Sulfonylureas and Repaglinide

Actions of Sulfonylureas and RepaglinideTwo currently available classes of medications that work by in-creasing insulin secretion from the pancreas are the sulfonylureas and the meglitinide repaglinide, a new-er agent. One of the major advantages of sulfonylureas is that these drugs have the capacity to act quickly in responsive patients, generally within a few days of the start of therapy. This is in contrast to metformin and thiazolidinediones, which may take up to several weeks to generate a therapeutic response. Given the time frame within which most patients have had long-standing hyperglycemia, however, it is unusual that correction needs to be so rapid. Ap- proximately 50% of patients with newly diagnosed type 2 diabetes achieve acceptable glycemic control using sulfonylureas, and the primary nonresponder rate is about 15% to 20%. Sulfonylureas work best early in the course of diabetes, when ß-cell function is still sufficient to respond to the stimulation of insulin secretion promoted by these drugs.[19]

Clinical Effects of SulfonylureasSulfonylureas have been used for decades in the United States and can be an effective treatment mo-dality for glycemic regulation. However, these drugs do not directly alleviate the block to insulin action characteristic of the underlying insulin resistance in type 2 diabetes. Evidence is scant to support claims that sulfonylureas have ex-trapancreatic effects; if such effects exist, they would most likely occur secondary to a reduction in glu-cotoxicity once glycemic control improves.

Adverse Effects of SulfonylureasThe practical clinical disadvantages of sulfonylureas include the significant risk of hypoglycemia, especially when diabetes is well-controlled, and the tendency to cause weight gain. There is long-term therapeutic failure in 30% of patients, due to a loss of ß-cell responsiveness as the severity of type 2 diabetes progresses over time.[20] There are long-standing but unproven concerns that the use of sulfonylureas may be associated with increased cardiovascular risk, due to their effects on certain potassium channels in vascular tissues as well as the pancreatic islets. However, the UKPDS demonstrated that there were no adverse effects distinguishing sulfonylureas from other treatments in the intensively treated cohort.[8]

Available SulfonylureasThe many sulfonylurea agents currently available differ in their clinical potency and recommended dose range (Table 8). The longer-acting sulfonylureas with once-a-day dosing that are widely used include the glipizide sustained-release (GITS) system (Glucotrol XL) and glimepiride (Amaryl).[21] It is important to consider that the dose of any sulfonylurea agent should be in-creased only to the middle of the FDA-approved dose range, since essentially all of the clinical benefit is realized at that point.

RepaglinideRepaglinide (Prandin) is in a new class of agents that rapidly elicit an insulin secretion response following an oral dose. This profile of action potentially allows closer control of postprandial glucose excursions. Since patients are directed not to take repaglinide when they choose to skip a meal as part of a dietary plan, they can avoid hypoglycemia that might occur with a long-acting sulfonyl-urea under similar circumstances. While this dosing schedule is recommended for the pharmacologic action of the drug, some patients find it inconvenient to remember to take multiple doses of medications during the course of the day.

Repaglinide is indicated as monotherapy or in combination with metformin. Because of its similar mechanism of action, repaglinide should not be taken along with sulfonylureas. Repaglinide is taken from 0 to 30 minutes before meals (two to four times per day) in a recommended dose range from 0.5 to 4 mg, to a maximum of 16 mg/d. As with other oral agents for treatment of diabetes, repaglinide should be used cautiously in patients with impaired liver function.[22]

Previous PageSection 6 of 12Drug Benefit Trends 11(11sb):11-34, 1999. © 1999 Cliggott Publishing, Division of SCP Communications
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Pathophysiology of Type 2 Diabetes

