Recurrent optic disc and retinal vasculitis in a patient with drug-induced urticarial vasculitis

The purpose of this study was to report recurrent optic disc and retinal vasculitis in a patient with drug-induced urticarial vasculitis. Complete ophthalmological examination including fluorescein angiography and visual field examination were done. A 53-year-old woman with recurrent painful urticarial skin lesions following trimethoprim sulfamethoxazole usage had the clinical and histopathological diagnosis of urticarial vasculitis. Two years after cutaneous manifestations, she began to notice visual disturbances in both eyes that recurred at 1-year intervals. Her ophthalmological findings were consistent with recurrent vasculitis of the optic nerve and retina. Treatment with high-dose corticosteroids and hydroxychloroquine resulted in the resolution of cutaneous and ocular manifestations. This patient demonstrates that recurrent occlusive vasculitis of the optic nerve and retina can occur in this rare disease. These patients should be examined periodically by ophthalmologists.     

Urticaria and angio-oedema due to ziprasidone

Antipsychotic medications are commonLy associated with adverse cutaneous reactions (ACRs) in approximately 5% of patients. Angio-oedema accompanying urticaria is one of the most serious ACRs. The 36-year-old female patient who was diagnosed with ;Paranoid schizophrenia' 6 years ago, was commenced on ziprasidone 120 mg/day. On day 30 of the treatment, the patient presented urticarial papules and plaques all over the body and angio-oedema in the face. The patient was diagnosed as ;Urticaria + Angio-oedema'. The development of ACRs after the initation of ziprasidone monotherapy, disappearance of lesions after the discontinuation of this antipsychotic, and positive intradermal skin test all suggests a possible causal relationship between ACRs and ziprasidone. To our knowledge, this is the first reported case of urticaria and angio-oedema due to ziprasidone monotherapy. Ziprasidone is a valid and effective choice amongst antipsychotic medications, but this case calls for caution regarding ACRs at the time of prescribing.     

Sensitivity of doping biomarkers after administration of a single dose testosterone gel

Micro‐doping with testosterone (T) is challenging to detect with the current doping tests. Today, the methods available to detect T are longitudinally monitoring of urine biomarkers in the Athlete Biological Passport (ABP) and measuring the isotopic composition of excreted biomarkers to distinguish the origin of the molecule. In this study, we investigated the detectability of a single dose of 100 mg T gel in 8 healthy male subjects. We also studied which biomarkers were most sensitive to T gel administration, including blood biomarkers. The ABP successfully detected T gel administration in all 8 subjects. The most sensitive ratio was 5αAdiol/E, however, all ratios showed atypical findings. Isotope ratio mass spectrometry (IRMS) was performed on 5 subjects and only 2 met all the criteria for a positive test according to the rules set by the World Anti‐Doping Agency (WADA). The other 3 showed inconclusive results. Other markers that were affected by T gel administration, not used for this detection today, were serum dihydrotestosterone (DHT) and T as well as reticulocyte count and percentage in whole blood. miRNA‐122 was not significantly affected by the single T dose. A single dose of 100 mg T gel is possible to detect with today's doping tests. Since a single dose of T gel has an impact on some hematological biomarkers, access to both modules of the ABP when evaluating the athletes' profiles will increase the possibility to detect micro‐doses of T. In addition, serum DHT and T may be a useful addition to the future endocrine module of the ABP.     

The metabolism of 4-aminobiphenyl in rat. I. Reaction of N-hydroxy-4-aminobiphenyl with rat blood in vivo

1. ³H-4-Aminobiphenyl (ABP, 5?mg) given i.p. to rat had elimination half-lives of 15.6, 17 and 17?h, respectively, for urinary, faecal and total ³H elimination. ¹⁴C-ABP administered orally to rats at 100?mg/kg gave elimination half-lives of 31, 36.7 and 34?h, respectively, for urinary, faecal and total ¹⁴C elimination.

