve (DOR) in adulthood to screen high-risk population for early interventions.

METHODS

Forty-four patients with FGR and 88 normal women aged 18-40 years were enrolled. All the subjects were examined for serum levels of follicle-stimulating hormone (FSH), inhibin B (INH-B), and anti-mullerian hormone (AMH) using enzyme-linked immunosorbent assay method in the first 3-5 days of the menstrual cycle, and the counts of antrum ovarian follicle were detected by transvaginal or transabdominal ultrasonography.

RESULTS

The serum levels FSH, INHB, AMH, and AFC in FGR group differed significantly from those in the control group (P<0.05).

CONCLUSIONS

FGR will affect reproductive endocrine function in adulthood to cause a decreased ovarian reserve.

The purpose of the study described here was to evaluate the relationship between inhibin (INH) and bioactive FSH (B-FSH) or immunoreactive FSH (I-FSH) in oligoazoospermic patients. To accomplish this, the authors measured serum levels of INH, I-FSH, B-FSH, LH and testosterone (T) in 98 male patients attending the andrology Centre at Malphighi Hospital (Bologna) for infertility workup. On the basis of the mean sperm concentration, patients with sperm output>> or = 4 x 10(7) ml-1 (n = 30) formed the control group (group A), whereas oligozoospermic patients were divided arbitrarily into three groups. Sperm concentrations for these groups ranged as follows: B, 2-4 x 10(7) ml-1 (n = 14); C, 5 x 10(6)-2 x 10(7) ml-1 (n = 18); D, < 5 x 10(6) ml-1 (n = 17). In addition, the authors studied a group of patients with possible non-obstructive azoospermia (n = 19, group E), confirmed in 16 of them through testicular biopsy. There were no significant differences in serum levels of LH and T among groups. However, azoospermic patients had a significant reduction of the T/LH ratio. Similarly, B-FSH and B/I-FSH ratios were significantly elevated only in group E. INH serum levels did not show any appreciable changes among groups and in azoospermic patients INH correlated significantly and in a positive manner with I-FSH serum levels and negatively with B/I-FSH and T/LH ratios. Within the azoospermic patient group no consistent relationship was evident between INH serum concentration and various degrees of spermatogenetic arrest.(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE

To study the influence of fluorine on the transcription level of androgen binding protein (ABP) and inhibin B (INHB) mRNA in testis sertoli cells of Sprague Dawley rats.

METHODS

A method was set up the model to culture the Sertoli cells. Use a series of concentrations of NaF solutions of 2.5, 5.0, 10.0 and 20.0 mg/L to poison the cells and then, measure the relative expression amount of ABP and INHB mRNA by RT-PCR method.

RESULTS

(1) Compare the relative expression amount of ABP mRNA of each group of different concentration with the control group. 2.5 mg/L group was higher than that in the control group, and the difference has the statistical significance (P < 0.05). The 5.0 mg/L group was also higher than that of the control group, and the difference has no statistical significance (P>> 0.05). (2) Compare the relative expression amount of INH B mRNA of each group of different concentration with the control group. Both the 2.5 mg/L group and the 5.0 mg/L group were higher than that in the control group, and the difference has the statistical significance (P < 0.05). The rest 2 groups were lower than that in the control group and the difference has no statistical significance (P>> 0.05).

CONCLUSIONS

In the range of concentrations between 2.5 and 20.0 mg/L, no distinct influence of fluorine on the expression of androgen binding protein (ABP) and inhibin B (INHB) mRNA in testis sertoli cells of Sprague Dawley rats.

