Fixed Combination Tablet Research Articles

A sustainable HPLC method coupled with diode array detection for versatile quantification of telmisartan, chlorthalidone and amlodipine in a fixed-dose antihypertensive formulation and dissolution studies

Cardiovascular diseases, especially hypertension, stand as prominent contributors to global mortality. Hypertension, often referred to as a silent killer syndrome, necessitates the use of multiple medications for effective control and management. A new environmentally friendly HPLC–DAD method is introduced in this study for the concurrent analysis of telmisartan (TEL), chlorthalidone (CHT) and amlodipine besylate (AML), in both pure forms and combined pharmaceutical dosage form. An isocratic elution mode was employed to achieve chromatographic separation, utilizing an Inertsil C18 column (250 × 4.6 mm, 5.0 µm) and a mobile phase mixture of acetonitrile and phosphate buffer (pH 3.0 ± 0.1) with ratio of 35:65, v/v. The separation was achieved within 10 min at a flow rate of 1.0 mL/min. The proposed method's validation was carried out following the guidelines outlined by the International Council for Harmonisation (ICH). The achieved linearity range was 1.0–140.0 μg/mL for TEL and 1.0–100.0 μg/mL for CHT and AML with quantification limits of 0.061, 0.177, and 0.313 μg/mL for TEL, CHT, and AML, respectively. The fixed combination tablet dosage form demonstrated acceptable release profile, as indicated by the in-vitro dissolution studies. The studied dissolution media were phosphate buffer pH 7.5, 0.01 N HCl, and water, utilizing a USP type II apparatus at 37 ± 0.5 °C with a stirring rate of 75 rpm. The proposed method was applied successfully for the quality assessment of Telma-ACT® Tablets with good precision and accuracy. Various tools were used for evaluating the level of greenness, including Green Analytical Procedure Index (GAPI), Analytical Greenness Metric for Sample Preparation (AGREEprep), Analytical Eco-Scale (AES), and Analytical Method Greenness Score (AMGS). These tools had confirmed the eco-friendliness of the proposed method. Additionally, the newly introduced White Analytical Chemistry (WAC), and the Blue Applicability Grade Index (BAGI) have been specifically developed to evaluate the sustainability and the applicability of the method.

Developed and Validated for the Estimation of Bupropion and Dextromethorphan in a Fixed Dose Combination of the Tablet.

The aim of this study was to develop a simple, accurate, and precise method for the estimation of bupropion and dextromethorphan in a fixed-dose combination of tablets and robust high-performance liquid chromatography for assay analysis of such a fixed combination. Chromatographic analysis was performed and separations were achieved on a Denali C18 150 × 4.6 mm, 5 micron using a mobile phase composition of ortho-phosphoric acid and acetonitrile in the ratio of 600:400 (v/v), flow rate of 1.0 mL/min, injection volume is 10 µL and run time of 6 min in isocratic elution. Ultraviolet (UV) detection was performed at a wavelength of 221 nm. The temperature was maintained at 30 °C. Well-resolved peaks were observed with a high number of theoretical plates, lower tailing factor, and reproducible relative retention time. The method was validated, and all validation parameters were found to be within the acceptance limits. A simple, accurate, and precise method has been developed for estimating bupropion and dextromethorphan in a fixed dose combination of tablets. The optimized method included the following parameters: column temperature of 30 °C, 40% acetonitrile as the mobile phase, and flow rate of 1.0 mL/min. Retention times were 2.25 min and 3.12 min for bupropion and dextromethorphan, respectively. The method was found to be linear in the range of 17.5-105 µg/mL [for R2 < 0.999) and 7.5-45 µg/mL (for R2 > 0.999] for bupropion and dextromethorphan, respectively. Both active pharmaceutical ingredients dissolved more than 90% within 5 min. The current study describes a new, simple, reliable, and economical elution reversed-phase high performance liquid chromatography method for estimating bupropion and dextromethorphan in a fixed combination tablet dosage form. The forced degradation studies were conducted using several degradation conditions such as acidic, alkali, oxidation, thermal, UV, and neutral conditions; the proposed method was effectively employed from the resolution of sample peaks. To the best of our knowledge, no such detailed and stability-indicating method has been reported for a fixed tablet dosage form.

