Building the Momentum for A Stronger Pharmaceutical System in Africa.

Despite impressive progress, nearly two billion people worldwide have no access to essential medicines. The COVID-19 pandemic revealed Africa's vulnerability due to its reliance on imports for most vaccines, medicines, and other health product needs. The vaccine manufacturing is complex and requires massive financial investments, with global, regional, and national regulatory structures introducing consistent and urgent reforms to assure the quality and safety of medicines. In 2020, there were approximately 600 pharmaceutical manufacturers in Africa, 80% of which were concentrated in eight countries: Egypt, Algeria, Morocco, Tunisia, Nigeria, Ghana, Kenya, and South Africa. Only 4 countries had more than 50 manufacturers, while 22 countries had no local production. Out of the 600, around 25% were multinational companies. Africa is equally affected by modest scaled capacities substantially engaging in packaging and labelling, and occasionally fill and finish steps, facing criticalities in terms of solvent domestic markets. This article discusses the challenges in the development of a local pharmaceutical manufacturing in Africa and reflects on the importance of the momentum for strengthening the local medical production capacity in the continent as a critical opportunity for advancing universal health coverage (UHC).

Thyroid and renal tumors in patients treated with long-term lithium: case series from a lithium clinic, review of the literature and international pharmacovigilance reports.

BACKGROUND: Cancer had never been considered as a relevant problem in patients treated with lithium until 2015, when a document published by the European Medicine Agency concluded that long-term use of lithium might induce renal tumors. A few months later, we observed the case of a woman treated with lithium for 18 years who was diagnosed with both thyroid and renal tumors. METHODS: This study aimed to investigate the correlation between lithium treatment and thyroid or renal tumors. We analyzed clinical records in our lithium clinic database, causes of death of patients who had been visited at least once at the lithium clinic, reports of lithium adverse reactions in the European and WHO pharmacovigilance databases, and published cases of thyroid and renal tumors in long-term lithium-treated patients. RESULTS: Of the 1871 lithium patients who had been visited at least once between 1980 and 2013, eight had been diagnosed with thyroid papillary carcinoma and two with clear-cell renal-cell carcinoma. No cases of thyroid cancer and only one case of renal tumor were the cause of death according to the 375 available death certificates. VigiAccess database contained a total of 29 and 14 cases of renal and thyroid tumors, respectively. EudraVigilance database contained 21 cases of renal and 8 of thyroid neoplasms. Literature search yielded 6 published cases of thyroid papillary carcinoma and 25 cases of various renal tumors. However, two population-based studies did not find any increased risks of cancer in patients exposed to lithium, whereas two nationwide studies did not find any excess of renal tumors. CONCLUSION: So far it has not been possible epidemiologically to confirm an increased risk of thyroid or renal cancers associated with lithium. Such a conclusion is supported by the findings of low rates and mortalities of thyroid or renal cancers from the present lithium clinic data.

Interstitial lung disease induced by fluoxetine: Systematic review of literature and analysis of Vigiaccess, Eudravigilance and a national pharmacovigilance database.

We investigated a pulmonary adverse drug reaction possibly induced by fluoxetine, the Interstitial Lung Disease, by performing a systematic review of published case reports on this subject, a review of the World Health Organization VigiAccess database, of the European EudraVigilance database and of a national Pharmacovigilance database (Italian Pharmacovigilance Network). The research found a total of seven cases linking fluoxetine to Interstitial Lung Disease in the literature. 36 cases of interstitial lung disease related to fluoxetine were retrieved from the VigiAccess database (updated to July 2016), and 36 reports were found in EudraVigilance database (updated to June 2016). In the Italian Pharmacovigilance database (updated to August 2016), we found only one case of Interstitial Lung Disease, codified as "pulmonary disease". Our investigation shows that fluoxetine might be considered as a possible cause of Interstitial Lung Disease. In particular, although here we do not discuss the assessment of benefits and harms of fluoxetine, since this antidepressant is widely used, our review suggests that fluoxetine-induced Interstitial Lung Disease should be considered in patients with dyspnea, associated or not with dry cough, who are treated with this drug. An early withdrawn of fluoxetine could be useful to obtain a complete remission of this adverse drug reaction and special attention should be particularly devoted to long-term therapy, and to female and elderly patients. Although the spontaneous reporting system is affected by important limitations, drug post- marketing surveillance represents an important tool to evaluate the real world effectiveness and safety of drugs.

