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Proteinase-activated receptors, targets for kallikrein signaling.

Serine proteinases like thrombin can signal to cells by the cleavage/activation of proteinase-activated receptors (PARs). Although thrombin is a recognized physiological activator of PAR(1) and PAR(4), the endogenous enzymes responsible for activating PAR(2) in settings other than the gastrointestinal system, where trypsin can activate PAR(2), are unknown. We tested the hypothesis that the human tissue kallikrein (hK) family of proteinases regulates PAR signaling by using the following: 1) a high pressure liquid chromatography (HPLC)-mass spectral analysis of the cleavage products yielded upon incubation of hK5, -6, and -14 with synthetic PAR N-terminal peptide sequences representing the cleavage/activation motifs of PAR(1), PAR(2), and PAR(4); 2) PAR-dependent calcium signaling responses in cells expressing PAR(1), PAR(2), and PAR(4) and in human platelets; 3) a vascular ring vasorelaxation assay; and 4) a PAR(4)-dependent rat and human platelet aggregation assay. We found that hK5, -6, and -14 all yielded PAR peptide cleavage sequences consistent with either receptor activation or inactivation/disarming. Furthermore, hK14 was able to activate PAR(1), PAR(2), and PAR(4) and to disarm/inhibit PAR(1). Although hK5 and -6 were also able to activate PAR(2), they failed to cause PAR(4)-dependent aggregation of rat and human platelets, although hK14 did. Furthermore, the relative potencies and maximum effects of hK14 and -6 to activate PAR(2)-mediated calcium signaling differed. Our data indicate that in physiological settings, hKs may represent important endogenous regulators of the PARs and that different hKs can have differential actions on PAR(1), PAR(2), and PAR(4).

Amino Acid Sequence↗

Idiopathic segmental infarction of the greater omentum. Report of a case mimicking appendicitis.

Idiopathic segmental infarction of the greater omentum seldom enters into the differential diagnosis of acute abdominal pain, and diagnosis is usually not made until laparotomy. A preoperative clue to the diagnosis may be the lack of systemic gastrointestinal symptoms in the presence of impressive abdominal findings. Intraoperative clues are serosanguineous peritoneal fluid but normal appendix, distal small bowel, and mesentery. In this setting, careful examination of the omentum through the initial incision is recommended. Once identified, the infarcted omentum should be completely excised to prevent formation of adhesions and possible sepsis. In the case reported here, the serendipitous discovery of edematous omentum prompted a thorough--but technically difficult--exploration of the greater omentum, which eventually led to the correct diagnosis.

Adult↗

Structural characterization of metabolites after the microbial degradation of type A trichothecenes by the bacterial strain BBSH 797.

Contamination of feed with trichothecenes, a group of Fusarium mycotoxins, leads to losses in performance due to their immunosupressive effects and the negative effect on the gastrointestinal system in animal production. A possible way of detoxification is microbial degradation, which was the focus of this study. A bacterial strain--BBSH 797--which can degrade some mycotoxins of the trichothecene group, has already been isolated. It transforms deoxynivalenol (DON) into its metabolite DOM-1, the non-toxic deepoxide of DON. Analogous to the microbial degradation of DON, the transformation of six different type A trichothecenes was observed. The metabolites appearing were characterized by GC-MS after derivatization with TRI-SIL TBT. Two metabolites were additionally, identified by liquid chromatography-mass spectrometry with particle beam interface (LC-PB-MS) with electron impact (EI)-ionization mode. The major finding was that scirpentriol was completely transformed into its non-toxic metabolite deepoxy scirpentriol, while the mycotoxin T-2 triol underwent a more complicated metabolism. According to the study, T-2-triol was degraded into its non-toxic deepoxy form and into T-2 tetraol, which was then further metabolized to deepoxy T-2 tetraol. GC-MS after derivatization with TRI-SIL TBT was suitable for the structural characterization of trichothecenes and their degradation products. Besides the mass spectra of already known degradation products, spectra of new metabolites could be recorded by LC-PB-MS.

Animals↗

Spontaneous haemothorax: an uncommon presentation of Glanzmann thrombasthenia.

