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PubMed2003

Inhalation apparatus for generating sarin and soman toxic vapors.

The developed inhalation system is a dynamic and whole-body exposure model designated for generating sarin or soman vapors. It consists of an evaporating apparatus, an inhalation chamber and a carbon filter. The inhalation chamber is made of stainless steel and its total volume is 36 l. The concentration of organophosphorus compound depends on airflow through the chamber, syringe volume of the dosing pump and dosing speed. For determination of organophosphorus compound (OPC) concentration, a modification of Ellman method is used. At generating of vapors in the inhalation chamber the means of the yield were 61.4 +/- 6.6% for sarin and 35.8 +/- 3.5% for soman. The better yield for sarin than for soman, because of the higher volatility of sarin in comparison with soman was achieved. The stable concentration of the OPC for several hours could be maintained in the inhalation chamber when only relatively small amount of the OPC is used. Using the developed inhalation system LCt50 for sarin and for soman in rats was determined. At 1 h exposure the LCt50 values were 4.72 mg x h(-1) x m(-3) for sarin and 4.81 mg x h(-1) x m(-3) for soman. The results presented show that the inhalation chamber successfully fulfils the role of instrument for inhalation intoxication of small laboratory animals with highly toxic OPC.

Administration, Inhalation↗
PubMed2004

[Beta 2-adrenoceptor polymorphism and effects of inhaled beta 2-stimulant (procaterol) and an anti-cholinergic drug (oxitropium) on the airway resistance].

It has been suggested that the Arg 16/Gly 16 allele at codon 16 of beta 2-adrenoceptor polymorphism plays a role in down-regulating the stimulus of bronchodilatation caused by beta 2-agonists. This study was designed to evaluate the difference of bronchodilator responsiveness to beta 2-agonist (procaterol) and anti-cholinergic drug (oxitropium) between those who have Arg 16/Gly 16 allele (hetero type) and those who have Gly 16/Gly 16 allele (variant type) at codon 16 of in healthy women. Airway resistance and other pulmonary function tests were measured by a body plethysmography before and 5, 10, 15, 20, and 30 minutes after inhalation of procaterol or inhalation of procaterol and oxitropium. In healthy women inhaled procaterol, percent changes of respiratory airway resistance compared with values before inhalation were -2.8 after 5 minutes, -7.5 after 10 minutes, -11.2 after 15 minutes, -15.4 after 20 minutes, and -12.6 after 30 minutes. In healthy women inhaled porcaterol and oxitropium, percent changes of respiratory airway resistance compared with values before inhalation were -14.5 after 5 minutes, -18.9 after 10 minutes, -17.0 after 15 minutes, -20.8 after 20 minutes, and -20.4 after 30 minutes. Patterns of decrease of respiratory airway resistance differed between women who have Arg 16/Gly 16 allele (hetero type) and those who have Gly 16/Gly 16 allele (variant type). In women who have Gly 16/Gly 16 allele (variant type), although acute decrease of respiratory airway resistance was observed, the duration of bronchodilator effect by inhaled procaterol and oxitropium was shorter than those observed in Arg 16/Gly 16 allele (hetero type). The present study showed inhalation of procaterol and oxitropium had a differential bronchodilator effect in healthy women, depending on their genotype of beta 2-adrenoceptor polymorphism at codon 16.

Administration, Inhalation↗
PubMed2004

[Modeling of acute respiratory distress syndrome in canine after inhalation of perfluoroisobutylene and preliminary study on mechanisms of injury].

OBJECTIVE: To establish of acute respiratory distress syndrome (ARDS) model in canine after inhalation of perfluoroisobutylene (PFIB), and to observe the progressing of lung injury, and to study the mechanisms of injury. METHODS: A device of inhalation of PFIB for canine was made. The concentration of PFIB was 0.30 - 0.32 mg/L. Serum IL-6 and IL-8 were dynamically measured. Clinical manifestations, pathology of organs in canine were observed. RESULTS: (1) During inhalation, the concentration of PFIB remained stable; (2) After inhalation, blood arterial oxygen partial pressure fell gradually, and eventually met the criteria for diagnosing ARDS; (3) The level of IL-8 in serum rises significantly after inhalation (P < 0.05), whereas that of IL-6 was not obviously altered (P > 0.05); (4) Within 6 hours after inhalation, no abnormality in canine was observed, but afterwards symptoms gradually appeared, and typical breath of ARDS, such as high frequency and lower level could be seen in later phase; (5) Pathological examination showed severe congestion, edema and atelectasis in most part of both lungs, and signs of anoxia in other organs. CONCLUSIONS: (1) The device designed is capable of ensuring control of inhalation of PFIB; (2) Exposure to PFIB for 30 mins, canines all met the criteria for diagnosing ARDS 22 hours after inhalation, therefore the modeling is successful; (3) PFIB specifically damages the lung by causing excessive inflammation.

