Early Therapeutic Intervention for Crush Syndrome: Characterization of Intramuscular Administration of Dexamethasone by Pharmacokinetic and Biochemical Parameters in Rats.

Crush syndrome (CS) is the systemic manifestation of muscle cell damage resulting from pressure and crushing. It is associated with a high mortality rate, even when patients are treated with conventional therapy. We demonstrated the utility of intramuscular administration of dexamethasone (DEX) in disaster medical care by using a model of CS to characterize the pharmacokinetics and biochemical parameters. We compared intravenous (IV) and intramuscular (IM) injection. The IM sites were the right anterior limb (AL), bilateral hind limbs (bHL), and unilateral hind limb (uHL). DEX (5.0 mg/kg) was administered in sham-operated (sham, S-IV, S-AL, S-bHL, S-uHL groups) and CS rats (control, C-IV, C-AL, C-bHL, C-uHL groups). The survival rate in the IM groups was lower than that in the C-IV group. Survival was highest in the C-AL group, followed by the C-uHL and C-bHL groups. The blood DEX concentration of the C-AL group was similar to that in the C-IV group. The C-bHL and C-uHL groups had decreased blood DEX concentrations. Moreover, inhibition of inflammation was related to these changes. Administration of DEX to non-injured muscle, as well as IV administration, increased the survival rate by modulating shock and inflammatory mediators, consequently suppressing myeloperoxidase activity and subsequent systemic inflammation, resulting in a complete recovery of rats from lethal CS. These results demonstrate that injection DEX into the non-injured muscle is a potentially effective early therapeutic intervention for CS that could easily be used in transport to the hospital.

Inhibitory effects of azelnidipine tablets on morning hypertension.

BACKGROUND: Morning hypertension is a risk factor for cardiovascular and cerebrovascular events. Furthermore, it is a useful measure for definitive diagnosis of hypertension, and patients who self-assess their own blood pressure (BP) in the morning tend to exhibit better compliance with antihypertensive medication than those who do not. OBJECTIVE: The objective of this analysis was to determine the BP- and pulse rate-lowering effects of azelnidipine, a long-acting dihydropyridine calcium antagonist administered once daily in the morning. METHODS: We conducted the Azelnidipine Treatment for Hypertension Open-label Monitoring in the Early morning (At-HOME) Study by surveying patients who were taking azelnidipine. According to the study protocol, high systolic BP (SBP) was defined as ≥135 mmHg when measured at home in the morning and ≥140 mmHg when measured at the clinic during the day. A total of 5,433 hypertensive patients, who were registered at 1,011 medical institutions across Japan, were enrolled in the study. Data obtained from 4,852 of these patients (mean age, 64.8 years; female, 52.9 %; previous medication with other antihypertensive agents used concomitantly with the present study agent, 45.5 %) were used for efficacy analysis. RESULTS: At baseline, the subjects' mean [± standard deviation] SBP/diastolic BP values at home in the morning, at the clinic during the day, and at home in the evening were 156.9 ± 16.4/89.7 ± 12.0, 157.5 ± 18.7/89.1 ± 13.3, and 150.2 ± 17.6/85.6 ± 12.2 mmHg, respectively. The mean pulse rates were 72.7 ± 10.7, 74.9 ± 11.2, and 72.5 ± 9.6 beats/min, respectively. Patients whose BP was defined as high accounted for 83.4 % of the study population, whereas 9.9 % had 'masked' hypertension, defined as SBP of ≥135 mmHg at home in the morning and <140 mmHg at the clinic. However, from 4 weeks after initiation of azelnidipine treatment till the end of the study at week 16, all three daily BP determinations were significantly (p < 0.0001) lowered, and pulse rates at home in the morning, at the clinic, and at home in the evening were similarly and significantly reduced (by -3.7 ± 8.0, -3.5 ± 9.5, and -3.5 ± 7.3 beats/min, respectively). Whereas achievement of home SBP of <135 mmHg in the morning was noted in only 6.6 % of patients before the start of azelnidipine treatment, this was noted in 43.3 % after 16 weeks. Meanwhile, achievement of clinic SBP of <140 mmHg was increased from 12.9 % of patients to 56.1 % of patients at the same timepoints. After azelnidipine treatment, 32.2 % of patients had well-controlled hypertension in both the home and clinic settings. Adverse drug reactions occurred in 2.92 % of patients (154/5,265). All adverse drug reactions were as expected for the calcium antagonist class of agents. CONCLUSION: These data suggest that azelnidipine controlled morning hypertension well. Furthermore, azelnidipine reduced pulse rates significantly.

