Combination Of Other Drugs Research Articles

Haloperidol for Pain Management: A Narrative Review.

The use of haloperidol in pain management has been a topic of interest for several decades. Haloperidol is a widely used antipsychotic medication with unique pharmacologic properties that make it a potential candidate for pain management. However, the efficacy and safety of haloperidol for pain management remain controversial. This narrative review provides a summary of the current literature on the use of haloperidol for pain management, including its pharmacology, clinical effectiveness, adverse effects, and dosing regimens. We performed a comprehensive search of the literature for this review. The most robust clinical data from the past decade suggest that haloperidol has good efficacy in the treatment of pain related to gastroparesis and migraines and has shown promise for opioid use reduction in patients with chronic pain or receiving palliative care. The overall side effect profile is excellent, with zero reported events of QT-related cardiac arrest and minimal reports of sedation and transient extrapyramidal effects such as akathisia. Dosing regimens used were heterogeneous, with most ranging from 1 to 5 mg per dose via intravenous, intramuscular, or oral route. Studies with designs that isolated the effects of haloperidol from combinations of other drugs were extremely limited. Further high-quality prospective studies are needed to determine the ideal role of haloperidol in the routine clinical management of painful conditions.

Comparative Risk of Major Congenital Malformations With Antiseizure Medication Combinations vs Valproate Monotherapy in Pregnancy.

Valproate should be avoided in pregnancy, but it is the most effective drug for generalized epilepsies. Alternative treatment may require combinations of other drugs. Our objectives were to describe first trimester use of antiseizure medication (ASM) combinations that are relevant alternatives to valproate and determine whether specific combinations were associated with a lower risk of major congenital malformations (MCM) compared with valproate monotherapy. We conducted a population-based cohort study using linked national registers from Denmark, Finland, Iceland, Norway, and Sweden and administrative health care data from the United States and New South Wales, Australia. We described first trimester use of ASM combinations among pregnant people with epilepsy from 2000 to 2020. We compared the risk of MCM after first trimester exposure to ASM combinations vs valproate monotherapy and low-dose valproate plus lamotrigine or levetiracetam vs high-dose valproate (≥1,000 mg/d). We used log-binomial regression with propensity score weights to calculate adjusted risk ratios (aRRs) and 95% CIs for each dataset. Results were pooled using fixed-effects meta-analysis. Among 50,905 pregnancies in people with epilepsy identified from 7.8 million total pregnancies, 788 used lamotrigine and levetiracetam, 291 used lamotrigine and topiramate, 208 used levetiracetam and topiramate, 80 used lamotrigine and zonisamide, and 91 used levetiracetam and zonisamide. After excluding pregnancies with use of other ASMs, known teratogens, or a child diagnosed with MCM of infectious or genetic cause, we compared 587 exposed to lamotrigine-levetiracetam duotherapy and 186 exposed to lamotrigine-topiramate duotherapy with 1959 exposed to valproate monotherapy. Pooled aRRs were 0.41 (95% CI 0.24-0.69) and 1.26 (0.71-2.23), respectively. Duotherapy combinations containing low-dose valproate were infrequent, and comparisons with high-dose valproate monotherapy were inconclusive but suggested a lower risk for combination therapy. Other combinations were too rare for comparative safety analyses. Lamotrigine-levetiracetam duotherapy in first trimester was associated with a 60% lower risk of MCM than valproate monotherapy, while lamotrigine-topiramate was not associated with a reduced risk. Duotherapy with lamotrigine and levetiracetam may be favored to treat epilepsy in people with childbearing potential compared with valproate regarding MCM, but whether this combination is as effective as valproate remains to be determined. This study provides Class II evidence that in people with epilepsy treated in the first trimester of pregnancy, the risk of major congenital malformations is lower with lamotrigine-levetiracetam duotherapy than with valproate alone, but similar with lamotrigine-topiramate.

New insights into molecular signaling pathways and current advancements in prostate cancer diagnostics & therapeutics.