Administration, Inhalation↗
PubMed1992

[Microcirculation during inhalation of 100% oxygen in rabbits].

Using a rabbit ear chamber (REC), the author compared the effect of air inhalation and that of 100% oxygen inhalation on microcirculation of rabbits. Eight rabbits, weighing 3-4 kg, were used for this study. After observing the microcirculation under air inhalation, the inspired gas was changed to 100% oxygen and the microcirculation was again observed. This procedure was repeated twice to confirm any changes that had been observed. No significant changes were observed in the blood pressure, heart rate and pulse pressure by inhaling either O2 concentration. During the inhalation of 100% oxygen, the diameter, blood-flow velocity and blood-flow rate of the arterioles were markedly reduced (P less than 0.01). All these parameters observed in the venules during air inhalation showed no significant differences compared with the values taken during 100% oxygen inhalation. This study using REC has shown that inhalation of 100% oxygen causes microcirculatory changes especially affecting the arterioles.

Administration, Inhalation↗
PubMed1992

New method of evaluating patient preference for different inhalation delivery systems.

In order to assess patients' preferences for different inhalation devices a questionnaire has been developed. The questionnaire consisted of items covering various aspects considered important for patients who regularly use inhalation devices. The questions were designed to be of a general character so any inhalation device could be evaluated. We evaluated the questionnaire in a multicenter, open crossover study comparing patients' opinions of MDI with and without spacer and of a dry powder inhaler, Turbuhaler. One hundred twenty-three patients with stable asthma confirmed by daily peak expiratory flow rate (PEF) measurements used for 2 weeks MDI only and MDI with spacer and for 2 weeks Turbuhaler. The order was randomized. The drugs were terbutaline inhaled via MDI and Turbuhaler and budesonide inhaled via MDI with spacer and turbuhaler. At the end of each evaluation period the patients answered a number of questions about their opinion by marking on a visual analogue scale. A factor analysis revealed that the different questions represent a few common factors important for evaluating opinion about inhalation devices. These factors are handling of the device, use, time to learn how to use the device properly, how confident the patients feel about the use of it, and taste/irritation. A standardized questionnaire of reduced size seems to be a suitable method for evaluating patient preference for different inhalation devices.

Administration, Inhalation↗
PubMed2005

Bone mineral density in asthmatic patients using low dose inhaled glucocorticosteroids.

Inhaled glucocorticosteroids are clearly beneficial in subjects with moderate or severe asthma since they are well tolerated, reduce symptoms, and improve quality of life. Some studies suggest that inhaled glucocorticosteroids can adversely affect bone mineral density. The aim of this study is to determine the effects of inhaled glucocorticosteroid therapy on bone mineral density in female patients. Forty-five asthmatic female patients (36 premenopousal and 9 postmenopausal) and forty-six healthy control subjects were included in the study. Bone mineral density was measured from lumbar spine (L1-4) and femur (neck, trochanter, and Ward's triangle) by dual energy X-Ray absorptiometry. Age, occupation, menopause and smoking status, alcohol consumption, body mass index, previous fractures, family history of fractures, menstrual history, ooferectomy, number of pregnancies, the duration of lactation, physical activity and calcium intake were questioned according to the European Vertebral Osteoporosis Study Group (EVOS) form. Cumulative inhaled glucocorticosteroid dose was calculated. T score of femoral neck and T score and bone mineral density of Ward's triangle were significantly lower in asthmatic patients compared to control group but no statistically significant correlation was found between the disease duration, inhaled steroid treatment duration, cumulative inhaled dose and annual inhaled steroid dose and bone mineral density measurement. These results suggest that in asthmatic patients using low dose inhaled corticosteroids bone mineral density is lower than in healthy controls but it is still unclear if asthma by itself is a risk factor for osteoporosis.