Development and Optimization of a New UPLC-UV/MS Method through DoE and MLR for Detecting Substandard Drug Products to Treat Tuberculosis.

Drug products used for treating tuberculosis are one of the most widely reported medicines to be classified as falsified or substandard in low- and middle-income countries, representing a major hazard to health. The aim of this study was, firstly, to develop an ultra-performance liquid chromatography (UPLC) method which is able to analyze fixed combination tablets with up to four active pharmaceutical ingredients, including isoniazid, pyrazinamide, rifampicin, and ethambutol. Secondly, we aimed to optimize it through the design of experiments and multi-linear regression based on a central composite design and to validate it according to the guidelines of the International Conference on Harmonization. The application of this tools enabled the identification of the influential factors (flow rate, formic acid, and temperature) and their effects on the studied responses (retention factor and percentage for each drug) as part of the quality by design approach. The method proved to be to be linear in the range from 5.0 to 15 µg/mL for isoniazid, pyrazinamide, and rifampicin, being precise (<1%) and accurate (97–101%). In addition, the method validated for ethambutol proved to be linear from 1.4 to 4.2 µg/mL, as well as precise (0.54%) and accurate (97.3%). The method was stability indicated for all the active pharmaceutical ingredients studied and was able to detect two substandard formulations sampled on the African market.

Treatment of acute hepatitis C genotypes 1 and 4 with 8 weeks of grazoprevir plus elbasvir (DAHHS2): an open-label, multicentre, single-arm, phase 3b trial

Direct-acting antivirals effectively treat chronic hepatitis C virus (HCV) infection but there is a paucity of data on their efficacy for acute HCV, when immediate treatment could prevent onward transmission. We assessed the efficacy of grazoprevir plus elbasvir treatment in acute HCV infection and investigated whether treatment can be shortened during the acute phase of HCV infection. The Dutch Acute HCV in HIV study number 2 (DAHHS2) study was a single-arm, open-label, multicentre, phase 3b trial. Adult patients (≥18 years) with acute HCV genotype 1 or 4 infection (duration of infection 26 weeks or less, according to presumed day of infection) were recruited at 15 HIV outpatient clinics in the Netherlands and Belgium. All patients were treated with 8 weeks of grazoprevir 100 mg plus elbasvir 50 mg administered as one oral fixed drug combination tablet once daily. The primary efficacy endpoint was sustained virological response at 12 weeks after the end of treatment (SVR12; HCV RNA <15 IU/mL) in all patients who started treatment. Reinfection with a different HCV virus was not considered treatment failure in the primary analysis. This trial is registered with ClinicalTrials.gov, number NCT02600325. Between Feb 15, 2016, and March 2, 2018, we assessed 146 patients with a recently acquired HCV infection for eligibility, of whom 86 were enrolled and 80 initiated therapy, all within 6 months after infection. All patients who initiated treatment completed treatment and no patients were lost to follow-up. 79 (99%, 95% CI 93-100) of 80 patients achieved SVR12. All 14 patients who were infected with a virus carrying a clinically significant polymorphism in NS5A were cured. If reinfections were considered treatment failures, 75 (94%, 86-98) of 80 patients achieved SVR12. Two serious adverse events not considered related to the treatment were reported (traumatic rectal bleeding and low back surgery). The most common adverse event was a new sexually transmitted infection (19 [24%] of 80 patients). The most common reported possibly drug-related adverse events were fatigue (11 [14%] patients), headache (seven [9%] patients), insomnia (seven [9%] patients), mood changes (five [6%] patients), dyspepsia (five [6%] patients), concentration impairment (four [5%] patients), and dizziness (4 [5%] patients), all of which were regarded as mild by the treating physician. No adverse events led to study drug discontinuation. 8 weeks of grazoprevir plus elbasvir was highly effective for the treatment of acute HCV genotype 1 or 4 infection. The ability to treat acute HCV immediately after diagnosis might help physicians to reach the WHO goal of HCV elimination by 2030. Merck Sharp and Dohme and Health-Holland.