Prostate adenocarcinoma accounts for more than 20% of deaths among males due to cancer. It is the fifth-leading cancer diagnosed in males across the globe. The mortality rate is quite high due to prostate cancer. Despite the fact that advancements in diagnostics and therapeutics have been made, there is a lack of effective drugs. Metabolic pathways are altered due to the triggering of androgen receptor (AR) signaling pathways, and elevated levels of dihydrotestosterone are produced due to defects in AR signaling that accelerate the growth of prostate cancer cells. Further, PI3K/AKT/mTOR pathways interact with AR signaling pathway and act as precursors to promote prostate cancer. Prostate cancer therapy has been classified into luminal A, luminal B, and basal subtypes. Therapeutic drugs inhibiting dihydrotestosterone and PI3K have shown to give promising results to combat prostate cancer. Many second-generation Androgen receptor signaling antagonists are given either as single agent or with the combination of other drugs. In order to develop a cure for metastasized prostate cancer cells, Androgen deprivation therapy (ADT) is applied by using surgical or chemical methods. In many cases, Prostatectomy or local radiotherapy are used to control metastasized prostate cancer. However, it has been observed that after 1.5 years to 2 years of Prostatectomy or castration, there is reoccurrence of prostate cancer and high incidence of castration resistant prostate cancer is seen in population undergone ADT. It has been observed that Androgen derivation therapy combined with drugs like abiraterone acetate or docetaxel improve overall survival rate in metastatic hormone sensitive prostate cancer (mHSPC) patients. Scientific investigations have revealed that drugs inhibiting poly ADP Ribose polymerase (PARP) are showing promising results in clinical trials in the prostate cancer population with mCRPC and DNA repair abnormalities. Recently, RISUG adv (reversible inhibition of sperm under guidance) has shown significant results against prostate cancer cell lines and MTT assay has validated substantial effects of this drug against PC3 cell lines. Current review paper highlights the advancements in prostate cancer therapeutics and new drug molecules against prostate cancer. It will provide detailed insights on the signaling pathways which need to be targeted to combat metastasized prostate cancer and castration resistant prostate cancer.

Anti-Neuronal Autoantibodies (Cell Surface and Onconeural) and Their Association With Natural Autoantibodies in Synthetic Cannabinoid-Induced Psychosis.

Patients suffering from encephalitis may present psychiatric symptoms; however, the clinical relevance of anti-neuronal antibodies in patients experiencing a psychotic episode without encephalitis is still unclear. In this study, we examined the presence of anti-neuronal cell surface autoantibodies and onconeural autoantibodies in serum samples of 22 synthetic cannabinoid users presenting with psychosis. We found only two positive cases; however, seven patients had borderline results. Nonetheless, we found no significant correlation between anti-neuronal autoantibodies and the intensity of psychosis indicated by the Positive and Negative Syndrome Scale (PANSS) scores. The length of drug use and the combination of other drugs with synthetic cannabinoids have no significant effect on anti-neuronal autoantibody positivity. Nonetheless, the ratio of anti-citrate synthase (anti-CS) IgM and IgG natural autoantibodies was significantly lower (p = 0.036) in the anti-neuronal autoantibody-positive/borderline samples, than in the negative group. Interestingly, anti-CS IgM/IgG showed a significant negative correlation with PANSS-positive score (p = 0.04, r = −0.464). Our results demonstrated that anti-neuronal autoantibody positivity occurs in synthetic cannabinoid users, and the alteration of anti-CS IgM/IgG natural autoantibody levels points to immunological dysfunctions in these cases.

Ethno-pharmacology of Asaroon (Asarum europaeum L.) with special reference to Unani System of Medicine.