In healthy individuals, normal insulin secretion in response to intravenous glucose follows a biphasic pattern.[2] A rapid, sharp release of insulin into the portal circulation starts within minutes of glucose administration, lasts for about 10 min, and is followed by a slower and more prolonged phase of insulin release that begins at 10 min and lasts between 60 and 120 min.[2] Critical to the regulation of prandial and postprandial glycemia, the first phase of insulin secretion inhibits hepatic glucose production early in the absorptive state, whereas the second phase of secretion attenuates postprandial excursions by promoting glucose uptake by peripheral tissues.[2] Figure 1 illustrates the normal insulin response to an intravenous glucose tolerance test.[2] In individuals with type 2 diabetes, who have insulin resistance, the insulin secretory response can initially compensate for the insulin resistance; however, eventually, first-phase insulin secretion is lost, and second-phase secretion is impaired, causing postpran-dial hyperglycemia, one of the earliest markers of disease progression.[3] Abnormalities in hepatic, pancreatic and muscle metabolism all result from longstanding hyperglycemia.[4] By the time most patients experience symptoms significant enough to cause them to seek medical attention, type 2 diabetes has often been present, unrecognized, for years.

Figure 1. (click image to zoom) The normal two-phase response of insulin to an intravenously administered glucose bolus. Adapted with permission from Pfeifer et al.[2]

Previous PageSection 2 of 9Curr Med Res Opin 19(7):635-641, 2003. © 2003 Librapharm Limited
This is a part of article Clinical Significance of Targeting Postprandial Hyperglycemia Taken from "Glimepiride Amaryl Tablets" Information Blog

Patients aged 45 years and older are visiting the doctor's office more often than persons in that age group did 10 years ago. In 2001, persons aged 45 years and older accounted for 53.1% of all physician visits.

These findings are from the National Ambulatory Medical Care Survey (NAMCS), which was conducted by the CDC. The survey looks at medical care provided in physicians' offices.

The CDC reports that "seniors and older baby boomers are visiting the doctor more often to manage multiple chronic conditions, obtain newly available drugs, and seek preventive care."

The number of persons aged 45 years and older increased by 11% during the last decade, but the percentage of physician visits by this age group over this same period increased by 26%. The total number of physician visits per person per year for persons aged 45 years and older increased 17%, from 4 in 1992 to 4.7 in 2001.

During 2001, an estimated 880.5 million visits were made to physicians' offices in the United States, an average of 3.1 visits per person. Although the US population has increased 12% since 1992, the number of visits to physicians' offices increased 16%, from 762 million annual visits. Females had a higher visit rate than males, and whites had a higher rate of visits (3.4 visits per person) than blacks (1.9 visits).

More medications are being prescribed as well, according to the report. In 2001, 1.3 billion drugs were prescribed or ordered by physicians for their patients, compared with 922.6 million in 1992.

Between 1992 and 2001, physician visits on average became more complex, with patient age increasing, more diagnoses rendered per visit, and more patients having multiple medications to manage (Cover Figure). One reason for the increase in complexity is that the mean patient age increased from 40 years to 44.6 years.

About half of all visits were to the patient's primary care physician. More than one third of office visits were for chronic conditions, 35.3% were for acute conditions, 16.8% for preventive care, 11.2% for injuries, and 5.6% for pre- and postsurgical consultations. The percentage of visits by new patients decreased by 20% from 1992 to 2001.

Diagnostic and screening services were ordered or provided at 82.8% of visits, and therapeutic and preventive services were ordered or prescribed at 41.4% of visits.

A total of 1.3 billion drugs were prescribed or provided at 61.9% of office visits. Although the percentage of office visits with any drug mention remained fairly constant (63.8% in 1992 and 61.9% in 2001), the average number of drug mentions increased from 1.21 mentions per visit in 1992 to 1.43 in 2001, up 22%. On average, 2.4 medications were ordered or provided at each office visit with any mention of a medication. As the number of past visits to the physician increased, so did the average drug-mention rate. The percentage of visits with at least 1 drug mention ranged from 80.6% for psychiatrists to 21.6% for general surgeons.

In 2001, 89.2% of physician office visits had a duration of 6 to 30 minutes. Overall, the mean time spent with a physician was 18.6 minutes. Time spent in face-to-face contact between the physician and the patient was estimated and recorded by the physician.