Bioequivalence of a Fixed Dose Combination of Desloratadine/Betamethasone Tablets (Oradus Beta) in Healthy Human Volunteers

A fixed dose combination of desloratadine, a long-acting tricyclic antihistamine with selective peripheral histamine H1 receptor antagonistic activity, and betamethasone, a glucocorticoid, can potentially provide synergistic effect in the treatment of severe allergic conditions and improve clinical outcomes. Co-administration of an anti-allergy medication and a corticosteroid is extensively used in clinical practice, either as single drug tablets or as a fixed dose combination tablet. The current study was conducted to compare the pharmacokinetics of fixed combination tablets of desloratadine and betamethasone in 40 healthy human volunteers after a single oral dose in a randomized two-period, two-treatment, and two-sequence cross-over study. The study protocol was prepared in accordance to the requirements set in the EMA guidance for conducting bioequivalence studies. Reference (Frenaler Cort 5 mg desloratadine/0.6 mg betamethasone film coated tablet, Roemmers S.A.I.C.F., Argentina) and test (Oradus β 5 mg desloratadine/0.6 mg betamethasone film coated tablet, Pharmaline, Lebanon) drugs were administered to fasted volunteers and blood samples were collected up to 72 h and assayed for desloratadine, hydroxydesloratadine metabolite and betamethasone using a validated LC-MS/MS method. The pharmacokinetic parameters AUC0-t, Cmax, Tmax, T1/2, Ke, in addition to (for betamethasone only) AUC0-∞, MRTinf, and residual area (%) were determined from plasma concentration-time profile by non-compartmental analysis method using thermos Scientific Kinetica (version 5.1). The analysis of variance did not show any significant difference between the two formulations and 90% confidence intervals fell within the acceptable range for bioequivalence (80-125%). The resulting data demonstrated that when administered as fixed dose combination, the pharmacokinetics of desloratadine and betamethasone were bioequivalent and were well-tolerated.

Relative Bioavailability of a Fixed-Combination Tablet Formulation of Azithromycin and Chloroquine in Healthy Adult Subjects

A fixed-dose combination of azithromycin and chloroquine (AZCQ) is in development for intermittent preventive treatment of malaria in pregnant women (IPTp). The combination has demonstrated synergistic activity against chloroquine-resistant strains of Plasmodium falciparum in vitro and in vivo and efficacy in Phase 2 and 3 treatment studies in patients with symptomatic uncomplicated P. falciparum malaria. This was an open-label, randomized, single-dose, parallel-group study to estimate the relative bioavailability of two AZCQ tablets, each containing azithromycin base 250 mg and chloroquine base 155 mg (test treatment), compared with the coadministration of commercially available individual tablets of azithromycin base 500 mg and chloroquine base 300 mg (reference treatment) in 40 healthy male and female subjects (aged 18-55 years; body weight >50.0 kg). Fasting subjects were randomized 1:1 to receive either test or reference treatment. Blood samples for the determination of serum azithromycin and plasma chloroquine concentrations were collected at specified time points pre- and post-dose for noncompartmental pharmacokinetic analyses. Safety evaluations included monitoring adverse events and vital signs as well as performing clinical laboratory tests. All subjects completed the study. Area under the concentration– time curve from time zero to time of last measurable concentration (AUClast) of azithromycin and chloroquine for the two AZCQ tablets was comparable to the reference treatment. The relative bioavailability as measured by AUClast ratio of adjusted geometric means (90% confidence interval) for the two AZCQ tablets was 101% (85.4%, 119%) for azithromycin and 99.1% (84.0%, 117%) for chloroquine compared with the reference treatment. Maximum concentration values for the two AZCQ tablets were approximately 13.0% higher for azithromycin and 11.0% lower for chloroquine compared with reference treatment. Both treatments were well tolerated. This AZCQ tablet formulation is currently being evaluated in Phase 3 clinical trials for IPTp.

Editorial: Single-Tablet Ibuprofen/Double-Dose Famotidine for Reduction of Gastric and Duodenal Ulcers (REDUCE Trials): What Can be Reduced?