Endoglin (ENG) regulates signaling by transforming growth factor-β (TGF-β), a genetic modifier of cystic fibrosis (CF) lung disease severity. We hypothesized that ENG mediates TGF-β pathobiology in CF airway epithelia. Comparing CF and non-CF human lungs, we measured ENG by qPCR, immunoblotting and ELISA. In human bronchial epithelial cell lines (16HBE), we used CFTR siRNA knockdown and functional inhibition (CFTR_INH -172) to connect loss of CFTR to ENG synthesis. Plasmid overexpression of ENG assessed the direct effect of ENG on TGF-β transcription and signal amplification in 16HBE cells. We found ENG protein to be increased more than fivefold both in human CF bronchoalveolar fluid (BALF) and human CF lung homogenates. ENG transcripts were increased threefold in CF, with a twofold increase in TGF-β signaling. CFTR knockdown in 16HBE cells tripled ENG transcription and doubled protein levels with corresponding increases in TGF-β signaling. Plasmid overexpression of ENG alone nearly doubled TGF-ββ signaling in 16HBE cells. These experiments identify that loss of CFTR function increases ENG expression in CF epithelia and amplifies TGF-β signaling. Targeting ENG may offer a novel therapeutic opportunity to address TGF-β associated pathobiology in CF.

BACKGROUND

Inhibins are dimeric glycoproteins belonging to the TGF-<em>beta</em>1 family and are composed of an a-subunit (<em>INH</em>-alpha) and one of two possible <em>beta</em>-subunits (<em>beta</em>A or <em>beta</em>B; <em>INH</em>-<em>beta</em>A and <em>INH</em>-<em>beta</em>B). They have a substantial function in human reproduction and also seem to play an important role in endocrine-responsive tumors. Interestingly, there is an association between interferon and TGF-<em>beta</em> expression. However, this relationship has not been assessed in endometrial tissue regarding inhibin/activin expression. Therefore, the aim of this study was to determine expression changes of inhibin/activin subunits in the endometrial Ishikawa carcinoma cell line after stimulation with interferon-<em>beta</em>1a.

METHODS

The Ishikawa cell line was cultured until confluence was observed (after 2 days). After adding interferon-betaINH-alpha, INH-betaA and INH-betaB subunits. Experiments were performed in triplicates. The immunohistochemical expression was analyzed with a semiquantitative score (IRS) and statistical analysis was performed.

RESULTS

Immunohistochemical reaction with INH-alpha could not be demonstrated in unstimulated cells, while it was significantly up-regulated in interferon-stimulated cells (p < 0.02). INH-betaA and INH-betaB were primarily observed during the mitotic phases of unstimulated cells. After stimulation their expression was significantly higher (p < 0.05 each) compared to controls and could be observed not only during mitotic phases but also in nonmitotic cells.

CONCLUSIONS

For the first time, we demonstrated a functional relationship between interferon and inhibin/activin subunits. The expression of <em>INH</em>-alpha, <em>INH</em>-<em>beta</em>A and <em>INH</em>-<em>beta</em>B were immunohistochemical significantly up-regulated in the Ishikawa endometrial cell line after stimulation with interferon-<em>beta</em>1a. Since <em>INH</em>-alpha is thought to be tumor suppressive in the mouse model, interferon-<em>beta</em>1a might activate its gene. It remains to be clarified if this effect can be used as therapeutic options in endometrial carcinomas.

OBJECTIVE

In this work, role of the adrenergic nerve system (alpha1 and <em>beta</em>2) in adjustment of the bronchomotor tonus in healthy people was researched.

METHODS

Parameters of the lung function are determined by Body plethysmography. Raw and ITGV were registered and SRaw was calculated as well. Aerosolization is done with standard aerosolizing machines - Asema.

RESULTS

Results gained shows that following the blockade of beta-2 adrenergic receptor with Propranolol (20 mg-aerosol), stimulation of alpha adrenergic receptor with Oxedrine (120 mg-aerosol) and blockage of these receptors with Tolazoline (20 mg-aerosol), does not change significantly the bronchomotor tonus of the tracheobronchial tree (p>> 0.1). Meanwhile, stimulation of the beta-2 adrenergic receptor with Hexoprenaline (2 inh × 0.2 mg) is associated with a significant increase of the peripheral resistance of the airways (p < 0.01).