Preliminary Transcriptome Analysis in Lymphoblasts from Cluster Headache and Bipolar Disorder Patients Implicates Dysregulation of Circadian and Serotonergic Genes.

Bipolar disorder (BD) and cluster headache (CH) are distinct conditions with important similarities such as a temporal pattern of disturbances, dysregulation of the sleep-wake cycle, and response to lithium treatment in a proportion of patients. Aiming to identify common transcription signatures in these two disorders, we carried out an exploratory microarray gene expression analysis in lymphoblasts from 8 CH and 10 BD I patients selected for positive response to lithium and 10 healthy controls (CO). Gene expression levels of BD and CH were compared with CO to create two lists of differentially expressed genes. We then matched the two lists and focus on genes showing statistically significant difference and same change direction in both disorders. RNA binding motif protein 3 (RBM3) was the most significantly altered gene in the list (3.17 × 10(-13) in BD, 9.44 × 10(-14) in CH). Pathway analysis identified protein processing in endoplasmic reticulum as the most significantly enriched. For validation with quantitative reverse transcription PCR (qRT-PCR) using the same samples, we selected seven genes. Among these, we were able to validate the RBM3, nuclear receptor subfamily 1, group D, member 1 (NR1D1), and tryptophan hydroxylase 1 (TPH1). These genes encode for elements involved in circadian rhythm regulation (RBM3 and NR1D1) and in serotonin synthesis (TPH1), processes previously involved in both disorders, and in the mechanism of action of lithium.

Clozapine toxicity due to a multiple drug interaction: a case report.

INTRODUCTION: We report the case of a multiple drug interaction involving clozapine, antifungals and oral contraceptives, which resulted in an increased clozapine plasma level, pericarditis with pericardial effusion and eosinophilia in a young Caucasian woman. These symptoms and signs disappeared a few days after discontinuation of clozapine. At present, we are not aware of reports of clozapine-antifungals interaction, whereas there is only one other case report on the interaction between oral contraceptives and clozapine. The purpose of this case report is to show the risk of potentially serious adverse effects stemming from drug interactions involving medications routinely used in clinical practice. CASE PRESENTATION: A 29-year-old Caucasian woman diagnosed with a schizoaffective disorder was admitted to a psychiatric unit for acute psychosis (hallucinations, delusions and catatonic behavior). She denied smoking tobacco products and was on long-term oral contraceptives. During the first month of hospitalization she was treated with antipsychotics and for 1 week she took simultaneously fluconazole and miconazole gel, after being diagnosed with oral candidiasis. On the last day of antifungals treatment, 29 days after admission, clozapine was started with resolution of psychotic symptoms. After 3 weeks, her clozapine plasma level had increased to 542 ng/mL and eosinophilia was observed. She complained of nausea, vomiting and palpitations; echocardiography showed echocardiographic abnormalities and pericardial effusion. Oral contraceptives were discontinued and after 1 week clozapine was interrupted, with a complete resolution of side effects and pericardial effusion within 4 days. CONCLUSIONS: Clozapine is metabolized by cytochrome P450. The use of inhibitors or other substrates of cytochrome P450, such as antifungals and oral contraceptives, can cause long-lasting interactions and clozapine toxicity. The Naranjo algorithm shows clozapine is a definite cause of pericarditis (score 9) and both clozapine-antifungals and clozapine-contraceptives interactions resulted probable (score 5) in Drug Interaction Probability Scale. A good knowledge on drugs that act as substrates, inhibitors or inducers of cytochrome P450 is mandatory. When those drugs are used in patients taking clozapine, blood level monitoring of clozapine should be recommended, since a lower dose of clozapine might be required to prevent clozapine toxicity.

