Drug Of Choice For Prevention Research Articles

Emergency medicine: magnesium sulphate injections and their pharmaceutical quality concerns

ObjectivesWorld Health Organization has recognized magnesium sulphate as the drug of choice for prevention and treatment of fits associated with preeclampsia and eclampsia which are amongst the leading causes of maternal morbidity and mortality. In this study, the pharmaceutical quality of magnesium sulphate injections marketed in Anambra state was assessed. MethodsNinety samples of magnesium sulphate obtained from the 3 senatorial zones in Anambra state were subjected to identification tests, microbiological analysis consisting of Growth promotion test, sterility and endotoxin test. Content analysis using titrimetric method and pH analysis were also carried out on the samples. ResultsTwenty percent (20%) of samples obtained from Onitsha failed identification test as they had no Registration number in Nigeria. All samples subjected to the microbiology tests (sterility and endotoxin test) passed. Twenty percent (20%) and thirty-three percent (33.3%) of samples sourced from Onitsha and Nnewi respectively failed the pH analysis test. All the samples passed microbiological tests and had their Active Pharmaceutical Ingredients (API) within the acceptable limit. ConclusionsThis study reveals that there are still some substandard magnesium sulphate injections in circulation in the locality. The supply chain of these drugs should be monitored to ensure a reduction in the incidences of substandard magnesium sulphate and positive therapeutic outcome which translates to reduced maternal mortality associated with pre-eclampsia and eclampsia in Nigeria.

Thromboembolic complications in patients with active oncological disease

Patients with active malignant neoplasms have a high risk of developing both venous and arterial thrombosis, which complicate not only the treatment and quality of life of these patients but also significantly worsen the prognosis. Cancer associated hypercoagulation with has the main role in the pathogenesis of thrombotic complications and is a result of the interaction between tumor cells, the hemostasis system and the patient’s body. The risk-assessment of developing thromboembolic complications should be performed for all hospitalized therapeutic and surgical patients. Low molecular weight heparins are the drug of choice for prevention and treatment of venous thrombosis in cancer patients. Their usage before and after surgical interventions, as well as in the context of chemotherapy reduces the incidence of venous thromboembolic complications and prevents fatal pulmonary embolism, which increases the quality of life of cancer patients and significantly improves the prognosis. Features of treatment of thrombotic complications in patients with renal insufficiency, obesity and thrombocytopenia are mentioned.

Development and stability of a heat-stable formulation of carbetocin for the prevention of postpartum haemorrhage for use in low and middle-income countries.

Postpartum haemorrhage is a leading cause of maternal death worldwide. Oxytocin, currently the drug of choice for prevention of PPH, requires constant refrigeration. In pursuit of an alternative medicine, Ferring Pharmaceuticals have developed a heat‐stable formulation of carbetocin, an oxytocin analogue. This study aimed to define that formulation, and to investigate its stability under ICH climate zone IV conditions (30°C/75% relative humidity) for at least 3 years and at extreme temperatures, such as 60°C, for shorter periods of time. The development resulted in a heat‐stable carbetocin formulation consisting of 0.1 mg/mL carbetocin in sodium succinate buffer, mannitol, and methionine. The optimum pH was determined to be pH 5.45 (5.25–5.65). The generated stability data of this formulation show that ≥95% purity of the peptide was maintained for a minimum of 3 years at 30°C, 6 months at 40°C, 3 months at 50°C and 1 month at 60°C. In addition, the heat‐stable carbetocin formulation was not sensitive to freezing or light. The reported highly stable peptide formulation facilitates the distribution in low and middle‐income countries, where maintaining cold chain distribution is difficult.Ferring Pharmaceuticals, the World Health Organization, and MSD# for Mothers have established a collaboration to develop this heat‐stable formulation of carbetocin for the prevention of post‐partum hemorrhage in women after vaginal childbirth, with the aim of making the medicine available in the public sector of developing countries that have a high burden of maternal mortality.

