Antimicrobial functionalization of bacterial nanocellulose by loading with polihexanide and povidone-iodine.

Bacterial nanocellulose (BNC) is chemically identical with plant cellulose but free of byproducts like lignin, pectin, and hemicelluloses, featuring a unique reticulate network of fine fibers. BNC sheets are mostly obtained by static cultivation. Now, a Horizontal Lift Reactor may provide a cost efficient method for mass production. This is of particular interest as BNC features several properties of an ideal wound dressing although it exhibits no bactericidal activity. Therefore, BNC was functionalized with the antiseptics povidone-iodine (PI) and polihexanide (PHMB). Drug loading and release, mechanical characteristics, biocompatibility, and antimicrobial efficacy were investigated. Antiseptics release was based on diffusion and swelling according to Ritger-Peppas equation. PI-loaded BNC demonstrated a delayed release compared to PHMB due to a high molar drug mass and structural changes induced by PI insertion into BNC that also increased the compressive strength of BNC samples. Biological assays demonstrated high biocompatibility of PI-loaded BNC in human keratinocytes but a distinctly lower antimicrobial activity against Staphylococcus aureus compared to PHMB-loaded BNC. Overall, BNC loaded with PHMB demonstrated a better therapeutic window. Moreover, compressive and tensile strength were not changed by incorporation of PHMB into BNC, and solidity during loading and release could be confirmed.

Diffusion of Antimicrobials Across Silicone Hydrogel Contact Lenses.

OBJECTIVES: To measure the diffusion of topical preparations of moxifloxacin, amphotericin B (AmB), and polyhexamethylene biguanide (PHMB) through silicone hydrogel (SH) contact lenses (CLs) in vitro. METHODS: Using an in vitro model, the diffusion of three antimicrobials through SH CLs was measured. Diffused compounds were measured using a spectrophotometer at set time points over a period of 4 hr. The amount of each diffused antimicrobial was determined by comparing the experimental value with a standard curve. A biological assay was performed to validate the CL diffusion assay by testing antimicrobial activity of diffused material against lawns of susceptible bacteria (Staphylococcus epidermidis) and yeast (Saccharomyces cerevisiae). Experiments were repeated at least two times with a total of at least four independent replicates. RESULTS: Our data show detectable moxifloxacin and PHMB diffusion through SH CLs at 30 min, whereas AmB diffusion remained below the limit of detection within the 4-hr experimental period. In the biological assay, diffused moxifloxacin demonstrated microbial killing starting at 20 min on bacterial lawns, whereas PHMB and AmB failed to demonstrate killing on microbial lawns over the course of the 60-min experiment. CONCLUSIONS: In vitro diffusion assays demonstrate limited penetration of certain anti-infective agents through SH CLs. Further studies regarding the clinical benefit of using these agents along with bandage CL for corneal pathologic condition are warranted.

Selection and dosing of medications for management of diabetes in patients with advanced kidney disease.

Diabetes mellitus is a leading cause of kidney disease worldwide. A large and expanding array of treatments for diabetes is available to improve glycemic control, including newer classes of drugs, such as thiazolidinediones and incretin-based therapies. The presence of impaired kidney function with reduced glomerular filtration rate should influence choices, dosing, and monitoring of hypoglycemic agents, as some agents require a dosing adjustment in patients with kidney disease and some are entirely contraindicated. This article reviews the clinical use of insulin and other antidiabetic therapies, focusing on pharmacokinetic properties and dosing in patients with advanced kidney disease.

Incorporation of biguanide compounds into poly(GL)-b-poly(GL-co-TMC-co-CL)-b-poly(GL) monofilament surgical sutures.