Asaroon is the rhizome of Asarum europaeum L. and is commonly used in Unani medicines for its various pharmacological actions. It is an evergreen plant with glossy foliage. It belongs to the family of Aristolochiaceae and is native to Europe and the United State of America. Some species of Asaroon have been found in theEastern Himalayan region. Asaroon has actions like Muharrik-i-A'sab (nervine stimulant), Mudirr-i-Bawl (diuretics), Mudirr-i-Hayd (emmenagogue), Musakkin-i-Alam (analgesic), Mufattit-i-sudad (remove obstructions) and Muqawwī-i-Jigar (hepatotonic), etc. It is used in the management of Hummā (fevers), Waja 'al-Mafasil (polyarthritis), Sara (epilepsy), Falij (paralysis), Ihtibās al-Tamth (amenorrhea) and Niqris (gout), etc. as per the Unani system of medicine (USM). It is used as a single herb as well as with a combination of other drugs to manage many diseases. The A.europaeum L. contains volatile oils and flavonoids along with other secondary metabolites. In the Indian market, Valeriana wallichii DC has been sold as Tagar but in some cases, it is sold as Asaroon. It is a clear case of adulteration by replacement of costly foreign drugs with a similar-looking indigenous drug. In this manuscript, we have discussed the Ethno-pharmacology of the A.europaeum L. with special reference to USM and basic differences with V.wallichii DC to show that both drugs are different and their actions and uses are also different from each other.

Meta-Analysis of the Efficacy and Adverse Reactions of Ibrutinib in the Treatment of Refractory/Relapsed Mantle Cell Lymphoma

Objective: Therapeutic results of relapsed/refractory mantle cell lymphoma (R/R MCL) are very disappointing at present, and there is no standard effective treatment regimen. Ibrutinib has been proved to be effective for R/R MCL, however, the sample size of these individual clinical studies was relatively small. Hence, current clinical experience in its usage is still limited. It is necessary to systematically analyze the efficacy and adverse reactions of ibrutinib in the treatment of R/R MCL. Methods: The PubMed, Cochrane Library, and Embase databases were searched using English search terms, mantle cell lymphoma, MCL, and ibrutinib; the VIP, Wanfang, and China National Knowledge Infrastructure (CNKI) databases were searched using the Chinese search terms, ibrutinib and mantle cell lymphoma. The extracted data were subjected to meta-analysis using R software to deduce the effective rate and occurrence rate of serious adverse reactions. Results: A total of 12 cohort studies were included in this analysis. The results demonstrated that ibrutinib could be an efficient therapy regimen for R/R MCL patients and the effect of combination therapy was better than that of single-drug therapy. During the treatment with ibrutinib, the adverse reactions mainly included hematological toxicity, infection, atrial fibrillation, and bleeding. Discussion: Our analysis showed ibrutinib is an optimal second-line treatment for R/R MCL, and the combination therapy is more effective than monotherapy as it was well-tolerated by the patients. Therefore, the combination of other drugs for R/R MCL should be considered for patients with poor efficacy of ibrutinib alone or relapse after treatment.

New Approach for the Synthesis of Aryloxy 1,3-Oxazines

Oxazinne compounds have drew the attention of many researchers to find different approaches to the synthesis of this type of compounds according to the success of their use in a wide range of pharmaceutical application during the last decades .It is also for the difference reactivity of these analogues is exhaustively depicted and illustrates the rich versatility of this class of starting material. They proved to have most of actions of a combination of other drugs. We are herein investigate the synthesis of ethyl aryloxy acetate(S1-6) from the reaction of the corresponding ethyl bromo acetate with aryl phenols .These intermediates were cyclized with antharanilic acid affording the titled compounds

New Approach for the Synthesis of Aryloxy 1,3-Oxazines

Oxazinne compounds have drew the attention of many researchers to find different approaches to the synthesis of this type of compounds according to the success of their use in a wide range of pharmaceutical application during the last decades .It is also for the difference reactivity of these analogues is exhaustively depicted and illustrates the rich versatility of this class of starting material. They proved to have most of actions of a combination of other drugs. We are herein investigate the synthesis of ethyl aryloxy acetate(S1-6) from the reaction of the corresponding ethyl bromo acetate with aryl phenols.These intermediates were cyclized with antharanilic acid affording the titled compounds.