Loading Dose only versus Standard Dose Magnesium Sulfate Seizure Prophylaxis in Severe Pre-eclamptic Women

Magnesium sulfate is the drug of choice for prevention of seizures in the pre-eclamptic woman. There is no agreement in the published randomized trials regarding the optimal time to initiate magnesium sulfate, the dose to use (both loading and maintenance) as well as the duration of therapy. The objective of this study is to determine whether magnesium sulfate prophylaxis is needed for up to 24 hours postpartum in all patients with severe pre-eclampsia for the prevention of seizure. It is a randomized controlled trial conducted on 60 pregnant women with severe preeclampsia randomized into standard dose and loading dose only regimen. Out of 30 cases in each group 1 (3.3%) patient in standard regimen and 2 (6.7%) patients in loading dose only developed seizure. The occurrence of seizure is not significant statistically. In both regimens, there was no maternal mortality. Total of 3 patients needed MICU care and 12 patient developed maternal complications. MgSO4 toxicities were seen only in standard dose regimen that is in 17 (56.7%) of the patients. The median number of IM injections of MgSO4 received in standard dose regimen was 8±2.176. In standard dose regimen 73.3 percent baby were alive whereas in case of loading dose only regimen 93.3 percent of baby were alive after 48 hours of delivery. Single dose of magnesium sulfate is equally effective as standard dose regimen in terms of seizure prophylaxis in severe pre eclamptic women, with added advantage of reduced maternal toxicity and better neonatal outcome.

Development of Novel High Density Gastroretentive Multiparticulate Pulsatile Tablet of Clopidogrel Bisulfate Using Quality by Design Approach.

Myocardial infarction, i.e., heart attack, is a fatal condition which is on the increase all over the world. It is reported that a large number of heart attack occur in morning hours which are attributable to platelet aggregation. Chronotherapy at this stage can be crucial. Clopidogrel bisulfate (CLB) is an antiplatelet agent and has become a drug of choice for prevention of heart attack. It is soluble in acidic pH and has a narrow absorption window. So, its long residence time in stomach is desirable. Therefore, a novel high density tablet was developed comprising multiparticulate pellets with pulsatile release necessary to maintain chronotherapy of heart attack. The pellets were prepared by extrusion-spheronization and coated in fluidized bed processor with different coating material to achieve pulsatile release. The size, shape of pellets, and drug release were evaluated. High density tablet containing coated pellets was formulated and evaluated for retention in stomach. Quality by design tools was used to design and optimize the processes. Timed release observed by dissolution study showed lag time of 6h followed by burst release of drug up to 94% in 1h. Density of tablets was found to be 2.2gcm-3 which is more than gastric fluid. In vivo x-ray studies in rabbit revealed 8h of gastric retention of tablet at the bottom of the stomach. Thus, CLB high density pulsatile system looks to open up a window of opportunity for developing formulations with drugs that are stable in gastric region and needed chronotheraupetic activity.

Guidelines for the prevention and treatment of venous thromboembolism in non-surgically treated cancer patients

Guidelines for the prevention and treatment of venous thromboembolism (VTE) are aimed to improve patients’ safety and quality of life by appropriate prophylaxis and treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE). These guidelines relate to adult cancer patients treated non-surgically. Recommendations included in those guidelines do not relate to paediatric patients. The guidelines presented here directed to physicians and other healthcare professionals taking care of mentioned patients: clinical oncologists, haematologists, radiotherapists, pulmonologists, oncological gynaecologists, internal medicine physicians, and GPs. Venous thromboembolism (VTE) comprises a serious problem in oncology because it is the most common complication as well as the second most common cause of cancer-related deaths. The term “venous thromboembolism” includes the cases of DVT and PE; however, the former is a primary event and the latter is a secondary result. Active malignant disease classifies patients to a group with at least moderate risk of VTE. D-dimer levels could be increased in cancer patients without concomitant VTE. D-dimer levels below cut-off value (negative D-dimer) do not exclude VTE in cancer patients. In patients with active malignant disease with clinical symptoms suggesting VTE ultrasound (US) examination of deep veins or computed tomography angiography (angio-CT) should be performed, depending on the symptoms. Low-molecular-weight heparins (LMWH) are the drugs of choice in prevention and treatment of VTE in cancer patients. Antithrombotic treatment in cancer patients with DVT does not differ from treatment of cancer patients with PE, except clear indications to thrombolytic therapy. Cancer patients with clinical symptoms suggesting PE (dyspnoea, chest pain or tachycardia) are per definition classified into the group of moderate or high clinical probability of PE. The majority of PE cases account for embolism, which do not warrant thrombolytic treatment and should be treated with LMWH, UFH, or fondaparinux; LMWHs are the treatment of choice in cancer patients with VTE. Cancer patients have increased risk of recurrence of VTE. Available evidence does not justify the use of antithrombotic drugs to prolong survival in cancer patients.