2. Semi-log plots of percentage dose remaining in the body versus time indicated that: (i) 82% of ³H activity was excreted in 36?h with a half-life of 14.4?h and 18% with a half-life of 46.2?h, and (ii) 77% of ¹⁴C activity was excreted in 48?h with a half-life of 15?h and 23% with a half-life of 180?h.

3. After i.p. injection of 10?mg/kg ¹⁴C-ABP to rats, ferrihaemoglobin (HbFe³⁺) concn increased to 60% in 2h, accompanied by accumulation of ¹⁴C activity in erythrocytes, indicating that the active metabolite, N-hydroxy-4-aminobiphenyl (N-hydroxy-ABP) had oxidized haemoglobin-Fe²⁺ (HbFe²⁺) and was bound to the erythrocyte.

4. ABP given i.p. to rats at 0.24 mmol/kg rapidly appeared in blood, disappeared with a half-life of 30?min, and blood concn plateaued at 30 nmol/ml. The concn of 4-acetyl-aminobiphenyl (AABP) plateaued at 17 nmol/ml after 15?min, indicating a dynamic equilibrium between N-acetylation of ABP and N-deacetylation of AABP. The concn of 4′-hydroxy-4-acetylaminobiphenyl (4′-hydroxy-AABP) increased slowly at 1.65 nmol/h.

5. AABP given i.p. to rats at 0.88 mmol/kg slowly appeared in the blood, accompanied by the appearance of ABP and 4′-hydroxy-AABP and formation of HbFe³⁺. After 4?h the concn of AABP and ABP was 27.35 mmol/ml, indicating a dynamic equilibrium between N-deacetylation of AABP and acetylation of ABP. Neither N-hydroxy-ABP nor N-hydroxy-4-acetylaminobiphenyl (N-hydroxy-AABP) were found.     

Altitude training causes haematological fluctuations with relevance for the Athlete Biological Passport

The impact of altitude training on haematological parameters and the Athlete Biological Passport (ABP) was evaluated in international‐level elite athletes. One group of swimmers lived high and trained high (LHTH, n = 10) for three to four weeks at 2130 m or higher whereas a control group (n = 10) completed a three‐week training camp at sea‐level. Haematological parameters were determined weekly three times before and four times after the training camps. ABP thresholds for haemoglobin concentration ([Hb]), reticulocyte percentage (RET%), OFF score and the abnormal blood profile score (ABPS) were calculated using the Bayesian model. After altitude training, six swimmers exceeded the 99% ABP thresholds: two swimmers exceeded the OFF score thresholds at day +7; one swimmer exceeded the OFF score threshold at day +28; one swimmer exceeded the threshold for RET% at day +14; and one swimmer surpassed the ABPS threshold at day +14. In the control group, no values exceeded the individual ABP reference range. In conclusion, LHTH induces haematological changes in Olympic‐level elite athletes which can exceed the individually generated references in the ABP. Training at altitude should be considered a confounding factor for ABP interpretation for up to four weeks after altitude exposure but does not consistently cause abnormal values in the ABP. Copyright © 2014 John Wiley & Sons, Ltd.     

Determination of sedative and amnestic doses of lorazepam in children

An open-label, dose-escalation study was conducted to determine doses of lorazepam required to induce anterograde amnesia and sedation in children without producing excessive toxicity. Oncology patients 4 to 17 years of age undergoing lumbar puncture or bone marrow aspiration were eligible; a patient could be entered in the study for a second procedure at a different lorazepam dose. A single oral dose of lorazepam was administered 45-60 minutes before the procedure. Starting with 0.02 mg/kg, the same dose was given to three patients; if no dose-limiting effects occurred, dose was increased by 0.01 mg/kg. Before the procedure the patient was shown a toy that he or she was later asked to identify. Immediately after the procedure (usually 60-75 minutes after the lorazepam dose), sedation was assessed on a scale of 0 (alert) to 4 (coma), and the clinician performing the procedure was asked to subjectively evaluate sedation. Patients were rated for amnesia 24 hours after the procedure; a scale of 0 (recalls procedure and toy without prompting) to 4 (recalls nothing since procedure) was used. Twenty patients received 28 doses of lorazepam. The study was terminated when two patients who received 0.10 mg/kg had excessive ataxia. Sedation was subjectively considered adequate for 24 of the procedures. Sedation and amnesia scores were not well correlated with increased dose. Amnesia occurred in some patients with doses as low as 0.03 mg/kg. In children undergoing lumbar puncture or bone marrow aspiration, premedication with oral lorazepam 0.02-0.09 mg/kg generally produced adequate sedation for the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lowering of elevated ambulatory blood pressure by HMG-CoA reductase inhibitors

