A comparison of hypotension and bradycardia following spinal anesthesia in patients on calcium channel blockers and β-blockers

Objectives:

Hypotension is a common complication of spinal anesthesia and is frequent in patients with hypertension. Antihypertensive agents decrease this effect by controlling blood pressure. There are conflicting reports on the continuation of antihypertensive drugs on the day of surgery in patients undergoing spinal anesthesia. Sudden hypotension could have detrimental effect on the organ systems. This study was undertaken to compare the variation in blood pressure in hypertensive patients on β-blockers and calcium channel blockers undergoing spinal anesthesia.

Materials and Methods:

Ninety patients were enrolled for the study, 30 each in the control, β-blocker and the calcium channel blocker groups.

Results:

The incidence of hypotension was not different among the three groups. However, the number of times mephentermine used to treat hypotension was significant in the patients receiving calcium channel blockers while incidence of bradycardia in patients treated with β-blockers was significant (P<0.001).

Conclusion:

The incidence of hypotension following spinal anesthesia is not different in patients receiving β-blockers and calcium channel blockers among the three groups.KEY WORDS: β-blockers, calcium channel blockers, hypotension, spinal anesthesia     

Effects of cadmium on calcium transporter SPCA, calcium homeostasis and β-casein expression in the murine mammary epithelium

Maternal cadmium (Cd) exposure during lactation causes neurobehavioral effects in the suckling offspring as well as involution like disturbances in the mammary glands of rodents. The aim of the present study was to examine Cd-induced effects in secreting mammary epithelial cells in relation to calcium (Ca) transport and β-casein expression. Reduced protein expression of secretory pathway Ca-ATPase (SPCA) was revealed in the mammary glands of lactating mice exposed to Cd during peak lactation. In concordance, SPCA gene expression was down regulated and total intracellular Ca levels reduced in murine mammary epithelial HC11 cells treated with Cd for 72 h. Cd reduced β-casein gene expression in a concentration dependent manner in the HC11 cells. Our findings on Cd-induced reduction of Ca levels, SPCA and β-casein expression in the mammary epithelium resemble the effects observed in the mammary glands as a result of forced weaning. In conclusion, maternal Cd exposure during lactation may disturb Ca regulation and decrease the levels of β-casein in milk with potential nutritional and developmental implications for the breast-fed newborn.     

GC-MS method for the simultaneous determination of β-blockers, flavonoids, isoflavones and their metabolites in human urine

A sensitive and selective method based on gas chromatography hyphenated to mass spectrometry (GC-MS) for the screening of 23 different compounds including β-blockers, flavonoids, isoflavones and metabolites in human urine sample was developed and validated. The present paper reports, for the first time, the method for the simultaneous determination of β-blockers, isoflavones, flavonoids and metabolites in human urine samples. When flavonoids are ingested in combination with drugs that have a narrow therapeutic range, interactions between flavonoids and drugs should be investigated.Substances of interest were extracted from urine samples by solid-phase extraction (SPE) employing a mixture of tert-butyl methyl ether:methanol:formic acid (4.5:4.5:1; v/v/v) as a mobile phase and Oasis HLB (Waters) as a stationary phase. Before extraction, urine samples were incubated with β-glucuronidase/sulfatase in order to achieve enzymatic hydrolysis. Before GC-MS analysis the analytes had to be derivatized with N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) into their trimethylsilyl derivatives by incubating for 60 min at 60 °C. Statistical central composite design and response surface analysis were used to optimize the derivatization reagent. These multivariate procedures were efficient in determining the optimal separation condition, using peak areas as responses.The calibration curves were indicative of high linearity (r² ≥ 0.9992) in the range of interest for each analyte. LODs (S/N = 3) ranged between 0.6 and 9.7 ng/ml. Intra-day and inter-day precision (CV, %) was less than 4.96%, accuracy between 0.01 and 4.98% and recovery was found in the range from 70.20 to 99.55%.The developed method can be applied to the routine determination of examined compounds’ concentrations in human urine. Moreover the method is suitable for detecting pharmaceutical compounds containing β-blockers, isoflavones and flavonoids in urine after administration to humans.     