A new biodegradable coating was developed for bioabsorbable monofilament sutures. Specifically, a random copolymer having 35wt-% and 65wt-% of lactide and trimethylene carbonate units showed appropriate flexibility, stickiness and degradation rate, as well as capability to produce a complete and uniform coating. Monofilament sutures of polyglycolide-b-poly(glycolide-co-trimethylene carbonate-co-ε-caprolactone)-b-polyglycolide were loaded with chlorhexidine (CHX) and poly(hexamethylene biguanide) (PHMB) to explore the possibility to achieve antimicrobial activity without adverse cytotoxic effects. To this end, two processes based on single drug adsorption onto the suture surface and incorporation into the coating copolymer were used and subsequently evaluated. Although the second process could be considered more complex, clear benefits were observed in terms of drug loading efficiency, antimicrobial effect and even lack of cytotoxicity. In general, drugs could be loaded in an amount leading to a clear bacteriostatic effect for both Gram-negative and Gram-positive bacteria without causing significant cytotoxicity. Release profiles of PHMB and CHX were clearly different. Specifically, adsorption of the drug onto the fiber surface which prevented complete release was detected for PHMB. This polymer had advantages derived from its high molecular size, which hindered penetration into cells, thus resulting in lower cytotoxicity. Furthermore, bacterial growth kinetics measurements and bacterial adhesion assays showed greater effectiveness of this polymer.

In-vitro release pharmacokinetics of amikacin, teicoplanin and polyhexanide in a platelet rich fibrin-layer (PRF)-a laboratory evaluation of a modern, autologous wound treatment.

OBJECTIVES: Platelet rich fibrin (PRF) is an autologous fibrin glue, produced from patients' blood, which, besides intraoperative use, has applications in the treatment of infected wounds. The combination with antimicrobial agents results in a prolonged antibacterial effect allowing for wound dressing change intervals of seven days even in infected wounds. The aim of this study was to evaluate release kinetics of amikacin, teicoplanin or polyhexanide from a PRF-layer. METHODS: PRF mixed with teicoplanin, amikacin or polyhexanide was sprayed on a silicon gauze patch and put on a colombia agar with bacteria with known minimal inhibitory concentration (MIC) and incubated for 24 hours and afterwards transferred to another agar with the same bacterial strain. Inhibition zones were measured every 24 hours. This was repeated on 7 consecutive days. Antibiotic concentrations were calculated by interpolation. RESULTS: More than 1000 mg/L teicoplanin were released within the first 24 hours and 28.22 mg/L after 168 hours. Amikacin release was above 10,000 mg/L within the first 24 hours and still 120.8 mg/L after 120 hours. A release of polyhexanide could be verified for the first 24 hours only. Consequently teicoplanin and amikacin released from PRF showed antimicrobial in-vitro effects for almost a week, whereas an antimicrobial effect of polyhexanide could only be verified for the first 24 hours. CONCLUSIONS: Our Results show that a weekly dressing regimen may be justified in wounds treated with PRF plus amikacin or teicoplanin, since bacteria will be eradicated over a considerable period of time after a single application of PRF.

L503F variant of carnitine/organic cation transporter 1 efficiently transports metformin and other biguanides.

OBJECTIVES: Carnitine/organic cation transporter 1 (OCTN1) is involved in gastrointestinal absorption and mitochondrial toxicity of biguanides in rodents, but its pharmacokinetic roles in humans are largely unknown. The purpose of this study was to clarify the transport activities of two major OCTN1 variants, L503F and I306T, for gabapentin and three biguanide drugs, metformin, buformin and phenformin. METHODS: HEK293 cells were transfected with OCTN1 gene, its variants, or vector alone, and the uptake and cytotoxicity of each drug were examined. KEY FINDINGS: Buformin was identified to be an OCTN1 substrate. Uptake of biguanides, especially metformin, mediated by OCTN1 variant L503F, which is commonly found in Caucasians, was much higher than that by the wild-type transporter (WT-OCTN1). Cytotoxicity of metformin was also greater in HEK293 cells expressing the L503F variant, compared with WT-OCTN1. Uptake of gabapentin mediated by OCTN1 variant I306T, which is commonly found in both Asians and Caucasians, was lower than that by WT-OCTN1, although uptake of the typical OCTN1 substrate ergothioneine was similar. CONCLUSION: Organic cation transporter 1 variant L503F transports biguanides, especially metformin, more efficiently than WT-OCTN1, whereas the I306T variant transports gabapentin less efficiently than WT-OCTN1, suggesting that the common OCTN1 variants may alter pharmacokinetics of these drugs.

In vitro metabolism of phenoxypropoxybiguanide analogues in human liver microsomes to potent antimalarial dihydrotriazines.