UNLABELLED: Glanzmann thrombasthenia is a rare hereditary qualitative platelet disorder characterized by a lifelong bleeding tendency due to quantitative and qualitative abnormalities of the platelet integrin alpha(IIb)beta3. Common clinical manifestations include purpuric type skin bleeding, prolonged bleeding from minor cuts, epistaxis, gingival bleeding and menorrhagia. Less frequently, gastrointestinal system bleeding may occur. Haemarthrosis, haematuria, intracranial and visceral haemorrhage are very rare symptoms. This study reports a 3-y-old girl with Glanzmann thrombasthenia who presented with life-threatening haemothorax. There was no history of recent trauma or drug usage and no vascular or parenchymal abnormalities to explain the development of haemothorax. CONCLUSION: To the authors' knowledge this is the first case of Glanzmann thrombasthenia complicated by spontaneous haemothorax.

Child, Preschool↗

Tuberculosis.

Tuberculosis is caused by Mycobacterium tuberculosis, transmitted primarily by inhalation of aerosolized droplets containing the organisms. There is an infection of the respiratory tract and the tubercle bacilli spread via lymphatic system and bloodstream to many different organs. Generally, the pulmonary tuberculosis infections are asymptomatic and a positive skin test result is the only indication of it. Approximately 10% of infected individuals develop active disease. Immunosuppression caused by systemic diseases or medication increases the risk of developing tuberculosis. In addition to the pulmonary tract, tuberculosis may affect many organs and systems, including lymph nodes, larynge, middle ear, genitourinary tract, musculoskeletal system, central nervous system, gastrointestinal tract, pericardium, and skin. Ocular involvement is an uncommon event in tuberculous infection, and there are several presentations involving the iris, ciliary body, choroid, retina and optic nerve. The diagnosis is based in the detection of mycobacteria in fluids and tissues. If there is no available material for analysis, a presumptive diagnosis is made and therapeutic test initiated. The therapy is based in anti-tuberculous drugs and corticosteroids. The standard treatment protocol in Brazil includes isoniazid, rifampim, and pyrazinamid for two months, followed by isoniazid and rifampin for four months for susceptible organisms. Alternative regimens are necessary in the presence of drug resistance.

Antibiotics, Antitubercular↗

Pinealectomy does not affect the healing of experimental colonic anastomoses.

Gastrointestinal system anastomoses, especially colonic anastomoses, have significant morbidity and mortality despite recent technical improvements. Besides regulating the circadian rhythm, the pineal gland and its main neurohormone product melatonin have widespread actions in the organism. The purpose of this study was to investigate the effects of pinealectomy on the healing of colonic anastomoses. One hundred male albino Wistar rats were used in this study. The rats were separated into three groups: control, pinealectomy, and sham groups. In the control group, only colonic resection and anastomoses were performed. Following pinealectomy, colonic anastomosis was performed 2 weeks later on one half and 2 months later on the other half of the pinealectomy group. Only craniotomy was performed on the sham group, and the rats were separated and evaluated like the pinealectomy group. Colonic anastomoses were evaluated on postanastomotic day 3 and 7 by measuring the bursting pressure and the hydroxyproline levels in the anastomotic segments. There was no difference in the bursting pressure measurements between the groups on both postoperative day 3 and 7. Although hydroxyproline levels were different between groups on both postanastomotic days 3 and 7, it has been observed that neither normal nor anastomotic hydroxyproline levels influenced the anastomotic bursting pressure measurements. The percent deviation from the normal values was compared in the anastomotic segments, and no differences were found regarding the bursting pressure and hydroxyproline levels. It was concluded that pinealectomy has no effect on the healing of colonic anastomoses.

Anastomosis, Surgical↗

Primary duodenal diffuse large cell non-hodgkin lymphoma with involvement of ampulla of Vater: report of 3 cases.

Primary gastrointestinal system lymphomas constitute about one third of all extranodal lymphomas. Duodenal involvement of the lymphoma is a rare condition. Periampullary lymphoma or lymphomatous involvement of ampulla of Vater is even rarer. Since, periampullary lymphoma is not easy to differentiate from epithelial carcinoma of these sites clinically and radiologically, accurate histopathological diagnosis is essential to plan optimal treatment strategy. Obstructive jaundice and the need for some form of drainage procedure and dose modification of the chemotherapy are additional challenges. In this report, we present three cases of duodenal diffuse large cell lymphoma with involvement of ampulla of Vater, two of whom presented with the initial signs of obstructive jaundice. One of the icteric patients was only diagnosed histopathologically following an explorative laparotomy with the initial diagnosis of carcinoma.