Study of sustained blood pressure-lowering effect of azelnidipine guided by self-measured morning and evening home blood pressure: subgroup analysis of the At-HOME study.

BACKGROUND: Morning hypertension is a risk factor for cardiovascular and cerebrovascular events, and consequently diagnosis and control of morning hypertension are considered very important. We previously reported the results of the Azelnidipine Treatment for Hypertension Open-label Monitoring in the Early morning (At-HOME) Study, which indicated that azelnidipine effectively controlled morning hypertension. OBJECTIVES: The objective of this At-HOME subgroup analysis was to evaluate the sustained blood pressure (BP)-lowering effect of azelnidipine, using mean morning and evening systolic BP [ME average] and morning systolic BP minus evening systolic BP (ME difference). METHODS: We analyzed the self-measured home BP data (measured in the morning and at bedtime) from this 16-week prospective observational study to clarify the effect of morning dosing of azelnidipine (mean [± standard deviation] maximum dose 14.3 ± 3.6 mg/day). A subgroup of patients from the At-HOME Study who had an evening home BP measurement within 28 days prior to the baseline date were used for efficacy analysis (n = 2,546; mean age, 65.1 years; female, 53.6 %). RESULTS: Home systolic BP/diastolic BP levels in the morning and evening were significantly lowered (p < 0.0001) by -19.4 ± 17.1/-10.3 ± 10.6 and -16.9 ± 17.0/-9.4 ± 10.6 mmHg, respectively. Home pulse rates in the morning and evening were also significantly lowered (p < 0.0001) by -3.5 ± 7.8 and -3.5 ± 7.3 beats/min, respectively. At baseline, patients whose ME average was ≥135 mmHg and whose ME difference was ≥15 mmHg (defined as morning-predominant hypertension) accounted for 20.4 % of the study population. However, at the end of the study, the number of such patients was significantly reduced to 7.9 % (p < 0.0001). Patients whose ME average was ≥135 mmHg and whose ME difference was <15 mmHg (defined as sustained hypertension) accounted for 71.1 % of the study population at baseline. This was reduced significantly to 42.8 % at the end of the study (p < 0.0001). ME average decreased significantly from 153.8 ± 15.5 mmHg to 135.6 ± 11.9 mmHg, and ME difference also decreased significantly from 6.7 ± 13.1 mmHg to 4.7 ± 10.8 mmHg (both p < 0.0001). CONCLUSION: These results suggest that azelnidipine improved morning hypertension with its sustained BP-lowering effect.

Artist® tablets (carvedilol) for hypertensive patients in Japan: results of a long-term special survey.

BACKGROUND: In Japan, when pharmaceutical companies launch a new drug, they are obligated to conduct a post-marketing survey to evaluate the safety and efficacy of the drug in accordance with Good Post-Marketing Surveillance Practice under Article 14-4 (re-examination) of the Pharmaceutical Affairs Law at contracted medical institutions. We report the results of a long-term special survey that we conducted as a post-marketing survey. OBJECTIVE: The results of a prospective post-marketing survey that was conducted to assess the safety and efficacy of the ß-adrenergic receptor antagonist (ß-blocker) Artist® tablets 10 mg, 20 mg (carvedilol) in patients with hypertension in Japan, were investigated in order to examine the safety and efficacy of the drug during long-term treatment (18 months). PATIENTS: Patients were carvedilol-naive and had essential hypertension or renal parenchymal hypertension. METHODS: We performed this survey as a prospective cohort study (special survey) utilizing a centralized registration method over 3 years (starting from April 1994), for an observation period of 18 months of carvedilol treatment. RESULTS: Sixty-one medical institutions across Japan collected 380 case report forms of patients who received long-term administration of carvedilol, with 363 and 341 cases evaluated for safety and efficacy, respectively. The discontinuation rate was 7.2% and the incidence of adverse drug reactions was 5.23% (19 of 363) in the safety population. There was no significant change in fasting plasma glucose levels from baseline (118.1 ± 46.5 mg/dL) to after carvedilol treatment (114.6 ± 43.3 mg/dL).[n = 141; p = 0.310]. In 341 evaluable patients in the efficacy population, decreases in both blood pressure and pulse rate were statistically significant at all assessment points in comparison with baseline data (p < 0.001). Similarly, in hypertensive patients with diabetes mellitus, decreases in blood pressure were statistically significant at all assessment points in comparison with baseline data (p < 0.001). CONCLUSIONS: The results of this study show that carvedilol exerted stable antihypertensive effects leading to favorable blood pressure control throughout long-term treatment, without showing any safety concerns. It was concluded that there were no clinically significant issues in terms of safety or efficacy with the long-term treatment of carvedilol in patients with hypertension.