Phenoxypropoxybiguanides, such as 1 (PS-15), are prodrugs analogous to the relationship of proguanil and its active metabolite cycloguanil. Unlike cycloguanil, however, 1a (WR99210), the active metabolite of 1, has retained in vitro potency against newly emerging antifolate-resistant malaria parasites. Unfortunately, manufacturing processes and gastrointestinal intolerance have prevented the clinical development of 1. In vitro antimalarial activity and in vitro metabolism studies have been performed on newly synthesized phenoxypropoxybiguanide analogues. All of the active dihydrotriazine metabolites exhibited potent antimalarial activity with in vitro IC(50) values less than 0.04 ng/mL. In vitro metabolism studies in human liver microsomes identified the production of not only the active dihydrotriazine metabolite, but also a desalkylation on the carbonyl chain, and multiple hydroxylated metabolites. The V(max) for production of the active metabolites ranged from 10.8 to 27.7 pmol/min/mg protein with the K(m) ranging from 44.8 to 221 microM. The results of these studies will be used to guide the selection of a lead candidate.

Oral antidiabetic agents: current role in type 2 diabetes mellitus.

Type 2 diabetes mellitus is a progressive and complex disorder that is difficult to treat effectively in the long term. The majority of patients are overweight or obese at diagnosis and will be unable to achieve or sustain near normoglycaemia without oral antidiabetic agents; a sizeable proportion of patients will eventually require insulin therapy to maintain long-term glycaemic control, either as monotherapy or in conjunction with oral antidiabetic therapy. The frequent need for escalating therapy is held to reflect progressive loss of islet beta-cell function, usually in the presence of obesity-related insulin resistance. Today's clinicians are presented with an extensive range of oral antidiabetic drugs for type 2 diabetes. The main classes are heterogeneous in their modes of action, safety profiles and tolerability. These main classes include agents that stimulate insulin secretion (sulphonylureas and rapid-acting secretagogues), reduce hepatic glucose production (biguanides), delay digestion and absorption of intestinal carbohydrate (alpha-glucosidase inhibitors) or improve insulin action (thiazolidinediones). The UKPDS (United Kingdom Prospective Diabetes Study) demonstrated the benefits of intensified glycaemic control on microvascular complications in newly diagnosed patients with type 2 diabetes. However, the picture was less clearcut with regard to macrovascular disease, with neither sulphonylureas nor insulin significantly reducing cardiovascular events. The impact of oral antidiabetic agents on atherosclerosis--beyond expected effects on glycaemic control--is an increasingly important consideration. In the UKPDS, overweight and obese patients randomised to initial monotherapy with metformin experienced significant reductions in myocardial infarction and diabetes-related deaths. Metformin does not promote weight gain and has beneficial effects on several cardiovascular risk factors. Accordingly, metformin is widely regarded as the drug of choice for most patients with type 2 diabetes. Concern about cardiovascular safety of sulphonylureas has largely dissipated with generally reassuring results from clinical trials, including the UKPDS. Encouragingly, the recent Steno-2 Study showed that intensive target-driven, multifactorial approach to management, based around a sulphonylurea, reduced the risk of both micro- and macrovascular complications in high-risk patients. Theoretical advantages of selectively targeting postprandial hyperglycaemia require confirmation in clinical trials of drugs with preferential effects on this facet of hyperglycaemia are currently in progress. The insulin-sensitising thiazolidinedione class of antidiabetic agents has potentially advantageous effects on multiple components of the metabolic syndrome; the results of clinical trials with cardiovascular endpoints are awaited. The selection of initial monotherapy is based on a clinical and biochemical assessment of the patient, safety considerations being paramount. In some circumstances, for example pregnancy or severe hepatic or renal impairment, insulin may be the treatment of choice when nonpharmacological measures prove inadequate. Insulin is also required for metabolic decompensation, that is, incipient or actual diabetic ketoacidosis, or non-ketotic hyperosmolar hyperglycaemia. Certain comorbidities, for example presentation with myocardial infarction during other acute intercurrent illness, may make insulin the best option. Oral antidiabetic agents should be initiated at a low dose and titrated up according to glycaemic response, as judged by measurement of glycosylated haemoglobin (HbA1c) concentration, supplemented in some patients by self monitoring of capillary blood glucose. The average glucose-lowering effect of the major classes of oral antidiabetic agents is broadly similar (averaging a 1-2% reduction in HbA1c), alpha-glucosidase inhibitors being rather less effective. Tailoring the treatment to the individual patient is an important principle. Doses are gradually titrated up according to response. However, the maximal glucose-lowering action for sulphonylureas is usually attained at appreciably lower doses (approximately 50%) than the manufacturers' recommended daily maximum. Combinations of certain agents, for example a secretagogue plus a biguanide or a thiazolidinedione, are logical and widely used, and combination preparations are now available in some countries. While the benefits of metformin added to a sulphonylurea were initially less favourable in the UKPDS, longer-term data have allayed concern. When considering long-term therapy, issues such as tolerability and convenience are important additional considerations. Neither sulphonylureas nor biguanides are able to appreciably alter the rate of progression of hyperglycaemia in patients with type 2 diabetes. Preliminary data suggesting that thiazolidinediones may provide better long-term glycaemic stability are currently being tested in clinical trials; current evidence, while encouraging, is not conclusive. Delayed progression from glucose intolerance to type 2 diabetes in high-risk individuals with glucose intolerance has been demonstrated with troglitazone, metformin and acarbose. However, intensive lifestyle intervention can be more effective than drug therapy, at least in the setting of interventional clinical trials. No antidiabetic drugs are presently licensed for use in prediabetic individuals.