NEW APPROACH FOR THE SYNTHESIS OF ARYLOXY 1,3-OXAZINES

Oxazine compounds have drew the attention of many researchers to find different approaches to the synthesis of this type of compounds according to the success of their use in a wide range of pharmaceutical application during the last decades .It is also for the difference reactivity of these analogues is exhaustively depicted and illustrates the rich versatility of this class of starting material. They proved to have most of actions of a combination of other drugs. We are herein investigate the synthesis of ethyl aryloxy acetate(S1-6) from the reaction of the corresponding ethyl bromo acetate with aryl phenols .These intermediates were cyclized with antharanilic acid affording the titled compounds

Strategies to Overcome Resistance Mechanisms in T-Cell Acute Lymphoblastic Leukemia.

Chemoresistance is a major cause of recurrence and death from T-cell acute lymphoblastic leukemia (T-ALL), both in adult and pediatric patients. In the majority of cases, drug-resistant disease is treated by selecting a combination of other drugs, without understanding the molecular mechanisms by which malignant cells escape chemotherapeutic treatments, even though a more detailed genomic characterization and the identification of actionable disease targets may enable informed decision of new agents to improve patient outcomes. In this work, we describe pathways of resistance to common chemotherapeutic agents including glucocorticoids and review the resistance mechanisms to targeted therapy such as IL7R, PI3K-AKT-mTOR, NOTCH1, BRD4/MYC, Cyclin D3: CDK4/CDK6, BCL2 inhibitors, and selective inhibitors of nuclear export (SINE). Finally, to overcome the limitations of the current trial-and-error method, we summarize the experiences of anti-cancer drug sensitivity resistance profiling (DSRP) approaches as a rapid and relevant strategy to infer drug activity and provide functional information to assist clinical decision one patient at a time.

Characterization, Purity Determination and Decomposition Kinetics of Ezetimibe Under Non-Isothermal Conditions

Background:Ezetimibe is a lipid-lowering agent used therapeutically alone or in combination of other drugs. The properties of the solid-state of drugs are critical factors in the pharmaceutical formulation development. Several instrumental techniques can be employed in the analysis of new formulations, but the thermoanalytical techniques, provide a fast and careful evaluation of physicochemical properties of a compound. </P><P> Objective: To carry out the physicochemical characterization, purity evaluation and non-isothermal kinetic studies of ezetimibe raw material.Methods:A combination of the following different analytical technics was employed: Differential Scanning Calorimetry, Thermogravimetric, Scanning Electron Microscopy, X-ray powder diffraction.Results:The results evidenced the crystalline characteristic of ezetimibe. The sample purity was 99.06 % ± 0.02 and the thermal decomposition followed a zero order kinetic, with activation energy of 96.56 kJ mol–1 and Arrhenius frequency factor of 3,442 x 109 min-1.Conclusion:The characterization of ezetimibe together with the non-isothermal kinetic degradation represents important studies for the pharmaceutical area, since it provides crucial information for the pharmacotechnical/quality control/production areas that should establish the specifications necessary to standardize the requirements of the raw material acquire to ensure the batch-to-batch reproducibility.

Pentavalent Antimonials Combined with Other Therapeutic Alternatives for the Treatment of Cutaneous and Mucocutaneous Leishmaniasis: A Systematic Review.

The first choice drugs for the treatment of cutaneous and mucocutaneous leishmaniasis are pentavalent antimonials, sodium stibogluconate, or meglumine antimoniate. However, the treatment with these drugs is expensive, can cause serious adverse effects, and is not always effective. The combination of two drugs by different routes or the combination of an alternative therapy with systemic therapy can increase the efficacy and decrease the collateral effects caused by the reference drugs. In this systematic review we investigated publications that described a combination of nonconventional treatment for cutaneous and mucocutaneous with pentavalent antimonials. A literature review was performed in the databases Web of Knowledge and PubMed in the period from 01st of December 2004 to 01st of June 2017, according to Prisma statement. Only clinical trials involving the treatment for cutaneous or mucocutaneous leishmaniasis, in English, and with available abstract were added. Other types of publications, such as reviews, case reports, comments to the editor, letters, interviews, guidelines, and errata, were excluded. Sixteen articles were selected and the pentavalent antimonials were administered in combination with pentoxifylline, granulocyte macrophage colony-stimulating factor, imiquimod, intralesional sodium stibogluconate, ketoconazole, silver-containing polyester dressing, lyophilized LEISH-F1 protein, cryotherapy, topical honey, and omeprazole. In general, the combined therapy resulted in high rates of clinical cure and when relapse or recurrence was reported, it was higher in the groups treated with pentavalent antimonials alone. The majority of the articles included in this review showed that cure rate ranged from 70 to 100% in patients treated with the combinations. Serious adverse effects were not observed in patients treated with drugs combination. The combination of other drugs or treatment modalities with pentavalent antimonials has proved to be effective for cutaneous and mucocutaneous leishmaniasis and for most seemed to be safe. However, new randomized, controlled, and multicentric clinical trials with more robust samples should be performed, especially the combination with immunomodulators.

