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In well designed studies in patients with mild to moderate hypertension, combinations of the sustained-release (SR) formulation of the nondihydropyridine calcium channel antagonist verapamil 120 to 240 mg/day and the ACE inhibitor trandolapril 0.5 to 8 mg/day were significantly more effective in reducing sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) from baseline than placebo. In most randomised studies, combinations of verapamil SR 120 to 240 mg/day and trandolapril 0.5 to 8 mg/day were significantly more effective in lowering sitting DBP and SBP than the corresponding monotherapies administered at the same dosage. Trandolapril/verapamil SR 2/180 mg/day provided significantly more effective 24-hour ambulatory blood pressure (BP) control than of the corresponding monotherapies. Moreover, trandolapril/verapamil SR reduced BP in patients inadequately controlled with either of the corresponding monotherapies. The antihypertensive efficacy of trandolapril/verapamil SR 2/180 mg/day was generally similar to that of other combinations of antihypertensive agents (metoprolol/hydrochlorothiazide, atenolol/chlorthalidone, lisinopril/hydrochlorothiazide, enalapril/hydrochlorothiazide) in patients with hypertension, including those with type 2 diabetes mellitus. Trandolapril/verapamil SR reduced BP in patients with hypertension and type 2 diabetes or primary renal disease, Black patients and elderly patients. Trandolapril/verapamil SR was more effective than the individual components administered as monotherapy in reducing proteinuria in patients with type 2 diabetes or primary renal disease. Trandolapril/verapamil SR had a neutral or beneficial effect on metabolic parameters (glucose, insulin, lipids) in patients with hypertension, including those with type 2 diabetes. Trandolapril/verapamil SR preserved left ventricular function in patients with heart failure. Fewer cardiac events occurred after therapy with trandolapril/verapamil SR than after trandolapril alone in post-myocardial infarction patients with congestive heart failure. The incidence of adverse events in recipients of trandolapril/verapamil SR was similar to that of the individual components, and that of other combination therapies. In placebo-controlled trials conducted in the US, headache, upper respiratory tract infections, cough, constipation, atrioventricular block (first degree) and dizziness were the most commonly reported adverse events in recipients of combinations of verapamil SR (120 to 240 mg/day) and trandolapril (0.5 to 8 mg/day). In conclusion, the fixed-dose combination of trandolapril/verapamil SR is an effective treatment for patients with hypertension, including those with type 2 diabetes. Trandolapril/verapamil SR tended to be more effective than monotherapy with either verapamil SR or trandolapril, and generally showed antihypertensive efficacy similar to that of other combination antihypertensive therapies. Current data support the use of trandolapril/verapamil SR as an alternative treatment when monotherapy with either agent is not effective. Data from large clinical trials currently being conducted will assist in fully defining the role of trandolapril/verapamil SR as a cardio- and renoprotective agent.
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PMID:Fixed combination trandolapril/verapamil sustained-release: a review of its use in essential hypertension. 1242 Nov 12

A non-invasive alternative to insulin injections would represent a major improvement for Type 1 and 2 insulin-treated patients. The lung is the only route which allows bio-availability of insulin, approaching 10% without absorption enhancers. However, the reproducibility of the plasma response to the pulmonary insulin is similar to subcutaneous insulin analogues, that is to say, relatively poor. In the Exubera Project, the device is a dry powder inhaler. The insulin powder (Aventis) is packaged into a single dose blister containing 1 or 3 mg; the 1 mg blister corresponding to approximately 3 U of insulin. Phase II studies have shown similar efficacy than regular insulin. Data are available on 328 Type 1 and 309 Type 2 patients after 6 months of Phase III trials. The inhaled insulin group developed increased insulin antibodies. A total of 25% of the patients experienced cough after inhalation. The number of overall and severe hypoglycaemic episodes were similar in the two groups. Pulmonary function tests remained stable and normal except for minor reductions of carbon monoxide diffusion capacity. The AERx IDMS system is a microprocessor-controlled, aqeous mist inhaler. The insulin (regular 100 U/ml, Novo Nordisk) is delivered by 1 U increments. The clinical experience reported with this system so far is limited to 107 Type 2 insulin-treated patients. The results are similar to those obtained in the Exubera trials. In the Alkermes project, large, porous, regular insulin of low-mass density have been developed by the Advanced Inhalation Project. Results from human studies in normal subjects show similar pharmacokinetics as the two other devices above. Other projects seem less advanced than the projects cited above e.g., Aerodos and Oralin. Current clinical experience with inhaled insulin seems promising. It represents currently the only viable non-invasive alternative to insulin injections. However, long-term local tolerance of the pulmonary tissue is a crucial issue.
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PMID:Inhaled insulin for the treatment of diabetes: projects and devices. 1287 44