Invitro Anti-mycotic Activity of Hydro Alcoholic Extracts of Some Indian Medicinal Plants against Fluconazole Resistant Candida albicans.

Candidiasis is one of the most common opportunistic infections caused by Candida albicans. Fluconazole is the drug of choice for prevention and management of this condition. However, the emergence of fluconazole resistant candidal strains has become a major concern. Many herbs like fenugreek, cinnamon, papaya, oregano, garlic are rich in phytochemical constituents known to express antimycotic activity. With the available information, the present research study was carried out to assess the invitro anti-mycotic activity of hydro alcoholic extracts of Trigonella foenum-graecum seeds, Cinnamomum verum bark and Carica papaya leaves and seeds against fluconazole resistant Candida albicans. Hydro alcoholic extracts of Trigonella foenum-graecum (seeds), Cinnamomum verum (bark), Carica papaya CO.2 strain (male and female leaves) and Carica papaya CO.2 strain (seeds) were prepared by maceration. The anti-mycotic activity of the prepared extracts against Candida albicans was assessed by agar well diffusion method. Three independent experiments were performed in triplicates and the mean and standard deviation were calculated. Minimum inhibitory concentration was determined. The results of the present study revealed that all the extracts exhibited anti-mycotic activity in a dose dependent manner and minimum inhibitory concentration of all the extracts was found to be 15.62 μg/ml. The results of the present study shed light on the fact that plant extracts could be used not only as an alternate drug for management of fluconazole resistant candidiasis but also explored further for oral cancer prevention as a therapeutic adjunct.

The Impact Of Dietary Vitamin K On The Pharmacological Activity Of FXa Inhibitor, Rivaroxaban, In Man

Introduction/Background Over several decades, warfarin has been used as the drug of choice for prevention and treatment of thromboembolic disorders. The impact of dietary vitamin K intake on anticoagulation response to warfarin is well established. However, the effect of dietary vitamin K on the activity of the novel oral anticoagulants is less well known. Since the activation of both factor X and thrombin is inextricably linked to the vitamin K cycle in the coagulation cascade, there is the possibility that the pharmacological activity of agents that inhibit these proteins could be influenced by alterations in vitamin K availability. Aim To examine the influence of dietary vitamin K intake on the pharmacological activity of rivaroxaban in man. Methods The pharmacological activity of rivaroxaban was evaluated ex-vivo. Thirty one medically stable elderly inpatients (12 males) with a poor dietary intake in terms of calories and nutrients including vitamin K (12 males) and 28 healthy subjects (7 males) with adequate diets were enrolled into the study. An overnight fasted venous blood sample (20 ml) was taken from each subject. The plasma was stored at -80 degree C for the later measurement of the effects of rivaroxaban on clotting times and clotting factor activity. Each subject completed a validated dietary questionnaire for quantification of vitamin K content of foods eaten in the past week. The plasma samples from each subject were incubated with a range of rivaroxaban concentrations (100 - 500 ng/ml) in order to simulate the therapeutic drug plasma concentrations. Normal prothrombin time (PT), modified prothrombin time (mPT), and vitamin K dependent clotting factors activity were measured according to established in-house methods. Results The mean±SD age of elderly patients and healthy subjects was 87±6 and 36±10 years, respectively. Rivaroxaban produced a greater prolongation of both PT (P=0.01) and m-PT (P=0.02) in the plasma of elderly subjects than the younger healthy subjects over the drug concentration range studied. The mean difference in PT between the two groups ranged from 1.8s to 5.0s at 100 ng/ml and 500 ng/ml plasma rivaroxaban concentrations respectively. The mean difference in m-PT between the two groups ranged from 10.0s to 34.0s at 100 ng/ml and 500 ng/ml plasma rivaroxaban concentrations respectively. There was also a greater inhibition of factor Xa (P=0.005) activity by rivaroxaban in the elderly subjects compared to the healthy subjects, whereas factor IXa (P=0.03) activity was significantly inhibited in the healthy subjects compared to the elderly subjects. However, there were no significant differences between the two groups in factors II and VII activity and fibrinogen concentration. The analysis of dietary questionnaires for vitamin K intake and plasma for fasting vitamin K levels is in progress and the results will be presented. Conclusion We have previously demonstrated in a proof-of-concept study in rats that vitamin K deficiency significantly enhanced the pharmacological activity of the prototype DTI, ximelagatran [1]. The present study findings suggest that the anticoagulation response to rivaroxaban may be influenced by poor dietary vitamin K intake. Assessment of whether dietary vitamin K influences anticoagulation response as well as any influence of age, co morbidities and drug intake in patients taking rivaroxaban is warranted. [1] Kamali F, Wood P, Ward A. Vitamin K deficiency amplifies anticoagulation response to ximelagatran: possible implications for direct thrombin inhibitors and their clinical safety. Annals of Hematology 2009; 88:141-149. Disclosures: No relevant conflicts of interest to declare.