Multispectroscopic and molecular modeling studies on the interaction of bile acids with bovine serum albumin (BSA)

Bile acids (BAs) as the main components in two Traditional Chinese Medicine (TCM) of Calculus bovis (niu huang) and Bear bile (xiong dan) have been used for curing hepatic and biliary disorders for decades. However, their severe side effects as injections dramatically hampered their medical development. In this study, the interaction of BAs with bovine serum albumin (BSA) was investigated through multispectroscopic and molecular docking techniques to primarily reveal the physiological effects of BAs at the molecular level. The Stern-Volmer analysis of fluorescence quenching data showed the presence of static quenching mechanism. Thermodynamic parameters of this interaction revealed that the predominant intermolecular force between BAs and BSA was the hydrogen binding or Vander walls interactions. The number of binding sites was calculated by Langmuir adsorption model of single molecule. The combination of BAs-BSA was moderate intensity because the binding constant KLB was lower than the combination of other drugs with BSA. This indicated the safety of BAs. Furthermore, the results from synchronous fluorescence technique and Fourier transform infrared spectroscopy represented that BAs had little effects on the structure of BSA. The diverse binding sites for various BAs with the protein BSA were substantiated by molecular docking studies. These results can contribute to the development and renovation of BAs drugs through revealing the interaction between BAs and BSA.

Predictive Simulation Modeling in JAK2-Mutant MPNs Identified Ruxolitinib and Sorafenib As a Synergistic Drug Combination for Disease Modifying Therapy