Patients using nonsteroidal anti-inflammatory drugs (NSAIDs) who are at high risk of gastroduodenal ulcer complications often do not receive gastroprotective co-therapy. Fixed-dose combination tablets of an NSAID and a proton-pump inhibitor or misoprostol are intended to improve adherence. Whether the use of these combination tablets will improve adherence and clinical outcome remains largely uninvestigated. Unlike proton-pump inhibitors and misoprostol, the efficacy of histamine-2-receptor antagonists in preventing gastroduodenal ulcers associated with NSAID use is questionable. Nonetheless, a new fixed-dose combination tablet of an NSAID and famotidine will soon be available on the market. The study by Laine et al. is a pooled analysis of two large-scale, carefully designed randomized trials (REDUCE trials) of a fixed-combination tablet of ibuprofen and famotidine on the incidence of endoscopic ulcers. How the study findings may influence clinical practice deserves further consideration.

Sumatriptan-naproxen fixed combination for acute treatment of migraine: a critical appraisal.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including naproxen and naproxen sodium, are effective yet nonspecific analgesic and anti-inflammatory drugs, which work for a variety of pain and inflammatory syndromes, including migraine. In migraine, their analgesic effect helps relieve the headache, while their anti-inflammatory effect decreases the neurogenic inflammation in the trigeminal ganglion. This is the hypothesized mechanism by which they prevent the development of central sensitization. Triptans, including sumatriptan, work early in the migraine process at the trigeminovascular unit as agonists of the serotonin receptors (5-HT receptors) 1B and 1D. They block vasoconstriction and block transmission of signals to the trigeminal nucleus and thus prevent peripheral sensitization. Therefore, combining these two drugs is an attractive modality for the abortive treatment of migraine. Sumatriptan-naproxen fixed combination tablet (Treximet [sumatriptan-naproxen]) proves to be an effective and well tolerated drug that combines these two mechanisms; yet is far from being the ultimate in migraine abortive therapy, and further research remains essential.

Zielwerterreichung unter lipidsenkender Therapie mit Ezetimib/Simvastatin bei Patienten mit Atherosklerose und/oder Diabetes mellitus – eine österreichische Anwendungsbeobachtung

In patients at risk for cardiovascular complications, established LDL cholesterol (LDL-C) target levels are frequently not achieved using standard statin therapy regimens. The additional lipid-lowering efficacy of the fixed combination ezetimibe/simvastatin was evaluated in a countrywide non-interventional observational study in Austria. About 3,156 subjects with clinically manifest atherosclerosis and/or diabetes at high cardiovascular risk and with LDL-C-levels >113 mg/dl under statin therapy met the inclusion criteria and 2,903 of these patients were treated by primary care physicians, in hospitals and in rehabilitation centers with 10 mg ezetimibe and 10-40 mg simvastatin daily in a fixed-combination tablet (Inegy). During the follow-up period of 4-12 weeks, LDL-C levels were reduced by a median of 27-31% of baseline values (mean 153.1 +/- 33.5 mg/dl) mainly regardless of previous statin therapy (rosuvastatin, atorvastatin, simvastatin, pravastatin, fluvastatin, and lovastatin) and dosing (pooled median values). LDL-C reduction correlated proportional with baseline LDL-C values and increased with increasing simvastatin dosage. Overall, 45.3% (10/10 mg), 43.9% (10/20 mg) and 62.7% (10/40 mg ezetimibe/simvastatin) achieved LDL-C target levels of <100 mg/dl. The fixed combination therapy with ezetimibe/simvastatin showed a clinically significant additional lipid-lowering potential as compared with established statin monotherapies and enabled more patients at cardiovascular risk to reach the LDL-C target level of <100 mg/dl.

Combination Therapy with Candesartan Cilexetil 32 mg and Hydrochlorothiazide 25 mg Provides the Full Additive Antihypertensive Effect of the Components