CONCLUSIONS

This suggests that the activity of the alpha1-adrenergic receptor, unlike the activity of the <em>beta</em>2-adrenergic receptor in the healthy people smooth musculature, is not significant and as such is insufficient to oppose to the tonic activities of the cholinergic system.

The effects of six inducers and malotilate on 7-alkoxycoumarin O-dealkylase activities in rat liver microsomes were examined. Phenobarbital (PB) (100 mg/kg) was administered intraperitoneally to rats for 6 days; 3-methylcholanthrene (3-MC) (40 mg/kg), beta-naphthoflavone (beta-NF) (40 mg/kg), isosafrole (150 mg/kg) and polychlorinated biphenyls (PCB) (100 mg/kg) were administered intraperitoneally for 3 days; isoniazid (INH) (50 mg/kg) was administered intraperitoneally for 10 days; and malotilate (500 mg/kg) was administered orally for 3 days. The O-dealkylase activities toward 7-methoxycoumarin (7-MC), 7-ethoxycoumarin (7-EC) and 7-propoxycoumarin (7-PC) were examined 24 hr after the final administration of the drugs. The ratios of 7-EC O-deethylase and 7-PC O-depropylase to 7-MC O-demethylase activity in the control and six inducer-treated groups were compared. The ratios in the groups treated with the six compounds, each of which induces a different form(s) of cytochrome P-450 (P-450), were clearly different from each other. Therefore, the measurement of 7-alkoxycoumarin O-dealkylase activities should be extremely useful for the routine determination of the molecular species of P-450. On the other hand, the ratio in the malotilate-treated group was different from that in any other inducer-treated group, so that there might be a possibility that malotilate induced a form(s) of P-450 that is different from any of the already known species.

A simple method is described for the preparation of proteolytically processed forms of beta 2-microglobulin suitable for structural and biological studies. PEG 6000 was added to the serum of healthy individuals to precipitate the C1 complement complex from C1 esterase inhibitor (C1-inh). After dissolving the precipitate containing the C1 complement in Tris-HCl buffer, pH 7.6, efficient conversion of added beta 2-microglobulin to desLys58 beta 2-microglobulin was observed. Addition of a specific carboxypeptidase B inhibitor (Plummers inhibitor) could partly prevent the deletion of Lys-58 from cleaved beta 2-microglobulin, whereby Lys58-cleaved beta 2-microglobulin was obtained. The proteolytically processed forms were subsequently purified by G-75 Sephadex gel filtration followed by chromatofocusing. A yield of 10-40% of proteolytically processed beta 2-microglobulin was obtained. Only one component was seen by SDS-PAGE stained with Coomassie Brilliant Blue.

The current study explores a new strategy to incorporate single wall carbon nanotubes (SWNTs)/doped SWNTs as carrier modules in target-specific administration of antitubercular chemotherapeutics through covalent and noncovalent functionalization onto the nanotube sidewall. Density functional studies illustrate that noncovalent functionalization of isoniazid (INH) is preferred over covalent attachment, exhibiting low adsorption energy values, HOMO-LUMO gap and comparison of quantum molecular descriptors performed in (5,5) and (9,0) SWNT systems. Substitution doping of boron facilitates the adsorption of INH onto the otherwise inert nanotube. Frontier orbital analysis reveals reorientation of electronic charge in the nanotubes after functionalization, the effect being more pronounced in the case of doped nanotubes. The charge transfer is significant in covalent functionalization of INH via the B-dopant atom, whereas in noncovalent functionalization a small amount of charge transfer is noted. Solvation studies demonstrate the dissolution of INH in B-doped (5,5) and (9,0) SWNTs to be higher compared to pristine nanotube-INH complexes. Functionalization of nanotubes via covalent and noncovalent means can foster pioneering prospects especially for experimental studies in this area of research.