Adult↗

A single-blind, randomised, comparative study of clarithromycin and amoxycillin suspensions in the treatment of children with lower respiratory tract infections.

One hundred and forty-five children with signs and symptoms of lower respiratory tract infections were entered into this multicentre, General Practice, investigator-blind study, designed to demonstrate equivalent efficacy between clarithromycin and amoxycillin suspensions. Seventy one children were randomised to treatment with clarithromycin suspension 7.5 mg/kg bodyweight twice daily and 74 to treatment with amoxycillin suspension 125 mg (bodyweight < 25 kg) or 250 mg (bodyweight > or = 25 kg) three times a day according to bodyweight. Duration of therapy was 5-10 days as determined by the investigator. Clinical evaluations were performed pretreatment, during treatment and post-treatment within 72 hours of cessation of therapy. Fifty two children in the clarithromycin group and 57 in the amoxycillin group were clinically evaluable. Both study medications were effective and there were no significant differences between the groups with respect to clinical cure rate (60% for clarithromycin and 63% for amoxycillin), clinical success rate (cure plus improvement, 96% for clarithromycin and 95% for amoxycillin) or rate of resolution of clinical signs and symptoms in clinically evaluable patients. The intention to treat analysis for all patients entered similarly showed no significant differences in efficacy. The two treatment groups did not differ significantly with respect to incidence or severity of adverse events which were generally mild and associated with the gastrointestinal system. Therapy was withdrawn because of adverse events in three children on clarithromycin and one on amoxycillin. Bacteriological cure rates could not be determined because of an insufficient number of evaluable pre-treatment sputum samples.(ABSTRACT TRUNCATED AT 250 WORDS)

Amoxicillin↗

Chronic arsenic toxicity in Bangladesh and West Bengal, India--a review and commentary.

Fifty districts of Bangladesh and 9 districts in West Bengal, India have arsenic levels in groundwater above the World Health Organization's maximum permissible limit of 50 microg/L. The area and population of 50 districts of Bangladesh and 9 districts in West Bengal are 118,849 km2 and 104.9 million and 38,865 km2 and 42.7 million, respectively. Our current data show arsenic levels above 50 microg/ L in 2000 villages, 178 police stations of 50 affected districts in Bangladesh and 2600 villages, 74 police stations/blocks of 9 affected districts in West Bengal. We have so far analyzed 34,000 and 101,934 hand tube-well water samples from Bangladesh and West Bengal respectively by FI-HG-AAS of which 56% and 52%, respectively, contained arsenic above 10 microg/L and 37% and 25% arsenic above 50 microg/L. In our preliminary study 18,000 persons in Bangladesh and 86,000 persons in West Bengal were clinically examined in arsenic-affected districts. Of them, 3695 (20.6% including 6.11% children) in Bangladesh and 8500 (9.8% including 1.7% children) in West Bengal had arsenical dermatological features. Symptoms of chronic arsenic toxicity developed insidiously after 6 months to 2 years or more of exposure. The time of onset depends on the concentration of arsenic in the drinking water, volume of intake, and the health and nutritional status of individuals. Major dermatological signs are diffuse or spotted melanosis, leucomelanosis, and keratosis. Chronic arsenicosis is a multisystem disorder. Apart from generalized weakness, appetite and weight loss, and anemia, our patients had symptoms relating to involvement of the lungs, gastrointestinal system, liver, spleen, genitourinary system, hemopoietic system, eyes, nervous system, and cardiovascular system. We found evidence of arsenic neuropathy in 37.3% (154 of 413 cases) in one group and 86.8% (33 of 38 cases) in another. Most of these cases had mild and predominantly sensory neuropathy. Central nervous system involvement was evident with and without neuropathy. Electrodiagnostic studies proved helpful for the diagnosis of neurological involvement. Advanced neglected cases with many years of exposure presented with cancer of skin and of the lung, liver, kidney, and bladder. The diagnosis of subclinical arsenicosis was made in 83%, 93%, and 95% of hair, nail and urine samples, respectively, in Bangladesh; and 57%, 83%, and 89% of hair, nail, and urine samples, respectively in West Bengal. Approximately 90% of children below 11 years of age living in the affected areas show hair and nail arsenic above the normal level. Children appear to have a higher body burden than adults despite fewer dermatological manifestations. Limited trials of 4 arsenic chelators in the treatment of chronic arsenic toxicity in West Bengal over the last 2 decades do not provide any clinical, biochemical, or histopathological benefit except for the accompanying preliminary report of clinical benefit with dimercaptopropanesulfonate therapy. Extensive efforts are needed in both countries to combat the arsenic crisis including control of tube-wells, watershed management with effective use of the prodigious supplies of surface water, traditional water management, public awareness programs, and education concerning the apparent benefits of optimal nutrition.