Fixed-combination tablets of candesartan (orally administered as the pro-drug candesartan cilexetil and hereafter referred to as candesartan) and hydrochlorothiazide (HCTZ) 8/12.5 mg and 16/12.5 mg are effective and well tolerated. However, some patients require higher doses to attain target blood pressure, and combination tablets containing candesartan and HCTZ at the upper end of their respective dose ranges are now being developed. This study aimed to assess the antihypertensive effect and tolerability of the combination of candesartan 32 mg and HCTZ 25 mg versus candesartan 32 mg monotherapy, HCTZ 25 mg monotherapy, and placebo. This was a randomized, double-blind, parallel-group study, with 8 weeks of follow-up, carried out in primary-care outpatients. 1524 men or women (age 20-80 years) with mild to moderate primary hypertension and sitting diastolic blood pressure (DBP) 90-114 mmHg after 4 weeks' single-blind placebo treatment were included in the study. Candesartan/HCTZ 32/25 mg combination therapy, candesartan 32 mg monotherapy, HCTZ 25 mg monotherapy, and placebo, allocated in a 5 : 5 : 5 : 1 ratio, were administered once daily. The main outcome measure was adjusted (analysis of covariance) mean reductions in systolic blood pressure (SBP) and DBP. Mean reductions in SBP and DBP were significantly greater with candesartan/HCTZ 32/25 mg (21/14 mmHg) than with candesartan 32 mg (13/9 mmHg), HCTZ 25 mg (12/8 mmHg) or placebo (4/3 mmHg) [p < 0.001 for all comparisons]. The proportion of patients with controlled blood pressure (SBP <140 mmHg and DBP <90 mmHg) at the end of the study was also significantly greater in the candesartan/HCTZ 32/25 mg group (63%) than in the other treatment groups (p < 0.001 for all comparisons). All study treatments were generally well tolerated. The antihypertensive effect of candesartan/HCTZ 32/25 mg represents fully additive contributions from each of its components, and is generally well tolerated in patients with mild to moderate primary hypertension. This combination adds to the treatment options for improving blood pressure control in patients with hypertension.

Pa, a Novel Combination of Delayed Release (DR) Aspirin (ASA) and Immediate-Release (IR) Omeprazole, Is Associated with a Decreased Risk of Gastroduodenal Mucosal Injury

Purpose: To evaluate via endoscopy the gastroduodenal effects of the fixed combination tablet of DR ASA 325 mg and IR omeprazole (20 or 40 mg). Methods: We conducted 3 Phase I, single-blind, randomized, controlled trials in healthy volunteers (>50 yrs) with normal baseline endoscopy (Lanza score 0). Two studies evaluated PA32520 (DR ASA 325 mg + IR omeprazole 20 mg) vs. either enteric-coated (EC)-ASA 81 mg or 325 mg. The third study compared PA32540 (DR ASA 325 mg + IR omeprazole 40 mg) with EC-ASA 325 mg. All medications were dosed once daily for 4 weeks. The primary endpoint was the proportion of subjects with Grade 3 or Grade 4 Lanza scores at Week 4. Additional assessments included incidence of gastric or duodenal ulcers (GU/DU) at 4 weeks and pharmacokinetics. Data were pooled across the 3 studies. Results: A total of 240 subjects participated. As shown in the Figure, Grade 3 or 4 Lanza scores and the incidences of GU/DU for the PA products were lower than for EC-ASA. With regard to Grade 3 or 4 Lanza scores: PA32520 vs. EC-ASA 81 mg (9.9 vs. 20.5%, P= 0.151); PA32520 vs. EC-ASA 325 mg (9.9% vs. 42.5%, P < 0.001); PA32540 vs. EC-ASA 81 mg (2.5% vs. 20.5%, P= 0.014); PA32540 vs. EC-ASA 325 mg (2.5% vs. 42.5%, P < 0.001). With regard to the incidence of GU/DU: PA32520 vs. EC-ASA 81 mg (2.5% vs. 5.1%, P= 0.595); PA32520 vs. EC-ASA 325 mg (2.5% vs.13.8%, P= 0.009); PA32540 2.5% vs. EC-ASA 81 mg (2.5% vs. 5.1%, P= 0.615); PA32540 vs. EC-ASA 325 mg (2.5% vs. 13.8%, P= 0.059). Plasma salicylic acid pharmacokinetics was similar following dosing with PA32520 or PA32540 and EC-ASA 325 mg following both single-dose and repeat-dose administration.FigureConclusion: Gastroduodenal Grade 3 or 4 Lanza scores and incidence of GU/DU for EC-ASA were dose-related. The fixed dose combination of DR ASA and IR omeprazole was associated with a significant reduction in gastroduodenal Grade 3 or 4 Lanza scores and GU/DU that were dose-related to the proton pump inhibitor. PA32540 demonstrated the least gastroduodenal damage and may provide an important option for at-risk patients who require long-term ASA therapy.

