Pharmacological treatment of oro-facial pain - health technology assessment including a systematic review with network meta-analysis.

This health technology assessment evaluated the efficacy of pharmacological treatment in patients with oro-facial pain. Randomised controlled trials were included if they reported pharmacological treatment in patients ≥18 years with chronic (≥3 months) oro-facial pain. Patients were divided into subgroups: TMD-muscle [temporomandibular disorders (TMD) mainly associated with myalgia]; TMD-joint (TMD mainly associated with temporomandibular joint pain); and burning mouth syndrome (BMS). The primary outcome was pain intensity reduction after pharmacological treatment. The scientific quality of the evidence was rated according to GRADE. An electronic search in PubMed, Cochrane Library, and EMBASE from database inception to 1 March 2017 combined with a handsearch identified 1552 articles. After screening of abstracts, 178 articles were reviewed in full text and 57 studies met the inclusion criteria. After risk of bias assessment, 41 articles remained: 15 studies on 790 patients classified as TMD-joint, nine on 375 patients classified as TMD-muscle and 17 on 868 patients with BMS. Of these, eight studies on TMD-muscle, and five on BMS were included in separate network meta-analysis. The narrative synthesis suggests that NSAIDs as well as corticosteroid and hyaluronate injections are effective treatments for TMD-joint pain. The network meta-analysis showed that clonazepam and capsaicin reduced pain intensity in BMS, and the muscle relaxant cyclobenzaprine, for the TMD-muscle group. In conclusion, based on a limited number of studies, evidence provided with network meta-analysis showed that clonazepam and capsaicin are effective in treatment of BMS and that the muscle relaxant cyclobenzaprine has a positive treatment effect for TMD-muscle pain.

Cholesterol catabolism in patients with acute myelogenous leukemia and hypocholesterolemia: suppressed levels of a circulating marker for bile acid synthesis.

Hypocholesterolemia is a frequent finding in patients with acute myelogenous leukemia (AML) and in other types of malignancies. Since bile acids are major excretion products of cholesterol, the hepatic degradation of cholesterol to bile acids was investigated in AML patients by analyzing a circulating marker for bile acid synthesis. In addition, plasma levels of a marker for cholesterol synthesis were determined. The plasma levels of 7alpha-hydroxy-4-cholesten-3-one, reflecting bile acid production, were markedly lower in patients with AML than in healthy controls. The median levels were 3.3 and 18.5ng/ml (P<0.0001) in the AML patients (n=29) and the healthy subjects (n=16), respectively. The plasma levels of 7-dehydrocholesterol, reflecting hepatic cholesterol synthesis, were similar for the AML patients and the controls. The results show that the conversion of cholesterol to bile acids was suppressed in AML patients, a phenomenon that may result in a decreased intestinal absorption of cholesterol and subsequent hypocholesterolemia.

Feedback on prescribing rate combined with problem-oriented pharmacotherapy education as a model to improve prescribing behaviour among general practitioners.

OBJECTIVE: To develop a working model with which prescribing behaviour among general practitioners might be influenced. DESIGN: Intervention based on feedback on prescribing rates and problem-oriented educational outreach visits, using educational material and local opinion leaders. Randomised study with three parallel intervention groups of general practitioners, which also served as controls for each other. The pharmacotherapeutic fields chosen were hypertension, peptic ulcer/dyspepsia and depression. Prescription data were retrieved from the electronic patient records for periods of 1 year before and after the intervention. SETTING: Six health care centres and three continuing medical education groups in Stockholm. SUBJECTS: Forty general practitioners. MAIN OUTCOME MEASURES: Drug prescribing rates and patterns before and after the intervention. RESULTS: In the hypertension field, desired trends in fractional prescribing (favouring diuretics and beta blocking agents) were recorded, with a significant (P < 0.05) effect on prescriptions for agents acting on the renin-angiotensin system, despite a pre-existing prescribing behaviour already much in line with the goals. In the peptic ulcer/dyspepsia field, desired trends were recorded for both types of therapies addressed. The fractional prescribing rates for proton-pump inhibitors decreased from 61.0% to 52.6% in the intervention arm and increased from 68.1% to 76.0% in the control arm (not significant due to low power). The depression group focused on better general attention to the disease and only minor changes were registered. CONCLUSION: Feedback of individual prescribing rates, combined with problem-oriented educational outreach visits, is a promising model for the improvement of prescribing behaviour. Data from the electronic patient record were feasible for feedback on prescribing rates.