Safety and effect intrapulmonary administration (by inhalation) of 60 % honey solution, 10% dextrose or distill water on blood sugar, plasma insulin and C-peptide, blood pressure, heart rate, and peaked expiratory flow rate (PEFR) in normal or diabetic subjects were studied. - Twenty-four healthy subjects, 16 patients with type 11 diabetes mellitus and six patients with hypertension were entered for study. They were underwent complete physical examination and laboratory investigations. Twelve healthy subjects were subjected for distill water inhalation for 10 min, and after one week they received inhalation of honey solution (60% wt/v) for 10 min. Another 12 healthy subjects received inhalation of 10% dextrose for 10 min. Blood glucose level, plasma insulin and C-peptide, blood pressure, heart rate and PEFR were estimated before inhalation and during 2-3 hrs after inhalation, at 30 min intervals. Random blood glucose level was estimated in eight patients with poorly controlled diabetes mellitus, and repeated 30 min after honey inhalation. One week later, fasting blood glucose level was estimated in each patient and blood glucose level was re-estimated during three hrs after honey inhalation, at 30 min intervals. Glucose tolerance test was performed in another eight patients with type-2 diabetes mellitus, and after one week the procedure was repeated with inhalation of honey, which was started immediately after ingestion of glucose. Six hypertensive patients received honey inhalation for 10 min; supine blood pressure and heart rate were measured before and after inhalation. - Results showed that in normal subjects distill water caused mild elevation of blood glucose level, mild lowering of plasma insulin, and significant reduction of plasma C-peptide. 10% dextrose inhalation caused mild reduction of plasma insulin and C-peptide and unremarkable changes in blood glucose level. No significant changes were obtained in blood pressure, heart rate or PEFR after distill water or 10% dextrose inhalation. Honey inhalation caused lowering of blood glucose level and elevation of plasma insulin and C-peptide, mild reduction of blood pressure and up to 11 and 16 percent increase in PEFR. Honey inhalation significantly reduced random blood glucose level from 199 +/- 40.9 mg/dl to 156 +/- 52.3 mg/dl after 30 min (p = 0.0303). Fasting blood glucose level was reduced after honey inhalation during three hr post-inhalation, which was significant at hr three (p<0.05). Intensity of hyperglycemia was significantly lowered in glucose tolerance test when patients received honey inhalation. Systolic and diastolic blood pressure was reduced by honey inhalation in hypertensive patients; significant changes were obtained at 60 and 120 min after inhalation. No adverse effects were observed with inhalation of distill water, 10% dextrose and 60% honey solution except for nasal watery discharge experienced by all subjects and mild cough that was experienced by seven subjects after honey inhalation. - The results demonstrated that honey inhalation was safe and effective in reducing blood glucose level, in normal and diabetic subjects, it could improve glucose tolerance test, elevate plasma insulin and C-peptide and PEFR, and reduce elevated blood pressure in hypertensive patients.
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PMID:Intrapulmonary administration of natural honey solution, hyperosmolar dextrose or hypoosmolar distill water to normal individuals and to patients with type-2 diabetes mellitus or hypertension: their effects on blood glucose level, plasma insulin and C-peptide, blood pressure and peaked expiratory flow rate. 1291 66

