Substandard and Falsified Antibiotics and Medicines against Noncommunicable Diseases in Western Cameroon and Northeastern Democratic Republic of Congo.

Falsified and substandard medicines may undermine the progress toward the Sustainable Development Goals. The present study investigated the quality of 13 essential medicines in Cameroon and the Democratic Republic of Congo (DR Congo). Five hundred six medicine samples were collected from the government and faith-based health facilities, private pharmacies, and informal vendors (total 60 facilities). Collected samples were analyzed according to the U.S. Pharmacopeia (USP) for identity, content, and dissolution of their active pharmaceutical ingredients (APIs) and for uniformity of dosage units. Three samples (0.6%) were identified as falsified. Overall, 8.5% of the samples failed USP specifications for the content of the API and 11.7% failed dissolution testing. Medicines from informal vendors showed a higher out-of-specification rate (28.2%) than other types of drug outlets (12.3%; P < 0.0001). All three falsified medicines had been sold by informal vendors. The failure rate of medicines stated to be produced in Europe (5.1%) was lower than that for medicines from Asia (17.7%; P = 0.0049) and Africa (22.2%; P = 0.0042). Medicines against noncommunicable diseases showed a higher failure rate than antibiotics (25.3% versus 12.1%; P = 0.0004). Four hundred fifty-one of the samples were analyzed in Cameroon and the DR Congo with the Global Pharma Health Fund Minilab (thin-layer chromatography and disintegration testing). The three falsified medicines were readily detected in Minilab analysis. However, substandard samples were detected with low sensitivity. A well-enforced ban of medicine sales by informal vendors and increased attention to supplier qualification in the procurement process may reduce the prevalence of substandard and falsified medicines.

Association between furosemide administration and outcomes in critically ill patients with acute kidney injury.

BACKGROUND: Although current guidelines for AKI suggested against the use of furosemide in AKI management, the effect of furosemide on outcomes in real-world clinical settings remains uncertain. The aim of the present study was to investigate the association between furosemide administration and outcomes in critically ill patients with AKI using real-world data. METHODS: Critically ill patients with AKI were identified from the Medical Information Mart for Intensive Care (MIMIC)-III database. Propensity score (PS) matched analysis was used to match patients receiving furosemide to those without diuretics treatment. Linear regression, logistic regression model, and Cox proportional hazards model were used to assess the associations between furosemide and length of stay, recovery of renal function, and in-hospital and 90-day mortality, respectively. RESULTS: A total of 14,154 AKI patients were included in the data analysis. After PS matching, 4427 pairs of patients were matched between the patients who received furosemide and those without diuretics treatment. Furosemide was associated with reduced in-hospital mortality [hazard ratio (HR) 0.67; 95% CI 0.61-0.74; P < 0.001] and 90-day mortality [HR 0.69; 95% CI 0.64-0.75; P < 0.001], and it was also associated with the recovery of renal function [HR 1.44; 95% CI 1.31-1.57; P < 0.001] in over-all AKI patients. Nevertheless, results illustrated that furosemide was not associated with reduced in-hospital mortality in patients with AKI stage 0-1 defined by UO criteria, AKI stage 2-3 according to SCr criteria, and in those with acute-on-chronic (A-on-C) renal injury. CONCLUSIONS: Furosemide administration was associated with improved short-term survival and recovery of renal function in critically ill patients with AKI. Furosemide was especially effective in patients with AKI UO stage 2-3 degree. However, it was not effective in those with AKI SCr stage 2-3 and chronic kidney disease. The results need to be verified in randomized controlled trials.

A High-Demanding Strategy to Ensure the Highest Quality Standards of Oral Liquid Individualized Medicines for Pediatric Use.