Growth modulation of low density lipoprotein receptor sterol sensitivity in cultured human fibroblasts.

Sterols regulate low density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase gene expressions by end product repression. Studies on cultured cells have shown that growing cells have a higher LDL uptake than quiescent cells and that incubation of cells with growth factors or mitogenic compounds leads to sterol-resistant upregulation of LDL receptor gene expression. The recent finding that elevated LDL receptor activity in acute myelogenous leukemia cells was characterized by a decreased sensitivity to downregulation by sterols raises the possibility that the mechanism behind this is related to the cellular growth rate. By using cultured human fibroblasts as a model system we therefore studied whether growth modulation of sterol sensitivity takes place in normal actively growing cells. Judging from the ability of sterols (25-hydroxycholesterol + cholesterol) to inhibit 125I-LDL degradation, we found that the sensitivity to sterols varied markedly between cells of different densities. The lowest sensitivity to sterols and highest 125I-LDL degradation rate were found in subconfluent cells, whereas sparse and confluent cells were the most sensitive ones. In contrast to the LDL receptor, HMG-CoA reductase sterol sensitivity did not appear to be growth regulated. We conclude that growth-dependent modulation of sterol sensitivity and LDL receptor activity takes place in normal human fibroblasts. Modulation of sterol sensitivity may be an important mechanism to ensure an adequate cholesterol supply in growing cells.

Low density lipoprotein as a carrier of cytostatics in cancer chemotherapy: study of stability of drug-carrier complexes in blood.

Several solid tumour and leukemia cell types have a higher low density lipoprotein (LDL) uptake than the corresponding normal cells. We are investigating the possibilities to use LDL as a drug carrier to increase the selectivity of antineoplastic drugs in cancer chemotherapy. We have developed a method to incorporate lipophilic cytotoxic agents without interfering with the in vitro and in vivo properties of LDL. In this study, we examined the stability of some drug-LDL complexes in blood and plasma as this is an important prerequisite to achieve a selective therapy. The in vitro dialysis of N-trifluoroacetyl-adriamycin-14-valerat-LDL (AD-32-LDL) against plasma revealed a slow dissociation of the complex. The same method showed a fast and total leakage of paclitaxel from paclitaxel-LDL into the plasma chamber. The dissociation of paclitaxel was confirmed by an autoradiographic study of the distribution of paclitaxel-LDL in tumour-bearing mice. In patients with leukemia the rapid plasma dissociation of AD-32 from LDL illustrated a much higher in vivo instability of this complex. With this method, cholesteryl-linoleate only could be incorporated into LDL in a stable manner as shown by dialysis and autoradiography results. The incorporation of cytotoxic drug derivatives, containing lipophilic anchors, is now under study in order to obtain LDL complexes with better plasma stability.

Plasma stability and cytotoxicity of lipophilic daunorubicin derivatives incorporated into low density lipoproteins.

The selective targeting of antineoplastic drugs to tumours by incorporation in low density lipoproteins (LDL) is an attractive possibility if the drug-LDL complex remains stable in the circulation and is taken up by the tumour. In previous studies we have shown that vincristine- and N-trifluoroacetyladriamycin-14-valerate-LDL complexes were unstable in vivo. We synthesized five N-substituted lipophilic derivatives of daunorubicin and studied their incorporation into LDL. Three out of five daunorubicin derivatives incorporated successfully into LDL. In vitro these complexes were more cytotoxic towards LDL receptor positive Chinese hamster ovary cells than LDL receptor negative cells. Non-specific cytotoxicity was explained by slow dissociation of the drug-LDL complex in plasma. Our results underline the importance of careful studies of plasma stability when investigating lipoproteins and other carriers in drug targeting.