Artist® tablets (carvedilol) for hypertensive patients in Japan: results of a drug use survey.

BACKGROUND: In Japan, when pharmaceutical companies launch a new drug, they are obligated to conduct a post-marketing survey to evaluate the safety and efficacy of the drug in accordance with Good Post-Marketing Surveillance Practice under Article 14.4 (re-examination) of the Pharmaceutical Affairs Law at contracted medical institutions. We report the results of a drug use survey, which we conducted as a post-marketing survey. OBJECTIVE: This prospective post-marketing drug use survey was conducted to assess the safety and efficacy of the ß-adrenergic receptor antagonist (ß-blocker) Artist® Tablets (carvedilol) in patients with hypertension in Japan. PATIENTS: Patients were carvedilol-naive and had essential hypertension or renal parenchymal hypertension. METHODS: This was a prospective survey conducted over 3 years from October 1993 to September 1996. The standard observation period for the patients was defined as 12 weeks of treatment with carvedilol. RESULTS: We collected data on 4961 patients at 561 medical institutions who had not been previously treated with carvedilol; 4574 patients were included in the safety analysis and 4422 in the efficacy analysis. The incidence of adverse drug reactions (the proportion of patients with adverse drug reactions) was 4.31% (197 of 4574 patients), which is less than that shown in the pre-approval clinical trial of carvedilol (6.85% [68 of 993]). The most common adverse drug reactions were bradycardia, dizziness, hypotension, headache, and feeling light-headed. After 12 weeks' treatment with carvedilol, systolic/diastolic blood pressure (SBP/DBP) was reduced from 168.2 ± 18.6/95.7 ± 11.3 mmHg at baseline to 144.3 ± 17.3/83.4 ± 10.8 mmHg. Patients were classified according to which antihypertensive drug they had been using when carvedilol treatment was initiated. Coadministered agents were calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), diuretics, and α-adrenergic receptor antagonists (α-blockers). At 12 weeks, the change in SBP/DBP in the monotherapy group was -22.7/-12.2 mmHg and that of each combination therapy subgroup, CCB, ACEI, diuretic, and ß-blocker, was -26.1/-12.7 mmHg, -25.4/-11.9 mmHg, -26.3/-13.0 mmHg, and -24.4/-11.5 mmHg, respectively. The achievement rates for target BP (<140/90 mmHg) were 29.5% in the monotherapy group, 34.8% in the CCB group, 31.3% in the ACEI group, 31.8% in the diuretic group, and 32.4% in the ß-blocker group. There was no significant difference in the achievement of target BP among the four combination therapy subgroups (p = 0.475). These results indicate that carvedilol exerts reasonable BP reduction regardless of whether it is used as monotherapy or in combination therapy, and that the effect is not influenced by the coadministered drug. Moreover, carvedilol was also effective in reducing BP levels in elderly patients (≥65 years) and in patients with diabetes mellitus or renal diseases. CONCLUSIONS: The results of this study reflect the results of clinical trials up to the time of approval and it was confirmed that carvedilol is a highly useful drug in the treatment of hypertension.

Influence of guidelines on physicians' assessment of blood pressure lowering effects and achievement rate of blood pressure target during transitional period of guidelines.

We studied the agreement rate between achievement of blood pressure (BP) target according to the 2002 Japanese Guidelines for Treatment of Hypertension in the Elderly (EG 2002) and the Japanese Society of Hypertension Guidelines 2004 (JSH 2004) versus a physicians' assessment of BP-lowering efficacy of olmesartan medoxomil in elderly patients. The physicians' assessment more closely agreed with the achievement rate of the BP target according to the EG 2002 than that according to the JSH 2004. This study was started in July 2004, shortly after JSH 2004 was published. Our data suggest that guidelines at the time strongly influence the physicians' assessment and their treatment strategy for individual patients in daily clinical practice.