Administration, Inhalation↗
PubMed1992

[Inhaled corticosteroids in the treatment of childhood asthma].

During the last fifteen years, inhaled corticosteroids were increasingly used for prophylaxis in childhood asthma. The development of inhaled corticosteroids with a high ratio of topical vs systemic potency, now makes possible their use in large doses which are needed to control the most severe forms of the disease, in order to avoid long term oral corticosteroid treatment for these patients. The efficacy of inhaled corticosteroids depends on an optimal pulmonary deposition of the drug which is obtained with children by inhaling the drug via a large volume spacer. Beyond their beneficial effects on the clinical condition of the patients and on pulmonary function, inhaled corticosteroids should improve the long term prognosis of asthma, by reducing chronic inflammation in the airways and the associated bronchial hyperreactivity. At usual dosages, inhaled corticosteroids are free of harmful side effects. However, caution and close observation of adrenal function and growth development are required when prescribing inhaled corticosteroids at high dosages for a long period. Nevertheless, inhaled corticosteroids present very few serious side effects compared with those induced by long term oral corticosteroid treatment.

Administration, Inhalation↗
PubMed2005

[Smoke inhalation injury: diagnosis and respiratory management].

Smoke inhalation is a significant comorbid factor following major thermal injury. Smoke exposure is only a trigger for the sequence of events responsible for the development of inhalation injury. Noxious chemicals generated by incomplete combustion injure the exposed bronchoepithelium and stimulate the release of chemical mediators that cause a progressive inflammatory process. Airway inflammation and pulmonary edema impair gas exchange and increase the susceptibility to pulmonary infection. Earlier diagnosis and treatment of inhalation injury is an important element to improve the clinical course of severe burn patients. The American Burn Association, however, recently concluded that there are insufficient data to support a treatment standard for the diagnosis of inhalation injury. At present, the diagnosis of inhalation injury is supported by the combination of history, physical examination, bronchoscopy, and laboratory findings For accurate diagnosis of inhalation injury, helical CT scanning and examination to detect activated leukocytes in bronchoalveolar lavage fluid may be warranted. In the respiratory management of inhalation injury, repeated removal of pseudomembrane by fiberoptic bronchoscopy and the use of adequate PEEP to avoid airway obstruction are essential. High-frequency percussive ventilation can be a suitable mode of ventilation for inhalation injury.

Bronchoalveolar Lavage Fluid↗
PubMed1990

[Elimination of secretions in CF patients under amiloride inhalation].

Inhaled amiloride reduces active absorption of sodium of respiratory epithelium in CF patients and so, transiently, diminishes loss of water. 10 CF patients, 8 to 28 years of age, were examined on two days. First day, they inhaled in a randomised order isotonic saline and a solution of amiloride hydrochloride (0.3 mg/ml) one after another, each inhalation taking twenty minutes. Second day, inhalations were performed in an inverse order. To intensify the effect of inhalation, the inhalation procedure was combined with "autogenic drainage", a special kind of physiotherapy. Main criterion for evaluation was the amount of expectorated sputum. Mean increase of sputum during amiloride inhalation in comparison to saline was +50.4%. Patients and physiotherapist observed a liquefaction of secretion and a decrease of coughing by amiloride and a support of physiotherapy. These results suggest a beneficial clinical effect of regular amiloride inhalation in CF patients.

Absorption↗
PubMed1981

Measurement of lung water in inhalation injury.

Pulmonary inhalation injury is a major cause of morbidity and mortality rates in burn victims. But the pathophysiology of parenchymal inhalation injury has not been fully elucidated. In this study, extravascular lung water volume (EVLW) was measured in burn patients with and without inhalation injury. Patients with parenchymal inhalation injury (group II) had elevated admission extravascular lung water volumes (10.12 +/- 3.43 ml/kg), whereas patients without parenchymal injury (group I) had significantly lower lung water values (3.91 +/- 1.49 ml/kg). Both accumulation of EVLW and ventilation-perfusion abnormalities in the group II patients occurred within hours of smoke inhalation. But the severity of inhalation injury did not consistently correlate with the elevation of EVLW. This indicated that both interstitial edema and ventilation-perfusion imbalance contributed, in varying degrees, to the pathophysiology of inhalation injury. In this study, the general clinical criteria for inhalation injury--presence of facial or oropharyngeal burns, carboxyhemoglobin levels, carbonaceous sputum, or closed space injury--did not differentiate patients with airway injury only from those with parenchymal injury. Patients in both groups who died of sepsis had significant (P less than 0.01) increases in EVLW 24 to 48 hours after the clinical onset of sepsis. The normal hydrostatic pressures in these septic patients suggested that the increase in EVLW observed with sepsis was due to an increase in pulmonary capillary membrane permeability.

