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PubMed1980

[An experimental study on the effects of the chronic administration of an angiotensin converting enzyme inhibitor (captopril) on blood pressure and the renin-angiotensin-aldosterone system (author's transl)].

The chronic effects of the oral administration of an angiotensin converting enzyme inhibitor (captopril, 63-80 mg/kg/day) on blood pressure and the renin-angiotensin-aldosterone system were studied in normotensive male Wistar rats. The blood pressure (BP), plasma renin activity (PRA), plasma renin concentration (PRC), plasma renin substrate concentration (PRS), plasma aldosterone concentration (PAC), and renal renin content (RRC) were measured 2, 9, 19, 29 and 58 days after the administration of the agent. Blood pressure was determined in unanesthetized rats, and blood samples were obtained by decapitation. Furthermore, blood pressure responses to bolus injections of angiotensin II (AII, 80 ng/kg), angiotensin I (AI, 80 ng/kg) and bradykinin (BK, 10 micrograms/kg) were examined in unanesthetized rats which had been given the agent for 20 days. The BP of the rats which had been given captopril for 9 days or more was significantly lower than in the control rats. The reduction in heart weight in the captopril rats reached a statistically significant level 58 days after the administration of the agent. The PRA and the PRC markedly increased, and the PRS and the PAC both decreased in the captopril rats. The RRC which was reduced after 2 days of captopril administration markedly increased thereafter. In the captopril rats, significant negative correlations were observed between PRC and PRS (r=-0.43, p<0.01), and between BP and PRC (r=-0.60, p<0.001). The PRC significantly correlated with the RRC in the control rats (r=-0.44, p<0.01) while such a relationship did not exist in the captopril rats. Although the pressor responses to AII were similar in the captopril and the control rats, the responses to AI were reduced to 50% of the responses to AII in the captopril rats. The blood pressure reduction in response to BK in the captopril rats was 2.3 times as great as that in the control rats. Thus, it is suggested that the increases in PRA, PRC and RRC in the captopril rats may be related to both the blood pressure reduction and interruption of the negative feedback inhibition of renin synthesis and release by AII, and that the decrease in PRS in the captopril rats is due to the increased consumption and probably to the decreased rate of substrate production in the liver which is secondary to the decrease in plasma AII. The lack of significant positive correlation between PRC and RRC in the captopril rats seems to demonstrate that captopril may modify the relationship between them. The results also show that the chronic administration of captopril lowers blood pressure in normotensive animals. The blood pressure reduction by captopril may be related to the decreased kininase activity which is suggested by the enhanced depressor responses to BK, as well as the lowered plasma level of AII.

Aldosterone↗
PubMed2003

Oestrogen receptor downregulation: an opportunity for extending the window of endocrine therapy in advanced breast cancer.

BACKGROUND: Advanced breast cancer is largely incurable and current treatment modalities are aimed towards restricting tumour growth, prolonging survival, palliating symptoms and maintaining quality of life (QoL). The development of breast cancer is strongly influenced by endogenous oestrogens (and other growth factors), leading to a strong focus on the development of antioestrogenic compounds for the treatment of hormone-sensitive advanced disease. DESIGN: This is a review of current endocrine therapies available for postmenopausal women with advanced breast cancer, examining the likely impact of newer agents on treatment strategies. RESULTS: In postmenopausal women, current treatment options include tamoxifen, aromatase inhibitors (AIs) and megestrol acetate. Fulvestrant ('Faslodex') is a new, well-tolerated, oestrogen receptor antagonist that has no known agonist effect and is at least as effective as the AI anastrozole for the treatment of postmenopausal patients with metastatic or advanced breast cancer who have progressed on prior endocrine therapy. Fulvestrant maintains QoL throughout successful treatment. CONCLUSIONS: Fulvestrant represents a new treatment option for postmenopausal women with advanced disease. New agents that appear to lack cross-resistance with existing treatments may be used to extend the time period during which endocrine therapy may be employed before the need for cytotoxic chemotherapy.

Aged↗
PubMed1975

Spermatogenetic clones developing from repopulating stem cells surviving a high dose of an alkylating agent.