Evaluation of the efficacy and safety of β-d-mannuronic acid in patients with ankylosing spondylitis: A 12-week randomized,placebo-controlled,phase I/II clinical trial

ObjectiveTo evaluate the efficacy, safety and tolerability of β-d-mannuronic acid (M2000) in the treatment of ankylosing spondylitis (AS).MethodsThe study was a 12-week randomized, double-blind, placebo-controlled, phase I/II clinical trial with 3 treatment arms: placebo, β-d-mannuronic acid and naproxen. Patients who had AS according to the modified New York criteria, with active disease at baseline were eligible for study. Primary outcome measure was the Assessment of SpondyloArthritis international Society (ASAS) 20 response rate at week 12.ResultsOf the 85 randomized patients, 27 were allocated to receive placebo, 28 naproxen, and 30 β-d-mannuronic acid. There were no statistically significant differences between treatment groups at baseline. Of the patients receiving β-d-mannuronic acid, 57.7% achieved an ASAS20 response at week 12, compared with 59% of the patients in the naproxen group (P > 0.05) and 19% of the patients in the placebo group (P = 0.007). In comparison with patients receiving placebo over the 12-week treatment period, those receiving β-d-mannuronic acid and naproxen demonstrated statistically significantly greater improvement in all secondary endpoints. Interestingly, β-d-mannuronic acid reduced some parameters associated with inflammation more effectively than naproxen and placebo. The incidence of gastrointestinal and other adverse events were higher on naproxen than on β-d-mannuronic acid and placebo.ConclusionThe present study demonstrated similar efficacy, but with a more favorable safety profile for β-d-mannuronic acid than naproxen and, therefore, suggest that β-d-mannuronic acid is suitable for the management of AS.Trial registrationIranian registry of clinical trials; www.irct.ir; IRCT2013062213739N1.     

How has treatment changed for blast phase chronic myeloid leukemia patients in the tyrosine kinase inhibitor era? A review of efficacy and safety

Introduction: Management of chronic myeloid leukemia (CML) patients in advanced phases of disease has drastically changed since the introduction of tyrosine kinase inhibitors (TKIs) which provide tailored treatment strategies.

Areas covered: In this review, efficacy data of different TKIs are reported and reviewed when used as single agent or in combination for the management of blast phase (BP) CML.

Expert opinion: Although brilliant results were achieved, the outcome of BP patients did not change when TKIs were used as single agents. Newer strategies of association of TKI with intensified chemotherapy or new agents for different pathways are strongly needed as a bridge to possible allogeneic transplant.     

Prolonging β-lactam infusion: A review of the rationale and evidence,and guidance for implementation

Given the sparse antibiotic pipeline and the increasing prevalence of resistant organisms, efforts should be made to optimise the pharmacodynamic exposure of currently available agents. Prolonging the infusion duration is a strategy used to increase the percentage of the dosing interval that free drug concentrations remain above the minimum inhibitory concentration (fT > MIC), the pharmacodynamic efficacy driver for time-dependent antibiotics such as β-lactams. β-Lactams, the most commonly prescribed class of antibiotics owing to their efficacy and safety profile, have been the mainstay of therapy since the discovery of penicillin over 60 years ago. Mounting evidence, including the use of population pharmacokinetic modelling and Monte Carlo simulation, suggests that prolonging the infusion time of β-lactam antibiotics may have advantages over standard infusion techniques, including an enhanced probability of achieving requisite fT > MIC exposures, lower mortality and potentially reductions in infection/antibiotic-related costs. As a result of these favourable attributes, clinical practice guidelines support the use of prolonged-infusion β-lactams in the treatment of many severe infections. This article discusses the rationale and evidence for prolonging the infusion of β-lactam antibiotics and provides guidance for the implementation of a prolonged-infusion programme.     

Anti-MRSA β-lactams in development,with a focus on ceftobiprole: the first anti-MRSA β-lactam to demonstrate clinical efficacy

Ceftobiprole is the first of the investigational β-lactam antibiotics with in vitro activity against methicillin-resistant staphylococci to reach and complete Phase III therapeutic trials. Its antibacterial spectrum includes methicillin-resistant Staphylococcus aureus (MRSA), Enterococcus faecalis, penicillin-resistant streptococci and many Gram-negative pathogens. It has demonstrated in vivo activity against many experimental infections caused by these pathogens. Ceftobiprole has completed Phase III clinical trials for complicated skin and skin structure infections, is being studied in Phase III pneumonia trials and has demonstrated non-inferiority compared with vancomycin in a Phase III complicated skin and skin structure infections trial, resulting in > 90% clinical cures of infections caused by MRSA. Other anti-MRSA β-lactams in therapeutic clinical trials include the carbapenem CS-023/RO-4908463 and the cephalosporin ceftaroline (PPI-0903). The future of all of these agents will depend on their clinical efficacy, safety and their ability to be accepted as β-lactams for the reliable treatment of a broad spectrum of infections, including those caused by MRSA.     