Abstract Background: Despite the identification of a number of genes that underlie the genetic complexity of the myelofibrosis (MF) phenotype and even with the subsequent FDA approval of a targeted therapy for MF that is ruxolitinib, the median overall survival time of MF patients is still only 5-6 years. This unchanged survival may be explained, in part, via the complex mutation patterns that contribute to MF. Consequently, treating MF patients remains a significant challenge in the hematology clinic. Aim: To identify new drugs for MF patients, we used predictive simulation modeling of JAK2-V617F expressing MPN cells that could readily be re-purposed for MF. Methods: : To identify combinations of other drugs that can enhance the effect of Ruxolitinib, we (1) employed predictive simulation to model a JAK2-V617F bearing cell line (2) identified the key molecular disease characteristics of the JAK2-driven disease network, and (3) experimentally validated the predictions. The predictive simulation approach from Cellworks provides a representation of disease physiology incorporating signaling and metabolic networks with an integrated phenotype view. We modelled the JAK2-V617F expressing SET2 cell line based on its genomic aberration data. We then screened a library of drugs on the computational model in combination with Ruxolotinib, by assessing the impact on disease specific biomarkers and phenotypes of proliferation, viability, and apoptosis. Results: The modeling and digital drug screening identified a short list of drugs that were predicted to inhibit Jak2 signaling. Validation studies were conducted with the representative JAK2 driven SET2 cell line which harbors the JAK2-V617F mutation and was predicted to lead to subsequent activation of STAT3, STAT5, ERK via SHC1, AKT via IRS1-PIK3CA and STAT1 (Fig 1). JAK2 is known to phosphorylate STAT3 on Y705. Predictive modeling also discovered activation of parallel signaling via mutations of ALK, IRS2 and RPTOR. ALK is also known to activate STAT3 via Y705 phosphorylation and ERK via SHC1. IRS2 leads to activation of PIK3CA-AKT-MTOR. SET2 cells also harbor a RPTOR mutation which also activates MTOR pathway further. With higher ERK and MTOR signaling, there was S727 phosphorylation of STAT3. Using digital drug screening on the SET2 simulation model, sorafenib mitigated the effect of JAK2 mutation by inhibiting pathways downstream of JAK2, rather than decreasing the JAK2 mutation burden itself. Sorafenib is a small molecule kinase inhibitor that targets multiple proteins including VEGFR, PDGFR, and several Raf family kinases. It is approved for use in renal, liver, and thyroid cancers and is under clinical investigation for a number of other neoplasias. A potential role for sorafenib in MF has not been fully investigated. Sorafenib is known to inhibit ERK via inhibition of RAF. Sorafenib was also predicted to inhibit STAT3, STAT5, STAT1 and AKT1 via activation of PTPN6 in the SET2 model. With down-regulation of ERK and AKT1-MTOR pathway, Sorafenib was predicted to inhibit STAT3 S727 phosphorylation. Hence, with sorafenib and ruxolitinib, not only was JAK2 burden reduced, but also parallel pathway signaling via ALK, IRS2 and RPTOR. Using in vitro validation, we found that sorafenib was highly efficacious in reducing Jak2-V617F cell viability in a dose-dependent manner (GI50 = 6 uM) . Moreover, when Jak2-V617F cells were treated with both ruxolitinib and sorafenib, there was synergy, suggesting that the compounds were acting on multiple, cooperating signaling pathways. A prior report also showed synergistic MPN regression with ruxolitinib and sorafenib in BaF3/Jak2-V617F and HEL cell lines and primary specimens (PMID: 23560534), thereby providing independent evidence for the rationale use of these compounds in MF patients harboring mutation of PDGFRA/B, NRAS, KRAS in addition to JAK2 mutations. Conclusion: Thus, in addition to identifying a novel drug regimen for MF, we demonstrate that successful treatment of MF likely requires targeting multiple, non-redundant, constitutively active, and cooperative signaling pathways, rather than a one-biomarker/one-drug approach as is the current clinical standard. Further, we demonstrate how predictive simulation modeling can be used for precision medicine purposes in MF to inform clinical treatment decision-making of FDA approved drugs, with the intent of providing significant health and cost benefits. Download : Download high-res image (220KB) Download : Download full-size image Figure 1 . Disclosures Singh: Cellworks Research India Pvt. Ltd: Employment. Pampana: CellWorks: Employment. Usmani: Cellworks: Employment. Sauban: Cellworks: Employment. Kushwaha: CellWorks: Employment. Ramakrishnan: CellWorks: Employment. Abbasi: Cellworks Group Inc.: Employment. Vali: Cellworks Group Inc.: Employment. Cogle: Celgene: Other: Membership on Steering Committee for Connect MDS/AML Registry.

A novel point mutation promotes growth phase-dependent daptomycin tolerance in Staphylococcus aureus.

Recalcitrance of genetically susceptible bacteria to antibiotic killing is a hallmark of bacterial drug tolerance. This phenomenon is prevalent in biofilms, persisters, and also planktonic cells and is associated with chronic or relapsing infections with pathogens such as Staphylococcus aureus. Here we report the in vitro evolution of an S. aureus strain that exhibits a high degree of nonsusceptibility to daptomycin as a result of cyclic challenges with bactericidal concentrations of the drug. This phenotype was attributed to stationary growth phase-dependent drug tolerance and was clearly distinguished from resistance. The underlying genetic basis was revealed to be an adaptive point mutation in the putative inorganic phosphate (Pi) transporter gene pitA. Drug tolerance caused by this allele, termed pitA6, was abrogated when the upstream gene pitR was inactivated. Enhanced tolerance toward daptomycin, as well as the acyldepsipeptide antibiotic ADEP4 and various combinations of other drugs, was accompanied by elevated intracellular concentrations of Pi and polyphosphate, which may reversibly interfere with critical cellular functions. The evolved strain displayed increased rates of survival within human endothelial cells, demonstrating the correlation of intracellular persistence and drug tolerance. These findings will be useful for further investigations of S. aureus drug tolerance, toward the development of additional antipersister compounds and strategies.