We investigated stem cell renewal and differentiation in 10- and 15-days-old spermatogonial clones developing in mouse seminiferous epithelium after an extremely large cell loss, inflicted by high doses of the alkylating agent Myleran. The spermatogonial clones arise from cells that resemble the Ais spermatogonia but have a larger nuclear diameter. In spite of their mitotic activity these 'repopulating stem cells' lie mainly isolated or in pairs. This explained by migration and differentiation. Migration appeared to occur at random in all directions along the basement membrane of the seminiferous tubule. After one or more divisions of the stem cells, a second type of cell appears, which is called the 'differentiating spermatogomium'. The time elapsing before this type of cell appears, depends on the dose of Myleran: the larger the dose the later differentiation starts. A relation could be demonstrated between the stage of the cycle of the seminiferous epithelium and the start of differentiation. Differentiating cells were found isolated or in groups of two, four, eight or sixteen cells. Hence we concluded that at least up to their fourth division differentiating cells divide synchronously without degenerations. Three types of division of repopulating stem cells were distinguished, producing (1) two repopulating stem cells, (2) one repopulating stem cell and one cell starting spermatogonial differentiation, or (3) two differentiating cells. Type 1 divisions were found most frequently.

Animals↗
PubMed2005

Blockade of the ERK pathway markedly sensitizes tumor cells to HDAC inhibitor-induced cell death.

Constitutive activation of the extracellular signal-regulated kinase (ERK) pathway is associated with the neoplastic phenotype of a large number of human tumor cells. Although specific blockade of the ERK pathway by treating such tumor cells with potent mitogen-activated protein kinase/ERK kinase (MEK) inhibitors completely suppresses their proliferation, it by itself shows only a modest effect on the induction of apoptotic cell death. However, these MEK inhibitors markedly enhance the efficacy of histone deacetylase (HDAC) inhibitors to induce apoptotic cell death: such an enhanced cell death is observed only in tumor cells in which the ERK pathway is constitutively activated. Co-administration of MEK inhibitor markedly sensitizes tumor cells to HDAC inhibitor-induced generation of reactive oxygen species, which appears to mediate the enhanced cell death induced by the combination of these agents. These results suggest that the combination of MEK inhibitors and HDAC inhibitors provides an efficient chemotherapeutic strategy for the treatment of tumor cells in which the ERK pathway is constitutively activated.

Antineoplastic Agents↗
PubMed2005

New developments in the treatment of postmenopausal breast cancer.

In recent years, new agents have challenged tamoxifen as the standard endocrine therapy for postmenopausal breast cancer. This article reviews developments with regard to the third-generation aromatase inhibitors (AIs)--anastrozole, letrozole and exemestane--and fulvestrant, the first of a new type of estrogen receptor antagonist that, unlike tamoxifen, has no partial agonist activity. The final results of the "Arimidex", Tamoxifen, Alone or in Combination (ATAC) trial, at a median follow-up of more than five years, and recent results from switching studies with anastrozole and exemestane, strengthen the position of these AIs as adjuvant treatment for hormone receptor-positive early breast cancer. Sequencing options for the future are also discussed because non-steroidal AIs are increasingly used early in the treatment sequence.

Anastrozole↗
PubMed2026

Whole genome sequence of a superbug-Escherichia coli strain KAB-AI-497 isolated from the vagina of a 20 year old pregnant woman with premature rupture of membrane (PROM) in a resource limited setting, Kabale Regional Referral Hospital, in Uganda.

OBJECTIVES: The objective of the study is to sequence the whole genome of multidrug resistant E. coli strain KAB-AI-497 that causes bacterial vaginosis and implicated in premature rupture of membrane in pregnant woman. DATA DESCRIPTION: The DNA of the E. coli strain KAB-AI-497 was extracted using the MagAttract HMW DNA Kit, and the extracted DNA was sequenced using an MGI DNBSEQ G99ARS platform. FastQC was used to perform quality control analysis and the reads were trimmed by Trimmomatic. De novo genome assembly was performed by SPAdes and it resulted to a draft assembled genome that has 5.1 Mb genome size, 153 contigs, and 50.5% GC content. Quality analysis of the assembled genome revealed it has 98.46% completeness and 0.97% contamination. The closest E. coli strain to this strain KAB-AI-497 in terms of similarity was Escherichia coli SMS-3-5 with an average nucleotide identity of 98.43% and genome coverage of 86.19%, which confirmed the species level identity of the strain. The assembled genome was annotated using the NCBI Prokaryotic Genome Annotation Pipeline which identified 4,726 protein coding genes in the strain genome. Furthermore, the annotation revealed the genome has resistant genes responsible for resistance against many antibiotic classes such as tetracycline, fluoroquinolone, and penicillin.