Severe and resistant hypoglycemia occurred in two patients with diabetes mellitus who were receiving concomitant gatifloxacin and glyburide. An 84-year-old woman treated with glyburide for type 2 diabetes mellitus experienced, for the first time, a severe episode of hypoglycemia after 2 days of gatifloxacin 400 mg/day for nonproductive cough. Her blood glucose level on hospital admission was 28 mg/dl. Gatifloxacin and glyburide were discontinued, and the patient was treated with intravenous dextrose infused over 36 hours. Glyburide was restarted before her discharge, with no recurrence of hypoglycemia. A 79-year-old man with type 2 diabetes mellitus treated with glyburide was prescribed gatifloxacin 400 mg/day for pneumonia. After 1 day of therapy, the patient was admitted to the emergency department in a coma. His blood glucose level was 18 mg/dl. Despite discontinuation of gatifloxacin and oral hypoglycemic therapy, hypoglycemia was reversed only after administration of multiple boluses of intravenous dextrose, followed by intravenous dextrose infused over 48 hours. On hospital day 7, gliclazide and levofloxacin were started; the patient experienced no recurrence of hypoglycemia and was discharged on day 10. Several cases of severe and resistant hypoglycemia associated with gatifloxacin therapy have been reported in the recent literature. Although the exact mechanism is not fully understood, it may be linked to a gatifloxacin-induced closing of the adenosine 5'-triphosphate-sensitive potassium channels in the pancreatic beta cells, leading to insulin secretion. The onset of hypoglycemia in relation to the start of gatifloxacin suggests that the drug precipitated this adverse event. Patients receiving oral hypoglycemic agents are at greater risk of experiencing gatifloxacin-induced hypoglycemia than patients not receiving these agents. Clinicians should be aware of this potentially life-threatening adverse event and monitor blood glucose levels in all patients receiving concomitant oral hypoglycemic agents and gatifloxacin.
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PMID:Severe and resistant hypoglycemia associated with concomitant gatifloxacin and glyburide therapy. 1530 56

There are promising data in the field of inhaled insulin. This article describes the current devices being developed for insulin delivery via inhalation. Encouraging advanced clinical data are available in Type 1 diabetes, where inhaled insulin is used in conjunction with basal insulin. Moreover, patients with Type 2 diabetes who have failed oral therapy show improved control when inhaled insulin therapy is initiated. Safety data show that cough is the most common side effect. Pulmonary function tests have shown some changes in carbon monoxide diffusion in the lung. Further studies are needed to clarify the significance of this finding. Inhaled insulin appears to be a non-invasive, well-tolerated and -liked modality of treatment, with potential in both Type 1 and 2 diabetes.
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PMID:Inhaled insulin: recent advances in the therapy of Type 1 and 2 diabetes. 1557 76

Mucormycosis is an extremely rare case of pulmonary mycosis, its prognosis is very poor, and known as an opportunistic infection among immunocompromised hosts accompanied with other primary chronic disease. We report here a case of bilateral lower lobectomies carried out by two-stage operation for pulmonary mucormycosis combined with diabetes mellitus (type I) and severe resistance to an antimycobiotics under biblicographical considerations. A 36-year-old female was diagnosed as a diabetes mellitus (type I), and has been administrated with an insulin injection in 1989 at the age of 22-year-old. The patient was suffered a dry cough in June and the bilateral abnormal shadows were pointed out by the chest X-ray film in November, 2002. By transbronchial lung biopsy, Mucor fungus was confirmed in grannulomatous lung specimen. Intravenous injection of amphotericin B could not be continued due to the unavoidable side-effects from this agent. As the lung mass shadow was enlarged increasing and strongly suggested an abscess, formation in its focus, and then the left lower lobectomy was performed as the first step of surgical treatment and the right lower lobectomy was done on the postoperative forty-fourth day as the second step. The postoperative prognosis was considerably uneventful. After bilateral lower lobectomies, the patient could try a walk and go upstairs with a moderate dyspnea. A possible surgical resection should be conducted for the pulmonary mucormycosis, when the medicinal therapy showed an uneffectiveness and/or an infectious lesion was shown as restricted lesion.
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PMID:[Bilateral lower lobectomies for pulmonary mucormycosis]. 1560 54