Adult↗
PubMed1995

Recreational use of inhalant drugs by adolescents: a challenge for family physicians.

BACKGROUND AND OBJECTIVES: This paper assesses the incidence and prevalence of inhalant use in an adolescent population. The purpose was to document patterns of incidence and prevalence. METHODS: A survey study was conducted, in which self-reported measures of inhalant use were assessed during 3 consecutive years. All surveys were completed as part of a school-based study. The responses of 10,198 middle school and high school students were analyzed. The primary measures included self-reported use of substances that were inhaled to create a state of euphoria. RESULTS: Of the responding students, overall rates of 12.8% for lifetime use and 4.6% for past-month use were observed. Cross-sectional analysis revealed increasing inhalant use among students in grades 6-8 that leveled off in grade 9 and decreased in grades 10-12. Incidence of inhalant use was found to be increasing in younger adolescents. CONCLUSIONS: Inhalant use may be an early marker of substance abuse and should be the focus of increased prevention and early diagnosis and treatment. Family physicians may be among the first to suspect inhalant use in casual users and should be alert to inhalant use among adolescent patients.

Administration, Inhalation↗
PubMed1994

[Inhaled corticotherapy sparing effect by sodium nedocromil in moderate to severe asthma].

BACKGROUND: The increased use of high dose inhaled steroid in the treatment of asthma has revealed the risk of dose-dependent side effects. Nedocromil sodium is a non steroidal agent with anti-inflammatory properties. OBJECTIVE: To demonstrate whether nedocromil sodium may have some therapeutic benefit in asthmatic patients treated with high dose inhaled steroids and whether it has an inhaled steroid sparing effect. PATIENTS: 134 adults with moderate to severe asthma not adequately controlled with high dose inhaled steroids (750 to 1,500 micrograms/day). METHOD: After a two week baseline period, patients were randomized to receive either nedocromil sodium (4 mg qid) or placebo for 24 weeks in a double blind fashion. During the first 12 weeks of treatment, the dose of inhaled steroid was maintained constant whereas it was altered during the last 12 weeks according to asthma scores. RESULTS: Among 108 patients reaching the reduction phase, a decrease of 250 micrograms of inhaled steroid or more was possible in 79% of patients on nedocromil sodium and in 60% of patients on placebo (p < 0.03). Symptoms scores were improved on both treatments during the 12 first weeks, more on nedocromil sodium than on placebo, treatment difference reaching significance for daytime asthma (p < 0.02). FEV1 improved during the trial for patients on nedocromil (from 69 +/- 18% to 74 +/- 21%; p < 0.005) whereas it did not for those on placebo. CONCLUSION: Nedocromil sodium is effective in improving moderate to severe asthma in addition to inhaled steroid and has some steroid sparing effect in patients treated with high dose inhaled steroid.

Administration, Inhalation↗
PubMed1993

[Efficacy of a powder inhaler (Turbuhaler) in moderate asthmatic crises in children].

The use of a metered dose inhaler can be difficult in children, and requires the juxtaposition of an inhalation chamber. Powder inhalers offer different means of administration and are simpler to use and can be easily carried in the pocket or in a school satchel. The aim of this study is to assess the use of a beta-2-mimetic powder inhaler (Bricanyl Turbuhaler) in children presenting with an exacerbation of asthma. Thirty children aged from 4 to 14 years were included in an open random study in parallel groups. After a baseline measure of pulmonary function, the children inhaled 500 microgram of powdered terbutaline, or with metered dose aerosol attached to a spacer device (Nebuhaler). A significant bronchodilatation was apparent in the two groups of children which was measured at 15 and 30 minutes after the inhalation of the drug (measures of peak flow and forced expiratory volume in one second and of specific airways resistance were made). The bronchodilator response was similar whatever the method of inhalation. Although the inspiratory flow is decreased in an exacerbation this work shows that it is possible to advise the use of a powder inhaler in children presenting with a moderate exacerbation of asthma.