Lamotrigine in pregnancy: pharmacokinetics during delivery, in the neonate, and during lactation.

PURPOSE: To investigate the pharmacokinetics of lamotrigine (LTG) during delivery, during the neonatal period, and lactation. METHODS: High-performance liquid chromatography was used to determine plasma and milk levels of LTG in nine pregnant women with epilepsy treated with LTG, and plasma levels in their 10 infants. Samples were obtained at delivery, the first 3 days postpartum, and at breast-feeding 2-3 weeks after delivery. RESULTS: At delivery, maternal plasma LTG concentrations were similar to those from the umbilical cord, indicating extensive placental transfer of LTG. There was a slow decline in the LTG plasma concentration in the newborn. At 72 h postpartum, median LTG plasma levels in the infants were 75% of the cord plasma levels (range, 50-100%). The median milk/maternal plasma concentration ratio was 0.61 (range, 0.47-0.77) 2-3 weeks after delivery, and the nursed infants maintained LTG plasma concentrations of approximately 30% (median, range 23-50%) of the mother's plasma levels. Maternal plasma LTG concentrations increased significantly during the first 2 weeks after parturition, the median increase in plasma concentration/dose ratio being 170%. CONCLUSIONS: Our data demonstrate a marked change in maternal LTG kinetics after delivery, possibly reflecting a normalization of an induced metabolism of LTG during pregnancy. LTG is excreted in considerable amounts in breast milk (the dose to the infant can be estimated to >/=0.2-1 mg/kg/day 2-3 weeks postpartum), which in combination with a slow elimination in the infants, may result in LTG plasma concentrations comparable to what is reported during active LTG therapy. No adverse effects were observed in the infants, however.

Etoposide-induced DNA strand breaks in relation to p-glycoprotein and topoisomerase II protein expression in leukaemic cells from patients with AML and CLL.

Elevated expression of the membrane transporter p-glycoprotein (pgp) and impaired expression of the nuclear enzyme topoisomerase II (topo II) are well-known mechanisms for in vitro acquired drug resistance. The clinical relevance of topo II remains unclear, whereas a relationship between pgp levels and treatment results has been shown in acute myelogenous leukaemia (AML). We have investigated the relationships between the levels of topo II and pgp, and in vitro sensitivity to etoposide in mononuclear blood cells from 24 patients with AML, 16 with chronic lymphocytic leukaemia (CLL) and five healthy blood donors. Following incubation with etoposide, AML cells showed more DNA damage, determined by a DNA unwinding technique, than CLL cells (P = 0.001), whereas there was no difference in cellular etoposide accumulation. Pgp and topo IIbeta levels, determined by Western blot, showed a pronounced variation between patients, but no correlation with induced DNA damage, whereas topo IIalpha protein was undetectable. In the AML group, topo IIbeta expression correlated with pgp expression (rho = 0.7, P = 0.001, n = 24). The topo IIbeta expression was 147.4(+/-74.6)% in the pgp+ AML cells (n = 10), compared to 33.4(+/-27.8)% in pgp- AML cells (n = 14) (P = 0.0001). Our results show a previously unknown coexpression of topo IIbeta and pgp in AML, thereby suggesting that topo IIbeta is a potentially interesting resistance factor in AML.

Transient triglyceridemia in healthy normolipidemic men increases cellular processing of large very low density lipoproteins by fibroblasts in vitro.

Exaggerated and prolonged postprandial triglyceridemia is a characteristic of patients with precocious coronary heart disease. Although large very low density lipoprotein (VLDL) particles accumulate during alimentary lipemia, the biological properties of the postprandial VLDL remain unknown. In the present study, an intravenous infusion of a chylomicron-like emulsion was given to healthy normolipidemic men to examine the effects of transient triglyceridemia in vivo on compositional and cell biological characteristics of VLDL. The postinfusion large(Svedberg flotation rate (Sf) (60-400) VLDL was found to have increased capacity to inhibit low density lipoprotein (LDL) binding to the LDL-receptor and a greater ability to suppress the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity of cultured fibroblasts compared to VLDL isolated from fasting plasma. These alterations in cellular interactions were accompanied by increases in the number of apolipoprotein (apo) E, C-I, and C-III molecules per large VLDL particle and loss of apoC-II, compositional changes similar to those observed after an oral fat load. The increase in number of apoE molecules per large VLDL particle correlated positively and significantly with the increase in the capacity of large VLDL to inhibit LDL binding to the LDL receptor (r = 0.76, P = 0.01, n = 10). In contrast, the composition of the small (Sf 20-60) VLDL particles did not change significantly, nor was the LDL receptor-mediated processing of these particles altered consistently. These observations indicate that large VLDL particles that accumulate during alimentary lipemia undergo compositional changes that render them more prone to cellular binding and uptake.