Controversial results were reported as to a possible blood pressure-lowering effect of statins. This may relate to methodological limitations (blood pressure measuring techniques) or to putative different effects of statins in different biologic conditions (cholesterol or blood pressure levels, age, etc). Patients with cholesterol>200 mg/dL and no previous statin treatment underwent 24-hour ambulatory blood pressure (ABP) monitoring and were classified as normotensives or hypertensives according to their ABP. They were randomized to statin (n=51, simvastatin or pravastatin, 10-20 mg/d; atorvastatin, 5-10 mg/d) or control treatment (n=23, soy lecithin, 20 g/d) for 2 months, after which ABP assessment was repeated. No consistent treatment-related reduction in ABP was observed in lecithin-treated patients (either hypertensives or normotensives) or in statin-treated normotensive patients (-0.7+/-5.1/-1.0+/-4.6 mm Hg, both P=ns). In contrast, statin-treated hypertensive patients showed lower systolic and diastolic blood pressure (-5.7+/-5.8/-3.5+/-3.9 mm Hg, both P<0.001), the effect was entirely accounted for by reduced daytime values with no change in nighttime values, and it was unrelated to the concomitant statin-induced cholesterol reduction. Statins moderately but significantly lower blood pressure in patients with high (but not with normal) ABP; the effect is confined to the daytime period and is unrelated to the extent of the cholesterol lowering.     

The metabolism of 4-aminobiphenyl in rat. II. Reaction of N-hydroxy-4-aminobiphenyl with rat blood in vitro

1. N-Hydroxy-4-aminobiphenyl (N-hydroxy-ABP) reacts with HbFe2+ of rat blood in vitro at a molar ratio of 1:47 to produce 20% HbFe3+ within 1 min; N-hydroxy-ABP oxidized 9.4 equiv. of HbFe2+. N-hydroxy-ABP rapidly disappeared and HbFe3+ was reduced at a rate of 44 microM/min. 2. On titration of rat blood in vitro with N-hydroxy-ABP up to 0.81 mM, 4-nitrosobiphenyl (nitroso-BP) disappeared within 5 min; with concn of N-hydroxy-ABP greater than 0.81 mM, N-hydroxy-ABP was present also as nitroso-BP, indicating saturation of reactive binding sites. When N-hydroxy-ABP reacted with HbFe2+ at a molar ratio of 1:103 to 1:1.9, 13 to 1.3 equiv. of HbFe3+ were formed per mol of N-hydroxy-ABP in 5 min, indicating that with increasing N-hydroxy-ABP concn side-reactions increased. 3. After incubation of N-hydroxy-ABP (1.72 mM) with rat Hb (7.66 mM HbFe2+), nitroso-BP disappeared with a half-life of 1 min, maximal HbFe3+ of 72% occurred at 47 min, and the concn of 4-aminobiphenyl (ABP) increased at a rate of 51 nmol/ml per h. 4. In rats injected with 0.24 mmol/kg ABP, HbFe3+ concn plateaued at 56% after 75 min, indicating an equilibrium between HbFe3+ formation and HbFe3+ reduction. Such equilibrium was simulated by titrating rat blood in vitro with N-hydroxy-ABP for 1 h. 5. The long-lasting HbFe3+ formation by ABP in rat results from a cycle of activation of ABP to N-hydroxy-ABP, its rapid co-oxidation with HbFe2+ to form HbFe3+ and nitroso-BP, and binding of nitroso-BP to erythrocyte thiol groups. ABP is released from the Hb adduct and enters a new cycle of activation and inactivation, until terminated by ring-hydroxylation.     