Analysis of usage of diuretics in Medical intensive care unit of SIMS-Shimoga a tertiary care hospital.

Background: Patients are admitted in the intensive care unit (ICU) with a history of various acute and chronic clinical conditions associated with organ failures. Compared to the patients admitted in the general wards the mortality and morbidity are high in ICU patients. The patients in ICU are subjected to multiple drugs; diuretic agents are liberally and deliberately used in this setup despite the lack of evidence supporting their benefits. Methods: The main aim of the study was to know the extent of use of diuretics in the ICU set up, to categorize the use of diuretics in different clinical conditions and different classes of diuretics used. The study also tried to determine adverse events and outcome in critically ill patients. The study was a retrospective cross-sectional of 3 months duration conducted in all patients admitted in the medical ICU of the tertiary care center. The study mainly concentrated on the usage of diuretics and related aspects. Results: Loop diuretics (54.81%) composed the major class, thiazides (30.84%). Potassium sparing diuretics (7%) and osmotic diuretics (7%) and carbonic anhydrase inhibitors (1%) were the other class of diuretics. The classes of drugs used in ICU along with diuretics were antibiotics (30%), analgesics (9.5%), anti-inflammatory (6.36%), and drugs acting on blood (10.18%) of total drugs used in ICU. Antacids/laxatives (7.3%) and antiemetic (4.8%), the rest of drugs (15%) of drugs used in ICU. Conclusion: In almost 95% of cases, the combination of other drugs along with diuretics was considered to be rational.

Auto-évaluation chimioprophylaxie du paludisme

More than 600 million people are still exposed to malaria, and eradication is still far away. Protection for some of those at risk—only a fraction of those exposed can therefore be obtained only by chemoprophylaxis.Schizontocide drugs are in 2 categories:— 1.1. Those acting rapidly, to which resistance appears only slowly—quinine, mepacrine, the 4-aminoquinolines (the best). Dosages of the 4-aminoquinolines used by French workers are higher than those used by Anglo-Saxons—for instance, for prophylaxis 100 mg. daily, and for cure 2100 mg. during 5 days. Resistance (of type R 1) in P. falciparum is not world-wide, and has not been reported in Africa and Madagascar.2.2. Those acting slowly, to which resistance appears quickly—the anti-folinic group (pyrimethamine, proguanil, cycloguanil) and the anti-folic group (sulphonamides and sulphones). Partial cross resistance between these groups has been found, but not between categories 1 and 2.Various combinations of these drugs have been used—4-aminoquinolines + 8-aminoquinolines; chloroquine + pyrimethamine; chloroquine + primaquine + DDS; antifolic + antifolinic drugs.Individual chemoprophylaxis is not difficult, in that there are no strains of malaria parasites resistant to all antimalarials. Chemoprophylaxis of indigenous populations, more or less immune, is more complex. P. falciparum is directly responsible for the death of about 5% of children in hyperendemic areas, and 15% in holoendemic areas; chemoprophylaxis is therefore in the sphere of maternity and child health. In the absence of resistance, chloroquine and amodiaquine are the drugs of choice; the object is to prevent death without interfering with the acquisition of immunity, and this is quite possible. If chloroquine resistance exists, various combinations of other drugs are called for.