Escherichia coli↗
PubMed2026

A comprehensive review of AI innovations for tackling antimicrobial resistance.

Antimicrobial resistance (AMR) represents a major global public health concern, rendering available antimicrobials ineffective and leading to infections that are difficult to treat. Artificial intelligence (AI) has been increasingly applied across the AMR continuum, including resistance prediction, rapid diagnostics, new antimicrobial discovery, drug repurposing, antimicrobial surveillance, and clinical decision support. In this review, we aim to highlight recent developments in the use of artificial intelligence (AI) to address antimicrobial resistance (AMR). In addition, we review computational methods that help interpret genomic, phenomic, clinical, and epidemiological data to support the development of treatment strategies and novel antimicrobial agents. The key issues addressed include data quality, model interpretability, external validation, regulatory requirements, privacy, and fairness. While AI is not a complete solution to AMR, it can certainly strengthen the global AMR response by complementing key areas of AMR such as antimicrobial stewardship, infection prevention, laboratory diagnostics, and global surveillance.

Antimicrobial resistance (AMR)↗
PubMed2006

Aromatase inhibitors in breast cancer: a review of cost considerations and cost effectiveness.

Aromatase inhibitors (AIs) have been evaluated clinically in a wide range of breast cancer treatment settings. Although these agents appear to have clinical superiority, they are more expensive than the therapies (primarily tamoxifen) they have been compared with, thus economic evaluation is required to consider their incremental value to the payer. This paper reviews published economic evaluations of AIs as first-line therapy for advanced cancer, and as adjuvant therapy for early breast cancer. The evaluations in the advanced setting demonstrate a range of different modelling techniques and consider the payer's perspective in three healthcare systems. There is broad similarity in the application of standard cohort Markov modelling techniques to evaluate AIs in the early breast cancer setting, covering four separate health system perspectives. AIs appear cost effective compared with current practice. An analysis in the advanced setting suggests that letrozole may be the more cost-effective AI. No direct comparisons of alternative AIs in the adjuvant setting are reported, although indirect comparisons may be feasible. Future evaluations of treatment strategies over the entire course of the disease may also be needed.

Aromatase Inhibitors↗
PubMed2000

Albumin inhibits apolipoprotein AI and AII production in human hepatoblastoma cell line (Hep G2): additive effects of oleate-albumin complex.

Although the role of multiple humoral agents (such as plasma albumin, glucose, hormones etc.) are implicated in lipoprotein metabolism, the mechanism of action of these agents on various steps of the synthesis and secretion of lipoproteins and apolipoproteins (protein moieties of lipoproteins) are not completely understood. Specifically, the hepatocellular mechanisms of the effect of albumin and fatty acids on apolipoprotein (apo) AI and AII [major proteins of high density lipoproteins (HDL)] synthesis and secretion are not known. Using human hepatoblastoma cells (Hep G2) as an in vitro model system, this study examined the effect of albumin and fatty acids on the synthesis, secretion, and the steady-state mRNA expression of apo AI and AII. The data indicated that the incubation of Hep G2 cells with albumin, dose-dependently, inhibited apo AI and AII accumulation (secretion) in the media, de novo synthesis, and the steady-state mRNA expression. Albumin did not alter total protein synthesis; thus the effect of albumin appeared to be specific for the synthesis and secretion of apo AI and apo AII. Free fatty acids (FFA) are transported by albumin and diseases characterized by enhanced FFA mobilization (e.g. diabetes mellitus) are associated with low HDL levels. Studies were therefore performed to examine the effect of albumin-bound-oleic acid on apo AI and apo AII production. The results showed that the albumin-oleate complex further increased the inhibitory effects of albumin on apo AI and apo AII production. These data suggest how HDL metabolism may be affected at the hepatocellular level by alterations in plasma albumin concentrations and/or fatty acid mobilization in clinical situations characterized by altered HDL levels.