Pharmacokinetic-pharmacodynamic relationships of oral hypoglycaemic agents. An update.

Oral hypoglycaemic drugs, sulphonylureas and biguanides, occupy an important place in the treatment of Type II (non-insulin-dependent) diabetic patients who fail to respond satisfactorily to diet therapy and physical exercise. Although the precise mechanisms of action of these compounds are still poorly understood, there is sufficient agreement that sulphonylureas have both pancreatic and extrapancreatic effects, whereas biguanides have predominantly extrapancreatic actions. By using labelled compounds or measuring the circulating concentrations, the main pharmacokinetic properties of oral hypoglycaemic agents have been assessed and, in some cases, their pharmacokinetic-pharmacodynamic relationships have been evaluated. A correlation between diabetes control and plasma sulphonylurea or biguanide concentrations is generally lacking at the steady-state, with the possible exception of long-acting agents; after either oral or intravenous dosing, the reduction of plasma glucose is usually related to the increased circulating drug concentrations. The toxic effects of oral hypoglycaemic drugs are more frequent in the elderly and in the presence of conditions that may lead to drug accumulation or potentiation (increased dosage, use of long-acting compounds, hepatic and renal disease, interaction with other drugs); however, a relationship between toxic effects and drug plasma levels has been reported only for biguanides.

Pharmacokinetic optimisation of oral hypoglycaemic therapy.

Two main classes of oral hypoglycaemic drugs, the sulphonylureas and the biguanides, are currently used in the therapy of type II, non-insulin-dependent diabetes mellitus (NIDDM). The basic pharmacokinetic properties of these agents are discussed with a view to efficient and safe treatment. Both first- and second-generation sulphonylureas are rapidly absorbed from the gastrointestinal tract. In the plasma compartment, these drugs are strongly bound to serum proteins. All sulphonylureas are metabolised in the liver, and the metabolites and the parent drugs are eliminated mainly in the urine, but also (second-generation derivatives) in the faces. Rapid- and short-acting sulphonylureas may improve early insulin release and promote better postprandial glucose control. Long-acting derivatives may ensure better control of overnight glycaemia. The elderly are at risk of developing severe sulphonylurea-induced hypoglycaemia, and in this population the agent chosen should have a short or intermediate duration of action and no active metabolites. Caution is needed when prescribing any sulphonylurea in patients receiving drugs known to affect sulphonylurea action, and in those with impaired liver and/or kidney function. The bioavailability of the biguanides ranges from 40 to 60%. Binding to plasma proteins is absent or very low. Metformin and buformin are not metabolised and are excreted in the urine; phenformin undergoes hepatic hydroxylation and is excreted in both urine and faeces. Metformin is the only agent of this class currently recommended for clinical use. The main indications of metformin treatment are NIDDM associated with obesity and/or hyperlipidaemia, and in combination with sulphonylurea both as primary treatment and when secondary failure occurs with sulphonylurea alone. Lactic acidosis may develop in patients receiving therapy with biguanides, especially in the presence of a preexisting contraindication to their use.

Insulin sensitizers.