An integrative review of the side effects related to the use of magnesium sulfate for pre-eclampsia and eclampsia management

BackgroundPre-eclampsia/eclampsia is one of the most common causes of maternal and perinatal morbidity and mortality in low and middle income countries. Magnesium sulfate is the drug of choice for prevention of seizures as part of comprehensive management of the disease. Despite the compelling evidence for the effectiveness of magnesium sulfate, concern has been expressed about its safety and potential for toxicity, particularly among providers in low- and middle-income countries. The purpose of this review was to determine whether the literature published in these global settings supports the concerns about the safety of use of magnesium sulfate.MethodsAn integrative review of the literature was conducted to document the known incidences of severe adverse reactions to magnesium sulphate, and specific outcomes of interest related to its use. All types of prospective clinical studies were included if magnesium sulfate was used to manage pre-eclampsia or eclampsia, the study was conducted in a low- or middle-income country, and the study included the recording of the incidence of any adverse side effect resulting from magnesium sulfate use.ResultsA total of 24 studies that compared a magnesium sulfate regimen against other drug regimens and examined side effects among 34 subject groups were included. The overall rate of absent patellar reflex among all 9556 aggregated women was 1.6%, with a range of 0-57%. The overall rate of respiratory depression in 25 subject groups in which this outcome was reported was 1.3%, with a range of 0–8.2%. Delay in repeat administration of magnesium sulfate occurred in 3.6% of cases, with a range of 0-65%. Calcium gluconate was administered at an overall rate of less than 0.2%. There was only one maternal death that was attributed by the study authors to the use of magnesium sulfate among the 9556 women in the 24 studies.ConclusionConcerns about safety and toxicity from the use of magnesium sulfate should be mitigated by findings from this integrative review, which indicates a low incidence of the most severe side effects, documented in studies that used a wide variety of standard and modified drug regimens. Adverse effects of concern to providers occur infrequently, and when they occurred, a delay of repeat administration was generally sufficient to mitigate the effect. Early screening and diagnosis of the disease, appropriate treatment with proven drugs, and reasonable vigilance for women under treatment should be adopted as global policy and practice.

Prophylactic Use of Enoxaparin in Morbidly Obese Adolescents During Bariatric Surgery