Adult↗

Amyloid goiter in Familial Mediterranean Fever (FMF): a clinicopathologic study of 10 cases.

FMF Amyloidosis is an important etiological factor of end stage renal disease (ESRD) in Mediterranean Countries. Apart from major target organs as cardiovascular, respiratory and gastrointestinal system, endocrine organs can also be involved. We planned to investigate the thyroid involvement in our amyloidosis group. The aim of this study was to determine clinical characteristics of amyloid goiter in FMF patients and the abnormalities of thyroid function, as well as to identify pathologic characteristics. Twenty-two hemodialysis patients (mean age 34.1 +/- 14 years, range 17-68) whose ESRD secondary to FMF amyloidosis were evaluated with physical examination, serum levels of thyroid hormones, ultrasound examination of thyroid glands, thyroid syntigraphic studies. Goiter was found in 10 patients (4 male, 6 female) having enlarged neck mass (mean age 35 +/- 14 years, range 23-64). The serum levels of thyroid hormones and TSH were normal in 4 patients. Other four cases had euthyroid sick syndrome. Only one patient developed tender enlarged neck mass with subacute thyroiditis symptoms and one had primary hyperthyroidism. Ultrasound examination showed; hypoecoic nodules in 6 patients diffuse multinodular enlargement in 4 patients. Thyroid syntigraphic studies revealed hypoactive nodules in 7 patients and hyperactive nodules in 3 patients. After the laboratory tests were completed, in 10 patients diagnosis were made with fine needle aspiration biopsy. Of 10 patients 5 underwent subtotal thyroidectomy. Immunohistochemical evaluation demonstrated the presence of amyloid AA immunoreactivity in all cases. In conclusion fine needle aspiration from the thyroid when enlarged is useful in the diagnosis of suspected amyloidosis, especially since it is a safe, easily performed procedure. With the help of amyloid goiter diagnosis the patient's prognosis on hemodialysis and with renal transplantation can be predicted. Amyloid goiter must be searched in hemodialysis patients especially in Mediterranean Countries.

Adult↗

Methylphenidate blood levels and therapeutic response in children with attention-deficit hyperactivity disorder: I. Effects of different dosing regimens.

BACKGROUND AND PURPOSE: Methylphenidate (MPH) is a drug of choice for treating attention-deficit/hyperactivity disorder (ADHD), although its use has been complicated by its short duration of action. The development of ideal long-acting preparations requires detailed understanding of the pharmacokinetic and pharmacodynamic consequences of complex dosing regimens. The purpose of this study was to ascertain if administration paradigms that produce stable or rising MPH levels alter the rate with which MPH is absorbed, and to determine how effectively long-acting administration paradigms compare with thrice daily administration of immediate-release MPH. METHOD: Forty-eight boys diagnosed with ADHD (mean age 10.6 +/- 1.1 year) participated in this double-blind, parallel group study to evaluate the pharmacokinetics and efficacy and of 1 mg/kg/day MPH administered in five different paradigms and placebo. Objective measures of activity and attention (McLean Motion Attention Test; M-MAT) and plasma measures of d- and l-MPH were obtained hourly during the course of a 12-hour laboratory session. RESULTS: The rate of absorption and elimination of d-MPH was dependent on the pattern of administration, particularly on the initial bolus concentration. This suggests that d-MPH may act on the gastrointestinal system to slow absorption of additional d-MPH. There were significant differences among regimens on time course and degree of therapeutic response. Pulsatile administration produced greater improvement than escalating levels.

Attention↗

Postpartum changes in pattern of gastrointestinal regulatory peptides in human milk.