Simvastatin impairs mitogen-induced proliferation of malignant B-lymphocytes from humans--in vitro and in vivo studies.

Chronic lymphocytic leukemia (CLL) cells express lower low density lipoprotein (LDL) receptor activity and higher 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase activity than normal mononuclear blood cells indicating that CLL cells may depend on cholesterol synthesis for their proliferation. We studied the effects of competitive inhibitors of HMG-CoA reductase on malignant lymphocyte proliferation in vitro and in vivo. Tumor B-cells from 13 patients with CLL, hairy cell leukemia, or immunoblastic B-cell lymphoma were cultured for 4 d in the presence of B-cell mitogens and cholesterol synthesis inhibitors. Simvastatin and lovastatin suppressed, in a concentration-dependent manner, the mitogen-induced cellular thymidin uptake in medium with 10% human AB-serum or lipoprotein-deficient serum. Pravastatin was active only in medium with lipoprotein-deficient serum. Ten previously untreated patients with CLL received simvastatin orally, 40 mg daily for 12 wk. Mean reductions in total plasma and LDL cholesterol were 30% (range 9-46%) and 37% (range 16-63%), respectively. Cells from four patients showed moderate to minor increases in the degradation rate of 1251-LDL suggesting that the need for exogenous cholesterol had increased, three patients showed an increase in HMG-CoA reductase activity, and the cells from one patient showed both. There was no significant change in the clinical disease status during medication. However, four of the ten patients developed a therapy-demanding progressive disease during the subsequent year. Further clinical studies with cholesterol synthesis inhibitors in leukemia are warranted.

Decreased feedback regulation of low density lipoprotein receptor activity by sterols in leukemic cells from patients with acute myelogenous leukemia.

Leukemic cells from patients with acute myelogenous leukemia (AML) have higher low density lipoprotein (LDL) receptor activity than normal white blood and bone marrow cells. The underlying mechanism behind this is unclear. We studied the inhibitory effect of sterols on induction of LDL-receptor activity in leukemic cells from 27 patients with AML and in white blood cells from 13 healthy individuals. The high affinity degradation rate of 125I-labeled LDL was determined in mononuclear blood cells directly after isolation from blood and after incubation for 2 days in medium with 10% lipoprotein-deficient serum with or without various concentrations of 25-hydroxycholesterol + cholesterol. The median sterol concentration for 50% inhibition (IC50) of induction was more than five times higher for leukemic cells than for normal mononuclear cells. At the highest sterol concentration (0.400 microg/mL 25-hydroxycholesterol + 8 microg/mL cholesterol), the LDL-receptor activity was abolished in cells from all healthy individuals while the induction of LDL-receptor activity in cells from three AML patients was unaffected. The LDL-receptor activity of leukemic cells, directly after isolation from blood, correlated with IC50 values (r = 0.53, P = 0.007) and WBC counts (r = 0.72, P = 0.0001) but not with cellular cholesterol levels. The results demonstrate decreased feedback regulation of LDL-receptor activity by sterols in AML cells and support the conclusion that elevated LDL-receptor activity is associated with sterol resistance and cell proliferation. The findings are of potential interest for diagnosis and specific treatment of leukemia.

Lamotrigine in pregnancy and lactation: a case report.