Inhaled human insulin (Exubera®): its pharmacologic profile,efficacy and safety in the treatment of adults with diabetes mellitus

Exubera^® (EXU, insulin human [rDNA origin]) is the first inhaled insulin approved for the treatment of diabetes in adults. Its pharmacokinetic properties make it suitable as therapy for postprandial glycemia. Clinical trials have demonstrated equal efficacy with short-acting subcutaneous regular and analog insulin in both Type 1 and 2 diabetes, and have also shown that it has value as adjunctive therapy in Type 2 patients inadequately controlled on maximal doses of oral hypoglycemic agents. EXU is well tolerated and associated with a high level of patient satisfaction. Hypoglycemia is the most common adverse event but its incidence does not exceed that expected for the degree of glycemic improvement. Minor reductions in some measures of pulmonary function have been observed in EXU-treated patients but safety studies of up to 2 years duration reveal that they occur early, do not progress and resolve quickly after treatment cessation. Longer-term postregistration pulmonary function studies that include assessment of insulin antibodies and the associated risk of allergic/immune disorders are in progress. EXU overcomes problems associated with the invasive nature of subcutaneous injection without loss of efficacy. Depending on cost and confirmation of safety, it could be a valuable part of future treatment strategies for both Type 1 and 2 diabetes.     

Effect of short-term and long-term treatments with σ ligands on the N-methyl-D-aspartate response in the CA3 region of the rat dorsal hippocampus

1. Long-term treatments with the σ ligand haloperidol decrease the density of σ receptors in mammalian CNS. We have shown that σ ligands, such as di(2-tolyl)guanidin (DTG), potentiate dose-dependently, with bell-shaped dose-response curves, the neuronal response of pyramidal neurones to N-methyl-D-aspartate (NMDA) in the CA₃ region of the rat dorsal hippocampus. σ Ligands producing such a potentiation were denoted ‘agonists''. This potentiation was suppressed by low doses of other σ ligands denoted ‘antagonists''. High doses of DTG and JO-1784 did not modify the NMDA response but acted as ‘antagonists'' by suppressing the potentiation induced by σ ‘agonists''.
2. Following a 21-day treatment with haloperidol as well as with high doses of DTG or JO-1784, after a 48 h washout, the acute administration of σ ‘agonists'' failed to induce any potentiation of the NMDA response. Following a 21 day treatment with a low dose of DTG or JO-1784, after a 48 h washout, the neuronal response to microiontophoretic applications of NMDA was markedly increased. A 21 day treatment with low or high doses of (+)-pentazocine, after a 48 h washout, did not produce any change.
3. Following a two day treatment with a high dose of haloperidol, DTG, JO-1784 and (+)-pentazocine, after a 24 h washout, the potentiation of the NMDA response induced by the acute administration of the σ ‘agonists'' was unchanged.
4. With the minipumps on board, with DTG and JO-1784, a dose-dependent enhancement of the NMDA response was seen but no effect was observed in the groups of rats treated at the same doses with haloperidol or (+)-pentazocine.
5. The present data suggest that long-term treatments with σ ‘antagonists'' induce a desensitization of the σ receptors, whereas long-term treatments with σ ‘agonists'' induce a supersensitivity of the σ receptors.

     

Fenoterol functionally activates the β₃-adrenoceptor in human urinary bladder, comparison with rat and mouse: implications for drug discovery

Fenoterol has been reported to be a potent and selective β(2)-adrenoceptor agonist and is currently used clinically to treat asthma. Electrical field stimulation (EFS) of isolated urinary bladder mimics the voiding contraction by stimulating parasympathetic nerves, resulting in neurogenic contractions. To determine if stimulation of β(2)-adrenoceptors can inhibit this response, fenoterol was tested against EFS-induced contractions in human isolated urinary bladder and compared with mouse and rat. Bladder strips were mounted in organ baths and reproducible contractions induced by EFS. Fenoterol was added cumulatively in the presence of the β(2)-adrenoceptor antagonist ICI118551 or the β(3)-adrenoceptor antagonist L-748337. Fenoterol inhibited neurogenic contractions in all three species in a concentration-dependent manner with pEC(50) values of 6.66 ± 0.11, 6.86 ± 0.06 and 5.71 ± 0.1 in human, mouse and rat respectively. In human bladder strips ICI118551 (100 nM) did not affect responses to fenoterol, while L-748337 (0.3-3 μM) produced rightward shifts of the concentration-response curves with a pA(2) value of 8.10. In mouse bladder strips ICI118551 (30 nM) blocked the inhibitory effect of fenoterol (pA(2)=8.80), while L-748337 (10 μM) inhibited the response with a pA(2) of 5.79. In rat bladder ICI118551 (30 nM) was without effect, while L-748,337 (10 μM) inhibited the response to fenoterol with a pA(2) of 5.40. From these results it is clear that fenoterol potently activates β(3)-adrenoceptors in human isolated urinary bladder to inhibit EFS-induced contractions. Fenoterol also activates β(3)-adrenoceptors in rat, but β(2)-adrenoceptors in mouse bladder to inhibit EFS-induced contractions.     