Concentrations of gastrointestinal neuropeptides in serial human milk samples from 28 women were determined over the first 6 postpartum mo. All gut neuropeptides were present during the first postpartum week. Gastric inhibitory peptide (GIP) concentration remained constant but the others decreased by 6 wk. Bombesin concentration in breast milk was threefold greater than concurrent plasma concentration (p less than 0.001); all other neuropeptides were at the same or lower concentrations in milk than in plasma. At 36 wk gestation plasma concentrations of GIP were lower and concentrations of vasoactive intestinal peptide were higher than concentrations in age-matched control subjects. Concentrations of gastrin and cholecystokinin, bombesin, peptide histidine methionine, peptide YY, and neurotensin in plasma were similar in pregnant and nonpregnant women. These gut neuropeptides in milk may be important for growth and maturation of the gastrointestinal system in neonates. Bombesin may contribute to neonatal hypergastrinemia.

Adult↗

Consequences of severe copper deficiency are independent of dietary carbohydrate in young pigs.

The ability of carbohydrates (CHO), such as fructose and sucrose, to aggravate copper deficiency in rats and the recent dietary trends of Western human populations led to the suggestion that the Cu X CHO interaction may be pertinent to public health. This hypothesis was tested with pigs because their cardiovascular and gastrointestinal systems closely resemble those of humans. Weanling pigs were fed a diet containing either 59% sucrose or cornstarch with either deficient (0.8 mg/kg diet) or adequate (6.4 mg/kg) copper for 10 wk. Plasma and tissue copper, the activities of plasma ceruloplasmin ferroxidase and erythrocyte Cu,Zn-superoxide dismutase, hematocrits, and serum cholesterol and triglyceride were all decreased (p less than 0.05) and relative cardiac mass was increased (p less than 0.05) by severe dietary copper deficiency. The type of dietary CHO did not differentially influence the values of these variables. Thus, these data fail to support the hypothesis that the Cu X CHO interaction observed in rats represents a health risk for humans.

Animals↗

Cellular adhesion molecules in urologic malignancies.

Cell adhesion molecules (CAMs) are important in cell-cell interaction and interactions between cells and components of the extracellular matrix. CAMs have been associated with invasion and metastasis in a wide variety of human malignancies, including tumors of the genitourinary tract. Cadherins are transmembrane glycoproteins that bind cells by homophilic, homotypic interactions. Loss of expression of E-cadherin has been associated with dedifferentiation, invasion, and metastasis in prostate cancer and transitional cell neoplasia of the urinary bladder. CD44, a family of transmembrane glycoproteins principally involved in cell-extracellular matrix interactions, also has been associated with invasion and metastasis in urologic malignancies. Through alternative splicing, a variety of CD44 isoforms can be expressed that can undergo extensive posttranslational modification. CD44 variants have been associated with metastasis in a variety of human malignancies, particularly in the gastrointestinal system. Although loss of expression of CD44 standard form has been associated with aggressive prostate gland and bladder cancers, no specific isoform has been associated with metastasis of these neoplasms. Integrins are transmembrane glycoproteins with wide cellular distribution that bind a variety of extracellular matrix components. Integrins have been studied extensively in prostate cancer in which altered integrin expression has been associated with malignant prostatic epithelium. Additional adhesion molecules that have been studied to a variable degree in urologic malignancies include selectins and the immunoglobulin super-family. CAMs are fundamental to diverse biologic processes and appear capable of regulating intracellular signaling events that appear to have significant importance in human malignancy, including cancers of the urogenital tract.

Cell Adhesion Molecules↗

Signaling pathways in self-renewing hematopoietic and leukemic stem cells: do all stem cells need a niche?

Many adult tissue stem cells, such as the cells of the hematopoietic system, gastrointestinal epithelium, brain, epidermis, mammary gland and lung have now been identified, all of them fulfilling a crucial role in supplying organisms with mature cells during normal homeostasis as well as in times of tissue generation or repair. Two unique features characterize adult stem cells: the ability to generate new pluripotent stem cells (to self-renew) and the ability to give rise to differentiated progeny that has lost its self-renewal capacity. Our understanding of the mechanisms that determine whether, where and when a stem cell will self-renew or differentiate is still limited, but recent advances have indicated that the stem cell microenvironment, or niche, provides essential cues that direct these cell fate decisions. Moreover, loss of control over these cell fate decisions might lead to cellular transformation and cancer. This review addresses the current understandings of the molecular mechanisms that regulate hematopoietic stem cell self-renewal in the niche and how leukemic transformation might change the dependency of leukemic stem cells on their microenvironment for self-renewal and survival.