Albumins↗
PubMed2006

Beneficial effects of ondansetron as an adjunct to haloperidol for chronic, treatment-resistant schizophrenia: a double-blind, randomized, placebo-controlled study.

BACKGROUND: Previous studies suggest that the serotonin-3 (5-HT3) receptor antagonist ondansetron possesses the therapeutic potential for schizophrenia. This study was designed to determine whether ondansetron as an adjunct to haloperidol could enhance the clinical efficacy and reduce the adverse side effects in chronic treatment-resistant schizophrenia. METHODS: Under double-blind, randomized conditions, 121 treatment-resistant inpatients with chronic DSM-IV-diagnosed schizophrenia received haloperidol (4-30 mg/day) combined with either placebo (N=63) or a fixed dose of 8 mg/day of ondansetron (N=58) for 12 weeks. Efficacy was defined as the change from baseline to endpoint in score on overall scale and subscales of the Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression-Severity (CGI-S). Side effects were evaluated using the Treatment Emergent Symptom Scale and Extrapyramidal Symptom Rating Scale. RESULTS: Ondansetron combined with haloperidol produced a significantly greater improvement on PANSS overall scale and subscales for negative symptoms, general psychopathology, and cognition at endpoint compared to placebo with haloperidol, but no between-treatment group difference was observed on the subscale for positive symptoms and CGI-S. The ondansetron-treated group had a significantly higher proportion of patients with a 30% or greater baseline-to-endpoint reduction in PANSS total score than placebo. Patients in adjunctive ondansetron therapy also experienced significantly lower incidence and severity of parkinsonism and akathisia as well as fewer behavioral hyperactivity, cardiac, and gastrointestinal side effects. CONCLUSIONS: Ondansetron is an effective adjunctive agent in enhancing the effectiveness and reducing some adverse side effects of antipsychotic therapy for chronic, treatment-resistant schizophrenia, particularly for negative and cognitive symptoms.

Adolescent↗
PubMed2006

Hypolipidemic effects of acute and sub-chronic administration of an aqueous extract of Ajuga iva L. whole plant in normal and diabetic rats.

Diabetes is often accompanied by lipid abnormalities, which contribute significantly to cardiovascular (CV) morbidity and mortality in diabetic patients. The plant Ajuga iva (L.) Schreiber (Labiatea) is used in the treatment of diabetes in Moroccan folk medicine. Previously, we have demonstrated potent hypoglycemic activity and relatively non-toxic nature of a lyophilized aqueous extract of the whole plant (AI-extract) in normal (normoglycemic) and streptozotocin (STZ)-diabetic rats. In this study, we examined the AI-extract for its possible lipid-lowering activity in normal and STZ-diabetic rats. Taurine (TR) and glibenclamide (GLB) were used as reference substances. As shown previously, the AI-extract (10 mg/kg; oral) reduced plasma glucose levels after acute (single) and sub-chronic (3 weeks) dosing both in normal and diabetic rats. In normal rats, single and repeated oral administration of the AI-extract, at a dose of 10 mg/kg produced a small but significant decrease in plasma CHL levels (P<0.05). A single dose of the AI-extract did not produce a significant change in plasma TG, but sub-chronic dosing (for up to 21 days) caused a significant decrease in plasma TG (P<0.05). In STZ-diabetic rats, a single dose as well as repeated (3 weeks) treatment with the AI-extract produced a significant decrease in plasma CHL (P<0.01), and triglyceride (P<0.01) levels. The AI-extract also prevented weight loss in the diabetic animals. In summary, an aqueous extract of the Ajuga iva whole plant showed hypolipidemic activity, in addition to its hypoglycemic effect in normoglycemic and diabetic rats. In view of the hypoglycemic and hypolipidemic activity, and its relatively non-toxic nature (shown previously), Ajuga iva may be a candidate for development as an anti-diabetic agent in humans. Further studies are warranted to confirm our results and fractionate the AI-extract to isolate and identify the active principle(s), and to determine the exact mechanism(s) of action.