(<em>b</em>)Introduction</<em>b</em>): Hereditary angioedema (HAE) with C1 esterase inhi<em>b</em>itor deficiency (C1-<em>INH</em>-HAE) is a rare disease that manifests with cutaneous and/or su<em>b</em>mucosal swellings due to uncontrolled activation of the contact/kinin system. Attacks recur with unpredicta<em>b</em>le frequency and severity, laryngeal edema is potentially lethal, and the disease <em>b</em>urden may severely disrupt patients' lives.(<em>b</em>)Areas covered</<em>b</em>): This review provides an overview on lanadeluma<em>b</em>, a human monoclonal anti<em>b</em>ody targeted against plasma kallikrein that was recently approved for prevention of symptoms in C1-<em>INH</em>-HAE.(<em>b</em>)Expert opinion</<em>b</em>): The phase III HELP Study demonstrated the efficacy of lanadeluma<em>b</em> in reducing HAE attacks. These positive results are <em>b</em>eing further confirmed in the open-la<em>b</em>el extension study. This agent addresses some of the limitations of existing prophylactic options as tolera<em>b</em>ility issues, the need for intravenous administration and frequent dosing. Therefore, lanadeluma<em>b</em> can profoundly improve quality of life of patients with C1-<em>INH</em>-HAE.

Inhibins (INH) are dimeric glycoproteins composed of an alpha-subunit (INH-alpha) and one of two possible beta-subunits (INH-betaA or -betaB), with substantial roles in human reproduction and in endocrine-responsive tumours. The aim of the present study was the determination of the frequency and tissue distribution patterns of the inhibin/activin subunits in endometrial carcinoma cells of the cell line RL-95-2 after stimulation with estradiol and cortisol compared to unstimulated controls.

METHODS

Cells of the endometrial carcinoma cell line RL-95-2 were grown on quadriperm tissue slides and incubated with different concentrations (0.1 and 0.01 micromol/ml) of estradiol or cortisol. Expression of INH-alpha, betaA and betaB was analysed by immunocytochemistry with specific monoclonal antibodies directed against the inhibin subunits.

RESULTS

Expression of INH-alpha and -betaB was higher in cortisol-stimulated RL-95-2 cells, whereas INH-betaA expression was lower. In contrast to these, INH-betaB expression was increased by estradiol while INH-alpha and -betaA were unchanged under estradiol treatment.

CONCLUSIONS

Expression of INH-subunits in RL-95-2 cells was described. Cortisol and estradiol showed an influence on INH expression. The RL-95-2 cell line could act as a useful model for the investigation of INH regulation, particularly for endometrial cancer.

To clarify the non-enzymatic radical-scavenging activity of beta-carotene-related compounds and other polyenes, we used differential scanning calorimetry to study the kinetics of radical polymerization of methyl methacrylate (MMA) by 2,2'-azobisisobutyronitrile (AIBN) or benzoyl peroxide (BPO) in the absence or presence of polyenes under nearly anaerobic conditions at 70 degrees C, and analyzed the results with an SAR approach. The polyenes studied were all-trans retinol, retinol palmitate, calciferol, beta-carotene and lycopene. Polyenes produced a small induction period. The stoichiometric factor (n) (i.e. the number of radicals trapped by each inhibitor molecule) of polyenes was close to 0. Tetraterpenes (beta-carotene, lycopene) suppressed significantly more of the initial rate of polymerization (R(inh)) than did diterpenes (retinol, retinol palmitate). The inhibition rate constants (k(inh)) for the reaction of beta-carotene with AIBN- or BPO-derived radicals were determined to be 1.2-1.6x10(5) l/mol s, similar to published values. A linear relationship between (k(inh)) and the kinetic chain length (KCL) for polyenes was observed; as (k(inh)) increased, KCL decreased. KCL also decreased significantly as the number of conjugated double bonds in the polyenes increased. Polyenes, particularly beta-carotene and lycopene, acted as interceptors of growing poly-MMA radicals.

A method has been developed for the determination of isoniazid (INH) at microgram level in pharmaceutical preparations based on the oxidation of isoniazid by radiochloramine-B. Interference of vitamin C has been overcome by precipitation as lead ascorbate and that of rifampicin and p-aminosalicylic acid by selective extraction. Amounts as low as 25 micrograms of INH can be determined.