Efficacy and safety of silodosin in the medical expulsion therapy for distal ureteral calculi: a systematic review and meta‐analysis

Aims

Using a selective α‐adrenoceptor blocker for medical expulsive therapy (MET) is an effective treatment approach widely used for ureteral stones. The aim of the review was to assess the efficacy and safety of silodosin in medical expulstion therapy compared with placebo and tamsulosin.

Methods

A systematic search was performed in PubMed, Cochrane Library and Embase to identify randomized controlled trials that compared silodosin with a placebo or tamsulosin for ureteral calculi.

Results

Eight publications involving a total of 1048 patients were used in the analysis, which compared silodosin with placebo and tamsulosin. We found that silodosin was effective in treating ureteral calculi in our meta‐analysis and was superior to tamsulosin in its efficacy. The expulsion rate of all ureteral stones (OR 1.59, 95% CI 1.08, 2.36, P = 0.02), the expulsion rate of distal ureteral stones (OR 2.82, 95% CI 1.70, 4.67, P < 0.0001) and the expulsion time (days) of distal ureteral stones (standard mean difference (SMD) −4.71, 95% CI −6.60, −2.83, P < 0.00001) indicated that silodosin was more effective than the placebo. Moreover, expulsion rate (OR 2.54, 95% CI 1.70, 3.78, P < 0.00001), expulsion time (days) (SMD −2.64, 95% CI −3.64, −1.64, P < 0.00001) and pain episodes (P < 0.00001) indicated that silodosin was more effective than the tamsulosin. Even though silodosin had a significant increase in abnormal ejaculation compared with tamsulosin, no significant differences were observed for complications (OR 1.00, 95% CI 0.58, 1.74, P = 1.00).

Conclusions

This meta‐analysis indicated that silodosin was superior to placebo or tamsulosin in the efficacy for distal ureteral calculi with better control of pain. The safety profile of silodosin was similar to tamsulosin though retrograde ejaculation was worse for silodosin use. We conclude that silodosin might have potential as a MET for ureteral stones.     

The effects of glyburide and insulin on the decreased β-adrenergic responsiveness of the gastrointestinal tract in rats with non-insulin-dependent diabetes

• 1.1. Decreased β-adrenergic responses have been reported in gastro-intestinal tract of rats with diabetes mellitus. Effects of glyburide and insulin on the decreased β-adrenergic responsiveness of the gastro-intestinal tract due to non-insulin-dependent diabetes were investigated using duodenum, jejunum and ileum from rats which were injected with alloxan in their neonatal periods.
• 2.2. Insulin treatment of non-insulin-dependent diabetic rats for 10 days corrected the decreased β-adrenergic responses of the isolated duodenum, jejunum and ileum confirming the previous results obtained from insulin-dependent diabetic rats.
• 3.3. Glyburide treatment alone for 3 weeks also reversed the changes in the gastro-intestinal β-adrenergic responses of non-insulin-dependent diabetic rats. Combination of glyburide with insulin, however, did not cause an additive or supra-additive interaction in terms of β-adrenergic sensitivities of the diabetic tissues.
• 4.4. The results obtained in the present study strongly suggested that non-insulin-dependent diabetes may cause a decrease in the number of gastro-intestinal β-adrenoceptors, while glyburide and insulin treatments correct the changes related to β-adrenoceptors. The effect of insulin on the β-adrenergic sensitivity of diabetic rat duodenum, jejunum and ileum may occur via a direct mechanism, whereas glyburide seems to be effective on the β-adrenergic responses through the increases in the insulin secretion and/or in the number of gastro-intestinal insulin receptors.