Chronic High-Dose Buprenorphine Does Not Block Subjective High from Diacetylmorphine in a Patient in Heroin-Assisted Treatment

ABSTRACT

We present the case of a 35-year-old woman in heroin-assisted treatment (HAT) expressing the wish for the transition to oral opioid agonist treatment. After failed attempts to change to oral diacetylmorphine and slow-release oral morphine, respectively, she was induced on overlapping buprenorphine (BUP) treatment with the Bernese method. Gradual dose increases to BUP 48 mg per day did not result in attenuation of subjective effects of IV diacetylmorphine (DAM) 190 mg. Instead, the patient showed increased sedation. BUP was then reduced to 32 mg per day. After the gradual reduction of IV DAM, she reinitiated illicit substance use. IV DAM was again raised to an effective dose leading to stabilization and reduction of illicit substance use. BUP was subsequently reduced to 8 mg per day. This combination was continued as the patient felt comfortable and reported less early morning withdrawal than with exclusive DAM treatment. We discuss possible underlying mechanisms and explanations as well as clinical implications.     

The metabolism of 4-aminobiphenyl in rat. II. Reaction of N-hydroxy-4-aminobiphenyl with rat blood in vitro

1. N-Hydroxy-4-aminobiphenyl (N-hydroxy-ABP) reacts with HbFe²⁺ of rat blood in vitro at a molar ratio of 1:47 to produce 20% HbFe³⁺ within 1 min; N-hydroxy-ABP oxidized 9.4 equiv. of HbFe²⁺. N-hydroxy-ABP rapidly disappeared and HbFe³⁺ was reduced at a rate of 44 μ/min.

2. On titration of rat blood in vitro with N-hydroxy-ABP up to 0.81 mM, 4-nitrosobiphenyl (nitroso-BP) disappeared within 5 min; with concn of N-hydroxy-ABP >0.81 mM, N-hydroxy-ABP was present also as nitroso-BP, indicating saturation of reactive binding sites. When N-hydroxy-ABP reacted with HbFe²⁺ at a molar ratio of 1:103 to 1:1.9, 13 to 1.3 equiv. of HbFe³⁺ were formed per mol of N-hydroxy-ABP in 5 min, indicating that with increasing N-hydroxy-ABP concn side-reactions increased.

3. After incubation of N-hydroxy-ABP (1.72mM) with rat Hb (7.66 mM HbFe²⁺), nitroso-BP disappeared with a half-life of 1 min, maximal HbFe³⁺ of 72% occurred at 47 min, and the concn of 4-aminobiphenyl (ABP) increased at a rate of 51 nmol/ml per h.

4. In rats injected with 0.24 mmol/kg ABP, HbFe³⁺ concn plateaued at 56% after 75 min, indicating an equilibrium between HbFe³⁺ formation and HbFe³⁺ reduction. Such equilibrium was simulated by titrating rat blood in vitro with N-hydroxy-ABP for 1 h.

5. The long-lasting HbFe³⁺ formation by ABP in rat results from a cycle of activation of ABP to N-hydroxy-ABP, its rapid co-oxidation with HbFe²⁺ to form HbFe³⁺ and nitroso-BP, and binding of nitroso-BP to erythrocyte thiol groups. ABP is released from the Hb adduct and enters a new cycle of activation and inactivation, until terminated by ring-hydroxylation.     