The 20 most frequently reported primary diagnoses for 2001 accounted for 41.7% of all physician office visits. Essential hypertension, ar throp athies and related disorders, acute upper respiratory tract infections (excluding pharyngitis), and diabetes mellitus were the leading illness-related primary diagnoses.

The top 5 therapeutic classes for drugs mentioned during visits were cardiovascular-renal drugs (14.7% of mentions), pain relievers (12.1%), respiratory tract drugs, hormones, and CNS drugs. Increases were seen in the use of CNS agents, metabolic and/or nutrient agents, and hormones. The increase in metabolic drugs is directly related to the increase in the use of lipid-lowering drugs.

In 1992, the 5 drugs prescribed most often were amoxicillin, Amoxil, Lasix, Ceclor, and Zantac. In 2001, the top 5 drugs were Lipitor, Celebrex, Vioxx, Claritin, and Lasix (Table). Changes also occurred in the types of services provided by physicians. There were more diagnostic services, counseling services, and surgical procedures ordered or provided in 2001 than in 1992.

Half of office-based physicians were in primary care, 22.1% were in surgical specialties, and 2.6% were in medical specialties. Approximately one third of office-based physicians were in solo practice, 40.8% were in a single-specialty group practice, and 25.9% were in a multispeciality group practice. During a typical week, physicians in office-based practices averaged 80 office visits, 16 telephone consults, 13 hospital visits, 0.9 house calls, and 0.5 e-mail consultations. Approximately 10% of physicians reported not having any managed care contracts, while 35.1% reported having more than 10 contracts.

Private insurance was the primary expected payment source (58% of visits). Government agencies (Medicare and Medicaid and/or state Children's Health Insurance Program) were the payment source for 29% of office visits, with Medicare accounting for 21.8%.

From 1997 through 2001, the percentage of visits by patients with private insurance increased from 53.1% to 58.8%. This was offset by a decline in percentage of visits by patients who self-paid, which dropped to 4% in 2001 from 7.7% in 1992. The percentage of visits paid by Medicare and Medicaid remained fairly constant between 1997 and 2001.

The 2001 NAMCS survey also found that 18.2% of office-based physicians had electronic patient medical records.

Data for the Cover Figure and in "Trend of the Month" are from the National Ambulatory Medical Care Survey: 2001 Summary. Additional information about physician office visits is available from the NCHS Ambulatory Health Care Web site: www.cdc.gov/nchs.

Drug Benefit Trends 15(9):6-7, 2003. © 2003 Cliggott Publishing, Division of SCP Communications
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Conclusion

The inherent chemical reactivity of cephalosporins implies that the opening of the β-lactam ring by nucleophilic reagents generates an intermediate cephalosporoyl which is chemically unstable and that suffers multiple fragmentation reactions. Despite the structural similarities with penicillins, those cephalosporins that have a good R2 leaving group undergo the process of expulsion when they conjugate to carrier proteins by opening of the β-lactam ring. For these cephalosporins the unstable dihydrothiazine moiety is enough to undergo further degradation processes. As a result, conjugation of cephalosporins by the β-lactam ring leads to loss of the R2 side chain and to fractionation of the dihydrothiazine ring and this does not form part of the epitope presented in the hapten-carrier conjugate. Only the R1 side chain and a fragment of the β-lactam ring remain bound to the carrier protein, constituting the epitope resulting from these conjugates. The presence of an R2 side chain that may act as a good leaving group is closely related to enhanced reactivity of the β-lactam ring for nucleophilic attack. The effect of the R2 side chain on the conjugation of the carrier protein can be interpreted only from a kinetic perspective, such that an increase in the capacity of the R2 as a leaving group results in increased reactivity for the attack of nucleophiles to the β-lactam ring, increasing the facility and kinetics of the conjugation process.  Printer- Friendly Email ThisAcknowledgements