AbstractAbstract 4367 Introduction:Obesity has increased exponentially in recent years and currently a substantial number of children and adolescents are morbidly obese. This development has resulted in the need for bariatric surgery in adolescents. Therefore, a bariatric surgery program has been initiated at Children’s National Medical Center (CNMC) and enoxaparin has been used as prophylaxis for venous thromboembolism (VTE). Enoxaparin is the drug of choice for prevention and treatment of VTE in children and adults. The standard of care at CNMC is to dose enoxaparin 40 mg SC q 12 hrs in patients with a BMI < 50 and 60 mg SC q 12 hrs for patients with a BMI > 50 with no routine use of anti-FXa monitoring. Nationally and internationally there are no well defined guidelines for prophylactic doses of enoxaparin and the approach varies among different institutions. This study was therefore designed and conducted to investigate if the current dosing regimens are indeed appropriate. Patients and Methods:Four morbidly obese adolescents aged 16 to 18 years and with a body weight ranging between 118 and 174 kg were studied. Anti-FXa assay concentrations were collected before (predose) and at 1, 2, 4, 6, and 12 hrs after the administration of the first dose of enoxaparin. In addition, after an extensive literature search, two pharmacokinetic (PK) studies were found that investigated comparable doses of enoxaparin in adult lean healthy volunteers with a mean age of 24 years. Results:The results are shown in Figure 1 and Table 1. The peak anti-FXa level (Cmax) ranged from 0.2–0.23 IU/ml in the 4 studied adolescents and these values are significantly lower as compared to the range of concentrations (0.38–0.5 IU/ml) detected in the two control groups from the literature. The time to reach Cmax (T max) was delayed, along with a lower area under the time vs concentration curve and the mean residence time. Conclusions:We conclude, based on our results, that the use of 40–60 mg enoxaparin as the current standard of care for VTE prophylaxis in morbidly obese adolescents results in different and probably insufficient anti-FXa levels as compared to those found in lean patients of comparable age. The clinical significance of this finding still needs to be determined.Table-1Participant-1 (60 mg)Participant-2 (40 mg)Participant-3 (60 mgParticipant-4 (60 mg)Control group-1* (Mean, SD)Control group-2** (Mean SD)Control group-2*** (Mean SD)Tmax (hr)7.404.216.007.513.1 ± 0.43.0 (median range: 2–5)3.5 (median range: 3–6)Cmax (IU/ml)0.200.230.220.200.45 ± 0.050.38 ± 0.090.51AUC (IU/mL)2.071.0821.541.153 ± 0.68––MRT (hr)6.663.206.424.546.7 ± 0.8)5.83 ± 0.866.19 ± 0.74*Azizi et al 40 mg,**Frydman et al 40 mg,***Frydman et al 60 mg. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Streptococcus agalactiae increase in resistance to erythromycin and clindamycin in vaginal-anal colonization in third quarter of pregnancy in one decade of universal screening

Streptococcus agalactiae (GBS) is the main causative agent of early perinatal sepsis. The acquisition of prevention policies has led to frequent use of intrapartum antibiotics. Surveillance of antimicrobial resistance is indispensable for defining drugs of choice and alternatives for such prophylaxis. To determine the evolution of antimicrobial resistance of GBS from maternal colonization to drugs used in the prevention of neonatal sepsis, between 2002 and 2008. We studied 100 GBS positive vaginal and anal samples from pregnant women. Disc diffussion susceptibility method was performed for penicillin, ampicillin, cefazolin, erythromycin and clindamycin according to the Clinical and Laboratory Standards Institute (CLSI). We analyzed the susceptibility of 99 strains. Seventeen were resistant to erythromycin (17.1%) and 13 were resistant to clindamycin (13.1%). Thirteen of the 17 strains resistant to erythromycin had the MLS phenotype (resistance to erythromycin and clindamycin) and 4 had the M phenotype (resistance to erythromycin only). Within the MLS phenotype, resistance was constitutive in 9 strains, and induced in 4 strains (positive D test). Compared with 2002 there was a significant increase in resistance to clindamycin (from 3.27% to 13.1% p < 0.002) and erythromycin (1.09% to 17% p < 0.001). 100% GSB remained sensitive to penicillin and ampicillin. GBS remains highly susceptible to drugs of choice for prevention of perinatal sepsis. There is a significant increase in antimicrobial resistance to clindamycin and erythromycin. Therefore, it is necessary to request susceptibility testing in GBS from third trimester of pregnancy screening in patients allergic to penicillin.