Use of 24-Hour Ambulatory Blood Pressure Monitoring to Assess Antihypertensive Efficacy

INTRODUCTION: Goal rates, the percentage of patients with hypertension achieving recommended SBP/DBP, are a clinically important assessment of an antihypertensive agent's efficacy. Twenty-four-hour ambulatory blood pressure monitoring (ABPM) allows accurate assessment of a patient's hypertension and risk for cardiovascular events, and provides the most accurate measure of an antihypertensive agent's efficacy throughout a 24-hour dosing interval. METHODS: A 12-week (4-week single-blind placebo run-in phase followed by an 8-week double-blind active treatment phase) randomized, parallel-group study reported that the recommended starting dose of the angiotensin II receptor antagonist (angiotensin receptor blocker; ARB) olmesartan medoxomil (Benicar(trade mark)) 20 mg/day was more effective than starting doses of losartan potassium (Cozaar) 50 mg/day, valsartan (Diovan) 80 mg/day, or irbesartan (Avapro) 150 mg/day in reducing cuff DBP in patients with essential hypertension. The present report includes analyses of secondary efficacy variables from this 12-week trial. RESULTS: The mean reduction in blood pressure from baseline to week 8 (end of treatment) was significantly greater with olmesartan medoxomil than with valsartan for all ABPM times analyzed (24 hours, daytime, night-time, and last 2 and 4 hours of monitoring). Statistical significance was reached for comparisons of olmesartan medoxomil with losartan potassium for a majority of times analyzed and with irbesartan for SBP in the last 4 hours of monitoring. Goal rates for accepted critical ambulatory blood pressure (ABP) values of <130/80 mm Hg for mean 24-hour ABP, <135/85 mm Hg for mean daytime ABP, and <120/75 mm Hg for mean night-time ABP were significantly greater for patients receiving olmesartan medoxomil than for those receiving losartan potassium or valsartan. Goal rates were numerically superior, but not statistically significant, to those achieved with irbesartan. Compared with losartan potassium or valsartan recipients, a significantly higher percentage of patients treated with olmesartan medoxomil achieved the 24-hour ABP goal of <130/85 mm Hg. The last 2 and 4 hours of ABPM indicated that olmesartan medoxomil maintained larger mean decreases in blood pressure through the morning surge. DISCUSSION/CONCLUSION: ABP goal rates are a meaningful measure of antihypertensive efficacy. The effects on mean change from baseline in ABP and ABP goal rates after 8 weeks of treatment were numerically better, but not statistically significant, for olmesartan medoxomil than for irbesartan. However, olmesartan medoxomil was significantly more effective than losartan potassium or valsartan.     

Increased thyroid-stimulating hormone levels associated with concomitant administration of levothyroxine and raloxifene

A 47-year-old Caucasian woman had a 3.5-year history of primary hypothyroidism treated with levothyroxine. Her levothyroxine dosage of 0.05 mg/day had been stable for the past 15 months. She was then prescribed raloxifene for prevention of osteoporosis secondary to early menopause. During the next 30 months, her levothyroxine dosage had to be gradually increased. The patient had been taking levothyroxine and raloxifene at the same time each day on an empty stomach. During the months of her levothyroxine dosage changes, however, she separated administration of levothyroxine and raloxifene by 12 hours; the patient then became hyperthyroid. Eventually, her levothyroxine needs decreased, and she returned to the same levothyroxine dosage she had taken before separating administration of the two drugs. These findings suggest that raloxifene decreased the absorption of levothyroxine when the two agents were coadministered. Assessment of causality using the Naranjo adverse drug reaction probability scale resulted in a possible association for this adverse event. Another published case report provides findings similar to our patient's experience. The possibility of a malabsorption interaction between levothyroxine and raloxifene is significant, as hypothyroidism is common among postmenopausal women-the same population that is the target of osteoporosis therapy with agents such as raloxifene. The mechanism by which raloxifene decreases levothyroxine absorption is unknown. Further investigation of this potential interaction is warranted. Until then, clinicians should be alert to the potential for an interaction between raloxifene and levothyroxine.     

Octreotide- or Trimethoprim-Induced Hyperkalemia?