Individualized medicines for pediatrics are a useful alternative if there is no correct dosage marketed for this segment (easy to swallow, adequate volume and content, correct composition for pediatrics, good organoleptic properties, etc.). Its validation process must ensure quality testing: its content uniformity, physical (homogeneity after shaking), chemical, and microbiological stability. Some of these attributes are checked by the recommendations of European Pharmacopoeia (Ph. Eur.), International Conference of Harmonization (ICH), and National Formularies but others are not. The aim of this study is to develop a general high-demanding strategy to ensure the final quality of liquid dosage forms testing and developing standard operating processes (SOPs) for the elaboration of individualized oral liquid medicines for pediatric use. Furosemide was used as an example of the validation of an individualized liquid solution for pediatric use. Three SOPs were selected according to their composition and the recommendations of liquid dosage forms for pediatric use. Quality attributes according to National Formularies, Ph. Eur., and ICH were tested: pH, organoleptic properties, uniformity of mass of delivered dose from multidose containers, and chemical stability. In this study, a general high-demanding strategy was elaborated to validate oral liquid dosage forms, including validation of the analytical method used to test their quality. A second part focuses on the elaboration of liquid formulations for pediatrics with the highest standards of quality taking into account CQAs that were not contemplated by official compendial such as content uniformity and physical stability.

[Choosing wisely recommendations in nephrology]. / Klug-entscheiden-Empfehlungen in der Nephrologie.

The German Society of Internal Medicine ("Deutsche Gesellschaft für Innere Medizin", DGIM) founded the Choosing wisely initiative in order to address diagnostic and therapeutic procedures that are frequently inappropriately applied, whether this be in terms of over-, under-, or misuse of health services. The German Society of Nephrology ("Deutsche Gesellschaft für Nephrologie," DGfN) strongly supports the initiative and has contributed five positive and five negative recommendations. These ten recommendations are discussed in the current publication. The positive recommendations reflect the importance of early recognition of renal disease via simple blood and urine tests, the use of radiocontrast media in cases of impaired renal function, as well as the problems associated with low vaccination rates. Three of the negative recommendations are focused on hydration and diuretics. The remaining two negative recommendations concern angioplasty in cases of renal artery stenosis and the unconsidered use of nonsteroidal anti-inflammatory drugs.

Association of obstructive sleep apnea with arterial stiffness and nondipping blood pressure in patients with hypertension.

Whether sex influences the association of obstructive sleep apnea (OSA) with markers of cardiovascular risk in patients with hypertension is unknown. In this study, 95 hypertensive participants underwent carotid-femoral pulse wave velocity, 24-hour ambulatory blood pressure monitoring, echocardiogram, and polysomnography after a 30-day standardized treatment with hydrochlorothiazide plus enalapril or losartan. OSA was present in 52 patients. Compared with non-OSA patients, pulse wave velocity values were higher in the OSA group (men: 11.1±2.2 vs 12.7±2.4 m/s, P=.04; women: 11.8±2.4 vs 13.2±2.2 m/s, P=.03). The proportion of diastolic dysfunction was significant in men and women with OSA. Compared with non-OSA patients, nondipping systolic blood pressure in OSA was higher in men (14.3% vs 46.4%) and in women (41.4% vs 65.2%). OSA was independently associated with pulse wave velocity (ß=1.050; P=.025) and nondipping systolic blood pressure (odds ratio, 3.03; 95% confidence interval, 1.08-8.55; P=.035) in the regression analysis. In conclusion, OSA is independently associated with arterial stiffness and nondipping blood pressure in patients with hypertension regardless of sex.

Stability of furosemide and chlorothiazide stored in syringes.