Aumento de resistencia de Streptococcus agalactiae vaginal-anal en el tercer trimestre de gestación a eritromicina y clindamicina al cabo de una década de tamizaje universal

Streptococcus agalactiae (GBS) is the main causative agent of early perinatal sepsis. The acquisition of prevention policies has led to frequent use of intrapartum antibiotics. Surveillance of antimicrobial resistance is indispensable for defining drugs of choice and alternatives for such prophylaxis.To determine the evolution of antimicrobial resistance of GBS from maternal colonization to drugs used in the prevention of neonatal sepsis, between 2002 and 2008.We studied 100 GBS positive vaginal and anal samples from pregnant women. Disc diffussion susceptibility method was performed for penicillin, ampicillin, cefazolin, erythromycin and clindamycin according to the Clinical and Laboratory Standards Institute (CLSI).We analyzed the susceptibility of 99 strains. Seventeen were resistant to erythromycin (17.1%) and 13 were resistant to clindamycin (13.1%). Thirteen of the 17 strains resistant to erythromycin had the MLS phenotype (resistance to erythromycin and clindamycin) and 4 had the M phenotype (resistance to erythromycin only). Within the MLS phenotype, resistance was constitutive in 9 strains, and induced in 4 strains (positive D test). Compared with 2002 there was a significant increase in resistance to clindamycin (from 3.27% to 13.1% p < 0.002) and erythromycin (1.09% to 17% p < 0.001). 100% GSB remained sensitive to penicillin and ampicillin.GBS remains highly susceptible to drugs of choice for prevention of perinatal sepsis. There is a significant increase in antimicrobial resistance to clindamycin and erythromycin. Therefore, it is necessary to request susceptibility testing in GBS from third trimester of pregnancy screening in patients allergic to penicillin.

English

Tacrolimus has been the drug of choice for prevention of graft rejection following organ transplantations. This systematic review and meta-analysis [UiTM1] was conducted to evaluate the efficacy of tacrolimus in organ transplantation. Publication in English of randomized clinical trials, which used tacrolimus to prevent graft rejection in adult patients were included in this analysis. Articles were searched from PubMed, Science Direct, Blackwell and Ovid Gateway, which were published since 1980 to 2007. The outcomes measured were biopsy-proven acute rejection at three months; graft survival at one year; post-transplant diabetes mellitus; hypertension and neurotoxicity. Seven reports, which involved 2415 participants showed that tacrolimus was associated with reduced odds of biopsyproven acute rejections three months of post-transplantation (pooled odds ratio of 0.69; 95% CI 0.49 to 0.96) and improved graft survival at one year (pooled odds ratio of 1.11 and 95% confidence interval 0.72 to 1.71). In terms of adverse effects, tacrolimus-treated patients were significantly at high odds of developing post-transplant diabetes mellitus (pooled odds ratio of 1.90; 95% CI 1.09 to 3.30) and neurotoxicity (pooled odds ratio of 1.61; 95% CI 1.15 to 2.25) but reduced odds of developing hypertension (pooled odds ratio of 0.80; 95% CI 0.65 to 0.98). Low to moderate heterogeneity between trials existed for the incidences of biopsy-proven acute rejections, graft survival, post-transplant diabetes mellitus and incidence of hypertension; but the analysis showed a significant increment of neurotoxicity by tacrolimus.

Histological changes in bladders of patients submitted to ifosfamide chemotherapy even with mesna prophylaxis

Hemorrhagic cystitis (HC) is a limiting side effect of chemotherapy with ifosfamide (IFS). Mesna is the drug of choice for prevention of HC. In this study, we analyzed cystoscopic and histological changes present in bladders of patients using IFS with mesna prophylaxis. Thirty-three patients selected for IFS plus three doses of mesna chemotherapy regime were assigned at random to two groups: Group I or reference group consisted of 18 patients yet untreated. Group II consisted of 15 patients in whom urinalysis and cystoscopy plus vesical biopsy were performed only 24 h after receiving the last dose of IFS. The cystoscopic and histological findings were used as parameters for evaluating the results. For the former the criterion adopted was macroscopic vesical changes in accordance with Gray's criteria. Histological analyses were performed by evaluation method especially adapted to this study. Even under treatment with three doses of mesna, 66.7% of patients presented cystoscopic alterations and 100% showed bladder mucosa microscopic alterations such as edema, exocytosis, and hemorrhage. The standard protocol used for prevention of IFS-induced HC with three doses of mesna does not completely prevent bladder damage. The histopathological criteria used in this study for observation of inflammatory events allowed staging the intensity of IFS-induced urothelial and mucosal injury.