Felodipine–Metoprolol Combination Tablet: Maintained Health-Related Quality of Life in the Presence of Substantial Blood Pressure Reduction

Most treated hypertensive patients do not achieve adequate blood pressure (BP) control. Initiating therapy with two drugs has been suggested when BP is >20/10 mm Hg above goal. To ensure patients' compliance, such treatment needs to be well tolerated and must not compromise health-related quality of life (HRQL). The primary objective of this study was to compare the effects on HRQL of initiating treatment with felodipine + metoprolol (F+M) fixed combination tablets, or enalapril (E), or placebo (P). A total of 947 patients of both sexes with primary hypertension (diastolic BP 95 to 110 mm Hg), aged 20 to 70 years, participated in this randomized, double-blind, parallel group, 12-week, multicenter trial. Treatment was initiated with F+M 5 + 50 mg, or E 10 mg, or P. Doses were doubled after 4 or 8 weeks if diastolic BP was >90 mm Hg. The HRQL was measured at baseline and at the last visit using two validated questionnaires: the Psychological General Well-being Index (PGWB) and the Subjective Symptom Assessment Profile (SSA-P). Office BP was measured at trough, that is, 24 h after the previous dose. The HRQL was high at baseline and generally well maintained during the study. For example, the mean (SD) PGWB total score was 104 (16) at baseline and 105 (16) at 12 weeks in all three treatment groups. The BP reductions after F+M (18/14 mm Hg) and E (12/9 mm Hg) were significantly greater than after P (7/7 mm Hg), and the reduction after F+M was significantly greater than after E. The HRQL is maintained in the presence of substantial BP reduction during antihypertensive treatment with F+M fixed combination tablets.

Development of a glyburide-metformin fixed combination tablet with optimized glyburide particle size

The bioavailability-guided development of a fixed combination tablet formulation of glyburide and metformin hydrochloride, resulting in the identification of specific particle properties for the glyburide component that confer desirable in vivo performance, is described. Four separate pharmacokinetic studies were undertaken in healthy volunteers using fixed combination tablet formulations containing glyburide with differing particle properties. These studies directed first to the appropriate particle size in laboratory scale studies and subsequently confirmed the required, narrow particle size range in product made at commercial scale. Glyburide with particle size properties of 25% volume undersize of ≤6 µm, 50% volume undersize in the range 7–10 µm, and 75% volume undersize of ≤21 µm was identified for use in a fixed combination with metformin hydrochloride. The optimized combination provided for bioequivalence to single entity metformin and acceptable bioavailability, though not bioequivalence, to single entity glyburide whilst having unique and potentially clinically valuable pharmacokinetic properties. Drug Dev. Res. 66:25–35, 2006. © 2006 Wiley-Liss, Inc.

Towards single-tablet therapy for type 2 diabetes mellitus. Rationale and recent developments.

Type 2 diabetes mellitus emerges as a result of multiple pathophysiologic changes. If the pharmacotherapy of type 2 diabetes should be tailored to the underlying pathophysiology, it would be necessary to use a combination of agents with complementary mechanisms of action. The two principal defects in type 2 diabetes are insulin deficiency and insulin resistance. Therefore, combining an insulin-providing agent with an insulin-sensitizing agent will augment the efficacy of current antihyperglycemic agents. This is the rationale for the development and marketing of sulfonylurea/metformin combination tablets.Randomized double-blind clinical trials have shown the safety and efficacy of these fixed combination tablets in both drug-naive individuals as well as in those individuals not achieving glycemic goals on sulfonylurea or metformin monotherapy. These studies have also shown that these tablets may be associated with better postprandial glycemic control compared with monotherapy. However, the risk of hypoglycemia is increased with the use of combination tablets, especially in drug-naive individuals with baseline glycosylated hemoglobins of <8.0%. Combining two insulin-sensitizing agents that have different mechanisms of action and that target different biochemical pathways, would also enhance efficacy. This can be accomplished by combining metformin with rosiglitazone or pioglitazone. The recently developed fixed formulation tablet of metformin/rosiglitazone is available for use as second-line therapy in individuals who have not reached their glycemic goals while on metformin. The advantages of combining several agents in one tablet include convenience and enhanced adherence to therapy. The main disadvantage is the loss of administration flexibility.