A 41-year-old male with insulin-dependent diabetes mellitus was admitted for an elective arthroscopic release of adhesive capsulitis of his left shoulder. At the end of the surgical procedure, he appeared to regain consciousness but then became unresponsive at the time of tracheal extubation after a violent bout of coughing, developing bilateral up-going plantar responses, decorticate posturing and abnormal pupillary reflexes. He was transferred to the intensive care unit. The following day, the patient made a full neurological recovery. Contrast echocardiography, performed using agitated saline delivered through a femoral venous line, revealed a large patent foramen ovale with evidence of right to left shunting. In the absence of risk factors for air embolism, the clinical diagnosis was one of paradoxical embolism of venous thrombus resulting in brain stem ischaemia. The patient was commenced on life-long aspirin to minimise future embolic risk.
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PMID:Paradoxical embolism through a patent foramen ovale: an unexpected complication of tracheal extubation. 1581 72

Clinical studies of inhaled insulins suggest that pulmonary delivery is well tolerated, with a level of safety comparable to that of subcutaneous (SC) insulin. Questions about the safety of Exubera focus primarily on the lungs, which are probably exposed to two to three times more insulin than an SC injection site. Pulmonary function tests (forced expiratory volume in 1 s and carbon monoxide-diffusing capacity) are routinely included as primary endpoints in Exubera clinical trials. Completed phase 2 and 3 studies up to 4 years in duration indicate that the differences over time in pulmonary function changes between patients treated with Exubera and control patients are small, non-progressive, clinically insignificant and reverse after discontinuation of Exubera therapy. However, it would be useful to understand the physiologic mechanisms responsible for these changes, and ongoing studies should continue to monitor the effects of inhaled insulin on pulmonary function and other parameters in patients with diabetes. In clinical trials of patients with type 1 or 2 diabetes who were treated with Exubera, the only significant clinical adverse effect was cough. This was generally characterized as mild to moderate in severity, decreased over time and was not associated with declines in lung function. Thus, insulin administration via the lung appears to be generally safe in patients with type 1 or 2 diabetes.
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PMID:Unlocking the opportunity of tight glycaemic control. Inhaled insulin: safety. 1613 34

Inhaled human insulin ((insulin human [rDNA origin]) Inhalation Powder) is a prandial insulin approved in the EU and the US for the treatment of adults with diabetes. Its glycaemic control is comparable to subcutaneous insulin in Type 1 and 2 diabetes, and has superior efficacy versus oral antidiabetic agents in Type 2 diabetes. Hypoglycaemia and mild-to-moderate cough are the main side effects. The treatment group differences in pulmonary function occur early, and are small, nonprogressive for up to 2 years and reversible following discontinuation. Patient-reported outcomes data displays higher diabetes treatment satisfaction, improvements in some quality-of-life scores, and treatment preference with inhaled human insulin versus traditional means. Availability of inhaled insulin may increase insulin acceptance and thus improve glycaemic control in patients with diabetes.
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PMID:Inhaled human insulin ((insulin human [rDNA origin]) Inhalation Powder) in diabetes mellitus. 1701 94

Many patients with diabetes mellitus view subcutaneous injections of insulin as a daily burden. Pulmonary delivery of insulin offers an alternative route of administration and may as such improve diabetes treatment. Inhaled insulin provides a rapid absorption of insulin, but with low bioavailability. Phase III clinical trials in type 1 and type 2 diabetes have disclosed clinical equivalence between three inhaled insulin products (Exubera, AErx idMs, and hIIp) and regular human insulin, both in terms of glycaemic control and hypoglycaemic risk. Inhaled insulin cannot be used to replace basal insulin requirements. The most commonly reported adverse effects of inhaled insulin are cough and insulin antibody formation, the clinical significance of which is uncertain. No or minimal deterioration in pulmonary function parameters have been recorded, although studies were typically of short duration. Patients participating in inhaled insulin trials generally expressed satisfaction with the product and chose to remain on it. The availability of inhaled insulin may increase willingness in type 2 diabetic patients to consider insulin therapy. More studies of longer duration are required to determine (pulmonary) safety and cost-effectiveness of inhaled insulin, and to disclose which patients may benefit the most.
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PMID:Efficacy and safety of inhaled insulin in the treatment of diabetes mellitus. 1705 68


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