Type 2 diabetes mellitus is an increasingly prevalent disorder associated with multiple metabolic derangements. Insulin resistance is the most prominent feature common in both type 2 diabetes and its associated metabolic abnormalities. Until 1995, the only therapeutic interventions available in the United States were the insulin secretagogues sulfonylureas and insulin. With the introduction of metformin in the United States in the mid-1990s and the subsequent advent of thiazolidinediones, an opportunity exists to address and directly reverse, at least in part, the defects in insulin action seen in individuals with type 2 diabetes. Evidence shows that insulin sensitizers not only have beneficial effects on glycemic control but also have multiple effects on lipid metabolism and atherosclerotic vascular processes that could prove to be beneficial. We discuss safety issues of these agents, their potential use in preventing onset and progression of diabetes, and their use in other related metabolic conditions such as polycystic ovary syndrome.

Simultaneous measurement of proguanil and its metabolites in human plasma and urine by reversed-phase high-performance liquid chromatography, and its preliminary application in relation to genetically determined S-mephenytoin 4'-hydroxylation status.

A simple high-performance liquid chromatographic (HPLC) assay method was developed for the measurement of proguanil (PG) and its major metabolites, cycloguanil (CG) and 4-chlorophenyl-biguanide (CPB), in human plasma and urine. The assay allowed the simultaneous determination of all analytes in 1 ml of plasma or 0.1 ml of urine. The detection limits of PG, CG, and CPB, defined as the signal-to-noise ratio of 3, were 1 and 5 ng/ml for plasma and urine samples, respectively. Recoveries of the analytes and the internal standard (pyrimethamine) were > 62% from plasma and > 77% from urine. Intra-assay and interassay coefficients of variation for all analytes in plasma and urine were < 10% except for the values of CG and CPB, which ranged from 10% to 15% at one or two concentrations among 4-5 concentrations studied. The clinical applicability of the method was assessed by the preliminary pharmacokinetic study of PG, CG, and CPB in six healthy volunteers with the individually known phenotypes (extensive and poor metabolizers) of S-mephenytoin 4'-hydroxylation, suggesting that individuals with a poor metabolizer phenotype of S-mephenytoin have a much lower capacity to bioactivate PG to CG compared with the extensive metabolizers.

Comparative tolerability profiles of oral antidiabetic agents.

The sulphonylureas and the biguanides are widely used as adjuncts to dietary measures in the treatment of non-insulin-dependent (type 2) diabetes mellitus (NIDDM). Adverse effect profiles differ markedly between the sulphonylureas and biguanides, reflecting differences in chemical structure and mode of action. Sulphonylureas are generally well tolerated, although pharmacokinetic differences between these agents have important clinical implications. The main adverse effect associated with sulphonylureas is hypoglycaemia. This effect is a predictable consequence of the principal pharmacological effect of these drugs, i.e. sensitisation of the islet beta-cell to glucose, resulting in enhanced endogenous insulin secretion. Sulphonylurea-induced suppression of hepatic glucose production may cause profound and protracted hypoglycaemia, especially in elderly patients, in individuals with intercurrent illnesses and reduced caloric intake, or when taken in combination with other compounds with hypoglycaemic potential, e.g. alcohol (ethanol). Sulphonylureas with a longer duration of action, notably chlorpropamide and glibenclamide (glyburide), are more liable to induce serious hypoglycaemia, particularly when drug elimination is reduced by renal impairment. Other drugs such as salicylates may potentiate the actions of sulphonylureas, thereby increasing the risk of hypoglycaemia. Biguanide therapy is associated with alterations in lactate homeostasis which under certain clinical circumstances may result in fatal lactic acidosis. Phenformin is associated with a markedly greater risk of lactic acidosis than metformin. Phenformin has been withdrawn in many countries for this reason. All biguanides must be avoided in patients with renal impairment, hepatic dysfunction and cardiac failure--conditions where drug accumulation or disordered lactate metabolism may predispose to lactic acidosis. Phenformin should not be given to individuals who exhibit a severe, genetically conferred hepatic defect of hydroxylation which impedes metabolism of this drug. Less seriously, the biguanides are associated with a relatively high incidence of gastrointestinal adverse effects which limit compliance. Acarbose, a competitive inhibitor of intestinal alpha-glucosidases, has recently been introduced. In contrast to the sulphonylureas and biguanides, acarbose has not been associated with life-threatening adverse effects. This reflects the low systemic absorption of the drug and, predictably, its principal unwanted effects are gastrointestinal disturbances resulting from iatrogenic carbohydrate malabsorption.