The article by Sargent et al¹ associating hyperkalemia with octreotide in a 68-year-old, 91-kg trauma victim has little focus on other potential causes of her hyperkalemia. Her medical history was significant for noninsulin-dependent diabetes mellitus. The authors, however, do not state how long she had this disease and whether she had any evidence of end-organ damage. The episode of postoperative hypotension, as well as the assumed oliguria (her serum creatinine increased from 1.5 to 2.3 mg/dl) on day 3 of hospitalization, clearly contributed to renal hypoperfusion and potential renal injury. There was no other mention of renal impairment until the laboratory values revealed a serum creatinine of 2.5 mg/dl and a blood urea nitrogen of 91 mg/dl on day 14 of hospitalization. The patient appeared to be volume depleted (blood urea nitrogen:serum creatinine ratio > 20:1, serum sodium 154 mmol/L), and her potassium may have been lower (4.1 mmol/L) secondary to the effects of aldosterone. Interestingly, on day 11, oral (suspension?) trimethoprim-sulfamethoxazole (TMP-SMX) 180 mg twice/day (4 mg/kg/day TMP) was started for a urinary tract infection. The next day (day 12), this was changed to the intravenous route at a dose of 320 mg every 8 hours (∼11 mg/kg/day TMP) for suspected pneumonia. The patient's serum potassium was already beginning to rise slowly (4.1 to 4.6 mmol/L) even before the start of octreotide on day 16 despite improving serum creatinine (2.5 to 1.2 mg/dl) and serum sodium (154 to 147 mmol/L).     

Antihypertensive effects of cilazapril, 2.5 and 5 mg, once daily versus placebo on ambulatory blood pressure following single- and repeat-dose administration.

Ambulatory blood pressure (ABP) monitoring was used to evaluate the 24-h antihypertensive efficacy of single- and repeat-dose administrations of the nonsulfhydryl-converting enzyme inhibitor cilazapril, 2.5 and 5 mg, versus placebo in patients with mild to moderate essential hypertension. After a 2-week placebo run-in period, patients were randomized to receive, in a double-blind procedure, either 2.5 mg cilazapril (n = 14), 5 mg cilazapril (n = 14), or placebo (n = 14) for 4 weeks. In calculating the systolic/diastolic blood pressure (BP) trough-to-peak (T/P) ratio after subtraction of the placebo effect, 5 mg cilazapril appeared to be more effective than 2.5 mg cilazapril following single- (59/54% vs. 21/48%) and repeat-dose administration (47/76% vs. 31/49%). There were significant differences in 24-h and awake ABP for both 2.5 and 5 mg cilazapril as compared to placebo after single- and repeat-dose administrations. However, there were no significant differences in 24-h and awake ABP reduction between 2.5 and 5 mg cilazapril after single- and repeat-dose administrations. Furthermore, the percentages of "BP load" were identical with both regimens after the first dose (46 vs. 43%) and at steady-state (37 vs. 29%). These data demonstrate that 2.5 and 5 mg doses of cilazapril have equivalent antihypertensive efficacy using ABP and that 24-h ABP monitoring should also be performed in dose-response studies.     

A step towards removing plasma volume variance from the Athlete's Biological Passport: The use of biomarkers to describe vascular volumes from a simple blood test

The haematological module of the Athlete's Biological Passport (ABP) has significantly impacted the prevalence of blood manipulations in elite sports. However, the ABP relies on a number of concentration‐based markers of erythropoiesis, such as haemoglobin concentration ([Hb]), which are influenced by shifts in plasma volume (PV). Fluctuations in PV contribute to the majority of biological variance associated with volumetric ABP markers. Our laboratory recently identified a panel of common chemistry markers (from a simple blood test) capable of describing ca 67% of PV variance, presenting an applicable method to account for volume shifts within anti‐doping practices. Here, this novel PV marker was included into the ABP adaptive model. Over a six‐month period (one test per month), 33 healthy, active males provided blood samples and performed the CO‐rebreathing method to record PV (control). In the final month participants performed a single maximal exercise effort to promote a PV shift (mean PV decrease ?17%, 95% CI ?9.75 to ?18.13%). Applying the ABP adaptive model, individualized reference limits for [Hb] and the OFF‐score were created, with and without the PV correction. With the PV correction, an average of 66% of [Hb] within‐subject variance is explained, narrowing the predicted reference limits, and reducing the number of atypical ABP findings post‐exercise. Despite an increase in sensitivity there was no observed loss of specificity with the addition of the PV correction. The novel PV marker presented here has the potential to improve the ABP's rate of correct doping detection by removing the confounding effects of PV variance.     