Acute Disease↗
PubMed1993

Preliminary study of the efficacy of insulin aerosol delivered by oral inhalation in diabetic patients.

OBJECTIVE: To maximize deposition of an aerosolized dose of insulin (mean +/- SD = 0.99 +/- 0.06 U/kg of body weight) in the lungs of subjects with non-insulin-dependent diabetes mellitus (NIDDM), and investigate its efficacy in normalizing plasma glucose levels during the fasting state. DESIGN: Nonrandomized, placebo-controlled trial. SETTING: A primary care facility. PATIENTS OR OTHER PARTICIPANTS: Six nonobese, nonsmoking volunteers with NIDDM. No subjects withdrew from the study. INTERVENTION: Aerosolized insulin was administered by oral inhalation after a 12-hour period of fasting. Aerosol was generated by a raindrop nebulizer from regular 500 U/mL pork insulin. During inhalation, inspiratory flow was regulated at 17 L/min. Plasma samples were collected after inhalation and analyzed for insulin and glucose levels. MAIN OUTCOME MEASURES: Plasma insulin and glucose levels. RESULTS: Deposition of the aerosol was maximized within the lungs, with 79% +/- 17% of the inhaled dose depositing below the larynx. Geometric mean fasting plasma insulin level was 71 pmol/L (11.8 microU/mL), rising to 269 pmol/L (44.8 microU/mL) after insulin inhalation. Average time to peak insulin level was 40 +/- 34 minutes. The mean fasting plasma glucose level (12.63 +/- 2.59 mmol/L [225.5 +/- 46.3 mg/dL]) was reduced to within the normal range in five subjects and was almost normal in the sixth subject (5.52 +/- 0.89 mmol/L [98.6 +/- 15.9 mg/dL]). Average maximum decrease in plasma glucose from baseline was 55% +/- 10% (n = 6) vs 13% +/- 9% after placebo aerosol inhalation (n = 3). No side effects were reported following insulin or placebo aerosol inhalation. CONCLUSIONS: These preliminary results indicate that a dose of approximately 1.0 U of aerosolized insulin per kilogram of body weight, delivered by oral inhalation and deposited predominantly within the lungs, is well tolerated and can effectively normalize plasma glucose levels in patients with NIDDM.

Administration, Inhalation↗
PubMed1995

[Basic evaluation of nitric oxide inhalation therapy].

We studied the site of action of nitric oxide (NO) and the dose-response relationship between inhaled NO and PaO2. We also measured nitrosyl-hemoglobin (Hb-NO) levels in arterial and mixed venous blood and NO2 levels in our NO inhalation system to confirm the safety of NO inhalation. In an ovine model of ARDS induced by lung lavage, pressure-flow plots indicated that the site of action of inhaled NO was close to the alveoli. During hypoxia, pulmonary artery pressure decreased as the concentration of inhaled NO increased; PaO2 peaked at 10-20 ppm NO. The levels of Hb-NO in arterial and mixed venous blood during inhalation of 40-60 ppm NO under hypoxic conditions were greater than the levels under normoxic conditions, but Hb-NO still accounted for less than 0.1% of the total Hb. Less than 0.1 ppm on NO2 was generated during inhalation of 5 ppm NO. In conclusion, inhaled NO can dilate pulmonary vessels near alveoli without lowering the O2 carrying capacity of blood. In the present system, only a negligible amount of NO2 was produced.

Administration, Inhalation↗
PubMed1996

Different effect of inhaled nitric oxide on yucatan micropig with and without congenital ventricular septal defect.