Naphthoquine phosphate and its combination with artemisinine

Naphthoquine phosphate and artemisinine are two antimalarials developed in China. Both drugs have proven to be efficacious and well tolerated as monotherapy as well as in combination in patients suffering from malaria. The Co-naphthoquine, a novel antimalarial combination, is an oral fixed combination tablet of the naphthoquine phosphate and artemisinine. Artemisinin is characterised by a rapid onset of schizonticidal action and a short half-life. Parasite clearance is, however, often incomplete when it is employed as a single agent unless high dosages are used over several days, but such a regimen may reduce patient compliance and increase the danger of toxicity. Naphthoquine phosphate, by contrast, has a slower onset of action and a longer half-life, associated with a low recrudescence rate. The two components act synergistically in animal, and clinically provide more rapid relief of symptoms and a higher cure rate than either component alone. The combination tablet was initially developed by the Academy of Military Medical Sciences (AMMS), Beijing, China.

Tramadol/paracetamol.

The orally administered fixed combination tablet of tramadol (centrally-acting opiate) plus paracetamol (acetaminophen; nonopiate, nonsalicylate analgesic) [37.5/325 mg] provides effective analgesia in patients with moderate to severe acute pain and those with chronic painful conditions characterised by intermittent exacerbations of pain. Two tramadol/paracetamol 37.5/325 mg tablets provided greater relief of dental pain over an 8-hour period than either agent alone, with a faster onset of action than tramadol alone and a longer duration of action than either agent as monotherapy. In patients with postoperative dental pain, two tramadol/paracetamol tablets (37.5/325 mg) provided similar analgesia to hydrocodone/paracetamol 10/650 mg over an 8-hour period. The addition of one or two tramadol/paracetamol 37.5/32 5mg tablets (up to four times daily) for 5 days to existing NSAID or cyclo-oxygenase-2 inhibitor analgesic therapy provided effective pain relief in patients with osteoarthritis flare pain. Tramadol/paracetamol 37.5/325 mg provided similar efficacy to that of codeine/paracetamol 30/300 mg in patients with chronic back pain in a 4-week, randomised, double-blind trial (a maximum of 10 tablets or capsules per day of the active drug).

A pharmacoeconomic comparison of misoprostol/diclofenac with diclofenac.

To estimate the economic impact of misoprostol/diclofenac in a fixed combination tablet compared with diclofenac. Cohort study with a prospectively constructed, population-based, record-linkage database containing details of exposure to all community dispensed NSAIDs and all admissions to hospital for upper gastrointestinal (GI) diagnoses. Costs associated with each study drug exposure were analysed using generalized linear models. The population of Tayside, Scotland. Subjects aged 20 years and over who received misoprostol/diclofenac or any other NSAID between January 1989 and 31 December 1995. Total costs for the number of days of exposure to diclofenac and misoprostol/diclofenac, plus costs of concomitant ulcer healing drug therapy plus endoscopy procedures plus costs of admissions to hospital for upper GI diagnoses. The rate of hospitalization with gastrointestinal events was 30% higher among patients receiving diclofenac than that for patients receiving misoprostol/diclofenac. Among patients who received diclofenac and an ulcer-healing drug (UHD), the event rate was more than twice that for patients receiving misoprostol/diclofenac. In patients with a prior GI history, switching from diclofenac to misoprostol/diclofenac would reduce the costs of hospitalization. The resulting savings would more than offset the extra prescription costs. In patients without a prior GI history, the greatest potential saving would arise due to reduced use of UHDs and net savings would occur in subjects aged between 60 and 70 years of age or more. Use of misoprostol/diclofenac instead of diclofenac can produce cost savings due to reduced hospitalization rates and decreased use of UHDs in subjects with a prior history of GI disease and in older subjects without prior GI disease. These findings have implications for the management of patients who require treatment with NSAIDs.

