Birth outcomes after inadvertent use of category X drugs contraindicated in pregnancy: Where is the real risk?

Öztürk Z, Ölmez E, Gürpinar T, Vural K. Birth outcomes after inadvertent use of category X drugs contraindicated in pregnancy: Where is the real risk? Turk J Pediatr 2018; 60: 298-305. Drugs contraindicated in pregnancy are medicines that should be avoided by pregnant women, since they carry a concern for teratogenicity or there is no indication for their use during pregnancy. It does not mean that exposures to these drugs always cause harm. The aim of the present study was to investigate the risk of adverse outcomes following maternal exposure to the drugs contraindicated in pregnancy. We retrospectively analyzed prenatal drug exposure records of the pregnant patients referred to the clinical pharmacology consultation service in a tertiary-level university hospital from January 2007 until December 2012. Exposures to category X drugs (CXD) contraindicated in pregnancy were evaluated. After the expected date of delivery, we collected data about pregnancy complications and the outcomes. For comparison the women in the exposed group (N=52) were matched with a control group (N=162) of pregnant women without teratogenic exposure. We observed only one baby born with a birth defect (congenital cryptorchidism) in CXD group (2.6%) and four in control group (RR 0.91; 95% CI 0.10- 7.94). The rates of adverse pregnancy outcomes including miscarriage, preterm birth and congenital abnormality were not significantly different from controls. However, the rate of elective termination of pregnancy was higher in women exposed to CXD while pregnant (RR 2.54; 95% CI 1.11- 5.80, p = 0.027). Contraceptive failure and unintended pregnancy are the reasons for inadvertent drug exposure and choosing abortion. The high perception of teratogenic risk among pregnant women may cause terminations of pregnancies. Individual risk assessment and avoiding the phrase `CXD` or `contraindicated in pregnancy` in counseling may help to reduce maternal concerns about medication use in pregnancy.

Statins reduce testicular and ocular VEGF: A potential compromise to microcirculation.

Microcirculation has great importance in eye and testicular tissue and is necessary to have adequate and appropriate amount of angiogenesis. It is known that high levels of Vascular Endothelial Growth Factor (VEGF) trigger uncontrolled angiogenesis, whereas inadequate VEGF can lead to decreased tissue perfusion and oxygenation. The aim of this study was to investigate effects of VEGF in testicular and ocular tissues in both non-diabetic and diabetic rats treated by statin. Atorvastatin (10 mg/kg daily given by orally gavage) was administered for two weeks. Diabetes was induced by streptozotocin, (STZ, 45 mg/kg/ip) in diabetic group's rats. Two weeks later from STZ injection, atorvastatin treatment was initiated in diabetic group. VEGF levels were measured by using ELISA. The VEGF levels were decreased in vitrous, ocular and testicular tissues of all statin-administered rats. In diabetic group VEGF levels were found to be decreased in testicular tissue and increased in ocular tissues. CONCLUSION: Statin use decreased in VEGF levels of testicular and ocular tissues in diabetic and non-diabetic rats. Statin treatment (anti-VEGF effect) had a protective effect in the development of diabetic retinopathy, yet statins may have a negative impact on tissues that depend on microcirculation by reducing VEGF levels. Further research is needed for statins' microcellular effects.

Pregnancy outcomes following the use of thiocolchicoside.

Thiocolchicoside is a commonly used muscle relaxant in orthopedic, rheumatologic or musculoskeletal disorders to treat painful muscle spasms. It is contraindicated in pregnancy and lactation. There is no previously published experience with thiocolchicoside exposure during pregnancy. In this observational study, we collected and evaluated 18 pregnancy outcomes of the women referred to our prenatal consultation service for thiocolchicoside exposure between 2007-2012, and offspring were followed up until 2 years of age. There were 16 live births, 1 spontaneous abortion and 1 elective termination of pregnancy. No major birth defect was observed. The mothers and their babies were free of perinatal complications. No growth or developmental abnormalities were found during follow-up period. Our findings add information on inadvertent use of thiocolchicoside in pregnancy. Further large prospective cohort studies are required to investigate this issue.

Melatonin and L-carnitin improves endothelial disfunction and oxidative stress in Type 2 diabetic rats.

Vascular dysfunction is thought to play a major role in the development of diabetic cardiovascular disease. The roles of endothelial dysfunction, oxidative stress, and dyslipidemia will be considered. Melatonin as well as L-carnitine were shown to possess strong antioxidant properties. Diabetes induced with high fat diet (for 8 weeks) and multipl low doses intraperitoneal injection of STZ (twice, 30mg/kg/d i.p). The diabetic animals were randomly assigned to one of the experimental groups as follows: Control group (C), high fat diet (HFD), STZ-induced diabetic group (HFD+STZ) , HFD+STZ diabetic group received melatonin (10mg/kg/d i.p), HFD+STZ diabetic group received L-carnitine (0.6g/kg/d i.p), and HFD+STZ diabetic group received glibenclamide (5mg/kg/d, oral). The serum fasting blood glucose, insulin, total cholesterol, HDL- cholesterol, LDL-cholesterol, triglyceride and malondialdehyde (MDA) levels were tested. Acetylcholine induced endothelium-dependent relaxation and sodium nitroprusside induced endothelium-independent relaxation were measured in aortas for estimating endothelial function. Also, glutathione peroxidase (GPx), superoxide dismutase (SOD) and nitric oxide (NO) levels activities were determined in rat liver. According to our results melatonin and L-carnitine treatment decreased fasting blood glucose, total cholesterol, and LDL levels. MDA levels significantly decreased with the melatonin treatment whereas SOD levels were not significantly changed between the groups. The results suggest that especially melatonin restores the vascular responses and endothelial dysfunction in diabetes.