The effects of mibefradil and enalapril on 24-hour blood pressure control and left ventricular mass in patients with mild to moderate hypertension: double-blind, randomized trial

In this prospective, double-blind, monocenter drug trial, 48 primary care patients with mild to moderate essential hypertension were randomized to mibefradil, 50 mg, titrated to 100 mg, or enalapril, 20 mg, titrated to 2 x 20 mg. Ambulatory 24-h blood pressure measurements (ABPM) and echocardiography were performed at baseline and after 12 weeks' treatment. Complete data from 43 patients were analyzed. Mibefradil (n = 22; titration, 13 patients) reduced mean 24-h ABP from 159+/-14/102+/-7 mm Hg to 140+/-10/89+/-7 mm Hg after 12 weeks. Enalapril (n = 21; titration, six patients) reduced baseline ABP from 156+/-12/100+/-9 mm Hg to 140+/-17/89+/-10 mm Hg (12 weeks). Trough-to-peak ratios in DBP were 86% for mibefradil and 75% with enalapril. Left ventricular mass (LVM) decreased from 199+/-65 to 193+/-62 g [M-mode modified American Society of Echocardiography (ASE)] and from 184+/-65 to 173+/-50 g (truncated ellipsoid method) after 12 weeks in response to mibefradil (p > 0.2), and from 212+/-50 to 196+/-57 g and from 182+/-39 to 170+/-40 g (mean +/- SD, p < 0.02) with enalapril. Mibefradil matched enalapril in 24-h ABP control. Enalapril reduced LVM significantly after 12 weeks (p < 0.02). Mibefradil did not significantly reduce LVM after 12 weeks.     

Codeine influences the serum and urinary profile of endogenous androgens but does not interact with the excretion rate of administered testosterone

Today's doping tests involve longitudinal monitoring of urinary steroids including the testosterone glucuronide and epitestosterone glucuronide ratio (T/E) in an Athlete Biological Passport (ABP). The aim of this study was to investigate the possible influence of short‐term use of codeine on the urinary excretion of androgen metabolites included in the steroidal module of the passport prior to and after the co‐administration with testosterone. The study was designed as an open study with the subjects being their own control. Fifteen healthy male volunteers received therapeutic doses of codeine (Kodein Meda) for 6 days. On Day 3, 500 mg or 125 mg of testosterone enanthate (Testoviron®‐Depot) was administered. Spot urine samples were collected for 17 days, and blood samples were collected at baseline, 3, 6, and 14 days after codeine intake. The circulatory concentration of total testosterone decreased significantly by 20% after 3 days' use of codeine (p = 0.0002) and an atypical ABP result was noted in one of the subjects. On the other hand, the concomitant use of codeine and testosterone did not affect the elevated urinary T/E ratio. In 75% of the individuals, the concentration of urinary morphine (a metabolite of codeine) was above the decision limit for morphine. One of the participants displayed a morphine/codeine ratio of 1.7 after codeine treatment, indicative of morphine abuse. In conclusion, our study shows that codeine interferes with the endogenous testosterone concentration. As a result, the urinary steroid profile may lead to atypical findings in the doping test.     