PURPOSE: The results of a study to determine the stability of solutions of furosemide and chlorothiazide over 96 hours are reported. METHODS: Chlorothiazide and furosemide were diluted in 5% dextrose USP to final concentrations of 10 and 1 mg/mL, respectively, and combined. In addition, sample solutions of chlorothiazide in dextrose, furosemide in dextrose, and dextrose alone were prepared for control purposes. The resulting solutions were analyzed immediately after preparation and 24, 48, 72, and 96 hours later using a liquid chromatography-tandem mass spectroscopy (LC-MS/MS) system with an electrospray ionization source. Mixtures and samples were diluted 10,000-fold prior to LC-MS/MS analysis so that concentrations of both drugs would be within the assay's linear range of detection. RESULTS: LC-MS/MS analysis showed that chlorothiazide typically eluted at 2.6 minutes and furosemide at 4.8 minutes. Each compound was degraded by exposure to strong ultraviolet light in a time-dependent manner. Both unmixed and mixed solutions retained over 90% of the original concentrations of chlorothiazide and furosemide for up to 96 hours. Furosemide and chlorothiazide are commonly used concomitantly to maximize diuresis in pediatric patients; the study findings suggest that solutions of furosemide and chlorothiazide can be combined in the same syringe without loss of stability for up to 96 hours. CONCLUSION: Solutions of chlorothiazide (10 mg/mL) and furosemide (1 mg/mL) stored either separately or together in polypropylene syringes remained stable for up to 96 hours at room temperature and protected from light.

Papel actual de los diuréticos en el tratamiento de la hipertensión arterial / Current role of diuretics in the treatment of hypertension

El grupo de los diuréticos incluye las tiazidas y fármacos tiazida-like, los diuréticos de asa y los ahorradores de potasio. Las tiazidas son los fármacos más recomendados para el tratamiento inicial de la hiperpresión arterial esencial por razones económicas, su bajo coste, pero también por su eficacia y tolerabilidad tanto en monoterapia como en combinación con otros antihipertensivos. El uso de tiazidas puede reducir la incidencia de ictus y de enfermedad coronaria como han demostrado numerosos ensayos clínicos, desde la década de los sesenta hasta los más recientes, como el ALLHAT. Hidroclorotiazida en dosis de 12,5-25 mg una vez al día reduce la presión arterial en alrededor de la mitad de los pacientes tratados; dosis más altas no incrementan el efecto antihipertensivo, sino que favorecen la aparición de efectos adversos que son dosis-dependientes. La combinación de tiazidas con otros antihipertensivos aumenta la eficacia para bajar las cifras tensionales. El efecto adverso más común es la hipokaliemia; por ello, en los pacientes tratados con tiazidas deben vigilarse los niveles plasmáticos de potasio. Algunos estudios han demostrado que los pacientes tratados con diuréticos presentan un mayor número de nuevos diagnósticos de diabetes que los tratados con otros antihipertensivos. En conclusión, las tiazidas deben ser consideradas entre las primeras opciones para el tratamiento de la hipertensión esencial. Además, dado que muchos pacientes no alcanzan el objetivo terapéutico con un solo fármaco, si no existen contraindicaciones, debería incluirse un diurético en cualquier pauta terapéutica que asocie fármacos antihipertensivos (AU)

The diuretic group includes thiazides and thiazide-like agents, loop diuretics and potassium-sparing diuretics. Thiazides represent the most commonly recommended initial treatment for hypertension for economic reasons, their low cost, but also due to their tolerability and efficacy both as monotherapy and in combination with other agents. Hypertension treatments that use a diuretic-based strategy have been effective in preventing stroke and cardiac disease in the randomized clinical trials from the 1960s to contemporary trials such as ALLHAT. Hydrochlorothiazide 12.5-25 mg once daily or equivalent dosages of other similar agents reduce blood pressure in approximately one-half of treated patients. Higher doses add little to the effect on blood pressure and increase side effects. Some combinations of thiazide diuretics with an antihypertensive drug of a different class increase antihypertensive efficacy. The most common adverse effect is hypokaliemia. Thus, serum potassium in patients treated with thiazide should be monitored. Several studies have demonstrated that the incidence of new case of diabetes was higher among hypertensive patients who were treated with diuretics than in those who were treated with other antihypertensive drugs. In conclusion, thiazide diuretics must be considered among the first options for drug therapy in uncomplicated hypertension. Furthermore, since many patients required more than one drug to control their blood pressure, a diuretic should be included in the therapeutic regime, if posible (AU)

Risk:benefit assessment of old medicines.