The Role of Oral Direct Thrombin Inhibitors in the Prophylaxis of Venous Thromboembolism

Venous thromboembolism, which is manifested as deep vein thrombosis (DVT) and pulmonary embolism (PE), represents a significant cause of death, disability, and discomfort. Two million people/year are affected by VTE, making it the third most common cardiovascular disease after coronary heart disease and stroke. The rationale for VTE prophylaxis stems from the clinically silent presentation of the disease and its prevalence among hospitalized patients. At greatest risk are patients undergoing major orthopedic surgery and those admitted to the intensive care unit with acute myocardial infarction, heart failure, ischemic stroke, respiratory disease, systemic infection, or other medical conditions that immobilize patients for 5 days or longer. Several anticoagulant regimens have been effective in reducing the risk of VTE after major orthopedic surgery. For patients undergoing total hip or knee replacement, treatment with adjusted-dose warfarin, low-molecular-weight heparins, or fondaparinux may be used. Warfarin, which has been around for more than 50 years, is the only oral anticoagulant available for VTE prophylaxis. Ximelagatran, a new low-molecular-weight oral prodrug of the direct thrombin inhibitor melagatran, has advantages over warfarin that may make it the drug of choice for prevention of VTE.

Acute mountain sickness: controversies and advances.

This review discusses the impact of recent publications on pathophysiologic concepts and on practical aspects of acute mountain sickness (AMS). Magnetic resonance imaging studies do not provide evidence of total brain volume increase nor edema within the first 6 to 10 h of exposure to hypoxia despite symptoms of AMS. After 16 to 32 h at about 4500 m, brain volume increases by 0.8% to 2.7%, but morphological changes do not clearly correlate with symptoms of AMS, and lumbar cerebrospinal fluid pressure was unchanged from normoxic values in individuals with AMS. These data do not support the prevailing hypothesis that AMS is caused by cerebral edema and increased intracranial pressure. Direct measurement of increased oxygen radicals in hypoxia and a first study reducing AMS when lowering oxygen radicals by antioxidants suggest that oxidative stress is involved in the pathophysiology of AMS. Placebo-controlled trials demonstrate that theophylline significantly attenuates periodic breathing without improving arterial oxygen saturation during sleep. Its effects on AMS are marginal and clearly inferior to acetazolamide. A most recent large trial with Ginkgo biloba clearly showed that this drug does not prevent AMS in a low-risk setting in which acetazolamide in a low dose of 2 x 125 mg was effective. Therefore, acetazolamide remains the drug of choice for prevention and the recommended dose remains 2 x 250 mg daily until a lower dose has been tested in a high-risk setting and larger clinical trials with antioxidants have been performed.

Antihypertensive Therapy and Diabetic Microvascular Disease

Hypertension is commonly associated with diabetes and may represent either a manifestation or a cause of diabetic vascular injury. The following series of studies have explored the role of hypertension in accelerating diabetic microvascular injury. In addition, the role of various classes of antihypertensive agents in preventing or reversing diabetic vascular abnormalities in the presence and absence of systemic hypertension was assessed in both the experimental and clinical context. The induction of streptozotocin diabetes in SHR leads to accelerated development of nephropathy as assessed by both functional and structural parameters. ACE inhibitors but not dihydropyridine calcium channel blockers favourably influence the progression of experimental diabetic nephropathy even in the setting of a normal blood pressure. More recent studies have shown that the trophic changes in the mesenteric arteries from diabetic rats are also attenuated by ACE inhibition. Preliminary results from the Melbourne Diabetic Nephropathy Study Group suggest that the ACE inhibitor, perindopril, is more effective than the dihydropyridine calcium channel blocker, nifedipine, in retarding the rise in urinary albumin excretion in normotensive insulin and non- insulin dependent diabetic patients with microalbuminuria. In conclusion, ACE inhibitors appear to be the drugs of choice in prevention and treatment of diabetic renal disease and may also act as protective agents at other sites of vascular injury.