Animals↗

Sonic hedgehog promotes CD4+ T lymphocyte proliferation and modulates the expression of a subset of CD28-targeted genes.

Sonic hedgehog (Shh) is a crucial morphogen in the development of numerous tissues and organs, including the nervous system, gastrointestinal tract and lung. Recent findings suggest that Shh plays an important role in thymocyte development and peripheral T cell function. Here we report that the Shh receptors, patched and smoothened, are expressed in resting and activated T cells and their expression is regulated upon T cell activation. Shh protein is also detected on the surface of freshly isolated T cells. Although exogenous Shh alone does not activate resting T cells, it exhibits co-stimulatory activity which is reflected in its ability to potentiate CD3-mediated proliferation and cytokine production by CD4(+) T cells. The co-stimulatory effect is most prominent at sub-optimal TCR stimulation level. Gene expression analysis reveals that Shh signaling in CD4(+) T cells modulates a different set of transcriptional targets from that in neuronal cells. Furthermore, Shh co-stimulation modulates the expression of a subset of CD28-responsive genes, including cyclin A and B cell translocation gene 2.

Animals↗

A randomized, comparative study to evaluate the efficacy and tolerability of a 3-day course of azithromycin versus a 10-day course of co-amoxiclav as treatment of adult patients with lower respiratory tract infections.

Clinical and bacteriological efficacy and tolerability of azithromycin (500 mg once daily for 3 days) and those of a 10-day regimen of co-amoxiclav (37 mg three times daily) were evaluated in a large-scale, double-blind comparative study of 369 patients (> or = 18 years old) with acute lower respiratory tract infections. After treatment, 165/173 (95%) azithromycin- and 166/173 (96%) co-amoxiclav-treated patients had responded satisfactorily (cure or improvement). Baseline pathogens (mainly Streptococcus pneumoniae and Haemophilus influenzae) were eradicated in 82/82 (100%) azithromycin- and 73/74 (99%) co-amoxiclav-treated patients who were bacteriologically assessable. Adverse events, which were predominantly of mild to moderate severity and mostly affected the gastrointestinal system, were recorded in 13/186 (7%) azithromycin- and 19/183 (10%) co-amoxiclav-treated patients. Only two (1%) azithromycin-treated patients discontinued treatment due to adverse events compared with eight (4%) who received co-amoxiclav. The results show that azithromycin at a dose of 500 mg once daily for 3 days is an effective and safe alternative to a 10-day, three-times-daily course of co-amoxiclav in the treatment of lower respiratory tract infections in adults.

Adolescent↗

Once-daily, 3-day azithromycin versus a three-times-daily, 10-day course of co-amoxiclav in the treatment of adults with lower respiratory tract infections: results of a randomized, double-blind comparative study.

A 3-day regimen of azithromycin (500 mg once daily) and a 10-day regimen of co-amoxiclav (625 mg three times daily) were compared in a double-blind study of 67 patients with acute infectious exacerbations of chronic bronchitis (AIECBs, n = 54), acute bronchitis (n = 7), or pneumonia (n = 6). In patients treated with azithromycin, satisfactory clinical responses (cure or improvement) were seen in 24/28 (86%) patients with AIECBs, 2/4 (50%) with acute bronchitis and 2/2 (100%) with pneumonia. Responses were satisfactory in 24/26 (92%), 4/4 (100%) and 4/4 (100%) patients, respectively, receiving co-amoxiclav. Streptococcus pneumoniae and Haemophilus influenzae were the commonest pathogens isolated at baseline. At the end of treatment, baseline pathogens were eradicated in 9/10 microbiologically-assessable patients treated with azithromycin and in 10/10 treated with co-amoxiclav. Adverse events related or possibly related to treatment occurred in five patients in each treatment group; the majority of these events affected the gastrointestinal system. One patient in each treatment group discontinued therapy because of adverse events. The study, therefore, demonstrates that 500 mg azithromycin administered once daily for 3 days is as efficacious and well tolerated as co-amoxiclav given three times daily for 10 days in the domiciliary treatment of adults with acute lower respiratory tract infections.

Adolescent↗