The hypothesis for the present study is that the active immunization of female turkeys with inhibin (INH) would neutralize endogenous INH, and increase levels of circulating follicle stimulating hormone (FSH) and the number of preovulatory follicles, and subsequently enhance egg production. Two experiments were conducted with female turkeys in their first (30 wk of age) and second (62 wk of age) laying cycles. Treatment groups included control turkeys immunized with keyhole limpet hemocyanine (KLH) and experimental turkeys immunized with recombinant turkey inhibin alpha conjugated to KLH (rtINH), vasoactive intestinal peptide (VIP) conjugated to KLH or rtINH+VIP. Egg production increased (P < 0.05) in VIP and rtINH+VIP immunized birds, but not in rtINH immunized hens in comparison with a control group. A similar number of ovarian follicles, arranged in the follicular hierarchy of laying hens, was observed in all experimental groups. However, there was a larger number of nongraded yellow follicles in rtINH-immunized (62.5%) and rtINH+VIP-immunized (73.5%) groups compared with that of controls, suggesting overstimulation by FSH. Anterior pituitary FSH beta subunit, LH beta subunit, and prolactin (PRL) mRNA contents were determined by Northern blot analysis and reverse transcriptase-polymerase chain reaction (RT-PCR) in laying hens at the end of the experimental period. Hens immunized with rtINH showed increased FSH beta subunit mRNA content, but no change in the content of LH beta subunit or PRL mRNA. Hens immunized with VIP or rtINH+VIP had significant increases in both pituitary LH beta subunit and FSH beta subunit mRNA contents, accompanied by a decline in PRL mRNA abundance. The magnitude of the increase in FSH beta subunit to INH immunoneutralization was greater in first-cycle hens than in second-cycle hens. These data suggest that active immunization of female turkeys with INH neutralizes endogenous INH and increases both circulating FSH and the number of preovulatory follicles. However, no significant increase in egg production was observed in INH-immunized hens. The data confirm previous reports that VIP immunoneutralization increases egg production in turkey hens and shows for the first time that it also increases FSH beta subunit and LH beta subunit gene expression.

BACKGROUND

This work, partial pressure of the respiratory gases in the capillary blood (pH, PaO2, PaCO2) was studied, following the protective action of the betabeta-blocker-Propranolol.

METHODS

in patients with increased bronchial reactibility. pH, oxygen partial pressure (PaO2), dioxide carbon partial pressure (PaCO2) in the arterial blood, with the assistance of the analyzer IL, following some minutes of sample taking were defined in all patients. As a standard to verify the accuracy of the measurement, ampoule solutions of pH, PaO2 and PaCO2 were utilized (Acidobasel, Berlin).

CONCLUSIONS

Following the inhalation of the <em>beta</em>-blocker-Propranolol (20 mg/ml-aerosol), there was an evident decrease (p < 0.05) of pO2 and a non-significant increase (p>> 0.1) of pCO2. Beta2-adrenergcic stimulator-Hexoprenaline (2 inh x 0.2 mg), shows an protective effect in the decrease of pO2 (p < 0.05) following the bronchoconstriction being provoked by Propranolol. Alpha2-adrenergic blocker-Tolazoline (20 mg/ml-aerosol), has not shown a protective action in the bronchoconstriction caused with propranolol, therefore significant decrease (p < 0.05) of pO2 and a non-significant increase (p>> 0.1) of pCO2 appeared. This shows that stimulation of <em>beta</em>2-adrenergic receptor has protective action in changes of the respiratory gases. Meantime, blocker of the alpha2-adrenergic receptor (Tolazoline) has not shown a protective action in changes of the respiratory gases.