We thank Ian Johnston for the English version of the manuscript.Funding Information

Supported by grants from Ministerio de Sanidad (FIS PI02/0666, PI03/1165), Ministerio de Educacion y Ciencia (BQU 2001/3624) and Plan Andaluz de Investigacion Junda de AndaluciaAbbreviation Notes

RAST = radioallergosorbent test.Reprint Address

Correspondence to Ezequiel Perez-Inestrosa, Organic Chemistry, University of Malaga, 29071 Malaga, Spain E-mail: inestrosa@uma.es

Curr Opin Allergy Clin Immunol.  2005;5(4):323-330.  ©2005 Lippincott Williams & Wilkins
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Results

MCOT was used to evaluate palpitations in 76 patients, syncope/presyncope in 17 patients, and to determine outcome of therapy in 29 patients. The baseline characteristics for each group are provided in Table 1 . Overall, the mean age was 58 ± 17 years and 57% were women. Structural heart disease was present in 33 patients (27%). Evaluation of Symptoms (Table 2)

Palpitations. Of 18 patients without a previous arrhythmia diagnosis, 14 (73%, +/+) reported symptoms during monitoring, all of whom had a diagnostic arrhythmia. Two of the 14 patients also had an autodetected asymptomatic arrhythmia (VT-NS and Brady). Recorded symptomatic arrhythmias included: PVCs (n = 7); ST (n = 3); Brady (n = 2); SVT (n = 1); and PACs (n = 1). One of four asymptomatic patients (-/+) had an autodetected VT-NS during monitoring.

Fifty-eight patients had previously been diagnosed with an arrhythmia using another monitoring system. Previously documented arrhythmias included: PAF (n = 26); PSVT (n = 17); AT (n = 4); VT-NS (n = 6); AFl (n = 2); inappropriate ST (n = 2); and PACs (n = 1). During the MCOT monitoring period, 34 (59%) patients experienced recurrent palpitations. In this symptomatic group of 34 patients, 27 patients (+/+) had a documented arrhythmia and seven patients (±) had no arrhythmia correlating to their palpitations. Of the patients with a symptomatic arrhythmia (+/+), two also had PSVT as an autodetected asymptomatic arrhythmia. Detected symptomatic arrhythmias included: PAF (n = 10); ST (n = 4); PVCs (n = 4); AT (n = 4); PSVT (n = 3); AFl (n = 2); PACs (n = 2); and VT-NS (n = 1). Interestingly, the documented arrhythmia was often different (nine of 27) from the previously detected symptomatic arrhythmia (Fig. 1). Furthermore, one patient had AF detected as the likely initiating arrhythmia for AFl (Fig. 2). Of the seven patients with symptoms but no documented arrhythmia (±), one had autodetected asymptomatic VT-NS. The remaining 24 (41%) patients in this group with a previously diagnosed arrhythmia were asymptomatic; however, 15 (-/+) had an autodetected arrhythmia during MCOT monitoring. Patients with autodetected arrhythmias included: AF (n = 7); VT-NS (n = 5); Brady (n = 3); AFl (n = 2); and PSVT (n = 1). Two of the 15 had at least two different autodetected asymptomatic arrhythmias.

Figure 1.  (click image to zoom)

Symptomatic and asymptomatic arrhythmias in patients with palpitations and previously diagnosed arrhythmias. Note that many patients with a documented arrhythmia have a different arrhythmia on subsequent analysis.      

Figure 2.  (click image to zoom)

Tachycardia-induced tachycardia. Palpitations initially occurred during the onset of atrial fibrillation (A), which subsequently induced atrial flutter (B).      