Administration, Oral↗
PubMed2001

Synergistic chemosensitization and inhibition of progression to androgen independence by antisense Bcl-2 oligodeoxynucleotide and paclitaxel in the LNCaP prostate tumor model.

Bcl-2 expression is up-regulated in prostate cancer cells after androgen ablation and associated with development of androgen independence and chemoresistance. We recently reported that antisense Bcl-2 oligodeoxynucleotides (ODNs) delay progression to androgen independence in the androgen-dependent (AD) human LNCaP prostate tumor model. The objectives in this study were to determine whether antisense human Bcl-2 ODN enhances chemosensitivity of paclitaxel and whether combined antisense Bcl-2 ODN and paclitaxel further delays time to androgen-independent (AI) progression in the LNCaP tumor model. Semi-quantitative reverse transcriptast-polymerase chain reaction revealed that treatment of LNCaP cells with antisense Bcl-2 ODN decreased Bcl-2 expression in a dose-dependent and sequence-specific manner, whereas Bcl-2 expression was not affected by paclitaxel treatment. Antisense Bcl-2 ODN treatment significantly enhanced paclitaxel chemosensitivity in vitro, reducing cell viability after treatment with 1 nM paclitaxel from 76% to 42%. Characteristic apoptotic DNA laddering was demonstrated after combined treatment with 500 nM antisense Bcl-2 ODN and 1 nM paclitaxel but not with either agent alone. Adjuvant in vivo administration of combined antisense Bcl-2 and polymeric micellar paclitaxel after castration resulted in a significant delay of emergence of AI recurrent LNCaP tumors compared with either agent alone. By 15 weeks post castration, tumor volume in mice treated with antisense Bcl-2 ODN alone or mismatch control ODN plus paclitaxel was >3-fold higher than in mice treated with combined antisense Bcl-2 ODN and paclitaxel. Mean serum prostate-specific antigen levels returned to or were above precastration levels by 11 weeks post castration in mice treated with antisense Bcl-2 ODN alone or mismatch control ODN plus paclitaxel but remained 90% below the pre-castration level in mice treated with combined antisense Bcl-2 ODN and paclitaxel. These findings identify combined antisense Bcl-2 and paclitaxel as a potentially new therapeutic strategy for advanced prostate cancer by enhancing paclitaxel chemosensitivity and delaying progression of hormone-refractory prostate cancer.

Androgens↗
PubMed2006

What is the optimal pharmacological prophylaxis for the prevention of deep-vein thrombosis and pulmonary embolism in patients with acute ischemic stroke?

BACKGROUND: Pulmonary embolism after acute ischemic stroke (AIS) is associated with a high in-hospital mortality. The benefit from pharmacological prophylaxis for venous thromboembolism (VTE) is uncertain probably due to doubts about the optimal agent and dose. We evaluated the benefit/risk ratio of different anticoagulant regimens in the prevention of VTE in patients with AIS. METHODS: The MEDLINE, EMBASE, and Cochrane Library databases were searched up to January 2005. Randomized controlled trials (RCT) comparing early administration of either low-molecular-weight heparin (LMWH) or unfractionated heparin (UFH) with control were included. Endpoints were objectively diagnosed deep-vein thrombosis (DVT), pulmonary embolism, intracranial hemorrhage (ICH), and extracranial hemorrhage (ECH). Low-dose UFH was arbitrarily defined as < or =15,000 IU/day, low-dose LMWH as < or =6000 IU/day or weight-adjusted dose of < or =86 IU/kg/day. RESULTS: Sixteen trials involving 23,043 patients with AIS met the inclusion criteria. The number of events was small and different doses of anticoagulant treatment were used. Compared to control, high-dose UFH was associated with a reduction in pulmonary embolism (OR=0.49, 95% confidence interval (CI)=0.29-0.83), but also with an increased risk of ICH (OR=3.86, 95% CI=2.41-6.19) and ECH (OR=4.74, 95% CI=2.88-7.78). Low-dose UFH decreased the thrombosis risk (OR=0.17, 95% CI=0.11-0.26), but had no influence on pulmonary embolism (OR=0.83, 95% CI=0.53-1.31); the risk of ICH or ECH was not statistically significant increased (OR=1.67, 95% CI=0.97-2.87 for ICH; and OR=1.58, 95% CI=0.89-2.81 for ECH, respectively). High-dose LMWH decreased both DVT (OR=0.07, 95% CI=0.02-0.29) and pulmonary embolism (0.44, 95% CI=0.18-1.11), but this benefit was offset by an increased risk for ICH (OR=2.01, 95% CI=1.02-3.96) and ECH (OR=1.78, 95% CI=0.99-3.17). Low-dose LMWH reduced the incidence of both DVT (OR=0.34, 95% CI=0.19-0.59) and pulmonary embolism (OR=0.36, 95% CI=0.15-0.87), without an increased risk of ICH (OR=1.39, 95% CI=0.53-3.67) or ECH (OR=1.44, 95% CI=0.13-16). For low-dose LMWH, the numbers needed to treat were 7 and 38 for DVT and pulmonary embolism, respectively. CONCLUSIONS: Indirect comparison of low and high doses of UFH and LMWH suggests that low-dose LMWH have the best benefit/risk ratio in patients with acute ischemic stroke by decreasing the risk of both DVT and pulmonary embolism, without a clear increase in ICH or ECH.