A novel Plumbagin-Isoniazid Analog (PLIHZ) and its β-cyclodextrin inclusion complex (PLIHZCD) is prepared, characterized and evaluated for antitubercular activity under low and high iron conditions. PLIHZCD inclusion complex was characterized by Fourier Transform Infra-Red (FTIR), Differential Scanning Calorimetry (DSC), Powder X-ray Diffraction Studies (PXRD), (1)H NMR Studies and Scanning Electron Microscopic (SEM) analysis. The orientation and interaction of PLIHZ and CD was studied by molecular docking. PLIHZCD exhibited superior activity (MIC of 4 μg/ml) than PLIHZ and PL under 7H9 medium conditions. The standard anti-tubercular compound INH exhibited MIC values of 0.125 and 32 μg/ml under high and low iron conditions, whereas the conjugate PLIHZ exhibited MIC values of 0.5 and 2.0 μg/ml under high and low iron (corresponding to isoniazid resistant condition) indicating the advantage of combining plumbagin with INH overcoming resistance. The cyclodextrin conjugate offers improved aqueous solubility and thermal stability which are advantages in the treatment protocol.

<A<em>b</em>stractText>The prevalence of multidrug-resistant-tu<em>b</em>erculosis (MDR-TB) among new and previously treated cases is increasing worldwide as well as in India. Rapid detection of MDR-TB allows the esta<em>b</em>lishment of an effective treatment regimen; minimizes the risk of further resistance, and limits the spread of drug-resistant strains. Early diagnosis of MDR-TB is the need of the hour in high-TB <em>b</em>urden countries like India, and GenotypeMTBDRplus is quite sensitive and specific in determining the molecular resistance in drugs such as rifampicin and isoniazid.</A<em>b</em>stractText><p><div>(<em>b</em>)Methods</<em>b</em>)</div>The present study was done for molecular detection of rifampicin and isoniazid resistance and resistance patterns among MDR-TB suspects and comparison of resistance patterns among new and previously treated cases <em>b</em>y GenoType^® MTBDRplus Line Pro<em>b</em>e Assay. A total of 1268 sputum samples of MDR-TB suspects were su<em>b</em>jected to fluorescent microscopy. Fluorescent microscopy positive samples were su<em>b</em>jected to GenoType^® MTBDRplus (HAIN Lifescience) assay.</p><A<em>b</em>stractText>MDR-TB was detected 11.02%, 20.03% in new and previously treated cases. Among MDR-TB patients S531 L was the most common mutation detected in rpoB gene; 71.43% in new, and 72.17% in previously treated cases. S315T1 was the most common mutation noted in katG gene; 100% in new and 81.74% in previously treated. While in hA gene, it was C15T (7.8%) among previously treated cases.</A<em>b</em>stractText><A<em>b</em>stractText>MDR-TB has high prevalence in the western part of Uttar Pradesh, India. Previously treated cases have even more high rate of MDR-TB than new TB cases. The most dominant gene mutations associated with resistance to <em>INH</em> and RIF were o<em>b</em>served in codon 315 of the katG gene and codon 531 of the rpoB gene. While comparing the mutation patterns <em>b</em>y Genotype MTBDRplus assay, previously treated cases showed more diversity of mutations and had greater num<em>b</em>er of unknown mutations.</A<em>b</em>stractText>

The increasing number of reports for disease-related proteases has necessitated materials for the fast, sensitive, and specific assessment of protease activities. The purpose of this study was to synthesize and test a dityrosine-based substrate for the selective assay of a specific cysteine cathepsin. DBDY-Gly-INH)2 was synthesized from the conjugation of N,N'-diBoc-dityrosine (DBDY) with two molecules of glycine and isoniazid (INH) for this purpose. The fluorescence of DBDY (λex=284-320nm, λem=400-420nm) disappeared due to the quenching effect of INH. However, the protease-catalyzed hydrolysis resulted in the release of INH and recovered the fluorescence of DBDY. When reacted with 13 proteases, DBDY-Gly-INH)2 was hydrolyzed by the cysteine proteases only. Meeting the growing need to discriminate cysteine cathepsins (e.g., cathepsins B, L, and S found at high levels in various cancers), DBDY-Gly-INH)2 was tested as a substrate for cathepsins B, L, and S. Only cathepsin B catalyzed the hydrolysis reaction among the three cathepsins. The reaction rate followed the Michaelis-Menten kinetics, and the KM and kcat/KM values were 2.88μM and 3.87×10(3)M(-1)s(-1), respectively, which were comparable to those for the materials reported for the selective assay of cathepsin B. Considering the simple preparation of DBDY-(Gly-INH)2, DBDY-(Gly-INH)2 is believed to be valuable for the sensitive and selective assay of cathepsin B activity.