Investigation of in vitro antileishmanial activity of moxifloxacin, linezolid and caspofungin on Leishmania tropica promastigotes.

OBJECTIVE: This study aimed to evaluate the potential in vitro anti-leishmanial activities of moxifloxacin, linezolid and caspofungin against Leishmania tropica. METHODS: In vitro effects of all agents were studied by using the microdilution method. For this purpose, serial dilutions of the aforementioned agents were prepared in concentrations between 4096 µg/mL-0.008 µg/mL. Afterwards, promastigotes incubated in suitable medium were counted with the hemocytometer and adjusted as having a last concentration of 2.5 x 10(6) cells/mL in wells containing medium+antibiotic or antifungal. After incubation live promastigotes were counted with the hemocytometer and inhibitor concentrations (IC(50)) were determined by comparing with the control that contained no antibiotics or antifungal. RESULTS: IC(50) values of moxiloxacin, linezolid and caspofungin were found as 194.7 µg/mL, 896 µg/mL and 235.7 µg/mL, respectively. CONCLUSION: As a result, moxifloxacin was found to be effective in lower concentrations than the other studied agents against L. tropica promastigotes.

Combined treatment with progesterone and magnesium sulfate positively affects traumatic brain injury in immature rats.

AIM: It is well known that head trauma results in damage in hippocampal and cortical areas of the brain and impairs cognitive functions. The aim of this study is to explore the neuroprotective effect of combination therapy with magnesium sulphate (MgSO4) and progesterone in the 7-days-old rat pups subjected to contusion injury. MATERIAL AND METHODS: Progesterone (8 mg/kg) and MgSO4 (150 mg/kg) were injected intraperitoneally immediately after induction of traumatic brain injury. Half of groups were evaluated 24 hours later, the remaining animals 3 weeks after trauma or sham surgery. Anxiety levels were assessed with open field activity and elevated plus maze; learning and memory performance were evaluated with Morris Water maze in postnatal 27 days. RESULTS: Combined therapy with progesterone and magnesium sulfate significantly attenuated trauma-induced neuronal death, increased brain VEGF levels and improved spatial memory deficits that appear later in life. Brain VEGF levels were higher in rats that received combined therapy compared to rats that received either medication alone. Moreover, rats that received combined therapy had reduced hipocampus and prefrontal cortex apoptosis in the acute period. CONCLUSION: These results demonstrate that combination of drugs with different mechanisms of action may be preferred in the treatment of head trauma.

Serum IGF-1 levels correlate negatively to liver damage in diabetic rats.

Diabetes and insulin resistance frequently cause liver damage. Diabetes also causes reduction in liver and blood IGF-1 levels. We investigated the relation between liver damage and IGF-1 levels in diabetic rats. Fourteen Wistar albino rats were divided into control and diabetic groups. Diabetes was induced by streptozotocin. Rats were sacrificed for biochemical and histologic examinations 2 weeks after streptozotocin injection. Serum and liver IGF-1 levels were decreased, liver malondialdehyde (MDA) levels were increased, glutathione peroxidase (GPx) enzymes activities were decreased and serum alanine aminotransferase (ALT) levels were increased in diabetic group. Microscopic examination of liver revealed that normal tissue organization was disrupted in streptozotocin-induced diabetic rats. There was a strongly positive correlation between blood glucose levels and liver injury, and blood and liver IGF-1 levels. There was a strongly negative correlation between blood IGF-1 levels and hepatic injury. Our results suggest that reduction of blood IGF-1 levels correlates with hepatic injury and circulating IGF-1 levels may have predictive value for determining hepatic damage that results from diabetes. In addition, circulating IGF-1 levels are correlated with glutathione levels and the oxidative stress status of diabetic rat liver.

The effects of the melatonin treatment on the oxidative stress and apoptosis in diabetic eye and brain.

Oxidative stress plays an important role in the development of complications in diabetes mellitus. Antioxidant therapy has been thought to decrease oxidative stress. The objective of the present study was to explore the effects of melatonin (MLT) on oxidative stress in diabetic rat eye and brain tissue by using immunohistochemical methods. Diabetes was induced by streptozotocin, (STZ, 55 mg/kg/i.p) in adult rats. MLT was given 10 mg/kg/i.p once a day for 2 weeks beginning from the sixth week. Six weeks later, rats were divided into three groups: control (CR), STZ-induced diabetic (STZ), and STZ-induced diabetic group received melatonin (STZ+MLT). Although no significant difference was observed with respect to antioxidant status, NOS activity tended to be higher in the untreated diabetic rats than in the treated rats. It was observed that MLT treatment improved the histopathological changes including apoptosis and oxidative stress in brain and eye in diabetic rat.