Antihyperglycaemic agents. Drug interactions of clinical importance.

Non-insulin-dependent (type 2) diabetes mellitus (NIDDM) affects middle-aged or elderly people who frequently have several other concomitant diseases, especially obesity, hypertension, dyslipidaemias, coronary insufficiency, heart failure and arthropathies. Thus, polymedication is the rule in this population, and the risk of drug interactions is important, particularly in elderly patients. The present review is restricted to the interactions of other drugs with antihyperglycaemic compounds, and will not consider the mirror image, i.e. the interactions of antihyperglycaemic agents with other drugs. Oral antihyperglycaemic agents include sulphonylureas, biguanides--essentially metformin since the withdrawn of phenformin and buformin--and alpha-glucosidase inhibitors, acarbose being the only representative on the market. These drugs can be used alone or in combination to obtain better metabolic control, sometimes with insulin. Drug interactions with antihyperglycaemic agents can be divided into pharmacokinetic and pharmacodynamic interactions. Most pharmacokinetic studies concern sulphonylureas, whose action may be enhanced by numerous other drugs, thus increasing the risk of hypoglycaemia. Such an effect may result essentially from protein binding displacement, inhibition of hepatic metabolism and reduction of renal clearance. Reduction of the hypoglycaemic activity of sulphonylureas due to pharmacokinetic interactions with other drugs appears to be much less frequent. Drug interactions leading to an increase in plasma metformin concentrations, mainly by reducing the renal excretion or the hepatic metabolism of the biguanide, should be avoided to limit the risk of hyperlactaemia. Owing to its mode of action, pharmacokinetic interferences with acarbose are limited to the gastrointestinal tract, but have not been extensively studied yet. Pharmacodynamic interactions are quite numerous and may result in a potentiation of the hypoglycaemic action or, conversely, in a deterioration of blood glucose control. Such interactions may be observed whatever the type of antidiabetic treatment. They result from the intrinsic properties of the coprescribed drug on insulin secretion and action, or on a key step of carbohydrate metabolism. Finally, a combination of 2 to 3 antihyperglycaemic agents is common for treating patients with NIDDM to benefit from the synergistic effect of compounds acting on different sites of carbohydrate metabolism. Possible pharmacokinetic interactions between alpha-glucosidase inhibitors and classical antidiabetic oral agents should be better studied in the diabetic population.

Synthesis, characterization, and biodistribution of oxo complexes of technetium-99m with biguanide and N1-substituted ligands.

We report the synthesis, characterization, and biodistribution of 99mTc-complexes with the bidentate-N,N chelate biguanide (Big) and the N1-substituted ligands dimethyl (DMBig), phenyl (PBig), and phenethyl (PEBig). Dynamic gamma-camera studies with 99mTc-Big and 99mTc-DMSA in rabbits indicated distinct renal and urinary excretion profiles. 99mTc-Big was cleared more quickly than 99mTc-DMSA, and for the same acquisition times, the contrast in whole-body images favored 99mTc-Big. Also, the estimated radiation absorbed doses by kidneys and blood for 99mTc-DMSA were significantly higher than for 99mTc-Big. These preliminary studies show that 99mTc-Big has favourable practical and dosimetric features for renal imaging as an alternative to 99mTc-DMSA.

Evaluation in the baboon model of (99m)Tc-biguanide as a tracer for renal imaging.

Studies in various animal species have recently shown that (99m)Tc-BIG has practical and dosimetric benefits for renal imaging that could probably make it a good alternative to (99m)Tc-2, 3-dimercaptosuccinic acid ((99m)Tc-DMSA). In this study, using the baboon experimental model, the biodistribution of (99m)Tc-BIG and (99m)Tc-DMSA are compared. It is demonstrated that early good contrast imaging and more favourable dosimetry is possible with (99m)Tc-BIG compared to (99m)Tc-DMSA, confirming the quoted previous findings with small animals. Time-activity curves for kidneys and other organs support these findings, and MIRDOSE software provided the dosimetry.