PURPOSE: We investigated the effect of pregnancy on the kinetics of lamotrigine (LTG), passage of LTG over the placenta and the excretion of the drug in breast milk. METHODS: We used high-performance liquid chromatography to determine concentrations of LTG in plasma and in breast milk in a woman who was treated with LTG monotherapy during pregnancy and lactation. RESULTS: Plasma levels of LTG decreased as pregnancy progressed. The ratio of dose to plasma concentration was 5.8 times higher at delivery and 3.6 times higher in late pregnancy as compared with 5 months postpartum, suggesting enhanced clearance of LTG during pregnancy. The concentration ratio of umbilical cord to mother's plasma was 1.2 indicating extensive passage of LTG over the placenta. The LTG plasma concentration in the newborn was still 48 h after birth similar to the plasma levels of the mother at delivery and in the umbilical cord. The ratio of milk to plasma concentration was 0.6 2 weeks after delivery and the plasma concentration in the breast-fed child was 25% of the mother's plasma levels. No adverse effects were observed in the newborn. CONCLUSIONS: The kinetics of LTG may be influenced by pregnancy to such a degree that dose adjustments may be indicated. Due to an extensive passage of LTG into breast milk, and a slow elimination in the newborn, LTG concentrations in the nursed infant may reach levels at which pharmacological effects can be expected.

Expression of the low-density lipoprotein receptor, HMG-CoA reductase, and multidrug resistance (Mdr1) genes in colorectal carcinomas.

Some malignant cells have elevated uptake of plasma low-density lipoprotein (LDL). We determined the expressions in colorectal cancers of the LDL receptor gene, of the gene for the rate-limiting enzyme in cholesterol synthesis, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, and of the multidrug resistance gene (mdr1) by quantitative RNA-RNA solution hybridisation. LDL receptor RNA levels in tumor tissue exceeded those in normal mucosa in 20 of 23 patients (2-11-fold higher in 17 of 23 patients), with a mean +/- SD of 7.8 +/- 5.8 copies/cell in tumor tissue vs 3.5 +/- 2.5 in normal mucosa (P = 0.002). The HMG-CoA reductase gene was similarly expressed in tumor and normal tissue, with means and SD of 2.0 +/- 1.3 copies/cell versus 2.2 +/- 1.9 (pi = 21). Mdr1 RNA was undetectable ( < 0.15 copies/cell) in 5 of 20 tumors, with a mean +/- SD of 1.0 +/- 1.1 copies/cell vs 1.6 +/- 1.7 in normal mucosa. Expression of all three genes was, in most cases, higher in normal liver than in liver metastasis of colorectal carcinomas or normal colon mucosa. The results may form the basis for using LDL as a drug carrier for treatment of colorectal carcinomas, and may indicate that drug resistance in these tumors is not due to overexpression of the mdr1 gene.

Comparison of standardized initial doses of two antithyroid drugs in the treatment of Graves' disease.

OBJECTIVES: To obtain a simple standard regimen, suitable for general practice, and based upon the addition of antithyroid drug plus thyroxine for attaining euthyroidism in patients with Graves' disease. DESIGN: Prospective, randomized trial of patients with Graves' disease followed for 3 months after the initiation of therapy with an antithyroid drug and combined with the later addition of triiodothyronine to keep the patient euthyroid. The patients were randomized, according to birth date, between methimazole and propylthiouracil. Three dose schemes were tested for each antithyroid drug. SETTING: The study was performed at the thyroid outpatient units of two general hospitals, with the patients having been referred from primary care. SUBJECTS: Ninety-four patients with Graves' disease who were suitable for treatment with antithyroid drugs. INTERVENTIONS: The patients were allocated into six groups. Three groups received methimazole (10 mg every 6th, 8th or 12th h) and three received propylthiouracil (100 mg every 6th, 8th or 12th h). Twenty micrograms of triiodothyronine was added when the patients were euthyroid to avoid hypothyroidism. MAIN OUTCOME MEASURES: The lowest serum free thyroxine level within 3 months of the initiation of the antithyroid treatment. RESULTS: Fourteen per cent of the patients on methimazole 10 mg every 12th h and 29% on propylthiouracil 100 mg every 12th h did not achieve euthyroidism within the 3-month observation period. All but one patient on methimazole 10 mg every 8th h or propylthiouracil 100 mg every 8th h reduced the free serum thyroxine levels to the normal or hypothyroid range within the observation period. All of the patients on methimazole 10 mg every 6th h and 56% on propylthiouracil 100 mg every 6th h reduced the serum T4 values into the hypothyroid range within the period. CONCLUSION: A standard regimen, based upon the addition of methimazole 10 mg every 8th or 6th h or propylthiouracil 100 mg every 8th or 6th h and followed by the addition of thyroxine or triiodothyronine when euthyroid to avoid hypothyroidism, seems to be suitable for attaining euthyroidism within 3 months in patients with Graves' disease. A dose scheme based on methimazole 10 mg every 12th h or propylthiouracil 100 mg every 12th h were found to be unsuitable due to an unacceptably high incidence of failure to attain euthyroidism or hypothyroidism within 3 months.