Any meaningful discussion about the present value of old drugs requires appropriate comparisons with new drugs. While there is noisy propaganda claiming the superiority of new drugs, the evidence supporting these claims is often scanty and poor. Therefore, the database utilizable to evaluate old and new drugs is incomplete and fragile. There are several reasons, including the poor dossiers presented for the approval of new drugs, the lack of comparisons aimed at showing superiority of new drugs, the bias frequently involved in clinical trials and the conflict of interests. This brief discussion reviews these questions and gives some examples by comparing diuretics and new antihypertensive agents, ticlopidine and clopidogrel, and atypical and classical antipsychotic agents.

Comparative studies of the efficacy of parvaquone and parvaquone-plus-frusemide in the treatment of Theileria parva infection (East Coast fever) in cattle.

Comparative studies of the efficacy of parvaquone (Parvexon) and parvaquone-plus-frusemide (Fruvexon) Bimeda Chemicals, Ireland, were done on 60 naturally infected cases of East Coast fever (ECF; Theileria parva infection in cattle). Small-scale dairy farmers in the peri-urban of Dar Es Salaam city reported ECF-suspected cases from March to mid-October 2001 and were treated with the two drugs alternately, as were diagnosed positive for ECF. Four sub-groups of 15 cattle each (early stage, 15; advanced stage, 15) were treated with parvaquone and parvaquone-plus-frusemide. Twenty-eight out of 30 (93.3%) cattle treated with parvaquone-plus-frusemide were cured, so do 24 out of 30 (80.0%) cattle treated with parvaquone without frusemide. Early diagnosis and prompt management of pulmonary signs, which accounted for 30.0% of total ECF cases is advised in order to improve cure rates. Unlike parvaquone without frusemide (Parvexon), parvaquone-plus-frusemide (Fruvexon) proved useful in the management of pulmonary signs, hence, a drug of choice in the treatment of ECF cases that are accompanied by or are likely to manifest pulmonary signs.

Diuretic therapy in elderly heart failure patients with and without left ventricular systolic dysfunction.

Long term prescription of diuretics for heart failure is very prevalent among elderly patients, although the rationale for such a treatment strategy is often unclear, as diuretics are not indicated if volume overload is absent. The concept of diastolic heart failure in the elderly might particularly change the role of diuretic therapy, since diuretics may have additional adverse effects in these patients. This paper reviews the effects of diuretic therapy in elderly patients with heart failure, emphasising the differences between patients with normal and decreased left ventricular systolic function. Studies on diuretic withdrawal in elderly patients with heart failure are discussed, with emphasis on issues involved in decision making such as diuretic dose reduction and withdrawal in elderly patients and factors that have been established to predict successful withdrawal. Existing guidelines on the prescription of diuretics in elderly patients with heart failure with normal and decreased left ventricular systolic function and in those with diastolic heart failure are also discussed. By reducing intravascular volume, diuretics may further impair ventricular diastolic filling in patients with diastolic heart failure and thus reduce stroke volume. Indeed, preliminary studies demonstrate that diuretics may provoke or aggravate hypotension on standing and after meals in these patients. Therefore, it is suggested that elderly patients with heart failure with intact left ventricular systolic function should not receive long term diuretic therapy, unless proven necessary to treat or prevent congestive heart failure. This implies that physicians should carefully evaluate the opportunities for diuretic dose tapering or withdrawal in all of these patients, and that a cautiously guided intermittent diuretic treatment modality may be critical in the care for older patients with heart failure with intact left ventricular systolic function.

Assessment of pharmaceutical quality of furosemide tablets from multinational markets.