Oral antihyperglycaemics. Considerations in older patients with non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) is increasing in incidence as the population in most countries ages. Multiple pathology is common in the elderly, and cardiovascular disease is usually present at diagnosis. Patients who develop NIDDM at age 65 years may live long enough to develop microvascular complications. Others who are frail and have multiple pathologies may require treatment to prevent both symptomatic hyperglycaemia and dehydration, whilst avoiding hypoglycaemia. The goals in the management of NIDDM in elderly people are the prevention of complications and the relief of symptoms. Treatment must be tailored to the individual's expectations and should be reviewed regularly with the changing circumstances of aging. If dietary measures fail to control glucose levels, antihyperglycaemic sulphonylureas are the most frequently prescribed form of treatment. However, concern over the potential of these drugs to cause hypoglycaemia limits the choice to second generation sulphonylureas, agents that preserve the first phase of insulin release and have non-biologically active metabolites that are promptly eliminated. The biguanide agent metformin is also appropriate in elderly obese patients with NIDDM who do not have renal, liver or cardiac failure. The combination of a sulphonylurea and metformin can be effective in patients in whom insulin would otherwise be required. Novel compounds such as acarbose and the thiazolinediones may also be useful in the treatment of older diabetic patients.

Oral antihyperglycemic agents during pregnancy and lactation: a review.

The treatment approach of diabetes mellitus during pregnancy requires a combination of diet, exercise, multiple home glucose determinations and intensive insulin regimens. During the last decade there was an increased interest in the use of oral antihyperglycemic agents (OAHAs) as an alternative to insulin in achieving good glycemic control. OAHAs are divided into four groups: derivatives of sulfonylurea, biguanides, glucosidase inhibitors and thiazolidinediones. This review describes the possible teratogenic effects of the use of OAHAs during pregnancy and the effects of these drugs during lactation. Animal and human studies assessing the teratogenic effects of OAHAs have yielded conflicting data because the risk of major malformations in infants of mothers with diabetes appears to be related to maternal glycemic control rather than the antidiabetic therapy. A major concern with the use of OAHAs during pregnancy is neonatal hypoglycemia, which may be severe and persist for days. Therefore, insulin is still the drug of choice because it has not been implicated as a teratogen in human pregnancies. In addition, because of the lack of data regarding the use of OAHAs in pregnancy, we cannot draw firm conclusions about all of the available drugs. However, OAHAs, especially glibenclamide (glyburide), may be beneficial in a situation where the proper use of insulin is problematic. Because there are very limited clinical data on the exposure of OAHAs to the infant via breast milk, and the potentially serious effect of neonatal hypoglycemia, the safest recommendation is not to breast feed while taking OAHAs. Well-conducted, prospective, controlled studies regarding the feasibility of OAHAs in pregnant women with diabetes and during lactation are needed.

A new approach for the treatment of bacterial vaginosis: use of polyhexamethylene biguanide. A prospective, randomized study.

BACKGROUND: Bacterial vaginosis (BV) is the most common vulvovaginal infection and represents the 35% of all the infections occurring in women in the reproductive age. It is well recognised that serious forms of BV can induce several complications among women undergoing gynaecologic or obstetric surgery, having pelvic inflammatory diseases, temporary or absolute infertility, miscarriage and abortion. At present, the clinical treatment of choice of BV is the use of systemic or local (gel or cream) metronidazole and clindamycin, though systemic use has some limitations due to side-effects and contraindications. Polyhexamethylene biguanide (PHMB) is a new bi-biguanide compound having a broad spectrum activity and low toxicity, that have been successfully utilized in ophthalmology and dentistry. Aim of this study was to evaluate the efficacy and tolerability of a single-dose vaginal administration of a PHMB vaginal gel in the treatment of BV in comparison to clindamycin vaginal cream. METHODS: One-hundred and ten patients affected by BV were treated with PHMB vaginal gel in single administration or clindamycin vaginal cream 1 daily administration for 7 days. RESULTS: We demonstrated the therapeutic efficacy of mono-dose administration of a vaginal solution containing PHMB in BV treatment; this efficacy is similar to the one shown in antibiotic therapy. Furthermore, this product was well tolerated by all treated patients. CONCLUSIONS: Mono-dose PHMB treatment should be regarded as the therapy of choice for BV, using clindamycin and metronidazole only for relapses treatment.