Primary central nervous system lymphoma: recent progress, many remaining questions

To review what progress has been made in the treatment of primary central nervous system lymphoma since the time when it was first recognized that high-dose methotrexate based chemotherapy improved outcome over radiation therapy alone. Recent work has explored the use of high-dose methotrexate alone; the optimum dose of methotrexate; the need for intrathecal therapy; combinations of other drugs with high-dose methotrexate, most notably alkylators, high-dose cytarabine, and rituximab; and the use of myeloablative chemotherapy and autologous stem-cell rescue. Recent progress has also been made in the identification of clinical prognostic factors, and in identifying underlying biologic properties that may account for this tumor's distinctive clinical behavior. Further improvement in progression-free survival and in the proportion of patients achieving long-term disease-free survival does seem to be achievable, based on the results of nonrandomized data. Reduction in the risk of severe neurotoxicity by withholding or deferring radiation therapy also appears feasible. Existing treatment options can be individualized to the patient's circumstances. However, the optimal management of primary central nervous system lymphoma remains to be defined, and participation in a suitable clinical trial is highly appropriate.

Docetaxel-based regimens, the standard of care for metastatic androgen-insensitive prostate cancer

Patients with recurrent prostate cancer may be treated with androgen deprivation strategies; however, most patients will develop androgen-independent prostate cancer. Strategies for treatment of this group of patients have shown significant palliation but until recently, have had no definitive increase in survival. Two large Phase III studies evaluating docetaxel-based chemotherapy were initiated to see if these could improve overall survival over mitoxantrone with prednisone. The purpose of the Tax 327 Phase III study was to determine if either weekly or every-3-week administration of docetaxel plus daily prednisone regimen could improve the overall survival for these patients as compared with mitoxantrone and prednisone, which is approved by the US Food and Drug Administration as a palliative treatment. This study is of immense importance as it represents the first time any treatment has been shown to improve overall survival in an appropriately powered study in patients with androgen-insensitive metastatic prostate cancer. Newer approaches are now looking at combinations of other drugs with docetaxel to further improve the overall survival of patients with metastatic androgen-insensitive metastatic prostate cancer.

Diazepam for treating tetanus.

Clinical management of the muscle spasms and rigidity of tetanus poses a difficult therapeutic problem to physicians everywhere, especially in resource poor countries. There are wide variations in therapeutic regimens commonly used in clinical practice due to uncertainties about effectiveness of conventional drugs. Diazepam compared to other drugs (eg phenobarbitone and chlorpromazine) may have advantages because of combined anticonvulsant, muscle relaxant, sedative and anxiolytic effects. To compare diazepam to other drugs in treating the muscle spasms and rigidity of tetanus in children and adults. We searched the Cochrane Neonatal Group trials register (October 2003), Cochrane Central Register of Controlled Trials (The Cochrane Library, Issue 3, 2003), MEDLINE (1966 to October 2003), EMBASE (1980 to October 2003), LILACS (2003), CINAHL (October 2003), Science Citation Index, African Index Medicus, conference abstracts and reference lists of articles. We contacted researchers, experts and organizations working in the field and used personal communication. Randomized and quasi-randomized controlled trials. We independently identified eligible trials, assessed trial methodological quality and extracted data. Two studies met the inclusion criteria. Method of generation of allocation sequence, concealment of allocation and blinding were unclear in both studies. A total of 134 children were allocated to three treatment groups comprising diazepam alone, phenobarbitone and chlorpromazine, or phenobarbitone and chlorpromazine and diazepam.Meta-analysis of in-hospital deaths indicates that children treated with diazepam alone had a better chance of survival than those treated with combination of phenobarbitone and chlorpromazine (Relative Risk for death 0.36; 95% confidence interval 0.15 to 0.86; Risk Difference -0.22; 95% CI -0.38 to -0.06). Giving diazepam alone, or supplementing conventional anticonvulsants (phenobarbitone and chlorpromazine) with diazepam, was reported in one study to be associated with a statistically significantly milder clinical course and shorter duration of hospitalization. Although there is evidence that diazepam alone compared with combination of phenobarbitone and chlorpromazine is more effective in treating tetanus, the small size, methodological limitations and lack of data on drug safety from available trials preclude definite conclusions to support change in current clinical practice. The application of the present evidence should be moderated by local needs and circumstances, pending the availability of more evidence. We recommend a large multicenter, randomized controlled trial which compares diazepam alone with combinations of other drugs (excluding diazepam).