Felodipine–metoprolol combination tablet: a valuable option to initiate antihypertensive therapy?

The aim of the present study was to assess the efficacy and tolerability of a calcium antagonist/β-blocker fixed combination tablet used as first-line antihypertesnive therapy in comparison with an angiotensin converting enzyme inhibitor and placebo. Patients with uncomplicated essential hypertension (diastolic blood pressure between 95 and 110 mm Hg at the end of a 4-week run-in period) were randomly allocated to a double-blind, 12-week treatment with either a combination tablet of felodipine and metoprolol (Logimax), 5/50 mg daily (n = 321), enalapril, 10 mg daily (n = 321), or placebo (n = 304), with the possibility of doubling the dose after 4 or 8 weeks of treatment if needed (diastolic blood pressure remaining >90 mm Hg). The combined felodipine–metoprolol treatment controlled blood pressure (diastolic ≤90 mm Hg 24 h after dose) in 72% of patients after 12 weeks, as compared with 49% for enalapril and 30% for placebo. A dose adjustment was required in 38% of patients receiving the combination, in 63% of patients allocated to placebo, and 61% of enalapril-treated patients. The overall incidence of adverse events was 54.5% during felodipine–metoprolol treatment; the corresponding values for enalapril and placebo were 51.7% and 47.4%, respectively. Withdrawal of treatment due to adverse events occurred in 18 patients treated with the combination, in 10 patients on enalapril, and 12 patients on placebo. No significant change in patients’ well-being was observed in either of the three study groups. These results show that a fixed combination tablet of felodipine and metoprolol allows to normalize blood pressure in a substantially larger fraction of patients than enalapril given alone. This improved efficacy is obtained without impairing the tolerability. The fixed-dose combination of felodipine and metoprolol, therefore, may become a valuable option to initiate antihypertensive treatment.

Combination of cimetidine and alginic acid: an improvement in the treatment of oesophageal reflux disease. Cooperative Oesophageal Group.

A new chewable tablet containing cimetidine 200 mg and alginic acid 500 mg, at a dosage of one tablet four times daily, was compared in a 12 week randomised study with the standard dosage of cimetidine (400 mg four times daily) in the management of oesophageal reflux disease. The dose of cimetidine continued unchanged throughout the study but the dose of the combination drugs could be increased after six weeks to two tablets four times a day if response was unsatisfactory. A total of 312 patients had data suitable for analysis. Sixty three per cent of those on the combination tablet completed the study without increasing their dose - that is taking cimetidine equivalent to half the standard dosage used in the control group. The improvement in heartburn symptoms was significantly greater in the combination group than in the group taking full dose cimetidine. There were no significant differences between the treatment groups in healing and improvement of the appearances of oesophagitis after 12 weeks, and healing rates were as expected from previous studies. The addition of alginic acid to cimetidine in this fixed combination tablet is an improvement in symptomatic treatment of oesophageal reflux disease.

Comparison of the diuretic effect and absorption of a single dose of furosemide and free and the fixed combinations of furosemide and triamterene in healthy male adults

The absorption and diuretic effect of furosemide 40 mg alone (F), and of the free (F + T) and the fixed (FT) combinations of furosemide 40 mg and triamterene 50 mg have been compared in 12 healthy young men. A slight reduction in the area under the concentration-time curve (AUC) of plasma furosemide was found for the fixed combination (AUC480) F2.58 micrograms.h.ml-1; F + T 2.46 micrograms.h.ml-1; FT 1.97 micrograms.h.ml-1. There was a significant reduction in the AUC480 of plasma triamterene (F + T 204.9 micrograms.h.l-1; FT 130.2 micrograms.h.l-1). Sodium excretion after F + T and FT was more pronounced than after F (F + T 302 mmol; FT 311 mmol; F259 mmol). When compared to F alone, there was a reduction in the 24-hour potassium excretion after F + T as well as after FT (F 121 mmol; F + T 104 mmol; FT 107 mmol). It is concluded that the absorption of triamterene was significantly reduced after ingestion of the fixed combination tablet. However, in healthy male adults this had no influence on its natriuretic and potassium-sparing effect as compared to the free combination.