Blood pressure-lowering effects of angiotensin receptor antagonist monotherapy and in combination with other anti-hypertensive drugs in primary care settings in Japan.

Combination therapy with multiple anti-hypertensives is required to achieve target blood pressure (BP) control and is recommended as the first-line therapy in hypertension. Although angiotensin receptor blockers (ARBs) may be combined with other anti-hypertensives, it is unclear how the effects of ARBs are influenced by co-administered anti-hypertensives. We investigated the effect of olmesartan medoxomil (OLM) when it is given alone (monotherapy) or concomitantly with other anti-hypertensives in 6507 OLM-naive Japanese in "real world" clinical practice. After a 12-week treatment, BP was significantly reduced from baseline in both the monotherapy group and the combination therapy group (P < 0.0001). The BP-lowering efficacy after treatment and achievement rates of target BP were similar in both groups. In the combination therapy group, no significant difference of achieved BP level was detected between patients taking Calcium channel blockers and any other class of anti-hypertensive drugs. This study suggests that ARBs such as OLM-elicits BP-lowering efficacy as either a first- or second-line agent and its effects are minimally influenced by co-administered anti-hypertensives.

The use of olmesartan medoxomil as monotherapy or in combination with other antihypertensive agents in elderly hypertensive patients in Japan.

The efficacy and safety of the angiotensin receptor blocker olmesartan medoxomil (OLM) was assessed in 550 elderly Japanese hypertensive patients who were followed for 24 weeks in daily clinical practice. Patients were given OLM alone or in combination with other antihypertensive drugs at the discretion of the investigators. After 24 weeks of treatment, systolic and diastolic blood pressure (BP) significantly decreased from baseline (P<.0001). When patients were classified as either young-old (65-74 years) or older-old (75 years and older), with either isolated systolic hypertension (ISH) or systolic-diastolic hypertension (SDH), the reduction of diastolic BP in ISH patients was significantly smaller than that in SDH patients (5.0 vs 15.2 mm Hg; P<.0001), indicating that OLM did not cause excessive reduction of diastolic BP in ISH patients. Treatment was well tolerated in all groups. In conclusion, the medication was safe and effective in reducing BP levels in ISH patients aged 75 years and older, as well as in other elderly hypertensive patients.

Early antihypertensive efficacy of olmesartan medoxomil.

The authors assessed the early antihypertensive efficacy of olmesartan medoxomil (OM) in a 12-week prospective observational study. Of 2221 patients with untreated hypertension who received OM (mainly 10 or 20 mg), 331 patients whose blood pressure (BP) was measured at 1 week after initiation of treatment were defined as the "early BP determination group,'' whereas the remaining 1890 patients were defined as the ;;standard BP determination group.'' Baseline characteristics, doses of OM, concomitant drugs used, and BP during treatment did not differ between the 2 groups. The achievement rate of BP target (<140/90 mm Hg) was 28.4% at 1 week in the early BP determination group and 28.3% at 2 weeks in the standard BP determination group (P=NS). Rates of adverse drug reactions in the 2 groups were similar. The present study suggests that OM is safe and effective in reducing BP at an early time point of treatment.

Post-marketing surveillance of the safety of levofloxacin in Japan.

BACKGROUND: Central nervous system reactions to new quinolones, such as convulsions due to interaction with nonsteroidal anti-inflammatory drugs (NSAIDS), have attracted increased attention in Japan. METHODS: The safety of levofloxacin (LVX) was investigated in Japan by post-marketing surveillance and reviewing spontaneous reports. RESULTS: Post-marketing surveillance was performed in 16,117 patients between 1994 and 1996. The incidence of adverse reactions was 1.3% (203/16,117), being comparable with that for ofloxacin or that shown by phase II/III studies. Among 4,977 patients receiving concomitant NSAID treatment, the overall incidence of adverse reactions and the incidence of neurological reactions (including convulsions) did not significantly differ from those in patients without anti-inflammatory therapy. Review of the spontaneous reports on convulsions showed that patients with nephropathy, patients over 75 years and patients with a history of convulsive diseases were more likely to develop convulsions during LVX therapy. CONCLUSION: LVX should be used cautiously in patients with the above risk factors.