A comparison was made of the therapeutic efficiency and tolerance of rifampin-based regimens and that of the standard triple-drug combination in the treatment of 92 newly diagnosed cases of pulmonary tuberculosis. The three drug regimens investigated were: A, rifampin-INH; B, rifampin-INH-streptomycin; and C, INH-PAS-streptomycin. Therapeutic progress was measured in terms of sputum conversion on culture and microscopy. The rifampin combinations produced a somewhat earlier sputum conversion. With regimens containing this potent antibiotic the phenomenon of microscopically-positive but culture-negative specimens was more frequently observed. The tolerance exhibited to the rifampin regimens was far greater than that to the conventional triple-drug combination. Nevertheless, periodic laboratory examinations are essential during rifampin therapy for safe utilization of the drug. An incidental finding of this study was the increase in primary resistance to streptomycin particularly among recent immigrants to Canada.

Antituberculous treatment could be continued by using steroid as adjunctive therapy in two patients showing febrile reaction to antituberculous drugs in spite of desensitization therapy. Case 1 (39-year-old man) was admitted to our hospital with positive sputum-smear and bilateral cavitary tuberculosis (b II 2) on chest X-ray. He showed fever of 38-39 degrees C after 8 days of HREZ treatment. Desensitization therapy of RFP with the combined use of prednisolone was enforced, since the exothermic reaction continued in spite of stopping the 4 medicines, and the treatment became possible. Case 2 (40-year-old woman) was admitted with positive sputum-smear and bilateral cavitary tuberculosis (b II 2) on chest X-ray. The administration of drugs was stopped as temperature rose to 38-39 degrees C after 12 days of HREZ treatment. Though the DLST of INH was positive, the treatment with INH became possible by the combined use of PSL.

Hereditary angioedema (HAE) is characterized by unpredictable, recurring and painful swelling episodes that can be disabling or even life-threatening. Awareness of HAE has progressively grown worldwide, and options for treatment of acute attacks and prevention of future attacks continue to expand; however, unmet needs in diagnosis and treatment remain. In Japan, recognition of HAE within the medical community remains low, and numerous obstacles complicate diagnosis and access to treatment. Importance of timely treatment of HAE attacks with on-demand therapies is continually demonstrated; recommended agents per the WAO/EAACI treatment guidelines published in 2018 include C1 inhibitor (C1-INH) concentrate, ecallantide, and icatibant. In Japan, multiple factors contribute to delayed HAE treatment (potentially leading to life-threatening consequences), including difficulties in finding facilities at which C1-INH agents are readily available. Recognition of challenges faced in Japan can help promote efforts to address current needs and expand access to effective therapies. Icatibant, a potent, selective bradykinin B₂ receptor antagonist, has demonstrated inhibition of various bradykinin-induced biological effects in preclinical studies and has shown efficacy in treating attacks in various clinical settings (e.g. clinical trials, real-world studies), and HAE patient populations (e.g. with C1-INH deficiency, normal C1-INH). Icatibant was approved in Japan for the treatment of HAE attacks in September 2018; its addition to the HAE treatment armamentarium contributes to improved patient care. In Japan, disease awareness and education campaigns are warranted to further advance the management of HAE patients in light of the unmet needs and the emerging availability of modern diagnostic approaches and therapies.

Keywords: Bradykinin B(2) receptor antagonist; Hereditary angioedema; Icatibant; Japan; Treatment guidelines.