Anticoagulants↗
PubMed2005

[Experience of high-dose toremifene treatment for postmenopausal women with metastatic breast cancer].

Toremifene (TOR), a selective estrogen receptor modulator (SERM), showed efficacy equivalent to Tamoxifen (TAM) in terms of the objective response rate, stable disease, time to progression and overall survival in patients with metastatic breast cancer (MBC). High-dose TOR is also effective for patients with TAM-resistant breast cancer. We tried to study retrospectively the efficacy and the safety of high-dose TOR treatment for patients with MBC in our hospital. Ten patients received TOR 120 mg daily. Most of the patients were treated with one or more endocrine agents before high-dose TOR. Objective response and clinical benefits were found in 3 patients (30%) and 7 patients (70%), respectively. Median time to progression and median overall survival were 9 months and 21.5 months, respectively. In our study,we found the efficacy for patients with hormone receptor negative, TAM resistance and aromatase inhibitor (AI)-resistance breast cancer. Adverse events induced by high-dose TOR treatment were tolerable. High-dose TOR may be one of the optional treatments for patients with MBC after TAM and AI treatment.

Aged↗
PubMed2006

Aromatase inhibitors and breast cancer.

Oestrogens are involved in risk to, and progression of, breast cancer. Drugs that inhibit the production of oestrogens (aromatase inhibitors, AIs), are therefore extremely attractive strategies both to prevent the disease and to treat established tumours. AIs now have a central role in the treatment of established breast cancer and are being considered for prevention. Third generation agents have been derived from rational drug design. They are able to block oestrogen production and reduce oestrogen levels to a degree that has not been observed previously and without affecting levels of other hormones. Such selective reduction of endogenous oestrogen provides targeted therapy for hormone-dependent breast cancer. This has led to improved clinical benefits in patients with these tumours. Anastrozole, letrozole and exemestane all have impressive antitumour effects in postmenopausal women with breast cancer and they are at least as beneficial as or better than other established endocrine agents when used to treat hormone-sensitive cancer in the advanced setting or as an adjuvant to surgery in earlier stages of the disease; ongoing trials are exploring the use of AIs in the preventative setting. Third generation inhibitors are well tolerated, having no greater side effects than might be expected from oestrogen suppression. Important differences in endocrinological and molecular effects exist between AIs and SERMs. These have implications for the preferred drug sequence and setting in which AIs are used. Since the major obstacle to more widespread use is primary/acquired resistance, discovery of the mechanisms by which resistance occurs offers hope for the future. More detailed study of AIs will yield important information about the involvement of oestrogen on the development and progression of breast cancer. Consequently AIs offer major clinical benefits to patients with breast cancer and the promise of relatively nontoxic intervention in women at high risk of the disease.

Adipose Tissue↗
PubMedDate not supplied

Effects of a new calcium antagonist, Rec 15/2375, on cardiac contractility of conscious rabbits.