Disease-related hypocholesterolemia in patients with hairy cell leukemia. Positive correlation with spleen size but not with tumor cell burden or low density lipoprotein receptor activity.

BACKGROUND: Hypocholesterolemia is common in patients with various malignant diseases, and may be a risk factor for the development or a consequence of the tumor, by different possible mechanisms. METHODS: Serum lipids were analyzed in 66 patients with symptomatic hairy cell leukemia (HCL) before and repeatedly after treatment with cladribine. Low density lipoprotein (LDL) receptor activity of hairy cells from 12 patients was analyzed. RESULTS: The median pretreatment serum cholesterol was 4.78 mmol/l. Total cholesterol, LDL cholesterol, and triglycerides were inversely correlated with the spleen size, but not with other markers of tumor burden. High density lipoprotein (HDL) cholesterol correlated to serum beta 2-microglobulin. Anemia and hypocholesterolemia developed synchronously before diagnosis in one patient. After cladribine therapy, there was a highly significant increase in all serum lipids. Low density lipoprotein receptor activity of HCL cells was elevated in only one of 12 patients; this patient had high serum cholesterol. Hypocholesterolemia predicted posttreatment neutropenic fever. CONCLUSION: Hypocholesterolemia is a common disease-related finding in HCL, which is not caused by an increased LDL receptor activity of leukemia cells, but related to spleen size, predicts posttreatment fever, and is completely reverted after successful treatment of leukemia.

Multidrug resistance (Mdr1) gene expression in peripheral blasts from patients with acute leukemia only rarely increases during disease progression after combination chemotherapy.

Multidrug resistance gene (mdr1) RNA levels were determined in 55, and P-glycoprotein expression in 37 samples of peripheral leukemic cells from 17 patients with acute myeloblastic leukemia (AML) and 7 patients with acute lymphocytic leukemia (ALL). Between sample collections, patients were treated with various chemotherapy regimens. Mdr1 RNA levels were quantified by a RNA-RNA solution hybridization assay. P-glycoprotein was determined by Western blot analysis. Samples from 14 patients (9 AML, 5 ALL) had undetectable mdr1 RNA levels at initial analysis. Only two of these had detectable levels after chemotherapy. Ten patients (8 AML, 2 ALL) had detectable mdr1 RNA levels at initial analysis (median 1.0 transcript per cell, range 0.2-1.4). Increase of mdr1 RNA levels after chemotherapy were observed in cells from 3 patients, one patient had a lower level after chemotherapy and the 6 remaining patients had essentially unchanged mdr1 RNA levels in their leukemic cells. Samples from 13 patients were sequentially analysed for P-glycoprotein expression. In one patient, no P-glycoprotein was detectable at initial analysis but was weakly positive after chemotherapy. In the remaining 12 patients, P-glycoprotein levels stayed stable during disease progression. In conclusion, combination chemotherapy seems only rarely to be associated with an increase of mdr1 gene expression in residual leukemic cells. The addition of resistance modifiers to chemotherapy in order to overcome P-glycoprotein mediated resistance might therefore be more effective in chemotherapy naive patients since it is possible that during later disease progression additional mechanisms of resistance may be more operative.