Omeprazole Inhibits Acetylsalicylic Acid-Modified Histamine Stimulation of Acid Secretion in Rabbit Gastric Glands

The effects of misoprostol and omeprazole on basal-, histamine- and acetylsalicylic acid (ASA)-induced gastric acid secretion by isolated rabbit gastric glands were studied. The authors found that ASA at a concentration of 2.4×10-3 M significantly inhibited acid secretion in the isolated gastric glands to 65% of basal levels, and that ASA at a concentration of 2.4×l0-2 M significantly inhibited the histamine stimulation of acid secretion to 78% of maximal. Misoprostol inhibited acid secretion to 76% of basal acid secretion, while omeprazole inhibited secretion to 58% of basal values. Misoprostol inhibited the ASA-modified histamine stimulation to 82% of maximal stimulation. In contrast, omeprazole was able to inhibit the ASA-modified histamine stimulation to 48% of maximal. This omeprazole inhibition of secretagogue-induced acid production reduced acid secretion to levels below basal secretion, indicating that neither histamine nor ASA (at the concentrations used), alone or in combination, had any stimulatory effect in the presence of omeprazole. Misoprostol is the recommended drug of choice for prevention and treatment of nonsteroidal anti-inflammatory drug (NSAID)-induced gastrointestinal mucosal injury. In vitro results suggest that omeprazole appears to treat this condition more effectively if gastric acid secretion is a necessary prerequisite for NSAID-induced mucosal injury.

Antifungal prophylaxis in immunocompromised hosts.

To review the literature on the efficacy and safety of antifungal agents for prophylaxis of fungal infections in populations of immunocompromised hosts (key words: hematology-oncology, surgical, solid organ transplant, HIV infection), and to develop guidelines and recommendations regarding safe and effective drug regimens for antifungal prophylaxis in this patient population. Comprehensive review of clinical trials of antifungal prophylaxis published in the English literature, with an emphasis on controlled trials, and discussion of key clinical trials illustrating efficacy and safety of agents for antifungal prophylaxis in immunocompromised patients. Much of the clinical data evaluating the efficacy and safety of antifungal prophylaxis has been generated in cancer patients. The choice of antifungal agent for prophylaxis in this population remains controversial. However, azole compounds such as clotrimazole, ketoconazole and fluconazole appear to be more effective and better tolerated than nystatin suspension. Although ketoconazole has been shown to reduce fungal colonization in surgical patients, current data do not support the routine use of antifungal prophylaxis in this population. In renal transplant recipients, clotrimazole troches have been shown to be more effective than placebo or nystatin suspension. Selective bowel decontamination with nonabsorbable antibiotics and nystatin may be useful in reducing Candida colonization in liver transplant patients but no definitive recommendations may be made at this time regarding optimal antifungal prophylaxis in these patients. In patients with advanced HIV disease or history of prior fungal disease prophylaxis for oropharyngeal candidiasis is indicated, although the agent of choice remains controversial. Fluconazole is the drug of choice for prevention of relapse of cryptococcal meningitis in patients with AIDS. Finally, only limited data exist assessing the relationship between local colonization and systemic fungal infection. Adverse effects associated with antifungal prophylaxis, generally limited to nausea and vomiting and transient elevations in hepatic transaminases, occur with similar frequency among available oral or topical agents. However, the incidence of nausea and vomiting with resultant poor patient tolerance and compliance is usually higher with nystatin. Based on available data from controlled clinical trials, azole agents are currently the most effective and best-tolerated drugs for antifungal prophylaxis in immunocompromised hosts. Choice of one agent in this group over another may be dictated by cost. As new antifungal treatments are released onto the market, these drugs should be compared with existing agents in controlled clinical trials. Future studies should be designed to evaluate the relationship between local colonization and disseminated infection.

Most patients in France are not receiving the drugs of choice for prevention of secondary myocardial infarction

Most patients in France are not receiving the drugs of choice for prevention of secondary myocardial infarction