The new calcium antagonist Rec 15/2375, supposed to be selective for the vascular tissue, was compared to nifedipine, a non-selective agent that reduces blood pressure and impairs cardiac inotropism as well. Six rabbits, chronically catheterized and continuously monitored for systemic blood pressure, heart rate and the isovolumic contractility index dP/Tmax, were alternatively treated with Rec 15/2375 and nifedipine, according to a randomized cross-over design. Both drugs were given under either autonomically intact (AI) or suppressed (AS) heart function control, induced by cholinergic and beta-adrenoceptor blockade. The two agents reduced mean arterial blood pressure comparably and dose-dependently (P less than 0.01) under both experimental conditions (from 10 to 40%), thus causing heart rate to increase reflexly (P less than 0.01), similarly between drugs in AI rabbits, whereas the AS manoeuvre totally abolished such a response. Cardiac contractility, on the other hand, displayed opposing behaviour between the two drugs. Rec 15/2375 caused mild but significant (P less than 0.01) increases, which were similar at all doses (+10, +15%) and insensitive to the AS intervention, whereas nifedipine caused dose-dependent reductions (from -10 to -60%; P less than 0.01) of comparable intensity as mean blood pressure decrease in both protocols. We conclude that Rec 15/2375 effectively lowers blood pressure with no impairment, unlike nifedipine, of cardiac inotropism and we discuss the possibility that dP/dTmax may be increased as a result of the haemodynamic rearrangement following after-load reduction.

Animals↗
PubMed2003

Identification of the 'wrong' active pharmaceutical ingredient in a counterfeit Halfan drug product using accurate mass electrospray ionisation mass spectrometry, accurate mass tandem mass spectrometry and liquid chromatography/mass spectrometry.

Methodology is presented for identifying an unknown active (pharmaceutical) ingredient (AI) in a counterfeit drug product. A range of mass spectrometric techniques, i.e., accurate mass mass spectrometry, tandem mass spectrometry (MS/MS) and liquid chromatography/mass spectrometry (LC/MS), has been employed to determine the AI in a counterfeit Halfan suspension, an antimalarial drug. In particular, use of LockSpray accurate mass MS/MS allowed identification of parts of the molecule from fragments, hence limiting the number of possible elemental compositions for the nominal mass of 278 found for the AI in the counterfeit product. The analysis of the isotope pattern observed for the protonated molecule further reduced the number of possible elemental compositions. A literature search for readily commercially available compounds of molecular formula C(12)H(14)N(4)O(2)S suggested that the AI was either sulfamethazine or sulfisomidine. An LC/MS separation of those two compounds and reference MS/MS spectra obtained for sulfamethazine and sulfisomidine led to the conclusion that the AI in the counterfeit Halfan suspension is sulfamethazine, which is an antibacterial agent.

Chromatography, Liquid↗
PubMed2006

The non-steroidal anti-inflammatory drug, diclofenac, inhibits Na(+) current in rat myoblasts.

The inhibitory effect of diclofenac, a non-steroidal anti-inflammatory drug (NSAID), on the voltage-gated inward Na+ current (I(Na)) in cultured rat myoblasts was investigated using the whole-cell voltage-clamp technique. At concentrations of 10 nM-100 microM, diclofenac produced a dose-dependent and reversible inhibition of I(Na) with an IC50 of 8.51 microM, without modulating the fast activation and inactivation process. The inhibitory effect of diclofenac took place at resting channels and increased with more depolarizing holding potential. In addition to inhibiting the Na+ current amplitude, diclofenac significantly modulated the steady-state inactivation properties of the Na+ channels, but did not alter the steady-state activation. The steady-state inactivation curve was significantly shifted towards the hyperpolarizing potential in the presence of diclofenac. Furthermore, diclofenac treatment resulted in a fairly slow recovery from inactivation of the Na+ channel. The inhibitory effect of diclofenac was enhanced by repetitive pulses and was inflected by changing frequency; the blocking effect at higher frequency was significantly greater than at lower frequency. Both intracellular and extracellular application of diclofenac could inhibit I(Na), indicating that diclofenac may exert its channel inhibitory action both inside and outside the channel sites. Our data directly demonstrate that diclofenac can inhibit the inward Na+ channels in rat myoblasts. Some different inhibitory mechanisms from that in neuronal Na+ channels are discussed.

Animals↗