Vasodilator effects of cromakalim and HA 1077 in diabetic rat aorta.

BACKGROUND: Impairment of the vasorelaxant responses have been reported in diabetes mellitus. In this study, the roles of the K(ATP) channel and rho kinase pathway were evaluated by using the K(ATP) channel opener cromakalim and Rho-kinase inhibitor HA 1077 in diabetic rat aorta. METHODS: Adult male Wistar rats weighing (250-300 g) were divided into diabetic and control groups. Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ, 55 mg/kg/i.p). RESULTS: Vasodilator responses induced by cromakalim (10(-7) to 10(-3M)) and HA 1077 (10(-6) to 10(-4M)) were significantly less in diabetic rings compared with control rings (p <0.01). The decrease in the relaxant effect of cromakalim was more in endothelium-denuded rings compared to the endothelium-intact rings (p <0.05). There were no significant differences between endothelium intact and non-intact rings in the presence of HA 1077. When two drugs were administered together, relaxation was significantly less than with seperate administration of each drug in the diabetic group (p <0.01). Pre-treatment with N omega-nitro-L-arginine methylester (L-NAME) (10(-6) to 10(-4 M)), an NO synthase inhibitor, significantly decreased the relaxant response to cromakalime and HA 1077 in both the control and diabetic groups (p <0.05). CONCLUSIONS: These results suggest that the impaired relaxant effects were further decreased depending on K(ATP) channel activity but the effects of Rho-kinase enzyme inhibitors on relaxation responses were not significantly changed in diabetes mellitus.

Evaluation of antimicrobial susceptibilities of rapidly growing mycobacteria by Sensititre RAPMYCO panel.

This study used Sensititre RAPMYCO to test the activities of amikacin, cefoxitin, ciprofloxacin, clarithromycin, doxycycline, imipenem, linezolid, sulfamehoxazole, tigecycline and tobramycin against 25 clinical isolates of rapidly growing mycobacteria (RGM), including the common disease producing species Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium fortuitum and Mycobacterium peregrinum. Analysis of the four different RGM species showed that isolates of M. fortuitum and M. peregrinum were more susceptible than M. abscessus and M. chelonae. Different antimicrobials showed a variable sensitivity in all strains. Therefore, each species and strain must be individually evaluated, and it is always advisable to perform in vitro sensitivity tests before the treatment of infections due to RGM.

Relationship between circulating IGF-1 levels and traumatic brain injury-induced hippocampal damage and cognitive dysfunction in immature rats.

It is well known that traumatic brain injury (TBI) induces the cognitive dysfunction resulting from hippocampal damage. In the present study, we aimed to assess whether the circulating IGF-I levels are associated with cognition and hippocampal damage in 7-day-old rat pups subjected to contusion injury. Hippocampal damage was examined by cresyl violet staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Spatial memory performance was assessed in the Morris water maze. Serum IGF-1 levels decreased in both early and late period of TBI. Decreased levels of serum IGF-1 were correlated with hippocampal neuron loss and spatial memory deficits. Circulating IGF-1 levels may be predictive of cognitive dysfunction resulted from hippocampal damage following traumatic injury in developing brain. Therapy strategies that increase circulating IGF-1 may be highly promising for preventing the unfavorable outcomes of traumatic damage in young children.

A possible perianesthetic serotonin syndrome related to intrathecal fentanyl.

Serotonin syndrome occurs with selective serotonin reuptake inhibitors, opioids, and other serotonergic agents. We describe a possible serotonin syndrome related to intrathecal fentanyl in a patient taking multiple drugs and substances such as ergot alkaloids, marijuana, methylenedioxy-N-methylamphetamine, and ephedrine.

The effects of gender and menopause on serum lidocaine levels in smokers.

It has been established that human cytochrome P450 (CYP) enzymatic activity is affected by gender, or by hormonal factors such as the menopause in women. Gender differences have a more pronounced effect on cytochrome (CYP) 3A4 isoenzyme activity, whereas cytochrome (CYP) 1A2 isoenzyme activity is mainly induced by chronic smoking. Lidocaine is frequently used in the treatment of hemodynamic changes following laryngoscopy and tracheal intubation during general anesthesia, and is metabolized by CYP3A4 and CYP1A2 isoenzymes in the liver. The aim of this study was investigate the effects of gender and menopause on serum lidocaine levels in smokers under general anesthesia. Six men, six premenopausal women and six postmenopausal women were enrolled in the study and received i.v. lidocaine (1 mg/kg) 1 minute before they underwent general anesthesia. Serum lidocaine concentrations were measured using the EMIT method at 1, 5, 10, 20, 40 and 60 minutes post-administration. Statistical analyses were performed using the Mann-Whitney U-test. No statistically significant differences were found regarding the area under curve (AUC(0-60) microg/mL/min), elimination half-life (t1/2 [min]) of lidocaine and in the measured levels of serum lidocaine at any time point between the study groups (p > 0.05). These results suggest that gender and menopause may have no significant effect on serum lidocaine levels in smokers.