A strain of Yucatan micropigs is known to have heritable ventricular septal defects (VSDs) and thus may develop overflow pulmonary hypertension. Since inhaled nitric oxide (NO) selectively dilates pulmonary vessels, we determined its hemodynamic and co-agulatory effects in this new animal model. Eight Yucatan micropigs were anesthetized with midazolam, piritramide (a synthetic opioid) and vecuronium bromide. The presence and the size of the VSD were determined by using transesophageal color flow Doppler echocardiography. Four animals showed VSDs of 1-2 mm size. Inhaled NO was then administered with increasing inspired concentrations of 0, 5, 10, 20, 40, 80 and again 0 ppm NO for 10-min periods. NO inhalation did not affect heart rate, right cardiac output, mean arterial pressure, pulmonary arterial wedge pressure, or central venous pressure. Inhaled NO in animals with proven VSDs decreased pulmonary artery pressure (PAP) in a dose dependent manner; 5 ppm NO reduced mean PAP from 25 +/- 2.3 mm Hg to 18 +/- 0.8 mm Hg (p < 0.05), while pulmonary vascular resistance (PVR) decreased from 954 +/- 143 dyn.cm. s-5 to 661 +/- 88 dyn.cm.s-5 (p < 0.01) at the same dose. The maximum reduction in mean PAP and PVR occurred when 80 ppm NO was inhaled. Yucatan micropigs without VSDs did not respond hemodynamically to NO inhalation. Methemoglobin levels remained unchanged during the entire study. Platelet function was assessed according to the method of BREDDIN and BORN (BORN 1962). Initial aggregation and slope were affected when NO inhalation commenced. Yucatan micropigs with VSDs may represent a suitable model for further research of the in vivo effects of inhaled NO.

Administration, Inhalation↗
PubMed1996

Acute response to inhaled nitric oxide in newborns with respiratory failure and pulmonary hypertension.

OBJECTIVE: Systemic oxygenation is improved by inhaled nitric oxide therapy in some newborns with respiratory failure and pulmonary hypertension. Our results with inhaled nitric oxide were reviewed to determine factors associated with an acute improvement in systemic oxygenation. METHODS: Newborns with oxygenation indices of 25 to 40 were prospectively randomized to receive conventional therapy with or without 20 ppm inhaled nitric oxide. All newborns with oxygenation indices greater than 40 were treated with inhaled nitric oxide. Hemodynamic, blood gas, and Doppler ultrasound measurements were performed before and after 30 to 60 minutes of observation or therapy. The severity of lung disease was classified by the chest radiograph as: (1) normal or focal disease; (2) moderate diffuse disease-diffuse lung disease with well-defined heart borders; or (3) severe diffuse disease-diffuse lung opacification with indistinct heart borders. RESULTS: Heart rate, blood pressure, and ductal diameters did not change. Blood gases and ductal shunting acutely improved only in patients treated with inhaled nitric oxide. Patients with normal lung fields or focal disease had the greatest degree of improvement in systemic oxygenation. Changes in oxygenation were not influenced by gestational age, baseline blood gases, the proportion of right-to-left ductal shunting, prior treatment with a surfactant, or the use of conventional or high-frequency jet ventilation. Collectively, blood gases and ductal shunting did not improve with inhaled nitric oxide in patients with lung hypoplasia or severe diffuse lung disease. Sustained improvement in oxygenation occurred in 87% of patients with oxygenation indices greater than 40 in whom oxygenation indices less than 40 acutely developed after exposure to nitric oxide, whereas 90% of patients in whom oxygenation indices less than 40 did not acutely develop were treated with extracorporeal membrane oxygenation or ultimately died. CONCLUSIONS: Inhaled nitric oxide acutely improves systemic oxygenation in many newborns with respiratory failure and pulmonary hypertension. The diagnosis and chest radiograph are helpful in identifying patients who will have favorable acute responses to therapy. In patients with severe hypoxemia, the need for invasive support with extracorporeal membrane oxygenation may be determined by an acute trial of inhaled nitric oxide.

Acute Disease↗
PubMed1996

[Inhaled corticosteroid in out-patient management of asthma].

In 1988, we started to change our treatment policy, away from a polypharmaceutical approach including oral bronchodilators and oral anti-allergic agents available in Japan, toward an inhalation therapy including inhaled corticosteroids and inhaled beta-agonist. A marked decline in the number of asthma admission and death from asthma started coincidentally with the increased use of inhaled corticosteroid which were followed by the decreased use of inhaled beta-agonists and oral anti-asthma agents. The intensification of patient education mainly consisting of emphasizing on better understanding of benefits of inhalation therapy and a self-management is likely to play an important role in enhancing a protective effects of inhaled corticosteroids. Despite some limitations of inhaled corticosteroids, such as poorer dose response in elderly asthmatics and/or patients with severe disease, further introduction of guide-line treatment will result in a measurable improvement on asthma control.

Administration, Inhalation↗