Squamous-cell carcinoma of the tongue following therapy of rheumatoid arthritis with abatacept.

KEY CLINICAL MESSAGE: A patient affected by rheumatoid arthritis developed a squamous-cell carcinoma probably due to abatacept, according to Naranjo algorithm. The case describes this adverse reaction for the first time and highlights the need for additional studies to establish the long-term risk profile of abatacept.

Evaluation of lithium response in episodic cluster headache: a retrospective case series.

OBJECTIVE: In this study, we attempted to evaluate the response to lithium treatment and its tolerability in the prevention of episodic cluster headache (CH) and to identify clinical predictors of response. BACKGROUND: Verapamil and lithium are the most widely used drugs in the prevention of CH attacks. Lithium is considered a second-line treatment in part because of its potentially severe adverse drug reactions (ADRs). Evidence for the efficacy of lithium in CH prevention is greater in chronic than in episodic patients. In addition, because of its narrow therapeutic window and ADRs (which can be significantly reduced with proper periodical monitoring of blood levels), lithium is recommended only in chronic CH, when other drugs are ineffective or potentially harmful. METHODS: Our primary aim was to determine whether lithium reduced the number of attacks per day (attack frequency). We compared attack frequency in 3 periods: run-in, the first, and the second week of lithium treatment. Responders were defined as patients showing at least a 50% reduction in attack frequency. RESULTS: Lithium response was evaluated in 26 patients. Treatment led to a significant reduction in attack frequency within 2 weeks in a percentage of 77% of responders and 23% of nonresponders. Responders and nonresponders did not differ in terms of demographic and clinical characteristics. Only 15% of patients experienced mild ADRs. CONCLUSION: Our study provides additional evidence on the effectiveness of lithium in the prevention of episodic CH. It also shows the tolerability of lithium, given the short duration of treatment and low dosage.

Mixture analysis of age at onset in migraine without aura: evidence for three subgroups.

OBJECTIVE: To verify the presence of different age at onset (AAO) subgroups of patients in a sample of patients with migraine without aura (MWA) and compare clinical correlates among them. BACKGROUND: MWA is a long-lasting disease whose prognosis has not yet been fully investigated. Patients may present complete remission, partial clinical remission, persistence and progression (migraine attack frequency and disability may increase over time leading to chronic migraine). Limited evidence exists regarding the identification of risk factors or predictors which might influence migraine prognosis. AAO has been proven a useful tool in the investigation of the clinical, biological, and genetic characteristics able to influence the prognosis of a number of neuropsychiatric disorders. AAO distribution was studied using mixture analysis, a statistical approach that breaks down the empirical AAO distribution observed into a mixture of normal components. METHODS: A sample of 334 outpatients affected by MWA, recruited in a clinical genetic study at our Headache Center from 2004 to 2008, was enrolled for this study. Diagnosis was made according to International Headache Society criteria 2004. AAO distribution in patients was studied using mixture analysis. Chi-square test was used to compare clinical correlates among identified subgroups. Logistic regression was performed in order to correct for effect of possible confounders. RESULTS: Mixture analysis broke up the observed distribution of AAO into 3 normal theoretical distributions. Informational criteria clearly showed a better 3-component model rather than the 2-component one. An early-onset (≤ 7 years of age), an intermediate-onset (≥ 8 and ≤ 22), and a late-onset group (≥ 23) were identified. Comparison of clinical correlates among subgroups by means of chi-square test showed a statistically significant result for migraine frequency (χ(2) = 7.41, P = .02). Considering the frequency of migraine attacks as a main outcome, the regression model showed a higher AAO is associated with low frequency (odds ratio =0.95; P= .02). CONCLUSIONS: The significant association between AAO and attack frequency found in our study supports the hypothesis that AAO could act as a predictor factor able to influence prognosis. AAO could represent a phenotype suitable for identifying MWA susceptibility genes.