Evidence Suggesting the 58-kDa Acetaminophen Binding Protein Is a Preferential Target for Acetaminophen Electrophile

Acetaminophen is an analgesic and antipyretic which causes livertoxicity in humans and experimental animals with overdose. Acetaminophen(APAP) covalent binding to a cytosolic protein of approximately58 kDa (58–ABP) has been associated with target organtoxicity. Since hepatic content of 58–ABP varies, studieswere conducted to determine if this influences APAP bindingto other target proteins. In the liver, the amount of 58–ABPvaried with individual male CD-1 mice, but in kidneys of thesame mice there was no such variability in 58–ABP content.All male A/J mice tested had comparatively little detectable58–ABP in liver cytosol. Similarly, female CD–1mice had low 58–ABP content compared to males; however,administration of testosterone propionate to females significantlyincreased 58-ABP content in liver cytosol. At 4 hr after challengeof mice from the above-described groups with 600 mg APAP/kg,cytosolic covalent binding to proteins was determined by Westernblot analysis with anti–APAP antibody. The Western blotswere then stripped of antibody and blocking agents and reprobedwith antibody prepared against purified 58–ABP (anti–58–ABP).In the liver, the level of APAP bound to the 58-ABP target correspondedwith 58–ABP content. In cases where 58–ABP was poorlyexpressed, APAP adducts to other protein targets were more prominentlydetected. In the kidneys of the male CD–1 mice 58–ABParylation by APAP varied little among animals, reflecting therelatively consistent levels of renal 58–ABP. These datasuggest that binding to the 58–ABP may spare other potentialtargets of APAP electrophile attack and support a role of the58–ABP as a preferred target of APAP electrophile in cytosol.     

吲哚美辛栓致严重神经系统不良反应并抽搐1例

1例33岁女性患者因痛经给予处方吲哚美辛栓2/3枚,用药半小时后出现头晕、喘促不适、手足麻木、抽搐、角弓反张、颈项强直、严重的电解质紊乱、呼吸性碱中毒等症状。动脉血气分析：pH 7.459,PCO2 21.1 mmHg,PO2 144.2 mmHg,K+ 2.94 mmol·L-1。快速地西泮10 mg 肌内注射,症状逐渐缓解。4 h后再次发作,快速地西泮5 mg 肌内注射,苯巴比妥100 mg静脉注射,症状逐渐缓解,恢复正常。考虑吲哚美辛栓不良反应,患者症状未再出现,第3天即出院。随访3个月,患者未见复发。     

牛膝多糖对链佐星诱导性糖尿病小鼠的保护作用(英文)

目的研究牛膝多糖(ABP)对链佐星诱导性糖尿病小鼠的保护作用。方法将雄性ICR小鼠分为正常对照组、糖尿病模型组、ABP50和100mg.kg-1(ip,每天1次,共15d)治疗组。分别于给药前,给药8和15d时用血糖测量仪检测血糖水平,并进行血糖耐受试验。末次给药第2天测量小鼠体重,处死,测量心、肝、脾和肾脏器官重量,同时制备血清,采用放射免疫分析试剂盒检测血清胰岛素水平,比色法测定血清甘油三酯(TG)、总胆固醇(TC)、钙(Ca)和磷(P)含量及谷草转氨酶(GOT)、谷丙转氨酶(GPT)和碱性磷酸酶(ALP)活性。采用ELISA检测血清瘦素、脂联素、肿瘤坏死因子α(TNF-α)和白细胞介素6(IL-6)的浓度。结果与正常对照组相比,糖尿病模型组小鼠体重下降,血清胰岛素水平降低,血糖升高(P<0.05,P<0.01)。ABP50和100mg.kg-1在血糖耐受试验中能较好地调节血糖水平,其血糖在15d时分别比模型组下降了27.4%和16.3%(P<0.05,P<0.01)。ABP50mg.kg-1治疗组小鼠脾和肾脏指数,血糖、血清TG和TC浓度,GOT,GPT和ALP活性均显著低于糖尿病模型组(P<0.05),血清瘦素水平下降并接近正常水平,血清脂联素、TNF-α和IL-6水平均显著高于模型组(P<0.05,P<0.01);ABP100mg.kg-1对血清TC和TG水平及ALP和GPT活性无明显作用,对上述其他指标的作用与ABP50mg.kg-1相似。各组血清胰岛素浓度及Ca和P含量均无明显变化。结论ABP对链佐星诱导的糖尿病小鼠具有一定的保护作用。