There were 36 episodes of AF/AFl, 22 episodes of bradycardia/pauses, six episodes of NSVT, and one episode of PSVT. The mean ventricular rate of the AF/AFl was 103 ± 27 bpm with a mean duration of 10.7 ± 14.1 hours. The PSVT lasted <1 minute at a rate of 175 bpm. Most of the asymptomatic arrhythmia episodes occurred between 10 PM and 6 AM: AF/AFl (n = 17, mean duration 7 ± 10.7 hours), Brady (n = 13), and PSVT. The second most frequent time to have an asymptomatic episode was 6 AM to 2 PM; AF/AFl (n = 12, mean duration 16.6 ± 18.4 hours), Brady (n = 7), and NSVT (n = 6). The least common interval to have an asymptomatic arrhythmia was 2 PM to 10 PM; AF/AFl (n = 7, mean duration 11.5 ± 13.6), and Brady (n = 2).

Syncope. Ten of 17 (59%) patients evaluated for presyncope/syncope had their typical symptoms during monitoring. Five of the symptomatic patients (+/+) had an arrhythmia documented: Brady (n = 2); AVB-2 (n = 1); VT-NS (n = 1); and PVCs (n = 1). In addition, three patients had autodetected asymptomatic arrhythmias (PAF in two and VT-NS in one). Of the remaining seven asymptomatic patients (-/+), three had autodetected arrhythmias (VT-NS in two patients and AF, AVB-2, and VT-NS in one patient). Mean time to patient-activated first event was 3.7 ± 4.2 days.

Previous Negative Evaluation. Fourteen of the patients being evaluated for palpitations (n = 6) and presyncope/syncope (n = had a previous negative arrhythmia workup ( Table 3 ). Electrophysiology study, Holter monitor, event monitor, or tilt table testing was performed in six, five, three, and one patient, respectively. MCOT was diagnostic in all six patients with palpitations: PVCs (n = 2); PSVT (n = 1); Brady (n = 1); PACs (n = 1); and ST (n = 1). Five of the eight patients with a previous negative evaluation being re-evaluated for presyncope/syncope had their symptoms during MCOT monitoring: SR in three and Brady in two. Both Brady patients had prolonged pauses (>4 seconds) that were directly related to their symptoms (Fig. 3).

Figure 3.  (click image to zoom)

Presynope associated with a long pause after termination of atrial fibrillation.      

Evaluation of Therapy

Twenty-nine patients were prescribed MCOT to evaluate therapy efficacy, 21 for medication titration, and eight following radiofrequency ablation. Ventricular rate control of AF (n = 10) and AT (n = 4) was monitored with MCOT in 14 patients using AV nodal blocking drugs. The AV nodal blocking medications utilized included: beta-blockers (n = 10); digoxin (n = 5); and calcium channel blockers (n = 5). Seven patients required further medication titration for adequate ventricular rate control, which was accomplished in the outpatient setting with continued MCOT monitoring. Two patients treated for rate control of AF developed symptomatic prolonged pauses (up to 6.5 seconds) that MCOT monitoring documented, the drug doses were promptly changed, and the patients had no adverse consequences. Both patients ultimately underwent permanent pacemaker implantation for tachycardia-bradycardia syndrome. One patient with a history of poorly controlled hypertension and bradycardia was monitored with MCOT for beta-blocker initiation. Adequate blood pressure control was obtained without a recurrence of bradycardia. Six patients were monitored with MCOT for attempted rhythm control using antiarrhythmic medications: four with AF; one with VT-NS; and one with PVCs. Antiarrhythmic medications used for rhythm control in these patients included amiodarone (n = 6), sotalol (n = 3), propafenone (n = 1), and mexiletine (n = 1).

Eight patients underwent MCOT monitoring following radiofrequency ablation for AF (n = 5), AFL (n = 1), PVCs (n = 1), and inappropriate ST (n = 1). Two patients experienced symptoms during MCOT monitoring. One patient experienced symptomatic PACs and the other had SR during their symptomatic episode. There was one occurrence of asymptomatic AF in a patient following radiofrequency ablation of AF.  Printer- Friendly Email This

J Cardiovasc Electrophysiol.  2007;18(5):473-477.  ©2007 Blackwell Publishing
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