This report describes results of a collaborative study in which samples of the 40-mg strength of furosemide tablets were evaluated following a common protocol based on British (BP), European (Ph. Eur.), and US Pharmacopoeial (USP) specifications. Several tests, including identification, uniformity of mass, and dissolution, were performed. In total, excluding Lasix lots, results for 162 lots obtained from 115 manufacturers or suppliers were submitted. Also, 23 laboratories identified and submitted data for 34 lots of Lasix products available in their countries. There were no reported abnormalities in the physical test requirements of the products analyzed. The summaries (n, mean, and 95% CI) of the assay results for the "standard sample" (a common sample), Lasix lots from participating countries, and for all other furosemide products, respectively, are as follows: 30, 99.8%, 96-104; 33, 100.0%, 94-106; and 162, 99.6, 94-105. About half (approximately 62%) of the reported uniformity of mass results based on tablet weights were in the range 150-175 mg/tablet. However, there appears to be notable variability in tablet weights that would result in significant differences in the ratios (0.14 to 0.40) of active ingredient to excipient. The reported disintegration times ranged from 0 (instantaneous) to 18 min, with most less than 1 min. The drug dissolution testing was conducted with phosphate buffer at pH 5.8 (USP recommended). Another test was conducted with acetate buffer at pH 4.6 (noncompendial). There appears to be remarkable similarity in overall percentage of drug release from the three types of products (standard sample, Lasix lots, and other products). Although apparently there is a very wide spread in dissolution characteristics of the products tested, the analyses of variance did not detect differences among the products tested and, to this extent, would not indicate differences in bioavailability characteristics for most of these products. It is observed that about 20-38% of the variability in dissolution testing is not product related (i.e., it is from the dissolution testing itself), while the remaining 62-80% variability is product related (manufacturing, formulation, etc). The results of this multinational collaborative study showed that most of the furosemide products available in different countries met the required pharmaceutical quality standards, including drug-release characteristics. Based on an extensive statistical analysis, the main concern from the study was that the high variability in drug dissolution testing would require wide tolerance standards (e.g., pharmacopoeial standards). This may result in lack of needed discriminating ability of the test in revealing the impacts of formulation and manufacturing changes on in vitro, and perhaps in vivo, drug-release characteristics.

Safety and tolerability of fluvastatin with concomitant use of antihypertensive agents. An analysis of a clinical trial database.

The coexistence of hypercholesterolemia and hypertension often requires concomitant drug treatments. Thus, it is interesting to evaluate the efficacy, safety, and tolerability of the new lipid-lowering agent fluvastatin, a 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA)-reductase inhibitor, in patients receiving concomitant antihypertensive/cardiovascular drug treatments. A retrospective analysis was based on data from controlled clinical trials in which 1815 patients were treated with fluvastatin and 783 patients received placebo. The daily dose of fluvastatin was > or = 20 mg. At least one of the following drug treatments was taken by 445 of the fluvastatin-treated patients (24.5%) and 181 of those receiving placebo (23.1%): beta-adrenergic-receptor blockers (fluvastatin: n = 182; placebo: n = 84); diuretics (fluvastatin: n = 168; placebo: n = 72); calcium antagonists (fluvastatin: n = 161; placebo: n = 69); and angiotensin-converting enzyme (ACE) inhibitors (fluvastatin: n = 101; placebo: n = 30). The majority of patients received monotherapy with one of the above-mentioned antihypertensive agents (fluvastatin: 69%; placebo: 65%). The efficacy of fluvastatin in modifying low-density lipoprotein (LDL)- and high-density lipoprotein (HDL)-cholesterol and triglyceride levels was not consistently different in patients taking a given antihypertensive compared with the overall group and the patients not taking the antihypertensive agent. In patients taking fluvastatin and antihypertensives, confirmed (measured at two consecutive occasions) increases more than three times the upper limit of normal in aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) occurred in only two patients. One case involved the concomitant use of a beta-blocker (ASAT and ALAT) and the other a diuretic (ALAT).(ABSTRACT TRUNCATED AT 250 WORDS)